Canadian Journal of Diabetes



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A Publication of the Professional Sections of the Canadian Diabetes Association Une publication des sections professionnelles  te de l'Association canadiennedu diabe CONTENTS: April 2013 S1 S4 S8 S12 S16 Introduction Methods - Volume 37 - Supplement 1 Definition, Classification and Diagnosis of Diabetes, Prediabetes and Metabolic Syndrome Screening for Type 1 and Type 2 Diabetes Reducing the Risk of Developing Diabetes Management S20 S26 S31 S35 S40 S45 S56 S61 S69 S72 S77 S82 S87 S93 S94 S97 Organization of Diabetes Care Self-Management Education Targets for Glycemic Control Monitoring Glycemic Control Physical Activity and Diabetes Nutrition Therapy Pharmacotherapy in Type 1 Diabetes Pharmacologic Management of Type 2 Diabetes Hypoglycemia Hyperglycemic Emergencies in Adults In-hospital Management of Diabetes Weight Management in Diabetes Diabetes and Mental Health Influenza and Pneumococcal Immunization Pancreas and Islet Transplantation Natural Health Products Macrovascular and Microvascular Complications S100 S105 Vascular Protection in People with Diabetes Screening for the Presence of Coronary Artery Disease Publication Mail Agreement 41536048 Return undeliverable Canadian addresses to: Transcontinental Printing, 737 Moray St, Winnipeg, MB R3J 3S9 Printed in Canada (continued) CONTENTS (continued): April 2013 S110 S117 S119 S124 S126 S129 S137 S142 S145 S150 Dyslipidemia Treatment of Hypertension - Volume 37 - Supplement 1 Management of Acute Coronary Syndromes Management of Stroke in Diabetes Treatment of Diabetes in People with Heart Failure Chronic Kidney Disease in Diabetes Retinopathy Neuropathy Foot Care Erectile Dysfunction Diabetes in Children S153 S163 Type 1 Diabetes in Children and Adolescents Type 2 Diabetes in Children and Adolescents Diabetes in Special Populations S168 S184 S191 Diabetes and Pregnancy Diabetes in the Elderly Type 2 Diabetes in Aboriginal Peoples Appendices S197 S198 S200 S202 S204 S207 S209 S210 S211 S212 S212 Appendix 1: Etiologic Classification of Diabetes Mellitus Appendix 2: Sample Diabetes Patient Care Flow Sheet for Adults Appendix 3: Examples of Insulin Initiation and Titration Regimens in People with Type 2 Diabetes Appendix 4: Self-Monitoring of Blood Glucose (SMBG) Recommendation Tool for Healthcare Providers Appendix 5: Approximate Cost Reference List for Antihyperglycemic Agents Appendix 6: Therapeutic Considerations for Renal Impairment Appendix 7: Sick Day Medication List Appendix 8: Rapid Screening for Diabetic Neuropathy Appendix 9: Diabetes and Foot Care: A Patient’s Checklist Appendix 10: Diabetic Foot Ulcers: Essentials of Management Appendix 11: A1C Conversion Chart Can J Diabetes 37 (2013) A3–A13 Acknowledgment / Can J Diabetes 37 (2013) A3–A13 Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Acknowledgment / Can J Diabetes 37 (2013) A3–A13 . Simpson BSP PHARMD MSC T. Anderson PHD Alan Baron MD Stuart J. Dean MD FRCPC Timothy [email protected] Shen MD PHD Phillipe Halban PHD Len Harrison MD DSC FRACP FRCPA Robert Henry MD Cheri Ann Hernandez RN PHD CDE Ryuzo Kawamori MD PHD Karmeen Kulkarni RD MS CDE Willy Malaisse MD PHD Publications Coordinator Alarica Fernandes [email protected] Robin Conway MD Carol Fawcett RD CDE Rejeanne Gougeon PHD National Editorial Board Gillian Booth MD MSC FRCPC Peter E.PSYCH Peter A. Jr. Senior MBBS PHD Arya M. Light PHD International Editorial Board Stephanie Amiel MD FRCP Barbara J. MED CDE Sara Meltzer MD FRCPC le Pacaud MD FRCPC Danie Rémi Rabasa-Lhoret MD PHD Michael Riddell PHD Elizabeth Sellers MD MSC FRCPC Diana Sherifali RN PHD CDE Scot H. MD Paul Robertson MD Alicia Schiffrin MD Meng Tan MD FACP FRCPC Virginia Valentine RN MS CDE Paul Zimmett AM . Sharma MD PHD FRCPC Garry X. Cheng MD FRCPC J.ca Editor Emeritus Heather J. Kieffer PHD Sora Ludwig MD FRCPC Gail MacNeill RN. Michael Vallis PHD R.ca Kathy Mulcahy RN MSN CDE Stephen O'Rahilly MD FRCOI FRCF Daniel Porte.A Publication of the Professional Sections of the Canadian Diabetes Association Une publication des sections professionnelles de  te l'Association canadienne du diabe Editor-in-Chief David Lau MD PHD FRCPC Associate Editors Lori Berard RN CDE Sarah Capes MD MSC FRCPC Alice Y.Y. Brink MD Suad Efendic MD PHD George Eisenbarth MD PHD Martha Funnell RN MS CDE Diana Guthrie PHD RN CDE Managing Editor Ryan Moffat ryan. 905 King St. Extra Copies Copies of this document may be ordered.com. Website These guidelines are available at guidelines. 2007). It is incumbent upon healthcare professionals to stay current in this rapidly changing field. ON M6K 3G9.diabetes. These guidelines are intended to inform general patterns of care. these guidelines pertain to the care of adults with diabetes. commercial or promotional use. Can J Diabetes 2013. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. in whole or in part. Clement M.Notes to Readers Overview The Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada are intended to guide practice and are not intended to serve as a comprehensive text of diabetes management. Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada: pharmacologic management of type 2 diabetes. et al. at orders. Suggested Citation To cite as a whole: Canadian Diabetes Association Clinical Practice Guidelines Expert Committee. Example: Harper W. Two chaptersdType 1 Diabetes in Children and Adolescents and Type 2 Diabetes in Children and Adolescentsdare included to highlight aspects of care that must be tailored to the pediatric population.diabetes. W.ca.ca. for a nominal fee. Unless otherwise specified. Goldenberg R. et al. Ottawa. To order 50 or more copies for educational. is prohibited without written consent of the publisher. use clinical judgement and work with available human and healthcare service resources in their settings. . As per the Canadian Medical Association Handbook on Clinical Practice Guidelines (Davis D. These guidelines are also intended to enhance diabetes prevention efforts in Canada and to reduce the burden of diabetes complications in people living with this disease. First M. contact Zoe Aarden.” Healthcare professionals must consider the needs. Can J Diabetes [email protected]" Journal Year. These guidelines were developed using the best available evidence. values and preferences of individual patients. To cite a specific chapter: Last. Elsevier Canada.Vol(Number):XX-XX.37(suppl 1): S61-S68.37(suppl 1):S1-S212. ON: Canadian Medical Association. nor are they intended to set criteria for research protocols. Reproduction of the Guidelines Reproduction of the Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. E-mail: z. Toronto. guidelines should not be used as a legal resource in malpractice cases as “their more general nature renders them insensitive to the particular circumstances of the individual cases. "Chapter Title. that figure rose to over 150 million. the International Diabetes Federation (IDF) estimated that 371 million people had diabetes (2).  Inclusion of a drug cost appendix for pharmacological therapies as a reference for clinicians. where appropriate. nephrology. if applied properly. that number is expected to grow to 3. as well as recommendations for measures to delay the onset of diabetes for populations at high risk of developing type 2 diabetes. pharmacy. Expert Committee members bring expertise from diverse practice settings and include professionals from family medicine. exercise physiology and others. these guidelines will lead to improved quality of care. Diabetes and its complications increase costs and service pressures on Canada’s publicly funded healthcare system. ultimately. We are confident that. the Canadian Cardiovascular Society (CCS) and the Canadian Cardiovascular Harmonization of National Guidelines Endeavour (C-CHANGE). end stage renal disease (ESRD) and nontraumatic amputation in Canadian adults. Cheng MD.doi. reduced morbidity and mortality from diabetes and its complications.  Update and expansion of previous chapters and. They have served as a helpful resource and aid for anyone caring for people with diabetes and are recognized. internal medicine.to 4-fold more often than in people without diabetes. They then incorporated the evidence into revised diagnostic.org/10. FRCPC Every 5 years. expansion of the Duality of Interest policy) (see Methods chapter. since 1992. endocrinology. neurology. in some cases. evidence-based clinical practice guidelines (1). including the Canadian Hypertension Education Program (CHEP). amalgamation of previous chapters into others to increase utility and relevance. S4). and. ophthalmology. dietetics.g. p. nursing. in 2000. an estimated 30 million people around the world were diagnosed with diabetes. updated literature searches throughout the guideline development process. the estimated prevalence of diabetes in Canada was 6. not only in Canada but also internationally. and a better quality of life for people living with this chronic disease. Among adults aged 20 to 49 years. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.  Update and expansion of our Methodology process (e. those with . For these 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. People with diabetes are over 3 times more likely to be hospitalized with cardiovascular disease. That number is projected to rise to 552 million (or 1 in 10 adults) by 2030. in 2012.com Clinical Practice Guidelines Introduction Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Alice Y. rigour and process (1). obstetrics.2013.1016/j.009  Expanded harmonization of recommendations through collaboration with other organizations.4 million Canadians (3)da 230% increase compared to prevalence estimates in 1998. As of 2009. infectious disease.8% of the populationd2. 12 times more likely to be hospitalized with ESRD and over 20 times more likely to be hospitalized for a nontraumatic lower limb amputation compared to the general population (3). Cardiovascular disease is the leading cause of death in individuals with diabetes and occurs 2.01.  Inclusion and active participation of people with diabetes on the Expert Committee to ensure that their views and preferences informed the guideline development process and the recommendations. as high-quality. prognostic and therapeutic recommendations for the care of Canadians living with diabetes. to facilitate implementation of the recommendations. volunteer members of the Clinical Practice Guidelines Expert Committee assessed the peer reviewed evidence published since 2008 relevant to the prevention and management of diabetes. Although the largest increase is expected to be in countries with developing economies. In 1985. urology.canadianjournalofdiabetes.Can J Diabetes 37 (2013) S1eS3 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. which equates to 3 new cases per second (2). the Clinical & Scientific Section (C&SS) of the Canadian Diabetes Association has published comprehensive. evidence-based recommendations for healthcare professionals to consider in the prevention and management of diabetes in Canada. It is hoped that primary care physicians and other healthcare professionals who care for people with diabetes or those at risk of diabetes will continue to find the evidence compiled in these guidelines a vital aid and resource in their efforts.  Expanded dissemination and implementation strategy with increased use of technology.jcjd.Y. the Society of Obstetricians and Gynecologists of Canada (SOGC). pediatrics. In fact. By 2019.  Inclusion of a “Practical Tips” box. A number of important changes have occurred in the development of the 2013 clinical practice guidelines:  Expansion of the Expert Committee to include 120 healthcare professional volunteers from across Canada. an analysis by Bennett et al (1) demonstrated that the Canadian Diabetes Association clinical practice guidelines are among the best in the world with respect to quality. cardiology. The Challenge of Diabetes Diabetes mellitus is a serious condition with potentially devastating complications that affects all age groups worldwide. Canada also will be impacted significantly.7 million (3). psychology. Diabetes is the leading cause of blindness. blood pressure control. caution is required when identifying direct. an interprofessional team with the appropriate expertise is required. and disease prevention and management strategies be culturally appropriate and tailored to specific populations. However. In 2007. Cheng / Can J Diabetes 37 (2013) S1eS3 diabetes were 2 times more likely to see a family physician and 2 to 3 times more likely to see a specialist (3). Also. Nonetheless. The merits of each research study must be assessed individually so as to not block or restrict the pursuit of new information. which utilizes the data from the Canadian National Diabetes Surveillance System (NDSS) and the Economic Burden of Illness in Canada (EBIC) (11). The Canadian Diabetes Association welcomes the opportunity to work with regulatory agencies to enhance research in Canada and. the Canadian Diabetes Association commissioned a report to evaluate the economic burden of diabetes using a Canadian Diabetes Cost Model. A multifactorial approach utilizing an interprofessional team addressing healthy behaviours. p. individuals with diabetes must be supported in the skills of self-management since their involvement in disease management is absolutely necessary for success. In 2007. the estimated economic burden of diabetes was $12. but remains an active area of research. drug costs are included in Appendix 5. Research Canada continues to be a world leader in diabetes research. perhaps more importantly.6. the question of whether the committee should incorporate cost considerations was discussed again. the proposed 3-step approach was to A) identify those who may be at higher risk. and. It is suggested that study protocols may include guideline recommendations. ultimately. the 2011 Diabetes in Canada report from the Public Health Agency of Canada could not report the total economic burden of diabetes. considering feasibility and impact. Other Considerations In Canada. but concluded that the costs will only increase substantially as the prevalence of the disease increases over time (3). The issue of evidence-based vs. in 2009. Canada’s diverse population. As of 2013. It is certainly the hope and expectation of all stakeholders that the evidencebased prevention and management of diabetes in a multifactorial fashion will reduce the economic burden of the disease (3.g. hypoglycemia) in any cost-effectiveness analysis. There remains an urgent and increasing need for governments to invest in research to define effective strategies and programs to prevent and treat obesity and to encourage physical activity. All levels of government should commit to investing in chronic care management and support of the tools needed for successful self-management to ensure that optimal care can be delivered. Health outcomes depend on managing the disease effectively. The numerous reasons for this have been outlined in detail previously (13). including lower rates of cardiovascular disease and renal failure (4). However. consisting of health economists and health outcomes researchers. In addition. people with diabetes were 3 times more likely to require hospital admission in the preceding year with longer lengths of stay (3). Therefore. In this report. and a Cost Consideration Working Group. requires that health promotion.Y. to improve the care of people with diabetes.2 billion in 2010 and projected to increase by another $4. the IDF released a “Consensus on Type 2 Diabetes Prevention” and called upon the governments of all countries to develop and implement a National Diabetes Prevention Plan (4). problem solving and health monitoring. Therefore. Regulatory agencies should not apply these guidelines in a rigid way with regard to clinical research in diabetes. Canadians living with diabetes will not be able to achieve optimal results. without access to the necessary tools and strategies. B) measure the risk. Among those at high risk. indirect and induced costs for treating diabetes (10). In fact. S20). lipid management and vascular protection measures has been shown to effectively and dramatically lower the risk of development and progression of serious complications for individuals with diabetes (6e9). Optimal Care of Diabetes Effective diabetes care should be delivered within the framework of the Chronic Care Model and centred around the individual who is practicing. Based on issues of feasibility and philosophical considerations of our role as recommendation developers. the lack of expertise and resources to properly address the cost-effectiveness analyses needed for all the clinical questions within these clinical practice guidelines and. with some ethnic groups disproportionally affected by diabetes. the difficulty in truly accounting for all the important costs (e. it was decided that cost would not be included in the recommendations to ensure that they reflect the best available clinical evidence for the patient. have purposefully not taken into account cost effectiveness in the evaluation of the evidence surrounding best practice. The IDF proposed that strategies be implemented for 2 separate groups: those at high risk of developing type 2 diabetes. all of which are critical components of self-management.12). self-management (see Organization of Care chapter. there is good evidence that delaying the onset of type 2 diabetes results in significant health benefits. They also need access to a broad range of tools. Delaying the Onset of Type 2 Diabetes Prevention of type 1 diabetes has not yet been successful. The mandate of the group was to develop a proposal to the Clinical Practice Guidelines Steering Committee describing how cost issues might be incorporated into the guidelines. This research is essential for continued improvement in the lives of people with diabetes. Some of these reasons include the paucity of cost-effectiveness analyses using Canadian data. including medications. cholesterol and blood pressure targets. was convened.7 billion by 2020.Y. People with diabetes require training in goal setting. To achieve this. it is recognized and acknowledged that both the healthcare professional and the patient should consider cost when deciding on therapies. These clinical practice guidelines. the European Association for the Study of . cost-effective healthcare is an ethical debate that should involve all citizens because the outcome of this debate ultimately impacts every Canadian. the impact of diabetes is significant not only for individuals but also for their families and for society as a whole. Cost Considerations When it comes to the issue of cost. They also should include policies aimed at addressing poverty and other systemic barriers to healthcare (5). a consensus statement from the American Diabetes Association. and supported in. allowing for easy reference for both clinicians and patients alike. the philosophical question of which is more important: clinical benefit to the patient or cost to the system? At what level of cost effectiveness should one consider a therapy worth recommending? For these 2013 clinical practice guidelines.S2 A. and C) intervene to delay/prevent the onset of type 2 diabetes using predominantly health behaviour strategies to affect the modifiable risk factors for type 2 diabetes. like those published before. Canada does not have such a strategy in place. glycemic control. the glycated hemoglobin (A1C) continues to be reported using National Glycohemoglobin Standardization Program (NGSP) units (%). In addition. devices and supplies to help them achieve the recommended blood glucose. and the system needs to support and allow for sharing and collaboration between primary care and specialist care as needed. and the entire population at large. but individual decisions belong in the domain of the patientphysician relationship. 358:580e91. 2011. Diabet Med 2007. John WG. 14. However. In addition.353:2643e53. however.93(NGSP) e 23. 5. Conclusions Diabetes is a complex and complicated disease. Healthcare professionals are encouraged to judge independently the value of the diagnostic. patient values and preferences must be incorporated into clinical decision making (18). Consensus. 6. But the integration of evidence and judgment is what the healthcare provider does in order to dispense the best clinical care. Consensus Committee. Loewen P. it must be emphasized that treatment decisions need to be individualized. Wilson LM. 13. The hope is that these guidelines will provide government officials with the evidence they need when rationalizing access to healthcare so that the potentially beneficial health outcomes are maximized for people living with diabetes.idf. 15. The Diabetes Control and Complications Trial Research Group. The IFCC reference measurement system for HbA1c: a 6-year progress report. McCormack JP.35:2674e80. Cheng / Can J Diabetes 37 (2013) S1eS3 S3 Diabetes and the IDF called for A1C reporting worldwide to change to dual reporting of A1C with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) SI units (mmol/mol) and derived NGSP units (%) with the hope of fully converting to exclusive reporting in SI units (14). the consensus of expert opinions.31:1510e5. Time for action: a Canadian proposal for primary prevention of type 2 diabetes. therapeutic decisions are made at the level of the relationship between the healthcare professional and the patient. however. Berard L. The full guidelines will continue to be available online.22:149e64. Pedersen O. Palmet AJ. In those situations. Bowering K.329:977e86. 7. Judgment without evidence can be applied by a friend. 2012) demonstrated that only 13% of 5123 patients with type 2 diabetes had achieved all 3 metabolic targets (glycemia. Diabetes Care 2012. 19. 9.” (Hertzel Gerstein. N Engl J Med 2005. N Engl J Med 1993. Can J Diabetes 2012. 8. informed by whatever evidence is available. Leiter LA. Songer TJ. Pharmacoeconomics 2004. et al. et al. Ottawa. Lund-Andersen H. Bennett WL. Canada is not performing dual reporting. Guidelines are meant to aid in decision making by providing recommendations that are informed by the best available evidence. It is also important to note that clinical practice guidelines are not intended to be a legal resource in malpractice cases as outlined in the Canadian Medical Association Handbook on Clinical Practice Guidelines (19). A Dissemination & Implementation Committee was created to develop a strategic plan to be implemented at the launch of the guidelines and to continue for years thereafter. 2013.36:44e9. this has not been adopted worldwide. 4. Clin Chem 2008. and summary articles will be strategically placed in journals and newsletters. Gaede P. Measurement of hemoglobin A1c: a new twist on the path to harmony. is provided to help guide and aid the clinical decisions that need to be made at the level of the patient. Ann Intern Med 2012. Zhang P. Gaede P. www. 5th ed. Ottawa: Canadian Medical Association. Larsen N. Primary care physicians. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Toronto: Canadian Diabetes Association. Nathan DM. Goldman J.54:240e8. International Diabetes Federation. therefore. Strategies were developed to increase practitioner implementation and to improve patient care and health outcomes. Canadians living with diabetes and the general public continue to be the audiences for these campaigns. McManus R.29:376e8.53:1326e7. 18.24:451e63. International Federation of Clinical Chemistry and Laboratory Medicine. Therefore. Valentine WJ. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. healthcare providers. Cleary PA. . Sacks D. 10. Ettaro L. Diabetes Care 2008. Brussels: International Diabetes Federation. Alberti KGMM. 3. and the International Diabetes Federation. N Engl J Med 2003. Gaede P. key messages and tools supporting specific themes from the guidelines will be highlighted in technology-based and paper-based awareness campaigns over the next few years. et al. Evidence-based guidelines try to weigh the benefit and harm of various treatments. the following equation can be used: (16) IFCC ¼ 10. Canadian Medical Association Handbook on Clinical Practice Guidelines. Lank CN. Vedel P. Engelgau MM. Evaluation of guideline recommendations on oral medications for type 2 diabetes mellitus.Y. 12. At this time. Clinical Practice Guidelines and Clinical Judgement “Neither evidence nor clinical judgment alone is sufficient. Evidence without judgment can be applied by a technician. These volunteers from across Canada are involved in creating a 3-year plan to translate the evidence compiled in the guidelines into community practice. Can Fam Physician 2007. These 2013 clinical practice guidelines contain evidence-based recommendations that provide a useful reference tool to help healthcare professionals translate the best available evidence into practice. 16. 2012) People with diabetes are a diverse and heterogeneous group. European Association for the Study of Diabetes. However. prognostic and therapeutic recommendations published in the 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Diabetes Care 2007. Therefore. there are many other clinical situations where strong evidence may not be available. et al. and these are reflected in the recommendations within these guidelines. Palda VA. at the same time. 2. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Backlund JY. Cost of illness studies in diabetes mellitus. 2009. with both Canada and the United States still using the NGSP units (%) (15). IDF Diabetes Atlas. A Dissemination & Implementation Chair was appointed at the beginning of the guidelines process. Public Health Agency of Canada.Y. Adding “value” to clinical practice guidelines. et al.50. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. International Diabetes Federation: a consensus on type 2 diabetes prevention. a care gap remains and the effective dissemination and implementation of these 2013 clinical practice guidelines is critical. For those who wish to convert NGSP units to SI units.348:383e93. Cost-effectiveness of intensified versus conventional multifactorial intervention in type 2 diabetes. 11. the most notable disadvantage is the massive education effort that would be required to ensure recognition and adoption of the new units. cost-effectiveness and clinical practice guidelines: author’s response. N Engl J Med 2008. For some of the clinical decisions that we need to make with our patients. Diabetes in Canada: Facts and Figures from a Public Health Perspective.org/diabetesatlas. Davis D. 2007. Consensus statement on the worldwide standardization of the hemoglobin A1C measurement: the American Diabetes Association. Parving HH. lipids and blood pressure) (17). Effect of a multifactorial intervention on mortality in type 2 diabetes. Type 2 diabetes mellitus management in Canada: Is it improving? Can J Diabetes 2013: in press. Although there are some advantages to reporting in SI units. it is challenging for physicians and other healthcare professionals who care for people with diabetes. Zimmet P. strong evidence is available to inform those decisions. McFarlane P. et al.156:27e36.A. An Economic Tsunami: The Cost of Diabetes in Canada. 17. The burgeoning evidence on new technologies and therapeutic treatments is rapidly expanding our knowledge and ability to manage diabetes and its complications. Accessed February 21. or may never become available.30:2399e400. a recent national cross-sectional survey conducted around World Diabetes Day (November 14. patient preferences are not always included in clinical research. Dissemination and Implementation Despite the strength of the evidence supporting the multifactorial treatment of people with diabetes to reduce complications. Shaw J. the A1C will still be written in NGSP units (%). along with the importance of clinical judgement. therefore. can never be replaced by guideline recommendations. government officials. and. References 1. for reasons of feasibility. Canadian Diabetes Association. 2012. Mosca A. An Executive Summary will be distributed to healthcare professionals in Canada. Harris SB. That relationship. throughout this document. Weykamp C. Can J Diabetes 2005. However. Odelola OA. endocrinology.010 (CHEP). urology.ca/hiru/) of electronic databases (MEDLINE.doi. A librarian with expertise in literature reviews performed a comprehensive search of the relevant English-language.2). prevention and treatment of diabetes and its complications. and D) the clinically relevant outcomes being targeted. harmonization was sought with other Canadian guideline bodies. Identifying and Appraising the Evidence Authors for each chapter were assembled based on their relevant fields of expertise.com Clinical Practice Guidelines Methods Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Gillian Booth MD.  The strength of this evidence. Authors were to explicitly define A) the population to which a guideline would apply. Each citation that was used to formulate or revise a recommendation was assigned a level of evidence according to the prespecified criteria in Table 1.  Whenever possible. Committee members identified clinically important questions related to diagnosis. When evaluating papers. including the Canadian Cardiovascular Society (CCS). the citation(s) reporting this evidence had to be noted adjacent to the relevant guideline. cardiology.mcmaster. ophthalmology. prognosis. CINAHL. Cheng MD. as well as people with diabetes. peer-reviewed literature using validated search strategies (http://hiru. Alice Y. the Cochrane Central Register of Trials. authors were required to use standardized checklists that highlighted the most important . Health benefits. FRCPC Process Following the process used to develop previous Canadian Diabetes Association clinical practice guidelines (1. had to be noted (3e8). Patient preferences and values were sought from expert panel members with diabetes and the literature (where available).1016/j. risks and side effects of interventions were considered in formulating the recommendations.2013. psychology. MSc. based on prespecified criteria from the epidemiological literature and other guidelines processes. reflecting the methodological quality of the paper. nephrology. individual strategies were developed combining diabetes terms with methodological terms.Can J Diabetes 37 (2013) S4eS7 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. published.canadianjournalofdiabetes. This information was used to develop specific. empirical evidence that could be identified. 1 or 2 “evidence resource” persons trained or experienced in clinical epidemiology or clinical research methodology. FRCPC. risk factor or intervention being addressed. prevention or management of diabetes and its sequelae.  Guidelines based on biological or mechanistic reasoning. including literature published in September 2007 or later. Updated literature searches were performed at regular intervals throughout the development process. prognosis. which were used as a basis for our literature search strategy (outlined below). nursing. and additional authors. and PsycINFO [where appropriate]).01. C) the “gold standard” test or relevant intervention to which the test or intervention in question was compared. the Canadian Cardiovascular Harmonization of National Guidelines Endeavour (C-CHANGE) and the Society of Obstetricians and Gynecologists of Canada (SOGC). 120 volunteers. Elements covered by the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument were incorporated into the guideline development process. dietetics. At the outset of the process. where relevant. each recommendation had to be justified by the strongest clinically relevant. EMBASE. clinically relevant questions that were the focus of literature searches.  Each recommendation had to be assigned a grade based on the available evidence. neurology. Steering Committee and Expert Committee with broad expertise and geographic representation were assembled.jcjd. in order to ensure a consistent approach to the development of recommendations. B) the test. pediatrics. the search time frame included the literature published since 1990 or earlier.  Each recommendation had to address a clinically important question related to 1 or more of the following: detection. For topics that were covered in the 2008 guidelines. with 100% consensus. obstetrics. The following basic principles were adopted to ensure that the values and empirical basis underlying each recommendation were explicitly identified and to facilitate the critical scrutiny and analysis of each recommendation by other organizations and individuals. committee members from each section of the guidelines attended a workshop on evidence-based methodology. participated in the guideline development process. infectious disease. including health professionals from family medicine. its methodological strength and its applicability to the Canadian population. This was complemented by the authors’ own manual and electronic searches. For each question. expert opinion or consensus had to be explicitly identified and graded as such. Each chapter had 1 lead author. exercise physiology and others. pharmacy. In total. Key citations retrieved from the literature searches were then reviewed. an Executive Committee.org/10. as needed. For new topics.Y. internal medicine. the Canadian Hypertension Education Program 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.  Each recommendation had to be approved by the Steering Committee and Executive Committee. the literature searches focused on new evidence published since those guidelines. Further details on the grading process are described below.G. In those circumstances. Papers evaluating the cost effectiveness of therapies or diagnostic tests also were not included. some evidence relating to these problems was identified that either excluded. or judged to require further supporting evidence. was assigned a lower grade. * In cases where such blinding was not possible or was impractical (e. several treatment recommendations were based on evidence generated from the use of one therapeutic agent from a given class (e. each recommendation was assigned a grade from A through D (Table 2). for example.g. one of the statins). Higher levels were assigned if A) people with diabetes comprised a predefined subgroup. Booth. In the absence of new evidence since the publication of the 2008 clinical practice guidelines. The level of evidence was then determined by the cited paper’s objectives. A number of considerations were made when evaluating the evidence within a given area. For example.Y. methodological rigour.e. In some cases. elements of a well-conducted study. did not report on or did not focus on people with diabetes. The highest possible grade that a recommendation could have was based on the strength of evidence that supported the recommendation (i. susceptibility to bias and generalizability (Table 1). including the relative strengths of the studies from a methodological perspective and the studies’ findings. As such. A recommendation not deemed to be applicable to Canadians. meeting abstracts. the highest level of evidence assigned to studies on which the recommendation was based). Grading the Recommendations After formulating new recommendations or modifying existing ones based on new evidence. conventional insulin therapy). Guideline Development Expert Committee members evaluated the relevant literature. systematic overview or meta-analysis of level 3 studies Other S5 chance. B) the results in the diabetes subgroup were unlikely to have occurred by . Whenever such evidence was identified. Table 2 Criteria for assigning grades of recommendations for clinical practice Grade Grade Grade Grade Grade A B C D Criteria The The The The best best best best evidence evidence evidence evidence was was was was at at at at Level Level Level Level 1 2 3 4 or consensus Level 1B Level 2 Level 3 Level 4 Studies of prognosis Level 1 a) Inception cohort of patients with the condition of interest but free of the outcome of interest b) Reproducible inclusion/exclusion criteria c) Follow-up of at least 80% of subjects d) Statistical adjustment for extraneous prognostic factors (confounders) e) Reproducible description of outcome measures Level 2 Meets criterion a) above. However. Studies with conflicting outcomes were also considered and cited in the final recommendation where relevant. the grading also was lowered for subgroups that were not well represented in the study or in whom the beneficial effect of an intervention was less clear.Y. plus 2 of the other criteria Level 4 Meets criterion a) above. a level was assigned using the approach described above. the recommendation was written so as to be relevant to the class. all relevant studies were cited. but specifically studied therapeutic agents were identified within the recommendation and/or cited reference(s). a recommendation based on Level 1 evidence. and C) the evidence was generated in response to questions that were formulated prior to the analysis of the results. Lower levels (than those indicated in Table 1) were assigned to evidence that did not meet these criteria. was assigned a grade of A. Because they could not be critically appraised. the assigned grading was lowered in some cases. Only medications with Health Canada Notice of Compliance granted by February 15.g. regardless of the grading assigned to the recommendation. if the evidence was found not to be applicable to the Canadian population or. news reports and other sources could not be used to support recommendations. The final grading depended on the overall evidence available. Where available. renal failure and erectile dysfunction). there were additional concerns regarding the recommendation. Thus. A. and guidelines were developed and initially reviewed by the Expert Committee. the blinding of individuals who assessed and adjudicated study outcomes was felt to be sufficient. In some situations. 2013 were included in the recommendations. Cheng / Can J Diabetes 37 (2013) S4eS7 Table 1 Criteria for assigning levels of evidence to the published studies Level Criteria Studies of diagnosis Level 1 a) Independent interpretation of test results (without knowledge of the result of the diagnostic or gold standard) b) Independent interpretation of the diagnostic standard (without knowledge of the test result) c) Selection of people suspected (but not known) to have the disorder d) Reproducible description of both the test and diagnostic standard e) At least 50 patients with and 50 patients without the disorder Level 2 Meets 4 of the Level 1 criteria Level 3 Meets 3 of the Level 1 criteria Level 4 Meets 1 or 2 of the Level 1 criteria Studies of treatment and prevention Level 1A Systematic overview or meta-analysis of high quality RCTs a) Comprehensive search for evidence b) Authors avoided bias in selecting articles for inclusion c) Authors assessed each article for validity d) Reports clear conclusions that are supported by the data and appropriate analyses OR Appropriately designed RCT with adequate power to answer the question posed by the investigators a) Patients were randomly allocated to treatment groups b) Follow-up at least 80% complete c) Patients and investigators were blinded to the treatment* d) Patients were analyzed in the treatment groups to which they were assigned e) The sample size was large enough to detect the outcome of interest Nonrandomized clinical trial or cohort study with indisputable results RCT or systematic overview that does not meet Level 1 criteria Nonrandomized clinical trial or cohort study. Grading also was lowered if the findings from relevant (and equally rigorous) studies on the topic were conflicting. the number of patients that would need to be treated in order to prevent 1 clinical event (number needed to treat [NNT]) or to cause an adverse event (number needed to harm [NNH]) was considered in assessing the impact of a particular intervention. Finally. if based on the consensus of the Steering and Executive Committees. cardiovascular disease. plus 3 of the other 4 criteria Level 3 Meets criterion a) above. recommendations from the 2008 document were not changed. plus 1 of the other criteria RCT. randomized. narrative review articles. deemed to be very applicable to Canadians and supported by strong consensus.g. Whenever evidence relating to 1 or more agents from a recognized class of agents was available. key citations that influenced the final recommendation were not assigned the same level of evidence but rather were of varying levels of evidence. people with diabetes are at high risk for several sequelae that are not exclusive to diabetes (e. The studies used to develop and support each recommendation are cited beside the level of evidence. intensive vs. controlled trial. Finally. Varying grades of recommendations. such as the one pertaining to the periodic health examination in Canada. In the case of a potential duality or outright conflict of interest. they also frequently are faced with having to act in the absence of clinical evidence. assigned level of evidence and grade of each recommendation were reassessed and modified as necessary. Canadian Diabetes Association 2003 clinical practice guidelines for the prevention and management of diabetes in Canada. They also facilitate the ability of clinicians.Y. Based on this review. A. literature interpretation. Therefore. as noted above. Cheng / Can J Diabetes 37 (2013) S4eS7 The degree to which evidence derived from other populations was felt to be relevant to diabetes also was reflected in the wording and grading of the recommendation. Of note. Thus. many Grade D recommendations were deemed to be very important to the contemporary management of diabetes. committee members removed themselves from discussions. British Columbia. a high grade reflects a high degree of confidence that following the recommendation will lead to the desired outcome. Canadian Diabetes Association Clinical Practice Guideline Expert Committee. a lower grade reflects weaker evidence and a greater possibility that the recommendation will change when more evidence is generated in the future. Revised recommendations were reviewed and approved by the Executive and Steering Committees. and they did not have access to guideline meetings. in which harmful practices were assigned a grade of D (8). its assigned grade and supportive citations. Merck Canada Inc. Similarly.S6 G. Selected recommendations were presented at a public forum at the Canadian Diabetes Association/Canadian Society of Endocrinology and Metabolism Professional Conference and Annual Meetings in Vancouver. the decision to publish or any other aspect related to the publication of these guidelines. These companies were not involved in any aspect of guideline development. Dualities of interest were discussed during deliberations where relevant. External Peer Review and Independent Methodological Review In May 2012. However. prevention. In this way. Can J Diabetes 2003. healthcare providers and society. it should be noted that the authors of these guidelines focused on clinical practices that were thought to be potentially beneficial and did not seek out evidence regarding the harmfulness of interventions. However. in the absence of Level 1. to critically examine any recommendation and arrive at their own conclusions regarding its appropriateness. Eli Lilly Canada Inc. Updates to individual chapters may be published sooner in the event of significant changes in evidence supporting the recommendations. independently reviewed each recommendation.Y. recommendation to avoid any harmful practices would be graded in the same manner as all other recommendations. Other Relevant Guidelines Introduction. on October 13. based on clinical experience. these evidence-based guidelines and their graded recommendations are designed to satisfy 2 important needs: 1) the explicit identification of the best research upon which the recommendation is based and an assessment of its scientific relevance and quality (captured by the assignment of a level of evidence to each citation). physiological evidence and current concepts of disease pathophysiology. a draft document was circulated nationally and internationally for review by numerous stakeholders and experts in relevant fields. p. For example. or if the recommendation was based on the consensus of the Steering and Executive Committees. the wording. impractical or too expensive to generate (which implies that it would be impossible to develop Grade A recommendations). In this Canadian Diabetes Association guidelines document. Thus. the paucity of clinical evidence addressing the areas of therapy. Subsequently. the assigned grade contains no subjective information regarding the importance of the recommendation or how strongly members of the committee felt about it. Disclosure of Duality of Interest Committee members were volunteers and received no remuneration or honoraria for their participation. they provide a convenient summary of the evidence to facilitate clinicians in the task of “weighting” and incorporating ever increasing evidence into their daily clinical decision making. diagnosis or prognosis precluded the assignment of a higher grade. 2 or 3 supporting evidence. healthcare planners. 2012. it only contains information regarding the evidence upon which the recommendation is based. Interpreting the Assigned Grade of a Recommendation The grade assigned to each recommendation is closely linked to the methodological rigour and robustness of the relevant clinical research. This input was then considered by the Executive and Steering Committees. Booth. these guidelines facilitate their own scrutiny by others according to the same principles that they use to scrutinize the literature. therefore. S1 References 1. The Executive and Steering Committees of the 2013 revision will continue to remain intact to deliberate any potential updates to individual chapters until such time as the Executive and Steering Committees for the 2018 revision have been created. Therefore. However. Prior to the publication of the UKPDS results. the recommendation for glycemic control to prevent microvascular consequences was a Grade B recommendation (9). Clearly. Guideline Updates A process to update the full guidelines will commence within 5 years and will be published in 2018. . guideline drafts or committee deliberations. a panel of 6 methodologists.27(suppl 2): S1e152. Funding for the development of the guidelines was provided from the general funds of the Canadian Diabetes Association and from unrestricted educational grants from Novo Nordisk Canada Inc. clinicians need to base clinical decisions on the best available relevant evidence that addresses clinical situations. Bristol-Myers Squibb and AstraZeneca. the highest grade that could be assigned was D. reflect varying degrees of certainty regarding the strength of inference that can be drawn from the evidence in support of the recommendation. case series. in general. and Novartis Pharmaceuticals Canada Inc. and revisions were made accordingly. and there are many situations where good clinical evidence may be impossible. it took the United Kingdom Prospective Diabetes Study (UKPDS) Group >20 years to collect and publish Level 1 evidence leading to a Grade A recommendation in support of the role of tight glycemic control to reduce microvascular disease in people with type 2 diabetes. It is important to note that the system chosen for grading recommendations differs from the approach used in some other guideline documents. Members of all committees signed an annual duality of interest form listing all financial interests or relationships with manufacturer(s) of any commercial product(s) and/or provider(s) of commercial services. who were not directly involved with the initial review and assessment of the evidence. and 2) the explicit assignment of strength of the recommendation based on this evidence (captured by the grade). A. Haynes RB. 2001. Haynes RB. Straus SE.G. Haynes RB. ON: BC Decker Inc. ON: BC Decker Inc. Users’ Guides to the Medical Literature: Essentials of Evidence-based Clinical Practice. ON: BC Decker Inc. Battista RN. . The periodic health examination: 1. Harris SB.Y. IL: American Medical Association. Goldbloom R. Daneman D. Evidence-based Diabetes Care. 2001. Evidence-based clinical practice guidelines. Leiter L.134:721e3. 1998 clinical practice guidelines for the management of diabetes in Canada. Hamilton. Guyatt GH. American Medical Association. Can J Diabetes 2008. S7 6. 8. Evidence-based Diabetes Care. editors. McAlister FA. Canadian Diabetes Association Clinical Practice Guideline Expert Committee. 9. editors. Meltzer S. Cheng / Can J Diabetes 37 (2013) S4eS7 2. Clarke J-A. Holbrook AM. editors. et al. Raymond C. CMAJ 1986. 2001. Evidence-based Diabetes Care. Webster-Bogaert SM. et al. How should a particular problem be managed? Incorporating evidence about therapies into practice. CMAJ 1998. In: Gerstein HC. Jaeschke R. 2001. How should diagnostic tests be chosen and used? In: Gerstein HC. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada.159(suppl 8):S1e29.Y. 4. p. ON: BC Decker Inc. 13e23. 3. Hamilton. Evidence-based Diabetes Care. Chicago. p. 6e12. editors. p. Booth. 7. Introduction. 48e61. What is the prognosis? In: Gerstein HC. Hamilton. p. In: Gerstein HC. Haynes RB. Hamilton. 5.32(suppl 1):S1e201. 24e47. 2001. and each predicts the development of retinopathy (5e11).14).0 mmol/L correlates most closely with a 2-hour plasma glucose (2hPG) value of 11. FACE. studies of various ethnicities indicate that African Americans. The frequency of retinopathy begins to increase at lower A1C levels in American blacks than in American whites.11.5% (5e7. Although the diagnosis of diabetes is based on an A1C threshold for developing microvascular disease. impaired glucose tolerance or an A1C of 6. This permits the diagnosis of diabetes to be made on the basis of each of these parameters. and severe hepatic and renal disease (16). A1C testing also avoids the problem of day-to-day variability of glucose values as it reflects the average plasma glucose (PG) over the previous 2 to 3 months (1). A1C can be measured at any time of day and is more convenient than FPG or 2hPG in a 75 g OGTT. defective insulin action or both.4% higher than those of Caucasian patients at similar levels of glycemia (17.011 . kidneys and nerves.0% to 6. which suggests a lower threshold for diagnosing diabetes in black persons (19). but it may be difficult at the time of diagnosis in certain situations. such as anti-glutamic acid decarboxylase (GAD) or anti-islet cell antibody (ICA) antibodies.org/10. Classification of Diabetes The classification of type 1 diabetes. Appendix 1 addresses the etiologic classification of diabetes. a 2-hour plasma glucose value in a 75 g oral glucose tolerance test of 11.  A fasting plasma glucose level of 7.0 mmol/L. impaired glucose tolerance (IGT) (1) or a glycated hemoglobin (A1C) of 6.  The term “prediabetes” refers to impaired fasting glucose. each of which places individuals at high risk of developing diabetes and its complications. Clinical judgement with safe management and ongoing follow-up is a prudent approach. The diagnostic criteria for diabetes are based on thresholds of glycemia that are associated with microvascular disease. hemolytic anaemias. Research is required Definition of Diabetes and Prediabetes Diabetes mellitus is a metabolic disorder characterized by the presence of hyperglycemia due to defective insulin secretion. “Prediabetes” is a practical and convenient term referring to impaired fasting glucose (IFG). MSc. there are several advantages to using A1C for diabetes diagnosis (15). The relationship between A1C and retinopathy is similar to that of FPG or 2hPG with a threshold at around 6.1016/j. It is important to note that A1C may be misleading in individuals with various hemoglobinopathies.doi.2013. In order to use A1C as a diagnostic criterion. FRCPC. A1C must be measured using a validated assay standardized to the National Glycohemoglobin Standardization Program-Diabetes Control and Complications Trial reference.5% can predict the development of retinopathy. A1C is also a continuous cardiovascular (CV) risk factor and a better predictor of macrovascular events than FPG or 2hPG (13. The chronic hyperglycemia of diabetes is associated with relatively specific long-term microvascular complications affecting the eyes. Distinguishing between type 1 and type 2 diabetes is important because management strategies differ.0% to 6. Although many people identified by A1C as having diabetes will not have diabetes by traditional glucose criteria and vice versa. type 2 diabetes and gestational diabetes mellitus (GDM) is summarized in Table 1. A fasting plasma glucose (FPG) level of 7.12).01. In addition. especially retinopathy.Can J Diabetes 37 (2013) S8eS11 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. months of clinical stabilization may favour type 1 diabetes (2).canadianjournalofdiabetes. Hispanics and Asians have A1C values that are up to 0. These criteria are based on venous samples and laboratory methods. as well as an increased risk for cardiovascular disease (CVD).jcjd. Prediabetes and Metabolic Syndrome Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Ronald Goldenberg MD. FRCPC KEY MESSAGES  The chronic hyperglycemia of diabetes is associated with significant longterm microvascular and macrovascular complications. Classification and Diagnosis of Diabetes. American Indians. Zubin Punthakee MD.1 mmol/L or a glycated hemoglobin (A1C) value of 6. may be helpful.1 mmol/L in a 75 g oral glucose tolerance test (OGTT). iron deficiency. they are not helpful in acute hyperglycemia (3).4%. but have not been adequately studied as diagnostic tests in this setting.com Clinical Practice Guidelines Definition. Physical signs of insulin resistance and autoimmune markers.4%. While very low C-peptide levels measured after 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.18). Diagnostic Criteria Diabetes The diagnostic criteria for diabetes are summarized in Table 2 (1). each of which places individuals at high risk of developing diabetes and its complications. 5% (in adults) Using a standardized. Also. While people with prediabetes do not have the increased risk for microvascular disease as seen in diabetes. fasting plasma glucose. Indeed. Individuals identified as having both IFG and IGT are at higher risk for diabetes as well as CVD. confirmatory testing should not delay initiation of treatment to avoid rapid deterioration. but a random PG in the diabetes range in an asymptomatic individual should be confirmed with an alternate test. 2hPG in a 75 g OGTT) and the results are discordant. the term used to describe the small number of people with apparent type 2 diabetes who appear to have immune-mediated loss of pancreatic beta cells (4). Z.9 7. PG.0 mmol/L Fasting ¼ no caloric intake for at least 8 hours or A1C ‡6. 2hPG in a 75 g OGTT) must be done on another day. A1C. In individuals in whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia. A1C values also are affected by age.4% are associated with Table 4 Diagnosis of prediabetes Test FPG (mmol/L) 2hPG in a 75 g OGTT (mmol/L) A1C (%) Result 6. plasma glucose. a significant proportion of people who are diagnosed with IFG or IGT will revert to normoglycemia. FPG. oral glucose tolerance test.  Gestational diabetes mellitus refers to glucose intolerance with onset or first recognition during pregnancy.or ethnic-specific adjusted A1C thresholds are required for diabetes diagnosis. IGT or an A1C of 6. a repeat confirmatory laboratory test (FPG. hemoglobinopathies.4%. if a single laboratory test result is in the diabetes range. if a single laboratory test result is in the diabetes range. glycated hemoglobin.  Convenient (measure any time of day)  Single sample  Predicts microvascular complications  Better predictor of macrovascular disease than FPG or 2hPG in a 75 g OGTT  Low day-to-day variability  Reflects long-term glucose concentration  Cost  Misleading in various medical conditions (e. 2hPG in a 75 g OGTT) must be done on another day. the Canadian Diabetes Association defines IFG as an FPG value of 6. Prediabetes The term “prediabetes” refers to IFG.0% to 6.0e6. In the case of symptomatic hyperglycemia.  Type 2 diabetes may range from predominant insulin resistance with relative insulin deficiency to a predominant secretory defect with insulin resistance. FPG. impaired fasting glucose. population studies demonstrate that A1C levels of 6.21). * Includes latent autoimmune diabetes in adults (LADA).9 mmol/L (25). FPG. A1C. 2-hour plasma glucose. would benefit from CV risk factor modification. hemolytic anaemia. A1C. It is preferable that the same test be repeated (in a timely fashion) for confirmation.1% per decade of life (20. While there is no worldwide consensus on the definition of IFG (24. validated assay in the absence of factors that affect the accuracy of the A1C and not for suspected type 1 diabetes (see text) or 2hPG in a 75 g OGTT ‡11. More studies may help to determine if age.8e11. A1C. they are at risk for the development of diabetes and CVD (23). A1C versus glucose testing: a comparison. the diagnosis of diabetes is confirmed. impaired glucose tolerance. severe hepatic or renal disease)  Altered by ethnicity and aging  Standardized. adolescents. IGT. oral glucose tolerance test. S9 Table 3 Advantages and disadvantages of diagnostic tests for diabetes* (22) Parameter FPG Advantages     Established standard Fast and easy Single sample Predicts microvascular complications Disadvantages          Sample not stable High day-to-day variability Inconvenient (fasting) Reflects glucose homeostasis at a single point in time Sample not stable High day-to-day variability Inconvenient Unpalatable Cost 2hPG in a 75 g OGTT  Established standard  Predicts microvascular complications A1C to determine if A1C levels differ in African Canadians or Canadian First Nations. validated assay required  Not for diagnostic use in children.  Other specific types include a wide variety of relatively uncommon conditions. While there is a continuum of risk for diabetes in individuals with A1C levels between 5. 2-hour plasma glucose. a repeat confirmatory laboratory test (FPG. each of which places individuals at high risk of developing diabetes and its complications. IGT is more strongly associated with CVD outcomes than is IFG. A1C is not recommended for diagnostic purposes in children. the diagnosis has been made and a confirmatory test is not required before treatment is initiated. oral glucose tolerance test. particularly in the context of the metabolic syndrome. but a random PG in the diabetes range in an asymptomatic individual should be confirmed with an alternate test.1 mmol/L Random ¼ any time of the day. the test whose result is above the diagnostic cutpoint should be repeated and the diagnosis made on the basis of the repeat test. Each diagnostic test has advantages and disadvantages (Table 3). OGTT. Goldenberg. If results of 2 different tests are available and both are above the diagnostic cutpoints. In the case of symptomatic hyperglycemia. IFG.1 mmol/L or Random PG ‡11.0% to 6.0 6. adolescents. OGTT. fasting plasma glucose. rising by up to 0. especially with ketonuria or ketonemia). FPG. glycated hemoglobin. primarily specific genetically defined forms of diabetes or diabetes associated with other diseases or drug use (Appendix 1). In the absence of symptomatic hyperglycemia. the diagnosis has been made and a confirmatory test is not required before treatment is initiated. It is preferable that the same test be repeated (in a timely fashion) for confirmation. In individuals in whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia. without regard to the interval since the last meal In the absence of symptomatic hyperglycemia. Not all individuals with prediabetes will necessarily progress to diabetes. 2hPG.5% and 6. A1C.4 Prediabetes category IFG IGT Prediabetes 2hPG. pregnant women or those with suspected type 1 diabetes. This form includes cases due to an autoimmune process and those for which the etiology of beta cell destruction is unknown. Diabetes Care. . 2011. glycated hemoglobin. OGTT. especially with ketonuria or ketonemia). People with prediabetes. pregnant women or those with suspected type 1 diabetes 2hPG. When the results of more than 1 test are available (among Table 2 Diagnosis of diabetes FPG ‡7.1 to 6.25). iron deficiency. Punthakee / Can J Diabetes 37 (2013) S8eS11 Table 1 Classification of diabetes (1)  Type 1 diabetes* encompasses diabetes that is primarily a result of pancreatic beta cell destruction and is prone to ketoacidosis. the diagnosis of diabetes is confirmed.6 to 6.4% (Table 4).R. A1C. If results of 2 different tests are available and both are above the diagnostic cutpoints. fasting plasma glucose.34:518e523. * Adapted from Sacks D. confirmatory testing should not delay initiation of treatment to avoid rapid deterioration.g.9 mmol/L due to the higher risk of developing diabetes in these individuals compared to defining IFG as an FPG value of 5. The decision of which test to use for diabetes diagnosis (Table 2) is left to clinical judgement.1e6. 2-hour plasma glucose. . If results of two different tests are available and both are above the diagnostic cutpoints. South and Central American Elevated TG (drug treatment for elevated TG is an alternate indicatory) Reduced HDL-C (drug treatment for reduced HDL-C is an alternate indicatory) Elevated BP (antihypertensive drug treatment in a patient with a history of hypertension is an alternate indicator) Elevated FPG (drug treatment of elevated glucose is an alternate indicator) Women 102 cm 88 cm 94 cm 80 cm 90 cm 80 cm 1.S10 R.120:1640-1645. if a single laboratory test result is in the diabetes range.0% to 6.9 mmol/L and an A1C of 6. 2hPG in a 75 g OGTT) must be done on another day. 2009. Level 2 (11)]  A1C 6.20:1183e97. Patel P.0% to 6.0% (26). 2-hour plasma glucose. Level 2 (11)]  Random PG 11. United States  Europid. Japanese. Diabetes should be diagnosed by any of the following criteria:  FPG 7. with at least 3 or more criteria required for diagnosis (Table 5) (29).7% and 6. Punthakee / Can J Diabetes 37 (2013) S8eS11 Table 5 Harmonized definition of the metabolic syndrome: 3 measures to make the diagnosis of metabolic syndrome* (29) Measure Categorical cutpoints Men Elevated waist circumference (population. S163 Relevant Appendix Appendix 1.4% (for use in adults in the absence of factors that affect the accuracy of A1C and not for use in suspected type 1 diabetes) [Grade B. blood pressure.6 mmol/L BP. Etiologic Classification of Diabetes Mellitus References 1. Various diagnostic criteria for the metabolic syndrome have been proposed. FPG. high-density lipoprotein cholesterol. A1C. a higher risk for diabetes compared to levels between 5. syndromeda highly prevalent. * Adapted from Alberti KGMM. Level 1 (23)]  A1C 6. While metabolic syndrome and type 2 diabetes often coexist.4% as a diagnostic criterion for prediabetes (1). Individuals with the metabolic syndrome are at significant risk of developing CVD. 7. Thompson TJ. 350:1288e93. In the case of symptomatic hyperglycemia. impaired glucose tolerance. Level 2 (26)]. Goldenberg. While the American Diabetes Association defines prediabetes as an A1C between 5. triglycerides.1 to 6. HDL-C. hypertension. fasting plasma glucose. Diabetes mellitus: diagnosis and screening.1 mmol/L [Grade B. A1C levels below 6. the diagnosis has been made and a confirmatory test is not required before treatment is initiated. dyslipidemia and abdominal obesity. in the hope of significantly reducing CV morbidity and mortality. oral glucose tolerance test. Z.8e11. S12 Reducing the Risk of Developing Diabetes. High-dose omega-3 fatty acids presumes high TG. BMJ 1994. Diagnosis and classification of diabetes mellitus.0 mmol/L) [Grade A. dyslipidemia and elevated blood glucose. 3.and country-specific cutpoints):  Canada.4%. p. Comparison of fasting and 2-hour glucose and HbA1c levels for diagnosing diabetes. TG. especially with ketonuria or ketonemia). It is preferable that the same test be repeated (in a timely fashion) for confirmation. 6. sub-Saharan African. p.5% (for use in adults in the absence of factors that affect the accuracy of A1C and not for use in those with suspected type 1 diabetes) [Grade B. S153 Type 2 Diabetes in Children and Adolescents. 3. A1C. Am Fam Physician 2010. In the absence of symptomatic hyperglycemia. Consensus] 2. glycated hemoglobin.1e6. Evidence exists to support an aggressive approach to identifying and treating people. p.35(suppl 1):S64e71.28:119e21. PG. Diabetes Care 1997. Herman WH. p. Diabetologia 1985.4% is predictive of 100% progression to type 2 diabetes over a 5-year period (27).0%e6. y The most commonly used drugs for elevated TG and reduced HDL-C are fibrates and nicotinic acid. Turner R. Report of the expert committee on the diagnosis and classification of diabetes mellitus. not only those with hyperglycemia but also those with the associated CV risk factors that make up the metabolic syndrome. such as hypertension. Mediterranean  Asian. Grundy S. In 2009. Harmonizing the metabolic syndrome. multifaceted condition characterized by a constellation of abnormalities that include abdominal obesity. the Canadian Diabetes Association has based the definition on a higher risk group and includes an A1C of 6. Circulation. Charles MA. Engelgau MM. UK Prospective Diabetes Study Group. et al. Diagnostic criteria and performance revisited. Middle Eastern. Three or more criteriaare required for diagnosis. Unger RH. Stratton I. the diagnosis of diabetes is confirmed [Grade D.3 mmol/L in females Systolic 130 mm Hg and/or diastolic 85 mm Hg 5.5% and 6. et al. Eckel R. plasma glucose. Hyperglycemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. those with metabolic syndrome without diabetes are at significant risk of developing diabetes. The combination of an FPG of 6. Abbreviations: 2hPG. However.1 mmol/L [Grade D. confirmatory testing should not delay initiation of treatment to avoid rapid deterioration. fasting plasma glucose. a harmonized definition of the metabolic syndrome was established. Metabolic syndrome Prediabetes and type 2 diabetes are often manifestations of a much broader underlying disorder (28). FPG. including the metabolic RECOMMENDATIONS 1. Diabetes Care 1997. Lancet 1997. Macerollo A. McCance DR.81:863e70. a repeat confirmatory laboratory test (FPG. Horton V.20:785e91.0% can indeed be associated with an increased risk for diabetes (26). Hanson RL. IGT. et al. A patient taking 1 of these drugs can be presumed to have high TG and reduced HDL-C.7 mmol/L <1. Grundy S. 5. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. American Diabetes Association. impaired fasting glucose.9 mmol/L) [Grade A. Consensus].0 mmol/L in males. OGTT. Level 1 (23)]  IGT (2hPG in a 75 g OGTT 7. Diabetes Care 2012. Prediabetes (defined as a state which places individuals at high risk of developing diabetes and its complications) is diagnosed by any of the following criteria:  IFG (FPG 6. 2. S16 Type 1 Diabetes in Children and Adolescents.0 mmol/L [Grade B. et al.308:1323e8. UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Comparison of tests for glycated hemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes. but a random PG in the diabetes range in an asymptomatic individual should be confirmed with an alternate test. <1. 4. Level 2 (11)]  2hPG in a 75 g OGTT 11. In individuals in whom type 1 diabetes is likely (younger or lean or symptomatic hyperglycemia. IFG. Other Relevant Guidelines Screening for Type 1 and Type 2 Diabetes. Meigs JB. Ziemer DC. Diabetes Care 2009. Borch-Johnsen K. Evidence report/technology assessment no. Maeda R. Davis R. Harper CA. 128.120:1640e5. Comparison of diagnostic methods for diabetes mellitus based on prevalence of retinopathy in a Japanese population: the Hisayama Study. Zimmet PZ. Diabetic Med 2012.33:1665e73. Ma Y. International Expert Committee. 22. Role of insulin resistance in human disease. Diabetes Care 2011. Korenda L. Review of hemoglobin A1c in the management of diabetes. et al.87:415e21.32: 1327e34. Herman WH. Selvin E. EDEG. Bloomgarden ZT. et al. Miyazaki M. Sacks D. Zimmett PZ. Z. Diabetes 1988. 18. Eiriksdottir G. 26. Tsugawa Y. Weintraub WS. Balkau B. Chamany S. Tapp RJ. et al. Importance of OGTT for diagnosing diabetes mellitus based on prevalence and incidence of retinopathy. . Roith D. et al.31:1991e6. Rockville. Fujihara K. 16.34:145e50. Screening for pre-diabetes to predict future diabetes using various cut-off points for HbA1c and impaired fasting glucose: the Toranomon Hospital Health Management Center Study 4 (TOPICS 4). Driver C. Effect of aging on A1C levels in persons without diabetes: evidence from the Framingham Offspring Study and NHANES 2001-2004. Agency Healthcare Research and Quality Publication No 05-E026-2. Diabetes Res Clin Pract 2010. and cardiovascular risk in nondiabetic adults. Schriger DL.152: 770e7. Gallagher EJ. 21. Steffes MW. Banting Lecture 1988. September 2005. Diabetes Res Clin Pract 2000. Heianza Y. blackwhite differences in hemoglobin A1c levels. Diabetologia 2004. Glucose-independent. 11. Arase Y. 12. Diabetes Care 2010. diabetes. Use of glycated haemoglobin (HbA1C) in the diagnosis of diabetes mellitus. 15. 25. A1C level and future risk of diabetes: a systematic review. Gregg E. Grundy S. 13. Zhang X. Zhu H. J Diabetes 2009. Santaguida PL. N Engl J Med 2010. et al. Ann Intern Med 2012. Should the HbA1c diagnostic cutoff differ between blacks and whites? A cross-sectional study. Goldenberg. Diabetes Care 2011. et al. Kiyohara Y. Forouhi NG.362: 800e11. Diabetes Res Clin Pract 2006. Williamson D. 28.29:e279e85. et al. 29. Diagnostic thresholds for diabetes: the association of retinopathy and albuminuria with glycaemia. S11 19.R.49:181e6. Ann Intern Med 2010. and treatment of impaired glucose tolerance and impaired fasting glucose.7:e1000278. Alberti KG.93:299e309. Diagnosis.1:9e17. Ito C. Report of a World Health Organization Consultation. 10. Kolm P. Diabetologia 2006.30:2453e7. Markers of dysglycaemia and risk of coronary heart disease in people without diabetes: Reykjavik Prospective Study and systematic review. PLoS Med 2010. Aspelund T. Davidson MB. Kubo M. 14. Balion C. et al. et al.37:1595e607. Diabetes Care 2007. Mukamal K. Circulation 2009. The threshold for diagnosing impaired fasting glucose: a position statement by the European Diabetes Epidemiology Group. Diabetes Res Clin Pract 2011. Point: impaired fasting glucose: the case for the new American Diabetes Association criterion. Reaven GM. et al. International Expert Committee report on the role of the A1C assay in the diagnosis of diabetes. The DETECT-2 Collaboration Writing Group.47:1411e5. Pani L. Glycated hemoglobin. Harmonizing the metabolic syndrome. Fox CS. Alberti KGMM. MD: Agency for Healthcare Research and Quality. Diabetes Care 2006.29:1170e2. et al.34: 518e23. prognosis. Effect of age and race/ethnicity on HbA1c levels in people without known diabetes mellitus: implications for the diagnosis of diabetes. 17. 9. et al. Sarwar N. A1C versus glucose testing: a comparison.49:822e7. 20. Glycemic thresholds for diabetes specific retinopathy. Morrison K. 24. et al. Differences in A1C by race and ethnicity among patients with impaired glucose tolerance in the Diabetes Prevention Program. 157:153e9. 27. 23. et al. Eckel R. Uwaifo G. Diabetes Care 2008. Shaw JE.73:315e21. Punthakee / Can J Diabetes 37 (2013) S8eS11 8. Ishida S. 8). FRCPC. The loss of pancreatic beta cells in the development of type 1 diabetes passes through a subclinical prodrome that can be detected reliably in first. Tests for hyperglycemia can identify these individuals. and diabetes was detected in 0. Using various multistaged screening strategies. .01. Screening for diabetes will also detect individuals at increased risk for diabetes (prediabetes) or individuals with less severe states of dysglycemia who may still be at risk for type 2 diabetes. CSPQ.  Testing with a 2-hour plasma glucose (2hPG) in a 75 g oral glucose tolerance test (OGTT) should be undertaken in individuals with an FPG of 6.6). Given that the various serological markers are not universally available and in the absence of evidence for interventions to prevent or delay type 1 diabetes.5% (see Definition.com Clinical Practice Guidelines Screening for Type 1 and Type 2 Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Jean-Marie Ekoé MD. to screen for diabetes and prediabetes.1e6.4% in order to identify individuals with impaired glucose tolerance (IGT) or diabetes. Zubin Punthakee MD. routine diabetes care among screening-identified type 2 diabetes patients. S8).91. intensive management did not reduce cardiovascular events (hazard ratio 0. Screening for Type 2 Diabetes Adults Undiagnosed type 2 diabetes may occur in >2.  Screening for type 2 diabetes using a fasting plasma glucose (FPG) and/or glycated hemoglobin (A1C) should be performed every 3 years in individuals 40 years of age or in individuals at high risk using a risk calculator. However. screening for type 1 diabetes is not recommended.9 mmol/L and/or an A1C of 6.  Testing with a 2hPG in a 75 g OGTT may be undertaken in individuals with an FPG 5. MD. Screening strategies vary according to the type of diabetes and evidence of effective interventions to prevent progression of prediabetes to diabetes and/or reduce the risk of complications associated with diabetes.H.012 immunity and genetic markers (3). PD. Screening for diabetes implies testing for diabetes in individuals without symptoms who are unaware of their condition.05) or all-cause mortality (hazard ratio 0. MSc.83.09% of the target populations.0 mmol/L and/or A1C 5.  Diabetes will be diagnosed if A1C is 6. The growing importance of diabetes screening is undeniable (1). p. Prebtani BScPhm.65e1. Initial positivity for GADAs and/or IA-2As had a sensitivity of 61% (95% confidence interval [CI] 36e83%) for type 1 diabetes.doi. Ronald Goldenberg MD.0%e6. S8). The combined positivity for GADAs and IA-2As had both a specificity and a positive predictive value of 100% (95% CI 59e100%) (5).9% and 1 risk factor in order to identify individuals with IGT or diabetes. FRCPC. there is no distinction between screening and diagnostic testing. population-based screening would have to involve wide coverage and would have the goal of early identification and subsequent intervention to reduce morbidity and mortality. which was lower than expected (9). FRCPC. and the number increases to >10% in some populations (7.6e6.Can J Diabetes 37 (2013) S12eS15 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. To be effective.33% to 1. The clinical spectrum of diabetes ranges from a low-risk to a higher-risk individual or to the symptomatic patient who needs immediate treatment. In the subsequent ADDITIONEurope cluster randomized trial of intensive multifaceted cardiovascular risk factor management vs. Ongoing clinical studies are testing different strategies for preventing or reversing early type 1 diabetes in the presence of positive autoimmunity. FRCPC. Screening for Type 1 Diabetes Type 1 diabetes mellitus is primarily a result of pancreatic beta cell destruction due to an immune-mediated process that is likely incited by environmental factors in genetically predisposed individuals.and second-degree relatives of persons with type 1 diabetes by the presence of pancreatic islet autoantibodies in their sera (4). Thomas Ransom MD.1016/j.2013. Therefore. MSc. 95% CI 0.8% of the general adult population (6). preventable diabetes complications (5. the ADDITION-Europe study showed that 20% to 94% of eligible people in primary care practices attended the first blood glucose test of the screening process.jcjd. FACE KEY MESSAGES  In the absence of evidence for interventions to prevent or delay type 1 diabetes. the same tests would be used as for diagnosis of both medical conditions (see Definition. p.canadianjournalofdiabetes. one-time screening for glutamic acid decarboxylase antibodies (GADAs) and islet antigen-2 antibodies (IA-2As) in the general childhood population in Finland would identify 60% of those individuals who will develop type 1 diabetes over the next 27 years. no widespread recommendations for screening for type 1 diabetes can be made.5%e5. or will be at risk for. Classification and Diagnosis chapter. An individual’s risk of developing type 1 diabetes can be estimated by considering family history of type 1 diabetes with attention to age of onset and sex of the affected family members (2) and profiling 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. in a recent large study. Classification and Diagnosis chapter. Ally P.org/10. many of whom will have. In contrast to other diseases. A1C. oral glucose tolerance test. neuropathy. there is no current evidence of clinical benefit to support a strategy of population-based screening for type 2 diabetes.1e6. Aboriginal. obstructive sleep apnea. peripheral)  Presence of vascular risk factors: B HDL cholesterol <1. Asian. glycated hemoglobin.4%.0 mmol/L and/or A1C 5. Furthermore. peripheral)  Presence of vascular risk factors: B HDL cholesterol level <1. and more studies may help determine ethnic-specific A1C thresholds for diabetes diagnosis (see Definition. IGT. impaired glucose tolerance. S8). the prevalence of diabetes was assessed in >20. IGT. high-risk ethnic groups may have A1C levels that are slightly higher than those of Caucasians at the same level of glycemia.4% in order to identify individuals with IGT or diabetes [Grade D. but they also have an increased risk of macrovascular . However.9 mmol/L and/or A1C 6. human immunodeficiency virus-1. glycated hemoglobin. p. Routine testing for type 2 diabetes is. especially those with IGT or an A1C of 6. IFG or A1C 6. justifiable in some but not all settings (18. Although the relatively low prevalence of diabetes in the general population makes it unlikely that mass screening will be cost effective. <1. 2-hour plasma glucose.0 mmol/L and/or A1C is 5. While fasting plasma glucose (FPG) and/or glycated hemoglobin (A1C) are the recommended screening tests. IFG. The rate of diagnosed diabetes was 9% to 14%. These risk factors include:  First-degree relative with type 2 diabetes  Member of high-risk population (e.3 mmol/L in females B Triglycerides 1. HIV. x OSA is an independent risk factor for diabetes (hazard ratio 1. the low rate of type 2 diabetes in the screened population (3%) was likely too small to affect overall population mortality (11). Risk prediction tools for type 2 diabetes mellitus A number of risk scores based on clinical characteristics have been developed to identify individuals at high risk of having undiagnosed diabetes.-M.9 mmol/L (14) and/or A1C is 6.4%)  History of gestational diabetes mellitus  History of delivery of a macrosomic infant  Presence of end organ damage complications associated with diabetes: B Microvascular (retinopathy. particularly in the context of the metabolic syndrome (21). the impact of known risk factors RECOMMENDATIONS 1. OSA. for individuals with risk factors listed in Table 1) (Figure 1). highly active antiretroviral therapy. population-based screening for type 2 diabetes was not associated with a reduction in all-cause. HDL. impaired glucose tolerance. Aboriginal. OGTT and A1C.0 mmol/L in males.000 individuals diagnosed with schizophrenia.9% and 1 risk factor(s) in order to identify individuals with IGT or diabetes [Grade D. HAART. HAART. not only are at increased risk of developing type 2 diabetes. HIV. Screening individuals as early as age 40 years in family physicians’ offices has proved to be useful in detecting unrecognized diabetes (20).5% to 5. IFG. a 75 g oral glucose tolerance test (OGTT) is indicated when the FPG is 6. Consensus]. African. therefore. Using data collected in 1991.19).7 mmol/L* B Hypertension* B Overweight* B Abdominal obesity*  Presence of associated diseases: B Polycystic ovary syndrome* B Acanthosis nigricans* y B Psychiatric disorders (bipolar disorder. Nonetheless. 4. / Can J Diabetes 37 (2013) S12eS15 Table 1 Risk factors for type 2 diabetes  Age 40 years  First-degree relative with type 2 diabetes  Member of high-risk population (e. high-density lipoprotein. cardiovascular or diabetes-related mortality within 10 years compared to a no-screening control group. However. These individuals would benefit from cardiovascular risk factor reduction strategies (1).0%e6.g. highly active antiretroviral therapy. impaired fasting glucose. depression.6 to 6. It may be indicated when the FPG is 5.5. <1.g. However.0%e6. African. S13 complications. Ekoé et al. y The incidence of type 2 diabetes is at least 3 times higher in people with schizophrenia than in the general population (25.0%e6. z HIV and HAART increase the risk of prediabetes (IGT) and type 2 diabetes by 1. high-density lipoprotein.9% and suspicion of type 2 diabetes or impaired glucose tolerance (IGT) is high (e. schizophrenia) B HIV infection  Use of drugs associated with diabetes: B Glucocorticoids B Atypical antipsychotics B HAART B Other (see Appendix 1)  Other secondary causes (see Appendix 1) 3. Abbreviations: 2hPG. IFG.1 to 6.g.J. a very high proportion of the routine care group also received optimal cardiovascular risk factor management.3 mmol/L in females* B Triglycerides 1.5%e5. People with prediabetes. Consensus]. fasting plasma glucose.43) (29). cerebrovascular. FPG.4%)*  History of gestational diabetes mellitus  History of delivery of a macrosomic infant  Presence of end organ damage associated with diabetes: B Microvascular (retinopathy. Consensus].0 mmol/L in males. the high prevalence of hemoglobinopathies among these populations may considerably reduce the accuracy of A1C as a reliable screening tool in these populations.0% to 6. impaired fasting glucose. Asian. exceeding rates for the general population prior to the widespread use of new antipsychotic drugs (27).4%. Hispanic or South Asian descent)  History of prediabetes (IGT. human immunodeficiency virus-1. All individuals should be evaluated annually for type 2 diabetes risk on the basis of demographic and clinical criteria [Grade D. cerebrovascular. Testing with 2hPG in a 75 g OGTT should be undertaken in individuals with FPG 6. neuropathy. 95% CI 0. Of note. Consensus].7 mmol/L B Hypertension B Overweight B Abdominal obesity  Presence of associated diseases: B Polycystic ovary syndrome B Acanthosis nigricans B Obstructive sleep apnea B Psychiatric disorders (bipolar disorder. Members of high-risk ethnic populations (Table 1) should be screened for prediabetes and type 2 diabetes using the recommended screening tests. More frequent and/or earlier testing with either FPG and/or A1C or 2hPG in a 75 g OGTT should be considered in those at very high risk using a risk calculator or in people with additional risk factors for diabetes [Grade D. Hispanic or South Asian descent)  History of prediabetes (IGT. testing for diabetes in people with risk factors for type 2 diabetes or with diabetes-associated conditions is likely to result in more benefit than harm and will lead to overall cost savings (12e17). or A1C 6. Consensus]. OGTT. nephropathy) B Macrovascular (coronary. 2.0% to 6.6e6. schizophrenia ) z B HIV infection x B OSA  Use of drugs associated with diabetes: B Glucocorticoids B Atypical antipsychotics z B HAART B Other (see Appendix 1)  Other secondary causes (see Appendix 1) A1C. Classification and Diagnosis chapter. * Associated with insulin resistance. such as FPG. In ADDITION-Cambridge. which may have diluted any potential benefits. depression.26). HDL.69e1. nephropathy) B Macrovascular (coronary.to 4-fold compared to the general population (28). Testing with 2hPG in a 75 g OGTT may be undertaken in individuals with FPG 5.21) (10). Screening for diabetes using FPG and/or A1C should be performed every 3 years in individuals 40 years of age or at high risk using a risk calculator [Grade D. Classification and Diagnosis of Diabetes. 5. Islet Cell Antibody Register Users Study. Bingley PJ. / Can J Diabetes 37 (2013) S12eS15 Figure 1. Knip M. a repeat confirmatory test (FPG. 2. S163 Relevant Appendix Appendix 1. S16 Type 1 Diabetes in Children and Adolescents. 2hPG in a 75 g OGTT) must be done on another day. OGTT ¼ oral glucose tolerance test. Risk scoring systems must. p. be validated for each considered population in order to adequately detect individuals at risk and eventually implement efficacious preventative strategies (23). Etiologic Classification of Diabetes Mellitus References 1. Diabetes Care 2010. Classification and Diagnosis of Diabetes.48: 687e94. The growing importance of diabetes screening. Combined positivity for HLA DQ2/DQ8 and IA-2 antibodies defines population at high risk of developing type 1 diabetes. Diabetes Care 2010. Cowie CC. p. 6.S. on having undiagnosed type 2 diabetes differs between populations of different ethnic origins. the diagnosis of diabetes is confirmed.45:1720e8. or A1C 6. van der Auwera B. insulin autoantibodies. Byrd-Holt DD. O’Connor PJ. Decochez K. population: National Health And Nutrition Examination Survey 1999-2002. Diabetes Care 2006. p.-M. Other Relevant Guidelines Definition.29:1263e8. Gilmer TP.33:1206e12. Tuomilehto J. Prediction of type 1 diabetes in the general population. therefore. Differential transmission of type 1 diabetes from diabetic fathers and mothers to their offspring. Truyen I. if a single laboratory test is in the diabetes range. Prediabetes and Metabolic Syndrome. use the test that appears furthest to the right side of the algorithm. and risk scores developed in Caucasian populations cannot be applied to populations of other ethnic groups (22). Diabetes 2006. Harjutsalo V. p. S8). It is preferable that the same test be repeated (in a timely fashion) for confirmation. If results of 2 different tests are available and both are above the diagnostic cutpoints. Interactions of age. The Canadian Diabetes Risk Assessment Questionnaire (CANRISK) is a statistically valid tool that may be suitable for diabetes risk assessment in the Canadian population and is available on the Internet at www. 55:1517e24. Ekoé et al. islet cell antibodies. et al. Screening and diagnosis algorithm for type 2 diabetes. S153 Type 2 Diabetes in Children and Adolescents. Kulmala P. impaired glucose tolerance (IGT). the prevalence of individuals at risk for developing type 2 diabetes varies considerably according to the scoring system.php (24). Diabetes 1996. Rust KF. **Prediabetes ¼ impaired fasting glucose (IFG).ca/cd-mc/ diabetes-diabete/canrisk/index-eng.gc.S14 J. Prediabetes and Metabolic Syndrome. S8 Reducing the Risk of Developing Diabetes. *If both fasting plasma glucose (FPG) and glycated hemoglobin (A1C) are available but discordant. p. Furthermore.phac-aspc. Diabetologia 2005. et al. A1C. 4. Korhonen S. Belgian Diabetes Registry. 3.0% to 6. NA ¼ not available. zIn the absence of symptomatic hyperglycemia. and first-phase insulin response in predicting risk of progression to IDDM in ICAþ relatives: the ICARUS data set. .4% (see Table 4 in Definition. et al. Reunanen A.33:1695e7. Prevalence of diabetes and impaired fasting glucose in adults in the U. The KORA survey 2000.24:1038e43. 24. Rewers M. 27. Qiao Q. Sharp SJ. Williams R. The economics of screening and treatment in type 2 diabetes mellitus.378:156e67.cause and cardiovascular mortality in nondiabetic European men and women.34:1863e8. et al. Agarwal G. Arch Intern Med 2004. 16. Hu G. McGuire A. Hicks KA. Rahman M.J. Dixon L. Ekoé et al. Lancet 2012. Diabetes Care 2001. Centers for Disease Control and Prevention. Lancet 2011. Eddy D. High prevalence of undiagnosed diabetes mellitus in Southern Germany: target populations for efficient screening. Narayan KM. 14. Lambert PC. Alperin P. Screening for type 2 diabetes: lessons from the ADDITION-Europe study. Vollenweider P. et al.54:312e9. Am J Med 2009. et al. Mohsenin V.375:1365e74. et al. 24:1899e903. Glumer C. et al. Icks A. DECODE Study Group. / Can J Diabetes 37 (2013) S12eS15 7. Diabetologia 2011. et al. Screening for NIDDM. Haastert B. et al. 25. Simmons RK. Barr A. Diabetes Screening in Canada (DIASCAN) Study. Diabetes Obes Metab 2010. Rolka DB. Abrahms KR.S adults. Diabetes Care 2007. Bocola V. et al. Griffin SJ. Detect 2 Collaboration. Screening for type 2 diabetes: an update of evidence. 336:1180e4. 13. and prevention. Simmons RK. et al. Concato J. Borch-Johnsen K. Botros N. insulin resistance and glucose metabolism in HIV infection and its treatment.29:410e4. 20. Chisholm DJ. Simmons RK. Performance of recommended screening tests for undiagnosed diabetes and dysglycemia. Tuomilehto J. Opportunities for detection. Risk scores for type 2 diabetes can be applied in some populations but not all. 17. Schmid R. Rathmann W.164:1066e76. Compr Psychiatry 1996. Age at initiation of screening to detect type 2 diabetes: a cost-effectiveness analysis. Borch-Johnsen.26:903e12. Jakes RW. 2008. Kahn R. 23. 15. Raikou M. Validating the CANRISK prognostic model for assessing diabetes risk in Canada’s multi-ethnic population. 19.32:19e31. et al. et al. Delahanty J. Griffin SJ. Decina P. Waeber G. Diabetes Care 1994. . Vistisen D.-M. Hoerger TJ. Wilson PJ. Diabetes Care 2011. In: Ekoe JM. editors. 22. McKee HA.122:1122e7.30: 2874e9. p. Diabetes. CDC Diabetes Cost-Effectiveness Study Group. Diabetologia 2003.12:838e44. Diabetes Care 2006. Weiden P.28: 1416e26. 10. treatment.46:182e9. Screening for type 2 diabetes and population mortality over 10 years (ADDITION-Cambridge): a cluster-randomised controlled trial. et al. Effect of population screening for type 2 diabetes on mortality: long term follow-up of the Ely cohort. D’Arcy PF. 9. Mukherjee S. Knowler WC..380:1741e8. Cost-effectiveness of screening for prediabetes among overweight and obese U. Diabet Med 2011. Schizophr Bull 2000. Van den Donk M. J Clin Hosp Pharm 1986. Estimating the risk of developing type 2 diabetes: a comparison of several risk scores. Thompson TJ. 21. Bélanger A. Pharmacoeconomics 2003. Sandbaek A. et al.280:1757e63. Diabetes Screening in Canada (DIASCAN) Study: prevalence of undiagnosed diabetes and glucose intolerance in family physician offices. Effect of early intensive multifactorial therapy on 5-year cardiovascular outcomes in individuals with type 2 diabetes detected by screening (ADDITION-Europe): a cluster-randomised trial. 8. et al. The Epidemiology of Diabetes Mellitus. Lancet 2010. 12. 26. Diabetes and schizophrenia: a preliminary study. BMJ 2008. Prevalence of the metabolic syndrome and its relation to all. 11. 29. Diabetes mellitus in schizophrenic patients. Prevalence and correlates of diabetes in national schizophrenia samples. et al. UK: Wiley Blackwell. Leiter LA. JAMA 1998. Robinson CA. 665e75. Obstructive sleep apnea as a risk factor for type 2 diabetes. The Cohorte Lausannoise Study.11:297e9.21:543e64. 28. S15 18. Chron Dis Inj Can 2011. Diabetes Care 2001.37:68e73. Echouffo-Tcheugui JB.17:445e50. Gilles CL. et al. Sorensen SW. Different strategies for screening and prevention of type 2 diabetes in adults: cost-effectiveness analysis. Borch-Johnsen K. The cost-effectiveness of screening for type 2 diabetes. Chichester. Samaras K. et al. Echouffo-Tcheugui JB. Davies MJ. Ally P. including lower rates of cardiovascular disease (CVD). recruited first-degree relatives of people who were <20 years old when diagnosed with type 1 diabetes. but in a subset of participants with high levels of insulin autoantibodies. is investigating the effect of excluding cow’s milk protein and replacing it with hydrolyzed formula milk in genetically at-risk infants until 6 to 8 months of age.doi.01. Reducing the Risk of Developing Type 1 Diabetes Type 1 diabetes is a chronic autoimmune condition characterized by destruction of pancreatic beta cells. it is the individualized strategies that are sought. MD.canadianjournalofdiabetes. For the practicing healthcare professional. Enhancement of “regulatory” immune mechanisms currently shows the most promise in terms of slowing the progression of the disease and preserving beta cell mass (secondary prevention). development of safe and cost-effective interventions to reduce the risk of diabetes are needed to help decrease the burden of diabetes on individuals and the healthcare system.1016/j. Progress in the field has been appropriately slow due to important ethical considerations. As safe and effective preventive therapies for type 1 diabetes have not yet been identified. The European Nicotinamide Diabetes Intervention Trial (ENDIT).013 Two major trials of interventions to prevent or delay the onset of type 1 diabetes have been completed. Reducing the Risk of Developing Type 2 Diabetes Preventing type 2 diabetes may result in significant public health benefits. The exact nature of causative environmental factors continues to be debated. MSc. Amanda Mikalachki RN. were <40 years of age and had a normal oral glucose tolerance test (OGTT) result. The Diabetes Prevention TrialType 1 (DPT-1) studied the efficacy of low-dose insulin injections in high-risk (projected 5-year risk of >50%) first-degree relatives of subjects with type 1 diabetes. A third large trial. more group. An epidemiological analysis projected that if all diabetes could be avoided in white American males through effective primary prevention. at the time of diagnosis. MSc. A second strategy is to try and halt. the immune-mediated destruction of beta cells so as to preserve any residual capacity to produce insulin.jcjd. Prebtani BScPhm. any attempts to prevent type 1 diabetes should be undertaken only within the confines of formal research protocols. Preventive strategies would differ depending on the type of diabetes. FRCPC.com Clinical Practice Guidelines Reducing the Risk of Developing Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Thomas Ransom MD. double-blind. Namely.  Intensive and structured lifestyle modification that results in loss of approximately 5% of initial body weight can reduce the risk of progression from impaired fasting glucose or impaired glucose tolerance to type 2 diabetes by almost 60%. the . which may be amenable to therapeutic intervention to prevent disease. with both genetic and environmental factors playing a part. The prevention or delay of diabetes not only would alleviate the individual of the burden of disease but also could decrease associated morbidity and mortality. Preliminary data suggest there were fewer autoantibody-positive children at 10 years (4). Immunotherapeutic interventions continue to be the main focus of disease prevention. renal failure. no effect was observed in ENDIT during the 5-year trial period (1). FRCPC. acarbose (w30% reduction) and thiazolidinediones (w60% reduction). 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. FRCPC KEY MESSAGES  As safe and effective preventive therapies for type 1 diabetes have not yet been identified.  Progression from prediabetes to type 2 diabetes can also be reduced by pharmacological therapy with metformin (w30% reduction). There is a long preclinical period before the onset of overt symptoms. in the incidence of type 1 diabetes was observed (3). blindness and premature mortality. any attempts to prevent type 1 diabetes should be undertaken only within the confines of formal research protocols. Ronald Goldenberg MD. the ongoing Trial to Reduce IDDM in the Genetically at Risk (TRIGR) study.H.2013. CDE. a randomized. Zubin Punthakee MD. FRCPC. were islet cell antibody positive. a delay. Overall. Given the increasing incidence and prevalence of diabetes. placebo-controlled trial of high-dose nicotinamide therapy.or population-based strategies. and perhaps a reduction.Can J Diabetes 37 (2013) S16eS19 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. side effects from excessive immunosuppression/modulation cannot be tolerated because of the reasonable life expectancy with insulin substitution therapy. Although nicotinamide had proved protective in animal studies. Introduction Ideal preventive strategies for both type 1 and type 2 diabetes should range from focusing efforts on individuals identified as being at risk for developing diabetes to broader. the insulin treatments had no effect (2). The causes are multifactorial. FACE. but data on the overt development of diabetes by age 10 will not be available until 2017.org/10. 458 Japanese males with IGT were randomly assigned in a 4:1 ratio to a standard intervention (n¼356) or an intensive intervention (n¼102) and followed for 4 years (16). high-fibre diet and moderate-intensity physical activity of at least 150 minutes per week resulted in a moderate weight loss of approximately 5% of initial body weight. with an adjusted hazard ratio (HR) in the frequent intervention group of 0. history of gestational diabetes mellitus. In a more recent trial. placebo (24.44). lowfat. Primary approaches to preventing diabetes in a population include the following: 1) programs targeting high-risk individuals in the community (such as those with impaired glucose tolerance [IGT] or obesity). which was part of the original protocol (23). cardiovascular events or mortality (20. no identified reductions in nephropathy. These include older age. The drug was discontinued after a mean follow-up of 0. 641 overweight Japanese men (aged 30 to 60 years) with impaired fasting glucose (IFG) were randomized to either a frequent intervention group (n¼311) or a control group (n¼330) for 36 months. / Can J Diabetes 37 (2013) S16eS19 S17 risk of all-cause and cardiovascular mortality in the entire population could be reduced by up to 6.46). low-saturated fat. Pioglitazone decreased the conversion of IGT to type 2 diabetes by 72% (p<0. the multiple potential adverse effects of this class of medication makes it difficult to recommend their widespread use in IFG or IGT.37. certain ethnic backgrounds. overt coronary artery disease.97e1.25).2% and 9. The primary outcome of DREAM was a composite of development of diabetes or death.7 more years and benefits were sustained for up to 10 years (15). no treatment and an additional 14 years of passive follow-up.24e0. IGT and diabetes were diagnosed using a 100 g OGTT and the following diagnostic criteria: IGT ¼2-hour plasma glucose (2hPG) 8. a 43% (95% CI 19e59) relative risk reduction for incident diabetes persisted.8 years significantly decreased progression to diabetes by 31%. However. Pharmacotherapy Metformin Metformin was used in a second arm of the DPP (14).2 mmol/L (16). physical inactivity. 95% CI 1. the risk reduction for diabetes was 58% at 4 years. A 20-year follow-up of the Chinese Da Qing Diabetes Prevention Trial showed that after 6 years of active lifestyle interventions vs.41 (95% CI 0.4 years.001). In the Actos Now for the Prevention of Diabetes (ACT NOW) study.01). physical and biochemical variables associated with the subsequent development of type 2 diabetes. 2) programs targeting high-risk subgroups of the population.03.3 years (28). neuropathy. high fasting insulin levels and IGT (10e12). well-designed studies assessing lifestyle and pharmacological interventions in adults to prevent the progression from IGT to diabetes have been published. In both studies. diabetes ¼ 2hPG !13.0%. respectively (5). These studies included comprehensive. Alpha-glucosidase inhibitors The Study to Prevent Non-Insulin Dependent Diabetes (STOPNIDDM) used acarbose at a dosage of 100 mg tid in a 5-year study with a mean follow-up of 3.9 years (27). Dietary modification that targeted a low-calorie.1 mmol/L. there was a 25% reduction in the risk of progression to diabetes when the diagnosis was based on 1 OGGT and a 36% reduction in the risk of progression .87). The conclusion of the DREAM investigators was that the results suggest that ramipril may have favourable effects on glucose metabolism. Results of large. 95% CI 0. Post hoc subgroup analyses showed the HR reduced to 0.56 (95% confidence interval [CI] 0. Intensive treatment was associated with a 67. The results of this study suggested that 26% of the diabetes prevention effect could be accounted for by the pharmacological action of metformin (which did not persist when the drug was stopped). To determine whether the observed benefit was a transient pharmacological effect or was more sustained.38.12e0. 95% CI 0. These levels corresponded to the 1980 World Health Organization (WHO) diagnostic criteria using a 75 g OGTT (17.60e30. No pharmacological agent is approved for diabetes prevention in Canada.48) among those with a baseline A1C level >5. primarily due to a 62% relative reduction in the risk of progression to diabetes (HR 0.T.6% (19). The control group received similar individual instructions 4 times at 12-month intervals during the same period. the routine use of ramipril for the express purpose of preventing diabetes is not indicated. The benefits persisted for up to 10 years (15). For now. There were. Lifestyle Changes in lifestyle were assessed in the Finnish Diabetes Prevention Study (DPS) (13) and the Diabetes Prevention Program (DPP) (14). Eligible subjects were 30 years old and not known to have CVD. Ransom et al. A dosage of 850 mg bid for an average of 2. 602 high-risk IGT subjects were randomized to receive pioglitazone or placebo and were followed for 2. The frequent intervention group received individual instructions and follow-up support for lifestyle modification from medical staff 9 times.02) during the short period of time. Thiazolidinediones The DPP Research Group published the results from the troglitazone arm. Results showed an incidence of type 2 diabetes of 12.94) driven primarily by a significant increase in nonfatal congestive heart failure (HR 7.40.00001) (26). Overall.” Treatment with rosiglitazone resulted in a 60% reduction in the primary composite outcome of diabetes or death (HR 0. In another lifestyle intervention trial.35e0. such as those designed to promote physical activity and healthy eating in adults or children (7e9). not all trials have found such an association. and 3) programs for the general population.18). In the DPP population.9 years due to liver toxicity. 95% CI 0.33e0.2% in the frequent intervention group and 16. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM) trial randomized 5269 subjects with IGT and/or IFG. Despite the favourable effects of thiazolidinediones on delaying the development of type 2 diabetes. sustained programs to achieve these outcomes. Troglitazone 400 mg once daily resulted in a relative risk reduction of 75% (p¼0. On the basis of the observed benefits of lifestyle in the DPP.8 to 13. and vision-threatening retinopathy was reduced by 47% (95% CI 1e71). Combination therapy The combination of metformin 500 mg twice daily and rosiglitazone 2 mg twice daily was found to reduce the progression to diabetes by 66% (95% CI 41e80) among 103 people with IGT compared to 104 people randomized to placebo over a median of 3.36e0.9.24 (95% CI 0.69) among participants with IGT at baseline and to 0. Prospective cohort studies have identified historical. After the washout. there was a trend toward an increase in risk of the CV composite outcome with rosiglitazone (HR 1. all participants were offered further lifestyle interventions for a median of 5. however. to ramipril (up to 15 mg/ day) and/or rosiglitazone (8 mg/day) vs.21). a finding that is consistent with other reports.4% reduction in risk of diabetes (p<0. metformin did not have any significant effect in the older age group (!60 years) and in less obese subjects (body mass index [BMI] <35 kg/m2). obesity (especially abdominal obesity). p¼0. such as high-risk ethnic groups. in a 2 Â 2 factorial fashion. a repeat OGTT was undertaken after a short washout period. Although the trial was not powered to provide a definitive estimate of the effect of rosiglitazone on CV outcomes.6% in the control group. the incidence of diabetes was still reduced by 25% (22). Data from the US indicate that 28% of cardiovascular expenditures are attributable to diabetes (6). This effect was not sustained after discontinuation of troglitazone. More subjects in the voglibose group achieved normoglycemia than in the placebo group (66. Lancet 2009. Lancet 2004. References 1. Diabetes Prevention TrialeType 1 Diabetes Study Group. 51. Fowler SE. However. European Nicotinamide Diabetes Intervention Trial (ENDIT) Group. impaired glucose tolerance. Canada. orlistat treatment was associated with a further 37% reduction in the incidence of diabetes. Skyler JS.8:339e53. Prevention of type 2 diabetes by lifestyle intervention: a Japanese trial in IGT males. 12. et al. First.363:1900e8. 1982. 3. there was a very high dropout rated48% in the orlistat group and 66% in the placebo group. Harris MI.24(suppl):S59e62.032) and a 50% reduction in the progression of carotid intima-media thickness (29. Thomas H.2 mg three times per day (n¼897) or placebo (n¼883). Marion SA. RECOMMENDATIONS 1. Daniel M.8 mg. Finnish Diabetes Prevention Study Group. Effects of insulin in relatives of patients with type 1 diabetes mellitus.374:1677e86. Accessed April 25. Knowler WC. 2. Community-based approaches for the primary prevention of non-insulin-dependent diabetes mellitus. et al. Diabetes Care 2008. Charles MA. Narayan KM. Undiagnosed diabetes or impaired glucose tolerance and cardiovascular risk.20:127e8.344: 1343e50. Subjects were randomized to orlistat 120 mg or placebo tid with meals for 4 years. One must keep in mind that the measures of prevention must be delivered in a culturally sensitive manner to these populations.40:796e9. 7.433e0. n¼95) three times daily. N Engl J Med 2002. IFG.6% vs.8 mg. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Abbreviations: A1C. Paris prospective study. 31% of whom had IGT. Soc Sci Med 1999. p<0. 1. Eastman RC. 9. HR 0. 6.24%. et al. or to orlistat (120 mg. The Indian Diabetes Prevention Programme showed similar results in preventing diabetes with both lifestyle and pharmacological interventions where the progression to diabetes from IGT was quite high (55%) over 3 years (35). Noda M. Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention TrialeType 1. Ransom et al. the major modifiable risk factors for type 2 diabetes: a review of reviews. .595. Knowler WC. Swinburn B. Hamilton. Nonetheless.4% [Grade D. Diabetes Res Clin Pract 1994. In another trial. In this IGT population. Weight loss was observed in both groups. Second.9%. Switzerland: World Health Organization. liraglutide was administered to 564 obese individuals who did not have diabetes. Diabetes 1991.357e1. 16. However.2 mg. Subjects were randomized to 1 of 4 liraglutide doses (1. Kosaka K. As a result. Fontbonne A. 95% CI 1. 2 important methodological limitations affect the interpretation of these results. Thibult N. Economic costs of diabetes in the US in 2007. voglibose was better than placebo at reducing the progression to type 2 diabetes (5. Ministry of Health and Long-Term Care. 10.14:519e26. 15. Health Care Manag Sci 1999. WHO Expert Committee on Diabetes Mellitus.2: 223e7. et al. Many of them develop diabetes at a younger age and often have complications at the time of diagnosis due to longstanding. Primary prevention of non-insulindependent diabetes mellitus. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Eriksson JG.hamilton. The reasons for this are multifactorial and include genetic susceptibility. Gale EA. Compared to placebo.14)] and IFG [Grade B. Voyle J. Virtanen SM.67(2): 152e62. Diabetes Res Clin Pract 2005. American Diabetes Association. In a 20-week study. Wolfsdorf J. 11. N Engl J Med 2002. Diabetes Care 2005.4 mg. the effect of acarbose did not persist (28). pharmacological therapy with metformin [Grade A. ON: Public Health Research. et al. Education and Development Program. 1980. the last observation carried forward was used for analysis. Vohra J.1 weeks. Kosaka K. HR 1. 2nd report. n¼90e95) or to placebo (n¼98). Emmett CL.001). Diagnostic criteria for diabetes mellitus in Japan: from a report of the Japan Diabetes Society (JDS) Committee on the Diagnosis of Diabetes Mellitus. 2.0001). glycated hemoglobin. N Engl J Med 2001. Lindström J. 2. In individuals with IGT. Thompson TJ. Level 1A (27)] may be used to reduce the risk of type 2 diabetes.8% vs. The use of population attributable risk to estimate the impact of prevention and early detection of type 2 diabetes on population-wide mortality risk in US males. 95% CI 0. Effectiveness of community-directed diabetes prevention and control in a rural Aboriginal population in British Columbia. Level 2 (18)] and A1C 6. which is generally not favoured for prevention or survival studies. Zimmet P. Knip M. 13.30).4 mg and 3. 2012. Available at: http://old.34).8 vs. SFr 5. et al. over a mean of 48. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian subjects with IGT (IDPP-1). Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. WHO Technical Report Series No. Micucci S. 8. 18. et al. Green LW. Tuomilehto J. / Can J Diabetes 37 (2013) S16eS19 to diabetes when the diagnosis was based on 2 consecutive OGTTs.0014).S18 T. Risk factors for NIDDM in white population. Kuzuya T. (p¼0. Bingley PJ. are at very high risk for and have a high prevalence of type 2 diabetes (12%e15% in the Western world) (33. Lifestyle measures not only reduce the risk of diabetes but have other health benefits.28:1068e76. Diabetes prevention in high-risk ethnicities Ethnic groups. Krischer JP. IGT. A1C was reduced by 0. 14. 5.0 mg doses.346:393e403.31:596e615. Hispanics and Aboriginals. European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomized controlled trial of intervention before the onset of type 1 diabetes. but it remains to be proven with hard clinical endpoints. Diabetes Prevention Program Research Group. Diabetes Care 1997.363:925e31. such as South Asians.0 mg. The prevalence of prediabetes decreased by 84% to 96% with liraglutide 1.48:815e32. when the drug was discontinued. Simmons D. fewer complications and lower morbidity. altered fat distribution (more visceral fat with greater insulin resistance) and higher prevalence of metabolic syndrome. Barrett-Connor E. This approach of prevention may lead to cost savings. 1780 Japanese patients with IGT were randomly assigned to oral voglibose 0. Diabetes Prevention Program Research Group. Cowie CC. Geneva. Diabet Med 1997. 11. or 3. Seppa K.pdf. The effectiveness of school based strategies for the primary prevention of obesity and for promoting physical activity and/or nutrition. acarbose treatment was also associated with a 49% reduction in CV events (p¼0.539. 2. 17. Level 1A (14)] or acarbose [Grade A. impaired fasting glucose. 3 kg. et al. there may be a benefit of delaying the onset of diabetes in this population. Boyle JP. preexistent diabetes. et al.746. p<0. so the overall benefit is positive with little harm.5%.0%e6. Incretin-based therapies Liraglutide has been shown to effectively prevent IGT conversion to type 2 diabetes and cause reversion to normoglycemia (32). Consensus]. Results showed that.346: 1685e91. This beneficial effect was not affected by age or BMI. 4. N Engl J Med 2010.818. but the orlistat group lost significantly more (5. Level 1A (13. Tuomilehto J. Dietary intervention in infancy and later signs of betacell autoimmunity.ca/ phcs/ephpp/Research/Full-Reviews/Diabetes-Review.14% to 0. Orlistat The Xenical in the Prevention of Diabetes in Obese Subjects (XENDOS) study examined the effect of orlistat in combination with an intensive lifestyle modification program (diet and exercise) on the prevention of diabetes in 3305 obese individuals (31). A structured program of lifestyle modification that includes moderate weight loss and regular physical activity should be implemented to reduce the risk of type 2 diabetes in individuals with IGT [Grade A. 646. the significant weight loss would be expected to decrease the risk of diabetes as already shown in the DPS and the DPP. Diabetes Metab Rev 1992. 371:1783e9. Ramachandran A. Bosch J. Yusuf S. Arch Intern Med 2011. Diabetes Care 2004. Gong Q. Indian Diabetes Prevention Programme (IDPP). et al. NN8022e1807 Study Group. trial): a double-blind randomised controlled study. Gerstein HC. 23. 24. Lancet 2006. Effects of withdrawal from metformin on the development of diabetes in the Diabetes Prevention Program. et al. 21. Tripathy D. et al. Snehalatha C. Watanabe M. The long-term effect of lifestyle interventions to prevent diabetes in the China Da Qing Diabetes Prevention Study: a 20-year follow-up study. Wang J. et al. Schwenke DC. Gregg EW. Hauptman J.171:1352e60. Chowdhury TA. 26. Saito T. 33. et al.49: 289e97. STOP-NIDDM Trial Research Group. Dagogo-Jack S. Lancet 2002. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. DeFronzo RA. Yusuf S. Harris SB. Diabetologia 2011. Torgerson JS. Lancet 2010.35:1073e8. . Pioglitazone for diabetes prevention in impaired glucose tolerance.374:1606e16. Josse RG. 31. / Can J Diabetes 37 (2013) S16eS19 19. DREAM (Diabetes Reduction Assessment with ramipril and rosiglitazone Medication) Trial InvestigatorsGerstein HC. et al. 27. Effects of liraglutide in the treatment of obesity: a randomised. N Engl J Med 2011.327: 1059e60. JAMA 2003.T. 20. Lifestyle modification and prevention of type 2 diabetes in overweight Japanese with impaired fasting glucose levels: a randomized controlled trial. double-blind. Astrup A.54:1150e6. Acarbose for prevention of type 2 diabetes mellitus: the STOP-NIDDM randomised trial. Diabetologia 2006. Zhang P.359:2072e7. Chiasson JL. Zensharen Study for Prevention of Lifestyle Diseases Group. Edelstein SL. Chiasson JL. et al.89:949e75. Gomis R. N Engl J Med 2006. et al. Boldrin MN. 32. et al. Knowler WC. Effect of ramipril on the incidence of diabetes. Acarbose slows progression of intimamedia thickness of the carotid arteries in subjects with impaired glucose tolerance. 22. Epidemiology of type 2 diabetes: focus on ethnic minorities. 30. STOP-NIDDM Trial Research Group.54:300e7. 35.27:155e61. Long-term effects of a randomised trial of a 6-year lifestyle intervention in impaired glucose tolerance on diabetesrelated microvascular complications: the China Da Qing Diabetes Prevention Outcome Study. Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomized controlled trial. Koehler C. et al. Zinman B. Van Gaal L.368:1096e105. Rossner S. Chiasson JL. 34. Li G. Diabetes Prevention Program Research Group. Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE S19 28. et al. Mary S. 25. Lancet 2009. Gomis R. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. BMJ 2003. Nishida J.26:977e80. Wang J. et al. Ransom et al. Med Clin North Am 2005. Lancet 2008. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM Trial. et al. Diabetes 2005. Neuman J. Diabetes Prevention Program Research Group. Egede LE. Diabetes Care 2003. Hanefeld M. DREAM Trial InvestigatorsBosch J.364:1104e15. 290:486e94. The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Hamman RF. Josse RG.376: 103e11.355:1551e62. placebocontrolled study. 29. Stroke 2004. Preventing diabetes in South Asians. PhD. including patient education.8. Doreen M. This model has been adopted by many countries as well as several provinces in Canada (13). decision support. there has been a shift toward delivering diabetes care in the primary care 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.jcjd. interprofessional team with specific training in diabetes.  The following strategies have the best evidence for improved outcomes and should be used: promotion of self-management.org/10. Roscoe BScPharm. Early studies showed that the following interventions improved care in the chronically ill: educating and supporting the patient. provides a framework for the optimal care of persons with diabetes (6e8). Since almost 80% of the care of people with diabetes takes place in the primary care setting. with the support of the interprofessional diabetes healthcare team. Recall: Develop a system to remind your patients and caregivers of timely review and reassessment. this model aims to transform the care of patients with chronic illnesses from acute and reactive to proactive. the elements of which are evidence based. This is intended to assist the readers in increasing their understanding and use of the CCM framework in their daily practice. treatment adjustment. focused on the daily commitment of the individual with diabetes to self-management.10). interprofessional team-based care with expansion of professional roles. MSc. diabetes care has been the prototype for the CCM (Figure 1). Resource: Support self-management through the use of interprofessional teams which could include the primary care provider. incorporating most or all of the CCM elements has been associated with improved quality of care and disease outcomes in patients with various chronic illnesses. FRCPC. Although these are still critical elements of diabetes care.Can J Diabetes 37 (2013) S20eS25 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. The CCM and Organization of Diabetes Care In many ways. Despite the use of new terminology (Table 1). Developed in the late 1990s. to include monitoring or medication adjustment and disease (case) management. These elements facilitate planning and coordination among providers while helping patients play an informed role in managing their own care (6). which includes elements beyond the patient and healthcare provider. Betty Harvey RNEC.canadianjournalofdiabetes. A recent systematic review found that primary care practices were able to successfully implement the CCM (6). monitoring and care coordination. The CCM is an organizational approach as well as a quality improvement (QI) strategy in caring for people with chronic diseases. and 6) health systems. Register: Develop a registry for all of your patients with diabetes. 3) decision support. BScN. 2) selfmanagement support. Previous recommendations in this chapter. Rabi MD. delivery and organization of diabetes care. in 2008. dietitian. CDE. many of the previous recommendations have remained the same but have been reorganized to fall under specific components of the CCM and broadened to include elements such as the health system and the community (9). teambased care.01. increasing the healthcare provider’s skills and use of registry-based information systems (7. Robert S. pharmacist and other specialists.doi. Furthermore.2013.  Diabetes care should be structured. CCFP. HELPFUL HINTS BOX: ORGANIZATION OF CARE Recognize: Consider diabetes risk factors for all of your patients and screen appropriately for diabetes. there is a care gap between the clinical goals outlined in evidence-based guidelines for diabetes management and reallife clinical practice (1. Relay: Facilitate information sharing between the person with diabetes and the team for coordinated care and timely management changes. in cooperation with the collaborating physician. 5) the community. 4) clinical information systems. audits and feedback.014 . Diana Sherifali RN.  Diabetes care should be delivered using as many elements as possible of the chronic care model. clinician and patient reminders. MScN. evidence based and supported by a clinical information system that includes electronic patient registries. planned and population based. ACPR. including Introduction In Canada. including selfmanagement support and education. CDE KEY MESSAGES  Diabetes care should be organized around the person living with diabetes who is practising self-management and is supported by a proactive. setting using the chronic care model (CCM) (3e5). diabetes educator. nurse. increasing evidence suggests that the CCM.1016/j. The current CCM has expanded on this evidence to include the following 6 elements that work together to strengthen the provider-patient relationship and improve health outcomes: 1) delivery systems design. This chapter has been revised to reflect the importance of the CCM design. coaching.2).com Clinical Practice Guidelines Organization of Diabetes Care Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Maureen Clement MD. designing interventions. including internal and community resources. self-monitoring of blood glucose. 2-arm. other than the existing medical record (e. general practitioners and nurse practitioners Joint participation of primary care physicians and specialty care physicians in the planned delivery of care. glucose monitoring) A systematic intervention that involves active patient participation in self-monitoring (physiological processes) and/or decision making (managing) (see Self-Management Education chapter. when the QI components are used together. nurse or pharmacist has a more active role in monitoring or adjusting medications) Trained and accredited non-healthcare professional delivering a program that adopts a philosophy of self-management rather than the medical model Delivery of health-related services and information via telecommunications technology Clinician reminders Collaboration Continuous quality improvement Decision support Disease (case) management Facilitated relay of information to clinician Patient registry Patient reminders Self-management education (SME) Self-management support Team changes Other Terms Lay leader Telehealth A1C. Although some of the improvements were modest. there is a synergistic effect as noted in the above studies (12). ranging from a simple spreadsheet to one embedded in an electronic health record Any effort to remind patients about upcoming appointments or aspects of self-care (e. identify relevant subpopulations for proactive care. emphasizes prevention of exacerbations and complications utilizing evidence-based practice guidelines and patient empowerment strategies May include education.M.g. coaching. and share information with patients and providers to coordinate care or monitor performance of practice team and care system. informed by an enhanced information exchange over and above routine discharge and referral notices Can also refer to the sharing of responsibility for care between the patient and provider or team Quality Improvement Strategies Audit and feedback Summary of provider or group performance on clinical or process indicators delivered to clinicians to increase awareness of performance Clinical information systems The part of an information system that helps organize patient and population data to facilitate efficient and effective care. diabetes (6. cluster-randomized. with longer-term use of the model in clinical practice. Initially. May provide timely reminders for providers and patients. p. facilitate individual patient care planning. S26) In addition to SME strategies that enhance patients’ ability to manage their condition. 1) 2) 3) 4) 5) 6) Delivery systems designs Self-management support Decision support Clinical information The community Health systems Elements of CCM Primary care Shared care First contact and ongoing healthcare: family physicians. treatment adjustment.g. such as reductions in glycated hemoglobin (A1C) and low-density lipoprotein cholesterol (LDL-C) levels (20). These elements facilitate planning and coordination among providers while helping patients play an informed role in managing their own care. Techniques for examining and measuring clinical processes. however. CCM in Diabetes Initial analyses of CCM interventions for improving diabetes care suggested that a multifaceted intervention was the key to QI (8. improvements in clinical outcomes also are noted. testing their impacts and then assessing the need for further improvement Integration of evidence-based guidelines into the flow of clinical practice A structured. the degree to which care delivered in a primary care setting conforms to the CCM has been shown to be an important predictor of the 10-year risk of coronary heart disease (CHD) in patients with type 2 diabetes (19). multifaceted intervention that supports the practitioner/patient relationship and plan of care. the elements of which are evidence based. such as a diabetes registry May be paper based but increasingly is electronic. / Can J Diabetes 37 (2013) S20eS25 Table 1 Definition of terms (9e12) Terminology Chronic care model (CCM) S21 The CCM is an organizational approach to caring for people with chronic diseases as well as a quality improvement strategy.15. foot exam) A collaborative intervention is a method used to help healthcare organizations apply continuous quality improvement techniques and affect organizational change.g. using all 6 dimensions of the . monitoring and linage to self-management support/interest groups Changes to the structure of a primary healthcare team. it appeared as if only process outcomes.17). Clement et al. such as a physician. glycated hemoglobin. SMBG. it may be that. such as disease management with patient reminders. monitoring and care coordination. A1C) or do a specific task (e. are improved with the CCM. A large.g. often by a nurse. such as:  Adding a team member or shared care. Furthermore. A recent systematic review and metaanalysis of QI strategies on the management of diabetes concluded that interventions targeting the system of chronic disease management along with patient-mediated QI strategies should be an important component of interventions aimed at improving care. nurse specialist or pharmacist  Using an interdisciplinary team in primary routine management  Expansion of professional role (e. Paper-based or electronic system to prompt healthcare professionals to recall patient-specific information (e. QI trial.8. Organizations that provided diabetes care in accordance with the CCM provided better quality care than did organizations that were less likely to use elements of this model (18).10.g. This model has evolved from the original Wagner CCM (1999) to the expanded care model (9). such as behaviours of patients and caregivers.14e16). pharmacist sending SMBG results) A list of patients sharing a common characteristic. pharmacist or dietitian Clinical information collected from patients and sent to clinicians. S22 M. Clement et al. / Can J Diabetes 37 (2013) S20eS25 Figure 1. The Expanded Chronic Care Model: Integrating Population Health Promotion. Used with permission from Barr VJ, Robinson S, Marin-Link B, et al. The expanded chronic care model: an integration of concepts and strategies from population health promotion and the chronic care model. Hosp Q. 2003;7:73e80. CCM, found significant improvements in A1C and LDL-C and an increase in the use of statins and antiplatelet therapy among patients with diabetes (5). A recent meta-analysis of randomized controlled trials (RCTs) assessing the effectiveness of disease management programs for improving glycemic control found significant reductions in A1C with programs that included the fundamental elements of the CCM (21). Other trials found that use of the CCM improved cardiovascular (CV) risk factors in patients with diabetes (19,22). One large-scale analysis of a nationwide disease management program using the CCM and based in primary care reduced overall mortality as well as drug and hospital costs (23). The Assessment of Chronic Illness Care (ACIC) is a practical assessment as well as a research tool. It can help teams strategically involve themselves in a structured way to assess and identify gaps to develop into a more robust CCM (11). Elements of the CCM that Improve Care Delivery systems design The team Current evidence continues to support the importance of a multiand interprofessional team with specific training in diabetes within the primary care setting (10,12,21). The team should work collaboratively with the primary care provider who, in turn, should be supported by a diabetes specialist. Specialist support may be direct or indirect through shared care, an interdisciplinary team member or educational support (5,12). In adults with type 2 diabetes, this care model has been associated with improvements in A1C, blood pressure (BP), lipids and care processes compared to care that is delivered by a specialist or primary care physician alone (5,24e27). A reduction in preventable, diabetes-related emergency room visits also has been noted when the team includes a specifically trained nurse who follows detailed treatment algorithms for diabetes care (25). In Canada, observational data from primary care networks, whose approach is to improve access and coordinate care, suggest that patients who are part of these interdisciplinary teams have better outcomes and fewer hospital visits than patients who are not (28). Team membership may be extensive and should include various disciplines. Those disciplines associated with improved diabetes outcomes include nurses, nurse practitioners, dietitians, pharmacists and providers of psychological support. Nurses have always been, and continue to be, core members of the team. A systematic review (26) and recent meta-analysis (29) found that case management led by specialist nurses or dietitians improved both glycemic control and CV risk factors. Another study found improved BP outcomes with nurse-led interventions vs. usual care, particularly when nurses followed algorithms and were able to prescribe (30). In addition, a large RCT found that nurse-led, guideline-based, collaborative care management was associated with improvements in A1C, lipids, BP and depression in patients with depression and type 2 diabetes and/or CHD (31). Practices with nurse practitioners also were found to have better diabetes process outcomes than those with physicians alone or those employing only physician assistants (32). Small-group or individualized nutrition counselling by a registered dietitian with expertise in diabetes management is another important element of team-based care. A variety of individual and community healthcare support systems, particularly psychological support, can also improve glycemic control (33). Recent meta-analyses involving people with both type 1 and type 2 diabetes showed a significant 0.76% drop in A1C (34) as well as improved adherence and quality of life (QOL) and reductions in adverse drug reactions and LDL-C with collaborative pharmacist intervention (35). A Canadian randomized trial that added a pharmacist to primary care teams showed a significant reduction in BP for people with type 2 diabetes (36). Therefore, pharmacists can play a key role in diabetes management, beyond that of dispensing medications. Roles within the team and disease management Flexibility in the operation of the team is important. Team changes, such as adding a team member, active participation of professionals from more than one discipline and role expansion, have been associated with improved clinical outcomes (10,12,21). The greatest body of evidence for improved clinical outcomes in diabetes is with promotion of self-management, team changes and case or disease management programs (5,10,12,21,27,37,38). In a systematic review and meta-analysis of QI strategies, the following QI strategy improved clinical outcomes, such as A1C, BP and cholesterol, as well as process outcomes, medication use and screening for complications: promotion of self-management, team changes, case management, patient education, facilitated relay, electronic patient registries, patient reminders, audits and feedback, and clinician reminders. The effectiveness of different QI M. Clement et al. / Can J Diabetes 37 (2013) S20eS25 S23 strategies may vary based on the baseline A1C, with QI targeting professionals only beneficial when the baseline A1C control is poor. In practice, many of these QI strategies occur in concert with one another through the use of interprofessional teams. Another recent meta-analysis by Pimouguet et al. (21) defines disease management as the “ongoing and proactive follow-up of patients that includes at least 2 of the following 5 components: patient education, coaching, treatment adjustment (where the manager is able to start or modify treatment with or without prior approval from the primary care physician), monitoring, care coordination (where the manager reminds the patient about upcoming appointments or important aspects of self-care and informs the physician about complications, treatment adjustments, or therapeutic recommendations).” The meta-analysis found that a high frequency of patient contact and the ability of the disease manager to start or modify treatment with or without prior approval from the primary care physician had the greatest impact on A1C lowering. Disease management programs also were more effective for patients with poor glycemic control (A1C 8%) at baseline (21). Other disease management strategies that have been associated with positive outcomes are the delegation of prescription authority and the monitoring of complications using decision support tools (26,27,30). The primary care provider, who is usually a family physician, has a unique role in the team, particularly with regard to providing continuity of care. He or she is often the principal medical contact for the person with diabetes and has a comprehensive understanding of all health issues and social supports (39). In the past, there was some debate over whether specialist care or primary care yields better diabetes outcomes (40e43). Although physicians practising in hospital-based diabetes centres may be more likely to adhere to guidelines (44), general practice-based care is associated with higher patient follow-up (45). Certainly, there are patients with diabetes who may require ongoing, specialized care, such as children and pregnant women. There is also evidence that specialized care may be more beneficial in people with type 1 diabetes (46,47). In the CCM, collaborative, shared care is the ideal. However, the results of one Cochrane review did not support shared care (48). It should be noted, however, that several of the studies included in this analysis did not use all the elements of the CCM. Other, more recent studies have supported the shared care model (49) and have shown that specialist input into specialized diabetes teams at the interface of primary and secondary care improves care (5,50). Self-management support Self-management support, including self-management education, is the cornerstone of diabetes care in the CCM. Selfmanagement education goes well beyond didactic disease-specific information. It is a systematic intervention that involves active patient participation in self-monitoring (physiological processes) and/or decision making (managing). Self-management enables the person with diabetes to take an active role in managing his or her own care through problem solving and goal setting, which can be facilitated through the use of motivational interviewing techniques. Selfmanagement support, often through disease or case management, with strategies such as patient reminders, helps the individual in selfmanagement. Evidence for diabetes self-management support and education is robust (12) and is covered in more detail in the next chapter (see Self-Management Education chapter, p. S26). Decision support Providing healthcare practitioners with best practice information at the point of care to help support decision making has been shown to improve outcomes. In a systematic review, evidencebased guideline interventions, particularly those that used interactive computer technology to provide recommendations and immediate feedback of personally tailored information, were the most effective in improving patient outcomes (51). A randomized trial using electronic medical record (EMR) decision support in primary care found improvement in A1C (52), and a cluster randomized trial of a QI program found that the provision of a clear treatment protocoldsupported by tailored postgraduate education of the primary care physician and case coaching by an endocrinologistdsubstantially improved the overall quality of diabetes care provided, as well as major diabetes-related outcomes (50). Incorporation of evidence-based treatment algorithms has been shown in several studies to be an integral part of diabetes case management (10,26,30,31). Even the use of simple decision support tools, such as clinical flow sheets, have been associated with improved adherence to clinical practice guidelines for diabetes (53). Clinical information systems Clinical information systems (CIS) that allow for a populationbased approach to diabetes assessment and management, such as EMRs or electronic patient registries, have been shown to have a positive impact on evidence-based diabetes care (10,12,54,55). Practice-level clinical registries give an overview of an entire practice, which may assist in the delivery and monitoring of patient care. In addition to providing clinical information at the time of a patient encounter, CIS also can help promote timely management and reduce the tendency toward clinical inertia (56). Provincialand national-level registries are also essential for benchmarking, tracking diabetes trends, determining the effect of QI programs, and for resource planning. Other quality improvement strategies Audits and feedback generally lead to small but potentially important improvements in professional practice and seem to depend on baseline performance and how the feedback is provided (57). Facilitated relay of information to clinicians may include electronic or web-based methods through which patients provide self-care data and the clinician reviews have been shown to improve care. Ideally, this should occur in case management with a team member who has prescribing or ordering ability (12). Physician and patient reminders also have shown benefit (12,50). Community Environmental factors, such as food security, the ability to lead an active lifestyle, as well as access to care and social supports, also impact diabetes outcomes. Although community resources have not traditionally been integrated into care, community partnerships should be considered as a means of obtaining better care for patients with diabetes. For example, in addition to the diabetes health team, peer- or lay leader-led self-management groups have been shown to be beneficial in persons with type 2 diabetes (58,59). Health systems Support for diabetes care from the broader level of the healthcare system, such as the national and provincial systems, is essential. A number of provinces have adopted an expanded CCM (9) that includes health promotion and disease prevention (13). Many provinces and health regions also have developed diabetes strategies, diabetes service frameworks and support diabetes collaboratives. Some trials on diabetes-specific collaboratives have been shown to improve clinical outcomes (22,50,60), although a recent meta-analysis on continuous QI failed to show benefit (12). Provider incentives represent another area of health system support. Some provinces have added incentive billing codes for S24 M. Clement et al. / Can J Diabetes 37 (2013) S20eS25 patients with diabetes so that providers can be financially compensated for the use of flow sheets as well as time spent collaborating with the patient for disease planning (61). Pay-forperformance programs, which encourage the achievement of goals through reimbursement, are more commonly used outside of Canada. To date, these programs have had mixed results (62e64). Various payment systems also have been studied, but it is still unclear which of these may improve diabetes outcomes (65,66). Incentives to physicians to enroll patients and provide care within a nation-wide disease management program appears to be effective (23), as does infrastructure incentive payments that encourage the CCM (16). A meta-analysis that included physician incentives as a QI has shown mixed results for improved outcomes (12). Telehealth Although not a specific element of the CCM, telehealth technologies may help facilitate many components of this model. These technologies may be used for conferencing or education of team members; telemonitoring of health data, such as glucose readings or BP; disease management via telephone or internet; or teleconsultation with specialists. Telehealth also appears to be effective for diabetes self-management education and has been associated with improvements in metabolic control and reductions in CV risk (67). One RCT and 2 systematic reviews of telemonitoring of various disease management parameters, ranging from blood glucose results to foot temperature, found improved outcomes with telemonitoring, such as A1C lowering, a lower incidence of foot ulcerations and better QOL (4,68,69). These benefits were noted regardless of whether the teleconsultation was asynchronous or synchronous (69). Other Relevant Guidelines Self-Management Education, p. S26 Type 1 Diabetes in Children and Adolescents, p. S153 Type 2 Diabetes in Children and Adolescents, p. S163 Diabetes and Pregnancy, p. S168 Relevant Appendix RECOMMENDATIONS 1. Diabetes care should be proactive, incorporate elements of the chronic care model (CCM), and be organized around the person living with diabetes who is supported in self-management by an interprofessional team with specific training in diabetes [Grade C, Level 3 (6,23)]. 2. The following quality improvement strategies should be used, alone or in combination, to improve glycemic control [Grade A, Level 1 (12)]: a) Promotion of self-management b) Team changes c) Disease (case) management d) Patient education e) Facilitated relay of clinical information f) Electronic patient registries g) Patient reminders h) Audit and feedback i) Clinician education j) Clinician reminders (with or without decision support) 3. Diabetes care management by an interprofessional team with specific training in diabetes and supported by specialist input should be integrated within diabetes care delivery models in the primary care [Grade A, Level 1A (12,21)] and specialist care [Grade D, Consensus] settings. 4. The role of the diabetes case manager should be enhanced, in cooperation with the collaborating physician [Grade A, Level 1A (12,21)], including interventions led by a nurse [Grade A, Level 1A (29,30)], pharmacist [Grade B, Level 2 (34)] or dietitian [Grade B, Level 2 (70)], to improve coordination of care and facilitate timely diabetes management changes. 5. As part of a collaborative, shared care approach within the CCM, an interprofessional team with specialized training in diabetes, and including a physician diabetes expert, should be used in the following groups: a) Children with diabetes [Grade D, Level 4 (71)] b) Type 1 diabetes [Grade C, Level 3 (46)] c) Women with diabetes who require preconception counselling [Grade C, Level 3 (72e74)] and women with diabetes in pregnancy [Grade D, Consensus] d) Individuals with complex (multiple diabetes-related complications) type 2 diabetes who are not reaching targets [Grade D, Consensus] 6. Telehealth technologies may be used as part of a disease management program to: 1. Improve self-management in underserviced communities [Grade B, Level 2 (67)] 2. Facilitate consultation with specialized teams as part of a shared-care model [Grade A, Level 1A (69)] Abbreviation: CCM, chronic care model. Appendix 2. Sample Diabetes Patient Care Flow Sheet for Adults References 1. Harris SB, Ekoé J-M, Zdanowicz Y, et al. Glycemic control and morbidity in the Canadian primary care setting (results of the Diabetes in Canada Evaluation Study). Diabetes Res Clin Pract 2005;70:90e7. 2. Braga M, Casanova A, Teoh H, et al. Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada. Can J Cardiol 2010;26:297e302. 3. Jaakkimainen L, Shah B, Kopp A. Sources of physician care for people with diabetes. In: Hux J, Booth G, Slaughter P, et al., editors. Diabetes in Ontario: An ICES Practice Atlas, 6. Toronto, ON: Institute for Clinical Evaluative Sciences; 2003. p. 161e92. 4. Jaana M, Pare G. Home telemonitoring of patients with diabetes: a systematic assessment of observed effects. J Eval Clin Pract 2007;13:242e53. 5. Borgermans L, Goderis G, Van Den Broeke C, et al. Interdisciplinary diabetes care teams operating on the interface between primary and specialty care are associated with improved outcomes of care: findings from the Leuven Diabetes Project. BMC Health Serv Res 2009;9:179. 6. Coleman K, Austin B, Brach C, Wagner EH. Evidence on the chronic care model in the new millennium. Health Affairs 2009;28:75e85. 7. Wagner EH, Austin BT, Von Korff M. Organizing care for patients with chronic illness. Milbank Q 1996;74:511e44. 8. Renders CM, Valk GD, Griffin S, et al. Interventions to improve the management of diabetes mellitus in primary care, outpatient, and community settings. Cochrane Database Syst Rev 2001;1:CD001481. 9. Barr VJ, Robinson S, Marin-Link B, Underhill L, et al. The expanded chronic care model: an integration of concepts and strategies from population health promotion and the chronic care model. Hosp Q 2003;7:73e80. 10. Shojania KG, Ranjii SR, McDonald KM, et al. Effects of quality improvement strategies for type 2 diabetes on glycemic control: a meta-regression analysis. JAMA 2006;296:427e40. 11. Improving Chronic Illness Care. Available at: http://www.improvingchroniccare. org/index.php?p¼ACIC_Survey&s¼35. Accessed February 24, 2013. 12. Tricco AC, Ivers NM, Grimshaw JM, et al. Effectiveness of quality improvement strategies on the management of diabetes: a systematic review and metaanalysis. Lancet; 2012:12e21. 13. Health Canada Council. Progress Report 2011: Health care renewal in Canada. May 2011. Available at: http://www.healthcouncilcanada.ca/tree/2.452011Progress_ENG.pdf. Accessed February 24, 2013. 14. Minkman M, Kees A, Robbert H. Performance improvement based on integrated quality management models: what evidence do we have? A systematic literature review. Int J Qual Health Care 2007;19:90e104. 15. Piatt GA, Orchard TJ, Emerson S, et al. Translating the chronic care model into the community. Diabetes Care 2006;29:811e7. 16. Gabbay RA, Bailit MH, Mauger DT, et al. Multipayer patient-centered medical home implementation guided by the chronic care model. Jt Comm J Qual Patient Saf 2011;37:265e73. 17. Bodenheimer T, Wagner EH, Grumbach K. Improving primary care for patients with chronic illness: the chronic care model, part 2. JAMA 2002;288:1909e14. 18. Fleming B, Silver A, Ocepek-Welikson K, et al. The relationship between organizational systems and clinical quality in diabetes care. Am J Manag Care 2004;10:934e44. M. Clement et al. / Can J Diabetes 37 (2013) S20eS25 19. Parchman ML, Zeber JE, Romero RR, et al. Risk of coronary artery disease in type 2 diabetes and the delivery of care consistent with the chronic care model in primary care settings: a STARNet study. Med Care 2007;45:1129e34. 20. Chin MH, Drum ML, Guillen M, et al. Improving and sustaining diabetes care in community health centers with the health disparities collaboratives. Med Care 2007;45:1135e43. 21. Pimouguet C, Le GM, Thiebaut R, et al. Effectiveness of disease-management programs for improving diabetes care: a meta-analysis. CMAJ 2011;183: e115e27. 22. Vargas RB, Mangione CM, Asch S, et al. Can a chronic care model collaborative reduce heart disease risk in patients with diabetes. J Gen Intern Med 2007;22: 215e22. 23. Stock S, Drabik A, Buscher G, et al. German diabetes management programs improve quality of care and curb costs. Health Affairs 2010;29:2197e205. 24. vanBruggen R, Gorter K, Stolk R, et al. Clinical inertia in general practice: widespread and related to the outcome of diabetes care. Fam Pract 2009;26: 428e36. 25. Davidson MB, Blanco-Castellanos M, Duran P. Integrating nurse-directed diabetes management into a primary care setting. Am J Manag Care 2010;16: 652e6. 26. Saxena S, Misra T, Car J, et al. Systematic review of primary healthcare interventions to improve diabetes outcomes in minority ethnic groups. J Ambul Care Manage 2007;30:218e30. 27. Willens D, Cripps R, Wilson A, et al. Interdisciplinary team care for diabetic patients by primary care physicians, advanced practice nurses and clinical Pharmacists. Clin Diabetes 2011;29:60e8. 28. Manns BJ, Tonelli M, Zhang J, et al. Enrolment in primary care networks: impact on outcomes and processes of care for patients with diabetes. CMAJ 2012;184: e144e52. 29. Welch G, Garb J, Zagarins S, et al. Nurse diabetes case management interventions and blood glucose control: results of a meta-analysis. Diabetes Res Clin Pract 2010;88:1e6. 30. Clark CE, Smith LFP, Taylor RS, et al. Nurse-led interventions used to improve control of high blood pressure in people with diabetes: a systematic review and meta-analysis. Diabet Med 2011;28:250e61. 31. Katon WJ. Collaborative care for patients with depression and chronic disease. N Engl J Med 2010;363:2611e20. 32. Ohman-Strickland PA, Orzano AJ, Hudson SV, et al. Quality of diabetes care in family medicine practices: influence of nurse-practitioners and physician’s assistants. Ann Fam Med 2008;6:14e22. 33. Ismail K, Winkley K, Rabe-Hesketh S. Systemic review and meta-analysis of randomized controlled trial of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Lancet 2004;363:1589e97. 34. Collins C, Limone BL, Scholle JM, et al. Effect of pharmacist interventions on glycemic control in diabetes. Diabetes Res Clin Pract 2011;92:145e52. 35. Chisholm-Burns MA, Kim Lee J, Spivey CA, et al. U.S. pharmacists’ effect as team members on patient care: systematic review and meta-analyses. Med Care 2010;48:923e33. 36. Simpson SH, Majumdar SR, Tsuyuki RT, et al. Effect of adding pharmacists to primary care teams on blood pressure control in patients with type 2 diabetes: a randomized controlled trial (ISRCTN97121854). Diabetes Care. Available at: http://care. diabetesjournals.org/content/early/2010/10/05/dc10-1294.full.pdfþhtml; 2010. Accessed February 24, 2013. 37. vanBruggen JAR, Gorter K, Stolk R. Shared and delegated systems are not quick remedies for improving diabetes care: a systematic review. Prim Care Diabetes 2007;1:59e68. 38. Cleveringa FGW, Gorter KJ, Van Donk MD, et al. Combined task delegation, computerized decision support, and feedback improve cardiovascular risk for type 2 diabetic patients. Diabetes Care 2008;31:2273e5. 39. Cabana MD, Jee SH. Does continuity of care improve patient outcomes? J Fam Pract 2004;53:974e80. 40. Aron D, Pogach L. Specialists versus generalists in the era of pay for performance: “a plague o’ both your houses!”. Qual Saf Health Care 2007;16:3e5. 41. McAlister FA, Majumdar SR, Eurich DT, et al. The effect of specialist care within the first year on subsequent outcomes in 24 232 adults with new onset diabetes mellitus: population-based cohort study. Qual Saf Health Care 2007; 16:6e11. 42. Shah BR, Hux JE, Laupacis A, et al. Diabetic patients with a prior specialist care have better glycaemic control than those with prior primary care. J Eval Clin Pract 2005;11:568e75. 43. Post PN, Wittenberg J, Burgers JS. Do specialized centers and specialist produce better outcomes for patients with chronic disease than primary care generalists? A systematic review. Int J Qual Health Care 2009;21:387e96. 44. Gnavi R, Picariello R, Karaghiosoff L, et al. Determinants of quality in diabetes care process: the population-based Torino study. Diabetes Care 2009;32: 1986e92. 45. Griffin SJ, Kimonth AL. WITHDRAWN: Systems for routine surveillance in people with diabetes mellitus. Cochrane Database Syst Rev 2009;1:CD000541. 46. Zgibor JC, Songer TJ, Kelsey SF, et al. Influence of health care providers on the development of diabetes complications: long term follow-up from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2002;25: 1584e90. S25 47. Tabak A, Tamas G, Zgibor J. Targets and reality: a comparison of health care indicators in the U.S. (Pittsburgh Epidemiology of Diabetes Complications Study) and Hungary (Diab Care Hungary). Diabetes Care 2000;23:1284e9. 48. Smith SM, Allwright S, O’Dowd T. Effectiveness of shared care across the interface between primary and specialty care in chronic disease management. Cochrane Database Syst Rev 2007;3:CD004910. 49. Cheung N, Yue D, Kotowitz MA, et al. Care delivery: a comparison of diabetes clinics with different emphasis on routine care, complications assessment and shared care. Diabet Med 2008;25:974e8. 50. Goderis G, Borgermans L, Grol R, et al. Start improving the quality of care for people with type 2 diabetes through a general practice support program: a cluster randomized trial. Diabetes Res Clin Pract 2010;88:56e64. 51. de Belvis A, Pelone F, Biasco A, et al. Can primary care professionals’ adherence to evidence based medicine tools improve quality of care in type 2 diabetes? A systematic review. Diabetes Res Clin Pract 2009;85:119e31. 52. O’Connor PJ, Sperl-Hillen JM, Rush WA, et al. Impact of electronic health record clinical decision support on diabetes care: a randomized trial. Ann Fam Med 2011;9:12e21. 53. Hahn K, Ferrante C, Crosson J, et al. Diabetes flow sheet use associated with guideline adherence. Ann Fam Med 2008;6:235e8. 54. Grant RW, Hamrick HE, Sullivan CM, et al. Impact of population management with direct physician feedback on care of patients with type 2 diabetes. Diabetes Care 2003;26:2275e80. 55. Boren S, Puchbauer A, Williams F. Computerized prompting and feedback of diabetes care: a review of the literature. J Diabetes Sci Technol 2009;3:944e50. 56. Sperl-Hillen J, Averbeck B, Palattao K, et al. Outpatient EHR-based diabetes clinical decision support that works: lessons learned from implementing diabetes wizard. Diabetes Spectrum 2010;23:2010. 57. Ivers N, Jamtvedt G, Flottorp S, et al. Audit and feedback: effects on professional practice and healthcare outcomes. Cochrane Database Syst Rev 2012;6: CD000259. 58. Deakin T, McShane CE, Cade JE, et al. Group based training for selfmanagement strategies in people with type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;2:CD003417. 59. Foster G, Taylor SJ, Eldridge SE, et al. Self-management education programmes by lay leaders for people with chronic conditions. Cochrane Database Syst Rev 2007;4:CD005108. 60. Schouten LM, Hulscher ME, van Everdingen JJ, et al. Evidence for the impact of quality improvement collaboratives: systematic review. BMJ 2008;336: 1491e4. 61. Canadian Diabetes Association. Type of incentive billings by province. Available at: www.diabetes.ca/documents/for-professionals/Billing-Chart-Final.pdf. Accessed February 24, 2013. 62. Chen TT, Chung KP, Lin IC, et al. The unintended consequence of diabetes mellitus pay-for-performance (P4P) program in Taiwan: are patients with more comorbidities or more severe conditions likely to be excluded from the P4P program? Health Serv Res 2011;46:47e60. 63. Mannion R, Davies H. Payment for performance in health care. BMJ 2008;336: 306e8. 64. Dalton AR, Alshamsan R, Majeed A, Millett C. Exclusion of patients from quality measurement of diabetes care in the UK pay-for-performance programme. Diabet Med 2011;28:525e31. 65. Tu K, Cauch-Dudek K, Chen Z. Comparison of primary care physician payment models in the management of hypertension. Can Fam Physician 2009;55: 719e27. 66. Yan C, Kingston-Riechers J, Chuck A. Institute of Health Economics (IHE) report: financial incentives to physician practices. A literature review of evaluations of physician remuneration models. Alberta, Canada: IHE; March 2009. 67. Davis RM, Hitch AD, Salaam MM. TeleHealth improves diabetes selfmanagement in an underserved community: Diabetes TeleCare. Diabetes Care 2010;33:1712e7. 68. Stone RA, Rao RH, Sevick MA. Active care management supported by home telemonitoring in veterans with type 2 diabetes: The DiaTel randomized controlled trial. Diabetes Care 2010;33:478e84. 69. Verhoeven F, Tanja-Dijkstra K, Nijland N, et al. Asynchronous and synchronous teleconsultation for diabetes care: a systematic literature review. J Diabetes Sci Technol 2010;4:666e84. 70. Wolf AM, Conaway MR, Crowther JQ, et al. Translating lifestyle intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study. Diabetes Care 2004;27:1570e6. 71. Glasgow AM, Weissberg-Benchall J, Tynan WD, et al. Readmissions of children with diabetes mellitus to a children’s hospital. Pediatrics 1991;88: 98e104. 72. Ray JG, O’Brien TE, Chan WS. Preconception care and the risk of congenital anomalies in the offspring of women with diabetes mellitus: a meta-analysis. QJM 2001;94:435e44. 73. Kitzmiller JL, Gavin LA, Gin GD, et al. Preconception care of diabetes. Glycemic control prevents congenital anomalies. JAMA 1991;265:731e6. 74. McElvy SS, Miodovnik M, Rosenn B, et al. A focused preconceptional and early pregnancy program in women with type 1 diabetes reduces perinatal mortality and malformation rates to general population levels. J Matern Fetal Med 2000; 9:14e20. although they have been used mainly for research purposes. MS. social and emotional aspects of care must be integrated into the traditional knowledge and technical skills content of educational interventions (2). CDE. culture and literacy level. prevention and management of hypo-/ hyperglycemia. skills and motivation required to inform decisions and increase the individual’s capacity and confidence to apply these skills in daily life situations. using medications as recommended and adjusting medication (20. interactive and collaborative teaching methods that are tailored to the 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. S20) refers to policies and people that may support continuation of self-management behaviours across the lifespan but that are not specific to educational processes.3% over the 5 years (8).jcjd. MHSc KEY MESSAGES  Offer collaborative and interactive self-management education (SME) interventions as they are more effective than didactic SME. long-term clinical improvement 38. It recognizes that patient-provider collaboration and the enablement of problem-solving skills are crucial to the individual’s ability for sustained self-care (2). psychological and behavioural interventions.81% (1.13) share a 5-step problem-solving process aligned with the empowerment protocol (14) based on the principle that adults are more likely to make and maintain behaviour changes if these changes are personally meaningful and freely chosen (14). and his or her culture and literacy level.  Provide ongoing SME and comprehensive healthcare collaboratively to make SME most effective. and available resources (4. Models for systematizing.4). such as the Problem Areas in Diabetes (PAID) (16).11). organizing and/or guiding the development of SME programs (12.015 individual’s specific needs (9). SME refers to any of the educational processes that provide persons with the knowledge. healthy eating. FRCPC. pharmacotherapy.org/10. Self-management support (addressed in the Organization of Care chapter. Self-identification of a problem or need for self-care behaviour by the individual is crucial to all cognitive-behavioural interventions (14. Diabetes SME is evolving from a traditional didactic teaching program to one using a variety of educational.6%. percentage of improved outcomes reduced (immediate learning 78. Lori D. Interventions targeting knowledge and skills Basic knowledge and skill areas that are essential for SME are monitoring of relevant health parameters. Introduction Self-management education (SME) is defined as a systematic intervention that involves active patient participation in selfmonitoring (physiological processes) and/or decision making (managing) (1). Improved quality of life (QOL) for persons with either type 1 or type 2 diabetes also has been demonstrated (5).Can J Diabetes 37 (2013) S26eS30 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. Catherine Yu MD. and a combination of didactic. Gail MacNeill BNSc. barriers. .0%. MEd. CDE. motivation for learning and change. such as sustained weight loss and cardiovascular (CV) fitness for up to 4 years (6).canadianjournalofdiabetes.5%) (7).01. social and emotional aspects of care into the traditional knowledge and technical skills content of educational interventions. and prevention and surveillance of complications.doi. whereas the A1C in the control group rose 1.3. as measures progressed from immediate to long-term outcomes. physical activity. the patient’s ability. incorporating an exercise regimen. Self-care Inventory-Revised (SCI-R 2005) (17) or Summary of Diabetes SelfCare Activities (18). Several meta-analyses have demonstrated that SME is associated with clinically important benefits in persons with type 2 diabetes.15).  Design patient-centred learning to empower individuals to make informed decisions toward achievement of patient-chosen goals. RN.10. The content and skill-training components of SME must be individualized according to the type of diabetes and recommended therapy. One systematic review involving both type 1 and type 2 diabetes found that. may have value in this process (19).21). Skill training should include using self-monitoring of blood glucose (SMBG).36% to 0.1016/j. intermediate behaviour change 50. A 5-year follow-up of a patient-centred type 2 diabetes SME program resulted in no worsening of A1C. The healthcare provider’s role is to collaboratively facilitate this awareness process (2).” problemsolving skills for ongoing self-management of medical. Berard RN. CDE. the patient’s ability and motivation for learning and change. p. CDE. such as reductions in glycated hemoglobin (A1C) of 0. as have other important self-care outcomes in those with type 2 diabetes.com Clinical Practice Guidelines Self-Management Education Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Helen Jones RN. MSN.  Individualize SME interventions according to type of diabetes and recommended therapy. In order to meet the definition of “self-management education. These skills are needed to inform decisions and increase the individual’s capacity and confidence to apply these skills in daily life situations (2). Standardized instruments. making appropriate dietary choices.  Incorporate problem-solving skills for ongoing self-management of medical. Dana Whitham RD.2013. 57).33. / Can J Diabetes 37 (2013) S26eS30 S27 In general. Cognitive-behavioural interventions The acquisition of knowledge should be augmented with behavioural interventions to achieve longer-term change in self-care behaviours (3. such as e-Health and telemedicine with videoconferencing and teletransmission of home glucose monitoring. and having partners involved in care has been found to impact glycemic control (55). All of these recognize that personal awareness and alteration of causative (possibly unconscious) thoughts and emotions are essential for effective behaviour change (47).8% (32e35). some have used face-to-face group sessions (44).52). such as A1C.50) and increasing self-care behaviours (15. Family and social support has positively impacted metabolic control and self-care behaviours (32. Historically. In general. the development of problem-solving skills.43. education sessions provided to patients with diabetes have resulted in positive changes in diabetes-related knowledge (22). email.H. Effective patient-clinician communication may improve adherence to recommendations (54).55). self-efficacy and blood pressure (BP) (36).7% (22.53). RCTs have concluded that different behavioural strategies are needed at different times to sustain behaviour change in the long term (56. web-based education.49). The more appropriate term may be “cognitive behavioural” interventions.23. Behavioural interventions had a larger effect size (ES) on self-management behaviours (ES À0. skill-training interventions demonstrated positive changes or no significant differences in outcomes compared to control. Several trials have found various cognitive-behavioural interventions to be effective in lowering A1C (4. and the use of action plans directed toward patient-chosen goals (23. cognitive-behavioural therapy (CBT).g.28).5% to 1.or video-based education models have demonstrated improvements in at least 1 behaviour change related to healthy eating and physical activity (7. More recently. Using a combination of different instructional methods that consistently incorporate an interactive component has been found to have somewhat more favourable effects than didactic programs (9.33. Interventions for content and materials geared toward patients with low literacy and numeracy can be successful in improving outcomes. Several RCTs and systematic reviews have demonstrated that culturally competent healthcare interventions have resulted in lower A1C levels and improvements in diabetes-related knowledge and QOL (32. goal setting and relaxation. but there is no definitive conclusion as to which setting is superior (9. with A1C reductions ranging from 0.9. significant changes in behaviours related to physical activity (27). resulted in greater improvements in weight loss. collaborative patient-healthcare professional relationship is also important for improving self-care behaviours (4). Cognitive-behavioural interventions share common elements.23). as well as psychological (23e26) and behavioural (23. The Diabetes Education and Self-Management for Ongoing and Newly Diagnosed (DESMOND) trial. Most interventions were delivered by nurses (26. however. improving QOL (49. Communication technologies. Randomized trials of computer. All trials evaluating a culturally appropriate education module (which incorporated cultural or religious beliefs.46) have been proven to be more effective in increasing knowledge.23. SME reinforcers and technological innovation Incorporating booster sessions enhances the effectiveness of SME interventions (9). weight loss (27) and improvements in glucose control (30) have been noted. Several small trials have demonstrated improved outcomes when utilizing these technologies.52.15. however.46). Family and culturally tailored interventions are particularly relevant in minority communities. shared decision making. including a patient-centred approach.4% to 0.92) and on metabolic outcomes (ES 0. Both individual and group settings have been used for cognitivebehavioural interventions.44) or diabetes educators (42). Interventions that combine strategies for knowledge acquisition and self-care management (25.48). In both type 1 and type 2 diabetes.53).25.15.23).38). problem solving. between 4 and 12 months). show promise for delivering individualized messages over an extended time period (52).39. smoking cessation and positive improvements in illness beliefs up to 12 months after diagnosis. were offered in the patient’s native language.e. In those studies that used print-based education. With respect to A1C. text messaging [58e62]. stage-ofchange progression (29). patients are largely responsible for the majority of their own diabetes management. reminder systems and . rate of hypoglycemia. automatic telephone reminders [63]. healthcare providers have been challenged with providing continued selfmanagement support between visits. no significant effect on A1C was noted at 12-month follow-up (25). a combination of face-to-face group and individual sessions (26) and video-based programs for home viewing (45). Connecting with community partners and other chronic care model programs has proven to be a successful adjunct to cognitive-behavioural interventions (49. telehealth/telephone education [64e67] and reinforcement [68e72]) has provided an effective and timeefficient means of providing this ongoing support. whereas group interventions combined with individual follow-up sessions have resulted in lower A1C levels than either setting alone (10).46).26. interventions that have targeted the family’s ability to cope with stress have resulted in fewer conflicts. stress management. For example. ranging from 0. Training healthcare professionals in specific communication skills to address low literacy can also be effective (37. A trusting.51). the internet.25. adapted dietary advice to reflect cultural traditions and the patient’s needs. group settings have been found to be more effective for weight loss and short-term glycemic control. whereas the other found no difference in A1C and BMI but an improvement in total cholesterol (TC) and TC to highdensity lipoprotein cholesterol (HDL-C) ratio (41). While the majority of randomized controlled trials (RCTs) examining skill-training interventions used face-to-face individual sessions (39e43). Frequent communication is a key indicator for successful interventions. which include cognitive restructuring. and/or involved family members) have noted improvements in diabetes-related knowledge. differences in weight gain and time spent in follow-up appointments or calls favoured individual training sessions (44). low-density lipoprotein cholesterol (LDL-C). In general. While healthcare providers play an essential role in SME delivery. self-efficacy and self-care behaviours and in achieving metabolic control than programs that are didactic and knowledge oriented alone (4. whereas others have shown mixed results (3. BP.63) than knowledge-based or other psychological interventions (9).27) domains. body mass index (BMI) and self-care activities with skills training (40). contrasting results were found in the 2 trials examining the impact of SMBG skills training: 1 study found an improvement in A1C.56). however. lipid profile or QOL between the 2 approaches. Jones et al. most trials involving group-based education have shown sustained A1C reductions (i. One study that compared insulin-initiation skills training provided in a group vs. an individual setting found no difference in A1C. a structured group education program for persons with newly diagnosed type 2 diabetes. These findings demonstrate the importance of creating culturally relevant educational materials. whether done by a multidisciplinary team in a hospital or a community setting (33. self-management behaviours and clinical outcomes.31). the availability of several different technologies (e. Jones et al. However. video. 1 study of online diabetes education found no improvement in outcomes with the use of reinforcement methods (74). the magnitude of the effect varied across studies and appeared to be dependent on the background characteristics of the patient population (e. sample selection and the approach to the treatment of control subjects. A large study found that a peer-support intervention (i. telecare and telemedicine demonstrated a significant impact at the behavioural. Of note.g. but mixed effectiveness. of peer delivery of this standardized diabetes education program in Hispanic (71) and non-Hispanic populations (76).81). ability for self-management.65. PAID. Studies of the incremental effect of peer educators show much variability in terms of behaviour change and clinical outcomes (80. However. However.68). the specialist group scored significantly higher in process and participant evaluations (79). 9 group sessions over 2 years) was not effective when targeted at all patients with type 2 diabetes (78).63. decreased depressive symptoms. home monitoring. The DSMP was associated with significant A1C reductions in the Hispanic group (À0.76). improved global health. scheduled follow-ups compared to controls. Two studies of the 6-week Diabetes SelfManagement Program (DSMP) demonstrated the feasibility. a culturally tailored outreach and education program delivered by trained community health workers (CHW) was associated with significant improvements in self-care behaviours and similar A1C reductions compared to nurse-led case management and standard clinic care (77). scope of practice and issues of governance remain.S28 H.73) and weight (67. community health worker. improved self-efficacy (64e66) and QOL (70). were noted in both groups (71. / Can J Diabetes 37 (2013) S26eS30 Figure 1. culturally relevant and sustainable component to standard diabetes care (77).71). including decreased health distress. patient empowerment and improved patient understanding. Another large study comparing specialist (nurse and physician) delivery to peer delivery of a 6-week.g. improved self-efficacy and improved communication with physicians. CHW.e. Outcomes include increased frequency of SMBG (58. suggesting that the CHW may provide a trusted. The specifics of training requirements for peer educators have not been clarified. as well as improved clinical outcomes. face-to-face. Delivery No particular delivery strategy (e.4%) but not in the non-Hispanic group.69. Problem Areas In Diabetes scale. including reductions in A1C (59e62. These strategies also resulted in significant reductions in A1C and diabetes-related complications. phone. A meta-analysis of studies examining the use of telemonitoring. Professional and peer delivery Peer facilitators may augment multidisciplinary team practices in providing SME and/or social support. improved adherence to treatment algorithms (31). the dropout rate was significantly lower in the CHW group (28% vs. web-based/online. In another study. interactive diabetes education program found no significant differences in either knowledge or A1C outcomes between the groups. structured. and significant variations in training. Significant improvements in other outcomes. The superiority of peer-delivered programs over similar programs delivered by health professionals has not been demonstrated in general populations with type 2 diabetes. mixed) appears to result in consistently . clinical and structural levels (75). medical condition). 50% in the standard group). especially when developed as culturally relevant behavioural interventions for underserved populations (35). Steps to success in SME. 6. there has been a clear increase in the use of multifaceted programs that incorporate behavioural/psychosocial interventions. 20. S153 .85)]. J Adv Nurs 2009. Long-term effects of a lifestyle intervention on weight and cardiovascular risk factors in individuals with type 2 diabetes mellitus: four-year results of the Look AHEAD trial. Diabetes Educ 2009. Moller S. Byers T.23. Davies MJ. Diabetes Educ 2003. 24. SME that incorporates cognitive-behavioural educational interventions. Benediktsson R. Cochrane J.48).33: 1053e77. Whitlock S.33:18e26. Ann Fam Med 2005. Ellis S. the enablement of problem-solving skills and the use of action plans directed toward patient-chosen goals.170:1566e74. Friedman R. Abbreviations: A1C. Self-management education for adults with type 2 diabetes: a meta-analysis of the effect on glycemic control. Conclusions Since 2004. et al. Effectiveness of diabetes self-management education intervention elements: a meta-analysis. glycated hemoglobin. Weinger K. 2008. et al. 9. Diabetes Care 2005. Bessesen D.48. et al.29: 488e501. et al. et al. 15. and self-monitoring of health parameters. Patient self-management of chronic disease in primary care. Schaefer J. 5. 4.168:141e6. Level 1A (83. 11. 2. The most effective behavioural interventions involve a patient-centred approach. 29. p. self-management education. 7. Hearnshaw H. Chen HS. Educational interventions aiming at improving adherence to treatment recommendations in type 2 diabetes: a subanalysis of a systematic review of randomised controlled trials. 21. et al. Srisuphan W. Look AHEAD Research group. Hornsten A. and quality of life among Thai patients with type 2 diabetes. Bodenheimer T. Minet L. 25. Fox C. Chodosh J. as well as knowledge and skills training. S87 Type 1 Diabetes in Children and Adolescents. et al.34. A combination of didactic and interactive teaching methods.11. 27.and numeracy-sensitive materials to a comprehensive diabetes management and education program may be used to improve knowledge. ON: Canadian Diabetes Association. Diabetes Care 2005. Hampson S. S20 Monitoring Glycemic Control.52:97e105. Effects of the Diabetes Manual 1:1 structured education in primary care. Diabetes Care 2000. Diabetes patient education: a meta analysis and meta-regression. 5. which may include peer or lay educators. Speroff T. People with diabetes should be offered timely diabetes education that is tailored to enhance self-care practices and behaviours [Grade A. Hill-Briggs F. 10. Wolfe S. et al. such as problem solving.35:603e11. Wattana C. Can J Diabetes 2009. Reducing risks in diabetes selfmanagement: a systematic review of the literature. p. Effects of a diabetes selfmanagement program on glycemic control. coronary heart disease risk.77)]. 16. 18. 26. Clinic based support to help overweight patients with type 2 diabetes increase physical activity and lose weight. et al. Toronto. Reinhecker H. Tan F. Kulzer B. Ismail K. measuring diabetes self-care: a psychometric analysis of the Self-Care Inventory-revised with adults. Improvement of glycaemia control in subjects with type 2 diabetes by self-monitoring of blood glucose: comparison of two RECOMMENDATIONS 1. Gunlock TL. Toobert D. Technologically based home blood glucose monitoring systems may be integrated into SME interventions in order to improve glycemic control [Grade C. Wu TE. The Summary of Diabetes Self-Care Activities measure: results from 7 studies and a revised scale. Putting it together: finding success in behavior change through integration of services. Meta-analysis: chronic diseases selfmanagement programs for older adults. et al. Diabetes Educ 2007. Culturally appropriate SME. Diabetic Med 2007. et al. Funnell M.14:1e101.28:1346e52. Skinner TC.65:2118e30. shared decision making. et al. 19. Maissi E. Pothiban L. Assessing psychosocial distress in diabetes: development of the diabetes distress scale. et al. Meta-analysis of quality of life outcomes following selfmanagement training.33:1032e50. Adding literacy. American Association of Diabetes Educators. Fisher L. Heller S. S35 Diabetes and Mental Health.82)]. Instruments to tailor care of people with diabetes. Krist A. Jap TS. Thomas S. A tailored print-based physical activity intervention for patients with type 2 diabetes. 12. Glasgow RE. Sigurdardottir A. 9:135e41. Effectiveness of the diabetes education and self-management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cluster randomised controlled trial.24: 415e23. Ann Intern Med 2005. since both may be effective [Grade A. Lau J. Morton SC. Patient Educ Couns 2004. 23:943e55. References 1. 2. Polonsky W.47:409e11. / Can J Diabetes 37 (2013) S26eS30 S29 superior outcomes in persons with type 2 diabetes. Dittus R. In both type 1 and 2 diabetes. Mojica W. Scain SF. interventions that target families’ ability to cope with stress or diabetes-related conflict should be included in educational interventions when indicated [Grade B. Diabetes Res Clin Pract 2008. with a marked reduction in didactic educational programs that focus on knowledge or skill acquisition only (3). Diabetes Educ 2007. Stenlund H. et al. Welch G. Patient Educ Couns 2010. In: Jones H. Level 1A (3. 6. et al. Lach V.3(suppl 2):s20e7.H.79:377e88. self-efficacy and A1C outcomes for patients with low literacy [Grade C. Effects of self-management training in type 2 diabetes: a randomized prospective trial. Implementing an empowermentbased diabetes self-management education program. Level 3 (75. Arch Intern Med 2010. Jones et al. Interventions that increase patient participation and collaboration in healthcare decision making should be used by providers [Grade B. Vermeire E.31: 53e6. Meta-analysis of randomized educational and behavioral interventions in type 2 diabetes. 7. Diabetes Care 2002. Hermanns N. Guallar E. A randomised controlled trial of cognitive behaviour therapy and motivational interviewing for people with type 1 diabetes mellitus with persistent sub-optimal glycemic control: a diabetes and psychological therapies study. a cognitive-behavioural method and the practical application of content are more likely to improve glycemic control (11. Gross JL. Holman H. 30.336:491e5. appears to be most effective for persons with type 2 diabetes (9). All people with diabetes who are able should be taught how to selfmanage their diabetes [Grade A. Provost B. SME. Standards for outcome measures of diabetes self-management. et al. Lundman B. Fan L. Wens J. Level 3 (36)].29:804e16. Improvements in HbA1c remain after 5 years: a follow up of an educational intervention focusing on patients’ personal understandings of type 2 diabetes. Prev Med 2008. p. 4. 22. as well as group and individual sessions. Christian J. Level 2 (55)]. 28. JAMA 2001. may be used to increase diabetes-related knowledge and self-care behaviours and to decrease A1C [Grade B. Norris SL. 23. Diabetes Educ 2008. Diabetes Educ 2005. however. Gary T. 3.84)]. Level 2 (11. SME interventions should be offered in small group and/or one-on-one settings. Sidani S. Dutton G. Building Competency in Diabetes Education: The Essentials. Boren SA. should be implemented for all individuals with diabetes [Grade B.288:3470e5. 8. Level 2 (53)].34:815e23. 13. Smith CH.143:427e58. et al. Genkinger J. LaGreca A. Interventions that include face-to-face delivery. Earles J. larger effect sizes have been noted with strategies that involve personal contact with healthcare providers. 9. For people with type 2 diabetes. Steps to success in SME are summarized in Figure 1. et al. Nwankwo R. Diabet Med 2008.53)]. et al.80:29e41. either via face-to-face interactions or by telephone (9). 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Chowdhury FM. 85. Diabetes Educ 2007. Improving diabetes care and health measures among Hispanics using community health workers: results from a randomized controlled trial. Smith SM. Robles Y.2:203e11. 39. Carlson J. Weinger K. Lucisano G. White A. heart failure and hypertension: a systematic review. Rickheim PL. Lancet 2004. Systematic review and meta-analysis of randomized controlled trials of psychological interventions to improve glycaemic control in patients with type 2 diabetes. Glasgow R. Diabetes Care 2010. 77. Hawthorne K. Berger L. et al. Bensing J. Initiate insulin by aggressive titration and education (INITIATE): a randomized study to compare initiation of insulin combination therapy in type 2 diabetic patients individually and in groups. A pilot randomized clinical trial. 45. Diabetes Educ 2009. BMJ 2011. 44. 32. 31. deWalt DA.363:1589e97. Diabetes Technol Ther 2009.32:1614e9. Song H. Ullman R. Izquierdo R. Brooks M.29:768e803. Lorig K. Health Educ Behav 2009. 50.34:2e7. 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Narayan KMV. Blood glucose self-monitoring in type 2 diabetes: a randomised controlled trial. Nam S. Diabetes Obes Metab 2008. Impact of peer nutrition education on dietary behaviors and health outcomes among Latinos: a systematic literature review.171:1990e8. Moqadem K. Diabetes Care 2010. et al.33:660e70. 65. Trief PM. 83. Anderson R. 51. A systematic review of psychosocial outcomes following education.23:228e37. Thoolen B. 58. Magwood G. Community-based peer-led diabetes selfmanagement: a randomized trial. Diabet Med 2010.25: 1076e82. Pellegrini F. Tildesley HD. Vega-Lopez S. Benefits of self-monitoring blood glucose in the management of new-onset type 2 diabetes mellitus: the St. Results of a successful telephonic intervention to improve diabetes control in urban adults: a randomized trial. Culturally appropriate health education for type 2 diabetes in ethnic minority groups: a systematic and narrative review of randomized control trials. Cade JE. 59. Karlan V.2:CD003417. Rao RH. Int J Nurs Stud 2007. Samuel-Hodge C. Van Scoyoc EF. Jansa M.16:221e3. Gambling T. Juurinen L. Deakin T. Borges WJ.31: 408e13. Gerretsadik T. Zapka J. et al. Ostwald SK. Viaplana J. / Can J Diabetes 37 (2013) S26eS30 management programs adjusting bedtime insulin dosage. et al. 37. Wallston KA. et al.4:1479e81. J Eval Clin Pract 2007. Weaver TW.33:478e84. Controlled trial of nursing interventions to improve health outcomes of older African American women with type 2 diabetes. 33. et al. Diabetes Care 2011. Forbes A. Efficacy of a self-management education program for people with type 2 diabetes: results of a 12 month trial. 49. et al. Ritter PL. Franciosi M. Patient Educ Couns 2003. Alvarsson M. Active care management supported by home telemonitoring in veterans with type 2 diabetes: the DiaTel randomized controlled trial. et al.58:410e8. Vidal M.33:1275e81.11: 99e106. Diabetes Numeracy: an overlooked factor in understanding racial disparities in glycemic control. Long A. Gross CR. et al. Improvement in diabetes self-efficacy and glycaemic control using telemedicine in a sample of older.30:1266e8. et al. Home telemonitoring of patients with diabetes: a systematic assessment of observed effects. Jiang X. 78. Diabetes Educ 2003. Kuroe Y.79:230e6.24:237e54. Patients included had either a previous history of CVD or multiple risk factors for CVD. This association between CVD and 2-hour postprandial PG appears to be linear (6.9% (17.5%.6 mmol/L was associated with an increased risk of CV events (10).14). Both fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) are directly correlated to the risk of complications.016 values >10.2013. duration of diabetes. as well as more long-standing type 2 diabetes (15e19). their glycemic control became similar to that of patients who were previously in the standard arm (20e22).1%. during the subsequent follow-up period. In the UKPDS.doi. Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE). These trialsdthe DCCT in type 1 diabetes (13) and the Kumamoto (11) and the UKPDS (1.0% to 7. Values >7. with each 1. There is compelling evidence from randomized controlled studies that improved glycemic control reduces the risk of microvascular complications but has no significant effect on macrovascular outcomes in recently diagnosed type 1 (13) and type 2 diabetes (1. participants had a mean age of 62 years. presence or absence of cardiovascular disease and life expectancy. In the DCCT. In epidemiological analyses. type 1 diabetes) (2) and the United Kingdom Prospective Diabetes Study (UKPDS. with some evidence that postprandial might constitute a stronger risk factor for cardiovascular (CV) complications (4e9).0 mmol/L are associated with both microvascular complications (11) and the highest risk of MI (12). a 14% lower rate of myocardial infarction (MI) and a 21% reduction in deaths from diabetes (3). Postprandial hyperglycemia and the 2-hour post-challenge PG appears to be a better predictor of cardiovascular disease (CVD) and all-cause mortality than FPG (7). The follow-up data from these 2 studies also demonstrated a beneficial effect of improved glycemic control on CV outcomes. Similarly. although the absolute reduction in risk was substantially less at lower A1C levels (2).Can J Diabetes 37 (2013) S31eS34 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. this relationship was directly linear. ChB.jcjd.0% or standard therapy targeting an AIC level of 7. Ali Imran MBBS.01.com Clinical Practice Guidelines Targets for Glycemic Control Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by S.  Both fasting and postprandial plasma glucose levels correlate with the risk of complications and contribute to the measured glycated hemoglobin (A1C) value.0% (absolute) reduction in mean A1C associated with a 37% decline in the risk of microvascular complications. Stuart Ross MB. In the DCCT cohort. risk of severe hypoglycemia.1016/j. Three major trialsdthe Action to Control Cardiovascular Risk in Diabetes (ACCORD). with no apparent threshold of benefit. and 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. FRCPC KEY MESSAGES  Optimal glycemic control is fundamental to the management of diabetes. type 2 diabetes) (3) demonstrated a continuous relationship between A1C and diabetes complications. Subsequent observational data from long-term follow-up of both the DCCT and UKPDS cohorts showed a persistence of significant microvascular benefits in patients who had previously been in the intensively treated groups despite the fact that.8 mmol/L are associated with an increase in all-cause mortality (8).11. Data from the Diabetes Control and Complications Trial (DCCT. and Veterans Affairs Diabetes Trial (VADT)dlooked at the effect of intensive glycemic control on patients with long-standing type 2 diabetes. Rémi Rabasa-Lhoret MD. there was a significant reduction in MI (15%e33%) and all-cause mortality (13%e27%) in the UKPDS cohort in patients who had been originally randomized to intensive treatment (22). In a metaanalysis of 102 prospective studies. FRCP(Edin). At inclusion.7). a 10% reduction in A1C was associated with a 40% to 50% lower risk of retinopathy progression.canadianjournalofdiabetes.  Glycemic targets should be individualized based on the individual’s age.org/10. regardless of underlying treatment (1e3).14) in type 2 diabetesdconfirmed that improved glycemic control significantly reduced the risk of microvascular complications but had no significant effect on macrovascular (particularly CV) outcomes. stroke and CV death (57%) in previously intensively treated patients compared with those who were previously in the standard arm (23). A difference in A1C was rapidly obtained .0% are associated with a significantly increased risk of both microvascular and macrovascular complications. PhD. glycated hemoglobin (A1C) levels >7. and a baseline A1C level 7. The ACCORD trial randomly assigned 10 251 patients to intensive therapy targeting an A1C <6. The initial prospective randomized controlled trials were conducted in patients with recently diagnosed diabetes. FRACP. Introduction Optimal glycemic control is fundamental to the management of diabetes. diabetes duration of 10 years and a median baseline A1C level of 8. FPG >5. there was a significant reduction in CV outcomes (42%) as well as non-fatal MI. FRCPC.24). 0%. lowering A1C values to 7% in both type 1 and type 2 diabetes. whereas mean age was slightly higher at 66 years.0% in younger patients with recently diagnosed diabetes and a lower initial A1C value but with an increased risk of hypoglycemic risk. revealed fewer CVD events in these younger patients enrolled in the intensive treatment arm (28). Compared with the UKPDS and the DCCT. / Can J Diabetes 37 (2013) S31eS34 and maintained throughout the trial at 6. no evidence of significant CVD and longer life expectancy. the ADVANCE trial also reported a nonsignificant trend toward fewer events among younger patients in the intensive therapy group (15). meta-analysis of clinical trials designed to assess differences in CV outcomes in patients who had achieved lower versus higher levels of glycemia demonstrated that those treated with more intensive therapy. compared to less intensive glycemic control. These 3 trials confirmed the benefit of intensive glycemic control on microvascular outcomes. A major difficulty in attempting to use evidence-based observations to determine the value of tighter postprandial glucose control has been the lack of well-designed. None of the above studies independently confirmed a significant benefit of tight glycemic control on macrovascular outcomes. Conclusions Contrasting results from recent studies should not discourage physicians from controlling blood glucose levels. The frequency of severe hypoglycemia in these trials was 2 to 3 times higher in the intensive therapy groups. however. there is a greater contribution from PPG values (32.19). the duration of diabetes in the ACCORD. were found to have a 10% to 15% reduction in the risk of major CV events. mainly through a 21% relative reduction in nephropathy (15). In ADVANCE. history of severe hypoglycemic events. When A1C values are higher. More intensive glucose control. intensive therapy in ACCORD patients showed a favourable effect on microvascular outcomes. a randomized controlled trial of type 2 diabetes patients treated with insulin therapy after acute MI showed no benefit of insulin regimen targeting postprandial hyperglycemia compared with the regimen targeting preprandial glucose (36). Most of the large outcome trials conducted so far have been mostly based on preprandial glucose and A1C targets.0 mmol/L reduces progression of carotid atherosclerosis (35). individualization of A1C targets may be needed in some patients with type 1 diabetes who are unable to achieve an A1C <7. It also must be recognized that A1C measurement is a component of both the FPG and PPG.0 mmol/L correlates best with A1C <7. after a 5-year follow-up. which were conducted in younger individuals with recentonset diabetes. Duration of diabetes also may have played a role. but as the A1C value approaches the target value of 7. Hypothesis-generating secondary analysis from the ACCORD trial reported a nonsignificant trend toward lower all-cause mortality in individuals assigned to the standard arm who were younger than 65 years at baseline (27). might also provide a significant macrovascular benefit.2% and 8 years.5% (18. The ADVANCE trial randomly assigned 11 140 patients to standard (targeting A1C based on local guidelines) or intensive glucose control therapy aimed at reducing A1C levels to 6.5%) to either standard or intensive glucose therapy. In view of this. may be sought in patients with a shorter duration of diabetes. The primary outcome of this study was a composite of major CV events: nonfatal MI. respectively.36). Intensive glycemic control. The primary outcome in the ADVANCE trial was a composite of microvascular events (nephropathy and retinopathy) and macrovascular disease defined by major adverse CV events. established CV risk factors.6 years.24). these subanalyses confirmed that hypoglycemic events could not account for the difference in mortality between the intensive and standard therapy groups. The role of pre.0 to 8. if A1C targets cannot be achieved with a postprandial target of 5. irrespective of the different treatment arms in which individual patients were allocated.0% (34). utilizing computed tomography. rapidity to implement the intensive strategy or weight gain (24). Imran et al. Intensive glucose control. The difference in A1C in both arms was obtained less rapidly.4% and 7. The unexpected higher mortality rates seen in the intensive arm of the ACCORD study and the lack of clear macrovascular benefit in the ADVANCE and VADT trials have been further reviewed.5% (15). mortality was increased in patients randomized in the intensive arm but who failed to reduce their A1C despite treatment intensification (31).vs. weight gain and the rapid decrease in A1C values. ADVANCE and VADT trials ranged from 8 to 11.5 years due to higher mortality associated with assignment to this treatment (17. and a higher mortality was reported in participants with 1 or more episodes of severe hypoglycemia in both the ACCORD (29) and the ADVANCE (30) trials. However. the progression to albuminuria was significantly reduced in the intensive-treatment patients. but with no effect on stroke. including patient age.19). and. nonfatal stroke or death from CV causes. Patients were at least 55 years old with a history of major macrovascular or microvascular disease or at least 1 other risk factor for vascular disease.5%.0 mmol/L can be considered.3% in the standard group. Finally. Individualized and higher A1C targets may be indicated in older type 2 patients with longer duration of diabetes. A recent meta-analysis confirmed the positive impact of intensive glycemic control on microalbuminuria (25).A.S32 S.8% in the standard therapy group (19). Although there is evidence in type 2 diabetes that targeting postprandial hyperglycemia to <8. VADT randomly assigned 1791 United States military veterans with poor glycemic control (7.9% in the standard and intensive therapy groups. primarily because of a 15% reduced risk of MI. long-term outcome studies where assessing postprandial glucose values is the major objective of the study. severe hypoglycemia episodes and/or without A1C reduction despite treatment intensification. with 9. Increased mortality associated with intensive treatment could not be explained by the type of pharmacological treatment. In the VADT study. Following a median follow-up of 5. A1C levels were 8.0 mmol/L. mean A1C was 6. Similarly. particularly albuminuria and diabetic retinopathy (16).0% without being at increased risk of severe hypoglycemia.4% and 6. especially as part of a multifactorial treatment approach. CV death or all cause mortality (26). Further emphasis of the importance of duration of diabetes was identified in a substudy of the VADT patients when measurement of the coronary calcium score. respectively. patients in the intensive control group demonstrated a reduction in the incidence of major microvascular events. Similarly.33). if achieved early in the disease. However. Similarly. The primary outcome of the study was the time from randomization to the first occurrence of a major CV event (18. provides strong benefits for microvascular complications and. Several potential reasons for these findings have been suggested. respectively.1% of patients having significantly reduced progression compared to 13. duration of diabetes. presence of CVD. Another study using continuous glucose monitoring demonstrated that a 2-hour postprandial PG <8. which aimed for an overall reduction in A1C levels by 1. further postprandial BG lowering to 5.5% in the intensive group and 7. These findings suggest that microvascular and macrovascular events may be reduced by intensifying therapy targeting an A1C <7. A1C 6.0 to 10. was associated with more than a 2-fold increase in the risk of severe hypoglycemia (25). The intensive glucose control arm was prematurely terminated after 3.5 years.5% in the intensive and standard therapy groups. postprandial glucose control on reducing CV outcomes has been controversial (35. in the ACCORD trial. Median baseline A1C level and diabetes duration were lower than in the ACCORD trial at 7. the major contribution is the FPG levels. provided this does . Grade D.0e10. et al. Cavalot F. et al. and life expectancy [Grade D.0% cannot be achieved with a PPG target of 5. Fleg JL. ACCORD Trial Group. O’Brien PC. / Can J Diabetes 37 (2013) S31eS34 S33 Figure 1. Craven T. European Diabetes Epidemiology Group. fasting plasma glucose. Lancet 1998. FPG. The relation of fasting and 2-h postchallenge plasma glucose to mortality: data from the Baltimore Longitudinal Study of Aging with a critical review of the literature. further PPG lowering to 5. The Action to Control Cardiovascular Risk in Diabetes Study Group. Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study. Level 3 (22. Level 2 (2) for type 1. Effects of intensive glucose lowering in type 2 diabetes. Lancet 2010. Level 1 (15)]. glycated hemoglobin. Imran et al.358:2545e59. The ADVANCE Collaborative Group. Levitan EB. 16.5% in most cases) may be appropriate in patients with type 1 or type 2 diabetes with any of the following [Grade D. Diabetes 1995. a history of severe hypoglycemia. Service FJ. Stratton IM. Muller DC. et al.375:2215e22.5% may be targeted in some patients with type 2 diabetes to further lower the risk of nephropathy [Grade A. et al. N Engl J Med 2008. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. Postprandial blood glucose predicts cardiovascular events and all-cause mortality in type 2 diabetes in a 14-year follow-up: lessons from the San Luigi Gonzaga Diabetes Study.26:688e96. BG. fasting blood glucose concentration.783 individuals followed for 12. Coutinho M.0% despite effective doses of multiple antihyperglycemic agents.2)] and. Julius U. Less stringent A1C targets (7. Diabetes Care 1999.34:2237e43. Lancet 2010. et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. An A1C 6. Araki E. macrovascular complications [Grade B. Effect of intensive blood glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).321:405e12. The relation of glycaemia to the risk of development and progression of retinopathy in the Diabetic Control and Complications Trial. Diabetologia 2001.0 mmol/L should be achieved [Grade D.  If an A1C target 7. Pagliarino A. Grade B. if implemented early in the course of disease. Adler AI. References 1. Gerstein HC.358:2560e72.44:1215e20. Level 1 (24). The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. Consensus. 8. Ismail-Beigi F.23)]. but this must be balanced against the risk of hypoglycemia [Grade A. Abbreviations: A1C.28:2626e32. RECOMMENDATIONS 1. Valle M. 3.11) for type 2 diabetes]. et al.A. 2. 7. 4. PPG. Fischer S. duration of diabetes. risk of severe hypoglycemia. Song Y. Is nondiabetic hyperglycemia a risk factor for cardiovascular disease? Arch Intern Med 2004. Banerji MA. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. The Diabetes Control and Complications Trial Research Group.4 years. Ford ES. et al. and risk of vascular disease: a collaborative metaanalysis of 102 prospective studies. blood glucose. N Eng J Med 2008. people with diabetes should aim for:  FPG or preprandial PG target of 4. 3. 14. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial.S. Kishikawa H. Level 1 (15)] and retinopathy [Grade A.376:419e30.1%e8. 5. postprandial plasma glucose. Diabetes Care 2011. 13. Wang Y. DECODE Study Group.22:233e40. Therapy in most individuals with type 1 or type 2 diabetes should be targeted to achieve an A1C 7. Sorkin JD. In order to achieve an A1C 7. 6. presence or absence of cardiovascular disease.0e10. Diabetes Care 2005. higher level of functional dependency.0e8. Diabetologia 1996. 12. Level 1A (1. plasma glucose. Consensus]: a) Limited life expectancy b) High level of functional dependency c) Extensive coronary artery disease at high risk of ischemic events d) Multiple comorbidities e) History of recurrent severe hypoglycemia f) Hypoglycemia unawareness g) Longstanding diabetes for whom it is difficult to achieve an A1C 7.164:2147e55.44: 968e83. Ohkubo Y. The Diabetes Control and Complications Trial Research Group. 4.5% may be more appropriate in type 1 and type 2 patients with limited life expectancy. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). and a failure to attain established glucose targets despite treatment intensification (Figure 1). Diabetes Res Clin Pract 1995.33) for type 2 diabetes]. The Emerging Risk Factor Collaboration.0% in order to reduce the risk of microvascular [Grade A. Hanefeld M. Recommended targets for glycemic control. Diabetes mellitus.329:977e86. A metaregression analysis of published data from 20 studies of 95. 15. Lancet 1998.0 mmol/L [Grade B.0e7. Level 4 (32. UK Prospective Diabetes Study (UKPDS) Group.0 mmol/L and a 2-hour PPG target of 5. including intensified basal-bolus insulin therapy 5.39:1577e83. . Glycemic targets should be individualized based on age. Is current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular causes? Diabetes Care 2003. BMJ 2000.28:103e17.352: 837e53. PG. Consensus]. 9. 2. advanced comorbidities. Level 2 (1. 17. An A1C target 8.0 mmol/L. The relationship between glucose and incident cardiovascular events.352:854e65. United Kingdom Prospective Diabetes Study (UKPDS). et al. N Engl J Med 1993. 11-year follow-up.0%. 10. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomized trial. for type 1 diabetes. not result in a significant increase in hypoglycemia. 11. Neil HAW. 363:233e44.360:129e39. et al. Paul SK. Martin CL. Wilson PWF. Giugliano D. severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study.29:340e4. / Can J Diabetes 37 (2013) S31eS34 28. Cleary PA. 34. 26. Cochrane Database Syst Rev 2011. Chalmers J. . 19.A. Circulation 2004. Ambrosius WT.58: 2642e8. Brillo DJ.363:1410e8. et al. et al.32:381e6. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Investigators. 30. Epidemiologic relationships between A1C and all-cause mortality during a median 3.S34 S. Abraira C. Diabetes Care 2010. N Eng J Med 2005. et al. Abraira C. cardiovascular death. Strojek K. Zschau S. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Campanian Postprandial Hyperglycemia Study Group.340:4909. Bejan-Angoulvant T. 110:214e9. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 Diabetes: the HEART2D trial. Targeting intensive glycaemic control versus targeting conventional glycaemic control for type 2 diabetes mellitus. Holman RR. 24. Zoungas S. Simons-Morton DG. The ACCORD Study Group and ACCORD Eye Study Group. et al. et al. Regression of carotid atherosclerosis by control of postprandial hyperglycemia in type 2 diabetes mellitus. Moritz TE. N Engl J Med 2008.33:983e90. Calles-Escandón J. Colette C.33:721e7. 29. BMJ 2011. N Engl J Med 2010. 27. et al. Lovato LC. BMJ 2010. Effect of intensive compared with standard glycemia treatment strategies on mortality by baseline subgroup characteristics: the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Bonds DE. Moritz T.359:1577e89. Lund SS. Reaven PD. Bergenstal RM. The association between symptomatic. VADT Investigators. Schwenke DC. et al. Woerle HHJ. Monnier L. Neuropathy among the Diabetes Control and Complications Trial cohort 8 Years after trial completion. Monnier L. and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. Imran et al. et al. Effects of medical therapies on retinopathy progression in type 2 diabetes. Nathan DM.343:d4169. The loss of postprandial glycemic control precedes stepwise deterioration of fasting with worsening diabetes.30:263e9. Diabetes Care 2007. Patel A. 35. Duckworth W.26:881e5. Diabetes Res Clin Pract 2007. 31. Backlund JY. et al. Glucose control and vascular complications in veterans with type 2 diabetes. 36. 22. 32. 25. Riddle MC. Colette C. Miller ME. Diabetes Care 2010. Bethel MA. et al. Diabetes Care 2009. Effect of intensive glucose lowering treatment on all cause mortality.287:2563e9. Dunseath GJ. N Engl J Med 2009. 10-Year follow-up of intensive glucose control in type 2 diabetes. 20. Albers J. 77:280e5. 18. Duckworth W. Nappo F. Moritz T. Impact of fasting and postprandial glycemia on overall glycemic control in type 2 diabetes. N Engl J Med 2009. Saadatian-Elahi M. Diabetes Care 2003. et al. Importance of postprandial glycemia to achieve target HbA1c levels. Esposito K. Effects of intensive therapy on the microvascular complications of type 1 diabetes mellitus. Severe hypoglycemia and risks of vascular events and death. Lapinski H. Diabetes Care 2006. Raz I. et al. Neumann C.353: 2643e53. Veterans Affairs Diabetes Trial: corrections.361:1024e5.4-year follow-up of glycemic treatment in the ACCORD trial. N Eng J Med 2010. Herman WH. Hemmingsen B. Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA1c.6:CD008143. The Writing Team for the Diabetes Control and Complications Trial / Epidemiology of Diabetes Interventions and Complications Research Group. 21. Diabetes 2009. JAMA 2002. 33. Intensive glucose-lowering therapy reduces cardiovascular disease events in veterans affairs diabetes trial participants with lower calcified coronary atherosclerosis. Gluud C. et al. 23. et al. Boussageon R. S12). At this time. a consensus statement from the American Diabetes Association. Vincent Woo MD.org/10. and increase patient empowerment and adherence to treatment. the treatment prescribed.017 .jcjd. throughout this document. with both Canada and the United States still using the NGSP units (%) (8). the A1C will still be written in NGSP units (%).2013. (2) how to record the results in an organized fashion. SMBG is the only way to confirm. European Association for the Study of Diabetes and the International Diabetes Federation called for A1C reporting worldwide to change to dual reporting of A1C with the International Federation 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. and (4) how behaviour and actions affect SMBG results. propensity to hypoglycemia.3).93(NGSP) e 23. Ian Blumer MD. David Miller MD. the following equation can be used: IFCC ¼ 10. In 2007. adequacy of glycemic control. In situations where A1C does not accurately reflect glycemia (Table 1). Glycated Hemoglobin Testing Glycated hemoglobin (A1C) is a reliable estimate of mean plasma glucose (PG) levels over the previous 3 to 4 months for most individuals (1).  SMBG should not be viewed as an intervention but rather as an aid to assess interventions and hypoglycemia. literacy and numeracy skills. CDE. SMBG is most effective when combined with an educational program that incorporates behavioural changes (lifestyle modification and/or oral hypoglycemic agents) in response to BG values (13e17). patients should receive instruction on (1) how and when to perform SMBG. A1C may not accurately reflect glycemic status (Table 1). the A1C continues to be reported using the National Glycohemoglobin Standardization Program (NGSP) units (%). Most people with diabetes will benefit from SMBG for a variety of individual reasons (10. awareness of hypoglycemia. FRCPC. where the rate of red blood cell turnover is significantly shortened or extended. such as insulin dosing for people with type 1 or type 2 diabetes. this has not been adopted worldwide. FRCPC KEY MESSAGES  Glycated hemoglobin (A1C) is a valuable indicator of treatment effectiveness and should be measured every 3 months when glycemic targets are not being met and when diabetes therapy is being adjusted. FRCPC. A1C is now also being used for diagnosis of diabetes (see Screening for Type 1 and Type 2 Diabetes chapter.  Timing and frequency of SMBG should be determined individually based on the type of diabetes. Although there are some advantages to reporting in SI units. hypoglycemia. A1C is the preferred standard for assessing glycated hemoglobin. or the structure of hemoglobin is altered. of Clinical Chemistry and Laboratory Medicine (IFCC) SI units (mmol/mol) and derived NGSP units (%) with the hope of fully converting to exclusive reporting in SI units (7).01. and laboratories are encouraged to use assay methods for this test that are standardized to the Diabetes Control and Complications Trial (DCCT) reference (4e6). It can provide information to both the patient and healthcare professionals to facilitate longer-term treatment modifications and titrations as well as shorter-term treatment decisions. the most notable disadvantage is the massive education effort that would be required to ensure recognition and adoption of the new units.11). Frequency of SMBG The recommended frequency of SMBG must be individualized to each person’s unique circumstances. A1C is a valuable indicator of treatment effectiveness and should be measured every 3 months when glycemic targets are not being met and when diabetes therapy is being adjusted. provide the best information to assess glycemic control. occupational requirements and acute illness. (3) the meaning of various BG levels. The mean level of blood glucose (BG) in the 30 days immediately preceding the blood sampling (days 0 to 30) contributes 50% of the result and the prior 90 to 120 days contributes 10% (2. As part of this education. p. Factors influencing this recommendation will include type of diabetes. SMBG is essential (12).50 (9) (see Appendix 11 for conversion of A1C from NGSP units to IFCC SI units). type of therapy.Can J Diabetes 37 (2013) S35eS39 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. Self-Monitoring of Blood Glucose Self-monitoring of blood glucose (SMBG) can serve as a useful adjunct to other measures of glycemia.canadianjournalofdiabetes. the need for information about blood glucose (BG) levels and the individual’s capacity to use the information from testing to modify behaviours or adjust medications. FRCPC. However. For those who wish to convert NGSP units to SI units. Berard RN.com Clinical Practice Guidelines Monitoring Glycemic Control Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Lori D. It can provide feedback on the results of lifestyle and pharmacological treatments. Therefore. Testing at 6-month intervals may be considered in situations where glycemic targets are consistently achieved (4). Canada is not performing dual reporting.  SMBG and continuous glucose monitoring (CGM) should be linked with a structured educational and therapeutic program designed to facilitate behaviour change for improving BG levels.doi. Robyn Houlden MD. self-monitoring of blood glucose (SMBG) results and A1C. and appropriately treat. including A1C. In Canada.1016/j.  Awareness of both measures of glycemia. In uncommon circumstances. 02) were observed in the SMBG group compared with the usual care group. The evidence is less certain in people with type 2 diabetes treated with insulin.44. glycated hemoglobin. In a large. p<0. and who are meeting glycemic targets. In the STeP trial.04).9 kg/m2. p¼0. with or without oral antihyperglycemic agents. SMBG results were used as both an educational tool to adhere to lifestyle changes as well as a therapeutic tool for adjustment of pharmacologic therapy. all using different methodologies and inclusion criteria.38. not on insulin (mean A1C >8. including preprandial and 2-hour postprandial PG (18. significantly greater reductions in mean A1C (-0. However. more structured testing group subjects received a treatment change recommendation compared with active control group subjects. newly diagnosed patients with type 2 diabetes were randomized to either an SMBG-based intervention or an A1C-based intervention (45). iron or B12 Reticulocytosis Chronic liver disease Variable Change in A1C Iron deficiency B12 deficiency Decreased erythropoiesis Altered hemoglobin Fetal hemoglobin Hemoglobinopathies Methemoglobin Genetic determinants Alcoholism Chronic renal failure Decreased erythrocyte pH Increased erythrocyte lifespan: Splenectomy Ingestion of aspirin. The evidence is less clear about how often.0 kg. although the above principles likely apply (7). These analyses demonstrated greater A1C reductions in those performing SMBG when the baseline A1C was >8% (17. The magnitude of the benefit was small. . In a large cohort study.35. were randomized to either an active control group with enhanced usual care or a structured testing group with enhanced usual care and at least quarterly use of structured SMBG (17). there is no evidence that SMBG affects patient satisfaction. Treatment decisions for the A1C cohort were based strictly on A1C test results. Separate from one’s ability to use SMBG in order to lower A1C. On the other hand. Several recent. with or without oral antihyperglycemic agents associated with low risk of hypoglycemia. p¼0. In the ROSES (Role of Self-Monitoring of Blood Glucose and Intensive Education in Patients with Type 2 Diabetes Not Receiving Insulin) trial.1%. subjects were randomly allocated to either a self-monitoring-based disease management strategy with education on how to modify lifestyle according to SMBG readings or to usual care (44). for patients with type 2 diabetes who are managed with lifestyle.S36 Table 1 Factors that can affect A1C (74) Factor Erythropoiesis Increased A1C L. In the A1C group.9%). is less clear (10. After 1 year of follow-up. performance of 3 self-tests per day was associated with a statistically and clinically significant 1.5%.19) and occasional nocturnal BG measurements.45). In the St.01). vitamin C or vitamin E Hemoglobinopathies Increased erythrocyte pH Decreased erythrocyte lifespan: Chronic renal failure Hemoglobinopathies Splenomegaly Rheumatoid arthritis Antiretrovirals Ribavirin Dapsone Hypertriglyceridemia Hemoglobinopathies Altered glycation Erythrocyte destruction Assays Hyperbilirubinemia Carbamylated hemoglobin Alcoholism Large doses of aspirin Chronic opiate use A1C. the median A1C level and body mass index (BMI) were significantly reduced in patients in the SMBG intervention group (from 6.04) and body weight (-4. a series of recent meta-analyses. More frequent testing.D.3%. very infrequent checking may be needed.6% to 6.5%. general well-being or general health-related quality of life (43). with (absolute) A1C reductions in these meta-analyses ranging from 0. and from 29. the effectiveness of SMBG in terms of improving glycemic control. including unrecognized nocturnal hypoglycemia (20e24). Type 2 diabetes not treated with insulin For people with type 2 diabetes treated with lifestyle management. Type 1 and type 2 treated with insulin For people with type 1 diabetes. there was no change in median A1C or BMI. there was a significantly greater reduction in mean A1C in the structured testing group compared with the active control group (-0. SMBG is an essential daily activity. At 1 year.42). p¼0. recognition and treatment of hypoglycemia in persons whose regimens include an insulin secretagogue due to the higher risk of hypoglycemia with this class of agents (46). Carlos trial. After 6 months. SMBG should be considered for the prevention. have generally shown a small benefit to reducing A1C in those individuals performing SMBG compared to those who did not (35e41). p<0. as well as the optimal frequency.2% to 0. Berard et al. 483 poorly controlled subjects. Results of SMBG were discussed during monthly telephone contact.0%. once recommended. and these trials did not include a component of educational and therapeutic intervention in response to BG values. testing at least 3 times a day was associated with improved glycemic control (18). It is important to recognize that most trials in non-insulintreated patients with type 2 diabetes are of limited value as baseline A1C levels were typically <8.05. SMBG has been demonstrated to be most effective in persons with type 2 diabetes within the first 6 months after diagnosis (43). nonrandomized study of individuals with stable type 2 diabetes using insulin. / Can J Diabetes 37 (2013) S35eS39 Decreased A1C Use of erythropoietin. Also of significance.0% absolute reduction in A1C (7).6 to 27. In the SMBG intervention group.25e34). Significantly.11. well-designed randomized controlled trials that have included this component have demonstrated reductions in A1C (17. SMBG should be performed by persons with type 2 diabetes not treated with insulin. is often required to provide the information needed to reduce hypoglycemia risk. in the case of real-time CGM. Level 2 (58)] and reduce hypoglycemia [Grade B. Testing at least every 6 months should be performed in adults during periods of treatment and lifestyle stability when glycemic targets have been consistently achieved [Grade D. SMBG should be used as an essential part of diabetes self-management [Grade A. the glucose readings. Consensus]. Assays that measure acetoacetate through urine testing may not identify the onset and resolution of ketosis as quickly as those that quantify beta-OHB levels in blood.  If achieving glycemic targets or receiving medications not associated with hypoglycemia. Level 3 (10). Continuous Glucose Monitoring Systems Continuous glucose monitoring systems (CGMSs) measure glucose concentrations in the interstitial fluid. SMBG recommendations should be individualized depending on type of antihyperglycemic agents. self-monitoring of blood glucose. a display unit (which may be a standalone unit or be integrated into an insulin pump). Level 2 (33. For most individuals with diabetes. fasting plasma glucose.g. blood samples taken from the palm near the base of the thumb (the thenar area) demonstrate a closer correlation to fingertip samples at all times of day and during periods of rapid change in BG levels (52. ketone testing should be considered. and by providing alarm notifications in the event that the glucose level is above or below a preset limit. Individuals with type 1 diabetes should be instructed to perform ketone testing during periods of acute illness accompanied by elevated BG.69)]. Berard et al. Ketone Testing Ketone testing is recommended for all individuals with type 1 diabetes during periods of acute illness accompanied by elevated BG. During periods of rapid change in BG levels (e. when preprandial BG levels remain >14. Verification of accuracy of SMBG performance and results Variability can exist between BG results obtained using SMBG devices and laboratory testing of PG. an attached transmitter and.73)]. For individuals with type 2 diabetes not receiving insulin therapy. In order to ensure accuracy of BG meter readings. Accuracy of results over a wide range of BG levels and during periods of rapid change in BG levels is variable across sites. fingertip testing has been shown to more accurately reflect glycemic status than forearm or thigh testing (50. In people with type 1 diabetes.53). Consensus]. 6. For individuals using insulin more than once a day. At BG levels >4. vomiting or abdominal pain. as DKA also can occur in these individuals. blood glucose.49). but does not display. SMBG should be instituted [Grade B. Level 3 (18. for all individuals with diabetes. which are then downloaded onto a computer for viewing and retrospective analysis by the healthcare provider (typically in conjunction with the user). A “blinded” (sometimes referred to as “professional”) CGMS captures. Consensus]. thigh). a difference of <20% between SMBG and simultaneous venous FPG is considered acceptable (47). A1C should be measured every 3 months to ensure that glycemic goals are being met or maintained. 3. are present (4).  When glycemic control is not being achieved. During DKA. FPG. In comparison. In order to ensure accuracy of SMBG. For example. after exercise and during hypoglycemia). as they have been associated with earlier detection of ketosis and may provide information required to prevent progression to DKA (54e56). 5.38)] and should include periodic pre. Abbreviations: BG. palm of the hand. such as nausea. after meals. Alternate site testing Meters are available that allow SMBG using blood samples from sites other than the fingertip (forearm. Two types of devices are available. This may be especially useful for individuals with type 1 diabetes using continuous subcutaneous insulin infusion. as they have been associated with earlier detection of ketosis and response to treatment [Grade B.” which defines basic SMBG requirements to provide guidance to healthcare professionals regarding appropriate utilization of SMBG (Appendix 4) (available at: (http://www. as interruption of insulin delivery can result in rapid onset of DKA (54). icodextrin-containing peritoneal dialysis solutions may cause falsely high readings in meters utilizing glucose dehydrogenase. results should be compared with a laboratory measurement of FPG at least annually or when indicators of glycemic control (A1C) do not match SMBG readings. In rare situations. infrequent SMBG is appropriate [Grade D. therapeutic interventions may interfere with the accuracy of some SMBG devices.2 mmol/L. or when symptoms of diabetic ketoacidosis (DKA). DKA. . Level 2 (17)].0 mmol/L). level of glycemic control and risk of hypoglycemia [Grade D. Periodic re-education on correct SMBG technique may improve the accuracy of SMBG results (48. Level 2 (65. 7. Care should be taken to select an appropriate meter in such situations. In professional RECOMMENDATIONS 1. when preprandial BG levels remain elevated (>14. Level 2 (55)]. 2. Continuous glucose monitoring (CGM) technology incorporates a subcutaneously inserted sensor. If all of these conditions are present in type 2 diabetes. 4. the equilibrium that is usually present between ketone bodies shifts toward formation of beta-hydroxybutyric acid (beta-OHB).D. testing at least once a day at variable times is recommended [Grade D.18)] and include both pre. Grade C. Meters that quantify beta-OHB from capillary sampling may be preferred for self-monitoring of ketones.ca/documents/for-professionals/SMBG_HCP_ Tool_9. real-time continuous glucose monitoring may be used to improve glycemic control [Grade B. for type 2 diabetes] and should be undertaken at least 3 times per day [Grade C. Level 3 (10. As a result.and postprandial measurements [Grade C.L. In those with type 2 diabetes on once-daily insulin in addition to oral antihyperglycemic agents. Consensus]. testing methods that measure blood beta-OHB levels may provide more clinically useful information than those that measure urine acetoacetate or acetone levels. The “real time” (also called “personal”) CGMS provides information directly to the user by displaying moment-tomoment absolute glucose levels and trending arrows. / Can J Diabetes 37 (2013) S35eS39 S37 The Canadian Diabetes Association has published the “SelfMonitoring of Blood Glucose (SMBG) Recommendation Tool for Healthcare Providers.diabetes. diabetic ketoacidosis. Consensus]. In many situations. Blood ketone testing methods may be preferred over urine ketone testing.pdf).51). since acetoacetate or acetone can increase as beta-OHB decreases with effective treatment (47).and postprandial measurements and training of healthcare providers and patients on methods to modify lifestyle and medications in response to SMBG values [Grade B. Consensus]. meter results should be compared with laboratory measurement of simultaneous venous FPG at least annually and when indicators of glycemic control do not match meter readings [Grade D.19. SMBG. more frequent testing should be undertaken to provide information needed to make behavioural or treatment adjustments required to achieve desired glycemic targets and avoid risk of hypoglycemia [Grade D.0 mmol/L or in the presence of symptoms of DKA [Grade D. for type 1 diabetes. Consensus]. Level 1 (21). the “transmitter” captures and retains the data. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. et al.13:794e9. 30. The IFCC reference measurement system for HbA1c: a 6-year progress report. A criteria-based literature review. 26. 3. Impact of self monitoring of blood glucose in the management of patients with non-insulin treated diabetes: open parallel group randomised trial. Romanova M. Schikman CH. Sheppard P.11:775e84. p. Pre. 18. Consensus statement on the worldwide standardization of the HbA1c measurement. 36. Polonsky WH. Diabetes Care 2006. Diabetologia 2007. Little R.27:1761e73. Jansen JP. dependent on adherence with using the CGMS. S26 Targets for Glycemic Control. Self-monitoring of blood glucose in type 1 diabetes patients with insufficient metabolic control: focused selfmonitoring of blood glucose intervention can lower glycated hemoglobin A1C. Meta-analysis of the benefits of self-monitoring of blood glucose on glycemic control in type 2 diabetes patients: an update. Stettler C.26:3048e53.72). Lau J. Diabetes Outcomes in Veterans Study (DOVES). and the International Diabetes Federation. Chalew SA. Smith SJ. Self-management education for adults with type 2 diabetes: a meta-analysis of the effect on glycemic control. 25. Diabet Med 2000. 34. Bloemendal E. European Association for the Study of Diabetes.3:500e8. Diabetes Care 2002. Diabetes Care 1997. Diabetes Care 2001. Lorenz R. to confirm interstitial measurements prior to making therapeutic changes or treating suspected hypoglycemia. The impact of blood glucose self-monitoring on metabolic control and quality of life in type 2 diabetic patients: an urgent need for better educational strategies. European Association for the Study of Diabetes. CGM. et al. Murata GH.35:2674e80. Gale EAM. International Federation of Clinical Chemistry and Laboratory Medicine. J Diabetes Sci Technol 2009. Malekiani CL. Pellegrini F. Nijpels G. CGM is not a replacement for SMBG because SMBG is still required for calibration of the CGM device and.32(suppl 2):S205e10. Goyder E. Diabetes Care 2003. Davis WA. Measure of glycosylated hemoglobin. Price CP. Raptis SA. Lancet 1979. Frequency of blood glucose monitoring in relation to glycemic control in patients with type 2 diabetes. De Berardis G. QuED Study Group. Nijpels G. et al.118:422e5. Tattersall RB.62.cadth. Diem P. Coster S. Porter P. Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin. Hoffman RM.25:2903e14. 27. 76(suppl 3):59e62. Sacks DB. 7. Sherwin RS. Cochrane Database Syst Rev 2005. p.90:450e9. National Health and Nutrition Examination Survey (NHANES III). Cochrane Database Syst Rev 2012. Self-monitoring in type 2 diabetes mellitus: a meta-analysis. In Canada. Rattanasookchit S. van Eijk JT. 22. Diabetes Care 2006. 11.ca/media/pdf/BGTS_SR_Report_ of_Clinical_Outcomes. Effect of hemoglobinopathies on hemoglobin A1c measurements. Calisti L. 41. 2009. Kristensen GBB. Does self-monitoring of blood glucose improve outcome in type 2 diabetes? The Fremantle Diabetes Study. Suksomboon N.67.54:240e8. et al. Mosca A. Carlsen S. et al. Available at http://www. Derry S.S38 L. 28. Unrecognised nocturnal hypoglycaemia in insulintreated diabetics. Clin Chem 2008.29:352e5. Real-time CGM has been consistently shown to reduce A1C in both adults (57e66) and children (58. Houriet C. Parker MM. McGeoch G. 24. Sacks D. Wade A.2:CD005060. et al. Bruns DE. et al. Karter AJ. randomized trial.pdf. 5. 29.63. Moffet HH. typically the better the A1C (59. Self-monitoring of blood glucose in patients with type 2 diabetes who are not using insulin: a systematic review. one real-time CGMS and two professional CGMSs are available. Bending JJ. 43.329:977e86. 38. Am J Med 2008. 50:510e5. 37. Jones TW.24:129e41. 13. Am J Med 2005. 4. Fisher L.29:1764e70. 2012.D. 16. Self-monitoring of blood glucose levels and glycemic control: the Northern California Kaiser Permanente Diabetes Registry. Poolsup N. N Engl J Med 1993. Am J Med 1991. S31 Hypoglycemia. Diabetes Care 2001. Riphagen II. et al. Moore RA. Diabetologia 2007. Farmer A. Other Relevant Guidelines Self-Management Education. 8. 2. 21. Standards of medical care in diabetese2007.25:1159e71. noninsulintreated type 2 diabetes: results from the Structured Testing Program study.30:2399e400.1:1049e52. p. Gulliford MC. Welschen LMC. 23. Diab Technol Ther 2009. S153 Type 2 Diabetes in Children and Adolescents. S168 Relevant Appendix Appendix 4. The DCCT Research Group. 17. Norris SL. Measurement of hemoglobin A1c: a new twist on the path to harmony.30(suppl 1):S4e41.121:e6.50:2042e3. p. Welschen LM. Davidson JA. Self-Monitoring of Blood Glucose (SMBG) Recommendation Tool for Healthcare Providers Appendix 11. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Practical Diabetes Int 2005. Ackerson LM. Diabetes Care 2006. International Federation of Clinical Chemistry and Laboratory Medicine. Castellanos M. Bruce DG. Earles J. Davis WA. et al. The effect of self monitoring of blood glucose concentrations on glycated hemoglobin levels in diabetic patients not taking insulin: a blinded. 32. Smith S. Intensified blood glucose monitoring improves glycemic control in stable.24:979e82.338:1657e62. Boutati EI. Schellevis FG. Darbinian JA. Weykamp C. . Harris MI. Value of self-monitoring blood glucose pattern analysis in improving diabetes outcomes. Davis WA. Berard et al. 39. Towfigh A. et al. Tests of Glycemia in Diabetes. Accessed April 25. John WG. McCarter RJ.29:1757e63. Ganesan A.26:1759e63. Self-Monitoring of blood glucose as part of the integral care of type 2 diabetes. S163 Diabetes and Pregnancy. 31. Like SMBG. Am J Manag Care 2008. Acta Biomed 2005. 9. Malanda UL. Real-time CGM also has been shown to reduce the time spent in hypoglycemia (65. Franciosi M. Decreased epinephrine responses to hypoglycemia during sleep.60. Integrating medical management with diabetes self-management training: a randomized control trial of the Diabetes Outpatient Intensive Treatment program. van Doorn LG. Diabetes Care 2004. Hempe JM. 12. Davis TM. 6. A1C Conversion References 1.63. J Diabetes Sci Technol 2009.65e67) with type 1 diabetes. Karter AJ. Davis TM. CGM provides the best outcomes if it is associated with structured educational and therapeutic programs. Polonsky WH.17:755e61. unsurprisingly. Allemann S. Is self-monitoring of blood glucose appropriate for all type 2 diabetic patients? The Fremantle Diabetes Study. Kain D.111:1e9. et al. 20. Diabetes Care 2003. The Diabetes Control and Complications Trial Research Group. Parkin CG. Am J Med 2001. A study in insulin treated diabetic patients. Goldstein D. Decker CF. et al. BMJ 2007. Shah JH. Welschen LM. Tognetti S. p. et al. Structured self-monitoring of blood glucose significantly reduces A1C levels in poorly controlled.28:1510e7. Faas A. and to reduce A1C in adults with type 2 diabetes (68).335:132. et al. Diabetes Care 2012. and the International Diabetes Federation.22: 671e81. St John A. Successful use of CGM is. Huber JW.14:468e75. et al. Self-monitoring of blood glucose in non-insulin treated patients with type 2 diabetes: a systematic review and meta-analysis. Curr Med Res Opin 2009. Consensus Committee. The value of self-monitoring of blood glucose: a review of recent evidence. the greater the time wearing the device. S69 Type 1 Diabetes in Children and Adolescents. Bruce DG. Curr Med Res Opin 2006. Clin Chem 2002. Systematic review of use of blood glucose test strips for the management of diabetes mellitus. insulin-treated veterans with type 2 diabetes: the Diabetes Outcomes in Veterans Study (DOVES). Self-monitoring of blood glucose levels in patients with type 2 diabetes mellitus not taking insulin: a metaanalysis. Weinreb JE. / Can J Diabetes 37 (2013) S35eS39 15. The efficacy of self-monitoring of blood glucose in NIDDM subjects. Davis TME.3:83e8. Goldschmidt HM. et al.23:423e40.48:436e72. Professional CGM has been shown to reduce A1C in adults with type 2 diabetes (70) and in pregnant women with type 1 or type 2 diabetes (71).and post-prandial capillary glucose self-monitoring achieves better glycaemic control than pre-prandial only monitoring. Seed PT. Self-monitoring of blood glucose in patients with type 2 diabetes mellitus who are not using insulin.60. Vervoort G.1:CD005060.64. Diabetes Care 2009. 19. Goldstein DE. 10. Diabetes Care 2007. Sandberg S. for real-time CGM. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. Diabet Med 1996. Mean blood glucose and biological variation have greater influence on HbA1c levels than glucose instability: an analysis of data from the Diabetes Control and Complications Trial.24:1870e7. Bloemendal E. J Diabetes Complications 2010. American Diabetes Association.34:262e7. 33. 14. 35. Skeie S. Consensus statement on the worldwide standardization of the hemoglobin A1C measurement: the American Diabetes Association.22:15e22. Davidson MB. Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (> or ¼4) daily insulin injection regimens.69). Self-monitoring of glucose in type 2 diabetes mellitus: a Bayesian meta-analysis of direct and indirect comparisons. Diabetes Care 2007. p.20:1482e6. Canadian Optimal Medication Prescribing and Utilization Service. American Diabetes Association. N Engl J Med 1998. et al. Self-monitoring of blood glucose in type-2 diabetes: what is the evidence? Diabetes Metab Res Rev 2007. et al. Longitudinal study of new and prevalent use of self-monitoring of blood glucose. Diabetes Care 2011. 40. Diabetes Care 2005. 42. 35:247e9.48:436e72. Cosson E. Garg S. 66. Diabetes Care 2002.26:981e5.32:2245e50. 62.32:1378e83. Lancet 1998. glucose profiles. Sulmont V. Use of glycated hemoglobin (A1C) in the diagnosis of type 2 diabetes mellitus in adults. Glucose monitoring at the thenar: evaluation of upper dermal blood glucose kinetics during rapid systemic blood glucose changes. Clement M. Franciosi M. Yoo HJ.26:981e9. Koschinsky T. Donath S. et al. 59. 74.26:1137e41. UK Prospective Diabetes Study (UKPDS) Group. 65.26:582e9. Diabetes Educ 2000. Little RR. Effectiveness of sensoraugmented insulin-pump therapy in type 1 diabetes. Diabetes Metab 2009. Ahmann A. Effectiveness of continuous glucose monitoring in pregnant women with diabetes: randomised clinical trial. Incremental value of continuous glucose monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes. Diabetes Technol Ther 2008. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group. Bolinder J. Jungheim K.52:1250e7.34:325e9. Diabetes Care 2003. 50. 25:275e8. Diabetes Care 2011. 64. Guerci B. 56. Chase HP.29:2730e2. et al. Duran A. J Diabetes 2010. 51. N Engl J Med 2008. Diabetes Technol Ther 2010. Beatson C. Khan AS. A pilot randomized clinical trial. Effectiveness of self-management training in type 2 diabetes: a systematic review of randomized controlled trials.24:561e87. Stegmann JM. Floriot M. Battelino T. Evaluation of a bedside blood ketone sensor: the effects of acidosis. Cembrowski GS. Use of continuous glucose monitoring in subjects with type 1 diabetes on multiple daily injections versus continuous subcutaneous insulin infusion therapy. Park SY. Diabetologia 2009. et al. Ellison JM. 67. Hirsch IB. Engelgau MM. Point of care blood ketone testing of diabetic patients in the emergency department. Defining the relationship between plasma glucose and HbA(1c): analysis of glucose profiles and HbA(1c) in the Diabetes Control and Complications Trial. O’Neal DN. N Engl J Med 2010. 61.25:956e60. 54. Runkle I. Diabetes Care 2009.337:a1680.21:782e5. Horm Metab Res 2002. Juvenile Diabetes Research Foundation. Goldstein DE. O’Connell MA. Diabetes Care 2003. Phillip M. a prospective randomized clinic-based interventional study with parallel groups. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Goldenberg RM. 71. et al. Cheng AYY. Guerci B. Diabet Med 2004. Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial. Continuous Glucose Monitoring Study Group. Continuous Glucose Monitoring Study Group. 63. et al. 52. Koschinsky T. Lewis K. Narayan KM. Glucose monitoring at the arm: risky delays of hypoglycemia and hyperglycemia detection. Deiss D. 45. Diabetes Care 2006. . Endocr Res 2004. et al. et al. Diabetes Care 2002.30:395e402. Bratina N. Diabetes Care 2003. 72. Dufaitre-Patouraux L. Bode BW. Sacks DB. Clinical performance of CGMS in type 1 diabetic patients treated by continuous subcutaneous insulin infusion using insulin analogs.34:795e800. 73. Reznik Y. Bektas F. Sustained benefit of continuous glucose monitoring on A1C.2:203e11. Murphy HR. 32:2047e9. Identifying variables associated with inaccurate self-monitoring of blood glucose: proposed guidelines to improve accuracy. BMJ 2008. Johnson ML. S39 60. randomised. et al. Tieszen KL. Punthakee Z. 47. 68. Juvenile Diabetes Research Foundation. forearm.363: 311e20. Voelmle M. Pellegrini F. Tamborlane WV. et al.12:507e15. et al. Benichou M. Multicentre. Sari R. Lucisano G. Can J Diab 2011. Guidelines and recommendations for laboratory analysis in the diagnosis and management of diabetes mellitus. Diabetes Care 2001. / Can J Diabetes 37 (2013) S35eS39 44.10:377e83. Talbot JA. Bergenstal RM. hyperglycaemia and acetoacetate on sensor performance. et al. 58. Norris SL. Berard et al. 69. Clinical impact of prandial state.L. exercise.34: 574e9. Rayman G. Improved glycemic values control in poorly controlled patients with type 1 diabetes using real-time continuous glucose monitoring. and thigh sampling sites. Abelseth J. Eray O. et al. and site preparation on the equivalence of alternative-site blood glucose testing. Böhme P. Bergenstal R. Accuracy of an electrochemical sensor for measuring capillary blood ketones by finger stick samples during metabolic deterioration after continuous subcutaneous insulin infusion interruption in type 1 diabetic patients. Xing D. 55. Diabetes Care 2009. Floriot M.35:312e8. controlled study of the impact of continuous subcutaneous glucose monitoring (GlucoDay) on glycaemic control in type 1 and type 2 diabetes patients. Beck RW. Wiedmeyer HM. 46. Continuous glucose monitoring in youth with type 1 diabetes: 12-month follow-up of the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial. Use of a real-time continuous glucose monitoring system as a motivational device for poorly controlled type 2 diabetes. Anderson RL. The effect of continuous glucose monitoring in well-controlled type 1 diabetes.28:789e96.352: 837e53. Diabetes Care 2002. et al.33:17e22. 57. Sensor-augmented insulin pump therapy: results of the first randomized treat-to-target study. Diabetes Care 2010.82:73e9. and hypoglycemia in adults with type 1 diabetes. Diabet Med 2011. Benefits of self-monitoring blood glucose in the management of new-onset Type 2 diabetes mellitus: the St Carlos Study. ROSES: role of self-monitoring of blood glucose and Intensive education in patients with type 2 diabetes not receiving insulin. 70. et al. 48. 53. Effectiveness of continuous glucose monitoring in a clinical care environment. Diabetes Res Clin Pract 2008. Riveline JP. et al. An HG. 49. Pearson J. Hamo-Tchatchouang E. Rapid changes in postprandial blood glucose produce concentration differences at finger. et al. Rohlfing CL. Bruns DE. Bina DM.D. et al. Diabetes Care 2009. Clin Chem 2002. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). et al. et al. Jungheim K. Diabetes Care 2011. et al.25:961e4. et al. Continuous glucose monitoring and intensive treatment of type 1 diabetes.359:1464e76. Martin P. Raccah D. Colner SL. jcjd. MPH. a cohort study in people with type 1 diabetes found that 7-year mortality was 50% lower in those reporting more than 2000 kcal of weekly exercise (equivalent to about 7 hours per week of brisk walking) compared to those reporting <1000 kcal of physical activity per week (9). pushups) to increase muscle strength and/or endurance. we found no study demonstrating any impact of a pure flexibility program on metabolic control. For example. Flexibility exercise is a form of activity.org/10. Benefits of Resistance Exercise A systematic review of randomized trials found that resistance training improves glycemic control (as reflected by reduced glycated hemoglobin [A1C]). decreases insulin resistance and increases muscular strength in adults with type 2 diabetes (13). FRCPC.canadianjournalofdiabetes. Benefits of Physical Activity Physical activity can help people with diabetes achieve a variety of goals. Additional benefits of aerobic exercise include increased cardiorespiratory fitness in both type 1 and type 2 diabetes (10) and slowing of the development of peripheral neuropathy (11). Additionally. before beginning a program of physical activity more vigorous than walking. RD. in people with type 2 diabetes. resistance bands or one’s own body weight (e. including increased cardiorespiratory fitness.16). and cannot necessarily be generalized to other types of resistance exercise. Sonja M.01. Some types of exercise. Resistance exercise in these studies was carried out using weight machines and/or free weights. Similarly. At least 150 minutes per week of aerobic exercise.  Both aerobic and resistance exercise are beneficial for patients with diabetes. Marni J. Michael C. weight machines. Resistance exercise is physical activity involving brief repetitive exercises with weights. that involves continuous. blood pressure reduction and maintenance of weight loss (1e4).  For people with type 2 diabetes. and it is optimal to do both types of exercise.doi.Can J Diabetes 37 (2013) S40eS44 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. However. The terms “physical activity” and “exercise” are used interchangeably in this chapter. Large cohort studies have demonstrated that. Benefits of Other Types of Exercise Types of Exercise Aerobic exercise is physical activity. Plotnikoff PhD. In contrast to trials in type 2 diabetes. MSc. such as yoga. resistance training has been shown to increase lean muscle mass (14) and bone mineral density (15. Armstrong CEP. can incorporate elements of both resistance and flexibility exercise. decreased insulin resistance. Benefits of Aerobic Exercise Moderate to high levels of aerobic physical activity and higher levels of cardiorespiratory fitness are associated with substantial reductions in morbidity and mortality in both men and women and in both type 1 and type 2 diabetes. injury risk or any diabetes-related outcome. is recommended.  For most people. increased vigour. most clinical trials evaluating exercise interventions in people with type 1 diabetes have not demonstrated a beneficial effect of exercise on glycemic control (12). and producing modest but sustained weight loss. Glen P. CCFP. Sigal MD. improved lipid profile. reducing the need for antihyperglycemic agents and insulin. that enhances the ability of joints to move through their full range of motion. Kenny PhD. leading to enhanced functional status and prevention of sarcopenia and osteoporosis. people with diabetes should be assessed for conditions that might place the individual at increased risk for an adverse event associated with certain types of exercise. Riddell PhD KEY MESSAGES  Moderate to high levels of physical activity and cardiorespiratory fitness are associated with substantially lower morbidity and mortality in men and women with and without diabetes. regular physical activity (5e7) and/or moderate to high cardiorespiratory fitness (8) are associated with reductions in cardiovascular and overall mortality of 39% to 70% over 15 to 20 years of follow-up.1016/j.g.com Clinical Practice Guidelines Physical Activity and Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Ronald J. such as resistance bands or exercises utilizing only one’s own body weight. Pam Colby BSc. plus at least two sessions per week of resistance exercise. evidence for the beneficial effects of other types of exercise is not as extensive or as supportive as the evidence for aerobic and resistance exercise.018 To date. Ronald C. Reichert MD. rhythmic movements of large muscle groups lasting for at least 10 minutes at a time. PhD candidate. being sedentary has far greater adverse health consequences than exercise would. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. . supervised exercise programs have been particularly effective in improving glycemic control. bicycling or jogging.2013. such as walking. such as lower back or hamstring stretching. improved glycemic control. and to wear appropriate footwear.24). The quality of the included studies was low. It is important to note that the Hatha yoga program in this trial incorporated elements of both strength training (where the resistance load was the individual’s body weight) and aerobic exercise (repeated movements. body mass index and blood pressure to the same extent as aerobic exercise. In individuals whose diabetes is controlled by lifestyle or oral hypoglycemic agents that do not increase insulin levels. Unsupervised Exercise A systematic review and meta-analysis found that supervised programs involving aerobic or resistance exercise improved glycemic control in adults with type 2 diabetes. preproliferative or proliferative retinopathy and unstable angina. The risk of hypoglycemia during exercise is of concern for people with diabetes. However. and to a lesser extent in those with type 2 diabetes using insulin or insulin secretagogues (sulfonylureas and meglitinides).21). and 6. the group receiving the supervised aerobic and resistance exercise training had significantly better results: greater reductions in A1C. in cases where ischemia or arrhythmias are induced at higher exercise intensities. blood pressure.5 mmol/L. being sedentary is associated with far greater health risks than exercise would be. Although self-reported total physical activity increased substantially in both groups. A resting electrocardiogram (ECG) should be performed. A systematic review of trials evaluating yoga as an intervention for type 2 diabetes found modest reductions in A1C. exercise test results could be used to keep exercise intensity below the ischemic threshold. results were highly heterogenous and there was evidence of significant publication bias. therefore. and an exercise ECG stress test should be considered.7 mmol/L. the evidence for exercise ECG stress testing of asymptomatic individuals with type 2 diabetes before beginning an exercise program is neither strong nor clear-cut. given that lower aerobic capacity (27) and the presence of ischemic changes on ECG (28) are each associated with higher risks of cardiovascular and overall morbidity and mortality.g. A1C decreased nonsignificantly in the vibration group while it increased nonsignificantly in the strength and flexibility training groups. for individuals with possible cardiovascular disease who wish to undertake exercise more intense than brisk walking. Although previous guidelines stated that persons with severe peripheral neuropathy should avoid weight-bearing activity. (The actual amount will be dependent on injected insulin dose. Furthermore. done in a flowing manner. fasting glucose and total cholesterol. Sigal et al. prolonged endurance exercise. Another trial. further studies would be needed before we can be confident regarding the degree of effectiveness of vibration therapy. Exercise testing can also sometimes detect previously unsuspected coronary disease. as opposed to estimating target heart rate or work rate from age-predicted calculations. resulting in increased heart rate). Supervised vs. In these individuals. especially if they are considering intense. respectively.J. In addition. For most people with and without diabetes. In patients with type 1 diabetes. fasting glucose. Subjects in these 2 screening trials were not necessarily planning to begin exercise programs. In one trial. if pre-exercise blood glucose levels are <5. Baseline A1Cs were 7. If ketones are negative and the patient feels well. Preproliferative or proliferative retinopathy should be treated and stabilized prior to commencement of vigorous exercise.8%. who participate in daily weight-bearing activity. and that it involved three 2-hour exercise sessions per week.7 and the patient does not feel well. Exercise testing also can be useful for risk stratification. exercise counselling alone in patients with type 2 diabetes and the metabolic syndrome (23). before beginning a program of vigorous physical activity. The same meta-analysis found that unsupervised exercise only improved glycemic control if there was concomitant dietary intervention. Minimizing Risk of Exercise-Related Adverse Events People with diabetes should be prescribed and encouraged to incorporate regular exercise as a key part of their treatment plan. A 1-year randomized trial compared exercise counselling plus twice-weekly supervised aerobic and resistance exercise vs. If ketone levels are elevated. muscle strength and HDL-C. / Can J Diabetes 37 (2013) S40eS44 S41 A systematic review found that tai chi had no significant effects on glycemic control or quality of life (17). 40 people with type 2 diabetes were randomized to whole-body vibration. whether or not they included dietary co-intervention (22). waist circumference and estimated 10-year cardiac risk. A trial published after this systematic review’s search date found that Hatha yoga reduced A1C. with fewer self-reported symptoms of hypoglycemia (20. no trial has specifically assessed whether exercise stress testing before beginning an exercise program reduces coronary morbidity or mortality. and results of blood glucose monitoring). People with severe peripheral neuropathy should be instructed to inspect their feet daily. and greater increases in aerobic fitness. especially on days they are physically active. In individuals with type 1 diabetes who are severely insulin deficient (e.7% in vibration. Nevertheless. body mass index. it is not necessary to defer exercise due to hyperglycemia. such as marathon running. Examples of such conditions include severe autonomic neuropathy. Hyperglycemia prior to exercise also may be of concern in people with diabetes. the risk of developing hypoglycemia during exercise is minimal.R. people with diabetes should be assessed for conditions that might increase risks associated with certain types of exercise or predispose them to injury (2.3%. particularly those with type 1 diabetes. If capillary glucose levels are elevated >16. a recent randomized trial found that screening of asymptomatic people with diabetes and additional cardiac risk factors using exercise ECG stress testing (or dipyridamole single photon emission computed tomography for those unable to exercise) did not reduce the risk of major cardiovascular events in the subsequent 3. However. 6. due to insulin omission or illness). hyperglycemia can be worsened by exercise. Individuals with type 2 diabetes generally do not need to postpone exercise because of high blood glucose. approximately 15 to 30 g carbohydrate should be ingested before exercise. exercise duration and intensity.5 years compared to a no-screening strategy (29). and most individuals will not need to monitor their blood glucose levels or be required to supplement with carbohydrate for exercise lasting <1 hour. in which 1123 asymptomatic people aged 50 to 75 years with type 2 diabetes were randomized to screening adenosine-stress radionuclide myocardial perfusion imaging or usual care found that screening had no impact on major cardiovascular events over the subsequent 5 years (30). strength training or flexibility training (18). if capillary glucose is >16. This study’s findings cannot necessarily be extrapolated to all Hatha Yoga programs or to other forms of yoga. strength and flexibility groups. blood or urine ketones should be tested. it is important to ensure . provided they feel well. severe peripheral neuropathy. it is suggested that vigorous exercise be postponed and the patient take additional insulin. Maximal exercise testing can be useful for exercise prescription. total cholesterol. are at decreased risk of foot ulceration compared with those who are less active (26). recent studies indicate that individuals with peripheral neuropathy may safely participate in moderate weight-bearing exercise provided they do not have active foot ulcers (25). Studies also suggest that patients with peripheral neuropathy in the feet. as well as modest increases in high-density lipoprotein cholesterol (HDL-C) (19). This study’s sample size was small (n¼13 to 14 per group) so statistical power was limited. Exercise intensity can be prescribed and assessed more accurately when the actual maximum heart rate or maximum oxygen consumption (VO2max) is known from exercise testing. due to osteoarthritis). training (e. / Can J Diabetes 37 (2013) S40eS44 Table 2 Resistance exercise Definition Recommended frequency Examples  Exercise with weight machines  Exercise with free weights proper hydration and monitor for signs and symptoms (e. should be aware that they are at higher risk for heat illness. However. and elderly people with diabetes. along with associated health issues and advanced age. reduce the body’s ability to detect heat and impair its capacity to dissipate heat (32e34). repeated and continuous movements of the same large muscle groups for at least 10 minutes at a time Recommended for a minimum of 150 minutes per week (moderate intensity) Intensity Moderate: 50%e70% of person’s maximum heart rate Examples       Biking Brisk walking Continuous swimming Dancing Raking leaves Water aerobics Activities of brief Three times per week duration involving  Start with 1 set using a weight the use of weights. cardiovascular and neurological dysfunctions associated with diabetes. Metabolic. the maximum weight that can be lifted 8 times while maintaining proper form).e. especially those who are elderly and/or have autonomic neuropathy. particularly for patients with type 1 diabetes. especially for exercise to be performed in the heat.40). Multiple.42) or more (43. Initial instruction and periodic supervision are recommended. semirecumbent cycling may provide an alternative. . nausea.S42 R. For most middleaged individuals. When weather is hot. Canadian physical activity guidelines for children and youth are available from the Canadian Society for Exercise Physiology (www. starting with as little as 5 to 10 minutes per day. These diverging effects of exercise on blood glucose concentrations can make management challenging. especially during extended heat exposure and/or exercise in the heat. Individuals who wish to begin resistance exercise should receive initial instruction and periodic supervision by a qualified exercise specialist to maximize benefits while minimizing risk of injury. Minimizing Risk of Heat-Related Illness People with diabetes may have greater susceptibility to adverse effects from heat than those without diabetes (31). although some strategies are provided below.g.csep. However. blood glucose tends to decline due to increased glucose disposal and insulin sensitivity (38).45). Individuals with diabetes should also be recommended to reduce the amount of time spent doing sedentary activities. shorter exercise sessions (each lasting at least 10 minutes) in the course of a day should be considered as this regimen is as effective as a single longer session of equivalent length and intensity (48). Note: The evidence supporting exercise with resistance bands is not as strong as the evidence for free weights or weight machines. 3 times per week (41. Patients with diabetes. cardiac or pulmonary disease. such as an air-conditioned training centre. it seems logical to expect similar benefits from physical activity in children with type 2 diabetes as has been achieved in adults.33) and skin blood flow (35e37) decrease the body’s ability to maintain core temperature at safe levels. middle-aged. Exercise Prescription Details Both aerobic and resistance exercise are recommended for most people with diabetes (Tables 1 and 2). exercise should be performed in a cool environment. and especially after. severe fatigue. while brisk walking up an incline or jogging would be vigorous aerobic exercise. basketball. In the absence of direct evidence in this population. significant reductions in A1C and body fat have been achieved with twice-weekly resistance exercise in combination with regular aerobic exercise (23. The studies reporting the greatest impact of resistance exercise on A1C had subjects progress to 3 sets (with approximately 8 repetitions per set) of resistance-type exercises at moderate to high intensity (i. For those who struggle with pain upon walking (e. during. Resistance exercise performed 2 or 3 times per week may provide benefits that complement those of aerobic Table 1 Aerobic exercise Definition and recommended frequency Rhythmic. Beginning Exercise in People with Low Baseline Fitness Levels Vigorous: >70% of person’s maximum heart rate  Brisk walking up an incline  Jogging  Aerobics  Hockey  Basketball  Fast swimming  Fast dancing Previously sedentary individuals with limited exercise tolerance may have to gradually build up their amount of exercise. ensuring proper form is maintained. very intense exercise (e. Sigal et al.44). increased resting metabolic rate) (3. intense resistance training). If you cannot complete the required repetitions while maintaining proper form.13. increased strength and vigour. competitive track and field. Whenever possible. Acute Effects of Exercise on Blood Glucose During and after all but the most intense exercise. Reductions in sweating (32. moderately brisk walking on level ground or semirecumbent cycling would be an example of moderate aerobic exercise. therefore.g. with which you can perform weight machines 15 to 20 repetitions while or resistance maintaining proper form. insulin resistance and body composition than studies with greater supervision (13). blurred vision or headache). reduced body fat. bands to increase  Progress to 2 sets and decrease muscle strength the number of repetitions to and endurance 10e15 while increasing the weight slightly. The effects of resistance exercise and aerobic exercise on glycemic control are additive (46).g. exercise outdoors should be performed in the early or later hours of the day when the temperatures are cooler and the sun is not at its peak. brief.ca). Physical Activity in Children with Type 2 Diabetes The pathophysiology of type 2 diabetes in children is similar to that of type 2 diabetes in adults. A recent systematic review found no good-quality studies directly assessing the effects of physical activity in youth with type 2 diabetes (47).  Progress to 3 sets of 8 repetitions performed using an increased weight. it is reasonable to recommend that children with type 2 diabetes strive to achieve the same activity level recommended for children in general: 60 minutes daily of moderate to vigorous physical activity and limit sedentary screen time to no more than 2 hours per day. Walking is often the most popular and most feasible type of aerobic exercise in overweight. A meta-analysis found that trials evaluating resistance exercise with less supervision showed less beneficial impact on glycemic control. reduce the weight.g.J. hockey. increased thirst. blood glucose often increases as a result of increases in glucose production that exceed increases in glucose disposal (39). Abbreviations: CVD. and for many hours after. Med Sci Sports Exerc 2000. cardiovascular disease.74:211e20. Level 2. Sigal RJ. Level 2 (22. Conn VS. 6.137:74e81. Hopkins WG. Grade C. Other Relevant Guidelines Monitoring Glycemic Control. Diabetes Care 2001. Caspersen CJ.32:1541e8. it can be addressed by giving a small bolus of a short-acting insulin analogue or. Level 3. Level 2 (13)] in addition to aerobic exercise [Grade B. and neuropathy screening). or intermittently during an exercise session (57). Arch Intern Med 2003. competing commitments). Some studies have found that structured physical activity counselling by a physician (65). 7. Snowling NJ. Behavioral science research in diabetes: lifestyle changes related to obesity. or reduce overnight basal insulin infusion rates by approximately 20% from bedtime to 3 AM for insulin pump users (60).g. et al.g. Gregg EW. see references 53 and 54. Level 2 (62)]. physical examination (including funduscopic exam. develop strategies to overcome these barriers [Grade B. Parisi L. Level 3 (13)]. Level 2 (61)] and keep records of their physical activity [Grade B. 1. Am J Epidemiol 1993. LaMonte MJ. for type 1 diabetes (9)]. Insulin-dependent diabetes mellitus. 5. Another strategy to avoid hypoglycemia is to perform intermittent. Selfefficacy is a very strong cognitive predictor of both aerobic and resistance exercise participation in people with diabetes (64). Effects of different modes of exercise training on glucose control and risk factors for complications in type 2 diabetic patients: a meta-analysis. for type 2 diabetes (1. Petrella RJ. Arch Intern Med 2005. exercise ECG stress testing [Grade D. These strategies include the consumption of extra carbohydrates for exercise (50).29:2518e27. Structured exercise programs supervised by qualified trainers should be implemented when feasible for people with type 2 diabetes to improve glycemic control. if exogenous insulin and/or carbohydrate ingestion is not adjusted. Patients should be encouraged to set specific physical activity goals. skilled healthcare personnel or case managers (66. Atalay M. The evaluation would include history. These strategies can be used alone or in combination (53. very brief (10 seconds). Exercise training can modify the natural history of diabetic peripheral neuropathy. Ann Intern Med 2001.3. the impact of physical activity counselling on glycemic control. 13. Gordon BA.g.165:2114e210. In type 1 diabetes. one can reduce bedtime intermediate or long-acting injected insulin dose. Moy CS.46)]. Level 2 (23. CVD risk factors and physical fitness [Grade B.23)]. et al. 11. Hu FB. p. S69 Screening for the Presence of Coronary Artery Disease. People with diabetes should set specific physical activity goals. Niskanen LK. Jousilahti P. anticipate likely barriers to physical activity (e. Fernhall B. especially for women (69). anticipate likely barriers to physical activity (e. Consensus]. LaPorte RE. Resistance training improves metabolic health in type 2 diabetes: a systematic review.22).J. Relationship of walking to mortality among US adults with diabetes. Exercise and type 2 diabetes: the American College of Sports Medicine and the American Diabetes Association: joint position statement. If it occurs. case-based discussions of insulin and carbohydrate adjustment for exercise in type 1 diabetes. 8. Benson AC. 3. and produces modest but sustained weight loss (68). reduces the need for oral antihyperglycemic agents and insulin (67). social media and exercise trainers (70e72). limiting preprandial bolus insulin doses (51) and altering basal insulin for insulin pump users (52). 5. Diabetes Care 2011. p. Diabetes Res Clin Pract 2009. p. 28:799e805. Motivating People with Diabetes to Be Physically Active References Physicians and other healthcare professionals can heighten awareness of the importance of physical activity by promoting regular exercise as a key component of therapy and identifying resources in the community (61). 4. et al. and physical activity. S105 . et al. Barlow CE. Laaksonen DE. Wing RR. 4. Exercise performed late in the day or in the evening can be associated with increased risk of overnight hypoglycemia in people with type 1 diabetes (50).24:117e23. and death. maximal-intensity sprints either at the beginning (55) or end (56) of an otherwise moderate-intensity exercise session. electrocardiogram. Hu G. Small studies have explored several types of strategies for the prevention of hypoglycemia in type 1 diabetes. Blair SN. Sigal et al. spread over at least 3 days of the week. competing time commitments) and develop strategies to overcome these barriers (62). Physical activity and risk for cardiovascular events in diabetic women. However. 3. Stampfer MJ.to vigorous-intensity aerobic exercise each week. improves glycemic control (66). S35 Pharmacotherapy in Type 1 Diabetes. Another strategy is to perform resistance exercise immediately prior to aerobic exercise (59). Fraser SF. hypoglycemia often occurs. foot exam. eating behavior. Diabetes Res Clin Pract 2006. People with diabetes (including elderly people) should perform resistance exercise at least twice a week (23) and preferably 3 times per week [Grade B. Balducci S. 2. Chudyk A. et al. People with diabetes with possible CVD or microvascular complications of diabetes who wish to undertake exercise that is substantially more vigorous than brisk walking should have medical evaluation for conditions that might increase exercise-associated risk.34:1228e37. Songer TJ. et al. J Diabetes Complications 2006. fitness. People with diabetes should accumulate a minimum of 150 minutes of moderate. and mortality among Finnish adults with diabetes.134:96e105. In youth with type 1 diabetes. resting ECG and. Initial instruction and periodic supervision by an exercise specialist are recommended [Grade C. there is little or no endogenous insulin secretion and no physiological regulation of insulin levels. Aerobic exercise and the lipid profile in type 1 diabetic men: a randomized controlled trial. 12. physical activity adherence levels can be increased through structured programs involving pedometers. / Can J Diabetes 37 (2013) S40eS44 S43 Exercise in Type 1 Diabetes RECOMMENDATIONS Moderate intensity aerobic exercise causes increased insulin sensitivity during. Therefore. Having patients record their daily physical activity has been shown to increase physical activity levels and improve self-efficacy (confidence in one’s own ability to successfully carry out a behaviour) (63). Meta-analysis of the effect of exercise interventions on fitness outcomes among adults with type 1 and type 2 diabetes. Fear of hypoglycemia is an important barrier to exercise in people with type 1 diabetes (49) and advice on physical activity to patients with type 1 diabetes should include strategies to reduce risk of hypoglycemia.83:157e75.45. Diabetes Care 2005.R. exercising with a friend or partner) facilitates regular physical activity. The attenuation of hypoglycemia is due to transiently reduced glucose disposal (58). Acton KJ. Church TS. possibly. weather. physical activity. et al. Diabetes Care 2010. Colberg SR.67) increases physical activity levels. cardiovascular risk factors. To reduce this risk. Goldstein MG. Having social support (e. with no more than 2 consecutive days without exercise [Grade B. Gerzoff RB. Bird SR. 10. et al.33:e147e67. text messaging. For more detailed. 9. Solomon C.20:216e23. p. Nielsen PJ. ECG.163:1440e7. 2. Iacobellis G. et al. Cardiorespiratory fitness and body mass index as predictors of cardiovascular disease mortality among men with diabetes. by temporarily increasing the basal insulin infusion until euglycemia is restored. S56 Hypoglycemia. Hyperglycemia can occur after very intense exercise. the activity in people with and without diabetes. Effects of exercise on cardiovascular risk factors in type 2 diabetes: a meta-analysis. Barengo NC. Diabetes Care 2006. in insulin pump users. body composition and lipids is not as great as can be achieved through a supervised aerobic and resistance exercise program (23).54). 1. weather. Physical activity. Hafdahl AR. Clinical management of the physically active patient with type 1 diabetes. 69. et al.4:159e63. Berger M. Long-term maintenance of treatment outcomes: diabetes personal trainer intervention for youth with type 1 diabetes. Mircescu H. Social support in diabetes: a systematic review of controlled intervention studies. Strychar I. Goal setting in diabetes self-management: taking the baby steps to success. Jones TW. Diabetologia 2007. 53. 41. Cheng YJ. A 10-s sprint performed prior to moderate-intensity exercise prevents early post-exercise fall in glycaemia in individuals with type 1 diabetes. Exercise in type I (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion: prevention of exercise-induced hypoglycaemia. 63. Diabetes Care 2009.301:1547e55. Ann Intern Med 2010. Morrison EY. Cobry E. Ribeiro PA. Fisher M.272: 1909e14. Kemmer FW. Guidelines for premeal insulin dose reduction for postprandial exercise of different intensities and durations in type 1 diabetic subjects treated intensively with a basal-bolus insulin regimen (ultralente. 59.39:64e77. DeWalt DA. Effects of a 12-month physical activity counselling intervention on glycaemic control and on the status of cardiovascular risk factors in people with Type 2 diabetes. Diabetes Care 2001. 21.304:2253e62.7:399e408. et al.88:1385e98. Preventive Services Task Force. 45.49:247e53. Cardiac events in 735 type 2 diabetic patients who underwent screening for unknown asymptomatic coronary heart disease: 5-year follow-up report from the Milan Study on Atherosclerosis and Diabetes (MiSAD). Simons-Morton BG. Appl Physiol Nutr Metab 2011. Moulin P. Calia P. 20:1711e6. et al. Mayo Clin Proc 1989. Fealey RD. Simons-Morton BG. Strasser B. Am J Prev Med 1999. Nelson ME. et al.11: CR515e521. Paramalingam N. Diabetes Care 2004l.147:357e69. et al. Dube MC. Changes in clinical and metabolic parameters after exercise therapy in patients with type 2 diabetes. Thomas JE. et al.25:2032e6.100: 637e41.27:1570e6. 34. et al. 14. Diabetes Care 2006. et al. Riddell MC. et al.35:669e75. Layne JE. Lee MS. Effect of weight-bearing activity on foot ulcer incidence in people with diabetic peripheral neuropathy: feet first randomized controlled trial. Patient Educ Couns 2009. Patient Educ Couns 2005. Perkins BA. Effect of intermittent high-intensity compared with continuous moderate exercise on glucose production and utilization in individuals with type 1 diabetes. Yoga practice for the management of type II diabetes mellitus in adults: a systematic review. Sigal RJ.33:696e703. 66. Ann Intern Med 2007.47: 821e32.24:625e30. Stansberry KB. Diabetes Technol Ther 2010. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. Diabetes Care 1990. Muscle Nerve 1993. Castaneda C. Pedometers and text messaging to increase physical activity: randomized controlled trial of adolescents with type 1 diabetes. Smythe GA. Dunstan DW.25:1729e36.37:1276e82. et al. Jul 30 [Epub ahead of print]. J Appl Physiol 2006. 18. Hyperinsulinemia prevents prolonged hyperglycemia after intense exercise in insulin-dependent diabetic subjects.35:359e70. Newton KH. Chu L. 31. Low PA.30:2471e7.S44 R.59:1e12. or both on glycemic control in type 2 diabetes: a randomized trial. Diabetes Care 2006. Chin J Integr Med. Morganti CM. et al. et al. 51. Thermoregulatory sweating abnormalities in diabetes mellitus.12:1003e10. van der Horst FG.77:218e23. In search of quality evidence for lifestyle management and glycemic control in children and adolescents with type 2 diabetes: a systematic review. et al. Phys Sportsmed 2011. Schiab J. 62. Osteoporos Int 2006. Sonnenberg GE. Iannotti RJ. Predictors of physical activity in adults with type 2 diabetes. . Sigal RJ. Trinh L. Elley CR. Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and Exercise Study (IDES). Wick DE. et al. Can J Diabetes 2006.24:316e22. Efficiency of vibration exercise for glycemic control in type 2 diabetes patients. J Clin Endocrinol Metab 2012. Trivedi M. Effects of aerobic training. Gordon L. Balducci S. et al. Faglia E. Dela F. The effect of a short sprint on post-exercise whole body glucose production and utilisation rates in individuals with type 1 diabetes mellitus. Roberts SK. Flanders WD. et al. et al. Evidence-based risk assessment and recommendations for physical activity clearance: diabetes mellitus and related comorbidities. Mueller MJ.157:784e8. 38. Zanuso S. Reiber GE. Petrella RJ. Hill MA. muscular strength. Cauza E. 49. Arch Intern Med 2010. Effects of performing resistance exercise before versus after aerobic exercise on glycemia in type 1 diabetes. Patterson C. Church TS. Crowther JQ. et al. Barriers to physical activity among patients with type 1 diabetes.4:427e37. 25. 22. Diabetes Care 2002. Considerations for implementation at the population level. Diabetes Care 2009. 58. Thivolet C. Kramer CK. Diabetes Care 2012. Type 1 diabetes and vigorous exercise: applications of exercise physiology to patient management. Jones TW. McCullough JE. Behavioral counseling to promote physical activity and a healthful diet to prevent cardiovascular disease in adults: a systematic review for the U. 17. Chyun DA. Wallace AS. Sigal et al. 29. Med Sci Monit 2005. 42. Hanusch-Enserer U. et al.64:617e28. et al. Nansel TR.170:1794e803. Bussau VA. Zhang X. Fiatarone MA. Eves ND. Daily weight-bearing activity does not increase the risk of diabetic foot ulcers. Favales F. Riddell MC. 71. Diabetes Care 2007.153:736e50. Burr J. Diabetes Care 2002. Durak EP. Davis TC. Ducros F. et al. Ratnam N. Comparison of the effect of multiple short-duration with single long-duration exercise sessions on glucose homeostasis in type 2 diabetes mellitus. Arch Phys Med Rehabil 2005. Dahl-Petersen I. Diabetes Care 2002. Cunningham DA. Knoops L. Rabasa-Lhoret R. Paterson DH. Plotnikoff RC. Can J Diabetes 2006. Insulin action after resistive training in insulin resistant older men and women. Ferreira LD. 56. Iannotti RJ. Kirk A. Tai chi for management of type 2 diabetes mellitus: a systematic review. 23. et al. Lievre MM. Koval JJ. Avenell A. Gleeson-Kreig JM. 50.S.292:E865e70. resistance training. Phys Ther 2008. High-intensity resistance training improves glycemic control in older patients with type 2 diabetes.27:83e8. Weisnagel SJ.16:269e77. BMC Pediatr 2010. Wackers FJ. Smith DG. Diabetes Educ 2006. Ernst E. Low PA. 43.8:21. Fournier PA. Bourque J. Shapiro SA. et al. et al. The influence of aging and diabetes on heat transfer characteristics of the skin to a rapidly applied heat source. Messer L. 47. Blair SN. Petrofsky JS. Impairment of peripheral blood flow responses in diabetes resembles an enhanced aging effect.29:1933e41. 16. / Can J Diabetes 37 (2013) S40eS44 44. Basu A. Med Sci Sports Exerc 2003. 15. Chiasson JL. Engelke K. McGrowder DA. Diabetes personal trainer outcomes: short-term and 1-year outcomes of a diabetes personal trainer intervention among youth with type 1 diabetes. Davey RJ.29:601e6.50:2245e53. Excess hospital admissions during the July 1995 heat wave in Chicago.2:CD004095. Cochrane Database Syst Rev 2005. Kihara M. Jovanovic-Peterson L. JAMA 2010. Rabasa-Lhoret R. Peterson CM. 40. Opfer-Gehrking TL. 48. The step test exercise prescription (STEP) project. Umpierre D. et al. Church TS. Diabetes Care 2008. Lauber D. Young LH. Preventing post-exercise nocturnal hypoglycemia in children with type 1 diabetes. Al-Shehri B. Whitlock EP. JAMA 2011. Int J Med Sci 2007.79:1049e57. Arch Med Sci 2008. 12:23. et al. Nansel TR. et al. Gordon LA. 20. Guelfi KJ. Plotnikoff RC. Lee S. 46. Diabetes Care 2004. Comparison of directly stimulated with axon-reflex-mediated sudomotor responses in human subjects and in patients with diabetes. Reiber GE. Munoz-Orians L. Lavoie C. Johnson S. Chopra M. Aljasir B. Fournier PA. J Clin Endocrinol Metab 1994. 27. 61.32:813e5. Lemaster JW. et al. Semenza JC. Perkins BA. Bryson M. Mutrie N. Petrofsky J. Diabetologia 1990.35: 1093e9.86:1527e33. Hamilton J. et al.17:133e42. JAMA 1994. 70. Wolf AM. Bussau VA. et al.lispro). Boule NG. JAMA 2009. Conaway MR. Ferreira LD.305:1790e9. 37. Yardley JE. Can primary care doctors prescribe exercise to improve fitness?.30:63e71. Am J Health Behav 2011. J Am Geriatr Soc 2001. 35. Lin JS. McGrowder DA. and cholesterol in type I diabetic men. Nicolucci A. 24. 65. Beil TL. 19. Lott ME. 67. van Dam HA.30:72e9. et al. Ryan AS. 60. Courneya KS.36(suppl 1):S154e89. Am J Physiol Endocrinol Metab 2007. 33. Riddell MC. Owen N. Cardiac outcomes after screening for asymptomatic coronary artery disease in patients with type 2 diabetes: the DIAD study: a randomized controlled trial. et al. et al. Votteler T. Eriksen L. 64. MacIntyre P.16:655e60. 30. 68. Detection of silent myocardial ischemia in asymptomatic patients with diabetes: results of a randomized trial and meta-analysis assessing the effectiveness of systematic screening. Lee H. Cocreham S. et al. et al. Purdon C. Fahey AJ. Fisher SJ. Type 1 diabetes and exercise: using the insulin pump to maximum advantage. Physical activity advice only or structured exercise training and association with HbA1c levels in type 2 diabetes: a systematic review and meta-analysis. 72. 57.97: 4193e200. Exercise and newer insulins: how much glucose supplement to avoid hypoglycemia? Med Sci Sports Exerc 2005. Morrison EY. 36. Diabetologia 2007. et al. Effect of exercise therapy on lipid profile and oxidative stress indicators in patients with type 2 diabetes.J. 54.25:2335e41. 32:69e77. Kemmler W. 28. Long-term non-pharmacologic weight loss interventions for adults with type 2 diabetes. Kenny GP. Newton A. The relative benefits of endurance and strength training on the metabolic factors and muscle function of people with type 2 diabetes mellitus. Wiltshire EJ. Delayed threshold for active cutaneous vasodilation in patients with Type 2 diabetes mellitus. Perkins BA. Resistance training and type 2 diabetes. O’Connor E. BMC Complement Altern Med 2008. Self-monitoring of physical activity: effects on selfefficacy and behavior in people with type 2 diabetes. 26. Translating lifestyle intervention to practice in obese patients with type 2 diabetes: Improving Control with Activity and Nutrition (ICAN) study. Norris SL. Am J Prev Med 2003. 39.31:2108e9. 52. Riddell MC. 32.50:1815e8.32:807e9. J Pediatr 2010. Randomized crossover study of effect of resistance training on glycemic control. Hurlbut DE. Lemaster JW. Diabetes Care 1997. Diabetologia 2004. Daly RM.13:1039e43. Choi TY. Baum K. Taplin CE. Evid Based Complement Alternat Med 2010. Lim HJ. Prud’homme D. A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes. Earnest CP. 55. 2011. Kenny GP. Exercise maintains bone density at spine and hip EFOPS: a 3-year longitudinal study in early postmenopausal women. Trials 2011. Effects of high-intensity strength training on multiple risk factors for osteoporotic fractures. The 10-s maximal sprint: a novel approach to counter an exercise-mediated fall in glycemia in individuals with type 1 diabetes. Haugaard SB. Sweat production during global heating and during isometric exercise in people with diabetes.10:97. Brazeau AS. Exercise capacity and body composition as predictors of mortality among men with diabetes. strategies that include energy restriction to achieve weight loss are a primary consideration (26). Overall. including hands-on activities. This diet may help a person attain and maintain a healthy body weight while ensuring an adequate intake of carbohydrate (CHO). while group education has been shown to be more effective than individual counselling when it incorporates principles of adult education. Introduction Nutrition therapy and counselling are an integral part of the treatment and self-management of diabetes.e. associated comorbid conditions and concomitant disorders. Nadira Husein MD.org/10. activity level.  Reduced caloric intake to achieve and maintain a healthier body weight should be a treatment goal for people with diabetes who are overweight or obese. Energy As an estimated 80% to 90% of people with type 2 diabetes are overweight or obese. John L. problem solving. type and duration of diabetes. nutrition counselling should be individualized. and incorporate self-management education (22). diabetes.1016/j.  Replacing high glycemic index carbohydrates with low glycemic index carbohydrates in mixed meals has a clinically significant benefit for glycemic control in people with type 1 and type 2 diabetes. needs. nutrition knowledge and diabetes self-management (15).jcjd.24). delivered in either a small group and/or an individual setting (11e13). A modest weight loss of 5% to 10% of initial body weight can substantially improve insulin sensitivity. meat and alternatives). In general. It is well documented that nutrition therapy can improve glycemic control (1) by reducing glycated hemoglobin (A1C) by 1. CDE. preferences. regularly evaluated and reinforced in an intensive manner (19-21). stress-related overeating) (17) and work toward solutions to facilitate behaviour change. treatment goals. nutrition therapy and meal planning should be individualized to accommodate the individual’s age. Nutrition therapy provided by an RD with expertise in diabetes management (9. protein. can further improve clinical and metabolic outcomes.  Intensive lifestyle interventions in people with type 2 diabetes can produce improvements in weight management. The goals of nutrition therapy are to maintain or improve quality of life and nutritional and physiological health. fat and essential fatty acids. fitness. Diabetes education programs serving vulnerable populations should evaluate the presence of barriers to healthy eating (e. Sievenpiper MD. Kathryn Arcudi PDt. glycemic control. Williams MEd.g.doi. Figure 1 and Table 1 present an algorithm which allows for this level of individualization of therapy in an evidence-based framework.10). can further improve clinical and metabolic outcomes (3. fibre. As evidence is limited for the rigid adherence to any single dietary prescription (23.01.  A variety of dietary patterns and specific foods have been shown to be of benefit in people with type 2 diabetes. when used with other components of diabetes care. frequent follow-up (i.0% to 2. when used with other components of diabetes care.  The macronutrient distribution is flexible within recommended ranges and will depend on individual treatment goals and preferences.  Nutrition therapy can reduce glycated hemoglobin (A1C) by 1. Individual counselling may be 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. This involves consuming a variety of foods from the 4 food groups (vegetables and fruits.7).0% to 2. Sandra L. milk and alternatives. Dworatzek PhD.019 preferable for people of lower socioeconomic status (8). lifestyle.canadianjournalofdiabetes. vitamins and minerals. people with diabetes should follow the healthy diet recommended for the general population in Eating Well with Canada’s Food Guide (18). and webbased care management has been shown to improve glycemic control (16). economic status (25). RD. culture. culturally sensitive peer education has been shown to improve A1C. glycemic control and cardiovascular risk factors.Can J Diabetes 37 (2013) S45eS55 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. RD. Applying the evidence from the sections that follow. PhD. and to prevent and treat acute and longterm complications of diabetes.6.0% (2e5) and. values. has demonstrated benefits for those with. in people with type 2 diabetes. resulting in reduced hospitalization rates (8). with an emphasis on foods that are low in energy density and high in volume to optimize satiety and discourage overconsumption. readiness to change and abilities. FRCPC. grain products.2013. concurrent medical therapies.0% and. cost of healthy food.  Consistency in carbohydrate intake and in spacing and regularity in meal consumption may help control blood glucose and weight.4.com Clinical Practice Guidelines Nutrition Therapy Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Paula D. Réjeanne Gougeon PhD. hypertension and . CDE KEY MESSAGES  People with diabetes should receive nutrition counselling by a registered dietitian. Additionally. every 3 months) with a registered dietitian (RD) has been associated with better dietary adherence in type 2 diabetes (7). role playing and group discussions (14). Furthermore. or at risk for. oat products.31). high-density lipoprotein cholesterol (HDL-C). potatoes. watermelon). papaya. such as TC. It is recommended that the percentage of total daily energy from CHO should be no less than 45% to prevent high intakes of fat. Figure 1. as this is associated with reduced risk of chronic disease for adults (32). over 2 to 24 weeks (38). to prevent further weight gain. Glycemic index The GI provides an assessment of the quality of CHO-containing foods based on their ability to raise blood glucose (BG) (35). and 21 g and 30 g for women and men over 51 years. Due to the recognized beneficial effects of dietary fibre intake in people with diabetes. . the goals of the dietary treatment regimen and the individual’s preferences and lifestyle. pears. lentils. and to improve beta-cell function compared with a low-CHO. / Can J Diabetes 37 (2013) S45eS55 the short term (33). oranges. parboiled rice. it may contribute up to 60% of total energy. Long-term follow-up of 7 to 10 years of intensive lifestyle intervention (ILI) programs targeting 5% to 7% weight loss in people at risk for type 2 diabetes suggests that there is some weight regain following discontinuation of the intervention. puffed wheat). especially cereal fibre. The sustainability of weight loss remains an important issue.g. This dietary strategy also leads to improvements in cardiovascular risk factors. oats. bulgur. puffed rice. A systematic review and meta-analysis of controlled feeding studies in people with type 2 diabetes found that CHO-restricted diets (mean CHO from 4% to 45% of total energy per day) improved A1C and triglycerides (TG). to provide glucose to the brain (32). To decrease the glycemic response to dietary intake. higher intakes than those recommended for the general population [25 g and 38 g for women and men. puffed oats. The long-term sustainability and safety of these diets. pasta. plums. low-density lipoprotein cholesterol (LDL-C) or body weight compared with higher-CHO diets over Dietary fibre Evidence suggests that the addition of soluble dietary fibre (e. mineral and fibre intake. Dietary advice to consume a low-GI diet was shown to sustain improvements in glycemic control and HDL-C compared with a high cereal fibre diet over 6 months (41). and tropical fruit (pineapple. okra. however. Total calories should reflect the weight management goals for overweight and obese people with diabetes (i. peas. Carbohydrate The current recommended minimum intake for CHO is not less than 130 g/day. with improvements in glycemic and lipid control in adults with type 2 diabetes (34). berries).48). psyllium. cherries. although the diabetes prevention benefits persist (30. thereby improving postprandial BG control (45). cantaloupe. quinoa and temperate fruit (apples. improvements in postprandial glycemia and high-sensitivity C-reactive protein (hsCRP) over 1 year (40) in people with type 2 diabetes. If CHO is derived from low glycemic index (GI) and high-fibre foods. Very-low-CHO diets may not ensure sufficient vitamin. pumpernickel or rye breads. beans. A low-GI diet has also been shown to improve glycemic control compared with dietary advice based on the nutritional recommendations of the Japanese Diabetes Society over 3 months in Japanese people with impaired glucose tolerance (IGT) or type 2 diabetes (43) and to decrease the need for antihyperglycemic medications compared with the nutritional recommendations of the American Diabetes Association over 1 year in people with poorly controlled type 2 diabetes (44). Dworatzek et al.S46 P. remain uncertain. dyslipidemia in people with type 2 diabetes and those at risk for type 2 diabetes (27e29). Meta-analyses of controlled feeding trials of interventions replacing high-GI CHOs with low-GI CHOs in mixed meals have shown clinically significant improvements in glycemic control over 2 weeks to 6 months in people with type 1 or type 2 diabetes (37e39). More detailed lists can be found in the International Tables of Glycemic Index and Glycemic Load Values (36). cohort studies demonstrate that diets high in dietary fibre. respectively (47)] are recommended for adults with diabetes (25 to 50 g/day or 15 to 25 g per 1000 kcal) (45. low-GI CHO foods are exchanged for high-GI CHO foods. apricots. Examples of higher-GI food sources include white or whole wheat bread. Nutritional management of hyperglycemia in type 2 diabetes. highly extruded or crispy puffed breakfast cereals (corn flakes. barley. are associated with a decreased risk of cardiovascular disease (46).D. barley) slows gastric emptying and delays the absorption of glucose in the small intestine. Macronutrients The ideal macronutrient distribution for the management of diabetes may vary. depending on the quality of the various macronutrients. In addition. but should be based on the individual’s interest and ability. peaches. mango.e. to attain and maintain a healthy or lower body weight for the long term or to prevent weight regain). but not total cholesterol (TC). Teaching a person to use the GI is recommended. high monounsaturated fat diet over 1 year (42) in people with type 2 diabetes. eggplant. and reduces the number of hypoglycemic events over 24 to 52 weeks in adults and children with type 1 diabetes (39). Examples of typical low-GI food sources include beans. Dworatzek et al.g. CV ¼ Cardiovascular. salba) and long-chain omega-3 fatty acids (e. blood pressure (56) or uric acid (55. As a source of excess energy.57). fructose has also been shown to contribute to weight gain and an adverse metabolic profile in people without diabetes (54. as there is no evidence that sucrose intake up to this level has any deleterious effect on glycemic control or lipid profile in people with type 1 or type 2 diabetes (49e51).D. these fatty acids do improve lipid profile. CHO ¼ carbohydrate.g. y adjusted for medication changes. modify platelet aggregation and decrease cardiovascular mortality in people with diabetes (64). Consuming naturally occurring fructose obtained from fruit does not show evidence of harm. A randomized controlled feeding trial showed that naturally occurring fructose from fruit at a level providing w60 g/day decreased body weight without adverse effects on lipids. Intake of sucrose >10% of total daily energy may increase BG and TG concentrations in some individuals (52. LDL ¼ low-density lipoprotein. canola. A1C ¼ glycated hemoglobin. saturated fats (SFAs) should be restricted to <7% of total daily energy intake (63). MUFA ¼ monounsaturated fatty acid. However. In a prospective cohort study of women with type 2 diabetes. such as plant oils (e. fatty fish) should be included in the diet up to 10% of total energy intake (63). and may even lower A1C (55. which include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). FPG ¼ fasting plasma glucose. Fat Current recommendations for the general population to consume fats in the range of 20% to 35% of energy intake apply equally to people with diabetes (47). higher consumption (1 to 3 servings . A comprehensive review found that although long-chain omega-3 fatty acids from fish oils. and trans fatty acids arising from industrial hydrogenation should be kept to a minimum. Polyunsaturated fats (PUFAs).57).55). HDL ¼ high-density lipoprotein. TG ¼ triglycerides. Sugars Added sucrose intake of up to 10% of total daily energy (e.53). Eating Well with Canada’s Food Guide recommends up to 7 to 10 servings of vegetables and fruit per day (18).g. Encouraging low-GI fruit over high-GI fruit as sources of small doses of fructose also provided glycemic benefit without adverse metabolic effects in people with type 2 diabetes over 6 months (62). TC ¼ total cholesterol. As the risk of coronary artery disease (CAD) in people with diabetes is 2 to 3 times that of those without diabetes. CRP ¼ C reactive protein. blood pressure. do not show an effect on glycemic control. Systematic reviews and meta-analyses of controlled feeding trials have shown that consumption of added fructose in place of equal amounts of other sources of CHO (mainly starch or sucrose) is unlikely to have any harmful effect on body weight (54. uric acid or insulin resistance compared with a lowfructose control diet under matched hypocaloric feeding conditions in overweight subjects without diabetes (61). canola oil) with up to 20% of total calories (63). / Can J Diabetes 37 (2013) S45eS55 Table 1 Properties of dietary interventions S47 *Y ¼ <1% decrease in A1C. Meal plans should favour fats rich in monounsaturated fatty acids (MUFAs) (e. at doses >60 g/day or >10% of total daily energy. BP ¼ blood pressure. fructose may have a small TG-raising effect in people with type 2 diabetes (60). olive oil.P. 50 to 65 g/day in a 2000 to 2600 kcal/day diet) is acceptable. walnut. BMI ¼ body mass index.58. GI ¼ gastrointestinal.59) in most people with diabetes. flax.g. a highCHO/low-fat diet in the treatment of type 2 diabetes showed that neither diet was superior in helping to manage type 2 diabetes (93). Better improvement of cardiovascular risk profile has been observed with a high. 28% fat) for 1 year (83). without adversely affecting other blood lipids in individuals with type 2 diabetes (96). targeting a level of intake that does not exceed the recommended dietary allowance (RDA) of 0. A multidisciplinary team. the overall risk estimates for cardiovascular events and mortality were not significant (72). postprandial glucose and insulin concentrations and to lower HDL-C (86). improved HDL-C compared with a similar low-cholesterol diet. needs to be modified for people with diabetes (73). which would be of potential benefit in energy-reduced diets. cardiovascular risk factors and glycemic control have been reported in individuals with type 2 diabetes who followed either a high-MUFA diet (46% CHO. emphasizing natural foods.8 g per kilogram body weight per day is an important consideration (74). as several studies suggest that wide variations can be effective (82). Several randomized trials have shown that replacement of animal protein with plant protein (mainly from soy) results in improvements in albuminuria or proteinuria. Protein quality has been shown to be another important consideration in this cohort. half MUFAs) or a higher CHO diet (54% CHO. lowprotein diet in persons with type 2 diabetes despite similar weight loss with normal renal function being maintained (95). There may be benefit of replacing SFAs with PUFAs. does not affect postprandial plasma glucose and insulin concentrations in obese individuals with type 2 diabetes and. The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial failed to show a cardiovascular or mortality benefit of supplementation with omega-3 LC-PUFAs in 12 536 people with or at risk for diabetes (71). The CHO in these studies. A cohort analysis of the Diabetes Control and Complications Trial (DCCT) also showed that higher consumptions of omega-3 LCPUFAs from fish are associated with a decrease in the degree of albuminuria in type 1 diabetes (66). There remains a need for more evidence related to the benefits of supplementation with omega-3 LC-PUFAs in people with diabetes. A 15% increase of energy from dietary protein with a parallel decrease in fat. this intake in grams per kg per day should be maintained or increased with energy-reduced diets. postprandial glucose. Furthermore. Macronutrient substitutions The ideal macronutrient distribution for the management of diabetes may need to be individualized based on individual preferences and perceived palatability. however. over 4 weeks. This result was supported by a pooled analysis of prospective cohort studies. was not differentiated by its GI. body composition. harm due to malnutrition should not be ignored (81).vs. which was related to the long-term improvement in glycemic control (93. For example. improves TG and blood pressure (87). it has been shown that a high MUFA diet is as successful as a conventional diet in improving metabolic and anthropometric parameters in persons with type 2 diabetes (84). Similarly. The Study of Cardiovascular Events in Diabetes (ASCEND) in 15 480 people with diabetes free of cardiovascular disease (clinicaltrials. did not show a cardiovascular benefit of replacing SFAs with MUFAs. Greater incorporation of plant sources of protein may also require closer monitoring of potassium as CKD progresses. Furthermore. Those who consumed fatty fish >5 times per week had a 64% reduction in CAD compared with those in the low-intake category (65). energy-reduced diet. 15% protein. Rather. in nondiabetic adults. Replacing fat with refined CHOs should be avoided as it has been shown to elevate fasting insulin. similar beneficial effects on body weight. / Can J Diabetes 37 (2013) S45eS55 per month) of omega-3 long-chain polyunsaturated fatty acids (LC-PUFAs) from fish was associated with a 40% reduction in CAD compared with those with a low intake (<1 serving per month) (65).94). 6-week crossover feeding trials comparing high MUFA with high CHO isoenergetic diets.gov registration number NCT00135226) will provide more data on the outcomes of supplementation with omega-3 LC-PUFAs. showed similar energy balance. in which some of the trials included people with diabetes (90). A systematic review and meta-analysis of large clinical outcome trials replacing SFAs with PUFAs showed a 19% reduction in MI or CHD death in people with and without CHD.S48 P. it did show a significant reduction in incident cardiovascular disease and death from coronary heart disease (CHD) in the subgroup of participants with diabetes (70). A 12-month study comparing a high-protein/low-fat vs. insulin and LDL-C concentrations are lower in response to a meal with a low GI and low glycemic load compared with a MUFA-rich meal (85). increasing protein intake to 1. including RDs. When the data from this trial were included in the most recent metaanalysis. as well as improvements in albuminuria or proteinuria and A1C from meta-analyses of randomized controlled trials from 6 months to 4 years of follow-up in people with varying degrees of diabetic nephropathy (76).5 g per kg body weight per day). Large clinical outcome trials of supplementation with omega-3 LC-PUFAs have shown a significant reduction in cardiovascular events in participants.5 years of supplementation with omega-3 LC-PUFAs in all participants who had a previous MI.5 to 2 g per kilogram body weight was shown to promote satiety (88) and preserve lean body mass (89). provided as part of a high-protein. including people with diabetes who have elevated TC (67). there remains uncertainty regarding the benefits of supplementation with omega-3 LC-PUFAs. Intensive Lifestyle Intervention ILI programs in diabetes usually consist of behavioural interventions combining dietary modification and increased physical activity. and neither the pooled analysis nor the Women’s Health Initiative Randomized Controlled Dietary Modification Trial in postmenopausal womendof whom approximately 5% were treated for diabetes and 36% had the metabolic syndrome (92)dshowed a cardiovascular benefit of replacing SFAs with CHO. LDL-C. Two eggs per day. which showed similar reductions in the risk of CHD in people without diabetes (91). nurses and . necessitating adequate clinical and laboratory monitoring of nutritional status in the individual with diabetes and CKD. however. Adjustments in medication type and dosage may be required when embarking on a different macronutrient distribution (97) or energy reduction (98). Although the Alpha OMEGA trial did not show a significant mortality benefit after 3. TG. glycemic control and lipid profile (82). In people with diabetes who have chronic kidney disease (CKD). However. The pooled analysis. Replacement of red meat with either chicken or a low-protein diet with vegetable and dairy sources of protein has also been shown to result in significant reductions in albuminuria after 4 weeks in a randomized trial (80). TG and CRP up to 4 years (77e79). representing 15% to 20% of total energy intake. while maintaining CHO intake constant.D. 38% fat. those with chronic heart failure (68) or those who had a previous myocardial infarction (MI) (69). 15% protein. However. it is the degree of energy reduction. Protein There is no evidence that the usual protein intake for most individuals (1 to 1. Dworatzek et al. vegetables and fish. In patients on low-protein diets. not the variation in diet macronutrient composition. This level of restriction is based on evidence of reductions in end stage renal disease or mortality seen in a single randomized controlled trial in people with type 1 diabetes who have CKD (75). low-saturated-fat. However. Both the quantity and quality (high biological value) of protein intake must be optimized to meet requirements for essential amino acids. Mediterranean-style diet lowered fasting plasma glucose compared with calorie-reduced low-fat or low-CHO diets in a subgroup of moderately obese people with type 2 diabetes at 2 years (109). the feasibility of implementing an ILI program will depend on the availability of resources and access to a multidisciplinary team. randomized controlled trials in people with type 2 diabetes have also shown evidence of long-term benefits. including systolic blood pressure. One must note that. with the intensity of follow-up varying from weekly to every 3 months with gradually decreasing contact as programs progress. a calorie-restricted vegetarian diet was shown to improve body mass index (BMI) and LDL-C more than a conventional diet in people with type 2 diabetes (104). preferences and abilities may influence the decisions to use these dietary patterns. Compared with a diet based on the American Diabetes Association recommendations. While both diets were effective in reducing A1C. that both groups had a lower number of cardiovascular events compared to previous studies of people with diabetes (http://www. whereas only the low-CHO Mediterranean-style diet improved LDL-C and HDL-C at 1 year in overweight persons with type 2 diabetes (110). Although the available trials suggest an overall benefit of different ILI programs in people with diabetes.gov/ news/health/oct2012/niddk-19. The Lifestyle Over and Above Drugs in Diabetes (LOADD) trial showed that a 6-month ILI program of individualised dietary advice (according to the nutritional recommendations of the European Association for the Study of Diabetes) (100) improved glycemic control and anthropometric measures compared with usual care in persons with type 2 diabetes who had unsatisfactory glycemic control (A1C >7%) on optimized antihyperglycemic drug treatment (101). the vegan diet improved glycemia and plasma lipids more than the conventional diet (103). It contains smaller amounts of red and processed meat. TC. Vegetarian diets A low-fat. Although advice to the general population over 1 year of age is to achieve a sodium intake that meets the adequate intake (AI) target of 1000 to 1500 mg/day (depending on age. when taking medication changes into account. The Mediterranean Lifestyle Program (MLP) trial showed that a comprehensive 6-month ILI promoting a Mediterranean-style dietary pattern increased physical activity (including aerobic. there is recent concern from prospective cohort studies that low sodium intakes may be associated with increased mortality in people with type 1 (113) and type 2 diabetes (114). pregnancy and lactation) (112). Large. decrease in alcohol and sugar intake. randomized. fruits and low-fat dairy products. Dietary Patterns There are now several large studies that have suggested that a variety of dietary patterns are beneficial for people with diabetes. weekly or biweekly nutrition and cooking instruction was provided by a dietitian or cooking instructor (103). / Can J Diabetes 37 (2013) S45eS55 S49 kinesiologists. 30 minutes walking per day) reduced severe retinopathy by 47%. vegetables. It was noted.8 years (111). The DASH dietary pattern has been shown to lower systolic and diastolic blood . and larger amounts of potassium. Both types of Mediterranean diets were shown to reduce the incidence of major cardiovascular events by approximately 30% without any subgroup differences between participants with and without diabetes over a median follow-up of 4. however. both traditional and low-CHO Mediterranean-style diets were shown to decrease A1C and TG. An individual’s values. TC:HDL-C ratio. TG and HDL-C) compared with diabetes support and education over 4 years of follow-up in overweight people with type 2 diabetes (29). as well as low to moderate consumption of wine. a Spanish multicentre. The DASH dietary pattern does not target sodium reductions but rather emphasizes vegetables.116). poultry. mainly during meals (105. randomized trial of the effect of a Mediterranean diet supplemented with extra-virgin olive oil or mixed nuts compared with a low-fat control diet on major cardiovascular events in 7447 participants at high cardiovascular risk (including 3614 participants [49%] with type 2 diabetes). Similarly.D. seeds. respectively). more participants on the vegetarian diet had a decrease in diabetes medications compared to those on the conventional diet (43% vs. glycemic control and cardiovascular risk factors (blood pressure. Twenty-year follow-up of the China Da Qing Diabetes Prevention Outcome Study showed that 6 years of an ILI program targeting an increase in vegetable intake. Individually. The Dietary Intervention Randomized Controlled Trial (DIRECT) showed that a calorie-reduced. In 2012. General features include a high consumption of fruits. moderate-to-high consumption of olive oil (as the principal source of fat).106). Mediterranean diets A “Mediterranean diet” primarily refers to a plant-based diet first described in the 1960s (105). a reduction in fat (<30% of energy as total fat and <10% as saturated fat). and low consumption of red meat. 5%. strength-training and stress management exercises) and led to weight loss and improvements in glycemic control and quality of life in postmenopausal women with type 2 diabetes (102). magnesium. an increase in protein (15% of energy) and an increase in physical activity (175 min/week with an intensity similar to brisk walking) produced sustained weight loss and improvements in fitness. usually leads the ILI programs. and. and cholesterol. the Look AHEAD trial was stopped early as it was determined that 11 years of an ILI did not decrease the occurrence of cardiovascular events compared to the control group and further intervention was unlikely to change this result. Dworatzek et al. sweets and sugarcontaining beverages. legumes.htm). calcium. A systematic review of randomized controlled feeding trials showed that a Mediterranean-style dietary pattern improves glycemic control and cardiovascular risk factors. weight loss through energy restriction in overweight and obese participants. nuts. TC and LDL-C over 74 weeks in adults with type 2 diabetes. was stopped early for benefit. These metabolic advantages of a Mediterranean diet appear to have benefits for the primary prevention of cardiovascular disease in people with type 2 diabetes. sex. cereals and whole grains. clinical trials have shown benefit of ILI programs using different lifestyle approaches in diabetes.g. with both diets. low to moderate consumption of dairy products. A low-CHO Mediterranean-style diet reduced A1C and delayed the need for antihyperglycemic drug therapy compared with a low-fat diet in overweight individuals with newly diagnosed type 2 diabetes at 4 years (108). and TG in type 2 diabetes (107).nih. fish and poultry. well-powered. and includes whole grains. The Prevención con Dieta Mediterránea (PREDIMED) study. ad libitum vegan diet has been shown to be just as beneficial as conventional American Diabetes Association dietary guidelines in promoting weight loss and improving fasting BG. dietary fibre and protein than typical Western diets (115. whereas nephropathy and neuropathy outcomes were not affected compared with usual care in high-risk people with IGT (99). HDL-C. total and saturated fat. fish and nuts. and an increase in leisure-time physical activity (e. Interim analyses of the Look AHEAD (Action for Health in Diabetes) trial have shown that an ILI program targeting at least a 7% weight loss through a restriction in energy (1200 to 1800 total kcal/day based on initial weight). DASH and low-sodium dietary patterns Dietary approaches to reducing blood pressure have focused on sodium reduction and the Dietary Approaches to Stop Hypertension (DASH) dietary pattern.P. low-fat conventional diet. Furthermore. Another trial comparing the Atkins. including 1 trial in people with type 2 diabetes (129). randomized controlled trials in overweight and obese participants that included some people with diabetes. an increase in HDL-C was also found in a randomized controlled trial of a combination of dietary pulses and whole grains in partial replacement for rice in the diet of people with type 2 diabetes (123). in people with type 2 diabetes. While more research in people with diabetes would be beneficial. and Protein Power Lifeplan diets. Special Considerations for People with Type 1 Diabetes and Type 2 Diabetes on Insulin Consistency in CHO intake (131). improved fasting glucose. CHO counting) (140. 60 g of almonds per day for 4 weeks. peas. low BMI and consumers of Western diets (130). Weight Watchers. Intensively treated individuals with type 1 diabetes show worse diabetes control with diets high in total and saturated fat and low in CHO (135). depending on individual energy needs of participants) for 13 weeks as a replacement for CHO foods in people with type 2 diabetes lowered A1C. can be achieved when individuals with type 1 diabetes (138) or type 2 diabetes (139) receive education on matching insulin to CHO content (e. as well as decrease A1C. beans. Inclusion of snacks as part of a person’s meal plan should be individualized based on meal spacing. HDL-C and TG compared with a calorie-restricted. Diets emphasizing specific foods A systematic review and meta-analysis of randomized controlled trials found that diets high in dietary pulses (e. it was concluded that different types of nuts were effective in reducing TC and LDL-C.118). / Can J Diabetes 37 (2013) S45eS55 Table 2 Acceptable daily intake of sweeteners Sweetener Acesulfame potassium Aspartame Cyclamate Erythritol Neotame Saccharin Steviol glycosides Sucralose Tagatose Thaumatin Acceptable daily intake (mg/kg body weight/day) 15 40 11 1.134). The available evidence on popular weight-loss diets supports the approach of selecting the diet best suited to the preferences and treatment goals of the individual. BG and quality of life. These improvements in blood pressure have been shown to hold across high (3220 mg). metabolic control. A systematic review and meta-analysis of 4 trials of the Atkins diet and one trial of the Protein Power Lifeplan diet (a diet with a similar extreme CHO restriction) showed that these diets were no more effective than conventional energy-restricted. five 28-g servings of almonds per week for 12 weeks resulted in improvements in A1C and BMI (127). fasting BG. The Protein Power Lifeplan diet. waist circumference. percentage of body fat. have been subjected to investigation in longer-term. In another study. Intensive insulin therapy regimens that include multiple injections of rapid-acting insulin matched to CHO allow for flexibility in meal size and frequency (136. of whom 28% had diabetes (121). People with type 1 diabetes or type 2 diabetes requiring insulin. and a decrease in TG only in those with elevated TG levels. Ornish. Several of these diets. Furthermore. In studies of shorter duration and/or with smaller sample sizes.S50 P.132). including A1C. Popular weight-loss diets Numerous popular weight-loss diets are available to people with diabetes. similar results have been reported. however. using a basal-bolus regimen. in a pooled analysis of 25 nut intervention trials in people with normolipidemia or hypercholesterolemia. Another systematic review and meta-analysis of randomized controlled trials found that diets high in dietary pulses reduced TC and LDL-C compared with macronutrient and energy-matched control diets in nondiabetic participants with normal to high cholesterol (124). Another novel. compared to a National Cholesterol Education Program (NCEP) Step II diet.141).131. the effect of nut consumption was dose dependent. Two ounces of mixed. low-fat diets in inducing weight loss with improvements in TG and HDL-C offset by increases in TC and LDL-C for up to 1 year (119).000 2 5 4 8. TC. with no decrease in HDL-C.120).D. and should be balanced against the potential risk of weight gain (133. Ornish. Zone. . may help control BG levels (21. in people with and without diabetes (122). however. either alone or as part of low-GI or highfibre diets.g.8 80 0.116). the DASH dietary pattern compared with a control diet matched for a moderate sodium intake (2400 mg) has been shown to decrease systolic and diastolic blood pressure. A common finding across most of the available trials was poor dietary adherence (119. as well as less requirement for insulin. The development of nutritional deficiencies must also be considered in the context of diets that restrict food groups. medium (2300 mg). Dworatzek et al. and Zone diets showed similar weight loss and improvements in the LDL-C:HDL-C ratio without effects on fasting plasma glucose at 1 year in overweight and obese participants. In people with type 2 diabetes. and the greatest lipid-lowering benefits were seen in those with high baseline LDL-C. LDL-C and LDL-C:HDL-C ratio (128). In doing so. unsalted nuts daily (or 50 to 75 g.9 pressure compared with a typical American diet matched for sodium intake in people with and without hypertension. technique of encouraging intake of vegetables first and other CHOs last at each meal was also successful in achieving better glycemic control (A1C) than an exchange-based meal plan after 24 months of follow-up in people with type 2 diabetes (125). and spacing and regularity in meal consumption. these studies support the inclusion of nuts as a dietary strategy to improve lipid and A1C levels in this population. Overall. the Mediterranean-style diet had a more favourable effect on fasting plasma glucose at 2 years in the subgroup of participants with type 2 diabetes (109). inclusive of people with well-controlled diabetes (115.g. In addition to decreasing fasting BG. treatment regimen and risk of hypoglycemia. chickpeas. including the Atkins. lowered fasting BG and/or glycated blood proteins. and low (1495 mg) levels of matched sodium intake (116). weight. and yet simple. In 1 pilot study in people with type 2 diabetes. although greater adherence was associated with greater weight loss and reductions in cardiovascular risk factors irrespective of the diet (121). Improvements in A1C. lentils). more studies conducted specifically in people with diabetes are warranted. did show improved A1C compared with an energyreduced. although no available trials have been conducted exclusively in people with diabetes. DIRECT showed that. resulting in an improved TC:HDL-C ratio and no concomitant weight gain (126). should adjust their insulin based on the CHO content of their meals. TC and LDL-C with no decrease in HDL-C. although an Atkins diet produced weight loss and improvements in the TC:HDL-C ratio. low-fat diet at 1 year in a subset of participants with type 2 diabetes (120). Weight Watchers.137). LDL-C and CRP and to increase HDL-C over 8 weeks (117. its effects were not different from that of a calorie-restricted Mediterranean-style diet at 2 years (109). They vary in the degree to which they are absorbed. USA). however. / Can J Diabetes 37 (2013) S45eS55 S51 dietary fibre and sugar alcohol should be subtracted from total CHO. HMR (Health Management Resources Corp.158). 1 can of pop contains about 42 mg Ace-K or 200 mg aspartame. new interactive technologies. such as frying.hc-sc. or for use in chewing gum (Personal Communication with Health Canada. This weight loss results in greater improvements in glycemic control over 3 months to 34 weeks (154. Most have been shown to be safe when used by people with diabetes (143).ca/fn-an/securit/addit/sweeten-edulcor/indexeng. variable and usually minimal. but retinopathy does not. Sugar alcohols (erythritol. aspartame. steviol glycosides. effects not observed with white wine (166). 1 packet of sweeteners. isomalt.0 mg) is recommended for women who could become . Meal replacements with differing macronutrient compositions designed for people with diabetes have shown no clear advantage.154) weight loss compared with conventional reduced-calorie diets up to 1 year with maintenance up to 86 weeks in overweight people with type 2 diabetes. portioncontrolled. preferably in liquid. In contrast. A 4-month.hc-sc. xylitol) are also approved for use in Canada. Health Canada has set acceptable daily intake (ADI) values. Overweight participants with type 2 diabetes during week 3 to week 19 on the ILI intervention arm of the Look AHEAD trial were prescribed meal replacements: Glucerna (Abbott Laboratories. with increasing amounts of alcohol intake (167). there are limited data on the newer sweeteners. Thus. however. mannitol. Optifast (Nestlé. utilizing mobile phones to provide information. such as neotame and thaumatin.ca/fn-an/securit/addit/list/9-sweetener-edulcorant-eng. sorbitol. and http://www. Other Considerations Nonnutritive sweeteners Acesulfame potassium. neotame. Stevia extracts are approved by Health Canada for use in foods and beverages. however.gc. vitamin.P. Abbott Park. randomized dietary study in 36 participants with or without type 2 diabetes showed that restricting dAGEs by cooking foods at a low temperature.. broiling and grilling. Moderate alcohol consumption (6 to 18 g/day) is associated with a 25% to 66% lower risk of total and fatal CHD in persons with type 2 diabetes (163) and. Intake of up to 1 g steviol glycosides per day was shown to be safe in people with type 1 or type 2 diabetes and was not associated with hypoglycemia or hypotension (145. Alcohol The same precautions regarding alcohol consumption in the general population apply to people with diabetes (159). In addition. matching rapidacting insulin to the intake of sugar alcohols is not recommended (147). They also improved individual quality of life and treatment satisfaction (142). Switzerland) or Slimfast (Unilever. Although there are no long-term.155) without an increase in adverse or hypoglycemic events (153e155). Alcohol consumption should be limited to 2 standard drinks per day and <10 drinks per week for women and 3 standard drinks per day or <15 drinks per week for men (1 standard drink: 10 g alcohol. For people with type 1 diabetes. gc. Commercially available. sucralose. Randomized controlled feeding trials have shown partial meal replacement plans to result in comparable (152) or better (153. or 2 or 3 hours after. lactitol. Meal replacements Weight loss programs for people with diabetes may use partial meal replacement plans. consumed with food. Healthcare professionals should discuss alcohol use with their patients (173) to inform them of the potential weight gain and risks of hypoglycemia (172). Dworatzek et al. Alcohol ingestion may mask the symptoms of hypoglycemia (161). 341 mL 5% alcohol beer. Daily moderate red wine consumption for 12 months reverses the increased oxidative stress and inflammation associated with MI in persons with type 2 diabetes (165) and shows renoprotective effects and lower blood pressure after 6 months in those with nephropathy.and insulin-treated individuals with type 2 diabetes (172). Supplementation with folic acid (0. have been shown to decrease both weight gain and the time required for education. moderate consumption of alcohol with.D. results in formation of dietary advanced glycation endproducts (dAGEs). USA). reduce hepatic production of glucose and increase ketones (162).146). does not cause hyperglycemia or hypoglycemia (164). 43 mL 40% alcohol spirits. while light to moderate intake shows an inverse association with A1C (169). tagatose and thaumatin have been approved by Health Canada for use as either table-top sweeteners or food additives. and their conversion rate to glucose is slow. Netherlands). Those participants in the highest quartile of meal replacement usage were approximately 4 times more likely to reach the 7% and 10% weight loss goal than participants in the lowest quartile (156). 142 mL 12% alcohol wine) (160). maltitol. consumption of up to 10 g/day by people with diabetes does not appear to result in adverse effects (148). Routine vitamin and mineral supplementation is generally not recommended. cyclamate. a class of pro-oxidants of which 10% are absorbed. Indeed.170) and may impede cognitive performance during mild hypoglycemia (171). a level in agreement with that of the Food and Agricultural Organization (FAO) and the World Health Organization (WHO) (144).php). The same concern may apply to sulphonylurea. CHO/insulin bolus calculations and telemedicine communications with care providers. visual acuity declines. Boston. UK and Rotterdam.and mineral-fortified meal replacement products usually replace 1 or 2 meals per day in these plans. Dietary advanced glycation endproducts Thermal food processing at very high temperatures. although studies remain lacking (157. Meals high in dAGEs increase markers of endothelial and adipocyte dysfunction in adults with type 2 diabetes (149) and impair vascular function (150). Meal replacements have also shown benefit as part of ILIs. Vevey. The ADI is set at 4 mg/kg/ day of steviol. London. Vitamin and mineral supplements People with diabetes should be encouraged to meet their nutritional needs by consuming a well-balanced diet by following Eating Well with Canada’s Food Guide (18).155) and reductions in the need for antihyperglycemic medications up to 1 year (153.php. A1C was not measured (151). an evening meal may result in delayed hypoglycemia the next morning after breakfast or as late as 24 hours after alcohol consumption (161. randomized controlled trials of consumption of sugar alcohols by people with diabetes.4 to 1. which are expressed on a body weight basis and are considered safe daily intake levels over a lifetime (Table 2). http://www. Chronic high intake (w44 g ethanol per day) is associated with elevated blood pressure and TG in men with type 2 diabetes (168). and may have no significant effect on BG. there is no ADI (except for erythritol) as their use is considered selflimiting due to the potential for adverse gastrointestinal symptoms. saccharin. Supplementation with 10 mg (400 IU) vitamin D is recommended for people >50 years of age (18). 12 mg sucralose or 12 mg saccharin. improved insulin resistance in those with diabetes. These levels are considered high and are rarely achieved. 2. 2013. Mediterranean-style dietary pattern [Grade B. In adults with diabetes.106:109e12. et al.108)] b.ca/forprofessionals/resources/nutrition/alcohol. People with type 2 diabetes should maintain regularity in timing and spacing of meals to optimize glycemic control [Grade D. role playing and group discussions [Grade B. Level 4 (132)].diabetes. Available at: http://www.  Cholesterol and Diabetes. Level 1A (29)]. S117 Type 1 Diabetes in Children and Adolescents. 3. calorie-reduced diet should be followed to achieve and maintain a lower.diabetes.ca/ diabetes-and-you/nutrition/portion-guide. Accessed March 3. Gaetke L. Accessed March 3. p. Available at: http://www. 9. In overweight or obese people with diabetes. Grade D. 2013. 2013.ca)  Alcohol and Diabetes. Available at: http://www. Consensus]. et al. p. 2013. p.58. 8. Effectiveness of medical nutrition therapy provided by dietitians in the management of non-insulin-dependent diabetes mellitus: a randomized.  Handy Portion Guide. 15% to 20% protein and 20% to 35% fat to allow for individualization of nutrition therapy based on preferences and treatment goals [Grade D. S82 Natural Health Products. blood glucose. the evidence for their therapeutic role in diabetes has been reviewed in the Natural Health Products chapter. Level 1A (28. 3. pregnant (18). p. Available at: http://www. Vegan or vegetarian dietary pattern [Grade B. Maggio CA. Diabetes Care 1999. 7.95: 1009e17.22:191e7. such as hands-on activities. S26 Physical Activity and Diabetes. Daly A.ca/for-professionals/resources/ nutrition/basic-carb-counting. a nutritionally balanced. Diabetes Prevention and Management.  Health Canada. for those with type 2 diabetes. 12.51. People with type 1 diabetes should be taught how to match insulin to carbohydrate quantity and quality [Grade C.gc. The need for further vitamin and mineral supplements needs to be assessed on an individual basis. Dietary Approaches to Stop Hypertension (DASH) dietary pattern [Grade C. The evidence for the effectiveness of medical nutrition therapy in diabetes management.D. Truszczynska H. S168 Type 2 Diabetes in Aboriginal Peoples. p. p. Accessed March 3. p. 4. Nutrition education is effective when delivered in either a small group or a one-on-one setting [Grade B.104)] c. McCarron DA. p. J Am Diet Assoc 1995. S97 Dyslipidemia.diabetes. 2013. Pi-Sunyer FX. Accessed March 3. Accessed March 3.ca/ for-professionals/resources/nutrition/sugars-sweeteners. Matsuda M.diabetes. problem solving. Level 3 (8)]. People using insulin or insulin secretagogues should be informed of the risk of delayed hypoglycemia resulting from alcohol consumed with or after the previous evening’s meal [Grade C. Imai S. Added sucrose or added fructose can be substituted for other carbohydrates as part of mixed meals up to a maximum of 10% of total daily energy intake.  Healthier Cooking Options: Available at: http://www.ca/ for-professionals/resources/nutrition/eating-away.  Basic Carbohydrate Counting for Diabetes Management. Franz MJ. (including): a.35. for type1 diabetes] and to reduce hospitalization rates [Grade C.diabetes. Consensus].diabetes. Accessed March 3. 5. S191 Related Websites  Canadian Diabetes Association (http://www. ca/for-professionals/resources/nutrition/cholesterol-diabetes.  Sugars and Sweeteners. Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes. Pastors JG. Individuals with diabetes should be encouraged to follow Eating Well with Canada’s Food Guide (18) in order to meet their nutritional needs [Grade D. Eating Well with Canada’s Food Guide. An intensive lifestyle intervention program combining dietary modification and increased physical activity may be used to achieve weight loss and improvements in glycemic control and cardiovascular risk factors [Grade A. 2. 10. Castle G. Level 2 (122)] d. Level 2 (107.54.diabetes. Accessed March 3. Stuart M. Level 2 (41)]. Alternative dietary patterns may be used in people with type 2 diabetes to improve glycemic control. ca/for-professionals/resources/nutrition/healthier-cookingoptions.diabetes. .diabetes. Accessed March 3. p. 4. Level 3 (50. Dietary advice may emphasize choosing carbohydrate food sources with a low glycemic index to help optimize glycemic control [type 1 diabetes: Grade B. Level 2 (103. Intervention with delivery of diabetic meals improves glycemic control in patients with type 2 diabetes mellitus. J Am Diet Assoc 1998. S153 Type 2 Diabetes in Children and Adolescents. Available at: http://www. S163 Diabetes and Pregnancy.42:59e63.169). p. S110 Treatment of Hypertension. Consensus]. Consensus. J Am Diet Assoc 2006. Level 4 (131)]. et al. Level 3 (170. 2013. Warshaw H. controlled clinical trial. Available at: http://www. Dworatzek et al. Level 2 (118)] 11. Consensus] and should limit intake of trans fatty acids to a minimum [Grade D. Incorporation of dietary pulses (e. the macronutrient distribution as a percentage of total energy can range from 45% to 60% carbohydrate. 2013. J Clin Biochem Nutr 2008. et al.ca/forprofessionals/resources/nutrition/glycemic-index.  Just the Basics: Tips for Healthy Eating. healthier body weight [Grade A. type 2 diabetes: Grade B. 2013. Available at: http://www.98:62e70. Level 2 (138)] or should maintain consistency in carbohydrate quantity and quality [Grade D. Level 2 (14)]. Kozai H. Kulkarni K.  Eating Away from Home. Level 2 (34. Group education should incorporate adult education principles. 2013. A single nutrition counseling session with a registered dietitian improves short-term clinical outcomes for rural kentucky patients with chronic diseases. lentils) [Grade B. 13.172)] and should be advised on preventive actions such as carbohydrate intake and/or insulin dose adjustments and increased BG monitoring [Grade D. Barry B.  The Glycemic Index. peas. S40 Weight Management in Diabetes. provided adequate control of BG and lipids is maintained [Grade C.60)]. Accessed March 3. References 1. Abbreviation: BG.25: 608e13.ca/fn-an/food-guide-aliment/indexeng.php. 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Diabetologia 2009. and plasma homocysteine concentrations in patients with coronary artery disease: randomized controlled clinical trial. Alcohol causes hypoglycaemic unawareness in healthy volunteers and patients with type 1 (insulindependent) diabetes. Kim OY. Effects of the Dietary Approaches to Stop Hypertension (DASH) eating plan on cardiovascular risks among type 2 diabetic patients: a randomized crossover clinical trial. A pilot study of repeated exposures in some normotensive and hypotensive individuals and in Type 1 and Type 2 diabetics. Imai S. Association of diet with glycated hemoglobin during intensive treatment of type 1 diabetes in the Diabetes Control and Complications Trial. Alcohol and type 2 diabetes. BMJ 2002.33:216e21. Diabetes Care 2011. Meta-analysis of the relationship between alcohol consumption and coronary heart disease and mortality in type 2 diabetic patients.23:974e81. Non-soy legume consumption lowers cholesterol levels: a meta-analysis of randomized controlled trials. Piekarz A. Heller SR. Powers MA. et al. et al. Diabetes Educ 2008. 169. Azadbakht L.104: 560e6. 26:9e15. Beirness D. Banach MS. 160. Effect of non-oil-seed pulses on glycaemic control: a systematic review and meta-analysis of randomised controlled experimental trials in people with and without diabetes. van Eys J.31:1305e10. Diabetes Care 2011. Effects of low. QJM 2009. Sugars and starch in the nutritional management of diabetes mellitus. et al. 34:55e7. Negrean M. Apparent lack of pharmacological effect of steviol glycosides used as sweeteners in humans. et al. Annu Rev Nutr 1981. et al.98:897e905. et al. Dietary advanced glycation endproducts and oxidative stress: in vivo effects on endothelial function and adipokines. Diabet Med 2010. Lower postprandial glucose responses at baseline and after 4 weeks use of a diabetes-specific formula in diabetes type 2 patients. et al. Johnston CS. 145. Karter AJ. Lee JH. 170. Diabetes Care 1997. 128. Jhaveri AD. Lee K. Tunbridge FK. Matsuda M. 161. Barriocanal LA. placebo-controlled. van Laere KM. Hong K. 2011. J Am Diet Assoc 2004. 168. et al.8:833e8. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Zhao J. et al. 148. Hendricks HFJ.6:1312e7. Eur J Clin Nutr 2005. Hamad S. Liu Y-H. Alcohol and health in Canada: a summary of evidence and guidelines for low-risk drinking. The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial. Lefevre M. Addict Res Theory 2009. Diabetes Care 2003. Yip I.1126:276e9. 173. Spidel M. Influence of alcohol on cognitive performance during mild hypoglycaemia: implications for Type 1 diabetes. metabolic parameters. A review.17:135e51. Savoca MR. randomized study. Mitchell AM.93:421e9. Miller CK. Maki KC. Am J Clin Nutr 2002. Manto A.20:366e75. McCargar L. Ludwig DA. et al. et al. Weight Watchers. et al. Rossi MC. Sixty-ninth meeting.170:821e7. Diabet Med 2001. Metabolic effects of alcohol in the form of wine in persons with type 2 diabetes mellitus. Almond ingestion at mealtime reduces postprandial glycemia and chronic ingestion reduces hemoglobin A1C in individuals with well-controlled type 2 diabetes mellitus. Chiasson JL. JAMA 2005. Adler AI. Nordmann AJ. 158. Day after the night before: influence of evening alcohol on risk of hypoglycemia in patients with type 1 diabetes. Diabetologia 2006. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. 167. Nutr Metab Cardiovasc Dis 2011. 121. Karimi M.34:1610e6. van der Knaap HC. Bergenstal RM. Hermansen K. Macdonald IA. Lovejoy JC. Can J Diabetes 2004. a steviol glycoside. Ann Intern Med 2004. Mann JI. Ahmed AT. Ann N Y Acad Sci 2008. DAFNE Study Group. Gregersen S. Stolk RP. et al.12:2065e71. Should alcohol policies aim to reduce total alcohol consumption? New analyses of Canadian drinking patterns. Griffith JL. 127. Metabolism 2011.27:477e9. et al.28:1801e2. Effect of moderate red wine intake on cardiac prognosis after recent acute myocardial infarction of subjects with Type 2 diabetes mellitus. Wakabayashi J.20:161e8.34:118e27. 129. Liu J-F. Diabet Med 2004. Sugar alcohols and diabetes: a review. Am J Clin Nutr 2007. Siniscalchi M. Gallagher A. Johnson M. 149.21:230e7. Go VL. et al. Oda K. 139. Neiberg RH. 164. Innis S. et al. Dansinger ML. 133. Almond consumption improved glycemic control and lipid profiles in patients with type 2 diabetes mellitus. Ottawa. et al. Metabolism 2011. A simple meal plan of “eating vegetables before carbohydrate” was more effective for achieving glycemic control than an exchange-based meal plan in Japanese patients with type 2 diabetes. Restriction of advanced glycation end products improves insulin resistance in human type 2 diabetes: potential role of AGER1 and SIRT1. Lee CC. 153. Jenkins DJ. Cacciapuoti F. Scavone G. Gillespie SJ. 136.1:437e75. Int J Obes Relat Metab Disord 2003. Rome. Kulkarni KD. Li Z. Stockwell T. Wolever TM. van Mierlo CA. Sievenpiper JL. Effect of diets enriched in almonds on insulin action and serum lipids in adults with normal glucose tolerance or type 2 diabetes. 159. 130. 163. Di Bartolo P. 150.57: 241e5. lipid peroxidation. Hollands M. Effect of red wine on urinary protein. Effect of carbohydrate counting and medical nutritional therapy on glycaemic control in Type 1 diabetic subjects: a pilot study. J Gen Intern Med 2008. Nordmann A. Food habits are related to glycemic control among people with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2010.166:285e93. Kendall CWC. Asia Pac J Clin Nutr 2011. Kelly WF. et al. 126. Fujiwara N. Diabetes Care 2010. Effect of enteral nutritional products differing in carbohydrate and fat on indices of carbohydrate and lipid metabolism in patients with NIDDM. Sugaya T. 27:1130e7. Thomas G. 140. Kelley DE. Metabolism 2009. Bazzano LA. 125. multicenter. Warton M.26:356e62. 165. 51:37e41. general health. FRCPC. PhD. diet. Patients must receive initial and ongoing education that includes comprehensive information on how to care for and use insulin.  Insulin regimens should be tailored to the individual’s treatment goals. Insulin preparations are classified according to their duration of action and are further differentiated by their time of onset and peak actions (Table 1). insulin aspart and insulin lispro have been shown to be superior to regular insulin by improving postprandial glycemic control and reducing hypoglycemia (10e13).jcjd. lifestyle. This period is. FRCPC.doi. CDE. Insulin Regimens Insulin regimens should be tailored to the individual’s treatment goals. Human insulin and insulin analogues are preferred and used by most adults with type 1 diabetes. carbohydrate counting) and physical activity. some patients go through a “honeymoon period. adverse events.g. prevention. CSII may provide some advantages over other methods of 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.org/10.17). motivation.1016/j. Cheri Hernandez RN. Basal insulin is provided by an intermediate-acting insulin or a long-acting insulin analogue once or twice daily. exercise around mealtime KEY MESSAGES  Basal-bolus insulin regimens (e. Bolus insulin is provided by a short-acting insulin or a rapid-acting insulin analogue given at each meal. multiple daily injections or continuous subcutaneous insulin infusion) are the insulin regimens of choice for all adults with type 1 diabetes. recognition and treatment of hypoglycemia. This will involve both the selection of an insulin regimen and the start of education. Cindy Richardson MD.3). FACP intensive therapy. FRCPC. diet.2013. Pharmacotherapy for prevention of complications and treatment of risk factors will be addressed in other chapters.Can J Diabetes 37 (2013) S56eS60 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. PhD. The most successful protocols for type 1 diabetes rely on basal-bolus (basalprandial) regimens that are used as a component of intensive diabetes therapy. John Dornan MD. cost and mortality data are lacking (3).canadianjournalofdiabetes. Such protocols attempt to duplicate normal pancreatic insulin secretion. Insulin preparations are primarily produced by recombinant DNA technology and are formulated either as structurally identical to human insulin or as a modification of human insulin (insulin analogues) to alter pharmacokinetics. While fixed-dose regimens (conventional therapy) once were common and still may be used in some circumstances. however. over long-acting analogue regimens with less severe hypoglycemia (2. There may be a role for adjunctive therapy in some people with type 1 diabetes to aid in achieving optimal glycemic targets. hypoglycemia awareness status and ability for self-management. Social and financial aspects also should be considered. Introduction Insulin is lifesaving pharmacological therapy for people with type 1 diabetes. sick-day management.” during which insulin requirements may decrease. motivation.01. they are not preferred. and self-monitoring of blood glucose (SMBG). prevention and treatment of insulin-induced hypoglycemia.15). The Diabetes Control and Complications Trial (DCCT) conclusively demonstrated that intensive treatment of type 1 diabetes significantly delays the onset and slows the progression of microvascular and macrovascular complications (16. pen or pump (continuous subcutaneous insulin infusion [CSII]). lifestyle. age. age.g. adjustments for food intake (e. hypoglycemia awareness status and ability for self-management. For CSII and CGMS.com Clinical Practice Guidelines Pharmacotherapy in Type 1 Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Angela McGibbon MD. general health. in fewer studies. Advancements in basal insulins may lessen the value of CSII in type 1 diabetes.020 . preparations of animal-sourced insulin are still accessible in Canada (1). After insulin initiation. transient (usually weeks to months). Prandial insulin dose must take into account the carbohydrate content and glycemic index of the carbohydrate consumed. CSII therapy is a safe and effective method of intensive insulin therapy in type 1 diabetes and has shown improvements in glucose control over NPH-based regimens and.  All individuals with type 1 diabetes should be counseled about the risk. Initiation of Insulin Therapy Patients with type 1 diabetes will be initiated on insulin therapy immediately at diagnosis. Advances in continuous glucose monitoring systems (CGMSs) may augment CSII (14. Premixed insulin preparations are available and are not generally suitable for intensive treatment in patients with type 1 diabetes in whom frequent adjustments of insulin are required. Insulin Delivery Systems Insulin can be administered by syringe. particularly in individuals with higher baseline glycated hemoglobin (A1C) (4e9) In patients using CSII. and insulin requirements will increase with time. however. Insulin pen devices facilitate the use of multiple injections of insulin. their rapid onset of action allows for these insulins to be administered up to 15 minutes after a meal. However. and the fact that the carbohydrate-to-insulin ratio may not be the same for each meal (breakfast. the median incidence of severe hypoglycemia was 4. Hypoglycemia can be severe and result in confusion.5 h 1e3 h 5e8 h Up to 18 h (40). Adjunctive therapy for glycemic control As the incidents of obesity and overweight increase in the population. has been shown to have comparable safety and tolerability to insulin glargine when used as a basal insulin in type 1 diabetes and less hypoglycemia (47). In the DCCT. Compared with regular insulin. 15% to 30% of patients using insulin glargine will experience preinjection hyperglycemia. but it does not result in improved A1C (48). Canada) and product monographs for detailed information. symptomatic and counterregulatory hormonal responses to hypoglycemia induced by 90 min Not Up to 24 h applicable (glargine 24 h. Ottawa.or twice-daily NPH insulin (18.58). insulin aspart. requiring the assistance of other individuals. insulin aspart. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. 50/50 insulin to % of intermediatePremixed insulin analogues (cloudy) acting insulin) Biphasic insulin aspart Ò (NovoMix 30) Insulin lispro/lispro protamine (HumalogÒ Mix25 and Mix50) Physicians should refer to the most current edition of Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association. the long-acting analogues.42e46). insulin degludec. 35% of patients in the conventional treatment group and 65% in the intensive group experienced at least 1 episode of severe hypoglycemia (49. frequency. Studies have suggested that with adequate self-management education. which is prevented by twice daily administration of the insulin (41). McGibbon et al. insulin detemir and insulin glargine (with regular insulin or rapid-acting insulin analogues for meals). Insulin glulisine has been shown to be equivalent to insulin lispro for glycemic control. SMBG and professional support.28e37). recognition. better overall glycemic control (22. The negative social and emotional impact of hypoglycemia may make patients reluctant to intensify therapy. Insulin analogues vs. Regular insulin should ideally be administered 30 to 45 minutes prior to a meal. Due to concerns that alterations in the pharmacokinetics may occur. however. detemir 16e24 h) Premixed insulins A single vial or cartridge contains Premixed regular insulineNPH a fixed ratio of insulin (% of (cloudy) rapid-acting or short-acting HumulinÒ 30/70 NovolinÒ ge 30/70.75 h 6.42).6 and 7. Hypoglycemia Insulin-induced hypoglycemia is a major obstacle for individuals trying to achieve glycemic targets. intensive therapy may result in less hypoglycemia than reported in the DCCT (52e55). In fact. CGMS used in addition to CSII or with multiple daily injections is associated with less hypoglycemia than with the use of traditional glucose testing (57.5 h 10e15 min 1e2 h 30 min 2e3 h 3e5 h 3e5 h 3. Prandial insulins also can be used for correction doses to manage hyperglycemia. conventional insulin therapy Hypoglycemia is the most common adverse effect of intensive insulin therapy in patients with type 1 diabetes. In a meta-analysis of 14 trials. The diabetes healthcare team should review the patient’s experience with hypoglycemia at each visit. Metformin use in type 1 diabetes is off-label and potentially harmful in the setting of renal or heart failure. as well as the risk of driving mishaps with hypoglycemia. lunch and dinner).27).24. / Can J Diabetes 37 (2013) S56eS60 Table 1 Types of insulin Insulin type (trade name) Bolus (prandial) insulins Rapid-acting insulin analogues (clear) Insulin aspart (NovoRapidÒ) Insulin glulisine (ApidraÒ) Insulin lispro (HumalogÒ) Short-acting insulins (clear) HumulinÒ-R NovolinÒ ge Toronto Basal insulins Intermediate-acting (cloudy) HumulinÒ-N NovolinÒ ge NPH Long-acting insulin analogues (clear) Insulin detemir (LevemirÒ) Insulin glargine (LantusÒ) Onset Peak Duration S57 10e15 min 1e1. symptoms.A. The use of metformin in type 1 diabetes reduces insulin requirements and the total cholesterol/ low-density lipoprotein ratio and may lead to modest weight loss. mixing detemir or glargine with other insulins in the same syringe is not recommended by the manufacturers. An ultra-long-acting insulin analogue. results in improved postprandial glycemic control and A1C while minimizing the occurrence of hypoglycemia (when using insulin lispro or insulin aspart) (18e23). Among people with type 1 diabetes.50). appropriate glycemic targets. the avoidance of this complication is of critical clinical importance. When used as a basal insulin in patients with good glycemic control. This should include an estimate of cause.25). Insulin detemir has a flatter pharmacodynamic profile than NPH insulin (33). In contrast. Ontario. preprandial injections achieve better postprandial control and. respectively (51). regular and intermediate-acting insulins Although there are no differences in the magnitude and temporal pattern of the physiological. in combination with adequate basal insulin. with greater A1C reduction when given preprandially as opposed to postprandially (22.39). Intensive vs. coma or seizure.9 episodes per 100 patientyears in the conventionally treated and intensively treated patients. CSII leads to reductions in severe hypoglycemia compared to multiple daily injections (56).5 h 10e15 min 1e1. 40/60. severity and treatment. insulin glargine has been shown to have a longer duration of action compared with detemir . When compared with 4-times-daily NPH insulin. insulin glargine was associated with lower A1C and less hypoglycemia (32). there is increasing interest in the potential use of oral medications that improve insulin sensitivity for these patients. possibly. Twicedaily insulin detemir as the basal component of a basal-bolus insulin regimen has been shown to reduce nocturnal hypoglycemia compared with twice-daily NPH insulin (34. result in lower fasting plasma glucose levels and less nocturnal hypoglycemia compared with once. Patients report increased treatment satisfaction and quality of life with use of insulin glargine compared with use of NPH in a basal-bolus insulin regimen (38. Insulin aspart has been associated with improved quality of life (26). including those with type 1 diabetes. insulin glulisine and insulin lispro should be administered 0 to 15 minutes before meals. insulin glulisine or insulin lispro. Given the potential severe consequences of nocturnal hypoglycemia (discussed below). There has been a trend toward improved A1C with both insulin detemir and insulin glargine that has reached significance in several studies (36.38.5e4. 4. Gomis R.g. p.74). To reduce the risk of asymptomatic nocturnal hypoglycemia. Frequent hypoglycemia can decrease normal responses to hypoglycemia (82) and lead to hypoglycemia unawareness and defective glucose counterregulation.21. 2. SMBG before. Knowledge of the acute effects of exercise is mandatory. including periodic assessment during sleeping hours [Grade D. 2.82e88). Grade D. Consensus for glargine].S58 A. p. In contrast. particularly when bedtime plasma glucose levels are <7. and risk factors for severe hypoglycemia should be identified and addressed [Grade D. Severe hypoglycemia is often the primary barrier to achieving glycemic targets in people with type 1 diabetes (72) and occurs frequently during sleep or in the presence of hypoglycemia unawareness (73. Adding bedtime snacks may be helpful to prevent nocturnal hypoglycemia among those taking NPH as the basal insulin or in those individuals at high risk of severe hypoglycemia (regardless of insulin type). individuals using intensive insulin therapy should periodically monitor overnight BG levels at a time that corresponds with the peak action time of their overnight insulin.69). highintensity exercise raises BG levels during and immediately after the event. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus.37. care should be taken to develop an individualized meal and activity plan that the person can and will follow (67).gc.324: 705. Lifestyle factors Deviations from recommended or appropriate self-management behaviours (e.0 mmol/L (68. If ketosis is present (urine ketone level >8.0 mmol/L or blood ketone level >3. hypoglycemia was reported to occur at a mean rate of approximately 2 episodes per week.90). Level 3 (64) for glargine]. including nocturnal hypoglycemia [Grade B.77e80). taking more insulin. p. Consensus]. glargine) may be used as the basal insulin [Grade B. Hoogma RP. Misso ML.61e64). S119 Type 1 Diabetes in Children and Adolescents. Comparison of the effects of continuous subcutaneous insulin infusion (CSII) and NPH-based multiple daily insulin injections (MDI) on glycaemic control and quality of life: results of the 5-nations trial. Asymptomatic nocturnal hypoglycemia is common and often lasts >4 hours (73. Kerry S. Other Relevant Guidelines Targets for Glycemic Control. / Can J Diabetes 37 (2013) S56eS60 regular human insulin or rapid-acting analogues (59. Level 1A (16)]. Level 2 (19. improve A1C [Grade B.23:141e7. 3. in combination with adequate basal insulin. such that the first sign of hypoglycemia is confusion or loss of consciousness.1:CD005103. Level 2 (10. p. S69 In-hospital Management of Diabetes.91)]. increasing the risk of a hypoglycemic episode. p.60). resulting in seizures. Level 2 (23. Pickup J. S35 Physical Activity and Diabetes. S163 Diabetes and Pregnancy. during and especially for many hours after exercise is important for establishing response to exercise and guiding the appropriate management of exercise. Health Canada website. SMBG. These effects on BG levels can be modified by altering diet. exercise should not be performed as metabolic deterioration will occur (70). p. Increased frequency of SMBG. Rapid-acting bolus insulin analogues. the threshold for the neuroglycopenic symptoms. The sympathoadrenal response to hypoglycemia is reduced during sleep (75. basal-bolus insulin regimens or CSII as part of an intensive diabetes management regimen should be used [Grade A. BG awareness training) may help improve detection of hypoglycemia and reduce the frequency of severe hypoglycemia (89. Egberts KJ. Low. p. Glycaemic control with continuous subcutaneous insulin infusion compared with intensive insulin injections in patients with type 1 diabetes: meta-analysis of randomised controlled trials. Hammond PJ. BMJ 2002. Consensus] b. self-monitoring of blood glucose. the following strategies may be used to reduce the risk of hypoglycemia and to attempt to regain hypoglycemia awareness: a. A long-acting insulin analogue (detemir. www. Both hypoglycemia unawareness and defective glucose counterregulation are potentially reversible. A psychobehavioural intervention program (blood glucose awareness training) [Grade B. In individuals with hypoglycemia unawareness. RECOMMENDATIONS Insulin regimens for type 1 diabetes 1. should be used instead of regular insulin to minimize the occurrence of hypoglycemia. S40 Pharmacologic Management of Type 2 Diabetes. p. . McGibbon et al.hc-sc. Level 2 (63) for detemir. For patients managed with fixed-dose insulin regimens. S61 Hypoglycemia. Severe hypoglycemia.88)] c. Grade C. Diabetic Medicine 2005. p. 3. In type 1 diabetes. Level 2 (28-31)] to reduce the risk of hypoglycemia [Grade B. 4. Level 2 (90)] Abbreviations: CSII. Strict avoidance of hypoglycemia for a period of 2 days to 3 months has been associated with improvement in the recognition of severe hypoglycemia. Long-acting insulin analogues may reduce the incidence of hypoglycemia and nocturnal hypoglycemia when compared to intermediate-acting insulin as the basal insulin (36. Level 3 (87. S153 Type 2 Diabetes in Children and Adolescents.11)]. Less stringent glycemic targets with avoidance of hypoglycemia for up to 3 months [Grade C. To achieve glycemic targets in adults with type 1 diabetes. Exercise-induced hypoglycemia may be lessened with the use of detemir as the basal insulin (71). the counterregulatory hormone responses or both (52. 2013.23)] and achieve postprandial glucose targets [Grade B.76).66). S168 Diabetes in the Elderly. or lower than. 6. Page M. Structured educational and psychobehavioural programs (e.0 mmol/L). S77 Management of Acute Coronary Syndromes. S184 References 1. insulin. et al. Accessed February 28. Hypoglycemia unawareness and nocturnal hypoglycemia Hypoglycemia unawareness occurs when the threshold for the development of autonomic warning symptoms is close to.ca. is more likely to occur at night than during the day (81). All individuals with type 1 diabetes should be counselled about the risk and prevention of insulin-induced hypoglycemia. Level 2 (63) for detemir.g. et al. Cochrane Database Syst Rev 2010. Mattock M. S31 Monitoring Glycemic Control. Rapid-acting insulin analogues (aspart or lispro) should be used with CSII in adults with type 1 diabetes [Grade B. the frequency of hypoglycemic events has been shown to be reduced with rapid-acting insulin analogues compared with regular insulin (18e21). engaging in more activity) account for 85% of hypoglycemic episodes (65. Hypoglycemia 5. eating less food. p. continuous subcutaneous insulin infusion. p.to moderate-intensity exercise lowers blood glucose (BG) levels both during and after the activity. and the type and timing of exercise. Diabetes Care 2002. Philotheou A. Diabet Med 2006. Diabetes Care 2007. et al. Porcellati F. Diabetes Care 2011. Bott U. Diabetes Care 2001. Russell-Jones D. Diabetologia 2009. 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Bott U. Twice-daily compared with once-daily insulin glargine in people with Type 1 diabetes using meal-time insulin aspart.4: 311e20. Chatterjee S. Basu A. Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime.27:2590e6. A meta-analysis. Backlund JY. 32. Long-acting insulin analogues vs. Diabetes Care 2005. Efficacy comparison between preprandial and postprandial insulin aspart administration with dose adjustment for unpredictable meal size. DeVries JH. Preprandial vs. Garg S.20:626e34. Ashwell SG. 53. Treatment satisfaction and quality of life with insulin glargine plus insulin lispro compared with NPH insulin plus unmodified human insulin in individuals with type 1 diabetes. 18. et al. Moser E. Amiel SA. Bodenlenz M. Cleary PA. Glycaemic control in type 1 diabetes during real time continuous glucose monitoring compared with self monitoring of blood glucose: meta-analysis of randomised controlled trials using individual patient data. 7. Golicki D. A randomized controlled trial of a new-generation ultra-long-acting insulin compared with insulin glargine. Mannucci E. 47. et al. Warren E. 51. et al. Diabetes Care 1999. et al. Plosker GL. Bell D. Systematic review and economic evaluation of a long-acting insulin analogue. Insulin degludec in type 1 diabetes. 15. Diabetes Care 2003. et al. Sutton AJ. Ways K.23:285e92. Diabetes Care 2008. Diabetes Metab Res Rev 2004. 35.2:CD003287.A. 22. Bode BW. Monami M. 38. Weinstein R. Ashwell SG. Jenkins GD. Vaaler S.12:835e46.25:1541e77. 13. Continuous subcutaneous insulin infusion versus multiple daily insulin injections in type 1 diabetes: a meta-analysis. Tsui E. Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes. Hypoglycemia in the Diabetes Control and Complications Trial. Glycaemic impact of patient-led use of sensor-guided pump therapy in type 1 diabetes: a randomised controlled trial. post-prandial insulin lispro: a comparative crossover trial in patients with type 1 diabetes. Szypowska A. DeWitt DE. Acquistapace M. Continuous subcutaneous insulin infusion versus multiple daily injections: the impact of baseline A1c.28:10e4. 25.64:2577e95. O’Connell MA. 27.23:879e86. 43. Siebenhofer A. et al. Battelino T.46: 271e86. Rosenstock J. Chiasson JL.25: 442e9. Meticulous prevention of hypoglycemia normalizes the glycemic thresholds and magnitude of most of neuroendocrine responses to. Selam JL. Diabet Med 2003. Zinman B. Diabetologia 1997. Plank J. et al. Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial. Fontaine P. Diabetes Obes Metab 2005. Giammattei J. Garg SK. 19. Home PD. Pampanelli S. Meta-analysis of short-acting insulin analogues in adult patients with type 1 diabetes: continuous subcutaneous insulin infusion versus injection therapy. et al.20: 178e88. 40. Kudva YC. Bott S. Vergara CM. Health Technol Assess 2004. Jovanovic L. et al. Siebenhofer A. et al.34:661e5. Bartley PC. . Rodionova A.47:622e9. 29. Short acting insulin analogues versus regular human insulin in patients with diabetes mellitus. et al. A review of human and analogue insulin trials. 24. Jarvis-Kay J. Snoek FJ. Effect of the rapid-acting insulin analogue insulin aspart on quality of life and treatment satisfaction in patients with type 1 diabetes. 42. 55.289:2254e64. Dutch Insulin Pump Study Group.21:769e75. 12.26:1492e7. Diabetes Care 2004. Hermansen K. et al. 39. 56.52:1250e7.63:1743e78. Intensive insulin therapy with insulin lispro: a randomized trial of continuous subcutaneous insulin infusion versus multiple daily insulin injection. Kukolja KK. Bratina N. 11:372e8. 20. safety. and cost-effectiveness. Drugs 2003.28: 1107e12. Hypoglycaemia with insulin aspart: a double-blind.10:39e41. Birkeland KI. Hirsch IB. insulin glargine. Comparison of insulin aspart with buffered regular insulin and insulin lispro in continuous subcutaneous insulin infusion: a randomized study in type 1 diabetes. controlled trial.24:1722e7. Home P. Diabetes Care 2002. and cognitive function during hypoglycemia in intensively treated patients with short-term IDDM. 41. Marchionni N. Endocr Pract 2005.329:977e86. Diabet Med 2006. JAMA 2003. Larsen J. et al. N Engl J Med 2005. 36. et al.28:533e8. et al. The Diabetes Control and Complications Trial Research Group. Garg S. Severe hypoglycaemia and glycaemic control in Type 1 diabetes: meta-analysis of multiple daily insulin injections compared with continuous subcutaneous insulin infusion.22(suppl 2): B43e52. Intensified insulin therapy and the risk of severe hypoglycaemia. Barnie A. Clin Ther 2003. A randomized trial of continuous subcutaneous insulin infusion and intensive injection therapy in type 1 diabetes for patients with long-standing poor glycemic control. Wendisch U. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis. randomised. et al. Tildesley H. randomized. Bode B. Bogoev M. et al. Rambotti AM. Diabet Med 2008.18:1415e27. Efficacy and safety of insulin glulisine in patients with type 1 diabetes. Diabetes Care 2011. Diabetes 1993. Schernthaner G. Dunn CJ. properties of the long-acting insulin analog detemir. 9. et al. Diabetes Res Clin Pract 2007. Diabetologia 2004. Ahmann A. Plank J. et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.77:215e22. Tamborlane WV. DeVries JH. symptoms of. et al. Diabetologia 2010. 54.40:926e32. 10. The Diabetes Control and Complications Trial Research Group. NPH human insulin in type 1 diabetes. Home PD. Wang F. Sinner F. Fanelli CG. Continuous subcutaneous insulin infusion (CSII) of insulin aspart versus multiple daily injection of insulin aspart/insulin glargine in type 1 diabetic patients previously treated with CSII.30:2447e52.25: 765e74. Marchionni N. A double-blind. 37. Berger M. Lamanna C. Rossetti P.21:279e84. Diabetes Care 2005. Fanelli C. 28. et al.53:809e20. Vague P. Sutton AJ. Freeman SC. Chapman TM. et al.31:1112e7. 21.25:439e44. / Can J Diabetes 37 (2013) S56eS60 5. Hochman J. Diabetes Technol Ther 2010. McGibbon et al.90:450e9. Impact of bedtime snack composition on prevention of nocturnal hypoglycemia in adults with type 1 diabetes undergoing intensive insulin management using lispro insulin before meals: a randomized. The DCCT Research Group. 84. et al. Diabetologia 1977. Unrecognised nocturnal hypoglycaemia in insulintreated diabetics.6:589e95. Sharplin P. Keating B.39:502e7. Hermanns N. Kinsley BT. Kalergis M.131:27e33.47:1472e9. Diabetes Care 1999. et al. 72. Hypoglycemia. Pampanelli S. Buettner U. Diabetes Care 1997. Reversal of hypoglycemia unawareness. Insulin detemir: a new basal insulin analog. Improved glycemic control without an increase in severe hypoglycemic episodes in intensively treated patients with type 1 diabetes receiving morning. Diabet Med 1997. et al.26: 9e15. Symptomatic and physiological responses to hypoglycaemia induced by human soluble insulin and the analogue lispro human insulin. et al. Liu D. et al. The relationship between nonroutine use of insulin.29:1607e19. Am J Med 1994. Renn W. Cryer PE. J Behav Med 2005. Pharmacokinetics. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Clin Invest Med 1996. Pro(B29)] in IDDM. .97:535e42. et al. Diabet Med 2003. et al.23:55e8.13:794e9. 78. Negative binomial meta-regression analysis of combined glycosylated hemoglobin and hypoglycemia outcomes across eleven phase III and IV studies of insulin glargine compared with neutral protamine Hagedorn insulin in type 1 and type 2 diabetes mellitus.1:1049e52. Tattersall RB.115:681e5. Mullins P.17:734e55. Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus. Diabetes Educ 1997. Grimaldi A. Gottlieb PA. 86. Nocturnal blood glucose profiles in patients with type 1 diabetes mellitus on multiple (> or ¼ 4) daily insulin injection regimens. Dellweg S. et al. Diabetes Care 1999. Rambotti AM. 73. Nocturnal hypoglycemia in children and adolescents with insulin-dependent diabetes mellitus: prevalence and risk factors. Ovalle F. Diabetes Care 1994. Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. Diabetes Technol Ther 2004. 80. Clarke WL. Fisher JN. Garg SK. A randomized trial of insulin aspart with intensified basal NPH insulin supplementation in people with type 1 diabetes.22:1022e8.28:587e94. Reduced severe hypoglycemia with insulin glargine in intensively treated adults with type 1 diabetes. Perlman K. Karsten JI. 87.18:321e5.14:929e36. et al. or split dose insulin glargine. Stumvoll M. Weinger K. 69. Kaufman FR. Frank M. 59. 61. Cryer PE. Schiffrin A. Randomized controlled clinical trial of Blood Glucose Awareness Training (BGAT III) in Switzerland and Germany. food. Banting Lecture. Cryer PE. crossover trial.19:71e82. pharmacodynamics and glucose counterregulation following subcutaneous injection of the monomeric insulin analogue [Lys(B28). 91. Diabetes Res Clin Pract 1998. Gonder-Frederick LA. Diabetes Res Clin Pract 2004. Epifano L. Porter PA. Halvorson M. Cox DJ. Hisatomi ME. 77. Mellman M.13: 355e65. Stick S. Fanelli C. Jacobsen JL. 67. PLOS Med 2007. Gale EA. et al. 88. Kaufman ND. Paul JM. Bajaj M. Diabet Med 2009.43:1426e34. Diabetes teaching program improves glycemic control and preserves perception of hypoglycemia. deficient counterregulation and lack of cognitive dysfunction during hypoglycaemia. Vervoort G.20:22e5. but not defective glucose counterregulation. 83. Davis EA. Fanelli CG. blinded trial of uncooked cornstarch to diminish nocturnal hypoglycemia at diabetes camp. Hypoglycemia: the limiting factor in the management of IDDM. Benali K. Arutchelvam V. 76. Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. Daneman D. 82. in IDDM. Diabetes Care 1995.20:312e8. Garg SK. 65. J Pediatr 1997. Blood glucose awareness training and epinephrine responses to hypoglycemia during intensive treatment in type 1 diabetes. Yki-Jarvinen H. Lancet 1979. Diabet Med 1996. J Pediatr 1989. Schachinger H. Am J Med 1991.31:246e51. Dagogo-Jack S. 63. Berchtold P. Dagogo-Jack S. et al. Diabetologia 1994. Metabolic and hormonal effects of muscular exercise in juvenile type diabetics. Fritsche A. 74. Diabetes 1994. Diabetes 1994. A randomized. 79. Fanelli C. 64. McCrimmon RJ. Tubiana-Rufi N. Ryan EA. Berlin I. Ann Pharmacother 2005. Byrne G. Long-term recovery from unawareness. Diabetes Res Clin Pract 1995. Fanelli CG.4:0361e9. et al. 37:713e20. Frier BM. Friedman S. Cüppers HJ. Sachon CI.22:866e7. Diabetes Care 2003. Recovery of epinephrine response but not hypoglycemic symptom threshold after intensive therapy in type 1 diabetes. 60.43:1378e89. et al. et al. van Doorn LG. 70. McManus RM. et al. 90. Lingenfelser T. / Can J Diabetes 37 (2013) S56eS60 75. 89. Severe hypoglycemia in children with insulin-dependent diabetes mellitus: frequency and predisposing factors. Heise T. Cryer PE. Schultes B. Gais S.30:205e9.75:120e3. 66. following institution of rational.40:129e35. et al. 62. Lee KW. Martin J. Gougeon R. Berger M. evening.26:1027e32. Arch Dis Child 1996. Improved counter-regulatory hormonal and symptomatic responses to hypoglycemia in patients with insulin-dependent diabetes mellitus after 3 months of less strict glycemic control. et al.S60 A.37:1265e76. Goldschmidt HM. Clin Ther 2007. 85. Diabetes 1998. Jauch-Chara K. Byrne GC. Tri-Continental Insulin Aspart Study Group. Paramore DS. Hegar K. Plasma glucose and hypoglycaemia following exercise in people with Type 1 diabetes: a comparison of three basal insulins. 81. placebo-controlled. Rattarasarn C. Goldman-Levine JD. Identification of factors associated with impaired hypoglycaemia awareness in patients with type 1 and type 2 diabetes mellitus. Torlone E. and exercise and the occurrence of hypoglycemia in adults with IDDM and varying degrees of hypoglycemic awareness and metabolic control. DeVries JH.66:49e56. et al. Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM. Nocturnal hypoglycaemia and sleep disturbances in young teenagers with insulin dependent diabetes mellitus. 68. Davis M. intensive insulin therapy in IDDM. Lindholm A. Diabetes Metab 2005. et al. Shamoon H. 71. Diabetologia 1994. et al. Durable reversal of hypoglycemia unawareness in type 1 diabetes. et al. Beregszàszi M. With timely adjustments to and/ or additions of antihyperglycemic agents. Several classes of antihyperglycemic agents have greater efficacy at lowering postprandial BG levels (7e20). glycated hemoglobin [A1C] 8. PhD. When lifestyle interventions fail to control blood glucose (BG) levels adequately. sulfonylureas and meglitinides or dipeptidyl peptidase [DPP]-4 inhibitors and glucagon-like peptide [GLP]-1 agonists) is currently untested.g. There is also debate over which agents within a given . CDE. the greater the A1C reduction seen for each given agent. risk of hypoglycemia and effect on body weight. FRCPC.5). although adopting an approach of specifically targeting postprandial BG control has not been shown to be effective at reducing macrovascular diabetes complications (21). Jean-François Yale MD. combinations of agents are usually required. In general. with additional antihyperglycemic agents selected on the basis of clinically relevant issues. metformin should be the initial agent of choice. FACP.com Clinical Practice Guidelines Pharmacologic Management of Type 2 Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by William Harper MD.  In patients with marked hyperglycemia (A1C 8.e. pharmacological treatment becomes necessary.021 macrovascular complications at the time of diagnosis (2. Treatment Regimens The diagnosis of type 2 diabetes is often delayed. 1 of which may be insulin. the higher the baseline A1C. antihyperglycemic pharmacotherapy should be initiated. medication effectiveness at reducing diabetes complications (microvascular and/or macrovascular). Furthermore. Ravi Retnakaran MD. such as contraindication to drug. BCh. glucose lowering effectiveness. classes of agents that have different mechanisms of action should be used. taking into account the characteristics of the different medications. MSc. CSPQ. Amir Hanna MB. FRCPC KEY MESSAGES  If glycemic targets are not achieved within 2 to 3 months of lifestyle management. risk of hypoglycemia. Table 1 identifies the mechanism of action for all classes of antihyperglycemic agents to aid the reader in avoiding the selection of agents with overlapping mechanisms. In general. Lifestyle modification.3%). postprandial BG control assumes greater importance for further A1C reduction (6). There is debate over which antihyperglycemic agent (including insulin) should be used initially and which agents should be added subsequently. including nutritional therapy and physical activity. antihyperglycemic agents should be made to attain target glycated hemoglobin (A1C) within 3 to 6 months. CCFP. Simultaneous use of agents within the same class and/or from different classes but with similar mechanisms of action (e. medication side effects. with the maximum effect of oral antihyperglycemic agent monotherapy seen at 3 to 6 months (4. medication effects on body weight. A1C will decrease by about 0.2013. CDE. and treatment must be dynamic as therapeutic requirements increase with longer duration of disease.  Unless contraindicated.5% to 1.3). FACE.org/10.01.doi. FRCPC. should continue to be emphasized while pharmacotherapy is being used as many agent classes can cause weight gain as a side effect. may be less effective at improving glycemia and is not recommended at this time. Diana Sherifali RN. As type 2 diabetes is characterized by insulin resistance and ongoing decline in beta cell function. and/or additions of. FRCPC. ability to adhere to regimen and patient preferences. as A1C levels decrease toward target levels (<7. many patients on monotherapy with the late addition of another antihyperglycemic agent may not readily attain target BG levels (1). antihyperglycemic agents should be initiated concomitantly with lifestyle management.1016/j. FRCPC. Ronald Goldenberg MD.5% with monotherapy. requiring the clinician to consider many of the following factors when choosing medications: degree of hyperglycemia. When combining antihyperglycemic agents with or without insulin. treatment regimens and therapeutic targets should be individualized. Introduction As people with type 2 diabetes form a heterogeneous group. and consideration should be given to initiating combination therapy with 2 agents.5%). Maureen Clement MD. Andrea Main BScPhm. In the face of more severe hyperglycemia (i. the target A1C level should be attainable within 3 to 6 months. The initial use of combinations of submaximal doses of antihyperglycemic agents produces more rapid and improved glycemic control and fewer side effects compared to monotherapy at maximal doses (22e25). FRCPC. Vincent Woo MD. depending on the agent used and the baseline A1C level. glucose levels likely will worsen over time (1).5%). The number of available antihyperglycemic agents is ever expanding. concomitant medical conditions. The lag period before adding other antihyperglycemic agent(s) should be kept to a minimum. By and large.Can J Diabetes 37 (2013) S61eS68 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.  Timely adjustments to. and 20% to 50% of people with type 2 diabetes present with microvascular and/or 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.jcjd. TZDs.10. Novolin ge 30/70.82)  Not recommended as initial therapy in people with marked hyperglycemia (A1C 8. DPP-4 inhibitors and sulfonylureas Combined formulations Avandamet (metformin þ 0.53. Mix50) Significant risk (hypoglycemia risk highest with regular and NPH insulin)  Potentially greatest A1C reduction and no maximal dose  Numerous formulations and delivery systems (including subcutaneousinjectable)  Allows for regimen flexibility  When initiating insulin.50.8% rosiglitazone) Janumet (metformin þ sitagliptin) 0.7% Jentadueto (metformin þ linagliptin) Avandaryl (glimepiride þ 1.6% rosiglitazone) Sitagliptin (Januvia) Saxagliptin (Onglyza) Linagliptin (Trajenta) 0.S62 Table 1 Antihyperglycemic agents for use in type 2 diabetes Class* and mechanism of action Drug (brand name) Expectedy Relativey Hypoglycemia decrease A1C in A1C lowering 0. Harper et al.1% YYY Bolus (prandial) insulins Rapid-acting analogues Aspart (NovoRapid) Glulisine (Apidra) Lispro (Humalog) Short-acting Regular (Humulin-R. 50/ 50) Biphasic insulin aspart (NovoMix 30) Insulin lispro/lispro protamine suspension (Humalog Mix25.81.5%)  Weight neutral as monotherapy  GI side effects  See metformin.7% YY YY Negligible risk as monotherapy YYY YY Moderate risk W. Novolin ge Toronto) Basal insulins Intermediate-acting NPH (Humulin-N. / Can J Diabetes 37 (2013) S61eS68  Weight neutral  Improved postprandial control  Rare cases of pancreatitis        Improved postprandial control Significant weight loss Nausea and vomiting Administration parenteral Rare cases of pancreatitis Parafollicular cell hyperplasia Contraindicated with personal/family history of medullary thyroid cancer or multiple endocrine neoplasia syndrome type 2 DPP-4 inhibitor: amplifies incretin pathway activation by inhibition of enzymatic breakdown of endogenous GLP-1 and GIP (45) Negligible risk as monotherapy GLP-1 receptor agonist: activates incretin Exenatide (Byetta) pathway by utilizing DPP-4 resistant analogue Liraglutide (Victoza) to GLP-1 (45e48) 1.9%d1. 40/60.0% YY to YYY Negligible risk as monotherapy Insulin: activates insulin receptors to regulate metabolism of carbohydrate. Novolin ge NPH) Long-acting basal analogues Detemir (Levemir) Glargine (Lantus) Premixed insulins Premixed Regular-NPH (Humulin 30/70.6% Y Negligible risk as monotherapy Other therapeutic considerations Alpha-glucosidase inhibitor: inhibits pancreatic alpha-amylase and intestinal alphaglucosidase Acarbose (Glucobay) (7. consider adding bedtime long-acting basal analogue or intermediate-acting NPH to daytime oral antihyperglycemic agents (although other regimens can be used)  Basal-bolus regimen recommended if above fails to attain glycemic targets  Increased risk of weight gain relative to sulfonylureas and metformin . fat and protein (3.83e85) 0.11. (52. * Listed in alphabetical order.7% Y YY Minimal/moderate risk Minimal/moderate risk  Relatively rapid BG-lowering response  All insulin secretagogues reduce glycemia similarly (except nateglinide.108)  Rare risk bladder cancer with pioglitazone (109)  Promote weight loss  Orlistat can cause diarrhea and other GI side effects Metformin: enhances insulin sensitivity in liver Glucophage. z Combining insulin with a TZD is not an approved indication in Canada.8% YY Minimal/moderate risk Moderate risk Significant risk 0.95) activated protein kinase 1.111) with exception of metformin where A1C percentage/relative reduction reflects expected monotherapy efficacy. estimated glomerular filtration rate. generic) (86. / Can J Diabetes 37 (2013) S61eS68  Longer duration of glycemic control with monotherapy compared to metformin or glyburide  Mild BP lowering  Between 6 and 12 weeks required to achieve full glycemic effect  Weight gain  May induce edema and/or congestive heart failure  Contraindicated in patients with known clinical heart failure or evidence of left ventricular dysfunction on echocardiogram or other heart imaging  Higher rates of heart failure when combined with insulinz  Rare occurrence of macular edema  Higher occurrence of fractures (29. Diamicron insulin secretion MR. gliclazide is associated with the lowest incidence of hypoglycemia (94) and glimepiride is associated with less hypoglycemia than glyburide (90)  Nateglinide and repaglinide are associated with less hypoglycemia than sulfonylureas due to their shorter duration of action allowing medication to be held when forgoing a meal     Improved cardiovascular outcomes in overweight subjects Contraindicated if CrCl/eGFR <30 mL/min or hepatic failure Caution if CrCl/eGFR <60 mL/min Weight neutral as monotherapy. Glumetza. GLP-1. generic) (3) (Note: Chlorpropamide and tolbutamide are still available in Canada but rarely used) Meglitinides Nateglinide (Starlix) (91) Repaglinide (GlucoNorm) (92. the elderly.33. BP. glucagon-like peptide 1. gastrointestinal.35. eGFR. Physicians should refer to the most recent edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association. DPP-4. generic and peripheral tissues by activation of AMP. Euglucon. renal/hepatic failure)  If a sulfonylurea must be used in such individuals. promotes less weight gain when combined with other antihyperglycemic agents.33)  Possibility of increased risk of myocardial infarction with rosiglitazone (31. AMP. GIP.8% YY Negligible risk as monotherapy Weight loss agent: inhibits lipase Orlistat (Xenical) (105e107. CrCl. GI. Ontario. Canada) for product monographs and detailed prescribing information. y A1C percentage/relative reduction expected when agent from this class is added to metformin therapy (37. glycated hemoglobin. dipeptidyl peptidase 4.97e104) Pioglitazone (Actos) Rosiglitazone (Avandia) 0. S63 . creatinine clearance. gastric inhibitory peptide. blood glucose.87) Glimepiride (Amaryl) (88e90) Glyburide (Diabeta.105.Insulin secretagogue: activates sulfonylurea Sulfonylureas receptor on beta cell to stimulate endogenous Gliclazide (Diamicron.0%d1. BG.g. which is less effective)  Postprandial glycemia is especially reduced by meglitinides  Hypoglycemia and weight gain are especially common with glyburide  Consider using other class(es) of antihyperglycemic agents first in patients at high risk of hypoglycemia (e.5% Y None A1C.93) 0. adenosine monophosphate. including insulin  B12 deficiency (96)  GI side effects W.110) 0. blood pressure. Harper et al.5% YY Negligible risk as monotherapy Thiazolidinedione (TZD): enhances insulin sensitivity in peripheral tissues and liver by activation of peroxisome proliferator-activated receptor-gamma receptors (28e30. Ottawa.30. Ontario. congestive heart failure. thiazolidinedione. GI. Physicians should refer to the most recent edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association. dipeptidyl peptidase 4. GLP-1. Harper et al. . Management of hyperglycemia in type 2 diabetes. gastrointestinal. glycated hemoglobin. A1C. CHF. TZD. DPP-4. / Can J Diabetes 37 (2013) S61eS68 Figure 1. glucagon-like peptide 1. Canada) for product monographs and for detailed prescribing information.S64 W. Ottawa. DPP-4 inhibitors and GLP-1 receptor agonists have been shown to be effective at further lowering glucose levels when combined with insulin therapy (55e58). although heart failure and increased fractures are still concerning side effects (35.W. There is no evidence that exogenous insulin accelerates the risk of macrovascular complications of diabetes. the evidence for pioglitazone suggests a possible reduced risk of cardiovascular events. but more recent evidence has been equivocal on this matter (27). glomerular filtration rate.g. Based on product monograph precautions.30) and inconsistent data regarding myocardial infarction (MI) risk (31e33) significantly limit the clinical utility of this drug class. GLP-1 receptor agonists are particularly effective at promoting concomitant glycemic control and weight reduction (45e48). This approach may result in better glycemic control with a smaller dose of insulin (51). Insulin can be used at diagnosis in individuals with marked hyperglycemia and can also be used temporarily during illness. depending on each individual’s situation (62). its long-term safety track record. While monotherapy with the thiazolidinedione (TZD) rosiglitazone produces more long-lasting glycemic control compared to metformin or glyburide therapy (28). CHF. there must be consideration of multiple factors. TZD. thiazolidinedione. use of insulin earlier in the course of type 2 diabetes can be an effective strategy over oral antihyperglycemic agents (60. The recommendation to use metformin as the initial agent in most patients is based on its effectiveness in lowering BG. the addition of such agents to insulin in carefully selected patients improves glycemic control and reduces insulin requirements (54).64) and superior with respect to glycemic lowering compared to biphasic insulin-based regimens (63). When insulin is used in type 2 diabetes. (insulin glargine or insulin detemir) (50) may be added. the majority of evidence remains equivocal in this regard as most clinical trials compared varying levels of glycemic lowering as opposed to direct comparison between agents used to achieve such glycemic control (38e40).34). Antihyperglycemic medications and renal function. There was a neutral effect on cardiovascular outcomes and cancer. Unfortunately. its relatively mild side effect profile. Although meta-analyses of smaller. and may induce less weight gain and less hypoglycemia than that seen when oral agents are stopped and insulin is used alone (52). The Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial studied the use of basal insulin titrated to a fasting glucose of 5. The addition of bedtime insulin to metformin therapy leads to less weight gain than insulin plus a sulfonylurea or twice-daily NPH insulin (53). consideration would be made towards the selection of agents with evidence demonstrating ability to not only lower glucose levels. While combining insulin with a TZD is not an approved indication in Canada. in few patients. the edema. Figure 2 illustrates the basis on which agent selection is influenced by renal function as dictated by product monograph precautions. When insulin is added to oral antihyperglycemic agent(s). In particular. its negligible risk of hypoglycemia and its lack of causing weight gain. Indeed. there is an increased risk of hypoglycemia. With intensive glycemic control. Harper et al. fluid retention and. but this risk is lower in people with type 2 diabetes than in those with type 1 diabetes. Conversely. First of all. Improved BG and A1C levels are associated with better outcomes. a reduction in new-onset diabetes and a slight increase in hypoglycemia and weight.36). The relative BG and A1C lowering of the various antihyperglycemic agent classes when added to metformin is shown in both Table 1 and Figure 1 and is based on network meta-analysis allowing the comparison between classes that have not yet had direct head-to-head comparison in a randomized clinical trial (37). additional doses of basal insulin (intermediate-acting or .g. even if recommended glycemic targets cannot be reached (3). chronic kidney disease. / Can J Diabetes 37 (2013) S61eS68 S65 class might be preferred in specific situations. The reduction in A1C achieved with insulin therapy depends on the dose and number of injections per day (63). the issue of how to reach glycemic targets may be less important than the need to achieve that target. Each of the agents listed in Table 1 and Figure 1 has advantages and disadvantages to consider. Insulin regimens based on basal or bolus insulin appear to be equally effective (21. increased risk of fractures (29. stress or for a medical procedure or surgery.61). risk of congestive heart failure (CHF). Symptomatic patients with high BG and A1C levels require agents that lower BG levels substantially and quickly (e. Table 1 and Figure 1 provide information to aid decision making. but also reduce the risk of diabetic microvascular and/or macrovascular complications. However. the agent’s effectiveness at BG lowering must be considered in terms of both the degree of baseline hyperglycemia needing correction and any heightened concerns regarding hypoglycemia (e. A combination of oral antihyperglycemic agents and insulin often effectively controls glucose levels. Such combinations can result in increased weight. but long-term efficacy and safety data are currently lacking for this class.3 mmol/L in people at high cardiovascular risk with prediabetes or early type 2 diabetes over 6 years. attention should be paid to the agent’s effects on body weight as this is a clinically relevant issue for many people with type 2 diabetes. The demonstrated cardiovascular benefit in overweight patients is also cited as a reason to select metformin as first-line treatment (26).32). and its appropriate use should be encouraged (59. Ideally. insulin). Designed by and used with the permission of Jean-François Yale MD CSPQ FRCPC. CKD. The number of insulin injections (1 to 4 per day) and the timing of injections may vary. pregnancy. More recent studies looking at the benefits seen with select agents are of such short duration that their results are still preliminary with respect to proving clinical event reduction (41e44) and confirmation awaits the results of more definitive long-term studies.60). elderly patients or those with renal or hepatic dysfunction). insulin requirements will likely increase. and some agents cause significant weight gain while others can help to promote significant weight loss. As type 2 diabetes progresses. this has not been demonstrated in a larger randomized clinical trial (33. the insulin regimen should be tailored to achieve good metabolic control while trying to avoid excessive hypoglycemia. a single injection of intermediate-acting (NPH) (49) or a long-acting insulin analogue Figure 2. In deciding upon which agent to add after metformin. weight gain. Multiple other agent-specific advantages and disadvantages should be weighed as treatment is individualized to best suit the patient’s needs and preferences. GFR. underpowered studies suggested possible risk of MI with rosiglitazone (31. It is estimated that hypoglycemia of any severity occurs annually in up to approximately 20% of patients taking insulin secretagogues (70). RECOMMENDATIONS 1. Concomitant metformin therapy. Turner RC. are usually discontinued. insulin glulisine) compared to those treated with short-acting (regular) insulin (19. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. JAMA 1999. however. 6. S56 Hypoglycemia. Level 2 (20)] and to reduce the risk of hypoglycemia [Grade D. Consensus]:  Patient characteristics: B Degree of hyperglycemia B Presence of comorbidities B Patient preference and ability to access treatments  Properties of the treatment: B Effectiveness and durability of lowering BG B Risk of hypoglycemia B Effectiveness in reducing diabetes complications B Effect on body weight B Side effects B Contraindications 5. Level 1A (3)]. Few large. and consideration should be given to initiating combination therapy with 2 agents. antihyperglycemic agents should be initiated concomitantly with lifestyle management. subsequently allowing adequate glycemic control with lifestyle management alone (66). Epidemiological evidence suggesting a possible link between insulin glargine and cancer has not been substantiated in review of clinical trial data for either glargine or detemir (60. Although these hypoglycemic episodes are rarely fatal. Therefore. if glycemic targets are not achieved using lifestyle management within 2 to 3 months. Frighi V. once bolus insulin is introduced into a treatment regimen. . to allow for improved glycemic control with less risk of weight gain and hypoglycemia (65). sulfonylurea. Level 1A (26. Other classes of antihyperglycemic agents. Use of long-acting basal insulin analogues (insulin detemir. antihyperglycemic agent therapy should be initiated [Grade A. i. Klein R. Consensus]. and 40% had a hypoglycemic episode of any severity (3). they can be associated with serious clinical sequelae. et al. recognize and treat hypoglycemic episodes secondary to the use of insulin secretagogues.75e79).72). and such interventions have been tested only in patients early in the course of disease where the degree of residual beta cell function is relatively preserved (67). insulin secretagogues. Moss SE. including insulin.68. Other Relevant Guidelines Targets for Glycemic Control. Protocols designed to achieve normoglycemia targets (A1C 6. Consensus]. p. Cull CA. p.281:2005e12. Choice of pharmacological treatment agents should be individualized. should be continued with regimens containing bolus insulin. Glycemic control with diet. S163 Diabetes and Pregnancy. and these adjustments to and/or additions of antihyperglycemic agents should be made in order to attain target A1C within 3 to 6 months [Grade D. When bolus insulin is added to antihyperglycemic agents. p. taking into consideration [Grade D. Individuals with symptomatic hyperglycemia and metabolic decompensation should receive an initial antihyperglycemic regimen containing insulin [Grade D. long-acting analogues (detemir or glargine) may be used instead of intermediateacting NPH to reduce the risk of nocturnal and symptomatic hypoglycemia [Grade A.5%. Consensus). The Wisconsin epidemiological study of diabetic retinopathy. S82 Type 2 Diabetes in Children and Adolescents. particularly for patients using insulin therapy (3). unless contraindicated. S31 Pharmacotherapy in Type 1 Diabetes. When basal insulin is added to antihyperglycemic agents. each year approximately 3% of patients treated with insulin in the UKPDS experienced a severe hypoglycemic episode. either as a separate meal time bolus or as part of a premixed containing regimen. Metformin may be used at the time of diagnosis. Level 1A (19. S69 Weight Management in Diabetes.S66 W.5%) further increase the risk of severe hypoglycemia without providing any substantial reduction in the incidence of diabetes complications (71. Lancet 1998. 7. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). including intensive basalbolus regimen. Consensus]. p. p. insulin lispro.50. or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). 3. ii. Grade D. the use of intensive insulin therapy (basal-bolus regimen or continuous subcutaneous insulin infusion pump).80) for overweight patients.352:837e53. Harper et al. recognition and treatment of drug-induced hypoglycemia [Grade D. III.102:527e32.69).74).79)]. et al. p. 3. metformin. S184 Relevant Appendix Appendix 3: Examples of Insulin Initiation and Titration Regimens in People With Type 2 Diabetes References 1. Metformin should be the initial drug used [Grade A. should be added to metformin. / Can J Diabetes 37 (2013) S61eS68 long-acting analogues) may need to be added and bolus insulin (short-acting or rapid-acting analogues) may also be required. p. Lower rates of hypoglycemia have been observed in some studies of patients with type 2 diabetes treated with rapidacting insulin analogues (insulin aspart. taking into account the information in Figure 1 and Table 1 [Grade D. Klein BE. rapid-acting analogues may be used instead of regular insulin to improve glycemic control [Grade B. has been shown to induce diabetes remission. S168 Diabetes in the Elderly. for a transient period of approximately 2 to 3 weeks at the time of diagnosis or early in the disease course. Hypoglycemia Medication-induced hypoglycemia is the most common cause of hypoglycemia. Arch Ophthalmol 1984. Generally. such as sulfonylureas and meglitinides. 2. Consensus)]. if glycemic targets are not met. the proportion of adults with type 2 diabetes who experienced a severe hypoglycemic episode per year was significantly higher in the intensive group than in the conventional group. If A1C 8. All individuals with type 2 diabetes currently using or starting therapy with insulin or insulin secretagogues should be counseled about the prevention. 4. 2. Consensus for nonoverweight patients]. Consensus). In people with type 2 diabetes. randomized clinical trials have compared the rates of hypoglycemia between these agents. in conjunction with lifestyle management (Grade D. UK Prospective Diabetes Study (UKPDS) Group. one of which may be insulin (Grade D. Although the risk of hypoglycemia was less than that seen in the patients with type 1 diabetes in the Diabetes Control and Complications Trial (DCCT). Consensus]. This normoglycemic state is often transient.78.73. In the United Kingdom Prospective Diabetes Study (UKPDS). Although not commonly practiced. insulin glargine) reduces the risk of nocturnal hypoglycemia compared to treatment with NPH insulin (19. or used in combination with each other. it is important to prevent. 25:472e84. Boussageon R. et al. 22. Diabetes Care 2009. Dormandy JA. et al. PLoS Med 2012. A Diabetes Outcome Progression Trial (ADOPT) Study Group.27:2277e82. Improved postprandial glycemic control during treatment with Humalog Mix25. Diabet Med 2002. Lunceford JK. Bergenstal RM. Barnett AH. et al. for treatment of patients with Type 2 diabetes mellitus inadequately controlled on maximum doses of metformin alone. Lapinski H. premixed human insulin 30/70 twice daily: a randomized trial in type 1 and type 2 diabetic patients. Meymeh RH. N Engl J Med 2006. Lau J. 56. 8:643e9. Derosa G. Lancet 2009. 17. Rosenstock J. Ross SA. and weight change in patients with type 2 diabetes: a network meta-analysis. Eckland DJ. 31:845e51. 27. Addition of thiazolidinedione or exenatide to oral agents in type 2 diabetes: a meta-analysis.29:2137e9. Nissen SE.151: 394. 37. Jaber LA. Inhaled Insulin Phase II Study Group.128:165e75. Larsen J. et al.and 52-week efficacy of the dipeptidyl peptidase IV inhibitor LAF237 in metformin-treated patients with type 2 diabetes. 43. Diabetes Care 1999. Raz I. Wolski K. 36. Insulin glulisine provides improved glycemic control in patients with type 2 diabetes. Liu SC. Exp Diabetes Res 2011.9:e1001204. Further improvement in postprandial glucose control with addition of exenatide or sitagliptin to combination therapy with insulin glargine and metformin: a proof-of-concept study. et al. 170:1191e201.121:928e35.27: 2363e8. 49. Rosenstock J. A systematic assessment of cardiovascular outcomes in the saxagliptin drug development program for type 2 diabetes. Rosenfalck AM. Improvement in glycaemic control with rosiglitazone/metformin fixed-dose combination therapy in patients with type 2 diabetes with very poor glycaemic control. or glyburide monotherapy. Tan A. Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. Kourides IA. Moses RG.29:2638e43. N Engl J Med 2007. Glucagon-like peptide-1 receptor agonists and cardiovascular events: a meta-analysis of randomized clinical trials. cardiovascular death. Diabetes Obes Metab 2012.373:1765. Glass LC.33:1859e64. Bazzano LA. Diabetes Care 2006. Lower baseline glycemia reduces apparent oral agent glucose-lowering efficacy: a meta-regression analysis. controlled trial.290:486e94. et al. Brown MB. CMAJ 2007. Chiasson J-L. Yki-Järvinen H.W. Goldstein BJ.130:389e96. Standl E. Buse JB. Ahmad F. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. et al. Ristic S. insulin. Eur J Endocrinol 2009. Mugellini A. and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials. Wijesuriya S. Efficacy and safety of insulin analogues for the management of diabetes mellitus: a meta-analysis.32:381e6. Campos RV. Inhaled insulin provides improved glycemic control in patients with type 2 diabetes mellitus inadequately controlled with oral agents: a randomized controlled trial. Supper I. Diabetes Obes Metab 2006. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre. Strojek K. et al. Rosenstock J. 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Ann Intern Med 1998. Diabetes Care 2004. 11. A comparative study of insulin lispro and human regular insulin in patients with type 2 diabetes mellitus and secondary failure of oral hypoglycemic agents. Colette C. Xia N. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin.24:292e8. et al.298:1180e8. 25. Diabetes Care 2001. Rosiglitazone revisited: an updated meta-analysis of risk for myocardial infarction and cardiovascular mortality. Diabetes Care 2010. Roach P. 42. et al. Clin Invest Med 2001.180: 385e97. Donovan M. Comparison between repaglinide and glimepiride in patients with type 2 diabetes mellitus: a one-year. Vinik AI. 10. 57. Monnier L. et al. 24. 52. Diabetes Care 2008. Chien KL. 35. Lincoff AM. Nicholls SJ. regular human insulin in type 2 diabetes: a meta-analysis. Liu J. Glycemic durability of rosiglitazone.19:393e9. 32. Initial treatment with rosiglitazone/ metformin fixed-dose combination therapy compared with monotherapy with either rosiglitazone or metformin in patients with uncontrolled type 2 diabetes. Bejan-Angoulvant T. Kahn SE. Marchionni N.29:2632e7. et al. et al. Rosiglitazone-associated fractures in type 2 diabetes: S67 31. Pinelli NR. Cincotta AH. Lachin JM. Yki-Järvinen H. Aschner P. Kjems L. JAMA 2007.352:854e65. 21:398e403. Nikkilä K. Harper et al. The effect of oral antidiabetic agents on A1C levels: a systematic review and meta-analysis. et al. Diabetes Care 2010. et al. et al. Arch Intern Med 2010. Use of twice-daily exenatide in basal insulin-treated patients with type 2 diabetes: a randomized.298:194e206. Diabetes drug pioglitazone (Actos): risk of fracture. Ann Intern Med 2011.2011:215764. et al. Kabadi UM. JAMA 2007. et al. Nissen SE. Diabetes Care 2010. N Engl J Med 2007. et al. Fiedorek FT. Diabetes Obes Metab 2009. Dodis R. 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Premixed insulin aspart 30 vs. Wright D. controlled trial. Gomis R. Karasik A. Boussageon R. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.22:1258e61. Arnolds S. et al. Cheng SL.26:881e5. 33. Pittas AG.154:103e12. et al. Weiss SR. Lancet 1998. JAMA 2003.37:41e6. Efficacy of insulin and sulfonylurea combination therapy in type II diabetes. Johnson JL. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. Postgrad Med 2010. 40. Monami M. et al. Josse RG. Pullenayegum E. Cobitz A. Saadatian-Elahi M. 30. Diabetes Obes Metab 2002. Zinman B. et al. 48.33:1503e8. 12. an analysis from A Diabetes Outcome Progression Trial. et al. A randomized. metformin. Clair J. 5. Kelly TN. Ann Pharmacother 2008. et al.27:2874e80.357:28e38. 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Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetic patients: variations with increasing levels of HbA(1c). 15. open-label trial. Lancet 2009. 9. Ray KK. Pecher E. Effects of prandial versus fasting glycemia on cardiovascular outcomes in type 2 diabetes: the HEART2D trial. Ann Intern Med 1994. Collober-Maugeais C. Seshasai SR. Diabetes Care 2003. Kahn SE. A multicenter controlled clinical trial. Behrend C. Monami M.33:1509e15. BMJ 2011. Clin Ther 2003. Randomized clinical trial of quick-release bromocriptine among patients with type 2 diabetes on overall safety and cardiovascular outcomes. Pocock SJ. Comparison of insulin regimens in patients with non-insulin-dependent diabetes mellitus. 19. 327:1426e33. et al. Cobitz A. UK Prospective Diabetes Study (UKPDS) Group. Ahren B.11:53e9. Cremasco F. Frederich R. 8. Pharmacology 2010. United Kingdom Prospective Diabetes Study Group.160:909e17. Bejan-Angoulvant T. 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Implications of the United Kingdom Prospective Diabetes Study. et al. Pioglitazone hydrochloride in combination with sulfonylurea therapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized. randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. or placebo in NIDDM patients. Dills DG. 69.358: 2545e59. Diabetes Care 2005.103:491e7. Black C. controlled trial. A randomized trial of adding insulin glargine vs. et al. placebo-controlled. Fritsche A. Comparison of basal insulin added to oral agents versus twice-daily premixed insulin as initial insulin therapy for type 2 diabetes.28: 426e9. et al. Wulffelé MG.11:361e71. Diabetes Metab Res Rev 2001. Hollander P. No evidence of increased risk of malignancies in patients with diabetes treated with insulin detemir: a meta-analysis.17:287e94.25: 1123e8. 98. 94. A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over 3 years (U. 90. Lower incidence of severe hypoglycaemia in patients with type 2 diabetes treated with glimepiride versus glibenclamide. Diabetes Care 2002. et al. Peng T. Colwell JA.371:1073e84. Holstein A. Duncan TG. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. 109. Combination of insulin and metformin in the treatment of type 2 diabetes. . et al.17:561e6. Rastam J. Goodman AM. Glimepiride combined with morning insulin glargine. 72. Grimaldi A. et al. Diabetologia 2009. 70. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Diabetes Care 2002. Diabetes Care 2002. Tessier D. GUIDE study: double-blind comparison of once-daily gliclazide MR and glimepiride in type 2 diabetic patients. Combined randomised controlled trial experience of malignancies in studies using insulin glargine.22:960e4. 97. J Clin Pharmacol 1998. The Essen Study. Diabetes Care 1999. Harrower A. et al. Meier MK. Burden AC.S68 W. Effects of intensive glucose lowering in type 2 diabetes. 99. Holman RR. et al. Gliclazide modified release: from once-daily administration to 24 hour blood glucose control. Davies MJ. et al.34:535e42. Lehert P. Furberg CD. Diabetes Care 1989. Horvath K. 96. 82. Di Mario U. Aronoff S. Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VA CSDM). Donnelly P.81:184e9. et al. A double-blind randomized comparison of meal-related glycemic control by repaglinide and glyburide in well-controlled type 2 diabetic patients. 63. Ohkubo Y. Koivisto VA. Paisey RB. Lebovitz HE. double-blind. Vilsboll T. Lynggaard H. Lancet 2008. Yki-Järvinen H. 134:737e45. Diabetes Care 1999. et al. Bretzel RG. Am J Med 1997. Berghold A. Hauptman J. 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Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial.111:10e7. Li Y. Diabet Med 2004. bedtime neutral protamine hagedorn insulin. BMJ 2010. Glibenclamide vs gliclazide in type 2 diabetes of the elderly. Braithwaite S. Yale JF. Ward JD. N Engl J Med 2009. et al. Berne C. Rappaport EB. J Clin Endocrinol Metab 2001. Plewe G.18:1113e23. 62. Mannucci E. Schernthaner G. N Engl J Med 2008. Ryan EA.27:1028e32. Diabetes Care 1994. Lehert P. or bedtime insulin glargine in patients with type 2 diabetes. Cochrane Database Syst Rev 2007. et al.11:974e80. Loke YK. Diabetes Care 1995. Rosenstock J. 92.34:916e22. Clinical evaluation of glimepiride versus glyburide in NIDDM in a double-blind comparative study. Haak T. 59. et al. 73. 93. Jovanovic L. Brunelle RL. The Canadian INSIGHT (Implementing New Strategies with Insulin Glargine for Hyperglycaemia Treatment) Study. 86. Brunelle RL. Rosiglitazone monotherapy is effective in patients with type 2 diabetes.23:1605e11. Meglitinide analogues for type 2 diabetes mellitus. et al. randomized. Kipnes MS. Long-term risk of cardiovascular events with rosiglitazone: a meta-analysis. Mealtime treatment with insulin analog improves postprandial hyperglycemia and hypoglycemia in patients with non-insulin-dependent diabetes mellitus. Schneider J. Hirsch IB. 61. 102. Marchionni N.22:1395e409. Improved mealtime treatment of diabetes mellitus using an insulin analogue. Effect of orlistat in overweight and obese patients with type 2 diabetes treated with metformin. Diabetologia 2009. CSPQ. requiring the assistance of other individuals.canadianjournalofdiabetes.g. since this can result in rebound hyperglycemia and weight gain. Jean-François Yale MD. FRCPC KEY MESSAGES  It is important to prevent.jcjd. driving.8 mmol/L) is associated with increased mortality (15).doi. A meta-analysis concluded that lowered cognitive performance in people with type 1 diabetes appeared to be associated with the presence of microvascular complications but not with the occurrence of severe hypoglycemic episodes or with poor metabolic control (13). 2) a low plasma glucose level (<4.Can J Diabetes 37 (2013) S69eS71 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. to eliminate the risk of injury and to relieve symptoms quickly. The latter are rare and have been reported only in case studies. FRCPC. convulsions and encephalopathy. for further discussion of drug-induced hypoglycemia). The severity of hypoglycemia is defined by clinical manifestations (Table 2). This fear is associated with reduced self-care and poor glucose control (4e6).  It is important to avoid overtreatment.01. those with type 2 diabetes and previous severe hypoglycemia requiring presentation to the hospital have increased risk of subsequent dementia (14). this is potentially reversible (see Pharmacotherapy in Type 1 Diabetes. however. p. In patients with type 2 diabetes and established. acute hypoglycemia is proinflammatory (16) and may affect cardiac conduction (depolarization. S56. whether at home or at work (e. cardiovascular disease. and Pharmacologic Management of Type 2 Diabetes. or very high risk for. S61. As such. however. such as hemiparesis and pontine dysfunction. Unlike patients with type 1 diabetes. recognize and treat hypoglycemic episodes secondary to the use of insulin or insulin secretagogues (see Pharmacotherapy in Type 1 Diabetes.0 mmol/L for patients treated with insulin or an insulin secretagogue). however. and 3) symptoms responding to the administration of carbohydrate (7). it is important to prevent. symptomatic hypoglycemia (<2. Definition of Hypoglycemia Hypoglycemia is defined by 1) the development of autonomic or neuroglycopenic symptoms (Table 1).org/10. These changes were small but. The potential long-term complications of severe hypoglycemia are mild intellectual impairment and permanent neurologic sequelae. Hypoglycemia can be severe and result in confusion. This effect. FRCPC. Significant risk of hypoglycemia often necessitates less stringent glycemic goals. Recurrent hypoglycemia may impair the individual’s ability to sense subsequent hypoglycemia (8. S56).18). In addition. p. such as paresis. Complications of Severe Hypoglycemia Short-term risks of hypoglycemia include the dangerous situations that can arise while an individual is hypoglycemic. Frequency and severity of hypoglycemia negatively impact on quality of life (1) and promote fear of future hypoglycemia (2. could be clinically meaningful. recognize and treat hypoglycemic episodes secondary to the use of insulin or insulin secretagogues. may be related to sympathetic tone rather than glucose per se (17. operating machinery). Vincent Woo MD.022 transient neurological symptoms. Retrospective studies have suggested a link between frequent severe hypoglycemia (5 episodes since diagnosis) and a decrease in intellectual performance.3). Table 1 Symptoms of hypoglycemia Neurogenic (autonomic) Trembling Palpitations Sweating Anxiety Hunger Nausea Tingling Neuroglycopenic Difficulty concentrating Confusion Weakness Drowsiness Vision changes Difficulty speaking Headache Dizziness .  The goals of treatment for hypoglycemia are to detect and treat a low blood glucose (BG) level promptly by using an intervention that provides the fastest rise in BG to a safe level. Introduction Drug-induced hypoglycemia is a major obstacle for individuals trying to achieve glycemic targets.2013. MD.com Clinical Practice Guidelines Hypoglycemia Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Dale Clayton MHSc. prolonged coma is sometimes associated with 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. depending on an individual’s occupation. p. QT prolongation). coma or seizure. The neurohormonal counterregulatory responses to hypoglycemia may become blunted. Prospective studies in type 1 diabetes have not found an association between intensive insulin therapy and cognitive function (10e12).9). The mechanism for this increase is not certain.1016/j. recognition and treatment of hypoglycemia related to driving and be made aware of provincial driving regulations [Grade D. Patients receiving antihyperglycemic agents that may cause hypoglycemia should be counselled about strategies for prevention. Consensus].0 mmol/L) within 60 minutes (42). renal impairment and neuropathy (33). recognition and appropriate therapeutic RECOMMENDATIONS Treatment of Hypoglycemia The goals of treatment for hypoglycemia are to detect and treat a low BG level promptly by using an intervention that provides the fastest rise in BG to a safe level. Consensus]. Evidence suggests that 15 g glucose (monosaccharide) is required to produce an increase in BG of approximately 2. Individuals may need to have their insulin regimen adjusted appropriately to lower their risk. current low glycated hemoglobin (A1C) (<6.04 to 3. if unavailable. severe cognitive impairment (30). support persons should be taught how to administer glucagon by injection [Grade D. hypoglycemia unawareness (34). and Type 2 Diabetes in Children and Adolescents. are slower to increase BG levels and provide symptom relief (36. Glucagon 1 mg given subcutaneously or intramuscularly produces a significant increase in BG (from 3. Consensus]. b. Risk factors for severe hypoglycemia are listed in Table 3.S70 Table 2 Severity of hypoglycemia D.37). Patients should retest BG in 15 minutes and re-treat with another 15 g carbohydrate if the BG level remains <4. Consensus]. glucosidase inhibitor (acarbose) must use glucose (dextrose) tablets (41) or. Clayton et al. with adequate symptom relief for most people (Table 4) (35e39).0%) (20. Note: This does not apply to children. preferably as glucose tablets or equivalent.1 mmol/L within 20 minutes. Consensus]. Other choices. to eliminate the risk of injury and to relieve symptoms quickly. Hypoglycemia and driving Individuals with diabetes are a heterogenous group. BG should be retested in 15 minutes and then re-treated with another 15 g glucose if the BG level remains <4. The individual is able to self-treat. Unconsciousness may occur. degree of hypoglycemic awareness.44). medical technology and self-monitoring have increased the ability of patients with diabetes to control their disease and operate a motor vehicle safely.0 to 12. Individuals with diabetes should be encouraged to take an active role in assessing their ability to drive.37).5 g carbohydrate) 15 mL (1 tablespoon) of honey Mild: Autonomic symptoms are present. for treatment options in children. the risk of hypoglycemia is also increased by female gender (29). along with their significant others. poor health literacy (31). Consensus]. adolescence (28) and preschool-age children unable to detect and/or treat mild hypoglycemia on their own. Mild to moderate hypoglycemia should be treated by the oral ingestion of 15 g carbohydrate.26). preventing driving and industrial accidents through self-monitoring of blood glucose (BG) and taking appropriate precautions prior to the activity. the person should have the usual meal or snack that is due at that time of the day to prevent repeated hypoglycemia. and documenting BG readings taken during sleeping hours. Abbreviation: BG. Patients at high risk for severe hypoglycemia should be informed of their risk and counselled. hypoglycemia unawareness (25). For individuals at risk of severe hypoglycemia. presence of complications and many others. The major risk factors for severe hypoglycemia in patients with type 1 diabetes include prior episode of severe hypoglycemia (19e21). blood glucose.6 mmol/L at 45 minutes (36. A1C. such as milk and orange juice. 3. 5. PG is typically <2. plasma glucose. increased A1C (29. / Can J Diabetes 37 (2013) S69eS71 Table 4 Examples of 15 g carbohydrate for treatment of mild to moderate hypoglycemia      15 g glucose in the form of glucose tablets 15 mL (3 teaspoons) or 3 packets of table sugar dissolved in water 175 mL (3/4 cup) of juice or regular soft drink 6 LifeSavers (1 ¼ 2. In patients with type 2 diabetes and established cardiovascular disease (CVD) or age >54 years and 2 CVD risk factors. glycated hemoglobin. S153.0 mmol/L [Grade D. This has not been well studied in patients with gastropathy. Glucose gel is quite slow (<1. It is also important to avoid overtreatment since this can result in rebound hyperglycemia and weight gain. Severe hypoglycemia in a conscious person should be treated by oral ingestion of 20 g carbohydrate.0%) Hypoglycemia unawareness Long duration of insulin therapy Autonomic neuropathy Low economic status Food insecurity Low health literacy Cognitive impairment Adolescence Preschool-age children unable to detect and/or treat mild hypoglycemia on their own 1. 4. miles driven. Consensus]. 6. duration of insulin therapy. If a meal is >1 hour away. Once the hypoglycemia has been reversed. . Level 2 (35)]. Severe: Individual requires assistance of another person. preferably as glucose or sucrose tablets or solution. Patients taking an alphaTable 3 Risk factors for severe hypoglycemia            Prior episode of severe hypoglycemia Current low A1C (<6.0 mmol/L increase at 20 minutes) and must be swallowed to have a significant effect (35. The individual is able to self-treat. These are preferable to orange juice and glucose gels [Grade B. Caregivers or support persons should call for emergency services and the episode should be discussed with the diabetes healthcare team as soon as possible [Grade D. Risk factors for hypoglycemia in patients with type 2 diabetes include advancing age (29). Severe hypoglycemia in an unconscious individual a. With no IV access: 1 mg glucagon should be given subcutaneously or intramuscularly. With IV access: 10e25 g (20e50 cc of D50W) of glucose should be given intravenously over 1e3 minutes [Grade D. Advances in treatment. p.24) (45).0 mmol/L [Grade D. and the risk of motor vehicle accidents and driving violations may be only slightly increased or markedly increased (relative risk [RR] 1. 2. long duration of diabetes (23. on preventing and treating hypoglycemia (including use of glucagon). PG. Patients should have information concerning avoidance. level of A1C. Factors include age. See Type 1 Diabetes in Children and Adolescents. S163. autonomic neuropathy (27).22e24). The effect is impaired in individuals who have consumed more than 2 standard alcoholic drinks in the previous few hours or in those who have advanced hepatic disease (43. A 20 g oral glucose dose will produce a BG increment of approximately 3. The fitness of these patients to drive must be assessed on an individual basis. food insecurity (32).40). milk or honey to treat hypoglycemia. Moderate: Autonomic and neuroglycopenic symptoms are present.8 mmol/L. p. a snack (including 15 g carbohydrate and a protein source) should be consumed [Grade D.33). 17: 734e55. 15. Effects of intensive diabetes therapy on neuropsychological function in adults in the Diabetes Control and Complications Trial. et al. Type 1 diabetes among adolescents: reduced diabetes self-care caused by social fear and fear of hypoglycemia. Diabetes Educ 2009. p.43:313e7. p. Canadian Diabetes Association. / Can J Diabetes 37 (2013) S69eS71 S71 intervention for hypoglycemia. London. S168 Diabetes in the Elderly. VA: American Diabetes Association. Diabetes Care 1994. Garber AJ. Davey Smith G. neuropathy (autonomic. motor). Treatment of insulin reactions in diabetics. Blunted counterregulatory hormone responses to hypoglycemia in young children and adolescents with well-controlled type 1 diabetes. Brands AM. Liu JY. 2007. The Diabetes Control and Complications Trial Research Group. Mortality and treatment side-effects during long-term intensified conventional insulin treatment in the Stockholm Diabetes Intervention Study. 2007. Byrne GC. 37. 45.124:379e88.33:1591e7. Hypoglycemic episodes and risk of dementia in older patients with type 2 diabetes mellitus. Diabetes Care 1994. 11. Pihl M. Yale J-F. 134e43. et al. et al. Schillinger D. renal disease and cardiovascular disease. Other Relevant Guidelines Targets for Glycemic Control. Barnard K. Alvarez-Guisasola F. 2002. Frier BM. Diabetes Care 1998. Cognitive function and risks of cardiovascular disease and hypoglycaemia in patients with type 2 diabetes: the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Effects of controlled hypoglycaemia on cardiac repolarisation in patients with type 1 diabetes. glycaemia treatment approach.90:450e9.240:1611e2. JAMA 1978. Effect of intensive diabetes treatment on the development and progression of long-term complications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. Keating B. et al. 13.58:701e9. J Clin Endocrinol Metab 2010. Xing D. Sarkar U. 27. p. Effects of acute insulin-induced hypoglycemia on indices of inflammation: putative mechanism for aggravating vascular disease in diabetes. Tamborlane W. Jacobs IG. Available at: http://www. Seligman HK. p. 24. Frier BM. Koll C. Diabet Med 2010. In general. Diabetologia 2009. References 1. J Gen Intern Med 2010. Continuous glucose monitoring reveals associations of glucose levels with QT interval length. Gerstein HC. Brodows RG. Williams C. et al. Schopman JE. editors. Diabetologia 2008. Food insecurity is associated with hypoglycemia and poor diabetes self-management in a lowincome sample with diabetes. Published erratum appears in J Gen Intern Med.28:726e35.125:177e88. UK: Edward Arnold. Bioactivity of instant glucose. Greco L. p. Thomas S. 22. Salmela PI.95:2240e7. Prevalence of impaired awareness of hypoglycaemia and frequency of hypoglycaemia in insulin-treated type 2 diabetes. Diabetes Care 2010. et al. 44.87:64e8. Risk factors of severe hypoglycaemia in adult patients with type I diabetes: a prospective population based study. Overmann H. Diabetes Care 2009. 93e103. Chalmers J. Miller ME.18:1415e27. et al.21: 1227e33.361:1914. Alexandria. The Diabetes Control and Complications Trial Research Group. BMJ 2010. Canadian Diabetes Association’s clinical practice guidelines for diabetes and private and commercial driving. S31 Monitoring Glycemic Control. Canadian J Diabetes 2010. 2010. Glucagon [product monograph]. p. p. Bonds DE. Association of hypoglycemic symptoms with patients’ rating of their health-related quality of life state: A cross sectional study. Determinants of severe hypoglycemia complicating type 2 diabetes: the Fremantle diabetes study. The role of dietary sugars in diabetes mellitus.301(15): 1565e72. Diabetes Care 2005. et al. 28. 35. 41. Diabetes Care 1997.27:128e140. 19. 39. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research GroupJacobson AM. Veneman T. Yaffe K. Diabetes Res Clin Pract 2010. 30. Accessed April 30. Diabetes Research in Children Network (DirecNet) Study GroupTsalikian E. Koivikko ML. Frequency of severe hypoglycemia in patients with type I diabetes with impaired awareness of hypoglycemia. de Haan EH. 3. Diabetes and fitness to drive: a systematic review of the evidence with a focus on older drivers. Traynard PY. Stettler C. severe hypoglycaemia and mortality in type 2 diabetes: retrospective epidemiological analysis of the ACCORD study. Amsberg S. Health Qual Life Outcomes 2010. BMJ 2010.150:589e93. Kubiak T. Effects of intensive therapy and antecedent hypoglycemia on counterregulatory responses to hypoglycemia in type 2 diabetes.356:1842e52. The association between symptomatic. S56 Pharmacologic Management of Type 2 Diabetes. 20. Davis EA. Alanine and terbutaline in treatment of hypoglycemia in IDDM. The effects of type1 diabetes on cognitive performance: a meta-analysis. Karter AJ. and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. . Diabet Med 1997. Gunning RR. Stirling D. Karsikas M. Failure of absorption through oral mucosa. Diabetes Care 1994. 2012. Medical Management of Type 1 Diabetes. 7. Hepburn DA. JAMA 2009.340:b4909. Zoungas S. 23.340:b5444. Nocea G. solution. Mann S. Desplanque N. Bergenstal RM.27:72e8. et al.17:1397e403. Hypoglycemia. 51:426e35.. Chronic Illn 2009. sensory.ca/files/DrivingGuidelinesBeggJune03. Belendez M. S35 Pharmacotherapy in Type 1 Diabetes. 14. 25. Haugstvedt A. Davis SN. GlucaGenÒ (glucagon) [product monograph]. S184 Related Website Begg IS. Can J Diabetes. Bender R. 10. et al. Biessels GJ.pdf.46: 271e86. de Galan BE. et al. Amatruda JM.5:250e6. Hypoglycemia unawareness in IDDM. Epidemiology of severe hypoglycemia in the Diabetes Control and Complications Trial. Whitmer RA. 1998. Bagsvaerd. Geddes J. p. The Diabetes Control and Complications Trial Research Group. GlucobayÒ (acarbose) [product monograph]. editor. J Pediatr 1994.D. 12:283e6. In: Frier BM. 2. including eye disease. Meyer C. Gloizer J. 5. Cryer PE.8:86. Anderbro T. et al. Diabetes Care 1993. 31.25:962e8. Diabetes Technol Ther 2010.diabetes. Long-term effect of diabetes and its treatment on cognitive function.. Houlden RL. 2009. Newby DE. Arch Intern Med 1990. is knowledgeable about controlling BG levels and is able to avoid severe hypoglycemic episodes. Diabet Med 2010. 21. Wentzel-Larsen T. et al. 4. Diabetes 1994. Adverse events and their association with treatment regimens in the Diabetes Control and Complications Trial. Ryan CM. et al.252:3378e81. Kagan A. Effects of autonomic neuropathy on counterregulation and awareness of hypoglycemia in type 1 diabetic patients. 34. a patient is considered fit to drive if he or she is medically fit. et al. 6. Karter AJ. et al. Toronto. Diabetes Care 1995. Hypoglycemia: incidence and clinical predictors in a large population-based sample of children and adolescents with IDDM. MacLeod KM. Fear of hypoglycaemia in adults with Type 1 diabetes. Carbohydrates in tablets. ON: Bayer Inc. 12. Symptoms of hypoglycaemia. Fear of hypoglycaemia in mothers and fathers of children with Type 1 diabetes is associated with poor glycaemic control and parental emotional distress: a population-based study. 33. 3rd ed. et al. Cryer PE. S163 Diabetes and Pregnancy. or gel for the correction of insulin reactions.14:919e28. 1993. JAMA 1984. Special problems. 8. BMC Pediatr 2010. et al. Briscoe VJ. et al. p. 16. Risk of adverse effects of intensified treatment in insulin-dependent diabetes mellitus: a meta-analysis. Wittig A.25:1258. Di Battista AM. 17. Davis TM. 40. p.52: 2328e36. Slama G. The effects of baseline characteristics.10:50.17:697e703. Wiethop BV. 32. Shamoon H. Reichard P. J Health Care Poor Underserved 2010. 36. Am J Med 1991. Gold AE. Hypoglycemia in the Diabetes Control and Complications Trial.32:1954e9. The DCCT Research Group. Fear of hypoglycaemia in parents of young children with type 1 diabetes: a systematic review. Egger M.20:22e5. et al. et al. et al. 26.16:1131e6. Graue M. 9. Hart TA. Denmark: Novo Nordisk. Mitrakou A. In: Skyler JS. Korner-Bitensky N. Grossmann R. Diabetes 1997. Wolf MS. Musen G. Diabetes Control and Complications Trial Research Group. Beta Release 1991. 42. Hypoglycaemia and Diabetes: Clinical and Physiological Aspects. Fisher BM. et al. Toronto. Clayton et al. Mühlhauser I.41:1274e82. Diabetologia 1998. ON: Eli Lilly Canada Inc. Diabetes 2009.34:233e42.27:1151e8. N Engl J Med 2007. 29. S61 Type 1 Diabetes in Children and Adolescents. Mitrakou A. Hypoglycemia is more common among type 2 diabetes patients with limited health literacy: the Diabetes Study of Northern California (DISTANCE). Yin DD. 38. et al.35:465e75. Hernandez-Mijares A. Fisher JN. Davis TC. Beliefs about insulin as a predictor of fear of hypoglycaemia. 43. Wright RJ. Adamson U. Published erratum appears in N Engl J Med. 18. S153 Type 2 Diabetes in Children and Adolescents. The search for an optimized treatment of hypoglycemia. Mokan M. Drivers with diabetes should be assessed for possible complications. Bonds DE. Miller ME. Hashemi G.15:117e23.21:1960e6. Ann Intern Med 1996. Brown SG. 2003. Royle P. nausea. possibly. bicarbonate therapy should be considered only for extreme acidosis (pH 7. precipitating factors must be sought and treated.16. Diagnosis DKA or HHS should be suspected whenever patients have significant hyperglycemia. fluid balance. which will raise the bicarbonate level). thyrotoxicosis. cocaine. trauma and.3. If either DKA or HHS is diagnosed. including seizures and a stroke-like state that can resolve once osmolality returns to normal (2e4). the arterial pH is 7. interferon. Typically. Kussmaul respiration. acetone-odoured breath. serum and urine ketones. beta-OHB levels should be measured. lithium and atypical antipsychotics. osmolality and beta-hydroxybutyric acid (beta-OHB) (if available).canadianjournalofdiabetes.com Clinical Practice Guidelines Hyperglycemic Emergencies in Adults Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Jeannette Goguen MD. Note to readers: Although the diagnosis and treatment of diabetic ketoacidosis (DKA) in adults and in children share general principles. level of consciousness. Potassium is shifted out of cells. and ketoacidosis occurs as a result of elevated glucagon levels and absolute insulin deficiency (in the case of type 1 diabetes) or high catecholamine levels suppressing insulin release (in the case of type 2 diabetes). vomiting and abdominal pain. In both conditions.0 mmol/L but can be lower (18). abdominal crisis. Arterial blood gases may be required for sicker patients.jcjd. in HHS. possibly.  A normal blood glucose does not rule out DKA in pregnancy. there are significant differences in their application. If there is an elevated anion gap and serum ketones are negative. there can be a variety of neurological presentations.2). Jeremy Gilbert MD. It is.g. The clinical presentation of DKA includes symptoms of hyperglycemia. ECFV contraction. creatinine.doi. venous blood gases are usually adequatedthe pH is typically 0. Plasma glucose is usually !14. while in HHS. treatment with insulin infusion pumps.1016/j. DKA is more challenging to diagnose in the presence of the following conditions: 1) mixed acid-base disorders (e.org/10. there also may be evidence of a precipitating condition. leading to a return of the plasma anion gap toward normal. HHS is much less common than DKA (1. largely related to the increased risk of life-threatening cerebral edema with DKA in children and adolescents. therefore. Risk factors for DKA include new diagnosis of diabetes mellitus. In DKA. Otherwise. insulin omission. FRCPC. especially if they are ill or highly symptomatic (see above). and the anion gap is >12 mmol/L with positive serum and/or urine ketones (6.17). as a screening tool. p. associated vomiting. atypical antipsychotics and. Prevention Sick day management that includes capillary betahydroxybutyrate monitoring reduces emergency room visits and hospitalizations in young people (5). the following should be assessed: plasma levels of electrolytes (and anion gap). hyperglycemia causes urinary losses of water and electrolytes (sodium.  DKA and HHS are medical emergencies that require treatment and monitoring for multiple metabolic abnormalities and vigilance for complications.023 . There also may be a decreased level of consciousness.2013. Point-of-care capillary blood beta-hydroxybutyrate measurement in emergency is sensitive and specific for DKA and. important to measure ketones in both the serum and urine. HHS also has been reported following cardiac surgery and with the use of certain drugs.0). profound ECFV contraction and decreased level of consciousness (proportional to the elevation in plasma osmolality). including diuretics. MEd.03 lower than arterial pH (7e9). The specific issues related to treatment of DKA in children and adolescents are addressed in the Type 1 Diabetes in Children and Adolescents chapter. In addition. serum bicarbonate is 15 mmol/L. precipitating factors and complications (6). S153. FRCPC KEY MESSAGES  Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) should be suspected in ill patients with diabetes. Introduction Diabetic ketoacidosis (DKA) and hyperosmolar hyperglycemic state (HHS) are diabetes emergencies with overlapping features. blood gases. there is often more 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. chloride) and the resultant extracellular fluid volume (ECFV) depletion.015 to 0. to make the diagnosis and determine the severity of DKA or HHS. glucose.Can J Diabetes 37 (2013) S72eS76 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. when knowing the adequacy of respiratory compensation and the A-gradient is necessary.1 U/kg/h) for resolution. may allow more rapid identification of hyperglycemic patients at risk for DKA (10e15). glucocorticoids. As outlined in Figure 1. myocardial infarction. or 3) if the loss of keto anions with sodium or potassium in osmotic diuresis has occurred.  Ketoacidosis requires insulin administration (0. ketoacidosis is prominent. In HHS. the main features are ECFV depletion and hyperosmolarity. infection. There are no definitive criteria for the diagnosis of DKA. 2) if there has been a shift in the redox potential favouring the presence of beta-OHB (rendering serum ketone testing negative). In addition to the precipitating factors noted above for DKA. With insulin deficiency. potassium.01. ECFV. Goguen. zEffective plasma osmolality ¼ ([Naþ] Â 2) þ [Glucose (mmol/L)] þ [Urea (mmol/L)] reported as mmol/kg. yCorrected plasma [Naþ] ¼ Measured [Naþ] þ [3/10 Â ([Glucose (mmol/L)] À 5)].J. extracellular fluid volume. . J. IV. Gilbert / Can J Diabetes 37 (2013) S72eS76 S73 Figure 1. * Anion gap ¼ Plasma [Naþ] e Plasma [ClÀ] e Plasma [HCO3À]. Beta-OHB. intravenous. beta-hydroxybutyric acid. Management of diabetic ketoacidosis (DKA) in adults. It is reasonable to treat the potassium deficit of HHS in the same way. Measurement of serum lactate should be considered in hypoxic states. usually with the second litre of saline.17) with specialist care (22.3 mmol/L (6. may be beneficial (24. one should initially administer intravenous (IV) normal saline 1 to 2 L/h to correct shock. but minimal acid-base disturbance (6. there were 3 arms: a bolus arm (0. IV.23).3 mmol/L).0 mmol/L. In adults.16. electrocardiographic. DKA.0 mmol/L. otherwise. The use of subcutaneous boluses of rapid-acting insulin analogues at 1. initially as often as every 2 hours (6. insulinmediated reduced glucose production and increased cellular uptake of glucose. 3. Restoring ECFV improves tissue perfusion and reduces plasma glucose levels both by dilution and by increasing urinary glucose losses. * Severity of issue will dictate priority of action.S74 J. IV fluid alone has no impact on parameters of ketoacidosis (34). Patients with HHS have minimal or no acidosis. if initially hyperkalemic.07 units/kg/h). give 1e2 L/h initially to correct shock. After hypotension has been corrected. diabetic ketoacidosis. 0. results in decreased ECFV. If the patient is in shock. then 0. DKA.5 mmol/L and patient is diuresing. . Potassium deficit The typical potassium deficit range is 2 to 5 mmol/kg in DKA and 4 to 6 mmol/kg in HHS (29. Otherwise. A summary of fluid therapy is outlined in Table 2. respectively).or hypokalemic. and the diagnosis and treatment of coexistent illness.17). osmolality and glucose need to be monitored closely. glucose losses via osmotic diuresis (34).to 2-hour intervals results in similar duration of ketoacidosis with no more frequent occurrence of hypoglycemia compared to short-acting IV insulin 0.1 units/kg/h).21).40) and increases the risk of CE. hyperosmolar hyperglycemic state.16. Typical recommendations suggest that potassium supplementation should be started for plasma potassium <5.or hypokalemic. HHS. along with water losses (100 mL/kg and 100 to 200 mL/kg. at concentrations in the IV fluid between 10 and 40 mmol/L. resolution of ketoacidosis. Goguen. Management Objectives of management include restoration of normal ECFV and tissue perfusion.5 mmol/L once diuresis has been established. anion gap. otherwise 500 mL/h for 4 hours. ECFV contraction The sodium deficit is typically 7-10 mmol/kg in DKA (28) and 5 to 13 mmol/kg in HHS (29). using a rapid rate of initial fluid administration.07 units/kg/h).0 to 14. but there can be challenges with achieving adherence (26.16). Table 1 Priorities* to be addressed in the management of patients presenting with hyperglycemic emergencies Metabolic  ECFV contraction  Potassium deficit and abnormal concentration  Metabolic acidosis  Hyperosmolality (water deficit leading to increased corrected sodium concentration plus hyperglycemia) Precipitating cause of DKA/HHS  New diagnosis of diabetes  Insulin omission  Infection  Myocardial infarction  ECG changes may reflect hyperkalemia (57. neurological status. was associated with an increased risk of cerebral edema (CE) in 1 study (30) but not in another (31).7 mmol/L on average). However. Pregnant women in DKA typically present with lower glucose levels than nonpregnant women (19). extracellular fluid volume. only add potassium once serum potassium falls to <5 to 5. In the case of frank hypokalemia (potassium <3.25). Administer IV normal saline initially. Once plasma glucose reaches 14.27). 0. when followed. diabetic ketoacidosis. using an initial bolus of IV insulin does not result in faster resolution of ketoacidosis (39. ECFV re-expansion.30). and a double-dose infusion group (no bolus.14 units/ kg/h). switch normal saline to half-normal saline (with potassium chloride). potassium should be given immediately. 2.07 units/ kg. maintain IV fluids at higher osmolality (i.0 to 5.16.0e14. intravenous. there has been only 1 randomized controlled trial (RCT) in adults examining the effectiveness of this step (38). insulin should be withheld until potassium replacement at 40 mmol/h has restored plasma potassium to !3. In children.e. IV glucose should be started to prevent hypoglycemia. usually with decreased intracellular fluid volume (28.16). and there are case reports of euglycemic DKA in pregnancy (20. at a maximum rate of 40 mmol/h.0 mmol/L. a more prolonged duration of relative insulin insufficiency and inadequate fluid intake (or high glucose intake) results in higher glucose levels (typically !34.33). correction of electrolyte imbalances and hyperglycemia. a low-dose infusion group (no bolus. and a management algorithm and formulas for calculating key measurements are provided in Figure 1. add glucose to maintain plasma glucose at 12. Precipitating factors must be diagnosed and treated (6. Short-acting insulin (0.1 U/kg/h (41e43). hyperosmolar hyperglycemic state. then 250 mL/h of IV fluids (32. Outcomes were identical in the 3 groups. If the patient at presentation is normo.58)  A small increase in troponin may occur without overt ischemia (59)  Thyrotoxicosis (60)  Drugs Other complications of DKA/HHS        Hyper/hypokalemia ECFV overexpansion Cerebral edema Hypoglycemia Pulmonary emboli Aspiration Hypocalcemia (if phosphate used)  Stroke  Acute renal failure  Deep vein thrombosis ECFV. this study did not examine the standard dose of insulin in DKA (0. Add potassium immediately if patient is normo. There have been no randomized trials that have studied strategies for potassium replacement. Patients with DKA and HHS are best managed in an intensive care unit or step-down setting (6. including ECFV re-expansion (45). The issues that must be addressed in the patient presenting with DKA or HHS are outlined in Table 1. may need to maintain on normal saline). Unfortunately. HHS. Gilbert / Can J Diabetes 37 (2013) S72eS76 Table 2 Summary of fluid therapy for DKA and HHS in adults 1. Although the use of an initial bolus of IV insulin is recommended in some reviews (6). vital signs.0 mmol/L) and greater ECFV contraction. The dose of insulin should subsequently be adjusted based on ongoing acidosis (44). ECG. In HHS. In this study. and the double dose group had the lowest potassium (nadir of 3. Plasma glucose levels will fall due to multiple mechanisms. Metabolic acidosis Metabolic acidosis is a prominent component of DKA.29). then 250 mL/h for 4 hours. Protocols. Volume status (including fluid intake and output). using the plasma anion gap or beta-OHB measurements. 4. J.0 mmol/L. Insulin is used to stop ketoacid production.1 U/kg/h) is recommended (35e37). if plasma osmolality is falling more rapidly than 3 mmol/kg/h and/or the corrected plasma sodium is reduced. except 5 of 12 patients needed extra insulin in the no-bolus/low-dose infusion group. give 500 mL/h for 4 hours. targeting a plasma glucose of 12. plasma concentrations of electrolytes. Once plasma glucose reaches 14. which.17). 0 mmol/L to screen for DKA. it has been recommended that the plasma osmolality be lowered no faster than 3 mmol/kg/h (6.J.3% (2.0 (6. Level 2 (42)] as measured by the normalization of the plasma anion gap [Grade D. J Gen Med 1991. et al. Level 2 (36. Are blood ketones a better predictor than urine ketones of acid base balance in diabetic ketoacidosis? Pract Diabetes Int 2010. In individuals with DKA. Herron CA. repeated every 1 to 2 hours until pH is !7. Sinnock P. In adult patients with HHS.0. Singapore Med J 2007. Typically.31:459e65. J Am Geriatr Soc 1992. United States. Diabetes Care 2001. serum sodium concentration may be reduced due to shift of water out of cells. In HHS. Gilbert / Can J Diabetes 37 (2013) S72eS76 S75 Similar doses of IV insulin can be used to treat HHS. Other Relevant Guidelines Hyperosmolality Hyperosmolality is due to hyperglycemia and a water deficit. Naunheim R. 10. IV 0. Eng PH.3.10:836e41. For persons with a HHS. Brandenburg MA. Consensus]. IV fluid is switched to RECOMMENDATIONS 1. Hamblin PS. Goodwin JS. MacKay L. The insulin infusion rate should be maintained until the resolution of ketosis [Grade B. Mortality is usually due to the precipitating cause. Potential risks associated with the use of sodium bicarbonate include hypokalemia (50) and delayed occurrence of metabolic alkalosis. consideration should be given to increasing the sodium concentration of the infusing solution (6. 4) avoidance of rapidly falling serum osmolality. 2. plasma osmolality is usually 320 mmol/kg. Goguen. 2) avoidance of hypokalemia.62e64). Wachtel TJ. HHS. intravenous. et al. In patients with DKA. although subjects are not acidemic. Level 2 (32)] with consideration of a higher initial rate (1e2 L/h) in the presence of shock [Grade D. Type 1 Diabetes in Children and Adolescents. Goldman DL. Water imbalances can also be monitored using the corrected plasma sodium. Emerg Med 2003. hyperosmolar hyperglycemic state.37)]. by adding glucose to the infusions when plasma glucose reaches 14. p.16). 12. et al. 9. 3. Sefedini E. and 5) possibly insulin to further reduce hyperglycemia (as illustrated in Figure 1) [Grade D. Gennis B. Complications In Ontario.16). Insulin has been withheld successfully in HHS (46). Tetu-Mouradjian LM.48:986e9. and the fall in plasma glucose concentration is predominantly due to re-expansion of ECFV and osmotic diuresis (45). Comparison of arterial and venous pH. Umpierrez GE.6:495e502. Abbreviations: DKA. Rush MD.9% sodium chloride should be administered initially at 500 mL/h for 4 hours. Ann Emerg Med 1998. Metelko Z. Use of IV sodium bicarbonate to treat acidosis did not affect outcome in RCTs (47e49). one can administer 1 ampoule (50 mmol) sodium bicarbonate added to 200 mL D5W (or sterile water. Malone ML.24:131e53.37:73e8.and hyperkalemia) and CE. an infusion of short-acting IV insulin of 0. Dire DJ. bicarbonate. Reported mortality in DKA ranges from 0. et al. In individuals with DKA.65). Jang TJ. Laffel LM. 5. 5. Malatesha G.27:396e9. Emerg Med J 2007. The potassium in the infusion will also add to the osmolality. 1970-78. . Phosphate deficiency There is currently no evidence to support the use of phosphate therapy for DKA (53e55). Chosich N. J.151: 439e44.0 mmol/L to maintain it at that level and by selecting the correct concentration of IV saline. and a beta-hydroxybutyrate >1. et al. In adult patients with DKA. Consensus]. Diabet Med 2006. Am J Public Health 1983. Kitabchi AE. Point-of-care capillary beta-hydroxybutyrate may be measured in the hospital in patients with type 1 diabetes with capillary glucose >14. 3) avoidance of rapidly falling serum osmolality. 4. administration of potassium phosphate in cases of severe hypophosphatemia may be considered for the purpose of trying to prevent rhabdomyolysis. 4. Topliss DJ. About 50% of deaths occur in the first 48 to 72 hours. Point-of-care blood ketone testing: screening for diabetic ketoacidosis at the emergency department. and there is no evidence that hypophosphatemia causes rhabdomyolysis in DKA (56). Point-of-care test identifies diabetic ketoacidosis at triage. Bharija A. half-normal saline because urinary losses of electrolytes in the setting of osmotic diuresis are usually hypotonic. 6. Charles RA. Murphy MB. diabetic ketoacidosis.23:278e84. Management of hyperglycemic crises in patients with diabetes.16). Central pontine myelinolysis has been reported in association with overly rapid correction of hyponatremia in HHS (52). 4) search for precipitating cause. et al. et al. but included patients with mixed DKA and hyperosmolality (1. Acad Emerg Med 2006.73:1169e73. This can be achieved by monitoring plasma osmolality. However. Delaney S. Hyperosmolarity and acidosis in diabetes mellitus: a three year experience in Rhode Island. Deaths associated with diabetic ketoacidosis and hyperosmolar coma. Med J Aust 1989. because hypophosphatemia has been associated with rhabdomyolysis in other states. IV.24:569e71. S153 References 1. Godfrey MM. Consensus]. 3. Loughlin C. 2. Bee YM. Consensus]. 7. If osmolality falls too rapidly despite the administration of glucose. 3) insulin administration. Consensus]. Once the plasma glucose concentration reaches 14. However. For example. a protocol should be followed that incorporates the following principles of treatment: 1) fluid resuscitation. 11. IV fluid administration should be individualized based on the patient’s needs [Grade D. Level 2 (10e15)].5 mmol/L warrants further testing for DKA [Grade B. then 250 mL/h for 4 hours [Grade B. Gaddis G.10 U/ kg/h should be used ([Grade B. Prasek M. Use of capillary beta-hydroxybutyrate for the diagnosis of diabetic ketoacidosis at emergency room: Our one-year experience. Ma OJ. after volume re-expansion. In HHS. PCO2 in initial emergency department assessment. electrolyte imbalances (especially hypo.40:1100e4.65% to 3. 2) avoidance of hypokalemia. Sodium bicarbonate therapy can be considered in adult patients in shock or with arterial pH 7.13:683e5.22. Holman RC. IV dextrose should be started to avoid hypoglycemia [Grade D. Epidemiologic characteristics of mortality from diabetes with acidosis or coma. Comparison of arterial and venous blood gas values in the initial emergency department evaluation of patients with diabetic ketoacidosis. 8. in-hospital mortality in patients hospitalized for acute hyperglycemia ranged from <1% at ages 20 to 49 years to 16% in those over 75 years (61). 1973-1988. Banet G. recent studies found mortality rates to be 12% to 17%. The concentration of sodium needs to be corrected for the level of glycemia to determine if there is also a water deficit (Figure 1). 13. Because of the risk of CE with rapid reductions in osmolality (51). a protocol should be followed that incorporates the following principles of treatment: 1) fluid resuscitation. Sick day management using blood 3-hydroxybutyrate (3-OHB) compared with urine ketone monitoring reduces hospital visits in young people with T1DM: a randomized clinical trial. if available) over 1 hour. Diabetol Croat 2008. Singh NK. Lyall MJ. and 5) search for precipitating cause (as illustrated in Figure 1) [Grade D. et al. Wentzell K. Goh SY. Arterial blood gas results rarely influence emergency physician management of patients with suspected diabetic ketoacidosis academic. Characteristics of diabetic ketoacidosis in older versus younger adults. but generally its use is recommended to reduce plasma glucose levels (6.16). plasma osmolality is typically >320 mmol/kg.0 mmol/L. Consensus]. Relation of colloid osmotic pressure to arterial hypoxemia and cerebral edema during crystalloid volume loading of patients with diabetic ketoacidosis. Moran C. Crit Care Med 2007. Ng R. Goguen. Diabetes Care 1995. King J. Abromovici M. Point of care blood ketone testing of diabetic patients in the emergency department. 16. and not electrolyte-free water calculations. Saigi I. Bagg W. Lea AS. Am J Nephrol 1991. Young C.96:36e40. Sprung CL. J Emerg Med 2008. DelAguila M. Lindsay R. Insulin therapy for diabetic ketoacidosis. JAMA 1989. Treatment of diabetic ketoacidosis using normalization of blood 3-hydroxybutyrate concentration as the endpoint of emergency management.147:499e501. Akbas H. Belanger R. Bennet MA. Efficacy of subcutaneous insulin lispro versus continuous intravenous regular insulin for the treatment of patients with diabetic ketoacidosis. Diabetes Technol Ther 2010. Morris LR. Crawford R.96:570e5. 45. Metabolic effects of bicarbonate in the treatment of diabetic ketoacidosis. The hyperosmolar hyperglycemic syndrome. Karabell A. I. J Clin Endocrinol Metab 1983.157:669e75. Wilson HK. CMAJ 2003. Low-dose continuous insulin therapy for diabetic ketoacidosis. Vlcek BW. Gilbert / Can J Diabetes 37 (2013) S72eS76 41. Draman MS. Diagnosis and treatment of diabetic ketoacidosis and the hyperglycemic hyperosmolar state.27:308. et al. Diabetes Rev 1994. Resource utilization in treatment of diabetic ketoacidosis in adults. Ayyagari V. Fort P.29:87e95. Latif K. Arch Intern Med 1982. Tonicity balance. J Obstet Gynaecol Res 2008. 60. Lebovitz HE. Booth GL. Cessation of insulin therapy is the major precipitating cause of diabetic ketoacidosis. 39. Lancet 1972. Kitabchi AE. et al.34:324e30. Pseudo-myocardial infarction in diabetic ketoacidosis with hyperkalemia. et al. Lamberton P. 29. et al. Diabetic ketoacidosis in pregnancy tends to occur at lower blood glucose levels: case-control study and a case report of euglycemic diabetic ketoacidosis in pregnancy. Sathu A. Endocr Res 2004. Mallie JP. 36. 35. Fein IA.57: 177e80. Recant LL. et al. Prevention of hypophosphatemia by phosphate infusion during treatment of diabetic ketoacidosis and hyperosmolar coma. Bolus insulin injection versus continuous insulin infusion. 24. Diabetes 1979. Sari R.43:234e48. 46. Singhal PC. editors. Is a priming dose of insulin necessary in a low-dose insulin protocol for the treatment of diabetic ketoacidosis? Diabetes Care 2008.35:41e6. et al.88:681e95.289:1035e8.11:447e50. Intracerebral crises during treatment of diabetic ketoacidosis. Hyperglycemic crises in urban blacks. 30.30:395e402. Rackow EC. Ayer S. Toronto. Bull SV. 57. Mahoney CP. et al. Adrogue HJ.18:1187e90. Kleinberger G. Cuervo R. The use of an insulin bolus in low-dose insulin infusion for pediatric diabetic ketoacidosis. 34. Fang J. Chico A. Douglas IS. et al. Diabetes in urban African-Americans. Sperling MA. Arch Intern Med 1977. Bektas F. 62. Central pontine myelinolysis complicating treatment of the hyperglycaemic hyperosmolar state. Eray O. 17. Keller U.34: 459e61.28:604e8. Chiasson JL. 56. Castrejon M. Kitabchi AE. Diabetes 1971. Ann Intern Med 1976. Owen OE. Kelly JP. Silliman RA. 61. Murphy MB. Diabetes Care 1997.50. May ME. Euglycemic diabetic ketoacidosis. Barrero J. Diabetic ketoacidosis precipitated by subacute (De Quervain’s) thyroiditis. 65. Oseguera J. Passaro MD.306:287e94. O’Malley G. 38. Meyer T. Umpierrez GE. Eknoyan G. Stahl EJ.19e2. Does an integrated care pathway enhance the management of diabetic ketoacidosis? Diabet Med 2007. Anwar MN.345:767e72. Diabetes in Ontario: An ICES Practice Atlas. Harris S. BMJ 1973.27:1873e88. Diabetes 1981. Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Li LX. 27. Zhao XP. Pract Diabetes Int 2006. J Obstet Gynaecol 2007.5:77e9. Gerich JE.117:291e6. et al. 54. Gamba G. Aust N Z J Med 1998.27:921e4. Effect of physician specialty on outcomes in diabetic ketoacidosis. randomized placebo controlled trial.22:1790e5. In: Hux JE. Oliver R. Available at: http://www.on. Jablonski KA. McCuish AC. 44. 28.ices. Diabetic ketoacidosis in adults at Auckland Hospital. Ann Intern Med 1982. Butkiewicz EK. Cardiac troponin I concentrations in people presenting with diabetic ketoacidosis. Bellazzini MA.44: 391e3. O’Kane MJ. Adherence to protocol during the acute management of diabetic ketoacidosis: would specialist involvement lead to better outcomes? Int J Clin Pract 2010. Diabetes Care 2005. 49. Glycemic control and perinatal outcomes of pregnancies complicated by type 1 diabetes: Influence of continuous subcutaneous insulin infusion and lispro insulin. 18. et al. O’Brien PC. Petrov M.105:836e40.S76 J. Leibson CL. Widening of the QRS complex due to severe hyperkalemia as an acute complication of diabetic ketoacidosis. Booth GL. Harper R. 48.28:1856e61. Pediatr Neurol 1999. Treatment of diabetic ketoacidosis with subcutaneous insulin aspart. et al. 25. Wachtel TJ. Kitabchi AE.20:228e38. 55. et al. 50. Murphy MB.45(pt 4):440e3. Salahuddin M. Campos PR. Phosphate therapy in diabetic ketoacidosis. Hale PJ. Carlotti AP. Aris-Jilwan N. 20. Prospective comparison with “conventional” insulin therapy. Streat S. 58. 2012. et al.30:510e8.2:578e80. Crase J. Stoever J. 43. Korn A. 33. Fisher JN.24:359e63.23:76e7. Bicarbonate therapy in severe diabetic ketoacidosis. 26. Severe hyperglycemia: effects of rehydration on endocrine derangements and blood glucose concentration.31:2081e5. 31. Ann Intern Med 1978. Bicarbonate therapy in severe diabetic ketoacidosis: a double blind. Waters SM. Martin MM. Kitabchi AE. Licht JH. Della Manna T. 63. 2003:2. Br Med J Clin Res Ed 1984. 64. Acute complications of diabetes. Intensive Care Med 2001. et al.22:221e4. et al. Subcutaneous use of a fast-acting insulin analog: an alternative treatment for pediatric patients with diabetic ketoacidosis. Arch Intern Med 1997. 52. Umpierrez GE. et al.142:517e20.23:120e3. Diabetes Care 1990. . Predisposing factors for the diabetic hyperosmolar state. Petrov D. Bohn D. Delaney S. Am J Med Sci 1993. et al. 14. J Postgrad Med Inst 2009. Kreisberg RA. Potassium balance during treatment of diabetic ketoacidosis with special reference to the use of bicarbonate. Lancet 1995. 23. J Pediatr 1980.20:1347e52. Mandatory protocol for treating adult patients with diabetic ketoacidosis decreases intensive care unit and hospital lengths of stay: results of a nonrandomized trial. Rev Invest Clin 1991. et al.168: 859e66. Syed H. Waller SL. 42. et al. 59. Nikookam K. Diabet Med 2004. Bolte RG. Am J Med 2004. Ann Intern Med 1986. Diabetes Care 1995. et al. Salutary effects of modest fluid replacement in the treatment of adults with diabetic ketoacidosis. Nattrass M. J. Determinants of rhabdomyolysis in the diabetic state. Umpierrez GE.137:1377e80. Diabetes Care 2004.84:633e8. J Emerg Med 2010.13:22e33. Albert RK. Jagadeesan P.262:2108e13.2:721e7. Strachan MW. Foster M. Navarrete JE. Guerra SM. 19.ca. Slaughter PM. Keuer SP. Geddes J. Levetan CS. Steinmetz L. 1988-1996. 15. Diabetic ketoacidosis. Spencer J. more accurately guides therapy for acute changes in natremia.18:483e9. Talapatra I. 37. et al. Campbell IW.12:937e45.2:115e26. Diabetic ketoacidosis: new concepts and trends in pathogenesis and treatment. 51.39:e139e41. Waldhäusl W. Ann Clin Biochem 2008. 21. Hillson R. et al. Devalia B. Arch Intern Med 1987. Kreisberg RA. Musey VC. 47.64:1580e2. et al. Wiggam MI. Study on effectiveness of guidelines and high dependency unit management on diabetic ketoacidosis patients. Garcia-Patterson A. Molitch ME. Low-dose insulin infusion in the treatment of diabetic ketoacidosis: bolus versus no bolus. Deans KA. Sapir DG. The efficacy of low dose versus conventional therapy of insulin for treatment of diabetic ketoacidosis. Tymms DJ. Cormack A. Near patient blood ketone measurements and their utility in predicting diabetic ketoacidosis. 40.28:577e84. Berger W. Guo RX. Soler NG. Heber D. Howard RJ. Rosenbloom AL. Pediatr Emerg Care 1989. Lee JK. A randomized study of phosphate therapy in the treatment of diabetic ketoacidosis. Ennis ED. Lifshitz F. Yang LZ. Dixon K. et al. 53. ON: Institute for Clinical Evaluative Sciences. Diabetes 1980. Diabetes Care 1999. Risk factors for developing brain herniation during diabetic ketoacidosis. Accessed May 1. 32. 22. Ann Clin Biochem 2007. Munro JF.2:665e7. Renal function and effects of partial rehydration during diabetic ketoacidosis. Euglycaemic diabetic ketoacidosis in pregnancy: an unusual presentation. including cardiovascular disease. Acute illness results in a number of physiological changes (e.024 . Therefore.0 mmol/L.0 to 8.org/10. For patients with newly recognized hyperglycemia. management is rarely the primary focus of care. Maureen Clement MD. This is largely explained by the fact that the majority of hospitalizations for patients with diabetes are not directly related to the metabolic state.  For the majority of noncritically ill patients treated with insulin. in conjunction with random BG values <10. an admission BG measurement should be considered for all patients even in the absence of a prior diagnosis of diabetes (1). Although a growing body of literature supports the need for targeted glycemic control in the hospital setting.canadianjournalofdiabetes. even in those without a previous history of diabetes. length of hospital stay and mortality. due to a paucity of randomized controlled trials on the benefits and risks of “loose” vs.01.Can J Diabetes 37 (2013) S77eS81 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. bolus and correction (supplemental) insulin is the preferred method. 26% had a known history of diabetes.jcjd. Hyperglycemia. it is difficult to define glycemic targets for this population.g. increases in circulating concentrations of stress hormones) or therapeutic choices (e. should be discouraged. A proactive approach to management using scheduled basal.0 mmol/L.2013. Sara Capes MD.0 to 8. Of these patients. For patients with known diabetes. causes physiological changes that can exacerbate acute illness. preprandial glucose targets should be 5. which treats hyperglycemia after it has occurred. However. For the majority of noncritically ill patients treated with insulin.0 mmol/L. (1) reviewed the medical records of over 2000 adult patients admitted to a community teaching hospital in the United States (>85% were non-intensive care unit [non-ICU] patients) and found that hyperglycemia was present in 38% of patients. and is associated with increased in-hospital complications. should be clearly identified on the medical record. Glycemic targets for hospitalized patients are modestly higher than those routinely advised for outpatients with diabetes given that the hospital setting presents unique challenges for the management of hyperglycemia. and 12% had no history of diabetes prior to admission (1). blood glucose (BG) continues to be poorly controlled and is frequently overlooked in general medicine and surgery services. if present. cancer and lower-extremity amputations.0 mmol/L. This leads to a vicious cycle of worsening illness and poor glucose control (3). For critically ill patients. BG levels should be maintained between 8. such as decreased immune function and increased oxidative stress. as long as these targets can be safely achieved. Lower targets may be considered in clinically stable patients with a prior history of successful tight glycemic control in the outpatient setting. CCFP.8 mmol/L (5). such as variations in patient nutritional status and the presence of acute illness. David Miller MD. the A1C identifies patients who would benefit from efforts to improve glycemic control. glucocorticoid use) that can exacerbate hyperglycemia. and diabetes 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. The use of sliding-scale insulin (SSI). FRCPC.g.7e9). infection. glycemic control and other diabetes care issues are often not adequately addressed (4). Glycemic Control in the Noncritically Ill Patient A number of studies have demonstrated that inpatient hyperglycemia is associated with increased morbidity and mortality in noncritically ill hospitalized patients (1. Diabetes has been reported to be the fourth most common comorbid condition listed on all hospital discharges (2). Umpierrez et al. an elevated A1C may help differentiate patients with previously undiagnosed diabetes from those with stressinduced hyperglycemia (6).1016/j.0 and 10. In-hospital hyperglycemia is common.0 mmol/L. “tight” glycemic control in noncritically ill patients. Current recommendations are based on clinical experience and judgement. nephropathy. FRCPC KEY MESSAGES  Hyperglycemia is common in hospitalized patients.doi. preprandial blood glucose (BG) targets should be 5. Diagnosis of Diabetes and Hyperglycemia in the Hospital Setting A history of diabetes should be elicited in all patients admitted to hospital and.com Clinical Practice Guidelines In-hospital Management of Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Robyn Houlden MD.  Insulin is the most appropriate agent for effectively controlling glycemia inhospital. FRCPC. as long as these targets can be safely achieved. A glycated hemoglobin (A1C) level should be drawn in all patients with known diabetes or with hyperglycemia if this has not been performed within 2 to 3 months of the admission. in turn. In view of the high prevalence of inpatient hyperglycemia with associated poor outcomes. In-hospital hyperglycemia is defined as any glucose value >7. in conjunction with random BG values <10. while higher targets may be acceptable in terminally ill patients or in Introduction Diabetes increases the risk for disorders that predispose individuals to hospitalization. 0 and 10. Some trials showed that achieving normoglycemia (4. Stable patients without these contraindications can often have their home medications continued while in the hospital. NPH) and the balance given as bolus (rapid or short-acting) insulin divided equally before each meal (i. Role of Oral Antihyperglycemic Drugs To date. In these insulin-naïve patients. delirium. and exposure to intravenous (IV) contrast dye (39). The risk of hypoglycemia can be reduced by frequent BG monitoring and carefully designed management protocols. There are few intervention studies assessing the impact of tight glycemic control on morbidity or mortality in these settings.S78 R. a number of small studies that compared different methods of achieving glycemic control during minor and moderate surgeries did not demonstrate any adverse effects of maintaining perioperative glycemic levels between 5. therefore. is not recommended (5.9 mmol/L. However. However.0 mmol/L for minor and moderate surgeries. intensive insulin therapy has been associated with an increased risk of hypoglycemia in the ICU setting (12). Preexisting diabetes-related complications and comorbidities may also influence clinical outcomes. this benefit in surgical ICU patients was not demonstrated in the Normoglycemia in Intensive Care EvaluationSurvival Using Glucose Algorithm Regulation (NICE-SUGAR) study. Stable patients can usually be maintained on their home insulin regimen with adjustments made to accommodate for differences in meals and activity levels. Observational studies in humans have shown that hyperglycemia increases the risk of postoperative infections (16e18) and renal allograft rejection (19). Role of Subcutaneous Insulin In general.0 and 10. Acute hyperglycemia has been shown to adversely affect immune function (14) and wound healing (15) in animal models. no large studies have investigated the use of oral antihyperglycemic drugs (OADs) on outcomes in hospitalized patients with diabetes. lunch. These studies have typically started patients on 0. However.0 mmol/L in critically ill patients. if contraindications develop or if glycemic control is inadequate.3 mmol/L. acute or chronic renal failure. If BG values are 3. but not in medical patients (12). insulin is the preferred treatment for hyperglycemia in hospitalized patients with diabetes (5). supplemental doses of the bolus insulin are to be provided if BG values are above target. the benefits of improved perioperative glycemic control must be weighed against the risk of perioperative hypoglycemia. There are often short.0 mmol/L (27e29). unless the event is easily explained by other factors (e. Therefore. Appropriate glycemic targets for patients with preexisting diabetes who are critically ill (ICU setting) have not been firmly established.0 mmol/L) may be appropriate in select patients. the largest trial to date of intensive glucose control in critically ill patients (13). Sliding-scale insulin (SSI) (defined as the administration of a preestablished amount of short-acting insulin in response to hyperglycemia) as the sole regimen for the management of hyperglycemia in the hospital setting is ineffective in the majority of patients and. Given the data supporting tighter perioperative glycemic control during major surgeries and the compelling data showing the adverse effects of hyperglycemia. / Can J Diabetes 37 (2013) S77eS81 those with severe comorbidities. it is recommended to maintain BG levels between 8. a lower BG target (but not <6.e.4 to 6. rapid-acting insulin analogues are the preferred SC bolus insulins (32). Patients with type 1 diabetes must be maintained on insulin therapy at all times to prevent diabetic ketoacidosis (DKA). Insulin infusion protocols with proven efficacy and safety are recommended to minimize the risk of hypoglycemia (5). In patients undergoing coronary artery bypass grafting (CABG). it is reasonable to target glycemic levels between 5.5 units of insulin per kilogram of body weight per day. with 40% to 50% of the total daily dose (TDD) given as basal insulin (detemir. renal dysfunction.0 and 11. Acute hyperglycemia is common secondary to the physiological stress associated with surgery. and is associated with increased resource utilization (20). Insulin is often required temporarily inhospital. subsequent trials in mixed populations of critically ill patients did not show a benefit of targeting BG levels of 4. In the hospital setting. A meta-analysis of trials of intensive insulin therapy in the ICU setting suggested some benefit of intensive insulin therapy in surgical patients. Bolus insulin can be withheld or reduced in patients who are not eating regularly. including stress-induced counterregulatory hormone secretion and the effects of medications administered in the ICU (10). breakfast. However. Rapid institution of perioperative control should be carefully considered in patients with poorly controlled type 2 diabetes undergoing monocular phacoemulsification cataract surgery with moderate to severe nonproliferative diabetic retinopathy because of the possible increased risk of postoperative progression of retinopathy and maculopathy (30). Furthermore.1 mmol/L) in cardiac surgery patients or patients in postoperative surgical ICU settings may reduce mortality (11).and/or long-term contraindications to the use of OADs in the hospital setting.38). even in patients with type 2 diabetes not previously treated with insulin. bolus (prandial) and correction (supplemental) insulin components is the preferred method for achieving and maintaining glucose control in noncritically ill patients with diabetes or stress hyperglycemia who are eating (5). Perioperative glycemic control The management of individuals with diabetes at the time of surgery poses a number of challenges. a preexisting diagnosis of diabetes has been identified as a risk factor for postoperative sternal wound infections. however. glargine.33e36). Intraoperative hyperglycemia during cardiopulmonary bypass has been associated with increased morbidity and mortality rates in individuals with and without diabetes (24e26). a missed meal) (5). these drugs should be discontinued and the patient should be started on a basal-bolus-supplemental insulin regimen. basal insulin should not be withheld. Minor and moderate surgery The appropriate perioperative glycemic targets for minor or moderate surgeries are less clear. the glucose-lowering therapy should be modified. Glycemic Control in the Critically Ill Patient Acute hyperglycemia in the intensive care setting is not unusual and results from a number of factors. and dinner). Scheduled subcutaneous (SC) insulin administration that consists of basal. The outcome of vitrectomy does not appear to be influenced by perioperative control (31). Houlden et al. Anesthetic agents and postoperative analgesia may alter the patient’s level of consciousness and awareness of hypoglycemia. there is evidence demonstrating the superiority of basal-bolussupplemental insulin regimens over SSI (37. respiratory insufficiency and prolonged hospital stays (21e23). the effects of illness and the effects of other medications.4 to 0. The patient’s BG measurements should be reviewed daily and the insulin dose adjusted as required. such as irregular eating.4 to 8.g. Role of Medical Nutrition Therapy Medical nutrition therapy is an essential component of inpatient glycemic management programs and should include nutritional . Administering 60% to 80% of the total daily calculated dose as basal insulin has been demonstrated to be safe and efficacious in surgical patients (44). which is administered in divided doses to match feed times (39). nonpeaking basal insulin alone (once-daily glargine or twice daily detemir). The timely consultation of glycemic management teams has also been found to improve the quality of care provided. Staff education is a critical component of the implementation of an IV insulin infusion protocol. patients who are not eating or those who require prompt improvement in their glycemic control. most of these protocols have only been validated in the ICU setting. This should include the formation of a multidisciplinary steering committee to provide educational programs. a separate IV insulin infusion may be used. Patients receiving bolus enteral feeds are typically treated like patients who are eating meals. / Can J Diabetes 37 (2013) S77eS81 S79 assessment and individualized meal planning.or long-acting insulin is used. If intermediate. Patients should be asked to demonstrate or describe how to adjust their basal rate. however.g. computerized order entry systems (48. persistent insulin adjustments should be made to prevent hyper. Since nutrition is being provided continuously in patients receiving continuous enteral feeds. Dividing the total daily dose as a combination of basal and bolus insulin has been demonstrated to be safe and efficacious in medically ill patients (44. and produce standardized order sets. BG determinations should be performed every 1 to 2 hours until BG stability has been demonstrated. DKA. For management. the rate of change in BG). An IV infusion of regular insulin is often used initially to estimate the TDD of insulin required. Order sets for basal-bolus-supplemental insulin regimens. fill a reservoir. Although the optimal management of hyperglycemia in patients receiving high-dose oral corticosteroids has not been clearly defined. patients with type 1 diabetes must be given subcutaneous insulin if the total parenteral nutrition (TPN) is interrupted. patients receiving IV insulin should receive some form of glucose (e. The initial dose and distribution of SC insulin at the time of transition can be determined by extrapolating the IV insulin requirement over the preceding 6. For such individuals. the TDD of insulin can be administered as a long-acting. hospitals must have clear policies and procedures in place to guide the continued use of insulin pump therapy in the inpatient setting (42). glycemic monitoring for at least 48 hours is recommended for patients with or without a history of diabetes (5). to promote a collaborative relationship between the hospital staff and the patient.or rapid-acting insulin should be administered 1 to 2 hours before discontinuation of the IV insulin to maintain effective blood levels of insulin. Patients without a history of diabetes. gradual. protocols and algorithms for diabetes care within the institution. In the event that tube feeds are interrupted.R. With the exception of the treatment of hyperglycemic emergencies (e. with low rates of hypoglycemia. SC correction (supplemental) insulin is often used in addition to the insulin mixed with PN for unusual hyperglycemia.49) and specialized nurses reviewing insulin orders (50) all have been shown to improve glycemic control and/or reduce adverse outcomes in hospitalized patients. As an alternative to adding insulin to the PN. All patients admitted to hospital using insulin pumps must be assessed for their physical and mental competency to use their respective device. Approximately 50% of the TDD is provided as basal insulin and 50% as bolus insulin. with an emphasis on adjusting bolus insulin doses. who have hyperglycemia requiring more than 2 units of IV insulin per hour. have a stable level of consciousness and have the physical skills needed to self-administer insulin and perform self-monitoring of blood glucose (SMBG).and hypoglycemia. A consistent carbohydrate meal planning system may facilitate glycemic control in hospitalized patients and facilitate matching the prandial insulin dose to the amount of carbohydrate consumed (35. IV glucose or through TPN or enteral feeding). it should be given 2 to 3 hours prior to IV insulin discontinuation. Patients using insulin pump therapy Patients on insulin pump therapy do not necessarily need to discontinue this form of therapy while hospitalized.40). If the patient cannot competently demonstrate and/or describe the above-mentioned actions. insulin dosing should be proactively adjusted to prevent hypoglycemia.43). insulin pump therapy should be discontinued and the patient placed on a SC insulin regimen or an IV insulin infusion.to 8-hour period to a 24-hour period. Approximately 80% of the TDD of insulin needed to maintain BG levels within the target range on IV insulin is added to the PN bags as regular insulin. therefore. Patients receiving corticosteroid therapy Hyperglycemia is a common complication of corticosteroid therapy. Role of IV Insulin Most patients with type 1 or type 2 diabetes admitted to general medical wards can be treated with SC insulin. insulin management algorithms (46. During corticosteroid tapers. Several published insulin infusion protocols appear to be both safe and effective. should be transitioned to scheduled SC insulin therapy. adult patients who successfully self-manage their diabetes at home. administer a bolus dose. where the nurse-to-patient ratio is higher than on general medical and surgical wards (3.52). implement policies to assess and monitor the quality of glycemic management. IV insulin protocols should take into account the patient’s current and previous BG levels (and. The patient should also have adequate insulin pump supplies. and to ensure patient safety. IV insulin may be appropriate for patients who are critically ill.47). insulin is generally preferred. Patient self-management in the hospital setting may be appropriate for competent. However. suspend their pump and correct a capillary BG result outside their target range. Houlden et al. Supplemental insulin should be administered as needed with the bolus insulin. Depending on the glucose monitoring results.g. Transition from IV insulin to SC insulin therapy All patients with type 1 and type 2 diabetes should be transitioned to scheduled SC insulin therapy from IV insulin. Short. and the patient’s usual insulin dose. Short-acting regular insulin is usually selected over rapid-acting insulin in this group of patients because of the longer duration of action. insert an infusion set. a physician order for self-management should be written . hyperosmolar hyperglycemic state (HHS)). with prevalence between 20% and 50% among patients without a previous history of diabetes (41). The dose of insulin is adjusted based on BG monitoring results. insulin can be administered with the nutrition. Organization of Care Healthcare institutions should implement a program to improve glycemic control in the inpatient setting. Special Clinical Situations Patients receiving enteral or parenteral feedings In patients receiving parenteral nutrition (PN). reduce the length of hospital stays and lower costs (51. To prevent ketoacidosis.45). IV dextrose may be required to prevent hypoglycemia. enteral nutrition) (53).87:978e82. instead of the reactive sliding-scale insulin approach that uses only short. Nilsson G. should be used to reduce adverse events and improve glycemic control.38)].96:41Ee6E. Hypoglycemia Hypoglycemia remains a major barrier to achieving optimal glycemic control in hospitalized patients. Healthcare institutions must implement and maintain a quality control program to ensure the accuracy of bedside BG testing (54. Healthcare professional education. Patients and their primary care providers should be aware of the need for potential adjustments in insulin therapy that may accompany adjustments of other medications prescribed at the time of discharge. particularly when NPO or during diagnostic procedures [Grade D. Systematic strategies for improved outcomes for the hyperglycemic hospitalized patient with diabetes mellitus. Level 3 (46)]. To maintain intraoperative glycemic levels between 5. J Clin Endocrinol Metab 2002. 4. A systems approach that includes preprinted. including insulin and other glucoselowering medication.24:1371e6. Transition from hospital to home Patients and their family or caregivers should receive written and oral instructions regarding their diabetes management at the time of hospital discharge.0 mmol/L for most other surgical situations. Data management programs that transfer bedside BG monitoring results into electronic records allow evaluation of hospital-wide glycemic control (57). Umpierrez GE.15:353e69. a proactive approach that includes basal. 2. a continuous IV insulin infusion should be used to maintain glucose levels between 8 and 10 mmol/L [Grade D. monitor and improve glycemic control within the inpatient setting should be implemented. Consensus]. Moghissi ES.0 and 10. coronary artery bypass grafting.0 to 8. there are no studies that have examined the effect of the frequency of bedside BG testing on the incidence of hyper.355:1903e11. 8. bolus and correction (supplemental) insulin. 6. . p. Inzucchi SE. S119 Treatment of Diabetes in Patients with Heart Failure. Consensus]. Consensus]. CABG. Am J Cardiol 2005. Insulin administration errors Insulin causes the most harm and severe adverse events of the high alert medications (58). Consensus]. 9. Management of hyperglycemia in the hospital setting. 2. American Association of Clinical Endocrinologists and American Diabetes Association consensus statement on inpatient glycemic control. Consensus]. and identification and contact information for healthcare providers responsible for ongoing diabetes care and adjustment of glucose-lowering medication. The use of meters with bar coding capability has been shown to reduce data entry errors in medical records (56). such as corticosteroids or octreotide. Consensus]. / Can J Diabetes 37 (2013) S77eS81 with respect to selection of food. et al. Endocr Pract 2009. Bedside BG monitoring Currently. et al. Bazargan N. For most medical/surgical critically ill patients with hyperglycemia. unexpected transfer from the nursing unit after rapidacting insulin administration or a reduction in corticosteroid dose (35). discontinuation of PN or enteral nutrition. monitoring is typically performed before meals and at bedtime in patients who are eating. S126 References 1.0 mmol/L for patients with diabetes undergoing CABG. Healthcare workers should be educated about factors that increase the risk of hypoglycemia. S56 Pharmacologic Management of Type 2 Diabetes. et al.or hypoglycemia in the hospital setting. IV. people with diabetes should be maintained on their prehospitalization oral antihyperglycemic agents or insulin regimens [Grade D. Measures to assess. 7. Korytkowski MT. Perioperative glycemic levels should be maintained between 5. N Engl J Med 2006. such as sudden reduction in oral intake. SMBG. Hyperglycaemia is associated with poor outcomes in patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease.55). a continuous IV insulin infusion protocol administered by trained staff [Grade C. dietary intake and glycemic control are acceptable. Windows of opportunity to improve diabetes care when patients with diabetes are hospitalized for other conditions. Baker EH. Level 3 (60e62)] should be used. preprandial BG targets should be 5. Vasa F. Janaway CH. In hospitalized patients. recognition and management should be implemented with nurse-initiated treatment. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study. Consensus]. including glucagon for severe hypoglycemia when IV access is not readily available [Grade D.0 mmol/L in conjunction with random BG values <10. 5. 3. NPO. For hospitalized patients with diabetes treated with insulin.359:2140e4. intravenous. PN. 4.61:284e9. 5. Chassin MR. Healthcare institutions should have standardized treatment protocols that address mild. et al.0 mmol/L. 6. and every 1 to 2 hours for patients on continuous IV insulin. Houlden et al. 3. self-determination and administration of insulin dose and type. Some bedside BG testing is indicated in individuals without known diabetes but receiving treatments known to be associated with hyperglycemia (glucocorticoids. 7.S80 R. Level 2 (37. moderate and severe hypoglycemia. Tenerz A. octreotide.  Patients at risk of hypoglycemia should have ready access to an appropriate source of glucose (oral or IV) at all times. p. Roman SH. Abbreviations: BG. a reconciled medication list. unambiguous standard orders for insulin administration and/or a computerized order entry system may help reduce errors (59).5 and 10. every 4 to 6 hours in patients who are NPO (nothing by mouth) or receiving continuous enteral feeding.or rapid-acting insulin [Grade B. Hyperglycemia: an independent marker of in-hospital mortality in patients with undiagnosed diabetes. insulin protocols and order sets may be used to improve adherence to optimal insulin use and glycemic control [Grade C. Thorax 2006. blood glucose. Clinical practice. nothing by mouth. however. Provided that their medical conditions. Isaacs SD. along with pattern management. S72 Management of Acute Coronary Syndromes. Lancet 2002. p. For the majority of noncritically ill patients treated with insulin. S61 Hyperglycemic Emergencies in Adults. Norhammar A. Other Relevant Guidelines Pharmacotherapy in Type 1 Diabetes. The instructions should include recommendations for timing and frequency of home glucose monitoring. p. approved. hypoglycemia should be avoided. Safety RECOMMENDATIONS 1. DiNardo M. identification and management of hypoglycemia. as long as these targets can be safely achieved [Grade D. The frequency and timing of bedside BG monitoring should be individualized. Philips BJ. Diabetes Care 2001. with an appropriate protocol and trained staff to ensure the safe and effective implementation of therapy and to minimize the likelihood of hypoglycemia [Grade D.  Protocols for hypoglycemia avoidance. p. as well as diabetes-specific discharge planning [Grade D. 97:16e38. 59. et al. Qual Saf Health Care 2008. et al.13:293e300. Implementation of capillary blood glucose monitoring in a teaching hospital and determination of program requirements to maintain quality testing. Steed RD. Poretsky L.pdf (Accessed February 1.22:1408e14. 42. Complete prevention of impaired anastomotic healing in diabetic rats requires preoperative blood glucose control. Schmidt J. Effect of perioperative glycemic control in progression of diabetic retinopathy and maculopathy. Endocr Pract 2010. Donihi AC. et al. 22.27:553e91.99:22e8. Gao G. Clement S. Napier B. et al. et al. JAMA 1998.103:687e94. Anesthesiology 2005. Glulisine versus human regular insulin in combination with glargine in noncritically ill hospitalized patients with type 2 diabetes: a randomized double-blind study. Shrader P. 27. Diabet Med 2006. Mayo Clin Proc 2005. et al. Nathan DM. Intraoperative hyperglycemia and perioperative outcomes in cardiac surgery patients. et al. Wilets IF.23:1008e15. 34. Raval D. 360:1283e97. McClymont KL. Maynard G. Hellman R. Burns SM.34:281e6.17: 464e8.38:1243e51. 29. S81 37. Intensive insulin therapy and mortality among critically ill patients: a meta-analysis including NICE-SUGAR study data. 47.94:575e82. 31. et al. Intensive versus conventional glucose control in critically ill patients. Phillips G. vanDam RM. Continuous insulin infusion reduces mortality in patients with diabetes undergoing coronary artery bypass grafting. Cukierman T. et al. McAlister FA. NICE-SUGAR Study Investigators. 60.75:1392e9. et al.345:1359e67.280:1311e6. Diabetes care in hospitalized noncritically ill patients: more evidence for clinical inertia and negative therapeutic momentum. et al. Schmeltz LR.30:2181e6. Yamashita H. et al. 2013). Endocr Pract 2004. Continuous intravenous infusion compared with subcutaneous administration. during and after cardiac surgery. Saul M. 48. Diabetes Care 2010. Umpierrez GE. Sliding scale insulin use: myth or insanity? Am J Med 2007. 124:38e45. Le Manach Y. Endocr Pract 2006. / Can J Diabetes 37 (2013) S77eS81 8. et al. Grunkemeier GL. Schmidt K. Kawasaki R. Pretto Z. Bobek MG. et al. Palacio A. Diabetes Care 2005. Haga KK. Anaesthesia 1988.15:25e9. Lugrin D. Verhofstad MH. Intraoperative glycaemic control in non-insulin-dependent and insulin-dependent diabetes.27:461e7. 58. Hemmerling TM. J Parenter Enteral Nutr 1997. Koerbel G. Nuttall GA. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes (RABBIT 2 trial). Rushakoff R. Continuous subcutaneous insulin (insulin pump) therapy can be safely used in the hospital in select patients. Dhatariya K. Lecomte P.12: 358e62. Early peri-operative glycaemic control and allograft rejection in patients with diabetes mellitus: a pilot study. Smiley D. Schurizek BA. Diabetes Care 2003. Man J. 25. Noschese M. Donihi AC. Ann Clin Biochem 1997. et al. Effect of computerized physician order entry and a team intervention on prevention of serious medication errors. J Hosp Med 2009. Diabetes Res Clin Pract 2007. Cullen DJ. Schnipper JL. Influence of systemic conditions and glycemic control on complications of vitrectomy for diabetic retinopathy [Japanese]. Ann Thorac Surg 1999. Furnary AP. Sampson MJ. Smiley D. Randomized study of basal-bolus insulin therapy in the inpatient management of patients with type 2 diabetes undergoing general surgery (RABBIT 2 surgery). Ndumele CD. 55. Clarke S. J Hosp Med 2007. Thorac Cardiovasc Surg 2003. Levetan CS. et al.28:810e5. Bode BW. Impact of diabetes mellitus on cardiac surgery outcome. 49.33:2181e3. 43. Lane-Gill SL.78:392e7. Lewandrowski K. N Engl J Med 2001. Poor intraoperative blood glucose control is associated with a worsened hospital outcome after cardiac surgery in diabetic patients. Koproski J. Meyer C. et al. Immunologic effects of acute hyperglycemia in nondiabetic rats. Karkouti K. glycaemic control and satisfaction with standard and patient-controlled consistent carbohydrate meal plans in hospitalized patients with diabetes. Ouattara A. et al. Impact on perioperative outcome. 28. Griesdale DEG. 18. Tight glucose control in the intensive care unit: are glucose meters up to the task? Clin Chem 2001. The relation between hyperglycemia and outcomes in 2. 35. 62. Russ GR. Comparison of a continuous glucose-insulin-potassium infusion versus intermittent bolus application of insulin on perioperative glucose control and hormone status in insulin-treated type 2 diabetics. Conversion of intravenous insulin infusions to subcutaneously administered insulin glargein in patients with hyperglycemia. Bistritz L. 46. Houlden et al. Intensive insulin therapy for critically ill patients. CMAJ 2009. Furnary AP. Am J Med 1992. et al. Br J Surg 1996. et al. Hendriks T. . Golden SH. Braithwaite SS. Transplantation 2001. 30. et al. et al.67: 352e60.22:77e81. Schmidt RE. Leape LL. Partlow BJ. et al. et al. Wijeysundera D. Qual Saf Health Care 2010. 9. Professional practice recommendations for safe use of insulin in hospitals. Effects of an intervention by a diabetes team in hospitalized patients with diabetes. Babineau TJ. Abel MD. Improving the quality of near-patient blood glucose measurement. Trends in bed occupancy for inpatients with diabetes before and after the introduction of a diabetes inpatient specialist nurse service. 10. adult patient.28:2367e71. Maynard G. Perioperative glycemic control and the risk of infectious complications in a cohort of adults with diabetes. Siegel MD.80:862e6. Dinardo M. Gummert JF. Korytkowski MT. et al. 41.51:11e6. Diabetes Care 2010. Suto C. Zisman A. Folia Ophthalmol Jpn 2004. 16. 50. Bates DW. Christiansen CL. Curll M. Sherwin RS. et al. Umpierrez GE. Pomposelli JJ. Grunkemeier GL. Hyperglycemia during cardiopulmonary bypass is an independent risk factor for mortality in patients undergoing cardiac surgery. Bucerius J. et al. 32. Implementation of a safe and effective insulin infusion protocol in a medical intensive care unit. Available at: http://www. Bailon RM. 53. on patient mortality and morbidity: a systematic review and meta-analysis. Impact of endocrine and diabetes team consultation on hospital length of stay for patients with diabetes. 51. Umpierrez GE.43: 533e7. Baxter 3rd JK. Gandhi GY. et al. Chittock DR. Ann Thorac Surg 2003. and transition to subcutaneous insulin therapy. Korytkowski MT. 11. Weekers F.3(suppl 5): 17e28. Diabetes and coronary artery bypass surgery: an examination of perioperative glycemic control and outcomes. Diabetes Care 2004. et al. Diabetes Care 1999. 54.10(suppl 2):71e80. Diabetes Care 2007. Z Kardiol 2005.19:36e40. Malling B. Braithwaite SS. Lee J.471 patients admitted to the hospital with communityacquired pneumonia.1:141e4. Coronary artery bypass surgery in diabetic patients. Diabetes Care 2011. Thomas MC. et al. et al. Blitz S. Management of hyperglycemia in hospitalized patients in non-critical care setting: an endocrine society clinical practice guideline. Zerr KJ. Outcomes and peri-operative hyperglycemia in patients with or without diabetes mellitus undergoing coronary artery bypass grafting.120:563e7. Kao WH. 14. 24. J Parenter Enteral Nutr 1998. Diabetes in patients undergoing coronary artery bypass grafting. Liang CL. Raucoules-Aimé M. Mathew TH. Schmid MC. Hori S.34: 256e61.72:1321e4. et al.R. 57. Arch Ophthalmol 2006. McAlister FA. Insulin treatment of the insulindependent diabetic patient undergoing minor surgery. Peart-Vigilance C. Effects of a computerized order set on the inpatient management of hyperglycemia: a cluster-randomized controlled trial. Harder K. Walluscheck KP. Wouters P.130:1144. et al.83:1717e21. Bruns DE. 26. 52. Diabetes Care 2005. Sacks DB. et al.180:821e7. Boussofara M. Diabetes Care 2004. et al.73:443e9. 56.93:419e26. Scott MG. Improved inpatient use of basal insulin reduced hypoglycemia and improved glycemic control: effect of structured subcutaneous insulin order sets and an insulin management algorithm. Goldberg PA. Walther T. Wexler DJ. et al. Bucerius J. et al.55:105e9. J Cardiothorac Surg 2011. deSouza RJ. Lydon E.org/s_ashp/docs/ files/Safe_Use_of_Insulin. J Card Surg 2004. Ann Pharmacother 2004. 12. methods. Cook CB. Magee MF. O’Malley C. Management of diabetes and hyperglycemia in the hospital: a practical guide to subcutaneous insulin use in the non-critically ill. 38. Kwoun MO. 44. et al. Umpierrez G. Lewis KS.20:1553e5. J Thorac Cardiovasc Surg 2003. J Clin Anesth 2001. 33. Cheek R. Nifong LW.2:203e11. Glycemic chaos (not glycemic control) still the rule for inpatient care: how do we stop the insanity? J Hosp Med 2006.19:355e9. Su SY.ashp. Clinical outcomes associated with the use of subcutaneous insulin-by-glucose sliding scales to manage hyperglycemia in hospitalized patients with pneumonia. N Engl J Med 2009. Young JA. et al. Salas JR. Zaccaria C. Rumley AG. Effect of a diabetes order set on glycaemic management and control in the hospital. J Clin Endocrinol Metab 2012. J Thorac Cardiovasc Surg 2005. et al. Menu selection. Davidson PC. Umpierrez GE. Cheung NW. 61. J Hosp Med 2008. Walther T. 15. 45. et al.33:2496e501. 17. Noschese M.12:641e50. Wesorick D. Moldoveanu A. Estrada CA. Diabetes Care 1997. 23.26:1518e24. Institute of Safe Medical Practice. Effectiveness of a computerized insulin order template in general medical inpatients with type 2 diabetes: a cluster randomized trial. van den Berghe G. Boron A. Early postoperative glucose control predicts nosocomial infection rate in diabetic patients. Endocr Pract 2009. Prevalence and predictors of corticosteroidrelated hyperglycemia in hospitalized patients. et al.47: 209e14. 13. et al. Plummer E. Ling PR. Kamio S. Smiley D. Miller-Cage V. 39. Crowle T. Gummert JF.6:3. Majumdar SR. The effect of tight glycaemic control. Boyd JC. Endocr Pract 2006. Becker T. 21. Doenst T.4:3e15. Finfer S. Intensive insulin therapy in the critically ill patients. Management of diabetes and hyperglycemia in hospitals. Intravenous insulin infusion therapy: indications. et al. 20. Am J Med 1995. 40. DeSantis AJ. Br J Anaesth 1994. Kato S.125:1007e21. 36. Continuous intravenous insulin infusion reduces the incidence of deep sternal wound infection in diabetic patients after cardiac surgical procedures. Jacobs S. Hyperglycemia is associated with adverse outcomes in patients receiving total parenteral nutrition. Castro JC.21:91e5. Brandt M. 19.16:209e18. Many classes of antihyperglycemic medications are associated with weight gain. Analysis of 57 prospective studies in w900. These guidelines have not been fully validated against the development of clinical events. Obesity is also becoming more prevalent in people with type 1 diabetes. Psychological aspects of eating behaviours.com Clinical Practice Guidelines Weight Management in Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Sean Wharton MD. Metabolic comorbidities. and considerable population-based research is needed in this area. should also be assessed since they are highly correlated with increasing BMI (10. should be considered (17).9 !40. intensive insulin therapy and some glucoselowering medications are associated with weight gain (3.025 of BMI (kg/m2) (Table 1) (9) and waist circumference (WC) to assess the degree of abdominal obesity (Table 2) (9). Excessive abdominal adiposity is a strong independent predictor of metabolic comorbidities (12.5e24. Lau MD. calculation 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. Arya M. Cutoff values for WC vary among expert guidelines.org/10. People with diabetes often take medications that are associated with weight gain. Weight loss has been shown to improve glycemic control by increasing insulin sensitivity and glucose uptake and diminishing hepatic glucose output (5). . should be assessed (20).9 !30.  A modest weight loss of 5% to 10% of initial body weight can substantially improve glycemic control and cardiovascular disease risk factors. while some are weight neutral or associated with weight loss. such as hypertension. An estimated 80% to 90% of persons with type 2 diabetes are also overweight or obese (1).11). Table 1 Canadian guidelines for body weight classification in adults using BMI (8) Classification Underweight Normal weight Overweight Obese Class I Class II Class III BMI* category (kg/m2) <18. Furthermore. weight.13).4). The drug effects on body weight should be considered in glycemic management.9 25. can also impact the ability to lose weight (21). Introduction Obesity is widely considered a chronic health problem that is often progressive and difficult to treat.doi.9 35. Table 2 (14. Assessment of overweight and obese patients should include determining reasons for the previous or current positive energy balance that led them to become overweight or obese. these include antihyperglycemic. cardiovascular disease (CVD) and some forms of cancer increases with excessive body fat (6). PharmD.W. FRCPC KEY MESSAGES  An estimated 80% to 90% of persons with type 2 diabetes are overweight or obese. Comorbid conditions.0 30.000 adults by the Prospective Studies Collaboration indicated that each 5 kg/m2 higher body mass index (BMI) above 25 kg/m2 was associated with about 30% higher overall mortality (8). David C. Assessment of Overweight and Obesity The initial assessment of people with diabetes should include the following measurements: height.2013. antihypertensive. These conditions should be assessed and treated. The risk of death from all causes.1016/j.jcjd. including those !75 years of age (7). FRCPC. or to continually gain weight. such as osteoarthritis or dyspnea. An etiological approach assessing causes of lower metabolic rates. The International Diabetes Federation has proposed population specific WC cutoff values (Table 3) (16).15) lists National Cholesterol and Education Program Adult Treatment Panel III (NCEP-ATP III) WC values. a study has indicated a 7-fold increase in obesity in 20 years (2).0e34.0e39. Sharma MD. such as medications and hormonal imbalances. This relationship between increasing body fat accumulation and adverse health outcomes exists throughout the range of overweight and obese men and women in all age groups. dyslipidemia and CVD risk factors.0 Risk of developing health problems Increased Least Increased High Very High Extremely High * Body mass index (BMI) values are age and gender independent and may not be correct for all ethnic populations.  Bariatric surgery may be considered for appropriate patients when other interventions fail to achieve and maintain a healthy body weight.  Comprehensive health behaviour intervention should be implemented in overweight and obese people with diabetes or those at risk for diabetes to prevent weight gain and to achieve and maintain a reduced body weight. pain relief and antidepressant agents (18). PhD.5 18.canadianjournalofdiabetes.0e29. PhD.Can J Diabetes 37 (2013) S82eS86 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. FRCPC. binge eating and depression. Higher body mass index in people with diabetes is associated with increased overall mortality. such as osteoarthritis and obstructive sleep apnea. also should be assessed (19).01. such as emotional eating. Physical parameters that impede activity. even in persons with normal weight. supplements. Asian population [See Table 3]). prevention of weight gain can be considered a realistic and sustainable outcome. caloric and carbohydrate intake and how to select nutrient-rich meals (38. 3. Reasonable weight loss goals are set at 1 to 2 lb/week. The 1. Exercise is encouraged but physical activity is promoted at a gradual pace. Table 3 Ethnic-specific values for WC from International Diabetes Federation (13) Country or ethnic group Central obesity as defined by WC Men Europid* South Asian.39). 4.28). As understanding and adhering to healthy and nutritionally balanced meal plans can be challenging.6 e À3.5 * Waist circumference (WC) cutoffs may be lower in some populations (e.8 e þ11.0 e þ0.63) Dipeptidyl peptidase-4 (DPP-4) inhibitors (64. Chinese.2 e þ10.31). especially in the presence of the metabolic syndrome (e. y Increased WC can also be a marker for increased risk. registered dietitians) and diets are not less than 900 kcal/day. investigated the effects of lifestyle intervention on changes in weight. As individuals lose weight. * National Cholesterol and Education Program Adult Treatment Panel III (NCEPATP III) guidelines (11. Japanese South and Central American Sub-Saharan African Eastern Mediterranean and Middle Eastern (Arab) Women !94 cm !80 cm !90 cm !80 cm Use South Asian cutoff points until more specific data are available. The optimal rate of weight loss is 1 to 2 kg/month but is generally self-limiting due to physiological counterregulation (17. The National Institutes of Health (NIH)-sponsored multicenter Look AHEAD (Action for Health in Diabetes) trial.7 þ1.97 Weight effect À0.and 4-year interim data reported beneficial effects of modest weight loss of 5% to 10% in improving glycemic control. whose design is based largely on the United States (US) Diabetes Prevention Program. Greater improvement in risk factors occurred with greater weight losses. In general. BP and lipid levels (30. Healthy Behaviour Interventions The overall goal of health behaviour intervention in people with diabetes who are overweight or obese is to improve health status and quality of life (32. adjustment in antihyperglycemic medications may be required to avoid hypoglycemia. Cost is not prohibitive.0 e þ0. There was some expected weight regain at 4 years. Attaining and maintaining a healthy body weight and preventing weight regain are the short. exercise and behavioral programs and counselling. except under medical supervision. A negative energy balance of 500 kcal/day is typically required to achieve a weight loss of 0. In general. lowering of CV risk markers. All weight-loss diets must be well balanced and nutritionally adequate to ensure optimal health.88 À8. obese people with diabetes have greater difficulty with weight loss compared to similarly obese people without diabetes (22). and CVD risk factors and events in people with type 2 diabetes (30). NPH) (2) Thiazolidinediones (TZDs) (57) Sulphonylureas (2.88 þ0. increased and regular physical activity and behaviour therapy are the most effective (34e37). Use Europid cutoff points until more specific data are available. glargine) (59. pain and cramping  Steatorrhea  Fecal incontinence Gastrointestinal lipase Orlistat (Xenical) inhibitor . Treatment of Overweight and Obesity The goals of therapy for overweight and obese people with diabetes are to achieve optimal glycemic and metabolic control initially through health behaviour intervention. glycemic control. High-fibre foods are associated with greater satiety. 9.12) and Health Canada (6) define central obesity as waist circumference (WC) values !102 cm (40 inches) in men and !88 cm (35 inches). The program assesses and treats comorbid conditions. Wharton et al. There is no requirement to buy products.22 e þ0. Nutritional advice is provided by qualified experts (e. Many antihyperglycemic medications are associated with weight gain. a carbohydrate intake of at least 100 g/day is required to spare protein breakdown and muscle wasting and to avoid large shifts in fluid balance and ketosis.0 þ5.5 e þ5.S. 8. detemir.67) S83 Weight effect (lb) þ8.33). fitness. Structured interdisciplinary programs have demonstrated better short. / Can J Diabetes 37 (2013) S82eS86 Table 2 NCEP-ATP III WC and risk of developing health problems (8) WC cutoff points*.46 À6. Table 4 Checklist for weight management programs (46) 1.65) Glucagon-like peptide-1 (GLP-1) receptor agonists (66. Health behaviour interventions that combine dietary modification.g. Adequate protein intake is required to maintain lean body mass and other essential physiological processes.4 e þ0. A modest weight loss of 5% to 10% of initial body weight can substantially improve insulin sensitivity.45 kg/week (29). yet there continued to be beneficial metabolic effects. The program provides individualized nutritional.g.44 þ0. and there are no financial contracts.and long-term results (36).g. vitamins or injections. Reduced intake of saturated fat and energy-dense foods should be emphasized.57) Meglitinides (58) Weight neutral or decrease weight Insulin (basal analogues. 2.y Men !102 cm (40 inches) Women !88 cm (35 inches) Risk of developing health problems Increased Increased Table 6 Glucose-lowering medications and their effects on weight (17) Weight gain Insulin (fast acting. older individuals. people with diabetes should be counselled by qualified professionals on appropriate serving sizes. 5.54 e þ3. hypertriglyceridemia). For many patients.and long-term goals. high Table 5 Medication approved for the treatment of obesity in type 2 diabetes (36) Class Generic (trade) name Recommended regimen 120 mg tid (during or up to 1 hour after each meal) Action  Nonsystemic pancreatic lipase inhibitor reduces dietary fat digestion and absorption by about 30% Adverse effects  Abdominal bloating. The program does not make unsubstantiated claims.6 þ3. 7. Very-lowcalorie diets with <900 kcal/day are not recommended. and attempts should be made to minimize these medications without compromising glycemic control or to switch to alternative agents not associated with weight gain (18). The program has an established maintenance program.60) Metformin (61) Alpha-glucosidase inhibitors (62. Use Europid cutoff points until more specific data are available. 6. blood pressure (BP) and dyslipidemia (23e27). healthy eating habits and weight loss (42e45). A surgical stapler is used to create a small gastric pouch.35:115-122. When used to treat overweight and obese people with diabetes. (From Shukla A. The upper part of the stomach is encircled with a constrictive saline-filled tube. Programs and clinics dedicated to weight management may be beneficial. Biliopancreatic Diversion with Duodenal Switch. Can J Diabetes 2011. orlistat has been demonstrated to improve glycemic control and to reduce the doses of antihyperglycemic agents that can promote weight gain (47). Wharton et al. and many approved agents have been discontinued . (From Shukla A. Secretion and function of gastrointestinal hormones after bariatric surgery: their role in type 2 diabetes. / Can J Diabetes 37 (2013) S82eS86 Figure 1. Secretion and function of gastrointestinal hormones after bariatric surgery: their role in type 2 diabetes. The stomach and small intestine are surgically reduced so that nutrients are absorbed only in a 50-cm “common limb. Rubino F. Can J Diabetes 2011. the entire duodenum and a portion of the jejunum.35:115-122. Members of the healthcare team should consider using a structured approach to providing advice and feedback on physical activity. (From Shukla A. Ingested food bypasses w95% of the stomach.) Figure 3. Rubino F. Secretion and function of gastrointestinal hormones after bariatric surgery: their role in type 2 diabetes. pharmacotherapy options are limited in weight management. Rubino F.) Two large-scale reviews of >100 individual studies evaluating behaviour modification techniques support their effectiveness in promoting weight loss (40.35:115-122. Can J Diabetes 2011.35:115-122. The amount of restriction can be adjusted by injecting or withdrawing saline solution.) Figure 2. Gastric Sleeve.) Figure 4. However. particularly those that adhere to the checklist in Table 4 (46).S84 S. Secretion and function of gastrointestinal hormones after bariatric surgery: their role in type 2 diabetes.41). Adjustable Gastric Band. Pharmacotherapy Orlistat is currently the only approved medication in Canada for long-term management of obesity (Table 5) (47). Rubino F.” (From Shukla A. A longitudinal (sleeve) resection of the stomach reduces the functional capacity of the stomac and eliminates the ghrelin-rich gastric fundus. Roux-en-Y Gastric Bypass. Can J Diabetes 2011. orlistat also improves glucose tolerance and reduces the progression to type 2 diabetes (51). Beneficial health effects of modest weight loss. 4. 13.48). Orlistat should be avoided in patients with inflammatory or other chronic bowel disease. Clinical trials with antiobesity agents have confirmed a smaller degree of weight loss in people with diabetes compared with obese people who do not have diabetes (22. 2. Orlistat has been shown to be effective at improving glycemic and metabolic control in obese people with type 2 diabetes (47. calorie-restricted diet. and Blood Institute. Two year reduction in sleep apnea symptoms and associated diabetes incidence after weight loss in severe obesity.50). Després JP. Senthilselvan A. and the magnitude of weight gain can vary from 4 to 9 kg or more. CMAJ 1997.65:1447e55. CMAJ 1997. 8. Grunstein RR. In obese people with impaired glucose tolerance.org/webdata/docs/IDF_Meta_def_final. 15. S40 Nutrition Therapy. Lancet 1998. Leiter L. and mortality from cancer in a prospectively studied cohort of U. Grundy SM. 2003. diabetes should be implemented to prevent weight gain and to achieve and maintain a lower. medical surveillance after surgical therapy is necessary for most people. Chisholm D. Padwal R. et al. In overweight or obese adults with type 2 diabetes. 2008. 2000. Health Canada.S. surgical. Cai J.894:1e253. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Sharma AM. psychiatric and nutritional expertise. Sleep 2007.338:1e7. Chen Y. obesity. et al. There are several new antiobesity agents that may be available within the near future and that may have a beneficial impact on diabetes management. National Heart. Bariatric Surgery Bariatric surgery has emerged as an innovative alternative option in the management of type 2 diabetes. World Health Organization.0 kg/m2) may be considered for bariatric surgery when lifestyle interventions are inadequate in achieving healthy weight goals [Grade B. Jenkins AB.20:159e65. Surgery is usually reserved for people with class III obesity (BMI !40.373:1083e96. Lung.0 kg/m2) or class II obesity (BMI ¼ 35. insulin secretagogues. Level 2 (53e55)]. Miller RG. p.322:716e20. Wharton et al. et al. They are not recommended because of modest efficacy and frequent adverse side effects. Reeder BA.56)]. 16. p. Hedner JA. Obesity is a signeover-eating is a symptom: an aetiological framework for the assessment and management of obesity. Insulin is associated with the most weight gain. Arch Gen Psychiatry 2008. Niemeier HM. Conway B. physical activity and behaviour modification to achieve a target weight loss of 5% to 10% of initial body weight and for weight maintenance (32. Obes Rev 2010.49. Exercise capacity and cardiovascular/ metabolic characteristics of overweight and obese individuals with type 2 diabetes: the Look AHEAD clinical trial. Cleeman JI. Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Type II diabetic subjects lose less weight than their overweight nondiabetic spouses. Obesity: preventing and managing the global epidemic.16:397e415. 18. et al. Pi-Sunyer X. 6. Després JP. Level 1A (30. Risk factor correlates of body mass index. healthy body weight [Grade A.11:362e70. 17. depending on the choice of drugs (Table 6) (18). Epstein LH. 14. 19.157(suppl 1): S26e31. 24. thiazolidinediones). or at risk for.30:703e10. Diabetes Care 1987. Ruderman N. the effect of antihyperglycemic agents on body weight should be taken into account [Grade D. et al. Bariatric surgery procedures can be classified as restrictive. et al. Stenlof K. gastric sleeve (Figure 3) and laparoscopic adjustable gastric banding (Figure 4) have all demonstrated significant improvements and even remission in type 2 diabetes (53e55). Prospective Studies Collaboration. 3. Evaluation. Goldstein DJ. such as diethylpropion and phentermine. The metabolically obese. S45 References 1. Overweight. education. . Walker-Thurmond K. RECOMMENDATIONS 1. if not lifelong. The association of cardiovascular disease risk factors with abdominal obesity in Canada. 12.S. Circulation 2005. Prud’homme D. i-xii. Pharmacotherapy can be considered for people with BMI !30. Diabetes Care 1998. Inc. Diabet Med 2010. Available at: http://www. UK Prospective Diabetes Study (UKPDS) Group. 3. Markovic TP. Other available anti-obesity drugs.285:2486e97. normalweight individual revisited. 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Long-term.30:2679e84. Treatment of obesity: need to focus on high risk abdominally obese patients. 7. Biliopancreatic diversion with duodenal switch procedure (Figure 1). et al. N Engl J Med 1998. Orlistat leads to greater weight loss when coupled with healthy behaviour interventions (47). Hogan P. 10. Other Relevant Guidelines Physical Activity and Diabetes. 252e76. and Blood Institute Scientific Statement. Ottawa.9 kg/m2) in the presence of comorbidities (52) and the inability to achieve weight loss maintenance following an adequate trial of health behaviour intervention. International Diabetes Federation. Accessed September 1. Stevens J. and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).348:1625e38. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart. Temporal patterns in overweight and obesity in type 1 diabetes. 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Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. Supplement 1. et al. 54. Eriksson JG.24:378e88. Sanchez M. 62. Thompson TJ.49(5 suppl): 1115e23. Lifestyle intervention: results of the Treatment of Mild Hypertension Study (TOMHS). Walter LG. and treatment of overweight and obesity in adults: the evidence report. and related recommendations and documents for diabetes care. Diabetes Care 2001. standards. et al.5:249e56. Thun M.24:631e6.341:427e34. De Gaetano A. 38. Strecher VJ. and reduces glucagons levels in type 2 diabetes.346:393e403. Reduction of glycosylated haemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM. Rizzello M. N Engl J Med 2002. Exercise as an adjunct to weight loss and maintenance in moderately obese subjects. Diabetes Obes Metab 2000. Laing B. Wu M. Madder RD. J Am Diet Assoc 2004. Heise MA. Longterm pharmacotherapy in the management of obesity. LEAD-2 Study Group.S86 S. 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N Engl J Med 2012. Mingrone G. National Institutes of Health. Am J Public Health 1994. Diabetes Prevention Program Research Group. Long-term persistence of hormonal adaptations to weight loss. 56. Neiberg RH. Glycemic durability of rosiglitazone. Wing RR.6(suppl 2):51Se209S. Canadian Obesity Network.17:554e62. et al.104: 1570e6. Delbridge E. 67. Am J Public Health 1998. Scott R. Haffner SM. Guidelines for healthy weight. 65. Heymsfield SB. Schwartz SL. Long-term effects of exenatide therapy over 82 weeks on glycaemic control and weight in over-weight metformintreated patients with type 2 diabetes mellitus. Diabetes Care January 2012 vol. Wing RR.346: 393e403. Freedhoff Y. Bariatric surgery versus conventional medical therapy for type 2 diabetes. Acarbose in the treatment of type 1 diabetes.27:1265e70. Inhibition of dipeptidyl peptidase4 reduces glycemia. Diabetes Care 2004. evaluation. The effect of physician advice on exercise behavior.2:105e12. Lewis BS. 32.23:3e13. Frid A. 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Wing RR. Willett WC. Ahrén B.18:831e43. N Engl J Med 1999. Hollander P. et al. Meengs JS. 51. Roe LS. glimepiride. Diabetes Care 1997. et al. 57. 355:2427e43. Behav Ther 1986. et al. 52. Diabetes Care 2001. N Engl J Med 2001. Segal KR. 37. Sibutramine is effective for weight loss and diabetic control in obesity with type 2 diabetes: a randomised. et al.160:1321e6. Can Diabetes 2010. Diabetes Care 2000. Hermansen K. Behaviour therapy for obesity: a quantitative review of the effects of selected treatment characteristics on outcome. Maggs D. Hassaman DR. placebo-controlled study. 28.16:114e24. Krey S. Pavlou KN. Lindström J. 55. Annu Rev Nutr 2001. 64. double-blind.7:73e82. et al. Reduction in the incidence of Type 2 diabetes with lifestyle or metformin.344:1343e50. Steffee WP. et al. Swinburn BA. 41. 30. Ratner RE. 63. The feasibility of behavioral risk reduction in primary medical care. Bariatric surgery versus intensive medical therapy in obese patients with diabetes. et al. 47. Fowler SE. 2010. Int J Clin Pract 2007. 44. Pi Sunyer X. Hauptman J. coping skills training. Some evidence shows that treatment for mental health disorders may actually increase the risk of diabetes. stress management strategies.  All individuals with diabetes should be regularly screened for the presence of depressive and anxious symptoms. Depression in patients with diabetes amplifies symptom burden by a factor of about 4 (11).  Individuals taking psychiatric medications. Meera Luthra MD.2013. higher use of healthcare services and reduced adherence to medication regimens (26. Treating depressive symptoms more reliably improves mood than it does glycemic control (30e33). The prevalence of major depressive disorder (MDD) is approximately 10% (7. generalized anxiety disorder and eating disorders. One study found that the requirement for insulin was the factor associated with the highest rate of depression. Bipolar Disorder Patients with bipolar disorder have been found to have prevalence rates estimated to be double that of the general population for metabolic syndrome and triple for diabetes (34e36).jcjd. particularly with recurrent hypoglycemia Longer duration of diabetes Presence of long-term complications (15e19) KEY MESSAGES  Psychiatric disorders. . particularly atypical antipsychotics. particularly those with depressive symptoms or syndromes. Studies examining differential rates for the prevalence of depression in type 1 vs. increased healthcare costs and an increased risk of early mortality. leading to chronic hypothalamicpituitary-adrenal activation with cortisol release (20e25).doi. Individuals with depression have an 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. The prognosis for comorbid depression and diabetes is worse than when each illness occurs separately (10). The mechanisms behind these relationships are multifactorial. bipolar disorder and schizophrenia.8). Episodes of MDD in individuals with diabetes are likely to last longer and have a higher chance of recurrence compared to those without diabetes (12). Risk factors for developing depression in individuals with diabetes are as follows:         Female gender Adolescents/young adults and older adults Poverty Few social supports Stressful life events Poor glycemic control. Biochemical changes due to the mental health disorders themselves also may play a role (2). Michael Vallis PhD. Introduction Research is increasingly demonstrating a relationship between mental health disorders and diabetes. type 2 diabetes have yielded inconsistent results (4. and  Psychological stress. which leads to insulin resistance. Patients with serious mental illnesses. FAPA.1016/j. such as MDD.com Clinical Practice Guidelines Diabetes and Mental Health Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by David J. individuals with diabetes and mental health disorders have decreased medication adherence. regardless of the type of diabetes involved (14).org/10.  People diagnosed with serious mental illnesses. FRCPC. and patients with diabetes share reciprocal susceptibility and a high degree of comorbidity (Figure 1).01. reduce diabetes-related distress and improve outcomes: motivational interventions. benefit from regular screening of metabolic parameters. particularly major depressive disorder (MDD). decreased compliance with diabetes self-care. have a higher risk of developing diabetes than the general population. FRCPC.026 Risk factors (with possible mechanisms) for developing diabetes in patients with depression are as follows:  Physical inactivity and obesity.27).29).  Compared to those with diabetes only. Depression The prevalence of clinically relevant depressive symptoms among patients with diabetes is in the range of 30% (4e6).Can J Diabetes 37 (2013) S87eS92 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.13). RPsych approximately 60% increased risk of developing type 2 diabetes (9).  The following treatment modalities should be incorporated into primary care and self-management education interventions to facilitate adaptation to diabetes. particularly when second-generation (atypical) antipsychotic agents are prescribed (1). Lifestyle changes and symptoms of mental health disorders are also likely to contribute (3). resulting in lowered physical and psychological fitness. are more prevalent in people with diabetes compared to the general population. increased functional impairment. increased risk of complications associated with diabetes. which is double the overall prevalence in people without a chronic medical illness. Robinson MD. family therapy and collaborative case management. possibly because the accompanying lethargy lowers motivation for self-care. Depression also appears to worsen cardiovascular mortality (28. Comorbid depression worsens clinical outcomes in diabetes.canadianjournalofdiabetes. affecting up to 50% of patients (41). Table 1 outlines a Psychiatric Medication Metabolic Monitoring Protocol adapted from recommendations made by various organizations. Adapted from references 54e56. possibly due to a combination of the following factors (48):  Patient factors (e. obesity. with a mean increase of >6 kg over a 1-year span compared with 2 to 3 kg for quetiapine and risperidone. It interferes Figure 1. bulimia nervosa and binge eating. Night eating syndrome (NES) has been noted to occur in individuals with type 2 diabetes who have depressive symptoms.g. poor glycemic control and an increased number of diabetic complications (44).40). have been found to be more common in individuals with diabetes (both type 1 and type 2) than in the general population (39. individuals with psychotic disorders represent a particularly vulnerable population. body mass index. This is characterized by the consumption of >25% of daily caloric intake after the evening meal and waking at night to eat. Regular and comprehensive monitoring of metabolic parameters is recommended for all persons who receive antipsychotic medications. access to healthcare. and 1 kg for aripiprazole and ziprasidone. particularly alcohol. at baseline. The Clinical Antipsychotic Trials for Intervention Effectiveness (CATIE) study found. substance use.e. both type 1 and 2. NES can result in weight gain. this matter is still open to debate (45.30. The reported weight gain over a 1-year period ranges from <1 kg to >4 kg for various antipsychotic medications. that of the individuals with SZ who participated in the study. such as anorexia nervosa. low degree of implementation of education programs)  Illness factors (e. weight and lipids)  Environmental factors (e. however. / Can J Diabetes 37 (2013) S87eS92 Monitoring Metabolic Risks Patients with diabetes and comorbid psychiatric illnesses are at an elevated risk for developing metabolic syndrome. 11% had diabetes (type 1 and 2 combined) (1). including the American Diabetes AssociationeAmerican Psychiatric Association.50)  Medication factors (i. Depressive symptoms are highly comorbid with eating disorders. A study of patients with type 2 diabetes and SZ who were treated with antipsychotic medications also showed worsening glycemic control requiring the addition of insulin therapy over a 2-year period with a hazard ratio of 2. on average. People diagnosed with psychotic disorders were reported to have had insulin resistance/glucose intolerance prior to the advent of antipsychotic medication. One study estimated that 14% of individuals with diabetes suffered from generalized anxiety disorder. antipsychotic medications or other factors. The main impact on lipid profile is an increase in triglyceride and total cholesterol levels. olanzapine and quetiapine (1. Schizophrenia Schizophrenia (SZ) and other psychotic disorders may contribute an independent risk factor for diabetes.43) as well as through deliberate insulin omission or underdosing (called diabulimia). possible disease-related risks for developing diabetes) (49. is a psychologically challenging disease for patients and their family members (57). lipids and glycemic control in patients without diabetes (1. proinflammatory states from MDD or depressive symptoms. Anxiety Anxiety is commonly comorbid with depressive symptoms (37).46). lifestyle choices. Eating Disorders Eating disorders. Table 1 Psychiatric medication metabolic monitoring protocol Parameter Baseline 1 month 2 months 3 months Every Annually 3e6 months x x x x x x x x x x x x x x x x x x x x Weight (BMI) Waist circumference Blood pressure Fasting glucose and/or A1C Fasting lipid profile Personal history. The prevalence of metabolic syndrome was approximately twice that of the general population (47). and other psychiatric conditions. . Psychological Effects of Diabetes Diabetes. especially with clozapine. glycated hemoglobin. tobacco consumption. Robinson et al.J. Whether the increased prevalence of diabetes is due to the effect of the illness. education programs) Psychiatric medications (primarily second-generation/atypical antipsychotics. availability of screening and monitoring programs. both in terms of an increased prevalence of established eating disorder features (42.53). with double this figure experiencing a subclinical anxiety disorder and triple this figure having at least some anxiety symptoms (38).51). A weight gain of between 2 to 3 kg was found within a 1-year time frame with amitriptyline. Olanzapine and clozapine have been shown to have the greatest weight gain.g.0 (52). Type 1 diabetes in young adolescent women appears to be a risk factor for development of an eating disorder. at least 3 times per week. tobacco and recreational substance use Family history x x A1C. major depressive disorder. whether or not they have diabetes. The interplay between diabetes. exercise. mirtazapine and paroxetine (51). Australian and Belgian consensus groups. BMI.g. diet. but in some cases antidepressants as well) have the potential to affect weight. also over a 1-year time frame. psychiatric medications have a variable effect on glycemic control. social supports.S88 D. Online resources are available to help healthcare providers learn CBT skills (e.73) because these psychological experiences are different. identifying depressive syndromes in diabetes is important since depression is a risk factor for poor diabetes selfmanagement (66e68) and outcomes.D.g. Stress. thoughts of self-harm with quality of life and is a risk factor for diabetes-related distress as well as the psychiatric disorders listed above. such as agitation or slowing of movements Cognitive symptoms.59). Diabetes management strategies ideally incorporate a means of addressing the psychosocial factors that impact on individuals and their families.g. A website that contains a wide variety of downloadable scales that are in the public domain is https://www. efforts to promote well-being and moderate distress should be incorporated into diabetes management for all individuals (86). MDD and the presence of depressive symptoms is important (72.70). “when I am doing my best. Treatment of Psychological/Psychiatric Risk Factors Given the burden associated with the demands of diabetes selfmanagement. coping skills. Both symptom measures (e. depression Diabetes distress Assessment Instrument Format Features Diabetes Distress Scale (17 items) Self-report using ratings from 1e6 based on feelings and experiences over the past week Emotional Burden Subscale (5 items) Physician-Related Distress Subscale (4 items) Regimen-Related Distress Subscale (5 items) Diabetes-Related Interpersonal Distress Subscale (3 items) Major depressive disorder S89 Patient Health Questionnaire for Depression: PHQ-9 (9 items) Self-report using ratings from 0e3 based on feelings and experiences over the past 2 weeks Vegetative symptoms. including early mortality (69. minimization.J.87. deficient social supports and negative attitudes toward diabetes can impact on self-care and glycemic control (60e64).) Analyzing negative thoughts and promoting more functional ones Identifying basic assumptions about oneself (e. selfefficacy enhancement. and. diabetes distress may be most strongly related to adverse diabetes outcomes (72. Text Revision] [DSM-IV-TR] diagnoses [42]) have been assessed. either some type of psychotherapy or prescription medication. phqscreeners.g. / Can J Diabetes 37 (2013) S87eS92 Table 2 Comparison of main features and assessment methods: diabetes distress vs.org/scales_library. both solely or in combination (33. “unless I am very successful. such as sleep. personalization. Patient Health Questionnaire (PHQ) Screeners are available at www. lipids. Table 3 Features of cognitive behavioural therapy that can be applied to diabetes treatment (97) Cognitive component Screening instruments fall into three categories:  Diabetes-specific measures. blood pressure and depression scores (94).78) or the Diabetes Distress Scale (DDS) (79)  Quality of life measures.88). adherence to the treatment regimen and psychosocial difficulties at both a personal and an interpersonal level (58. the Patient Health Questionnaire (PHQ-9) (82.g. Currently available screening instruments have a sensitivity of between 80% and 90% and a specificity of 70% to 85% (76). Evidence from systematic reviews of randomized controlled trials supports cognitive behaviour therapies (CBT) and antidepressant medication. of the three. A pilot study of 50 patients with type 2 diabetes who initially had a moderate level of depression at baseline showed an improvement in the severity of their depression (moving to the mild range) with a 12-week intervention of 10 CBT sessions combined with exercise in the form of 150 minutes of aerobic activity weekly. Individuals with diabetes distress and/or psychiatric disorders benefit from professional interventions.php.outcometracker. learning assertive and effective communication skills Focusing on feelings of mastery and accomplishment Learning problem-solving strategies Exposure to new experiences Shaping behaviours by breaking them down into smaller steps to develop skills Record keeping to identify distressing automatic thoughts Understanding the link between thoughts and feelings Learning the common “thinking errors” that mediate distress (e. stress management (89. Case management by a nurse working with the patient’s primary care physician and providing guideline-based. structured interviews leading to Diagnostic and Statistical Manual of Mental Disorders [Fourth Edition. etc. the Centre for Epidemiological StudieseDepression Scale (CES-D) (84) or the Beck Depression Inventory (BDI) (85) Table 2 illustrates the differences between the principal features and assessment methods of diabetes distress and MDD. MDD has been found to be underdiagnosed in people with diabetes (71).74. Distinguishing between diabetes distress. appetite and energy level changes Emotional symptoms. Screening for Psychological/Psychiatric Symptoms Individuals with diabetes should be regularly screened for psychological distress and psychiatric disorders via directed interviews. such as the Hospital Anxiety and Depression Scale (HADS) (81). such as low mood and reduced enjoyment of usual activities Behavioural symptoms. the need for continual monitoring and treatment. Robinson et al. No data presently demonstrate the superiority of one particular depression screening tool over another (76). persistent concerns about complications and the potential erosion of personal and professional relationships.90) and family interventions (91e93) all have been shown to be helpful.com. such as poor memory or reduced concentration or feelings of guilt.83).75).moodgym. my life is not worth living”) and being encouraged to adopt healthier ones (e. all-or-nothing thinking. such as the Problem Areas in Diabetes (PAID) Scale (77. Diabetes distress describes the despondency and emotional turmoil related specifically to having the condition.95). Given that the person with diabetes carries out 95% of diabetes management (65). magnification.g. Behavioural component Strategies to help get the person moving (behavioural activation) Scheduling pleasant events. This effect was sustained at 3 months (96). No evidence presently shows that the combination of CBT and medication is superior to these treatments given individually.g. I should be proud of myself”) . www. patient-centred care resulted in improved glycated hemoglobin (A1C). such as the WHO-5 screening instrument (80)  Depressive/anxiety symptoms. self-report measures of depressive or anxiety symptoms) and methods to arrive at mental disorder diagnoses (e. Motivational interventions (68. Challenges accompanying the diagnosis of diabetes include adjustment to the disease. Peyrot M.S90 D. Katon W. 6. McCreadie RG. Katon W. Midthjell K.109). The CATIE study investigated 4 aspects of the effectiveness of antipsychotic medications: efficacy. 17. Nietert PJ.23:445e8. 28:2441e7. Level 1A for type 2 diabetes (111). for type 1 diabetes (112)]  Family therapy [Grade A. et al. 3. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. A comprehensive review and meta-analysis looked at the effect of antidepressants on body weight (51). Diabetes Care 2001. emergence of medical problems and patient choice (1. including  Motivational interventions [Grade D. The consensus statement issued by the American Diabetes Association in 2004 contains recommendations regarding almost all of the atypical agents currently available in Canada (55). 18. Anderson RJ. Clouse RE. Stone M. Lawlor DA. Nestadt G. Lancet 2007.183: 534e9. Rubin RR. 42:1222e9. Anagnostis P. Scottish Schizophrenia Lifestyle Group. Diet.31:2383e90. Consensus] or with a standardized questionnaire [Grade B. 7. evidence suggests interventions are best implemented in a collaborative fashion and when combined with self-management interventions (95). Other Relevant Guidelines Organization of Diabetes Care. Antipsychotic medications (especially atypical/second generation) can cause adverse metabolic changes [Grade A. Diabetes Care 2005. Diabetes Care 2004. Skinner T. 19. Robinson et al. Population-based study of first onset and chronicity in major depressive disorder. et al. 5. Diabet Med 2006.J. Level 1 (95)] may be used to treat depression in individuals with diabetes. Association of depression with medical illness: does cortisol play a role? Biol Psychiatry 2004. Salmenkaita I. et al. no conclusive statements could be made about which medications to clearly use or which to clearly avoid. 20. Depression and diabetes: a large population-based study of sociodemographic. Mykletun A. Depression and type 2 diabetes over the lifespan: a meta-analysis. 21. Br J Psychiatry 2003. Stroup TS. Chatterji S. Verdes E. The results did indicate that some antipsychotic medications were more likely to cause weight gain. Agam G. 2. glycemic control and lipid profile and.g. chronic diseases. Miller A. Peixoto S.49:1255e60. Depression and all-cause and coronary mortality among adults with and without diabetes. et al.106). Moussavi S. The prevalence of co-morbid depression in adults with type 1 diabetes. et al. Arch Gen Psychiatry 2008. Antidepressant medication should be used to treat acute depression [Grade B. Int J Soc Psychiatry 2008. Level 2. 8. Lima-Costa M.93. Varghese FP. Psychosocial interventions should be integrated into diabetes care plans. Level 3 (90)]  Coping skills training [Grade A. Lin EHB. Davis WA. Persistence of depressive symptoms in diabetic adults. and decrements in health: results from the World Health Surveys. Katon WJ. Egede LE. 9. adding a medication to address the emergent issue (e.69:723e8. side effect or medical complication) or changing the psychiatric prescription. Barnard K. tolerability and patient choice. S153 Type 2 Diabetes in Children and Adolescents. Timonen M. Grade B. Diabetes Care 2005. Regular metabolic monitoring is recommended for patients with and without diabetes who are treated with such medications [Grade D. McEvoy JP. Ebrahim S. Diabet Med 2006. S20 Type 1 Diabetes in Children and Adolescents. 14. et al.g. Russo J. However. J Clin Endocrinol Metab 2009. Jokelainen J. Clinical review: the pathogenetic role of cortisol in the metabolic syndrome: a hypothesis. Lieberman JA. Insulin resistance and depressive symptoms in young adult males: findings from Finnish military conscripts. N Engl J Med 2005. as to whether modifications such as diet or exercise.100e103). 370:851e8.50: 570e9.6:1069e78. Depression and diabetes symptom burden. Belmaker R. depressive and anxiety disorders) by interview [Grade D. et al. Peveler R. Ludman EJ. Russo J. Major depressive disorder. Kendler KS.54:447e56. 24.327:1383e4. Diabetes. Depression and diabetes: factors associated with major depression at five-year follow-up. the Bambui Health and Aging Study. et al. Biol Psychiatry 2001. 28:1904e9. Med Care 2004. Freedland KE. Furthermore. Treatment with Medication Psychiatric medications have the capacity to affect metabolic parameters and cause changes in weight. Consensus]  Stress management strategies [Grade C. Eaton W. Zheng D.353:1209e23. The prevalence of co-morbid depression in adults with diabetes. Individuals with diabetes should be regularly screened for subclinical psychological distress and psychiatric disorders (e. 13. Egede LE. Longitudinal predictors of reduced mobility and physical disability in patients with type 2 diabetes. p.26:430e6. Insulin resistance in patients with depression and its changes during the clinical course of depression: minimal model analysis. Brown ES. is the most reasonable step (107). Simon G. Cognitive behaviour therapy (CBT) alone [Grade B. RECOMMENDATIONS 1. on a case-by-case basis. Psychosomatics 2009.65: 513e20. Level 1 (1)]. Level 2 (31)] and for maintenance treatment to prevent recurrence of depression [Grade A. et al. Mezuk B. Smith GD.94:2692e701. when these effects were considered in the context of efficacy. Diabetes Care 2008. p. major depression. Level 2 (94)] 3. et al.358: 55e68. Level 1B (91. 23. Karkowski LM. et al. Diabetes Care 1999. and functional disability among US adults. 25. in some cases. can have immunomodulating effects (22. Consequently. Bruce DG.49:391e404. The prevalence of co-morbid depression in adults with type 2 diabetes: a systematic review and meta-analysis. Peters J.156: 837e41. Engum A. Diabetes Care 2005. 10. N Engl J Med 2008. Okamura F. Table 3 illustrates some of the major features of CBT as applied to diabetes care. tolerability. Utumi A. Prescott CA. Gains from treatment with psychotherapy are more likely to benefit psychological symptoms and glycemic control in adults than will psychiatric medications (which usually only reduce psychological symptoms) (98). Tashiro A. all 4 aspects are important and reinforce the need for regular and comprehensive metabolic monitoring. worsen glycemic control and induce unfavourable changes in lipid profile. S163 References 1. 22. BMJ 2003. Level 1A (32)]. 16. Consensus].113)]  Case management [Grade B. 15. 11. as does the Canadian Diabetes Association position paper from 2005 (105). Pariante C. Quality of depression care in a populationbased sample of patients with diabetes and major depression.27:421e8.28: 1339e45. Ali S. smoking and cardiovascular risk in people with schizophrenia. Metabolism 2000. The influence of socio-economic conditions on the prevalence of depressive symptoms and its covariates in an elderly population with slight income differences. Glucocorticoid receptors in major depression: relevance to pathophysiology and treatment. Carvalhais S. 4. 12. clinical judgement will dictate. Psychosom Med 2007.23:1165e73. Albrecht S. Should medical problems arise while a patient is taking psychiatric medications.55:1e9. / Can J Diabetes 37 (2013) S87eS92 org).22:448e52. Am J Psychiatry 1999. McEwan BS. Gen Hosp Psychiatry 2004. Shao H. Level 2 (110)]. Level 2 (33)] or in combination with antidepressant medication [Grade A. 4. Russo J. A meta-analysis of psychological interventions found that glycemic control (A1C) is improved in children and adolescents with type 1 diabetes (99). Depression. Eaton WW. et al. A key review estimated and compared the effects of antipsychoticsdboth the newer ones and the conventional onesdon body weight (104). Handbooks are available that allow clinicians to quickly review the major side effect profiles of psychiatric medications (108. . lifestyle and clinical factors associated with depression in type 1 and type 2 diabetes. Association of insulin resistance with depression: cross sectional findings from the British Women’s Heart and Health Study. 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Accessed November 2012.34:56e62.2013. those with diabetes are encouraged to receive pneumococcal vaccination. 7th ed. Influenza Immunization in Adults Data regarding influenza morbidity and mortality in people with diabetes are based on retrospective analyses during influenza epidemics (3. other acute respiratory diseases.Can J Diabetes 37 (2013) S93 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.361:1935e44. Revaccination is recommended as a 1time event for individuals >65 years of age if the original vaccine was given when they were <65 years of age and >5 years earlier. The rates of hospitalization for influenza.42:1093e101.1016/j. influenza vaccination was shown to be effective in reducing both death and hospitalization from influenza and pneumonia in a cohort that included people with diabetes (6). 2006. a 1-time revaccination is recommended if the original vaccine was administered when they were <65 years of age with at least 5 years between administrations. Consensus]. Kornum J.canadianjournalofdiabetes. Clinical recommendations for vaccination are derived from large cohort studies that included people with diabetes as trials specific to individuals with diabetes are currently lacking.2).4). Muller LMAJ. 2. Ottawa. et al.gc. 5. Impact of influenza vaccination on mortality risk among the elderly. Lervang H-H.33:1491e3. FRCPC KEY MESSAGES  Influenza immunization can reduce hospitalization rates by approximately 40% for those individuals deemed to be at high risk.  For those who are >65 years of age. A Dutch case control study documented that the incidence of complications was 2 times higher in the unvaccinated group compared to the vaccinated group (7). diabetes was considered a significant risk factor for hospitalization (3). and length of stay among hospitalized adults with community acquired pneumonia. Diabetes.com Clinical Practice Guidelines Influenza and Pneumococcal Immunization Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Nadira Husein MD. Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza. Campbell A. Introduction People with diabetes are considered to be at high risk for morbidity and mortality from influenza and pneumococcal disease (1. It is accepted that people with diabetes are at similar risk of developing pneumococcal disease as those with other chronic conditions (1). Nichol KL.  Pneumococcal immunization is desired in people with diabetes as they are considered as likely to be infected as those with other chronic diseases. et al. Kamimoto L. Gorter KJ.182:349e55. Looijmans-Van Den Akker I. Influenza immunization is associated with up to a 40% risk reduction in mortality (2). Increased risk of common infections in patients with type 1 and type 2 diabetes mellitus. and risk of hospitalization with pneumonia. et al.jcjd. Jain S. N Engl J Med 2007. People with diabetes should receive an annual influenza immunization to reduce the risk of complications associated with influenza [Grade D. 2. Clin Infect Dis 2006.29:1771e6. 4. Hak E.31:1541e5.doi. and. congestive heart failure. A single dose is recommended for those >18 years of age.phac-aspc. Groenwold RHH. CMAJ 2010. therefore. glycemic control. Canadian Immunization Guide. Prior pneumococcal vaccination is associated with a reduction in death and complications in hospitalized adults with community-acquired pneumonia (9). Pneumococcal Immunization in Adults People with diabetes are at increased risk of hospitalization for pneumococcal disease (1. RECOMMENDATIONS 1. Nelson DB.org/10. A 1-time revaccination is recommended for those >65 years of age (if the original vaccine was given when they were <65 years of age) with at least 5 years between administrations [Grade D. FRCPC. Nordin JD. Diabetes and the severity of pandemic influenza A (H1N1) infection. and stroke or diabetes events were reduced by 70%. Abrutyn E. pneumonia. et al. References 1. Rodin R.01.357:1373e81. Consensus]. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. Tannenbaum T.8). Clinical effectiveness of first and repeat influenza vaccination in adult and elderly diabetic patients. Effectiveness of influenza vaccine in the community-dwelling elderly. Thomsen RW. Diabetes Care 2010. 9. N Engl Med 2009. Spaude K. Fisman D. Bramley AM. et al. Related Websites National Advisory Committee on Immunization. A recent epidemiological analysis of pandemic influenza demonstrated that people with diabetes are more likely to be hospitalized or to require intensive care (5). Kropp R. Hoes AW. Hak E. 7. Nichol KL. 3. Allard R. April-June 2009. Available at: http://www. et al.41:281e8.php. 6. ON: Canadian Medical Association. Diabetes Care 2006. Pneumococcal immunization should be offered to people with diabetes. Verheij TJM. myocardial infarction. Vincent Woo MD. Prior pneumococcal vaccination is associated with reduced death. 8. et al. Eur Respir J 2009. Clin Infect Dis 2005. Hospitalized patients with 2009 H1Ni influenza in the United States.ca/publicat/ cig-gci/index-eng. Over a period of 10 influenza seasons. Diabetes Care 2008. During recent influenza epidemics.027 . LeClerc P. Tremblay C. complications. Can J Diabetes 37 (2013) S94eS96 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com Clinical Practice Guidelines Pancreas and Islet Transplantation Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Breay W. Paty MD, FRCPC, Angela Koh MD, Peter Senior MBBS, PhD, MRCP with diabetic nephropathy have been reported 5 to 10 years posttransplantation (9,10). Whether successful simultaneous pancreas kidney (SPK) transplantation improves renal graft survival is unclear. In 1 study, recipients of SPK transplantations had better renal graft survival over 72 months than deceased-donor kidney transplantations but lower graft survival than living-donor kidney transplantations (11). The impact of pancreas transplantation on overall patient survival also is uncertain. Studies suggest lower shortterm survival in the perioperative period up to 18 to 24 months after SPK, but for patients with successful functioning pancreas grafts at 12 months post-transplantation, survival was similar or improved compared to living- or deceased-donor kidney transplantation (12e14). A retrospective cohort study of individuals with diabetes and preserved kidney function who received a solitary pancreas transplantation suggested that overall survival was worse compared with wait-listed patients receiving conventional medical therapy (15). Improvement and/or stabilization of diabetic retinopathy have been demonstrated (16). Peripheral sensory and motor neuropathies also have been shown to improve after pancreas transplantation (17,18), but these findings are not consistent and may take years to achieve (19e21). Pancreas transplantation appears to improve cardiovascular (CV) function, carotid intimal medial thickness, blood pressure and lipid parameters (22e24). A single, small, nonrandomized study showed a reduction in CV events in SPK recipients compared to those undergoing kidney transplantation alone (25); however, this has not been examined in a randomized controlled fashion. Finally, diabetes-related quality of life (QOL) appears to improve after pancreas transplantation, although overall QOL appears to be unchanged (26,27). Islet Transplantation Islet allotransplantation Islet allotransplantation involves the infusion of islets isolated from cadaveric pancreata via the portal vein into the liver (28), either alone or in association with a renal transplantation (29,30). Successful islet transplantation can result in stable, near-normal glycemic control (A1C, glycemic variability) with a reduction or elimination of hypoglycemia (31) over and above what can be achieved with insulin injections or even insulin pump therapy (32). The ability of transplant recipients to achieve and maintain insulin independence varies between transplantation centres and is influenced by both donor and recipient factors (33,34). Insulin KEY MESSAGES  Simultaneous pancreas kidney transplantation in persons with type 1 diabetes and end stage renal disease can improve kidney graft survival and result in prolonged insulin independence.  Successful pancreas or islet allotransplantation can stabilize glucose and possibly result in insulin independence in persons with type 1 diabetes and glycemic lability or recurrent hypoglycemia.  Islet autotransplantation can stabilize glucose and possibly result in insulin independence in people undergoing total pancreatectomy for benign pancreatic disease. Introduction Restoring endogenous insulin secretion by whole pancreas or islet transplantation has been established as an alternative to insulin injection therapy in select individuals with type 1 diabetes (1,2). Nonrandomized studies demonstrate that both pancreas and islet transplantation can result in insulin independence and glucose stability, especially in the setting of glucose lability or frequent, severe hypoglycemia. Unfortunately, the absence of prospective randomized controlled trials makes it difficult to draw firm conclusions about the overall efficacy and safety of these therapies compared with exogenous insulin treatment. Also, the limited number of specialized islet and pancreas transplantation centres and the relatively small number of donor pancreases limit the availability of these treatments. Nevertheless, general recommendations regarding the role of pancreas and islet transplantation may be made in the context of current clinical experience. Pancreas Transplantation Pancreas transplantation can result in complete independence from exogenous insulin in the majority of cases (3). As shown in Table 1, worldwide, noncontrolled 1- and 3-year mean pancreas graft and patient survival rates differ slightly among the 3 major types of transplantations (4). Long-term pancreas graft survival declines with time, with a median graft survival of 9 years and <10% survival at 21 years (5). Glycemic control and glycated hemoglobin (A1C) are markedly improved after successful pancreas transplantation, with most recipients achieving normal glucose tolerance, albeit with hyperinsulinemia (6,7). A reduction in albuminuria has been noted at 1 year (8), and improvements in the histological changes associated 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2013.01.028 B.W. Paty et al. / Can J Diabetes 37 (2013) S94eS96 Table 1 Reported graft survival rates according to type of pancreas transplantation (4) Transplantation type SPK PAK PTA 1 year 83% 74% 78% 5 years 69% 45% 54% 10 years 51% 24% 28% 15 years 33% 13% 9% S95 RECOMMENDATIONS 1. Individuals with type 1 diabetes and ESRD who are being considered for kidney transplantation should also be considered for simultaneous pancreas transplantation [Grade D, Level 4 (12,14)]. 2. Individuals with type 1 diabetes with preserved renal function, or who have undergone successful kidney transplantation but have persistent metabolic instability characterized by severe glycemic lability and/or severe hypoglycemia despite best efforts to optimize glycemic control, may be considered for pancreas or islet allotransplantation [Grade D, Consensus]. 3. Individuals undergoing total pancreatectomy for benign pancreatic disease may be considered for islet autotransplantation but only in the context of an experienced islet transplantation centre [Grade D, Consensus]. Abbreviation: ESRD, end stage renal disease. SPK, simultaneous pancreas kidney; PAK, pancreas after kidney; PTA, pancreas transplant alone. independence can be achieved in most recipients but often requires 2 or more transplantation procedures. Insulin independence rates decline with time from approximately 70% at 1 year posttransplantation to approximately 10% after 5 years (31). However, patients who are not able to maintain insulin independence may still benefit from more stable blood glucose control (35) that results from ongoing graft function, as evidenced by the sustained secretion of C peptide and the reduced requirement for exogenous insulin (33). Small, short-term studies also suggest stabilization of retinopathy (36) and neuropathy (37) with islet allotransplantation. Renal outcomes vary, but recent reports suggest that the glomerular filtration rate achieved with the procedure does not differ significantly from that observed in the nondiabetic population (38,39). Successful islet transplantation can improve QOL by reducing the fear of hypoglycemia (40) but can be negatively impacted by adverse effects from immunosuppressive agents (27). Islet autotransplantation In islet autotransplantation, islets are isolated from an individual’s own resected pancreas following pancreatectomy for benign pancreatic disease (e.g. chronic, painful pancreatitis) (41,42). Islet yields from a resected, diseased pancreas may be lower than those from cadaveric donors, but immunosuppression is not required. Even if insulin independence is not achieved, islet autotransplantation may result in reduced exogenous insulin requirements and a lower risk of hypoglycemia (43). As a result, the ratio of benefit to risk of this procedure may exceed that noted with islet allotransplantation (44). Risks Associated with Pancreas and Islet Transplantation Pancreas transplantation is associated with significant perioperative risks, including graft thrombosis, hemorrhage, Table 2 Comparison of beta cell replacement modalities Islet Pancreas pancreatitis, wound infection, peripancreatic abscesses and duodenal stump leakage (45). Islet transplantation is associated with fewer procedural risks, which may include intraperitoneal hemorrhage, partial portal vein thrombosis or gallbladder puncture. These complications occur in <10% of procedures and usually are self-limited (31,34). Both pancreas and islet transplantations require long-term immunosuppression, which is associated with a number of risks and side effects (46). Drug side effects are generally mild and often respond to dose or agent adjustment. Although rare, life-threatening opportunistic infections and malignancies have been reported (34,46). These risks must be carefully weighed against the potential benefits of transplantation for each individual. See Table 2 for a detailed comparison of pancreas vs. islet transplantation. References 1. White SA, Shaw JA, Sutherland DER. Pancreas transplantation. Lancet 2009; 373:1808e17. 2. Halban PA, German MS, Kahn SE, et al. Current status of islet cell replacement and regeneration therapy. J Clin Endocrinol Metab 2010;95:1034e43. 3. Robertson RP, Abid M, Sutherland DE, et al. Glucose homeostasis and insulin secretion in human recipients of pancreas transplantation. Diabetes 1989;38(suppl 1):97e8. 4. Waki K, Kadowaki T. An analysis of long-term survival from the OPTN/UNOS Pancreas Transplant Registry. Clin Transplant 2007:9e17. 5. Everly MJ. Pancreas transplant in the United States: an analysis of the UNOS registry. Clin Transplant 2009:75e81. 6. Robertson RP, Sutherland DE, Kendall DM, et al. Metabolic characterization of long-term successful pancreas transplants in type 1 diabetes. J Investig Med 1996;44:549e55. 7. Lauria MW, Figueiro JM, Machado LJ, et al. Metabolic long-term follow-up of functioning simultaneous pancreas-kidney transplantation versus pancreas transplantation alone: insights and limitations. Transplantation 2010;89:83e7. 8. Coppelli A, Giannarelli R, Vistoli F, et al. The beneficial effects of pancreas transplant alone on diabetic nephropathy. Diabetes Care 2005;28:1366e70. 9. Fioretto P, Steffes MW, Sutherland DE, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998;339:69e75. 10. Fioretto P, Sutherland DER, Najafian B, et al. Remodeling of renal interstitial and tubular lesions in pancreas transplant recipients. Kidney Int 2006;69:907e12. 11. Young BY, Gill J, Huang E, Takemoto SK, et al. Living donor kidney versus simultaneous pancreas-kidney transplant in type I diabetics: an analysis of the OPTN/UNOS database. Clin J Am Soc Nephrol 2009;4:845e52. 12. Ojo AO, Meier-Kriesche HU, Hanson JA, et al. The impact of simultaneous pancreas-kidney transplantation on long-term patient survival. Transplantation 2001;71:82e90. 13. Reddy KS, Stablein D, Taranto S, et al. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Am J Kidney Dis 2003; 41:464e70. 14. Weiss AS, Smits G, Wiseman AC. Twelve-month pancreas graft function significantly influences survival following simultaneous pancreas-kidney transplantation. Clin J Am Soc Nephrol 2009;4:988e95. 15. Venstrom JM, McBride MA, Rother KI, et al. Survival after pancreas transplantation in patients with diabetes and preserved kidney function. JAMA 2003;290:2817e23. Outcomes Reduce or eliminate Yes Yes hypoglycemia Improve A1C Yes Yes Yes Insulin Yes* independence Effect on diabetes-related complications Improved Microvascular May be stabilizedy Macrovascular Not known May be improved Risks Procedural risks Minor procedural risk Major surgical risk Immunosuppression Similar agents,z life-long immunosuppression Other considerations ESRD Avoid Consider SPK Consider PAK if glycemic Functioning renal Consider IAK if glycemic lability or hypoglycemiax transplant lability or hypoglycemiax A1C, glycated hemoglobin; ESRD, end stage renal disease; IAK, islet after kidney; PAK, pancreas after kidney; SPK, simultaneous pancreas kidney. * More than 1 islet infusion may be required. y Retinopathy and neuropathy may be stabilized. z Steroids are avoided in islet transplantation but may be used in whole pancreas transplantation. x No additional risk from immunosuppression. S96 B.W. Paty et al. / Can J Diabetes 37 (2013) S94eS96 31. Ryan EA, Paty BW, Senior PA, et al. Five year follow-up after clinical islet transplantation. Diabetes 2005;54:2060e9. 32. Vantyghem MC, Marcelli-Tourvieille S, Fermon C, et al. Intraperitoneal insulin infusion versus islet transplantation: comparative study in patients with type 1 diabetes. Transplantation 2009;87:66e71. 33. Shapiro AM, Ricordi C, Hering BJ, et al. International trial of the Edmonton protocol for islet transplantation. N Engl J Med 2006;355:1318e30. 34. Alejandro R, Barton FB, Hering BJ, et al. 2008 update from the Collaborative Islet Transplant Registry. Transplantation 2008;86:1783e8. 35. Paty BW, Senior PA, Lakey JR, et al. Assessment of glycemic control after islet transplantation using the continuous glucose monitor in insulin-independent versus insulin-requiring type 1 diabetes subjects. Diabetes Technol Ther 2006;8:165e73. 36. Thompson DM, Begg IS, Harris C, et al. Reduced progression of diabetic retinopathy after islet transplantation compared with intensive medical therapy. Transplantation 2008;85:1400e5. 37. Del Carro U, Fiorina P, Amadio S, et al. Evaluation of polyneuropathy markers in type 1 diabetic kidney transplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis. Diabetes Care 2007; 30:3063e9. 38. Senior PA, Zeman M, Paty BW, et al. Changes in renal function after clinical islet transplantation: four-year observational study. Am J Transplant 2007;7: 91e8. 39. Fung MA, Warnock GL, Ao Z, et al. The effect of medical therapy and islet cell transplantation on diabetic nephropathy: an interim report. Transplantation 2007;84:17e22. 40. Poggioli R, Faradji RN, Ponte G, et al. Quality of life after islet transplantation. Am J Transplant 2006;6:371e8. 41. Robertson RP, Lanz KJ, Sutherland DE, et al. Prevention of diabetes for up to 13 years by autoislet transplantation after pancreatectomy for chronic pancreatitis. Diabetes 2001;50:47e50. 42. Bellin MD, Sutherland DE. Pediatric islet autotransplantation: indication, technique, and outcome. Curr Diab Rep 2010;10:326e31. 43. Blondet JJ, Carlson AM, Kobayashi T, et al. The role of total pancreatectomy and islet autotransplantation for chronic pancreatitis. Surg Clin North Am 2007;87: 1477e501. 44. Sutherland DE, Gruessner AC, Carlson AM, et al. Islet autotransplant outcomes after total pancreatectomy: a contrast to islet allograft outcomes. Transplantation 2008;86:1799e802. 45. Troppmann C. Complications after pancreas transplantation. Curr Opin Organ Transplant 2010;15:112e8. 46. Gruessner RW, Sutherland DER, Gruessner AC. Mortality assessment for pancreas transplants. Am J Transplant 2004;4:2018e26. 16. Giannarelli R, Coppelli A, Sartini MS, et al. Pancreas transplant alone has beneficial effects on retinopathy in type 1 diabetic patients. Diabetologia 2006; 49:2977e82. 17. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care 2007;30:2608e12. 18. Kennedy WR, Navarro X, Goetz FC, et al. Effects of pancreatic transplantation on diabetic neuropathy. N Engl J Med 1990;322:1031e7. 19. Solders G, Tydén G, Persson A, et al. Improvement of nerve conduction in diabetic neuropathy. A follow-up study 4 yr after combined pancreatic and renal transplantation. Diabetes 1992;41:946e51. 20. Tydén G, Bolinder J, Solders G, et al. Improved survival in patients with insulindependent diabetes mellitus and end-stage diabetic nephropathy 10 years after combined pancreas and kidney transplantation. Transplantation 1999;67: 645e8. 21. Boucek P, Havrdova T, Voska L, et al. Epidermal innervation in type 1 diabetic patients: a 2.5-year prospective study after simultaneous pancreas/kidney transplantation. Diabetes Care 2008;31:1611e2. 22. Coppelli A, Giannarelli R, Mariotti R, et al. Pancreas transplant alone determines early improvement of cardiovascular risk factors and cardiac function in type 1 diabetic patients. Transplantation 2003;76:974e6. 23. Larsen JL, Colling CW, Ratanasuwan T, et al. Pancreas transplantation improves vascular disease in patients with type 1 diabetes. Diabetes Care 2004;27: 1706e11. 24. Luan FL, Miles CD, Cibrik DM, et al. Impact of simultaneous pancreas and kidney transplantation on cardiovascular risk factors in patients with type 1 diabetes mellitus. Transplantation 2007;84:541e4. 25. La Rocca E, Fiorina P, di Carlo V, et al. Cardiovascular outcomes after kidneypancreas and kidney-alone transplantation. Kidney Int 2001;60:1964e71. 26. Sureshkumar KK, Patel BM, Markatos A, et al. Quality of life after organ transplantation in type 1 diabetics with end-stage renal disease. Clin Transplant 2006;20:19e25. 27. Speight J, Reaney MD, Woodcock AJ, et al. Patient-reported outcomes following islet cell or pancreas transplantation (alone or after kidney) in Type 1 diabetes: a systematic review. Diabet Med 2010;27:812e22. 28. Robertson RP. Islet transplantation as a treatment for diabetes: a work in progress. N Engl J Med 2004;350:694e705. 29. Gerber PA, Pavlicek V, Demartines N, et al. Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: a 5-year single centre follow-up. Diabetologia 2008;51:110e9. 30. Deng S, Markmann JF, Rickels M, et al. Islet alone versus islet after kidney transplantation: metabolic outcomes and islet graft survival. Transplantation 2009;88:820e5. Can J Diabetes 37 (2013) S97eS99 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes.com Clinical Practice Guidelines Natural Health Products Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Richard Nahas MD, CCFP, Jeannette Goguen MD, MEd, FRCPC demonstrated a reduction in the placebo-subtracted A1C of at least 0.5%. The following NHPs lowered A1C by 0.5% in trials lasting at least 3 months in adults with type 2 diabetes:            Coccinia cordifolia (4) Ganoderma lucidum (5) Salacia reticulata (6) Soybean-derived pinitol extract (7) Touchi soybean extract (8) Pterocarpus marsulium (vijayasar) (9) Gynostemma pentaphyllum (10) Marine collagen peptides (11) Silymarin (12,13) Citrullus colocynthis (14) Trigonellafoenum-graecum (fenugreek) (15) KEY MESSAGES  Seventy-eight percent of patients with diabetes reported taking a natural health product (NHP) for various indications.  Some NHPs have shown a lowering of A1C by 0.5% in trials lasting 3 months in adults with type 2 diabetes, but most are single small trials so it would be premature to recommend their widespread use.  Healthcare providers should always ask about the use of NHPs since some may result in side effects or drug interactions. Introduction Natural Health Products (NHPs) include herbal medicines, vitamins, minerals and other essential nutrients, probiotics and many other naturally occurring substances. Since 2004, they have been regulated in Canada by the Natural Health Products Directorate of Health Canada. Management These guidelines include NHPs because they are widely used by patients, but the evidence of their efficacy and safety is unknown to most prescribing physicians. In a recent Canadian study of 502 patients with diabetes, 78% reported taking an NHP, with similar frequency in people with type 1 and type 2 diabetes (1). While it is important to be aware of potential harms, side effects and drug interactions, some NHPs may be potentially important new therapeutic agents. Interestingly, metformin is derived from French lilac, a remedy used to treat diabetes since the Middle Ages, and identification of the active agent guanidine led to the synthesis of biguanides (2). In general, the current level of evidence for the efficacy and safety of NHPs in people with type 2 diabetes is lower than that for pharmaceutical drug treatments. Trials tend to be of shorter duration and involve smaller sample sizes. At the present time, concerns remain about standardization and purity of available compounds, including their contamination with regular medications and, in some cases, toxic substances (3). While a number of NHPs have been studied to evaluate their impact on cardiovascular and other outcomes in patients with type 2 diabetes, this guideline is limited to NHPs for improving glycemic control. Trials were considered for review if they were randomized, controlled, and reported changes in glycated hemoglobin (A1C) over at least 12 weeks of treatment. Positive trials were those that 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2013.01.029 These products are promising and merit consideration and further research, but, as they are mostly single, small trials, it is premature to recommend their widespread use. The following NHPs failed to lower A1C by 0.5% in trials lasting at least 3 months in adults with type 2 diabetes:               Tinospora crispa (16) French maritime pine bark (17) Soy phytoestrogens (18) Agaricus blazei (19) Antioxidants (fruit/vegetable extract) (20), (pomegranate extract) (21) Camellia sinensis (22) Cinnamomum spp (cinnamon) (23e27) Momordica charantia (bitter melon or bitter gourd) (28) Flaxseed oil (29) Ginseng (30) Coenzyme Q10 (31) Vitamin C (32) Vitamin D (33e35) Vitamin E (36e38) It should be noted that, in many cases, small sample sizes made the trials insufficiently powered to establish a significant benefit from NHP interventions. The following NHPs have demonstrated conflicting effects on A1C in trials lasting at least 3 months in adults with type 2 diabetes: Griscti O. et al. Wei J. Witham MD. total saponins in combination with sulfonylureas in the treatment of type 2 diabetes mellitus. Free Radic Res 2010.25:1709e14. In 1 trial of Tinospora crispa. Sangsuwan C. Larijani B. 16.31:216e20. Li GZ. 19. clinical trial. Huyen VTT. Fujita H. et al. Lin S-C. 4. 33. Effect of cinnamon on glucose and lipid levels in noninsulin-dependent type 2 diabetes. Goguen / Can J Diabetes 37 (2013) S97eS99     Ipomoea batatas (caiapo) (39. A double blind randomised placebo controlled cross over study of a herbal preparation containing Salacia reticulata in the treatment of type 2 diabetes. placebo-controlled clinical trial.13:97e102. J Med Assoc Thail 2006. Complications It is important to consider potential harm from the use of NHPs. . et al. Randomized controlled trial of Tinospora crispa for additional therapy in patients with type 2 diabetes mellitus.33:118e24. Liu X.) fruit in treatment of type II diabetic patients: a randomized.44:1445e53. (silymarin) in the treatment of type II diabetes: a randomized. Dove FJ.292:2868e73.22:507e12. et al. a trace element that is commonly used to treat type 2 diabetes. Peng HB. Effect of supplementation of Coccinia cordifolia extract on newly detected diabetic patients. Genc E. practitioners should consult previously published reviews (64). Supplementation with a combination of antioxidants does not affect glycaemic control. Kim JI. 9. 26. and serum lipids in diabetes mellitus type 2. For more detailed information about specific NHPs. Efficacy of vijayasar (Pterocarpus marsupium) in the treatment of newly diagnosed patients with type 2 diabetes mellitus: a flexible dose double-blind multicenter randomized controlled trial. controlled trial. Reaven GM. Vannasaeng S. Leyva MJ. Marceau C. 20. Suppapitiporn S. et al. oxidative stress or inflammation in type 2 diabetes subjects. et al. 25. The effect of different doses of vitamin D(3) on markers of vascular health in patients with type 2 diabetes: a randomised controlled trial. is an abortifacient (62). Rajendran R. Kilpatrick ES. double-blinded. Momordica charantia. Oubre AY. 13. Darvishzadeh F. Phytother Res 2009. and placebocontrolled clinical trial. Leary L. Blevins SM. JAMA 2004.18:242e5. J Clin Epidemiol 2007. Diabet Med 2001. Crawford P. Liao E. Qin Y.14:56e60. Karne RJ. but a systematic review concluded that the evidence does not support this concern (63). Thang P. Fenercioglu AK.Curt.42:353e7. 5. Yoon SY. High-dose oral vitamin C partially replenishes vitamin C levels in patients with type 2 diabetes and low vitamin C levels but does not improve endothelial dysfunction or insulin resistance. placebo-controlled. 8. John’s wort). The mushroom Agaricus blazei Murill in combination with metformin and gliclazide improves insulin resistance in type 2 diabetes: a randomized. Akilen R. type 2 diabetes: results of a randomized. J Diabetes 2010. Forsén TJ. Effects of vitamin E on cardiovascular and microvascular outcomes in high-risk patients with diabetes: results of the HOPE study and MICRO-HOPE substudy. J Endocrinol Invest 2010. References 1. 10. Consensus].60:554e9. Diabet Med 2010. Effectiveness of cinnamon for lowering hemoglobin A1C in patients with type 2 diabetes: a randomized. may not identify side effects or risks. 29. Jayagopal V.34:13e20. 3. Hall G. Dai XH. Chin J Integr Med 2008. Eriksson JG. A phase I/II study of Ling Zhi mushroom Ganoderma lucidum ( W. Life Sci 2004. Ryan EA. et al. Antidiabetic effect of gynostemma pentaphyllum tea in randomly assigned type 2 diabetic patients. Sievenpiper JL. Drug-herb interactions may also occur.131:2105e8. 30. Barre DE. et al. Cha IJ. placebo-controlled study of efficacy and safety. Hoogwerf B. double-blind. The effect of Momordica charantia capsule preparation on glycemic control in type 2 diabetes mellitus needs further studies. et al. double blind. Dryburgh M. Huseini HF.10:543e7. et al. Wolters M. 31. Udompanthurak S. et al. thus. The effect of an extract of green and black tea on glucose control in adults with type 2 diabetes mellitus: double-blind randomized study. double-blind clinical trial. Tsiami A. 2. Effects of a cinnamon extract on plasma glucose. et al. 2. et al. Horm Metab Res 2010. Yusuf S. 34.23:1186e9. Potential concerns should be addressed using a patientcentred approach that ensures patient safety while respecting their views to maintain a positive therapeutic relationship. which can affect the metabolism of many drugs. Saler T.30: 2236e7. 36. 11. Heshmat R. 15. Lu FR. 23. Lonn E.) Lloyd (Aphyllophoromycetidae) extract in patients with type 2 diabetes. et al. 7. The effect of cinnamon cassia powder in type 2 diabetes mellitus. The effects of polyphenol-containing antioxidants on oxidative stress and lipid peroxidation in Type 2 diabetes mellitus without complications. Some studies have reported poorer glycemic control in patients using glucosamine sulfate for osteoarthritis.) Gaertn. et al. Poretsky L.40:614e7. 24.56:1340e4. Eur J Clin Invest 2006. Kales SN. 35. Diabetes Care 2002. Silymarin as an adjunct to glibenclamide therapy improves longterm and postprandial glycemic control and body mass index in type 2 diabetes. Mortensen SA. et al. High dose flaxseed oil supplementation may affect fasting blood serum glucose management in human type 2 diabetics. 28. Jimeno CA. 22. Villarruz MV. Diabetol Croat 2005. Vuksan V.S98 Nahas. Suppapitiporn S. Dans AM.20:1036e9. Kuriyan R.53:2112e9.89(suppl 3): S200e5. Int J Med Mushr 2004.75:2505e13. Jorde R. Appl Physiol Nutr Metab 2010. Lan J. Shen L. J Oleo Science 2008. Supplementation with cholecalciferol does not improve glycaemic control in diabetic subjects with normal serum 25-hydroxyvitamin D levels. Long-term ingestion of a fermented soybean-derived Touchi extract with alpha-glucosidase inhibitory activity is safe and effective in humans with borderline and mild type-2 diabetes. has not been studied in trials evaluating glycemic control over a period of 3 months or longer. et al. Eur J Nutr 2009. 6. Diabetes Care 2002.18:46e56. Clinicians should ask all patients with diabetes about their use of NHPs. Albertazzi P. Chou P.57:269e73. et al. Mizier-Barre KA.9:182e6. Saper RB.6:33e9. 21. Chen H. placebo-controlled. HbA. et al. MacKenzie T. Pick ME. Gao YH.290:H137e45. Bantwal G. Heshmat R. J Am Board Fam Med 2009. Diabetes Care 2007. J. J Med Food 2006. 17. From plant to patient: an ethnomedical approach to the identification of new drugs for the treatment of NIDDM. Liao Y-L. but no side effects were reported in the lower doses used in 1 trial (14). Biofactors 1999. Schmitt B. Kang MJ. Hariharan RS. hepatotoxicity was seen in 2 patients (16). Kurpad AV. Kanpaksi N. J Med Food 2007. Sung MK.97:215e8. Heavy metal content of ayurvedic herbal medicine products.87:543e6. Diabetologia 1997. Carlson TJ. Brown J. Natural health products are not recommended for glycemic control for individuals with diabetes as there is insufficient evidence. Nutr Metab Cardiovasc Dis 2008.35:797e804. et al. Rytter E. Paquin J. 32. Hwang K-C. The most well described is Hypericum perforatum (St. Most clinical trials have evaluated small sample sizes over relatively short periods of time and. Treatment with marine collagen peptides modulates glucose and lipid metabolism in Chinese patients with type 2 diabetes mellitus. The efficacy of Silybum marianum (L.:Fr.2:36e40. Use of alternative medicines in diabetes mellitus. Huseini HF. Pinitol from soybeans reduces postprandial blood glucose in patients with type 2 diabetes mellitus. Hsu C-H. Kim JC. Asg AR. 14. Robinson N. The clinical investigation of Citrullus colocynthis schrad (L. Hafez K. Mang B. Healthcare providers should ask about the use of natural health products [Grade D. King SR. 27. Patel P. Am J Physiol Heart Circ Physiol 2006.40) Chromium (41e52) Magnesium (53e57) L-carnitine (58e61) It should be noted that vanadium. The effect of coenzyme Q10 administration on metabolic control in patients with type 2 diabetes mellitus. J Nutr 2001. Clinical observation on trigonellafoenum-graecum L. Zhu CF. 18. Diabetes Care 2008. Tan F. Glycated haemoglobin and blood pressure-lowering effect of cinnamon in multi-ethnic Type 2 diabetic patients in the UK: a randomized. Vessby B. Lack of effect of subtherapeutic vitamin D treatment on glycemic and lipid parameters in Type 2 diabetes: a pilot prospective randomized trial. doubleblind. Phytother Res 2006. Diabetologia 2010. et al. Ohshima K. Jayawardena MH.9:315e8. regarding efficacy and safety [Grade D. at this time.27:1159e67. Venkataraman S. Metab Clin Exp 2007. Brooks WB.25: 1919e27. J Altern Complement Med 2007. Phan DV. Figenschau Y. Consensus].36:340e4. J Ethnopharmacol 2005. including statins. Antidiabetic effect of Pycnogenol French maritime pine bark extract in patients with diabetes type II. Hettigoda V. J Med Assoc Thai 2004. 12. et al. Hussain SA. RECOMMENDATIONS 1. Large doses of Citrullus colocynthis can induce diarrhea. by inducing CYP3A4.48:349e54. Devendra D. Yamagami T. an NHP commonly used for glycemic control. Sunitha P. de Alwis NM. Beneficial effects of soy phytoestrogen intake in postmenopausal women with type 2 diabetes. Korean red ginseng (Panax ginseng) improves glucose and insulin regulation in well-controlled. et al. Oral magnesium supplementation in insulin-requiring type 2 diabetic patients. Lichtenstein AH.36:53e63. 48. Diabet Med 1998. Diabetes Care 2006. Bhattacharya B. Boshtam M. Maffioli P. Cicero AF.18:188e92. Trefil L. 43. Ferrari I. 49. Anderson RA. J Cardiometab Syndr 2007.109:215e30. 58. 47. Anderson RA. J Am Coll Nutr 2001. et al. et al. 54. Derosa G.43:191e8. Poolsup N. Eur J Clin Nutr 2005. Verkaaik R. 38. Intern Med 2010. Ghosh D. 56. Am J Clin Nutr 2002. Zhang XH. Antioxidant effects and insulin resistance improvement of chromium combined with vitamin C and E supplementation for type 2 diabetes mellitus. Efficacy of Ipomoea batatas (Caiapo) on diabetes control in type 2 diabetic subjects treated with diet. Effects of vitamin e supplementation on glycaemic control in type 2 diabetes: systematic review of randomized controlled trials. double-blind. Neuffer B. et al. Eisenberg DM. Chromium picolinate supplementation attenuates body weight gain and increases insulin sensitivity in subjects with type 2 diabetes. van Rijn HJ. Levitan EB. Kohvakka A. Leeds AR.27: 436e40. Roussel AM. Orlistat and L-carnitine compared to orlistat alone on insulin resistance in obese diabetic patients. double-blind. Geohas J. Ann Nutr Metab 1995. Althuis MD. Kopp HP. placebo-controlled trial. Fuqua BC. Hanefeld M. Kaptchuk TJ. 39. Diabetes Obesity Metab 2008.39:217e23. Maffioli P.15:503e7. J Clin Pharm Ther 2011. et al. deValk HW.26: 1277e94. The effect of L-carnitine on plasma lipoprotein(a) levels in hypercholesterolemic patients with type 2 diabetes mellitus. J Clin Biochem Nutr 2008. Pacini G. J. Sinprasert S. Goldfine ID. Golshadi ID. Nowak HR.49:1717e25. Gaddi A. 40. et al. 55. 46. Keding GB. Guerrero-Romero F.Nahas. 57. Bryden NA. Chromium picolinate and biotin combination improves glucose metabolism in treated. Cheng N. Shakerhosseini R.27:14e27. Endocr J 2010. Improved metabolic control by Ipomoea batatas (Caiapo) is associated with increased adiponectin and decreased fibrinogen levels in type 2 diabetic subjects. et al. Wang ZQ.20:212e8. Long term effects of oral vitamin E supplement in type II diabetic patients. Int J Vitam Nutr Res 2005. 53. 24:41e51.25:1429e39. et al. 44. uncontrolled overweight to obese patients with type 2 diabetes. Clin Ther 2003. 63. Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial. Racek J. Magnesium and ascorbic acid supplementation in diabetes mellitus. insulin-treated type 2 diabetes in an obese Western population: a randomized. Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients. J Nutr Biochem 2002. Role of chromium supplementation in Indians with type 2 diabetes mellitus. 52. and markers of oxidative stress in subjects with type 2 diabetes mellitus. 51. Eibl NL. Albarracin CA. Diabetes Care 2003. Eriksson J. 45. Lai M-H. Salvadeo SAT. Pacini G. Martin J. Kleefstra N. Diabetes Care 1995. 42.2:91e7. Bitter gourd (Momordica charantia): a dietary approach to hyperglycemia. Biol Trace Element Res 2006. Yeh GY. Diabet Med 2006. Effect of L-carnitine on plasma glycemic and lipidemic profile in patients with type II diabetes mellitus. placebo-controlled trial. Diabetes Metab Res Rev 2011. Diabetes Care 2003. Anderson JW. Goguen / Can J Diabetes 37 (2013) S97eS99 37. 41. Albarracin C. Song Y.13:690e7.57(9):777e86. A comprehensive review of oral glucosamine use and effects on glucose metabolism in normal and diabetic individuals. Ludvik B. Saadat N.64:331e7. et al. Influence of chromium-enriched yeast on blood glucose and insulin variables. Tatsioni A. double-blind randomized clinical trial. Effect of chromium supplementation on glucose metabolism and lipids: a systematic review of randomized controlled trials. Houweling ST. 59. et al. Rajdl D. Diabetes Care 2006. Chromium treatment has no effect in patients with type 2 diabetes in a Western population: a randomized. Ludington EA. Chromium treatment has no effect in patients with poorly controlled.30:2154e63. Diabetes Care 2004. Derosa G. Houweling ST. Kleefstra N. et al. Jansman FG. Ludvik B. Diabetes Metab Res Rev 2008. Diabetes Care 2007. He K. et al. Evans JL. Potential antioxidant effects of zinc and chromium supplementation in people with type 2 diabetes mellitus. blood lipids. et al. Systematic review of herbs and dietary supplements for glycemic control in diabetes. 64. Diabetes Care 2007. Effects of oral magnesium supplementation on glycaemic control in Type 2 diabetes: a meta-analysis of randomized doubleblind controlled trials. et al. Rodríguez-Morán M. Rafiei M. . et al. Diabetes 1997. et al. et al. Mukherjee B. Balk EM. Glucose and insulin responses to dietary chromium supplements: a meta-analysis. 61. et al. Elevated intakes of supplemental chromium improve glucose and insulin variables in individuals with type 2 diabetes.59:592e6.29:1826e32. Simon RR. Hypomagnesemia in type II diabetes: effect of a 3-month replacement therapy. S99 50. et al. Zouari N. Nutr Rev 2006.26:1147e52. Fuqua B.23:1050e6.76: 148e55. 60. Rahbar AR. Derosa G. 62. Krawinkel MB.75:341e6.10: 586e92. Bakker SJ. Combination of chromium and biotin improves coronary risk factors in hypercholesterolemic type 2 diabetes mellitus: a placebo-controlled. Marks V. Jordan NE.30:1092e6. Suksomboon N.46:1786e91.29:521e5. e. FRCPC. as well as traditional CVD risk factors.com Clinical Practice Guidelines Vascular Protection in People with Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by James A. the greater the vascular age and relative CVD event risk. such as elevated total cholesterol and low-density lipoprotein-cholesterol (LDL-C).g. pharmacological vascular protection. FRCPC. their proximate 10-year CVD event risk may be low (4). Lifetime CVD Risk Persons with both type 1 and type 2 diabetes mellitus are at significantly increased risk of atherosclerotic cardiovascular disease (CVD) presenting as coronary heart disease. weight modification. hypertension. consequently. duration of diabetes. The presence of CVD in people with type 1 diabetes is related to age. PhD. dyslipidemia. angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and acetylsalicylic acid) should be determined by both an individual’s proximate and lifetime CVD event risk. FRCPC. his or her long-term risk is very high. can be justified by the potentially substantial long-term benefits of earlier interventions and lifelong therapy (8e11). Proximate CVD Risk vs. MPA. presence of retinopathy.org/10. as a consequence. their vascular age far exceeds their chronological age.Can J Diabetes 37 (2013) S100eS104 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.01. younger and shorter duration of diabetes). as a consequence of diabetes. hypertension and smoking. glycemic and blood pressure [BP] control). PhD. Even if an individual with type 1 diabetes has a low proximate risk of a CV event (i. smoking cessation) and pharmacological therapies (anti-platelet agents. both the proximate 10-year and lifetime CVD event risk becomes sufficiently high (>20%) to justify both health behaviour modification and pharmacological interventions. Vascular Protection in the Patient with Diabetes Vascular protective measures in patients with diabetes include health behaviour interventions (diet. they have a relative proximate risk many fold greater than that of individuals without diabetes (1). In young adults (aged 20 to 39 years). as most individuals with diabetes have a very high lifetime risk for a CVD event.  The requirement for pharmacological vascular protection therapies (statins. Steven Grover MD.2013. statins. smoking and excess body weight (17).and low-risk individuals (12).030 event rate is reached may be beneficial (6e10). they underestimate risk in younger individuals and have a low specificity. higher glycated hemoglobin (A1C) levels and higher albumin excretion rates. Traditional CVD event risk models predict an individual’s proximate (5. David Fitchett MD.5).1016/j. the use of pharmacotherapy for CVD risk factor reduction in younger persons with diabetes. renal dysfunction) and. Such a high relative risk indicates that early intervention before the arbitrary high-risk 10-year 20% 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. The term “vascular age” refers to models of CVD event risk that predict an individual’s CVD event risk and compare the event risk to age-adjusted CVD event risk (6). The greater the risk factor burden. Furthermore. FRCPC. the majority of people with type 1 diabetes have at least 1 CV risk factor (18). However. Stone MD. For all age groups. who are not at a high proximate risk and yet. for many individuals. dyslipidemia. Consequently. significantly increasing their relative risk of CVD events.doi. These models discriminate poorly between high. Both type 1 and type 2 diabetes are associated with increased CVD risk. CCFP KEY MESSAGES  Diabetes promotes both the development and adverse impact of cardiovascular disease (CVD) risk factors (e. Thus. resulting in a reduced life expectancy of approximately 12 years (2).  All adults with diabetes require chronic disease care strategies that include health behaviour education and. in order to promote CVD event risk reduction. a strategy that includes early vascular protection is justified (8e15). type 1 diabetes is an independent risk factor for premature CVD and mortality (16). have a steep CVD event risk trajectory. for many younger individuals with diabetes.  Although young patients with diabetes rarely will have a high proximate risk for CVD events.jcjd. For these persons.to 10-year) CVD event risk based on risk factors. accelerates cardiovascular age. they cannot reliably exclude individuals with diabetes who are unlikely to benefit from long-term pharmacological vascular protection strategies before their proximate risk is high. Richard Lewanczuk MD. stroke and peripheral vascular disease (1e3). angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]. such as diabetes.  Advanced cardiovascular age substantially increases both the proximate and lifetime risk for CVD events. increased physical activity. Persons with diabetes generally have a cardiovascular age 10 to 15 years in advance of their chronological age (1).canadianjournalofdiabetes. yet both proximate and lifetime event rates are many times higher than for individuals of the same age without diabetes (1. Peter Lin MD. For the vast majority of older persons with diabetes (age >40 years). A systematic approach to all vascular protective measures has been proven to reduce the . Primary CVD prevention trials conducted specifically in people with diabetes also have shown very little benefit. where the goal was to optimize health behaviour and control BP. with an estimate of 1 to 2 per 1000 in . ASA increases gastrointestinal bleeding 50% to 70% (39). p. p. Stone et al. The number needed to treat (NNT) for mortality after 13 years was 5.88e1. ASA in primary prevention. and the Pharmacologic Management of Type 2 Diabetes chapter. British Male Doctors (BMD). It is likely the risk is higher in patients with diabetes.23). S40.18. p. The goals of treatment and options to achieve BP targets are discussed in the Treatment of Hypertension chapter. and is associated with poorer glycemic control. PHS.94) (34). Primary Prevention Project (PPP). Antiplatelet therapy Platelets play a pivotal role in the development of atherothrombosis.9).73) compared to usual care with a 20% absolute risk reduction. only 9 trials with 5000 people had diabetes. Microvascular complications were also substantially reduced. there was a 53% relative risk reduction in major CVD events (hazard ratio [HR] 0. and BP. although treatment targets were usually not achieved.J. such as WHS. ASA reduces nonfatal MI in men without a history of CVD (24). The Early Treatment of Diabetic Retinopathy Study (ETDRS) and the Japanese Prevention of Atherosclerosis with ASA in Diabetes (JPAD) trial included patients with diabetes without known atherosclerotic disease (27. S31. stroke by 30%. The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial in patients with diabetes and peripheral vascular disease showed that ASA 100 mg did not reduce CAD. Quitting smoking reduces CV risk. The goals for glycemic control and the cardiovascular benefits are discussed in the Targets for Glycemic Control chapter. Patients were randomized to receive either usual care or intensive multifactorial therapy. It increases the risk of myocardial infarction (MI) 3-fold. and HOT and showed a modest 12% reduction of CVD events (RR 0. Compared to a 22% reduction in the risk of major CV events among all 140 000 high-risk subjects on antiplatelet therapy. may have played a role in the apparently absent treatment effect in these patients with vascular disease.82e0. the benefits of tight glycemic control to reduce the risk for macrovascular disease have been more difficult to show. poor adherence to treatment. the originally intensively managed group had a significantly lower mortality rate (30% vs. with only 50% of patients taking assigned therapy after 5 years. is an independent risk factor for all-cause mortality. p. S61. After 8 years of follow-up. 95% CI 0. In women without a history of CVD. in individuals with diabetes. In the intensively managed group. also have suggested that ASA has little or no benefit for the primary prevention of CAD events (25. Exercise and physical activity Regular exercise and physical activity are key components in the vascular protection paradigm as they have been shown to significantly reduce morbidity and mortality in persons with diabetes (21). The STENO-2 trial showed the long-term benefits of an intensive multifactorial management strategy in patients with type 2 diabetes and microalbuminuria (8. S45. The Antithrombotic Trialists meta-analysis included 95 randomized trials of antiplatelet therapy published up to 1997. with a risk of approximately 3 per 10 000 in the overall population. p.02).00) yet no reduction of stroke (RR 1. After 13 years. S117. p. cholesterol and blood glucose to the treatment targets recommended by clinical practice guidelines. subjects with diabetes showed no significant benefit (7% Æ 8% risk reduction) (26). including a 46% lower mortality.24e0.28). 95% CI 0. Pharmacological interventions Glycemic control While optimal glycemic control is central to the prevention of microvascular complications of diabetes. The benefits of regular physical activity are described in the Physical Activity and Diabetes chapter. In the general population.58) (27). and Thrombosis Prevention Trial (TPT). in vitro tests of platelet aggregation suggest that patients with diabetes have platelets that are more likely to be resistant to the inhibitory effect of ASA (22. Nutrition therapy The benefits of a healthy diet are described in the Nutrition Therapy chapter. reduces the risk of renal disease and improves glycemic control (19. However. Thus. Weight modification Achievement and maintenance of a healthy body weight are discussed in the Weight Management in Diabetes chapter. The STENO-2 trial shows that a process-driven. the other 4 meta-analyses that also included ETDRS. 95% CI 0. TPT. 50%. However. JPAD. lipid and glycemic levels were lower than in the subjects receiving usual care. The Baigent meta-analysis included BMD.20).30e38). Of these. the evidence for benefits of ASA therapy for the primary prevention of coronary artery disease (CAD) events in persons with diabetes is less robust. This meant that only 5 patients with type 2 diabetes and microalbuminuria needed to be treated with the intensive multifactorial approach for 8 years to prevent 1 cardiovascular event. As patients with diabetes have increased in vitro platelet reactivity and aggregation. S56. but the absolute rates of bleeding are low. WHS. The ETDRS trial with ASA 650 mg demonstrated a borderline significant reduction of fatal and nonfatal MI (relative risk [RR] 0. all patients with diabetes should participate in a multifactorial strategy to reduce CVD risk.A.88. Meta-analysis of the diabetes cohorts from large clinical trials. and options for glycemic control are discussed in the Pharmacotherapy in Type 1 Diabetes chapter. death. S82. p.73e1. / Can J Diabetes 37 (2013) S100eS104 S101 risk of CVD events. the benefits in patients with diabetes are less apparent. BP control BP control is necessary in a high proportion of patients with diabetes.85. Yet. the Women’s Health Study (WHS) indicated that ASA reduces the risk for stroke but not for MI (25). nonfatal MI or stroke (29). behaviour interventions were more frequently achieved. Despite the proven advantages of ASA therapy in patients with established CVD. Strategies for Vascular Protection Health behaviour interventions for all patients with diabetes Smoking cessation Smoking. Hypertension Optimal Treatment (HOT). However. 95% confidence interval [CI] 0. and POPADAD showed no significant reduction in either CAD events or stroke for patients with diabetes (35e38). progression to end stage renal disease. p¼0. they might be expected to have enhanced benefit from platelet inhibition with agents such as acetylsalicylic acid (ASA). The JPAD trial used ASA 81 to 100 mg and showed no significant benefit for either MI or stroke (28). multifactorial management strategy optimizing behaviour and pharmacological interventions had a major impact on a wide range of CVD outcomes.47. Furthermore. with highly effective generic statins available. Furthermore. the poor predictive value of current risk models does not allow adequate selection of individuals who are likely (or not) to benefit from statin therapy. A recent meta-analysis indicates that ACE inhibitors and ARBs reduce CVD events in normotensive individuals with and without diabetes (48). ASA has been shown to reduce CVD events in patients with established CVD disease (40). The benefits of ACE inhibition in both the HOPE and EUROPA trials were observed in individuals with or without a history of hypertension. and in those with higher and lower BP readings (42. high-density lipoprotein <0.0 mmol/L (49).001) by atorvastatin compared to placebo. particularly microalbuminuria).059). recent analyses of BP trials have indicated a benefit of ACE inhibition beyond that of BP lowering (47). that may warrant statin therapy for a particular individual based on the 2012 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia (53).9 years with either atorvastatin 10 mg daily or placebo (51). In addition. cost effectiveness will likely improve further. Renin-angiotensin-aldosterone system inhibition The benefit of ACE inhibition for vascular protection with ramipril 10 mg daily was demonstrated by the Heart Outcomes Prevention Evaluation (HOPE) trial (42). the use of ACE inhibitors or ARBs for vascular protection with persons with diabetes !55 years or with any evidence of organ damage is recommended. Now. Lipid-modifying therapies The role of lipid-modifying therapies in the protection against CAD events in persons with diabetes is presented in the Dyslipidemia chapter. with a 36% reduction of acute coronary heart disease.2 mmol/L. p¼0. In summary. There is clinical trial evidence of the benefits of statin therapy for primary prevention in patients with diabetes at ages prior to achieving a high proximate 10-year CVD risk.9 mmol/L. aged !55 years.g. and individuals with a very elevated single risk factor) should receive statin therapy. hypertension. there remains sufficient uncertainty about the use of ASA in the primary prevention of CAD events in persons with diabetes. the sample size was too small to show a statistically significant benefit (44). supported by clinical trial evidence when there is no other compelling reason to use statins. diabetes of >15 years’ duration and age >30 years. However. pooled estimates suggest that for primary prevention of CVD events in people with diabetes. those with established macrovascular disease. of whom 49% had no evidence of CVD. ASA in secondary prevention. p. More recently. premature development of CVD and shorter life expectancy for the individual with diabetes. It was also shown in the Micro-HOPE subset analysis of patients with diabetes. Consequently. Stone et al. S110. ASA results in no reduction of CAD events and stroke but an important increase in gastrointestinal hemorrhage. The 2008 guidelines also recommended that. Consequently. CV events were reduced by 22% (95% CI 13e30) in the patients with diabetes receiving simvastatin 40 mg daily for the 5-year treatment period (50). supports the use of ASA 75 to 162 mg daily for the secondary prevention of CAD events in those with diabetes (41). the current guidelines have taken into account the impact of diabetes on lifetime risk for CVD. Thus. p¼0.S102 J. Earlier treatment is predicted to result in enhanced cost-effective benefit (52). and statins should be prescribed up to the maximally tolerated and approved dose. there was a similar (although not statistically significant) risk reduction as observed in the 5438 patients with type 2 diabetes (50). Whether the benefits of ACE inhibition result from a reduction of BP remains controversial. Given the wealth of experience with statin use. They were treated for an average of 3. with 1 other CV risk factor (total cholesterol >5. The Heart Protection Study (HPS) enrolled 5963 individuals from age 40 years with diabetes. not specific to diabetes.A. the benefits from perindopril 8 mg daily were similar to those observed in the overall group. the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) indicated similar vascular protective effect from the ARB telmisartan 80 mg daily as the ACE inhibitor ramipril 10 mg daily in a subset of patients with diabetes (45). patients with diabetes and higher CVD risk (e. despite a plethora of data. below these ages. 1 CV risk factor. / Can J Diabetes 37 (2013) S100eS104 middle-aged individuals and as high as >5 per 1000 in people >70 years old (39). a reasonable position is to recommend statin therapy for primary CVD prevention for all patients with diabetes !40 years of age. an ACE inhibitor or ARB should be considered as a first-line agent for BP control. LDL reduction should aim to achieve targets recommended in the current guidelines. The clinical trial evidence. the use of other lipid-lowering agents in addition to statins may be necessary in some patients to achieve LDL goals. The cost effectiveness of statin use for primary prevention in patients with diabetes has been shown to be similar to or greater than the benefits seen in individuals with established CVD and no diabetes (51). The current guidelines continue to support the use of statins in secondary prevention in those with evidence of end organ damage (macrovascular disease. and age >40 years. The Collaborative Atorvastatin Diabetes Study (CARDS) included 2838 patients with diabetes. however. Accordingly. and its routine use in primary CVD event prevention is not recommended. As a direct reflection of this evidence. In subjects with diabetes enrolled in the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study. which enrolled individuals with diabetes. the number of years of life saved is greater the earlier treatment is initiated. for patients with diabetes and hypertension. Furthermore. even in the absence of hypertension. Consequently. In addition. microalbuminuria or smoking) or established CVD (43).46). microvascular disease. In 2008. There was a strong trend toward a 27% reduction of all-cause mortality (95% CI À48% to 1%. the current guideline recommendations are for use of statins for primary prevention of CVD at the earliest time (or youngest age). the Canadian Diabetes Association recommended that all men with diabetes !45 years of age and women with diabetes !50 years of age be treated with a statin to reduce LDL-C to 2. CV events were reduced by 37% (95% CI À52% to À17%. microvascular disease. in this subgroup. increased vascular aging. In the 615 patients with type 1 diabetes. The CARDS study concluded with the statement: “The debate about whether all patients with type 2 diabetes warrant statin treatment should now focus on whether any patients can reliably be identified as being at sufficiently low risk for this safe and efficacious treatment to be withheld” (52). there is little safety concern for their long-term use. both the HPS and CARDS studies provided evidence supporting the use of statin therapy for all patients with diabetes !40 years of age with or without 1 CV risk factor. there are other circumstances. a 31% reduction of coronary revascularization and a 48% reduction of stroke. The same relative benefit was observed in patients with or without evidence of CVD. . as reflected in the 2011 Canadian Cardiovascular Society Guidelines on the Use of Antiplatelet Therapy in the Outpatient Setting. 45). adolescents. 6. Stock S. Am J Cardiol 2006.339:229e34. 24. Stone JA. et al. Clinical macrovascular disease [Grade A. et al. Framing CVD event risk prediction. 21. Wilson PW. Hecker W. HOT Study Group. Prediction of lifetime risk for cardiovascular disease by risk factor burden at 50 years of age. Diabetic patients who smoke: are they different? Diabetes Care 1999.174:801e9. Backlund JY. 13. MacCuish A. Lloyd Jones DM. DPV Initiative of the German Working Group for Pediatric Diabetology. Pellegrini F.97: 38e43. Health Affairs 2010. 33. German diabetes management programs improve quality of care and curb costs. Consensus. 14. Statin therapy should be used to reduce cardiovascular risk in adults with type 1 or type 2 diabetes with any of the following features: a. Fung K. 25. multifaceted approach to reduce cardiovascular risk.358:580e91.348:383e93. Consensus. ETDRS Investigators. Low-dose ASA therapy (81e325 mg) may be used for secondary prevention in people with established cardiovascular disease [Grade D. Diabetes Care 2008. Cross-sectional data from the German diabetes documentation and quality management system (DPV). 1996e1997.27:407e14. et al. Health benefits of physical activity: the evidence. Collaborative overview of randomised trials of antiplatelet therapydI: prevention of death. et al. Rönnemaa T. Belch J. Pedersen O. N Engl J Med 2003.296:313e6.23:375e88. Doerfer J.A. Roncaglioni MC. Gray R. Büscher G. et al. et al. et al. Nakayama M. et al. and young adults with type 1 diabetes. Grover SA. Fox CS. Collins R. Peto R. Clopidogrel 75 mg may be used in people unable to tolerate ASA [Grade D. 20. et al. Lifetime risk of CAD among individuals with and without diabetes stratified by obesity status in the Framingham heart study. 17. Roncaglioni MC. Gaede P. Level 1 (8. Health-related quality of life and health-adjusted life expectancy of people with diabetes in Ontario. Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study. N Engl J Med 2008. N Engl J Med 2008. Level 2 (36)]. 15. Stevens RJ. 4. 2. Ridker PM. acetylsalicylic acid. Blackwell L. Level 1 (43. ASA should not be routinely used for the primary prevention of cardiovascular disease in people with diabetes [Grade A. 5. 29.268:1292e300. Influence of aspirin resistance on platelet function profiles in patients on long-term aspirin and clopidogrel after percutaneous coronary intervention. 2. 10. Consensus].45)] b. Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Best Pract Res Clin Endocrinol Metab 2009. Consensus] 3. Consensus for type 1 diabetes] c. and stroke by prolonged antiplatelet therapy in various categories of patients. Diabet Med 1999. Gatling W. Age !40 years [Grade A Level 1 (50.51). Br Med J (Clin Res Ed) 1988. Drabik A. Parving HH. et al. JAMA 2006. Lancet 2009. at doses that have demonstrated vascular protection. O’Connor PJ. 32. Grade D. Lancet 2006. enzyme. 11. Grade D. Cleary PA. Larson MG. Lee IM. Do doctors accurately assess coronary risk in their patients? preliminary results of the coronary health assessment study. 5. Danielson E. Low-dose aspirin for primary prevention of atherosclerotic events in patients with type 2 diabetes: a randomized controlled trial. Mullee MA. Laing SP. Consensus]  Warrants therapy based on the presence of other risk factors according to the 2012 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia (53). for all others] c. et al. 22. Consensus].113:791e8. Diabetes Care 2004. Age <55 years and microvascular complications [Grade D. Leip EP. Lancet 1998. Hansson L. Diabetes Care 2003. American Diabetes Association. Guzder RN. Haire-Joshu D. Schwab KO. The British Diabetic Association Cohort Study. et al. 8. Lehto S. Spectrum and prevalence of atherogenic risk factors in 27. 27. Esrey KL. et al. et al. ASA may be used in the presence of additional cardiovascular risk factors [Grade D. ACE. for those with type 2 diabetes age >40 years with microalbuminuria]. Tibbs TL. Glasgow RE. et al.101:671e9. Angiolillo DJ. .300:2134e41. Baigent C. 31. 30.17:117e29. 6. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Tu JV. Canada. Avanzini F. JAMA 2008. Zanchetti A. ARBs or statins should only be used if there is reliable contraception. for children/adolescents. Warburton DE. Nathan DM. et al.9). Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Goldberger JJ. JAMA 1992. Lund-Andersen H. Kothari V. Clin Sci (Lond) 2001. N Engl J Med 2005. Smoking and diabetes. should be used to reduce cardiovascular risk in adults with type 1 or type 2 diabetes with any of the following: a.358 children.295:306e13.359:2195e207. The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. 3. Randomised trial of prophylactic daily aspirin in British male doctors. Age <40 years and 1 of the following:  Diabetes duration >15 years and age >30 years [Grade D. Solberg L. II: cause-specific mortality in patients with insulin-treated diabetes mellitus. BMJ 2008. Consensus] Note: Among women with childbearing potential. Schultz SE. N Engl J Med 1998. Desai JR. Campbell I. Level 1 (43. Morimoto T. Abbreviations: A1C. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial.31:1582e4. Can J Cardiol 2011. Lancet 1998.310:975e8. Early Treatment Diabetic Retinopathy Study report 14. Collins R. Lowensteyn I. Kapral MK. Multifactorial intervention and CAD in patients with type 2 diabetes. Consensus]. Diabetes Care 2006. et al. Sacco M. Fernandez-Ortiz A. Primary prevention of cardiovascular events with low-dose aspirin and vitamin E in type 2 diabetic patients: results of the Primary Prevention Project (PPP) trial. 352:1293e304. Consensus.16:466e71. 4.351:233e41.368:29e36. All individuals with diabetes (type 1 or type 2) should follow a comprehensive. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.353:2643e53.22:1887e98. 12. et al. Bernardo E. for type 2 diabetes. Age !55 years [Grade A. for type 1 diabetes. N Engl J Med 2005. 18. Booth GL. BMJ 1994.351:1755e62. Aspirin and clopidogrel: efficacy and resistance in diabetes mellitus.22:554e62.29:218e25. Ridker PM. Diabetes mellitus and sudden cardiac death: what are the data? Cardiol J 2010. Berger JS. The Medical Research Council’s General Practice Research Framework. et al. 19.373:1849e60. Level 1 (50)] b. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. ACE inhibitors.353:2643e53. 16. including:  Achievement and maintenance of healthy body weight  Healthy diet  Regular physical activity  Smoking cessation  Optimal glycemic control (usually A1C 7%)  Optimal blood pressure control (<130/80 mm Hg)  Additional vascular protective medications in the majority of adult patients (see recommendations below) [Grade D. Swerdlow AJ. Suryadevara S. ASA.J. myocardial infarction. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. / Can J Diabetes 37 (2013) S100eS104 S103 RECOMMENDATIONS 1. Grade A. glycated hemoglobin. Stone et al. Antiplatelet Trialists’ Collaboration. for those with an additional risk factor or end organ damage. Consensus]  Microvascular complications [Grade D.29:2197e205. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. 9. 23. 7. Intensive diabetes treatment and cardiovascular disease in patients with Type 1 diabetes.26: 3264e72. et al. Diabetes Care 2004. Clinical macrovascular disease [Grade A. Nichol CW. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. 34. CMAJ 2006. The UKPDS risk engine: a model for the risk of coronary heart disease in Type II diabetes (UKPDS 56). Fonseca FA. BMJ 1995. angiotensin receptor blocker. Circulation 2006.27:171e3. angiotensin-converting ARB.308:81e106. References 1. Bredin SSD. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. Cook NR. [Grade D.27(suppl 1):S74e5. Slater SD. Carruthers SG. N Engl J Med 2005. Gaede P. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. Larsen N. et al.337:a1840. Pencina MJ. ACE inhibitor or ARB. Vedel P. Ogawa H. et al. 26. Angiolillo DJ. Manuel DG. Haffner SM. Grade D. Diabet Med 2005. 28. Adler AI. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Bergner DW. Effect of a multifactorial intervention on mortality in type 2 diabetes. Loke YK. et al. Alberts MJ. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Fox KM. et al. Sacco M. Grégoire J. Aggarwal NR. 50.362:782e8. et al.342:145e53. Parish S. placebo-controlled. Coupal L. a scientific statement of the American Heart Association. 87:211e8. Effects of an angiotensin-converting-enzyme inhibitor. Bell AD. on death from cardiovascular causes. Diabetes Res Clin Pract 2010. et al. 42. myocardial infarction and stroke in high-risk patients. Gerstein HC. Risk of gastrointestinal haemorrhage with long term use of aspirin: meta-analysis. et al. McAlister FA. Yusuf S. EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Strippoli GF.339:b4531. Bhatt DL. 36. Leiter LA. Telmisartan. Roussin A. 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Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised.33:505e14. Hirsch AT. et al. New Engl J Med 2000. de Berardis G. Marso SP. The effect of perindopril on cardiovascular morbidity and mortality in patients with diabetes in the EUROPA study: results from the PERSUADE substudy. Sun A.361:2005e16. BMJ 2000. Effects of ramipril on CAD and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. 51.46:386e92. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are beneficial in normotensive atherosclerotic patients: a collaborative meta-analysis of randomized trials. The Heart Outcomes Prevention Evaluation Study Investigators. Can J Cardiol 2013. ramipril. Diabetes Care 2010.358:1547e59. Pogue J. Stone et al. Remme WJ. Can J Cardiol 2011. 41. multicentre trial (the EUROPA study). Pignone M. et al. Aspirin for primary prevention of cardiovascular events in patients with diabetes: a meta-analysis. Lancet 2003. 38. et al. 52. Am J Cardiol 2002. Betteridge DJ. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo controlled trial: Heart Protection Study Collaborative Group. 39. Yusuf S. Lewis G. How cost effective is the treatment of dyslipidemia in patients with diabetes but without cardiovascular disease? Diabetes Care 2001.321:1183e7. / Can J Diabetes 37 (2013) S100eS104 45. Teo K.A. and an expert consensus document of the American College of Cardiology Foundation. Calvin AD. Hypertension 2005. Daly CA. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Derry S. 53. ramipril. Armitage J. Verdecchia P.32:2300e6. N Engl J Med 2008.S104 J.29:151e67. Hegele RA. Eur Heart J 2005. et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. Can J Diabetes 2008. et al. et al. Reboldi G. 44. et al. BMJ 2009. or both in patients at high risk for vascular events. 37. Durrington PN. . Mann JFE. double-blind. 40. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society guidelines.26:1369e78. Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. 49. Cartier R.364:685e96. 35. A substantial portion of the DIAD population was defined as having intermediate/high baseline cardiovascular risk. The choice of initial stress test should be based on evaluation of the resting ECG.Can J Diabetes 37 (2013) S105eS109 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.031 (ECG) abnormalities or multiple risk factors for atherosclerosis. There are data with newer technology.jcjd. Cardiovascular Disease in Diabetes The majority (65% to 80%) of people with diabetes will die from heart disease (1. especially patients with established severe coronary artery disease (CAD). multiple risk factors for CAD did not help to predict the patients with positive screening tests for CAD.12). description of chest pain. such as dyspnea on exertion. Compared to people without diabetes. Most imaging techniques have been shown useful in prospective study in order to identify patients at higher risk. gender.canadianjournalofdiabetes.  In individuals at high risk of CAD (based on age. such as pharmacologic or nuclear stress imaging. FRCPC. a repeat resting ECG may detect changes that result from silent MI and lead to earlier detection of critical CAD.  Exercise capacity is frequently impaired in people with diabetes due to the high prevalence of obesity. and at an earlier age. people with diabetes (especially women) are at higher risk of developing heart disease.doi. There is evidence that early screening and intervention in people with diabetes and with silent ischemia is beneficial and may improve long-term survival (7.2013. ECG abnormalities that limit the diagnostic accuracy of a stress ECG include resting ST depression (1 mm). CSPQ. The baseline study showed either perfusion defects or stress-induced ECG abnormalities in 22% of patients and large defects in 6%. a randomized pilot study on the impact of stress testing to screen for CAD in asymptomatic subjects with diabetes suggested a significant reduction in cardiac death and MI (16). Yet. sedentary lifestyle. In this study. Recognition of such features is of clinical importance. there is. it is desirable to identify patients at high risk for vascular events. abnormal resting electrocardiogram and presence of several other risk factors). exercise stress testing is useful for the assessment of prognosis. For those unable to perform an exercise test. and at an earlier age. it is important to keep in mind that the goals of screening for CAD are to improve life expectancy and quality of life by preventing MI and heart failure through early detection. people with type 1 and type 2 (especially women) are at higher risk of developing heart disease. left bundle . The Definition of Ischemia in Asymptomatic Diabetes (DIAD) study was prospectively investigating the value of routine adenosine stress myocardial perfusion scanning in asymptomatic patients with type 2 diabetes 55 years for the prevention of coronary events (10).com Clinical Practice Guidelines Screening for the Presence of Coronary Artery Disease Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Paul Poirier MD. A high proportion of deaths occur in patients with no prior signs or symptoms of cardiovascular disease (CVD). FACC. Nevertheless. Unfortunately. Furthermore. Éric Larose MD.01. Role of Stress Testing Exercise stress testing is useful in patients at high risk of CAD for the assessment of prognosis and the identification of individuals who may benefit from coronary artery revascularization to improve long-term survival. people with diabetes have a high prevalence of silent myocardial ischemia. In patients considered to be at high risk for CAD. PhD. so far. peripheral neuropathy (both sensory and motor) and vascular disease. the individual’s ability to exercise. but these features will be absent in a significant number (20% to 50%) of people with diabetes (4e10). Hence. Larger and adequately powered studies are necessary to support this provocative observation before clinical practice is changed. FAHA. a large proportion will have no symptoms before either a fatal or a nonfatal myocardial infarction (MI). as the outcome of CAD events is worse in people with diabetes when shortness of breath is the primary symptom (4). The most predictive clinical observation for CAD in the person with or without diabetes is a history of chest pain or discomfort. FRCPC KEY MESSAGES  Compared to people without diabetes. FRCPC. and almost one-third of myocardial infarctions (MIs) occur without recognized or typical symptoms (silent MIs) (3). but the add-on effect of the latter on prognosis and quality of life is not clear. Screening with exercise ECG stress testing will find 3-vessel CAD in 13% to 15% of those with abnormal stress test findings (13) and lead to angiography with revascularization in 1% to 3% of asymptomatic individuals (13e15). may be required. However. Clinical findings. and local expertise and technology. history of prior MI. their annual cardiac event rate was low and not altered by routine screening for inducible ischemia. The presence of CAD risk factors and resting ECG abnormalities identify patients with diabetes at increased risk of important CAD burden and abnormal stress ECG or perfusion imaging results (11). The goals of screening are to improve life expectancy and quality of life by preventing MI and heart failure through the early detection of coronary artery disease (CAD).2). Robert Dufour MD. André Carpentier MD. may also indicate the presence of CAD. no head-to-head study showing which one will be best in a cost-effective way.org/10. MSc. resting electrocardiogram 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.1016/j. However. functional imaging testing. A resting ECG at the time of diagnosis of diabetes also provides a baseline to which future ECGs can be compared. Also. peripheral neuropathy (both sensory and motor). An ECG with ST-T abnormalities at rest has been shown to be most predictive for silent ischemia (Odds Ratio (OR) 9. The relevance of ST-T abnormalities as a predictive factor for silent ischemia emphasizes the importance of recording a resting ECG in most individuals with type 2 diabetes. the age-adjusted relative risk for CVD in type 1 diabetes is ten times that of the general population (28e30).29). male gender and AfricanAmericans have higher rates of CVD compared to Europeans (31). and vascular disease in this population.7 years) in both men (HR 3. is currently unknown in terms of guiding management decisions in patients with type 2 diabetes (24). The Diabetes UK longitudinal cohort study.5%) in type 1 diabetes (37). adenosine. etc. are likely higher in men than women (36). reported that type 1 diabetes is associated with markedly increased adjusted hazard ratio for major CAD events (median follow-up of 4. not only in that it presents at a younger age but also in relation to sex. and 0. acute coronary syndrome. Also. regardless of the reason for this incapacity. Poirier et al.. pharmacologic stress imaging. Stroke is still an important outcome in type 1 diabetes. an intraventricular conduction defect with QRS duration >120 ms.2% (50% of events were new-onset angina and 50% were cardiac death or MIs) (20). compared with 0. involvement of all 3 major coronary arteries and distal segment disease. making it the leading cause of death in that population (26.S106 P. Myocardial ischemia (whether silent or symptomatic) detected during exercise stress testing in individuals with diabetes is associated with poorer long-term survival compared to individuals without diabetes (7). Major CVD events occurred in type 1 diabetes on average 10 to 15 years earlier compared with matched nondiabetic controls. resulting in major cardiovascular events with poor outcome and/or early development of heart failure (28.97% in subjects with normal exercise ECG (16). including more than 7. It is important to emphasize that the cardiovascular risk burden and profile of patients with type 1 diabetes differs from type 2 diabetes.6) and women (HR 9.000 patients with type 1 diabetes. Despite the much younger age of onset. these risk increments are comparable to those observed in patients with type 2 diabetes (27). The choice of the optimal imaging modality to detect stress-induced MI is best determined by local availability and expertise. Individuals with these resting ECG findings should have a stress test with an imaging modality.34. Silent MI is common (40%) in older asymptomatic people with type 2 diabetes. the disease process seems to be more severe in type 1 diabetes. Coronary artery disease and cerebrovascular disease CAD appears more common than stroke.32). 5. sedentary lifestyle.4% (25e27). Perfusion imaging also provides important prognostic information. an abnormal scan was predictive of future CAD events in subjects with and without diabetes. For those unable to perform an exercise ECG stress test. For the most part. Peripheral vascular disease Peripheral vascular disease (PVD) is an important vascular complication of type 1 diabetes. Silent ischemia is most likely to occur in individuals with diabetes who are older (mean age 65 years) and have elevated total cholesterol and proteinuria (14). prevalence of silent brain infarcts or leukoaraiosis is extremely high (34. The utility of newer CAD diagnostic modalities. Difference from type 2 diabetes CVD in type 1 diabetes differs from type 2 diabetes. Individuals who cannot adequately exercise on a stress test have a poorer prognosis than those who can. and cardiac magnetic resonance imaging. and in those >40 years of age compared to those <40 years of age (36). / Can J Diabetes 37 (2013) S105eS109 branch block or right bundle branch block.74% per year in the EURODIAB Study (26).6 per 1000 person-years among individuals 25 to 44 years of age to as high as 7.29). People with diabetes and silent ischemia have an annual event rate for CAD of 6. silent presentation and disease severity (28. The strongest and most consistent prognostic marker identified during exercise ECG stress testing is the person’s maximum exercise capacity (4). such as CT angiography. but is more frequent (65%) in those with diabetes who also have microalbuminuria (19). and there is a high prevalence of silent CAD in young adults with type 1 diabetes. Mortality rates from CAD are reported between 6 and 8% (33. which may be related to cardiac autonomic neuropathy.27.2% (38). studies report incidences around 15% (27.98% per year (31) and was as high as 3% per year after age 55 years. The Pittsburgh Epidemiology of Diabetes Complications (EDC) study demonstrated that the incidence of major CVD events in young adults with type 1 diabetes (age 28 to 38 years) was 0. needs to be determined in individuals with diabetes.44-19. Gender and race/ethnicity are important features of increased risk of CVD. ventricular paced rhythm or preexcitation. Although exercise capacity is decreased in individuals with diabetes (17. using dipyridamole. The cumulative incidence of CAD ranges between 2.38) and was the only significant predictor of silent ischemia in women (14). Compared with nondiabetic controls. The role of other imaging modalities (anatomical imaging).3% over 6 years among African-Americans (27). By . non-fatal MI. such as coronary computed tomography (CT).9% over 20 years in the WESDR (Wisconsin Epidemiologic Study of Diabetic Retinopathy) (34). Incidence rates of lower extremity amputation vary by age from 3. in comparison to functional imaging. However. Reported prevalence rates of CVD in type 1 diabetes vary between 3% and 12.18). the cumulative incidence of stroke was 3. Exercise capacity is frequently impaired in people with diabetes due to the high prevalence of obesity. In a meta-analysis of perfusion imaging. coronary artery calcium scoring. 95% confidence interval [CI]. such as scintigraphic myocardial perfusion imaging or echocardiography. The risk of CAD mortality is comparable in women and men with type 1 diabetes. but no comparative data are available for the person with diabetes. Finally. it is still of prognostic importance (4).6). but also to potentially fatal events. An abnormal exercise ECG is associated with an annual CAD event rate of 2. it has been shown in a randomized trial in patients with silent ischemia (the vast majority of whom did not have diabetes) that long-term antiischemic drug therapy (w11 years follow-up) reduces cardiac events (cardiac death.1% (26) and 19% (33) depending on the characteristics of the population studied. patients with type 1 diabetes are more likely to have severe coronary stenosis. or revascularization) with preservation of ejection fraction (21). Thus.27.1%. 4. calcium score. is required. or dobutamine testing.35). silent MI is a prelude not only to symptomatic ischemia.35). the cardiac event rate in individuals with diabetes was significantly greater than in those without diabetes (23). CVD in Type 1 Diabetes Incidence and prevalence of CVD CVD complications are important causes of morbidity and mortality among individuals with type 1 diabetes which may have been under-recognized in the past. Of such. Stress echocardiography and stress nuclear imaging have similar values for cardiac events in the general population (23). Myocardial perfusion imaging has similar predictive value for cardiac death and non-fatal MI in individuals with diabetes as in those without diabetes (22). An abnormal ECG may indicate the need for further investigations and result in the earlier detection and treatment of CAD (14). male gender. Compared to the general population. In the same way.9 as the criterion for the presence of peripheral atherosclerotic disease instead of overt clinical events. Q waves) [Grade D. If one considers ankle-brachial index (ABI) <0. hypertension.g. subclinical carotid disease may be commonly associated with type 1 diabetes. many individuals will have had type 1 diabetes for 20 years and rates of CVD begin to approach the considered “high-risk” category (46). In the DCCT study. Consensus]. glomerular filtration rate. individuals who require stress testing and are unable to exercise should undergo pharmacological stress echocardiography or nuclear imaging [Grade C. stroke and PVD. despite the fact that all participants had at least subclinical CAD (48). In the Pittsburgh EDC study. People with diabetes should undergo investigation for CAD by exercise ECG stress testing as the initial test [Grade D. foot pathology.41). In the EDC study. While standardized mortality rates from ischemic heart disease were higher in men than women at all ages in the general population. Consensus]. Level 3 (4)]  Signs or symptoms of associated diseases B Peripheral arterial disease (abnormal ankle-brachial index) [Grade D. despite the fact that no overt CVD was apparent at baseline (47). lower extremity amputation and ECG abnormalities RECOMMENDATIONS 1. differences in mean A1C are clearly significant drivers (47). Compared to age-/sexmatched healthy controls. Patients with type 1 diabetes who have symptoms suggestive of CAD. does not support routine CAD screening beyond resting ECGs in patients with diabetes who do not have cardiovascular symptoms or an abnormal ECG. 3. In a large Norwegian cohort study. favouring instead global risk factor assessment and treatment. This study found that among those with type 1 diabetes. Consensus] in the presence of the following:  Typical or atypical cardiac symptoms (e. However. an abnormal resting ECG or clustering of cardiac risk factors yielding an intermediate or high global risk estimate. myocardial ischemia by ECG.P.62) and albuminuria (HR 0. Time course of events Although CAD rarely presents within the first 20 years of diagnosis. the treatment group effect of intensive treatment therapy on CVD risk persisted after adjustment for microalbuminuria (hazard ratio [HR] 0. Consensus] 4. left bundle branch block or ST-T abnormalities) [Grade D. 1 approach to identifying CVD in patients with type 1 diabetes is to apply the same CAD risk assessment and diagnostic strategies used in type 2 diabetes (see discussion above) or in the population in general (54). women had a 2. 45. however. The most recent population-based cohort study showed different results (53). the common thread in all these studies is that the presence of type 1 diabetes (as well as in type 2 diabetes) seems to dramatically increase the risk for CVD. Individuals with diabetes who demonstrate ischemia at low exercise capacity (<5 metabolic equivalents [METs]) on stress testing should be referred to a cardiac specialist [Grade D.7% in men (39). . The recent decline in diabetic kidney disease has not been accompanied by a corresponding fall in CAD rates. / Can J Diabetes 37 (2013) S105eS109 S107 age 65. history of sores or ulcers.6% of participants from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study developed PVD (41).5 times higher risk of having coronary artery calcifications (50). there was no difference in the cumulative incidence of CAD stratified according to year of diagnosis (1950-1980). the rate of PVD among those with type 1 diabetes may be very high (39). However. mortality rates from ischemic heart disease were higher in women with type 1 diabetes than in men or women without diabetes. Level 4 (9)] B Carotid bruits [Grade D. Thus. exercise treadmill testing remains the first-line diagnostic test due to the high cost efficacy and widespread availability. or 30 years’ duration of diabetes in the Pittsburgh EDC. Abbreviations: CAD. there was no difference in mortality from ischemic heart disease in men and women with type 1 diabetes <40 years of age (36). only 15% of the Oslo Study population had microalbuminuria. it clearly explains only a portion of the CVD risk. Consensus]. low-density lipoprotein. the cumulative probability of PVD is 11% in women and 20. Consensus] B Stroke [Grade D. macrovascular)  Cardiac risk factors 2. A repeat resting ECG should be performed every 2 years in patients with diabetes [Grade D. In fact. ECG. Effect of gender Compared to women without diabetes. In addition. was less common and a documented MI as more common in those with prior renal disease compared to those without (49). In addition to the clinical endpoints of CAD.5 to 3 times higher standardized mortality rate from CVD than men with type 1 diabetes. coronary artery disease. should have additional testing for CAD (54. Consensus]  Resting abnormalities on ECG (e.55). The DCCT intensive therapy intervention had a significant impact on the age and the duration of diabetes exposure at onset of CVD. despite at least a 50% decrement of the cumulative incidence of overt nephropathy (31). diastolic blood pressure. particularly in women. although diabetic kidney disease is important. Predictors of PVD include increasing age. Indeed. A baseline resting ECG should be performed in individuals with any of the following [Grade D. suggesting that. greater carotid intima-media thickness (IMT) has been observed in studies of children with type 1 diabetes with a mean age as young as 11 years (42e45). albumin excretion rate. diabetes duration. For patients able to walk on a treadmill without significant baseline ST segment abnormality (see discussion for type 2 diabetes).58). nephropathy or microalbuminuria no longer precedes CAD in the majority of cases. men with type 1 diabetes had higher mortality rates than women with type 1 diabetes (52). as the initial manifestation of CAD. women with type 1 diabetes had a 3. despite the well-recognized increase in CVD risk associated with proteinuria.40. smoking and retinopathy (38. despite substantial declines in renal failure as well as decline in overall mortality over the same time period (31). 5.g.g. Level 3 (22)]. chest discomfort) [Grade C. Consensus]:  Age >40 years  Duration of diabetes >15 years and age >30 years  End organ damage (microvascular. Poirier et al. Consensus] B Transient ischemic attack [Grade D. electrocardiogram. This. acknowledging that risk scores are more or less accurate in type 1 diabetes. no temporal decline was noted for the cumulative incidence of MI/CAD death at 20. Men with type 1 diabetes age 40 years had a higher mortality rate from CVD than women with type 1 diabetes (51). Testing for CVD in type 1 diabetes In the absence of data to the contrary. glycated hemoglobin (A1C). by age 30 years. 25. treadmill testing may not be possible due to the burden of peripheral neuropathy. Although not all the findings are consistent. Pharmacological stress echocardiography or nuclear imaging should be used in individuals with diabetes in whom resting ECG abnormalities preclude the use of exercise ECG stress testing (e. unexplained dyspnea. 46:760e5. Sophisticated testing has been reported in patients with type 1 diabetes. Impact of left ventricular diastolic dysfunction on maximal treadmill performance in normotensive subjects with well-controlled type 2 diabetes mellitus.111:3489e93. 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Weis U. et al. Conway B. no data are yet available to determine the utility of coronary artery calcium assessment for risk prediction in type 1 diabetes. Zinman B.24:5e10.25:543e50. et al. Bonura F. Faglia E. Milan Study on Atherosclerosis and Diabetes (MiSAD) Group. 22. Yamashita T. Garneau C. Rutter MK. Atherosclerosis 2010.30:2646e8.211:672e5. Marshall SM. Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients. Phillips RT. Schinkel AF. Paillole C. et al. and complications. Am J Cardiol 2000.149:e1e6. et al. Inzucchi SE. Putto-Laurila A. 35. Am J Cardiol 1997. 18. Zuber M. Diabetes Care 2001.51:493e8. Fox KM. Froelicher V. 32. Stensaeth KH. Turner B. Report of the National Heart. Effects of anti-ischaemic drug therapy in silent myocardial ischaemia type I: the Swiss Interventional Study on Silent Ischaemia type I (SWISSI I): a randomized. Kapral MK. Caccamo G.108: 1263e77.14:363e70. Myers J.28:2110e7.25:2032e6. Diabetes 1994. Jonasson JM. Identifying high-risk asymptomatic diabetic patients who are candidates for screening stress single-photon emission computed tomography imaging. 20. Am J Med 2004.94:623e30. Shaw LJ. et al. Fung K.55:1463e9. Ann Intern Med 1988. Villella M. Nesto RW. et al. et al. et al. Fuller JH. Sparen P. Glycemia (or. Risks of nontraumatic lower-extremity amputations in patients with type 1 diabetes: a population-based cohort study in Sweden. 21.108:170e5. Diabetes Care 2007. 25. Young LH. Warram JH. Hodge DO. Parsons L. Am J Cardiol 1999.58:2649e55. Diabetes Care 2006. 13. Cardiac events in 735 type 2 diabetic patients who underwent screening for unknown asymptomatic coronary heart disease: 5-year follow-up report from the Milan Study on Atherosclerosis and Diabetes (MiSAD). The presence of coronary artery calcium is independently associated with increased prevalence of CAD. Forsblom C. Abraham K. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. et al. Mortality from heart disease in a cohort of 23. Garneau C. Carotid artery intima-media thickness in children with type 1 diabetes. Insulin resistance and acute coronary syndrome. Erbey JR. 27. Rajagopalan N.57) and more frequent in patients with type 1 diabetes than in those without. Diabetes Care 1999. Yamasaki Y. Diabetes Care 2002. Weiner DA. Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus.72:1823e9. Significance of silent ischemia and microalbuminuria in predicting coronary events in asymptomatic patients with type 2 diabetes. Young LH.11:171e85.30:2729e36. Diabetes Care 2004.: a cohort study using the general practice research database. 4.K. 29.40:56e61. Poirier P. Bax JJ. McBride PE. Am J Cardiol 1991. 40. microalbuminuria. et al.51:248e54. Coronary artery calcium. et al. and retinal microvascular characteristics in type 1 diabetes: Wisconsin epidemiologic study of diabetic retinopathy. et al. While coronary artery calcium assessment has proven to predict subsequent cardiovascular risk in the general population and in cohorts of patients with type 2 diabetes (58). Margeirsdottir HD. Daly C. Rutter MK. Olson JC. 23. Jartti L. Circulation 2003. 30. 16. J Hypertens 2003.000 patients with insulin-treated diabetes. Costacou T.117:1e9.346:793e801. Metabolism 2002. 12. Chareonthaitawee P. Sorajja P. Klein R. 15. 2. Age of onset of type 1 diabetes in children and carotid intima medial thickness. Mulnier HE. 3. Lee WL. Umeda F. Kosinski EJ. Klein BE. References 1. Kawamori R. et al. Faglia E. et al. Nathan DM. Frye RL. Intensive treatment of diabetes is associated with a reduced rate of peripheral arterial calcification in the diabetes control and complications trial. Orchard T. The 30-year natural history of type 1 diabetes complications: the Pittsburgh Epidemiology of Diabetes Complications Study experience. with a stronger graded association in men than in women. 10. Prevalence of unrecognized silent myocardial ischemia and its association with atherosclerotic risk factors in noninsulin-dependent diabetes mellitus. Ruiz J. et al. Lung. and test performance in patients with type 1 diabetes is comparable to that of the general population. I. and Blood Institute-National Institute of Diabetes and Digestive and Kidney Diseases Working Group on Cardiovascular Complications of Type 1 Diabetes Mellitus. et al. Villella A. et al. et al. et al.79: 134e9.38:726e31. et al. 8. Lackland DT. 45. Larsen M.59:750e5.43:634e9. Kett KG. Forrest KY. Booth GL.47:37e44. 14. Angina and exertional myocardial ischemia in diabetic and nondiabetic patients: assessment by exercise thallium scintigraphy. Erne P. Putaala J. Klein R. Fuller JH. The British Diabetic Association Cohort Study. 48. Edmundowicz D. Brekke M. Backlund JY. Costacou T. Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. et al. The effect of intensive glycemic treatment on coronary artery calcification in type 1 diabetic participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study. Callister TQ. Alpert JS. et al. 54. Larsen J. et al. JAMA 2001. Raggi P. Beller GA. et al. Diabetes 2010. Diabetes 2002. Coronary calcium in adults with type 1 diabetes: a stronger correlate of clinical coronary artery disease in men than in women. J Am Coll Cardiol 2000. J Am Coll Cardiol 2004. Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes 2006. American Diabetes Association. Silent coronary atheromatosis in type 1 diabetic patients and its relation to long-term glycemic control.285:2486e97. Becker DJ. et al. Stene LC. et al. Greenland P. Diabetologia 2006. Prognostic value of coronary artery calcium screening in subjects with and without diabetes.49:1571e8. 57. et al. And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III).43:1663e9.55: 3556e65. Circulation 2010. 49. 51:2637e41. / Can J Diabetes 37 (2013) S105eS109 46. Genuth S. Orchard TJ. Colhoun HM. Cleary PA. 55. Rubens MB. Olson JC. Swerdlow AJ. N Engl J Med 2005. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. Sandvik L. 58. 50. II: cause-specific mortality in patients with insulin-treated diabetes mellitus. Underwood SR. Slater SD.P. Poirier et al.59:3216e22. Diabetes 2000. 47. Kelsey SF. Standards of medical care in diabetes-2011. Bangstad HJ.36:2160e7. 56.353: 2643e53.34(suppl 1):S11e61. Secrest AM. Laing SP. 51. et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Cleary PA. Skrivarhaug T.122:e584e636. Shaw LJ.49:298e305. Nathan DM. .10:48e54. Diabet Med 1999. The effect of type 1 diabetes mellitus on the gender difference in coronary artery calcification. When are type 1 diabetic patients at risk for cardiovascular disease? Curr Diab Rep 2010. Evaluation. Orchard TJ. Berman DS. Becker DJ.16:466e71. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection. 52. S109 53. Diabetes Care 2011. FACP.1016/j. to reduce CVD risk (11e22). A fast of >8 hours may be inappropriate for individuals with diabetes. Weight Management in Diabetes. FACP.032 .01. in the presence of even mild hyper-TG. most importantly. This proportion rose to 66% in those with diabetes for 15 years (10). FRCPC. Nutrition Therapy. Hegele MD. a fasting lipid profile (total cholesterol [TC].jcjd. A national cross-sectional chart audit study of 2473 Canadians with type 2 diabetes revealed that 55% of individuals with a diabetes diagnosis of 2 years’ duration also had dyslipidemia. which is generally achievable with statin monotherapy. use of alcohol in moderation and smoking cessation all are fundamental considerations to improve glycemic control. The most common lipid pattern in people with type 2 diabetes consists of hypertriglyceridemia (hyper-TG). Table 1 lists the components of dyslipidemia associated with diabetes (5. p. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. B. if the results are initially normal.  The primary treatment goal for people with diabetes is LDL-C 2. Therefore. low high-density lipoprotein cholesterol (HDL-C). FRCPC. Many of these abnormalities also are seen in patients with metabolic syndrome (7. LDL-C A number of studies and meta-analyses have shown that the degree of LDL-C lowering with statins and the beneficial effects of lowering LDL-C apply equally well to people with and without diabetes (23e34). published trials have demonstrated the benefits of statin therapy in both the primary and secondary prevention of vascular disease. p. FACP. may be used. and both glycation and oxidation are believed to increase the atherogenicity of LDL-C. 2. the overall lipid profile and. S153 and S163. more frequent testing is warranted.doi. For screening in children and adolescents.Can J Diabetes 37 (2013) S110eS116 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.canadianjournalofdiabetes. Lawrence A.com Clinical Practice Guidelines Dyslipidemia Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by G. TG and calculated LDL-C) should be conducted at the time of diagnosis of diabetes. S45. In fact. plant sterols. Both of these processes may impair function and/or enhance atherogenicity even in those with type 1 diabetes with a normal lipid profile.to 4-fold greater risk than that of individuals without diabetes). and. S100).org/10. inclusion of viscous fibres. Screening The burden of dyslipidemia is high in people with diabetes.  Achievement of the primary goal may require intensification of lifestyle changes and/or statin therapy and. p. S40. In addition.6). Achievement of ideal weight and aerobic activity level. on occasion. Robert A. Leiter MD. and efforts were made to ensure consistency between the guidelines. FAHA KEY MESSAGES  The beneficial effects of lowering low-density lipoprotein cholesterol (LDLC) with statin therapy apply equally well to people with diabetes as to those without the disease. nuts and soy proteins. is. John Mancini MD. the assessment should be repeated annually or as clinically indicated. FACC. HDL-C. compositionally well-balanced diet that is low in cholesterol. If treatment for dyslipidemia is initiated.2013. Lifestyle Modification Lifestyle interventions remain a key component of CVD prevention strategies and of diabetes management in general. chronic hyperglycemia promotes the glycation of LDL-C. Large. Each of these is discussed in more detail in accompanying chapters (Physical Activity and Diabetes. saturated and trans fatty acids and refined carbohydrates. S82). cardiovascular disease (CVD) is the primary cause of death among people with type 1 and type 2 diabetes (1e3).e. LDL-C particles are typically small and dense and may be more susceptible to oxidation. non-HDL cholesterol (TC minus HDL-C) or apolipoprotein B (apo B) measurements (see below). and subgroup analyses of these Dyslipidemia in Diabetes Diabetes is associated with a high risk of vascular disease (i. therefore. adoption of an energy-restricted. the addition of other lipidlowering medications. even in the nonfasting state. please refer to the chapters dedicated to diabetes in children and adolescents. Risk Assessment of Individuals with Diabetes A detailed overview of risk assessment deciding in whom to use statin therapy is provided in the Vascular Protection chapter (p. generally necessary in individuals with diabetes (4). Aggressive management of all CVD risk factors.0 mmol/L. Principles of risk assessment also are discussed in the 2012 Canadian Cardiovascular Society (CCS) Guidelines for the Management of Dyslipidemia (9). and relatively normal plasma concentrations of low-density lipoprotein cholesterol (LDL-C). p. Under these circumstances. including dyslipidemia.8). which are valid. FRCPC. especially if long-acting basal insulin is part of their treatment regimen. However. The mean baseline LDL-C of the study population was 3. repeated monitoring of the CVD risk status of patients with diabetes (as outlined in the Screening section above) is recommended. all CARDS subjects had at least 1 additional CVD risk factor (i. These study findings support the value of treating even so-called “normal” LDL-C levels in people with type 2 diabetes and no known vascular disease. apolipoprotein. Therefore. the CTT meta-analysis of >18 000 subjects with diabetes from 14 randomized statin trials found that the effects of statins on all fatal and nonfatal CV outcomes were similar for participants with or without diabetes (40). In the very small group of lower-risk individuals with type 2 diabetes. regardless of baseline LDL-C (39). however.e. microalbuminuria or macroalbuminuria. 3.0 mmol/L or 3.G. The results of the Heart Protection Study (HPS). However. The risk reduction was similar in the cohorts with and without diabetes.5 mmol/L (p¼0.5 mmol/L. This finding provides yet further evidence that people with diabetes and CAD are at extremely high risk of subsequent CVD events. statin therapy provides the same relative risk reduction in terms of outcomes. Results from the United States (US) Third National Health and Nutrition Examination Survey (NHANES III) indicate that 82% of people with diabetes and no clinically evident coronary artery disease (CAD) have at least 1 of the CARDS entry criteria risk factors (28).. HDL-C.6 mmol/L. this finding was not statistically significant and was generally considered to be related to the methodological limitations of the study design and the protocol changes. Notably. type 2) and glycated hemoglobin (A1C) (26). low-density lipoprotein.0001). The absolute risk. patients with diabetes (27). These results emphasized the benefits of statin treatment irrespective of the pre-existing serum LDL-C level. provide considerable insight into the importance of LDL-C lowering in the general population and.B. but the absolute benefit depends on the baseline level of absolute risk. The Cholesterol Treatment Trialists’ (CTT) Collaboration metaanalysis of >170 000 statin-treated subjects found that for every 1. high-density lipoprotein cholesterol. triglyceride.0 mmol/L and was associated with a reduced risk for CV events and stroke of 37% and 48%. The updated CTT metaanalysis of 170 000 subjects showed that additional reductions in . should drive the target levels” (28. In the overall study involving >20 000 subjects. Over the 4-year study period. in particular.0 mmol/L had 25% fewer major CVD events than did those treated with atorvastatin 10 mg daily who achieved a mean LDL-C of 2. those subjects treated with atorvastatin 80 mg daily who achieved a mean LDL-C of 2. or equivalent doses of other statins (average LDL-C reduction of approximately 30% to 40%). placebo on CVD prevention in 2410 people with type 2 diabetes (38). high-density lipoprotein. which compared simvastatin 40 mg daily to placebo. LDL. dense LDL Increased apo C-III Increased non-HDL-C Increased oxidized and glycated lipids S111 Apo. However.0 mmol/L). an increased event rate for all primary and secondary efficacy outcomes was noted in the diabetes subgroup compared to the overall study population. which is typically increased in people with diabetes. respectively. mean LDL-C was reduced by 29% in the atorvastatin group compared to placebo (p<0. As mentioned previously. The Atorvastatin Study for the Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) assessed the effect of atorvastatin 10 mg daily vs. The CARDS investigators concluded that the study findings “challenge the use of a particular threshold level of LDL-C as the sole arbiter of which individuals with type 2 diabetes should receive statin therapy. would be expected to provide comparable relative risk reductions to those seen with statin treatment initiated at higher baseline levels of LDL-C. prebeta-1 HDL. Indeed. sex. The proportional reductions were very similar in all subgroups. type of diabetes (type 1 vs. In fact. the protocol underwent several changes. TG. Across all subgroups.026) (30). Treatment resulted in a mean LDL-C of 2. A subanalysis of the AngloScandinavian Cardiac Outcomes TrialeLipid-Lowering Arm (ASCOT-LLA) revealed similar benefits of atorvastatin 10 mg vs. including 615 people with type 1 diabetes).28).6 mmol/L because of insufficient power. history of hypertension. but the absolute benefit from statin therapy is predicted to be smaller. Therefore. this analysis was not performed in the subgroup of people with diabetes who had baseline LDL-C values <2. and all subjects had at least 1 CVD risk factor in addition to diabetes. The Collaborative Atorvastatin Diabetes Study (CARDS) was the first completed statin trial to be conducted exclusively in people with type 2 diabetes without known vascular disease (28). including those with diabetes without pre-existing vascular disease (39). In the subgroup with diabetes (n¼5963. the global CVD risk of these individuals will increase with age and in the presence of additional CVD risk factors.0 mmol/L. the investigators questioned whether any individual with type 2 diabetes can be considered at sufficiently low risk for statin therapy to be withheld (28). treatment with 40 mg simvastatin daily resulted in a 27% reduction in cardiovascular (CV) events and a 25% reduction in stroke relative to treatment with placebo. Although originally designed as a secondary prevention trial. placebo in people with type 2 diabetes. vascular disease. alpha-3 HDL Increased apo B Increased LDL particle number Small.37). the relative reduction in CVD risk with statin therapy is likely to be similar to that seen in those at higher global risk for CVD. / Can J Diabetes 37 (2013) S110eS116 Table 1 Dyslipidemia components associated with type 2 diabetes and metabolic syndrome (5)            Increased TG and TG-rich lipoproteins Increased postprandial TG Low HDL-C Low apo AI Small HDL. The composite primary endpoint was reduced by 13. HPS did not demonstrate the effect of treating LDL-C to any particular preset target level. John Mancini et al.5 mmol/L and <3. including the addition of subjects without known CAD and the eventual conversion of all patients with known CAD to open-label.0 to 3. hypertension and at least 3 additional risk factors (36). Subgroup analyses from statin trials also have shown similar benefits of LDL-C lowering. retinopathy. and the treatment benefit was independent of baseline HDL-C and LDL-C levels (LDL-C <3. similar risk-ratio reductions were observed in subjects with baseline LDL-C >3. In a post hoc analysis of the entire study sample. However. lipid-lowering medication. regardless of baseline LDL-C (26. including stroke. treatment with a moderate dose of statin. HDL. CARDS demonstrated that treatment with atorvastatin 10 mg daily was safe and highly efficacious in reducing the risk of a first CV event. or current smoking). These analyses also have implications for patients with diabetes whose spontaneous LDL-C may already be below treatment goals.0 mmol/L reduction in LDL-C there was an approximate 20% reduction in CVD events. a profile that applies to an estimated 70% to 80% of people with type 2 diabetes (28. such as simvastatin 40 mg.7%.1 mmol/L. studies have shown similar benefits in subsets of participants with diabetes (23e25). determined by other risk factors in addition to LDL-C. In the subgroup with diabetes (n¼1051) of the Treating to New Targets (TNT) trial conducted in individuals with stable CAD. In this setting.35). the investigators found similar event reductions in individuals with baseline LDL-C values <2. statin use should be considered for any person with diabetes at risk of a vascular event. Intensive therapy with atorvastatin 80 mg daily also reduced the rate of all CVD and cerebrovascular events compared to atorvastatin 10 mg daily. small body frame and frailty. Therefore. To reduce the CVD morbidity and mortality associated with prediabetes and metabolic syndrome. Although niacin can cause deterioration of glycemic control (62). This form of dyslipidemia is considered more responsive to lifestyle modification (e. the potential benefit of additional lipid-lowering efforts with adjuvant pharmacotherapy has garnered tremendous interest. . an aggressive approach aimed at associated CVD risk factors. a mechanistic trial using carotid intima-medial thickness (CIMT) as a surrogate endpoint has been reported in adult native North American subjects with diabetes (42. Indeed. However. high-density lipoprotein cholesterol.0 to 2. given their increased CVD risk. some studies suggest that their vascular risk is almost as high as individuals with existing type 2 diabetes (47.55). these agents may be required to help achieve LDL-C targets. a TG level <1. highlight the importance of maintaining LDL-C lowering as the primary focus of treatment. small dense LDL particles and postprandial lipemia (32. alcohol abuse. such as low HDL-C. Subgroup and heterogeneity analysis revealed no difference in risk reduction between patients with or without diabetes using the statin/ezetimibe combination (44). perioperative periods. TG. which is characterized by elevated TG. Also. In this study. particularly with statins (54. reducing LDL-C to aggressive targets resulted in a similar regression of CIMT in patients who attained equivalent LDL-C reductions from a statin alone or a statin plus ezetimibe.g. y Listed in alphabetical order.0 mmol/L) with more intensive therapy further reduced the incidence of major vascular events and that these reductions could be achieved safely.S112 G. Tables 2A and 2B summarize considerations that should guide the choice of pharmacological agent(s) for the treatment of dyslipidemia. multisystem diseases (e. HDL-C. retinopathy and nephropathy). even in the face of an optimal LDL-C of 2. In the vast majority of people.46). To reduce the residual CVD risk despite statin therapy. the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial (cohort consisted exclusively of patients with diabetes) and the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial (34% of this study cohort had diabetes).5 mmol/L is considered optimal since. initial treatment should consist of intensifying lifestyle modification strategies and improving glycemic control through the use of glucose-lowering therapies as needed.B.61).g. however. No clinical trials of lipid-lowering agents have been conducted exclusively in people with IGT. niacin in either the immediate-release or extendedrelease formulation may be effective and is generally safe (62e65). Nonetheless.48). excessive grapefruit juice consumption. even in individuals with lower baseline LDL-C levels (41). it is reasonable to consider treating this population to the same targets as people with diabetes (49). there are fewer associated metabolic abnormalities. there is now evidence that this particular adverse effect may have been overemphasized (63. is warranted. hypothyroidism. Fenofibrate was used in ACCORD and niacin was used in AIM-HIGH. Specific TG targets are not provided in these guidelines because there are very few clinical trial data to support recommendations based on any specific plasma TG level. Although the linear relationship between the proportional CVD risk reduction and LDL-C lowering would suggest that there is no lower limit of LDL-C or specified LDL-C target (as the CTT authors suggest). if residual hyper-TG is high enough to impart a risk of pancreatitis. ON: Canadian Pharmacists Association) for product monographs and complete prescribing information. triglyceride. / Can J Diabetes 37 (2013) S110eS116 Table 2A First-line therapy to achieve a primary lipid target of LDL-C 2. neither niacin nor fibrates can be recommended as routine adjunctive therapy in patients already meeting LDL-C targets with statins since these agents appear to have no additional impact on macrovascular disease endpoints. however. The goal of both trials was to optimize the residual dyslipidemic profile of statin-treated patients with LDL-C at or near target levels through the use of agents known to lower TG and raise HDL. and it appears as if these beneficial effects are not solely due to the lipid changes induced by this drug class (51. despite initially and reversibly increasing plasma creatinine (51). Accordingly. including dyslipidemia.60. The results of 4 recent meta-analyses examining the effects of fibrate therapy on CV outcomes found that fibrates may be particularly beneficial in patients with atherogenic dyslipidemia. below this level.0 mmol/ L.0 mmol/L Statins* Generic namey Atorvastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Trade name Lipitor and generics Lescol Mevacor and generics Pravachol and generics Crestor and generics Zocor and generics Considerations Statins are drugs of choice to lower LDL-C and have modest TG-lowering and HDL-C raising effects at higher doses LDL-C (down to approximately 1.67e70). In some patients. recent evidence suggests that fibrate therapy may help reduce the microvascular complications associated with diabetes (i. However. such as fibrates (especially gemfibrozil) (refer to specific statin package inserts for others) (50). 2 recent studies. and specific concomitant medications.0 mmol/L is currently the most appropriate target for high-risk individuals. fibrates or niacin may be warranted. John Mancini et al. a bile acid sequestrant now approved in Canada. For example. such as age >80 years (especially women). the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found that long-term treatment with fenofibrate reduced albuminuria and slowed estimated glomerular filtration rate loss over 5 years. chronic renal insufficiency due to diabetes). For example. an increase in physical activity and weight reduction) and improvements in glycemic control than is an isolated LDL-C elevation. the clinical trial evidence summarized above would suggest that LDL-C 2. residual risk in treated patients. there are currently no completed clinical outcome trials using ezetimibe solely in patients with diabetes. If HDL-C is low and LDL-C is not at target. both of which are commonly seen in individuals with diabetes and often in individuals without diabetes. * Prevention of statin-induced myopathy requires attention to factors that increase risk. LDL-C. this target can be achieved with either a statin alone or a statin in combination with another lipid-lowering agent. The elevated TC/HDL-C ratio is considered to represent a source of lipid-derived. however. Furthermore. higher dose of statin. Note: Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa.43). Patients with diabetes and renal dysfunction or those requiring dialysis constituted 23% of the study population of the recently reported Study of Heart and Renal Protection (SHARP) trial. placebo. Lifestyle interventions aimed at reducing the risk of developing both type 2 diabetes and CAD are essential. Additional lipid markers of CVD risk The TC/HDL-C ratio is a sensitive and specific index of CVD risk (53) and is considered to be an important determinant of the need for lipid-lowering therapy.66). low-density lipoprotein cholesterol. People with impaired glucose tolerance (IGT) (particularly in the context of metabolic syndrome) are at significant risk for the development of CVD. small LDL particles and reduced HDL-C (56e59). The study showed that LDL-C reductions with simvastatin plus ezetimibe were associated with reductions in the incidence of major atherosclerotic events vs.e. An elevated TC/HDL-C ratio is usually associated with a low HDL-C and/or elevated TG. there is presently less support for the latter recommendation. multiple medications. Colesevelam. Both of these second-line adjunctive therapies failed to show any added clinical benefit compared to statin therapy alone. appears to have an ancillary effect on lowering A1C (45. each of which has an apo B [atherogenic triglyceride-rich elements. LDL-C.B. a fibrate is recommended for individuals with fasting TG levels >10. Because hyperTG is commonly seen in people with diabetes. as discussed above. nonprescription)  Long-acting (e. the measurement of apo AI is even less widely available than apo B. Apo AI is a surrogate marker of the number of HDL particles in the circulation. glycated hemoglobin. evidence has emerged to support the use of apo B in the management of patients with dyslipidemia (9. accounting for 50% of population-attributable events in an ethnically diverse population without diabetes (although its comparison to the TC/HDL-C ratio as a risk predictor was not reported in this study) (87). very low-density lipoprotein (VLDL) and intermediate-density lipoprotein (IDL) particle.G. / Can J Diabetes 37 (2013) S110eS116 Table 2B Other lipid-modifying medications Drug class* Generic name* (trade name) Bile acid sequestrants  Cholestyramine resin (Questran)  Colesevelam (Lodalis)  Colestipol HCl (Colestid) Cholesterol absorption inhibitor  Ezetimibe (Ezetrol) Principal effects  Lowers LDL-C Other considerations S113  GI intolerability. thus limiting the practical value of both this measurement and the apo B/apo AI ratio for clinical decision making. in order to reduce CVD risk among individuals with diabetes.76). Since non-HDL is available without further cost or separate assay. it would be reasonable to consider a statin as first-line therapy with the subsequent addition of a fibrate or niacin as needed. 0. however. To reduce the risk of pancreatitis and to do so rapidly. “no-flush”) niacin (generic. Further important information has emerged from CARDS with respect to alternative targets and therapeutic goals (28). Based on available evidence. remnant lipoproteins. As discussed above. which worsens with increasing doses  May elevate TG  Colesevelam has A1C-lowering effect  Lowers LDL-C  Less effective than statins as monotherapy  Effective when used in combination with a statin to further lower LDL-C (34)  May increase creatinine and homocysteine levels. TG-rich particles and the antiatherogenic role of HDL particles.708 g/L with an upper 95% confidence limit of 0. and it relates mainly to cholesterol contained in atherogenic particles. A non-HDL-C level of 2. While several studies have shown that fibrate therapy is associated with CVD prevention. presumably because they are so closely correlated.6 mmol/L is approximately equal to an apo B of 0. it is important to understand the atherogenicity of small. it is important to consider that there is one apo B molecule per LDL. nonprescription) not recommended  Lowers TG  Variable effect on LDL-C  Highly variable effect on HDL-C (more effective at raising HDL-C when baseline TG is high)  Raises HDL-C  Lowers TG  Lowers LDL-C A1C. gastrointestinal. lipoprotein (a) [Lp(a)]. The relationship between apo AI and HDL is more complicated than the 1:1 relationship of the number of apo B molecules and atherogenic particles because there may be 2 to 4 apo AI molecules per HDL particle.81). Mechanistically. John Mancini et al. but.37. Although there is general agreement that non-HDL and apo B are more predictive of CV risk than LDL-C.37).0 mmol/L who do not respond to other measures. all of which are atherogenic. the measurement of apo B and its monitoring in response to lipidlowering therapy have been advocated by some authors (9. the average apo B concentration in the subgroup with concomitant LDL-C 2 mmol/L was 0. TG.8 g/L (37). HDL-C. Apo B has repeatedly been shown to be a better risk marker for CVD events than LDL-C.e. no statistically significant reduction in the primary endpoint was demonstrated with fibrate therapy (76. there is much less evidence for CVD risk reduction with fibrates relative to statins. Although combination treatment with fenofibrate appears to be safe (54. In statin-treated patients. In an extensive analysis of both spontaneous and statin-induced changes in LDL-C.9 g/L (82) or. apo B was found to be a more consistent goal for statin treatment than LDL-C or nonHDL-C (37). Note: Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Ottawa. The calculated non-HDL cholesterol (TC minus HDL-C) has features similar to apo B: the calculation is valid in the nonfasting state. In summary.79) or bezafibrate plus a statin appears to be relatively safe if appropriate precautions are taken (Tables 2A and 2B). When there is no overriding concern for acute pancreatitis and when there is evidence of hyper-TG in association with an elevated apo B or high non-HDL-C. low-density lipoprotein cholesterol. Lipidil EZ. an optimal level of apo B can be considered to be at least w<0. and Lp(a)]. statins should not be used in combination with gemfibrozil due to an increased risk of myopathy and rhabdomyolysis (80). weight loss and restriction of refined carbohydrates and alcohol. y See Table 2A footnote for prevention of myopathy. Combination therapy with fenofibrate (78. knowledge of the apo B level may guide the aggressiveness with which lipid-lowering therapy is pursued (i. in Canada. the efficacy of these approaches in improving patient outcomes has not been established (54). apo B concentrations and non-HDL-C. ON: Canadian Pharmacists Association) for product monographs and complete prescribing information. GI. such as intensified glycemic control. The apo B/apo AI ratio has been proposed to be the best single predictor of CVD risk. and generics)  Gemfibrozil (Lopid) Nicotinic acid  Extended-release niacin (Niaspan. In some studies. more aggressive therapy in individuals with an elevated apo B level). specifically in people with diabetes (71e75). high-density lipoprotein cholesterol.8 g/L and may be considered alternate goals of therapy. Currently. such as VLDL and IDL. as supported by the CARDS study in subjects with diabetes. triglyceride. Consequently. It is also important to improve these metabolic parameters through lifestyle . * Listed in alphabetical order. however.77). A linear relationship between apo B and non-HDL exists over a broad range (83).720 g/L. Niaspan FCT)  Immediate-release niacin (generic. dense LDL particles. LDL-C. controversy exists regarding the superiority of either apo B or non-HDL. favourable effects on renal function have been noted with long-term fenofibrate treatment (51)  Do not use gemfibrozil in combination with a statin due to increased risk of myopathy and rhabdomyolysisy  Can cause dose-related deterioration of glycemic control  Extended-release niacin has similar efficacy and better tolerability than immediate-release niacin  Long-acting niacin should not be used due to increased hepatotoxicity and decreased efficacy (52) Fibrates  Bezafibrate (Bezalip SR and generic 200 mg)  Fenofibrate (micronized/microcoated/nano crystals) (Lipidil Supra.g. The measurement of apo B is most clinically useful in the individual with hyper-TG since it provides an indication of the total number of atherogenic lipoprotein particles in the circulation. it is attractive to consider it as supported by several analyses (84e86). Harris SB. Gaede P. Roglic G. 5. S45 Weight Management in Diabetes. non-HDL-C calculation) should be measured at the time of diagnosis of diabetes. Consensus) while also optimizing glycemic control and implementing lifestyle interventions (e. Wing RR.6:401e11. Sacks FM. triglyceride. p. optimal dietary strategies. Can J Cardiol 2013. HDL-C. Haddad E. the use of second-line LDLCelowering therapies (Table 2A) can be considered.132:605e11. Accordingly.127. Ekoé JM. CV.27:e1e33. Alberti KGMM. apolipoprotein B. 4.0 mmol/L. recent evidence has suggested that chronic statin use is associated with an increased risk of incident diabetes. 3. Glycemic control and morbidity in the Canadian primary care setting (results of the diabetes in Canada evaluation study). S153 Type 2 Diabetes in Children and Adolescents. 2012 update of the Canadian Cardiovascular Society Guidelines for the diagnosis and treatment of dyslipidemia for the prevention of cardiovascular disease in the adult. Vedel P. Consensus]. Am J Clin Nutr 1992. The impact of diabetes mellitus on mortality from all causes and coronary heart disease in women: 20 years of follow-up. et al. Gibbons LW. et al. these recent analyses do not affect the recommendation that statins are the preferred agents for lowering LDL-C in most instances. when indicated. et al. S163 References 1. Am J Clin Nutr 2006. Prediabetes and Metabolic Syndrome. et al. Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials. 12.55)]. p.28:2130e5. et al. including ezetimibe. including in patients with established diabetes or in those with risk factors for developing the disease. The obesity. p. In contrast.34:1481e6. Kendall CW. S117 Management of Acute Coronary Syndromes. Curr Atheroscler Rep 2004.4:113e9. et al. Cardiometabolic risk in Canada: a detailed analysis and position paper by the Cardiometabolic Risk Working Group. perhaps. Bennett PH. Solomon CG. a fibrate should be used to reduce the risk of pancreatitis (Grade D. Arch Intern Med 2001. high-density lipoprotein cholesterol. Diabetes Care 2005. reduction of alcohol). Jenkins DJ. Hermans MP. Circulation 2009. Statin Therapy and Incident Diabetes Although statins are the cornerstone of lipid-altering therapy for CVD risk reduction in people with or without diabetes. et al. Weight loss in the management of type 2 diabetes. Insulin-dependent diabetes mellitus. 9. LaPorte RE. For patients with indications for lipid-lowering therapy (see Vascular Protection chapter. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. improvements in glycemic control and.56:320e8. Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes. Moy CS.48). Wadden TA. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. et al.348:383e93. Eckel R. LDL-C. 7. 3. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. low-density lipoprotein cholesterol. Haynes RB. et al. S40 Nutrition Therapy. Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) showed an increase in incident diabetes (89). 4. MacCallum PR. / Can J Diabetes 37 (2013) S110eS116 modifications. 8. Laupacis A. Abbreviations: apo B. S126 Type 1 Diabetes in Children and Adolescents. J Cardiometab Syndr 2009. Zdanowicz Y. For individuals not at LDL-C target despite statin therapy as described above. Stampfer MJ. even these patients with risk factors for the development of diabetes enjoy a marked benefit in CVD risk reduction through the LDL-Celowering effects of statins. 2. p. such as those who are obese and/or who manifest metabolic syndrome. Level 1 (26. it is of paramount importance to realize that the current best outcome evidence for minimizing the atherogenic impact of lipid abnormalities in patients with diabetes is to remain focused on achieving very low plasma concentrations of LDL-C. Wei M. Ginsberg HN. Leiter LA. S82 Vascular Protection in People with Diabetes. Kendall CW. Booth GL. Level 3 (40)]. p. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. . Boulé NG. In: Hux JE. 18. Hegele RA.120:1640e5. 2001. p. Kampert JB. which actually showed a decrease in the incidence of new-onset diabetes with statin therapy (88). HDL-C. Diabetes and cardiac disease. 5. Dattilo AM.B. et al.95e5. increased cardiovascular disease risk and the importance of atherogenic dyslipidemia in persons with the metabolic syndrome and type 2 diabetes mellitus. In: Gerstein HC. S8 Physical Activity and Diabetes.286:1218e27. Booth G. p. 44(suppl 2):S14e21. p. Evidence-based Diabetes Care. 6. Jenkins DJ. p. Morrish NJ. Grundy S. Level 1 (54. 2002. it may be of relevance to patients who are at risk for developing diabetes irrespective of statin treatment. p. et al. Grégoire J. treatment should be initiated with a statin [Grade A. physical activity. metabolic syndrome. The interplay between statin therapy and incident diabetes was highlighted in a prespecified analysis of the West of Scotland Coronary Prevention Study (WOSCOPS). pharmacotherapy. et al. Anderson TJ. Pathophysiology of diabetic dyslipidemia: implications for atherogenesis and treatment. 13. However. S100. 20. S105 Treatment of Hypertension. Fitchett DH. 15. S100 Screening for the Presence of Coronary Artery Disease. p. and death. editors. Several meta-analyses suggest that there is indeed a small overall increase in diabetes with chronic statin use (90. Classification and Diagnosis of Diabetes. S100). typically with statin-centred therapy. and type 2 diabetes mellitus pandemic: part I. Diabetologia 2001.g. AHEAD Research Group. as this conclusion is based on the most extensive clinical trial evidence. et al. 2.28). 5. For patients who are not at goal. Stevens LK. a combination of statin therapy with second-line agents may be used to achieve the LDL-C goal [Grade D. RECOMMENDATIONS 1. TG. TC. bile acid sequestrants or niacin. 10. Can J Cardiol 2011. Rothwell D. John Mancini et al. Hu FB. Ann Intern Med 2000. Despite academic interest in various lipid parameters. Faulkner DA.. total cholesterol. N Engl J Med 2003.137:74e81. et al. Fung K. 16. Songer TJ. p. 14.6:492e8. Diabetes Vasc Dis Res 2008. Diabetes in Ontario: An ICES Practice Atlas: Institute for Clinical Evaluative Sciences. Larsen N. and calculated LDL-C) or nonfasting lipid profile (apo B. as discussed earlier. S119 Treatment of Diabetes in People with Heart Failure.29:151e67. Diabetes Care 2011. Clin Lipidol 2011. The burden of mortality attributable to diabetes: realistic estimates for the year 2000. Wang SL. p. weight loss. 19. Parhofer KG.161:1717e23. Lang W. Fruchart J-C. Diabetes Res Clin Pract 2005. If lipid-lowering treatment is not initiated.83:582e91. cardiovascular. ON: BC Decker Inc. TG. Assessment of the longer-term effects of a dietary portfolio of cholesterol-lowering foods in hypercholesterolemia. despite maximally tolerated stain therapy or in the case of statin intolerance. Unwin N. Kenny GP. p. 11. JAMA 2001. Consensus]. Gilbert RE. for indications) repeat testing is recommended yearly. Am J Epidemiol 1993. p.91) and that this risk may be related to the statin dose (92). Kris-Etherton PM.0 mmol/L [Grade C. Hamilton. A dietary portfolio: maximal reduction of low-density lipoprotein cholesterol with diet. Other Relevant Guidelines Definition. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in dyslipidemic patients. which appears to far outweigh any small risk of new-onset diabetes (47. Harmonizing the metabolic syndrome.S114 G.5:319e32. 252e76. For those who have serum TG >10. Although this finding is of little relevance to patients with established diabetes. et al. to achieve LDL-C 2. 17. Wing RR. A fasting (8-hour fast) lipid profile (TC. In patients achieving goal LDL-C with statin therapy. 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MD.com Clinical Practice Guidelines Treatment of Hypertension Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Richard E. evidence-based target for systolic blood pressure (SBP). patients with autonomic neuropathy). diabetes also is associated with an increase in the ageadjusted cardiovascular death rate. ARB. Consensus]. Little. FRCPC. FRCPC. Pierre LaRochelle MD. a prespecified outcome. Charlotte Jones PhD. Level 1A (15)]. Not only are patients with diabetes more likely to have coexistent hypertension. For persons in whom combination therapy with an ACE inhibitor is being considered. Level 1A (12)]. including microalbuminuria. obesity. Doreen Rabi MD. FRCPC. angiotensin-converting enzyme. However.g. been precipitated by the findings of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. 2.1016/j. FRCPC KEY MESSAGES  People with diabetes should be treated to achieve a blood pressure (BP) <130/80 mm Hg. premature arterial stiffening and endothelial dysfunction (1). FRCPC. involving interactions between genetic predisposition and a range of environmental factors that include sodium retention.Can J Diabetes 37 (2013) S117eS118 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. calcium channel blocker. multicentre clinical trials have shown that antihypertensive therapy is highly effective at reducing death and disability in people with diabetes (1). Vincent Woo MD. FRCPC. stroke. FRCPC.org/10. 3. FACP. or with cardiovascular risk factors in addition to diabetes and hypertension.4): 1.jcjd.01.2013. FRCPC. Together. to a large extent. a dihydropyridine CCB is preferable to hydrochlorothiazide [Grade A. if any. such as hypotension and hyperkalemia. Leiter MD. Most recently. which continue to recommend blood pressure targets of <130/80 mm Hg in hypertensive patients with diabetes (5). Its pathogenesis is complex. Luc Poirier BPharm MSc.7)] and DBP <80 mm Hg [Grade B. much discussion has focused on selecting an appropriate. these findings provide the rationale for the current Canadian Hypertension Education Program (CHEP) and the Canadian Diabetes Association harmonized clinical practice recommendations. Lowering SBP is associated with an increased risk of adverse events. 2. and cardiovascular death) was not significantly different between the 2 groups. MSc. Introduction Hypertension affects the vast majority of individuals with type 2 diabetes and many of those with type 1 diabetes also. an ACE inhibitor or an ARB is recommended as initial therapy [Grade A. Additional reduction in stroke can be achieved by lowering SBP to <120 mm Hg. Richard Ogilvie MD. FACP. CCB. systolic blood pressure. Lawrence A. Level 1A (15)]. several. These clinical trials also have provided some guidance in the choice of antihypertensive therapy. PhD. While the primary outcome (a composite of myocardial infarction. dihydropyridine CCBs [Grade A. appropriate choices include (in alphabetical order): ACE inhibitors [Grade A. However. which similarly show that (3. BP. Combination therapy using 2 first-line agents may also be considered as initial treatment of hypertension [Grade C. Level 1A (16)]. .10)] if SBP is 20 mm Hg above target or if DBP is 10 mm Hg above target. Abbreviations: ACE. stroke. but. 4. The findings of ACCORD are further supported by 2 meta-analyses. which compared the effects of targeting SBP <140 mm Hg with that <120 mm Hg (2). for any given systolic pressure. Level 1A (15)]. Sheldon Tobe MD. PhD. caution should be exercised in patients in whom a substantial fall in BP is more likely or poorly tolerated (e. additional reduction in cardiac events is achieved by lowering SBP to <140 mm Hg. For persons with diabetes and hypertension not included in the above recommendation. Persons with diabetes mellitus should be treated to attain SBP <130 mm Hg [Grade C. SBP. RECOMMENDATIONS 1. Level 1 (8)].canadianjournalofdiabetes. MSc. the majority of these are associated with SBP <120 mm Hg. (These target BP levels are the same as the BP treatment thresholds). Level 1A (11e14)]. additional antihypertensive therapy should be used [Grade D. These discussions have. large-scale. Gilbert MBBS. diastolic blood pressure. If target BP levels are not achieved with standard dose monotherapy.doi. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. elderly patients. For persons with cardiovascular or kidney disease. particularly among those with nephropathy or at high cardiovascular risk. was reduced by 41% in the group targeted to achieve the <120 mm Hg systolic target. Fortunately. ARBs [Grade A. Level 3 (6. DBP. and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Angeli F. Effects of aggressive blood pressure control in normotensive type 2 diabetic patients on albuminuria. 12. Cushman WC. Can Fam Physician 2011.S118 R. Adler AI.56: 77e85.E.29:1253e69. Clarke WR. Whelton PK. / Can J Diabetes 37 (2013) S117eS118 9. Neil HA. impaired fasting glucose concentration. Stratton IM. References 1. The losartan renal protection study: rationale. Weber MA. et al. et al. 11. Gilbert RE. de Zeeuw D. Lancet 2002. retinopathy and strokes.57: 997e1002. Leiter LA. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73. Messerli FH. et al. Khan NA. 2. 8.317:703e13. Can J Cardiol 2012.345:851e60.913 patients. Esler A. diagnosis. Effects of an angiotensin-converting enzyme inhibitor. Daskalopoulou SS. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. 14. and therapy. Zanchetti A. Lewis EJ. et al. assessment of risk.4:393e404. 7. Jamerson K.321:412e9. 16.342:145e53. et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. 351:1755e62. Cooper ME. on cardiovascular events in high-risk patients. Gilbert et al. N Engl J Med 2000.28:270e87. Arch Intern Med 2005. Cushman WC. N Engl J Med 2010. Reboldi G. N Eng J Med 2001. J Renin Angiotensin Aldosterone Syst 2000. Evans GW. study design and baseline characteristics of RENAAL (Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan). Carruthers SG. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Dahlof B. 359:1004e10. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lobach I. Campbell NR. et al. Lancet 1998. ramipril.362:1575e85. J Am Coll Cardiol 2010. J Clin Hypertens 2002. Clinical Outcomes in antihypertensive treatment of type 2 diabetes. Cardiovascular events during differing hypertension therapies in patients with diabetes. Brenner BM. 4. Cutler JA. The Heart Outcomes Prevention Evaluation Study Investigators.1:328e35. Lindholm L. Cushman WC. BMJ 1998. Hansson L. 5.61:1086e97. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. 6. . Ford CE. et al. 3. Success and predictors of blood pressure control in diverse north American settings: the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT). Gentile G. Bakris GL.165:1401e9. J Hypertens 2011. Barzilay J. Ibsen J. Hypertension in people with type 2 diabetes: update on pharmacologic management. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. et al. Byington RP. Hunsicker LG. Schrier RW. Quinn RR. 13. et al. et al.123:2799e810. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials. The 2012 Canadian hypertension education program recommendations for the management of hypertension: blood pressure measurement. UK Prospective Diabetes Study Group. Estacio RO. et al. 10. 15. Kumar S. Mehler P. Circulation 2011. Kidney Int 2002. et al. BMJ 2000. Bangalore S. L’Allier MD. the prevalence of diabetes in this population has 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx.Can J Diabetes 37 (2013) S119eS123 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.0 and 10. More than two-thirds of patients with MI have either diabetes or impaired glucose regulation (impaired glucose tolerance and impaired fasting glucose) (15). In most situations. A1C has been validated in an acute care population (19). which may contribute to adverse outcomes in the patient with diabetes (14). It is accepted that some patients with diabetes will be missed by screening with fasting blood glucose and A1C compared to the universal use of an OGTT. thrombolysis. Occurrence of acute coronary events 15 years earlier (4).8).  Patients with an AMI and hyperglycemia should receive insulin-glucose infusion therapy to maintain blood glucose between 7. Glycated hemoglobin (A1C) at or above 6. An increased incidence of post-infarction recurrent ischemic events. 4. FACC. Management of ACS in the Patient with Diabetes Guidelines for the management of patients with ACS have been developed by the American College of Cardiology (ACC)/American Heart Association (AHA) (21e23) and the European Society of Cardiology (24. David H. steadily increased from 18% in 1997 to 30% in 2006 (2).) 6.9).5% is currently a diagnostic criterion for diabetes as it captures long-term glucose exposure. FCAHS. the use of dual antiplatelet therapy with acetylsalicylic acid (ASA) and clopidogrel (29). Less utilization of guideline recommended care (10e13). 3. FRCPC KEY MESSAGES  Diabetes is an independent predictor of increased short.17). Using the OGTT as a gold standard for the diagnosis of diabetes and an A1C threshold of 6. it is likely that the patients most in need of glycemic control will be detected with these simple tests. beta blockers or acetylsalicylic acid than people without diabetes. patients with diabetes have: 1. However. FRCPC. Phillipe L.jcjd.4% should have an OGTT 6 to 8 weeks after discharge (20).doi.2013.0% to 6.canadianjournalofdiabetes.com Clinical Practice Guidelines Management of Acute Coronary Syndromes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Jean-Claude Tardif MD.6) and long-term mortality (5.1016/j.7. 5. A 3-fold increased risk of ACS (4). It has been suggested that individuals with A1C of 6. which can be widely applied.25).0%. However. diabetes is underdiagnosed in 39% compared to when the diagnosis is made from an oral glucose tolerance test (OGTT) (18).0 mmol/L for at least 24 hours. there are no clinical trials that specifically address management of the patient with diabetes and ACS. A 2-fold increased short. heart failure and cardiogenic shock (3. Incidence and Prognosis Diabetes (together with lipid abnormalities. The frequency of previously unrecognized diabetes in the ACS population is reported to be between 4% and 22% depending on the test used for the diagnosis of diabetes (3. such as revascularization. smoking and hypertension) is 1 of the top 4 independent risk factors for myocardial infarction (MI) (1). followed by strategies to achieve recommended glucose targets long term.  People with diabetes are less likely to receive recommended treatment. and as many as another 15% have undiagnosed diabetes (3). A significant care gap exists for patients with diabetes not receiving guideline-recommended treatment compared to patients Identification of Diabetes in Patients with ACS Although the absolute number of patients with MI has fallen in the United States. A similar benefit from guideline recommended management strategies (see below. approximately 15% to 35% of patients admitted with an acute coronary syndrome (ACS) have known diabetes (2).org/10. and b) an early invasive strategy (28).(5. Today. 2.01. Compared to individuals without diabetes. recurrent myocardial infarction (MI) and the development of heart failure in patients with acute MI (AMI). Efforts should be directed at promoting adherence to existing proven therapies in the high-risk patient with MI and diabetes. A1C had a sensitivity of 77% and a specificity of 87%. does not require fasting or timed samples and is currently used to guide management decisions. Abnormal glucose regulation is almost twice as prevalent in patients with MI compared to a matched control population and is a marker for adverse outcomes (16). subgroup analyses in patients with diabetes and ACS show either a similar or an enhanced benefit from treatment compared to the overall group for a) reperfusion with fibrinolysis (26) or primary angioplasty (27) for ST-segment elevation ACS. and glycoprotein (GP) IIb/IIIa inhibitors in patients with noneSTsegment elevation ACS (NSTE ACS) at high risk of recurrent ischemic events (30). Fitchett MD. If fasting glucose criteria is used alone in the ACS population.and long-term mortality.034 . S120 J.D Tardif et al. / Can J Diabetes 37 (2013) S119eS123 without diabetes (12e14,31). It is possible that underutilization of recommended treatment is 1 factor contributing to the adverse outcome of the ACS patient with diabetes. Antiplatelet Therapy Platelet aggregation plays a central role in the development of the occlusive thrombus responsible for acute coronary occlusion in patients with ACS. Patients with diabetes have a prothrombotic state due to dysfunctional and hyperactive platelets, endothelial dysfunction, elevated coagulation factors and decreased fibrinolysis (32). Increased platelet activity is due to multiple metabolic and cellular factors associated with diabetes that include endothelial dysfunction, the impact of hyperglycemia and deficient insulin action (32). Diabetes is associated with an increased incidence of recurrent atherothrombotic events (8), including stent thrombosis (33). Antiplatelet therapy has been shown to reduce atherothrombotic events in patients with ACS, both during the acute phase and in the longer term. The beneficial effect of ASA has been shown in multiple clinical trials in patients with NSTE ACS and ST-elevation MI (STEMI). The Antithrombotic Trialists’ Collaboration metaanalysis of antiplatelet therapy (mainly ASA) included 212 000 high-risk patients (with acute or previous vascular disease) and showed the incidence of vascular events to be reduced in both the overall population (16.8% to 12.8%; p<0.00001) and in patients with diabetes (22.3% to 18.5%; p<0.002) (34). Low-dose ASA (75 to 150 mg) was as effective as higher doses (>150 mg) with a lower incidence of bleeding complications. The CURRENT/OASIS 7 trial also was unable to show any benefit from higher-dose compared to low-dose (75 to 100 mg) ASA in patients with and without diabetes (35). The use of low-dose ASA is recommended to minimize gastrointestinal bleeding in patients with and without diabetes. Dual antiplatelet therapy with ASA and clopidogrel, administered from the time of presentation, has been the recommended standard of care for patients with NSTE ACS. Patients with diabetes in the CURE trial had a similar benefit with clopidogrel vs. placebo (14.2% vs. 17.7%, relative risk [RR] 0.84, 95% confidence interval [CI] 0.70e1.02) as the overall population (9.3% vs. 11.4%, RR 0.80, 95% CI 0.72e0.90) (29). Despite dual antiplatelet therapy with ASA and clopidogrel, recurrent atherothrombotic events continue to occur, especially in patient with diabetes. Clopidogrel is a relatively weak inhibitor of platelet aggregation with a wide variation of inhibition of in vitro platelet aggregation. There is a higher incidence of events in patients with residual platelet activity, and patients with diabetes have higher residual platelet activity despite ASA and clopidogrel treatment. Two new antiplatelet agents, prasugrel and ticagrelor, which are more effective and predictable inhibitors of platelet aggregation, have recently become available in Canada. In the TRITON study, prasugrel administered at the time of coronary angioplasty in patients with ACS reduced recurrent ischemic events, including stent thrombosis, compared to patients receiving clopidogrel (36). In subjects with diabetes, prasugrel treatment was associated with greater platelet inhibition and fewer poor responders (37). Prasugrel resulted in an important net clinical benefit in patients with diabetes (14.6% vs. 19.2%, hazard ratio [HR] 0.74; p¼0.001) due to a 30% reduction of the primary endpoint (cardiovascular [CV] death, nonfatal MI, or stroke) over the 14.4 months of the study (38). In this subgroup with diabetes, there was no significant increase in major bleeding. There was no statistical interaction between the subgroups with and without diabetes, indicating that the enhanced absolute benefit was the result of higher event rates in patients with diabetes. In the Platelet Inhibition and Patient Outcomes (PLATO) study, the P2Y12 receptor antagonist, ticagrelor, when compared with clopidogrel and administered early after presentation in patients with NSTE ACS or STEMI, reduced CV death, nonfatal MI and stroke (10.2% vs. 12.3%, HR 0.84; p¼0.0001), as well as CV death (4.0% vs. 5.1%, HR 0.49; p¼0.001) and stent thrombosis (2.2% vs. 2.9%, HR 0.75; p¼0.02), with a modest increase in bleeding in patients not undergoing coronary bypass surgery (39). In the diabetic cohort of the PLATO study, similar benefits were observed as in the overall group (40). The availability of more potent and reliable antiplatelet agents for the management of patients with ACS provides an opportunity to further reduce recurrent ACS and mortality. High-risk patients with diabetes with either STEMI or NSTE ACS should be considered for treatment with either prasugrel (after the coronary disease anatomy has been defined) or ticagrelor. Platelet aggregation is largely mediated by the GPIIb/IIIa receptor through its binding to fibrinogen. The GPIIb/IIIa receptor inhibitors abciximab, eptifibatide and tirofiban were shown to be effective for the management of ACS in patients with diabetes in a meta-analysis of 6 clinical trials. GPIIb/IIIa inhibitors were shown to reduce 30-day mortality by 26% (4.6% vs. 2.6%; p¼0.007) (30). In contrast, patients without diabetes had no mortality benefit. Although these trials were performed in an era before dual antiplatelet therapy with ASA and clopidogrel was used, recent studies indicate an additional benefit from a GPIIb/IIIa inhibitor for patients with high risk ACS, such as those with diabetes who are undergoing percutaneous coronary intervention (PCI) (41,42). Glycemic Control Hyperglycemia during the first 24 to 48 hours after admission for ACS is associated with increased early mortality, whether or not the patient has diabetes (43,44). Furthermore, in-hospital mortality has a closer relationship to hyperglycemia than to diabetic status (45,46). Higher baseline glucose and a failure of glucose to decrease are independent predictors of mortality (47). For patients undergoing primary angioplasty, mortality increases when the plasma glucose is >10.0 mmol/L (48). Although elevated mean blood glucose level in the first 24 hours after onset of ACS is associated with adverse outcomes (46), evidence to support reducing blood glucose levels (especially to levels close to the normal range) after ACS remains inconclusive. The Diabetes Mellitus Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) study indicated that tight glycemic control with the use of intravenous insulin in the early hours after presentation, followed by multidose subcutaneous insulin treatment over the subsequent months, resulted in a 30% reduction in 1-year mortality (49e53). The DIGAMI 2 study failed to achieve the study goals, both in the number of patients recruited and in glycemic targets (54). However, despite these limitations, it did demonstrate that outcomes were closely related to glycemic control, however achieved. Studies have shown that glucoseinsulin-potassium infusion in patients with AMI do not improve outcomes (55,56). However, these protocols often resulted in increased blood glucose levels and, therefore, cannot be used as evidence for outcomes associated with glycemic control. In the Hyperglycemia: Intensive Insulin Infusion in Infarction (HI-5) study of glucose and insulin in patients with AMI, patients with a blood glucose maintained at <8.0 mmol/L had lower mortality than did subjects with higher levels (57). The AHA Diabetes Committee of the Council on Nutrition, Physical Activity, and Metabolism issued a scientific statement in 2008 on hyperglycemia and ACS (58). They recommended blood glucose targets of 5.0 to 7.7 mmol/L in the intensive care unit (ICU) setting or <10.0 mmol/L in the non-ICU setting during hospitalization for ACS. More recent ACC/AHA guidelines for the management of patients with STEMI concluded that it was prudent to J.D Tardif et al. / Can J Diabetes 37 (2013) S119eS123 S121 change the recommendation for the use of insulin to control blood glucose in STEMI from a Class I to a Class II recommendation (Level of Evidence: B) and recommended treatment for hyperglycemia >10.0 mmol/L while avoiding hypoglycemia (59). The Canadian Diabetes Association recommends glucose targets of 8.0 to 10.0 mmol/L in the critically ill and premeal glucose of 5.0 to 8.0 mmol/L and random glucose levels <10.0 mmol/L (See Inhospital Management of Diabetes chapter, page S77). Post-ACS long-term glycemic control trials using agents from newer drug classes, such as dual peroxisome proliferator-activated receptor agonist, glucagon-like peptide-1 (GLP-1) receptor agonists, and acarbose, are currently under way (e.g. A Study of Aleglitazar in Patients With Type 2 Diabetes [ALECARDIO], Evaluation of Cardiovascular Outcomes in Patients With Type 2 Diabetes After Acute Coronary Syndrome During Treatment With AVE0010 [Lixisenatide] [ELIXA], Acarbose Cardiovascular Evaluation Trial). Until results from dedicated post-ACS studies become available, results from 5 large-scale clinical trials of stable patients with type 2 diabetes, and either known or at high risk of CAD, are helpful (60e64). A recent meta-analysis of these trials suggested a 17% relative reduction in nonfatal MI (10.0 vs. 12.3 per 1000 personyears) in subjects included in the intensive glucose control group (target A1C 6.0% to 6.5%; median A1C during follow-up 6.6%), yet there was no reduction of all-cause mortality (65,66). The same meta-analysis indicated the possibility that a greater benefit could be derived from treating patients with recently diagnosed diabetes more intensively. Revascularization ACS practice guidelines promote the same treatment strategies in patients with diabetes as for those without diabetes (67). An early invasive strategy with revascularization when possible in NSTE ACS provides a similar or greater reduction in death and MI (up to 5 years of follow-up) in the subset of patients with diabetes compared to the overall population (28,68,69). The 2011 ACC AHA non-STE ACS guidelines recommend that NSTE ACS should be considered for an early invasive, rather than a selective invasive (conservative), strategy. In patients with diabetes and NSTE ACS and multivessel disease, CABG with the use of internal mammary artery may provide benefit over PCI when revascularization is indicated (70). However, PCI (with drug-eluting stents whenever possible) is acceptable for patients with less extensive disease (i.e. single-vessel disease) (59). For patients with ST-elevation ACS, immediate reperfusion strategies with either fibrinolysis or primary PCI result in similar benefits for patients with and without diabetes. The benefits of primary PCI over fibrinolysis in patients with diabetes are similar to those without diabetes (mortality with primary PCI vs. fibrinolysis in patients with diabetes, odds ratio (OR) 0.49, 95% CI 0.31e0.79) (27). However, fibrinolysis should be administered when primary PCI is not available within acceptable timeframes. Ocular hemorrhage in patients with diabetic retinopathy is extremely rare and should not limit the use of fibrinolysis when it is indicated (71). References 1. Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004;364:937e52. 2. Ovbiagele B, Markovic D, Fonarow GC. Recent US patterns and predictors of prevalent diabetes among acute myocardial infarction patients. Cardiol Res Pract; 2011:145615. 3. Aguilar D, Solomon SD, Kober L, et al. Newly diagnosed and previously known diabetes mellitus and 1-year outcomes of acute myocardial infarction: the VALsartan In Acute myocardial iNfarcTion (VALIANT) trial. Circulation 2004; 110:1572e8. 4. Booth GL, Kapral MK, Fung K, Tu JV. Relation between age and cardiovascular disease in men and women with diabetes compared with non-diabetic people: a population-based retrospective cohort study. Lancet 2006;368:29e36. 5. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765e75. 6. Behar S, Boyko V, Reicher-Reiss H, Goldbourt U. Ten-year survival after acute myocardial infarction: comparison of patients with and without diabetes. SPRINT Study Group. Secondary Prevention Reinfarction Israeli Nifedipine Trial. Am Heart J 1997;133:290e6. 7. Kumler T, Gislason GH, Kober L, Torp-Pedersen C. Diabetes is an independent predictor of survival 17 years after myocardial infarction: follow-up of the TRACE registry. Cardiovasc Diabetol 2010;9:22. 8. Malmberg K, Yusuf S, Gerstein HC, et al. Impact of diabetes on long-term prognosis in patients with unstable angina and non-Q-wave myocardial infarction: results of the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry. Circulation 2000;102:1014e9. 9. Kannel WB, Thomas Jr HE. Sudden coronary death: the Framingham Study. Ann N Y Acad Sci 1982;382:3e21. 10. Hasin T, Hochadel M, Gitt AK, et al. Comparison of treatment and outcome of acute coronary syndrome in patients with versus patients without diabetes mellitus. Am J Cardiol 2009;103:772e8. 11. Hung J, Brieger DB, Amerena JV, et al. Treatment disparities and effect on late mortality in patients with diabetes presenting with acute myocardial infarction: observations from the ACACIA registry. Med J Aust 2009;191:539e43. 12. Norhammar A, Lindback J, Ryden L, et al, Register of Information and Knowledge about Swedish Heart Intensive Care Admission (RIKS-HIA). Improved but still high short- and long-term mortality rates after myocardial infarction in patients with diabetes mellitus: a time-trend report from the Swedish Register of Information and Knowledge about Swedish Heart Intensive Care Admission. Heart 2007;93:1577e83. 13. Brogan Jr GX, Peterson ED, Mulgund J, et al. Treatment disparities in the care of patients with and without diabetes presenting with non-ST-segment elevation acute coronary syndromes. Diabetes Care 2006;29:9e14. RECOMMENDATIONS 1. Patients with ACS should be screened for diabetes with a fasting blood glucose, A1C or 75 g OGTT prior to discharge from hospital [Grade D, Consensus]. 2. All patients with diabetes and ACS should receive the same treatments that are recommended for patients with ACS without diabetes since they benefit equally [Grade D, Consensus]. 3. Patients with diabetes and ACS undergoing PCI should receive antiplatelet therapy with prasugrel (if clopidogrel naïve, <75 years of age, weight >65 kg, and no history of stroke) [Grade A, Level 1 (36,38)] or ticagrelor [Grade B, Level 1 (39,40)], rather than clopidogrel, to further reduce recurrent ischemic events. Patients with diabetes and non-STE ACS and higher-risk features destined for a selective invasive strategy should receive ticagrelor rather than clopidogrel [Grade B, Level 2 (39,40)]. 4. Patients with diabetes and non-STE ACS and high-risk features should receive an early invasive strategy rather than a selective invasive approach to revascularization to reduce recurrent coronary events, unless contraindicated [Grade B, Level 2 (28)]. 5. In patients with diabetes and STE ACS, the presence of retinopathy should not be a contraindication to fibrinolysis [Grade B, Level 2 (71)]. 6. In-hospital management of diabetes in ACS should include strategies to avoid both hyperglycemia and hypoglycemia:  Blood glucose should be measured on admission and monitored throughout the hospitalization [Grade D, Consensus]  Patients with acute MI and blood glucose >11.0 mmol/L on admission may receive glycemic control in the range of 7.0 to 10.0 mmol/L, followed by strategies to achieve recommended glucose targets long term [Grade C, Level 2 (52,54)]. Insulin therapy may be required to achieve these targets [Grade D, Consensus]. A similar approach may be taken in those with diabetes and admission blood glucose 11.0 mmol/L [Grade D, Consensus] (see In-hospital chapter, p. S77).  An appropriate protocol should be developed and staff trained to ensure the safe and effective implementation of this therapy and to minimize the likelihood of hypoglycemia [Grade D, Consensus]. 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Abnormal glucose tolerance: a common risk factor in patients with acute myocardial infarction in comparison with population-based controls. J Intern Med 2004;256:288e97. 17. Mozaffarian D, Marfisi R, Levantesi G, et al. Incidence of new-onset diabetes and impaired fasting glucose in patients with recent myocardial infarction and the effect of clinical and lifestyle risk factors. Lancet 2007;370:667e75. 18. Bartnik M, Ryden L, Malmberg K, et al. Oral glucose tolerance test is needed for appropriate classification of glucose regulation in patients with coronary artery disease: a report from the Euro Heart Survey on Diabetes and the Heart. Heart 2007;93:72e7. 19. Silverman RA, Thakker U, Ellman T, et al. Hemoglobin A1c as a screen for previously undiagnosed prediabetes and diabetes in an acute-care setting. Diabetes Care 2011;34:1908e12. 20. Gholap N, Davies MJ, Mostafa SA, et al. A simple strategy for screening for glucose intolerance using glycated haemoglobin, in individuals with acute coronary syndrome. Diabet Med 2012;29:838e43. 21. Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction-executive summary: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation myocardial Infarction): developed in collaboration with the American College of Emergency Physicians, American College of Physicians, Society for Academic Emergency Medicine, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2007;50:652e726. 22. Kushner FG, Hand M, Smith Jr SC, et al. 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/ AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2009;54:2205e41. 23. Wright RS, Anderson JL, Adams CD, et al. 2011 ACCF/AHA focused update of the Guidelines for the Management of Patients with Unstable Angina/Non-STElevation Myocardial Infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2011;57: 1920e59. 24. Van de WF, Bax J, Betriu A, et al. Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J 2008;29:2909e45. 25. Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598e660. 26. Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet 1994;343:311e22. 27. Timmer JR, Van Der Horst ICC, et al. Comparison of myocardial perfusion after successful primary percutaneous coronary intervention in patients with STelevation myocardial infarction with versus without diabetes mellitus. Am J Cardiol 2005;95:1375e7. 28. O’Donoghue ML, Vaidya A, Afsal R, et al. An invasive or conservative strategy in patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes: a collaborative meta-analysis of randomized trials. J Am Coll Cardiol 2012;60:106e11. 29. Yusuf S, Zhao F, Mehta SR, et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001;345:494e502. 30. Roffi M, Chew DP, Mukherjee D, et al. Platelet glycoprotein IIb/IIIa inhibitors reduce mortality in diabetic patients with non-ST-segment-elevation acute coronary syndromes. Circulation 2001;104:2767e71. 31. Hung J, Brieger DB, Amerena JV, et al. Treatment disparities and effect on late mortality in patients with diabetes presenting with acute myocardial infarction: observations from the ACACIA registry. Med J Aust 2009;191: 539e43. 32. Ferreiro JL, Angiolillo DJ. Diabetes and antiplatelet therapy in acute coronary syndrome. Circulation 2011;123:798e813. 33. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005; 293:2126e30. 34. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71e86. 35. Mehta SR, Tanguay JF, Eikelboom JW, et al. Double-dose versus standard-dose clopidogrel and high-dose versus low-dose aspirin in individuals undergoing 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. J.D Tardif et al. / Can J Diabetes 37 (2013) S119eS123 Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2009;120:2271e306. Dormandy JA, Charbonnel B, Eckland DJ, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet 2005;366:1279e89. Duckworth W, Abraira C, Moritz T, et al. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med 2009;360: 129e39. Action to Control Cardiovascular Risk in Diabetes Study GroupGerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med 2008;358:2545e59. Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008;359:1577e89. ADVANCE Collaborative Group; Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560e72. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a metaanalysis of randomised controlled trials. Lancet 2009;373:1765e72. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, S123 60. 67. 61. 68. 62. 63. 64. 69. 70. 71. 65. 66. and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. J Am Coll Cardiol 2009;119: 351e7. Task Force on Myocardial Revascularization of the European Society of C, the European Association for Cardio-Thoracic S, European Association for Percutaneous Cardiovascular I, et al. Guidelines on myocardial revascularization. Eur Heart J 2010;31:2501e55. Fox KA, Clayton TC, Damman P, et al. Long-term outcome of a routine versus selective invasive strategy in patients with non-ST-segment elevation acute coronary syndrome a meta-analysis of individual patient data. J Am Coll Cardiol 2010;55:2435e45. Mehta SR, Cannon CP, Fox KA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA 2005;293:2908e17. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375e84. Mahaffey KW, Granger CB, Toth CA, et al. Diabetic retinopathy should not be a contraindication to thrombolytic therapy for acute myocardial infarction: review of ocular hemorrhage incidence and location in the GUSTO-I trial. Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries. J Am Coll Cardiol 1997;30:1606e10. Consensus]. that the use of insulin to maintain a glucose of 4. Consensus].1016/j.28) or final neurological deficit (Standardized Mean Difference À0.5 mmol/L in the first 24 hours after stroke symptom onset is not beneficial compared to usual care and may. the control groups within the 7 studies achieved mean glucose levels of <10. glycated hemoglobin (A1C) or 75 g oral glucose tolerance test soon after admission to hospital [Grade D. FRCPC Diabetes Management in the Acute Period The management of hyperglycemia in acute stroke (generally defined as within the first 24 hours of stroke symptom onset) remains controversial. All patients with diabetes and ischemic stroke or TIA should receive the same treatments that are recommended for patients with ischemic stroke or TIA without diabetes since they benefit equally [Grade D.23 to 0.035 RECOMMENDATIONS 1. Other than the many recognized risk factors associated with acute stroke (e. regularly updated. 95% confidence interval [CI] 0. hypertension. Therefore. Diabetes also doubles the risk of stroke recurrence.to 3-fold increase in men and a 2. with or without diabetes (5). The rate of symptomatic hypoglycemia was higher in the intervention group (OR 25. S77) remains applicable to those admitted with acute stroke. 2.ca). and of persons with a new diagnosis of diabetes after experiencing a stroke. Evidence from large clinical trials performed in patients with diabetes supports the need for aggressive and early intervention to target the cardiovascular (CV) risks of patients to prevent the onset. these factors are associated with an excess risk of stroke disease (2). and stroke outcomes are significantly worse among patients with diabetes. It was concluded.12.01. 95% CI 9. impaired glucose tolerance and hyperinsulinemia. FRCPC. The systematic review included 7 trials involving 1296 participants (639 participants in the intervention group and 657 in the control group). no difference was found for the outcomes of death and dependency or neurological deficit.78e1.  A comprehensive.strokebestpractices. Therefore.canadianjournalofdiabetes. specific risk factors attributable to diabetes also have been reported. recurrence and progression of acute stroke (2).Can J Diabetes 37 (2013) S124eS125 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. those with no diabetes. dyslipidemia. A Cochrane Systematic Review evaluated randomized controlled trials comparing intensively monitored insulin therapy (target blood glucose range 4. p.5 mmol/L (6e12). S100) is imperative to reduce the risk of this potentially devastating complication. Of note. resulting in a greater ischemic to hemorrhagic stroke ratio in people with diabetes compared with the general population. KEY MESSAGES  The assessment and general management of persons with diabetes who experience a stroke.to 5-fold increase in women (3. Gordon J.0 to 7.g. are the same as those without a stroke.4). Gubitz MD.org/10.00).0 mmol/L (see In-hospital Management of Diabetes chapter. diabetes increases the risk of ischemic stroke more than hemorrhagic stroke. such as insulin resistance. central obesity. blood pressure. The high stroke risk in diabetes may be due to the complex interplay between the various hemodynamic and metabolic components of the diabetes syndrome.00. evidence-based approach to the assessment and management of all patients (including those with diabetes) with stroke across the continuum of care is available on the Canadian Stroke Strategy (CSS) Best Practices Recommendations website (1) (http:// www. Estimates of risk of ischemic stroke in people with diabetes range from a 2.jcjd. the recommendation for the majority of noncritically ill hospitalized patients to have their glucose levels maintained below 10. 95% CI À0. and longer hospital stays (2).9. by the authors.7). Introduction Diabetes is an important modifiable risk factor for a first ischemic stroke. . However. the evidence to support tight glucose control immediately following acute ischemic stroke has not been supportive. glucose and the possible use of vascular protective medications to reduce overall CV morbidity and mortality among people with diabetes (see Vascular Protection in People with Diabetes chapter.5 mmol/L) vs. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. with increased hospital and long-term stroke mortality. lipids.com Clinical Practice Guidelines Management of Stroke in Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Mukul Sharma MSc. Both individually and collectively. and the combination of diabetes and stroke is a major cause of morbidity and mortality worldwide (2).0 to 7.2e72. From a clinical perspective. MD.2013. multifactorial strategy addressing healthy behaviours. more residual neurological and functional disability. be harmful with increased hypoglycemia. In the subgroup analysis of those with diabetes vs. the comprehensive. p. in fact. usual care in adult patients with acute ischemic stroke. Patients with ischemic stroke or transient ischemic attack (TIA) should be screened for diabetes with a fasting plasma glucose. there is no glucose target specific to patients presenting with stroke.doi. atrial fibrillation). There was no difference between treatment and control groups in the outcome of death or disability and dependence (odds ratio [OR] 1. Stroke patterns. Sandercock PA. Gilmore RM. Available at: http://www. Hammes HP. Cochrane Database Syst Rev 2011. Lehto S. Vinychuk S. Bruno A. Melnyk V.6: 397e406. et al. Weir CJ.20:150e4. significance and immediate control with insulin-potassium saline magnesium infusions.22:116e22. . Treatment of hyperglycemia in ischemic stroke (THIS): a randomized pilot trial. Neurology 2004. Idris I. Sharma. Intravenous insulin therapy in the maintenance of strict glycemic control in nondiabetic acute stroke patients with mild hyperglycemia.strokebestpractices. Stroke 1996. Insulin for glycaemic control in acute ischaemic stroke. Lees KR. Diabetes mellitus and stroke. Walters MR. Pragmatic management of hyperglycaemia in acute ischaemic stroke: safety and feasibility of intensive intravenous insulin treatment. Kent TA. The Canadian Best Practice Recommendations for Stroke Care. Staszewski J. Cerebrovasc Dis 2009. Bellolio MF. 3. GRASP Investigators.39:384e9.27:63e8. Coull BM. 5. et al. et al. Brodacki B. 10. Gubitz / Can J Diabetes 37 (2013) S124eS125 S125 References 1. et al. 12. Stead LG. Stepien A.60:48e56.J. Accessed February 27. Hildreth AJ. 9. A randomised.M. 2. Cerebrovasc Dis 2006.ca/. Kreisel SH. Pyörälä K. Gray CS. Hyperglycemia after acute ischemic stroke: prediction. Johnston KC. Berschin UM. 11. Predictors of stroke in middle-aged patients with non-insulin-dependent diabetes. 2013. Rönnemaa T. J Stroke Cerebrovasc Dis 2011. Glucose-potassium insulin infusions in the management of post-stroke hyperglycaemia: the UK Glucose Insulin in Stroke Trial (GIST-UK). Thomson GA. Stroke 2009. 7. Heart Drug 2005. Lancet Neurol 2007. G. 8. et al. Int J Clin Pract 2006. Piechowski-Jozwiak B. Margitich V.40: 3804e9. 6. Kotowicz J. Kissela BM. and prognosis in patients with diabetes mellitus. controlled pilot study to investigate the potential benefit of intervention with insulin in hyperglycaemic acute ischaemic stroke patients.62: 1558e62. Sharma JC. etiology. 4. Glucose Regulation in Acute Stroke Patients (GRASP) trial: a randomized pilot trial. Karapanayiotides T. Stroke 2008.5:197e204. van Melle G. et al.27:167e75.9:CD005346. Hall CE. although the elderly may have atypical symptoms (1).g. which are acutely released by ventricular myocytes when the myocardium is stretched due to increased filling pressures. shortness of breath. such as echocardiography. they are less likely to receive appropriate therapies. It is recognized that diabetes can cause heart failure independently of ischemic heart disease by causing a diabetic cardiomyopathy (3). in large clinical trials of subjects with cardiovascular disease or diabetes.2013. Additionally. Current tests. While an increase in glycated hemoglobin (A1C) among individuals with diabetes is a recognized risk factor for heart failure (6e10). and yet very effective proven therapies are widely available to most physicians. etc.canadianjournalofdiabetes. such as hypertension. anemia. from <10% to >60%. do usually fully characterize all aspects of systolic and diastolic dysfunction in individuals. studies have shown the occurrence of asymptomatic abnormalities of ventricular systolic and diastolic function. independently from ischemic heart disease or systemic hypertension. However.to 4-fold higher in people with diabetes compared to those without and. John C. In individuals with and without diabetes. when present.  Even though heart failure in people with diabetes should be treated similarly to heart failure in those without diabetes. smoking and obesity. Epidemiological studies have shown that the incidence of heart failure is 2. The results to date are mixed.to 4-fold) in the risk of heart failure development (8. This has significant clinical implications as the prognosis of untreated or undertreated heart failure is poor.12).to 4-fold higher in people with diabetes compared to those without diabetes (4. Heart Failure in People with Diabetes The diagnosis of heart failure is made by association of typical clinical signs and symptoms with objective evidence. fatigue). yet very effective proven therapies are widely available to most physicians. such as chronic obstructive pulmonary disease. many studies have explored the clinical utility of screening patients with diabetes for the presence of reduced LV function with BNP/NT-proBNP testing. The incidence of heart failure is 2.com Clinical Practice Guidelines Treatment of Diabetes in People with Heart Failure Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Jonathan G. such as renal dysfunction and propensity for hyperkalemia. peripheral edema. which together are strongly associated with atherosclerosis.5). occurs at an earlier age.036 fractions (LVEFs). may help make an accurate diagnosis where clinical uncertainty exists (2). such as that obtained from a chest x-ray. Introduction Type 2 diabetes often occurs in association with other cardiovascular risk factors. ischemic heart disease and left ventricular (LV) dysfunction. pneumonia. The presence of diabetes should not affect the decision for treatment of heart failure.  Diabetes can cause heart failure independently of ischemic heart disease by causing a diabetic cardiomyopathy that may manifest in the setting of normal or reduced left ventricular ejection fraction. although 1 is often reported to be predominant. dyslipidemia. the overlap between systolic and diastolic heart failure is considerable. the practising physician may still under-recognize and misdiagnose heart failure. MacFadyen MD.  Comorbidities. FACC. but also referred to as preserved systolic function or preserved EF). FSCAI. FRCPC KEY MESSAGES  Heart failure is still under-recognized and misdiagnosed.jcjd. with no clear consensus to institute this strategy. Microalbuminuria is also an independent risk factor for heart failure. and. depression. This has significant clinical implications as the prognosis of untreated or undertreated heart failure is poor. they have been shown to lower the risk of new-onset heart failure (13e15). . Because of this. Angiotensin-converting enzyme (ACE) inhibitors significantly reduce urinary albumin excretion.1016/j. LV dysfunction can be clinically silent or associated with the typical clinical signs and symptoms of heart failure (e.01.doi. an echocardiogram or plasma natriuretic peptide testing (brain natriuretic peptide [BNP] and prohormone of BNP [NT-pro-BNP]) (1). varicose veins. The measurement of plasma BNP and NT-pro-BNP. and many people have a combination of systolic and diastolic dysfunction. no prospective study to date has demonstrated that improved glycemic control significantly reduces the incidence of heart failure (11). both systolic (commonly defined as LVEF <40%) and diastolic (commonly defined as LVEF >50%.org/10. especially in people with diabetes. Howlett MD. are more prevalent in people with diabetes and may influence heart failure drug doses and monitoring of therapy but not therapeutic targets. These symptoms need to be differentiated from other conditions that may have similar presentations. Heart failure can occur over the entire range of LV ejection 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. increasing urinary albumin-to-creatinine ratio is associated with a stepwise increase (2. Diabetes is associated with increased prevalence of heart failure. Documentation of systolic and diastolic myocardial function is recommended at the time of diagnosis of heart failure or with any significant change in clinical stability.Can J Diabetes 37 (2013) S126eS128 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. FRCPC. However.  The target drug doses should be the same as those identified in the evidence-based Canadian Cardiovascular Society recommendations on heart failure (http://www.ccsguidelineprograms. Am J Cardiol 2010. Deswal A. Clinicians should be aware of this potential complication. Diabetes Metab 2008. References 1.23:344e8. Consensus]. Valle R. The BNP assay does not identify mild left ventricular diastolic dysfunction in asymptomatic diabetic patients. Diabetes Obes Metab 2007.ca). as well as heart failure symptoms and signs. asymptomatic patients with type 2 diabetes mellitus. RECOMMENDATIONS 1. Beta blockers should be prescribed when indicated for systolic heart failure. et al. Changes in diastolic dysfunction in diabetes mellitus over time. Comparison of patients with heart failure and preserved left ventricular ejection fraction among those with versus without diabetes mellitus. et al. 10. especially in view of current guidelines advocating the expanded use of combined RAAS blockade in patients with mild-to-moderate heart failure and low EF.ca).105:373e7. to the increased incidence of side effects and/or intolerance to RAAS blockade and the increased prevalence of renal disease in patients with diabetes. 13. Numerous registries and reports indicate that persons with diabetes are less likely than those without diabetes to receive efficacious and evidence-based therapies for systolic heart failure. et al. with metformin than with other antihyperglycemic agents if they have only mild-to-moderate renal dysfunction (estimated glomerular filtration rate >30 mL/min) (30). et al. Ramasubbu K. Mishra TK.97: 71e6. Howlett. Higa N. Bagolin E. 7. Level 2 (17. 9. 2. Diagnostic utility of brain-natriuretic peptide for left ventricular diastolic dysfunction in asymptomatic type 2 diabetic patients. As such. ccsguidelineprograms. Albertini J-P. 5. Lankisch M. In people with diabetes and heart failure and an estimated glomerular filtration rate <60 mL/min. This is particularly concerning considering the increased absolute benefit the agents confer to patients with heart failure and diabetes in comparison to unselected heart failure populations. blood pressure and body weight. Consensus]. Karavanaki K. MacFadyen / Can J Diabetes 37 (2013) S126eS128 S127 Treatment of Individuals with Both Diabetes and Heart Failure In nearly every clinical trial involving patients with heart failure. Diabetologia 2010. has been shown to be associated with improved glycemic control. In the large landmark clinical trials of heart failure. but. in comparison to other beta blockers. Individuals with diabetes and heart failure should receive the same heart failure therapies as those identified in the evidence-based Canadian Cardiovascular Society heart failure recommendations (http://www.31:289e96. 4. serum potassium and creatinine) [Grade D. Am J Cardiol 2009. Association of hypertension and diastolic dysfunction with type-2 diabetes mellitus. As such. Data to date suggest overall glycemic control for these patients improves as their heart failure syndrome improves on therapy (24e26). although comorbidities.28:311e8. Ashraf SMS.100:1336e40.27). Perhaps this is due. Usefulness of aminoterminal pro-brain natriuretic peptide testing for the diagnostic and prognostic evaluation of dyspneic patients with diabetes mellitus seen in the emergency department (from the PRIDE Study). Valensi P. Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography.  Dose-up titration should be more gradual (with monitoring of blood pressure. Aguilar D. Three beta blockers have been shown to reduce morbidity and mortality for patients with heart failure and diabetes: carvedilol. Am J Cardiol 2009. et al. Dinh W. Shimabukuro M. if not better. Grandi AM. they derive greater absolute benefit from efficacious therapies as compared to patients without diabetes (15e17). 6.7:40e4. et al. in part. Findings from left ventricular strain and strain rate imaging in asymptomatic patients with type 2 diabetes mellitus. Galderisi M.29).13:769e73. Oshiro Y.G. Left ventricular systolic and diastolic dysfunction and their relationship with microvascular complications in normotensive. J Endocrinol Invest 2008. J Am Coll Cardiol 2006. 3. 8. A detailed discussion of the rationale and evidence for the treatment approach to heart failure patients is available in the Canadian Cardiovascular Society consensus recommendations (http://www. The current evidence suggests that patients with heart failure fare at least as well. some data suggest the improvement in LVEF is also greater with carvedilol (17. In fact. Effect of glycemic control on left ventricular diastolic function in type 1 diabetes mellitus. Scott CG. Feldman AM. As such. metformin should still be considered as first-line therapy in heart failure patients with mildto-moderate renal dysfunction. heart failure in people with diabetes should be treated similarly to those without diabetes. Kenney P. However. 12.104:1398e401. 3. the differences persist. Bertini M. 14. Mohanty NK. For this reason. . et al. diabetes is present in over one-third of subjects. this has not been reported in clinical trials. Mishra SK. if well tolerated [Grade D.C. ccsguidelineprograms. Canali C. et al. 2. including heart failure. Meta-analyses have evaluated the occurrence of lactic acidosis with the use of metformin (over 70 000 patient-years) or other antihyperglycemic agents (over 55 000 patient-years) and they have consistently shown no increase in lactic acidosis in the metformin group (28. Metformin Metformin is an effective oral antihyperglycemic agent. Konstantopoulos I. 15. Diabet Med 2011. based on isolated case reports and a biochemical rationale for a risk of lactic acidosis. Franzetti I. In addition. cardiovascular outcomes in heart failure patients taking metformin were better than in those taking other antihyperglycemic agents (30). Consensus]. From AM. Kazianis G. such as renal dysfunction and hyperkalemia. Indian Heart J 2008. Piantanida E. Delgado V. J. prescribers must be diligent in providing these therapies. Am J Cardiol 2007. Eur J Echocardiogr 2006. et al. Am J Cardiol 2006. et al. Ghali JK.27)]. 11. J Card Fail 2007.9:323e9. Influence of diabetes on cardiac resynchronization therapy with or without defibrillator in patients with advanced heart failure. subgroup analysis of diabetic populations has shown that. some clinicians prefer carvedilol as the beta blocker of choice in such patients.  Serum electrolytes and creatinine. may be more prevalent in people with diabetes (http://www. should be monitored within 7e10 days of any initiation or titration of therapy [Grade D. patients with diabetes are at increased risk for development of hyperkalemia and worsening renal dysfunction in the setting of renin-angiotensin-aldosterone (RAAS) blocking agents (18e23). Cardiovascular autonomic neuropathy contributes to left ventricular diastolic dysfunction in subjects with Type 2 diabetes and impaired glucose tolerance undergoing coronary angiography. B-type natriuretic peptide. a marker of asymptomatic left ventricular dysfunction in type 2 diabetic patients. Futh R. In particular. Oestreicher E. Basir F. Rath PK. Pakistan J Med Sci 2007. Early signs of left ventricular dysfunction in adolescents with Type 1 diabetes mellitus: the importance of impaired circadian modulation of blood pressure and heart rate. Carvedilol. Consensus].ca) (31). even when controlled for these conditions. Ng ACT. While there is a theoretical concern for the occurrence of severe hypoglycemia without awareness associated with the use of nonselective beta blockers. it is approved for use under a warning in the setting of several conditions. Cohen R. Edelmann F.ca) [Grade D. Chen HH. O’Donoghue M.53: 1331e40. Consensus]. Association of glucose metabolism with diastolic function along the diabetic continuum. Stahrenberg R.60:548e53.ccsguidelineprograms. despite their increased risk of morbidity and mortality. Boehmer J. Mende M.103:1463e6. et al. or if combined renin-angiotensin-aldosterone blockade is employed:  Starting doses of angiotensin-converting enzyme inhibitors or angiotensin receptor II antagonists (angiotensin receptor blockers) should be halved [Grade D. bisoprolol and metoprolol.48:1548e51.34:355e62. as they provide similar benefits in people with diabetes compared with people without diabetes [Grade B.J. 41:193e200. et al. Lukas MA.25:326e33. J Am Coll Cardiol 2007. Holdbrook FK. Laboratory evaluation of potassium and creatinine among ambulatory patients prescribed spironolactone: are we monitoring for hyperkalemia? Ann Pharmacother 2007. 26. Are beta-blockers as efficacious in patients with diabetes mellitus as in patients without diabetes mellitus who have chronic heart failure? A meta-analysis of large-scale clinical trials.76:181e3.34(suppl 1):3e9. Adverse effects of combination angiotensin II receptor blockers plus angiotensin-converting enzyme inhibitors for left ventricular dysfunction: a quantitative review of data from randomized clinical trials. Ross C. et al. 16. . Early administration of trimetazidine may prevent or ameliorate diabetic cardiomyopathy. Curr Med Res Opin 2006. Metformin treatment is associated with a low risk of mortality in diabetic patients with heart failure: retrospective nationwide cohort study. Gigli M. et al. et al. Raebel MA. 17.53:2546e53.163:2594e602. Diabetes Metab 2008. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. MacFadyen / Can J Diabetes 37 (2013) S126eS128 24. Howlett JG. Long-term outcome in diabetic heart failure patients treated with cardiac resynchronization therapy. Clin Cardiol 2008. 20. 18.C.(4). Cianci G. Ghanem A. et al. Sadjadi SA. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzyme inhibitors versus angiotensin receptor blockers. Med Hypotheses 2011. Eur J Heart Fail 2008. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. et al.S128 J. Incidence and predictors of hyperkalemia in patients with heart failure.23:21e45. Arnold JMO. Darmellah A. et al. Andersson C.167:1930e6. Swedberg K. Diabetes and drug-associated hyperkalemia: Effect of potassium monitoring. et al.5:547e52. et al. Arch Intern Med 2007. Diabetologia 2010. 27. Dorian P. An analysis of the CHARM program. Vos T. Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: Prevention. Gilbert RE. Phillips CO. Safety of spironolactone use in ambulatory heart failure patients.10:298e307. J. Cochrane Database Syst Rev 2010. Qizhu T. and use of biomarkers. Lourenco AP. Salpeter SR. The effect of carvedilol on mortality risk in heart failure patients with diabetes: results of a meta-analysis. McMillan JI. Hansen PR. Bell DS. 30. management during intercurrent illness or acute decompensation.31:509e13. Fantoni C. McClure DL. 23. Effects of trimetazidine on myocardial perfusion and left ventricular systolic function in type 2 diabetic patients with ischemic cardiomyopathy. Greyber E. Lopes RJ. Arch Intern Med 2003. 25. Belardinelli R.G. Salpeter EE. Am Heart J 2003. Kashani A. Pasternak G. Pasternak GA. 29. 21. Chan KA. Jaipaul N. 31. McMurray JJV. 28. Raebel MA. Wenmeng W. Mascarenhas J. Haas SJ. Can J Cardiol 2007. Xu S. 146:848e53. Greyber E. Diabetes-related metabolic perturbations in cardiac myocyte. Ther Clin Risk Manage 2009. 19. et al. Regoli F. Desai AS. Olesen JB. J Cardiovasc Pharmacol 2008. J Gen Intern Med 2010.50:1959e66. Ko DK. CD 002967. 22. Salpeter S.51: 611e5. Feuvray D. Howlett. et al.22:287e96. Salpeter E. et al. However. as it is associated with significant reductions in both 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. The earliest stage of diabetic nephropathy is hyperfiltration.73 m2 per year).8).  The progression of renal damage in diabetes can be slowed through intensive glycemic control and optimization of blood pressure. Diabetic Nephropathy PRACTICAL TIPS Management of Potassium and Creatinine During the Use of Angiotensin-Converting Enzyme (ACE) Inhibitor or Angiotensin II Receptor Blocker (ARB) or Direct Renin Inhibitor (DRI)  Check serum potassium and creatinine at baseline and within 1 to 2 weeks of initiation or titration of therapy AND during times of acute illness. FRACP. ischemic damage related to vascular disease and hypertension.  Mild-to-moderate stable hyperkalemia: B Counsel on a low-potassium diet. as well as an assessment of renal function. obesity and cigarette smoking.12). FRCPC. This stage is referred to as “microalbuminuria.73 m2 per year) and not impressively higher than what is seen in the general population (0. estimated glomerular filtration rate [eGFR]. Many of these factors are modifiable. late in the overt nephropathy phase.e.  Severe hyperkalemia: B In addition to emergency management strategies.” The rate of progression from normoalbuminuria to microalbuminuria then to overt nephropathy usually is slow.com Clinical Practice Guidelines Chronic Kidney Disease in Diabetes Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Philip McFarlane MD. ARB or DRI). PharmD. as well as other renal diseases that are unrelated to diabetes (Figure 1) (7. PhD.e.2013. small amounts of albumin are leaked. Identification of hyperfiltration is not clinically useful.1016/j.” This can worsen so that the urinary albumin excretion is sufficiently high to be detectable by a urine dipstick. Richard E. Thus. where the glomerular filtration rate (GFR) is significantly higher than normal. B Consider temporarily holding renin-angiotensin-aldosterone system (RAAS) blockade (i. FACP. typically taking 5 years or longer to progress through each stage (11. It is important to note that the rate of progression can vary between individuals.  All individuals with CKD should be considered at high risk for cardiovascular events and should be treated to reduce these risks. In this chapter. Gilbert MBBS. PhD. male gender.037 The classic description of diabetic nephropathy is of a progressive increase in proteinuria in people with longstanding diabetes followed by declining function that eventually can lead to end stage renal disease (ESRD) (Figure 2) (1. as it is difficult to determine from routine testing. therapy should be reviewed and serum creatinine and potassium levels should be rechecked. B If persistent.01.6). FRCPC. length and quality of life (5. Initially.  If potassium becomes elevated or creatinine increases by more than 30% from baseline. A variety of forms of kidney disease can be seen in people with diabetes. the rate of loss of renal function is relatively slow (1 to 2 mL/min/1. Key risk factors for diabetic nephropathy include long duration of diabetes. MRCP KEY MESSAGES  Identification of chronic kidney disease (CKD) in diabetes requires screening for proteinuria. how to treat them with an aim to slow progression of CKD and discuss the impact of CKD on other aspects of diabetes management. hypertension. Peter Senior MBBS. nonepotassium-sparing diuretics and/or oral sodium bicarbonate (in those with a metabolic acidosis) should be considered.73 m2 per year).9. urinary albumin .Can J Diabetes 37 (2013) S129eS136 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. with up to half demonstrating signs of kidney damage in their lifetime (1e3). below the detection threshold of a urine dipstick. Progression of diabetic nephropathy can be slowed through the use of medications that disrupt the renin-angiotensin-aldosterone system.doi. including diabetic nephropathy. poor glycemic control.canadianjournalofdiabetes. Persistent albuminuria is considered the earliest clinical sign of diabetic nephropathy (Table 1). ACE inhibitor. Lori MacCallum BScPhm. and that the clinical markers of the disease (i.10).5 to 1 mL/min/ 1. we will discuss how to screen for and diagnose chronic kidney disease (CKD) in people with diabetes. a stage known as “overt nephropathy.org/10. significant renal dysfunction is not usually seen until late in the course of diabetic nephropathy (13). Diabetes is the leading cause of kidney disease in Canada (4).jcjd. the rate of decline of renal function can accelerate (5 to 10 mL/min/ 1. During the early stages of diabetic nephropathy. Introduction Diseases of the kidney are a common finding in people with diabetes. Kidney disease can be a particularly devastating complication. RAAS blockade should be held or discontinued. aggressive control of blood pressure (BP) and glycemia. the GFR usually will be less than half of normal before the serum creatinine exceeds the lab normal range (35). In addition to measurements of urinary albumin excretion. Figure 2. it is cumbersome to implement on a large scale and is often performed incorrectly (23e27). In most cases. In addition. lead to the diagnosis of kidney disease in people with diabetes. As mentioned. requiring such a person to undergo additional testing or referral (17e20). ACR. While these biopsy series are biased (biopsies are usually done in people with diabetes when nondiabetic renal disease is suspected). However. This equation requires knowledge of the patient’s age. the test of choice is the random urine albumin-to-creatinine ratio (urinary ACR). however. People with type 1 diabetes are not expected to have kidney disease at the time of onset of diabetes. Screening for Albuminuria When screening for albuminuria.22). levels) do not always correlate well with the severity of renal disease seen on biopsy (14). using the 4-variable MDRD (“Modification of Diet in Renal Disease”) equation (36).25e27). however. The 24-hour urine collection for protein/albumin remains the gold standard. screening for kidney disease should be delayed to avoid false positives. Kidney biopsy series in type 2 diabetes have found that nondiabetic glomerular disease. albumin-to-creatinine ratio. or significant urinalysis abnormalities. Causes of chronic kidney disease (CKD) in people with and without diabetes. A random urine ACR predicts 24-hour urinary albumin excretion sufficiently well and is the test of choice for screening for albuminuria (23. diagnosing a person as having albuminuria requires the elevated urinary albumin level to be persistent. particularly in extremes of patient age or size (33. . serum creatinine and race and is automatically computed and reported by many labs whenever a serum creatinine is ordered. so screening should be initiated immediately at the time of diagnosis in this group. Dehydration and other conditions that lead to intravascular volume contraction can lead to a transient decline in renal function. so screening can be delayed until the duration of diabetes exceeds 5 years. particularly hypertensive or ischemic nephropathy. The eGFR is useful for assessing chronic changes in renal function but should not be used in situations where kidney function is changing rapidly. There is substantial day-to-day variability in albuminuria. Additionally. Other Kidney Diseases in People with Diabetes People with diabetes (particularly type 2 diabetes) often develop kidney diseases other than diabetic nephropathy. Indeed. Estimation of GFR The serum creatinine is the most common measurement of kidney function. a variety of methods have been developed to better estimate the level of glomerular filtration by combining the patient’s serum creatinine with factors such as age. is as common as diabetic nephropathy in people with diabetes (7). other studies have suggested that half of everyone with diabetes and significant kidney function impairment do not have albuminuria (15). sex. transient increases in albuminuria can be provoked by a number of factors (Table 3) (28e32). For this reason. it can inaccurately reflect renal function in many scenarios. The most common method of estimating renal function in Canada currently is the eGFR. These studies suggest that testing for albuminuria may be insufficient in identifying all patients with diabetes who have renal disease. / Can J Diabetes 37 (2013) S129eS136 Screening for Kidney Disease in People with Diabetes Screening for kidney disease in people with diabetes involves an assessment of urinary albumin excretion and a measurement of the overall level of kidney function through an estimation of the GFR. the 24-hour urine collection can be difficult to perform accurately. The MDRD eGFR performs well when the GFR is <60 mL/min (37) and despite its flaws is generally a better estimate of glomerular filtration than the serum creatinine value. and gender. there can be significant overlap (Figure 1). the risk of ESRD in diabetes does not appear to matter whether the renal diagnosis is one of diabetic nephropathy or an alternative diagnosis as management is the same (16). The random urine for albumin is insufficient.S130 P.34). When such conditions are present. significant renal disease can be present at the time of diagnosis of type 2 diabetes (21. as the urinary albumin concentration can vary due to urine concentration (24). and the use of renal protective drugs can slow or stop progression of diabetic nephropathy. assessment of the level of kidney function may be clinically necessary but should Figure 1. In addition. At least 2 of 3 urine samples over time exhibiting elevations in urinary albumin levels are required before it is considered to be abnormal. Kidney diseases of all forms can be staged based on the degree of impairment of eGFR (Table 4). weight. As the delay between onset and diagnosis of type 2 diabetes can be many years and as nondiabetic kidney disease is common. estimations of the level of kidney function and urinalyses are required to identify patients with kidney disease other than diabetic nephropathy. Persistent abnormalities of either urinary albumin excretion or GFR. When such conditions are present. Table 2 lists some concerning clinical and laboratory features that would lead to suspicion of a kidney disease unrelated to diabetes. Furthermore. McFarlane et al. Level of urinary albumin by various test methods and stage of diabetic nephropathy. in people with diabetes. and 2 more random urine ACRs ordered during that interval. In the absence of any significant abnormalities other than proteinuria. Although persistent microscopic hematuria can occur in about 20% of people with diabetic nephropathy. Although 24-hour collections are not needed for routine screening in diabetes. so confirmatory testing is usually unnecessary. Once a diagnosis of CKD has been made. multiple myeloma) or when estimating daily sodium intake in an individual with refractory edema or hypertension. then a diagnosis of CKD is confirmed.g. its presence should lead to the consideration of other urological or nephrological conditions. The exception to this approach is when the random urine ACR indicates albuminuria in the overt nephropathy range. Screening Recommendations People with diabetes should undergo annual screening for the presence of kidney disease when they are clinically stable and not suspected of having acute kidney injury or nondiabetic renal disease. Such patients should undergo an appropriate assessment for the cause of their disease. A rapid decline in eGFR or development of severe hypertension would suggest prompt referral to a specialist. Blockade of the renin-angiotensin-aldosterone system (RAAS) with either an Table 2 Factors favouring the diagnosis of classical diabetic nephropathy or alternative renal diagnoses . / Can J Diabetes 37 (2013) S129eS136 Table 1 Stages of diabetic nephropathy by level of urinary albumin level S131 not be used to assess the stage of CKD. Because renal function can be transiently depressed. Optimal BP control also appears to be important in the prevention of diabetic nephropathy. a persistent reduction in eGFR is required before it is considered to be abnormal. This can be delayed 5 years from the onset of type 1 diabetes but should begin immediately at the time of diagnosis of type 2 diabetes.P. including the first morning urine of the next day. Screening for CKD in people with diabetes should be performed with a random urine ACR and a serum creatinine that is then converted into an eGFR (Figure 3). Treatment and Follow Up Optimal glycemic control established as soon as possible after diagnosis will reduce the risk of development of diabetic nephropathy (38e42). then a presumptive diagnosis of kidney disease due to diabetes is made. although the results have been less consistent (41. An abnormal screening test should be confirmed by repeat testing of the eGFR within 3 months. when screening for nonalbumin urinary proteins (e. Prevention. Table 2 lists other clinical clues that may point to a renal diagnosis other than kidney disease due to diabetes.43e45). they can be useful when there is doubt about the accuracy of an eGFR. Other Clinical Features and Urinary Abnormalities: When to Consider Additional Testing or Referral Urinalysis findings of red blood cell casts are not a common finding in renal disease due to diabetes. as this level of proteinuria rarely resolves spontaneously. The presence of clinical or laboratory abnormalities suggesting nondiabetic kidney disease indicates the need for appropriate workup or referral. and white blood cell casts or heme-granular casts are not compatible with a diagnosis of kidney disease due to diabetes. Screening should be delayed in the presence of conditions that can cause transient albuminuria (Table 3) or a transient fall in eGFR. If either the eGFR remains low or at least 2 of the 3 random urine ACRs are abnormal. a urine sample for dipstick and microscopy should be ordered. Individuals should be counseled to discard the first morning urine on the day of collection and then collect all subsequent urine for a 24-hour period. McFarlane et al. leads to a rise in serum creatinine of up to 30%. The safe use of RAAS blockers (ACE inhibitors. especially amongst individuals with a metabolic acidosis as demonstrated by a low serum bicarbonate level. p. RAAS blockade would need to be held or discontinued (83). and direct renin inhibitors [DRIs]) Drugs that block the RAAS reduce intraglomerular pressure. Treating Kidney Disease Safely The “sick day” medication list (see Appendix 7) Several classes of medications used commonly in people with diabetes can reduce kidney function during periods of intercurrent illness and should be discontinued when patients are unwell. In the case of severe renovascular disease that is bilateral (or unilateral in a person with a single functioning kidney). ACE inhibitors have also been shown to reduce the chance of developing new nephropathy (46. In type 2 diabetes. can increase urinary potassium excretion. in turn. S100) (50e52). Diuretics. independent of their effect on BP. The issue of whether ARBs and ACE inhibitors are similarly effective in CKD that is not caused by diabetic nephropathy remains controversial (72. further testing should be performed to ensure that these results have stabilized. Diuretics can exacerbate intravascular volume contraction during periods of intercurrent illness. Consideration should be given to providing patients with a “sick day” medication list. these patients may have an even larger rise in serum creatinine when these drugs are used (80e82). the serum creatinine and potassium should be checked between 1 and 2 weeks after initiation or titration of a RAAS blocker (82).58). ACE inhibitors have been shown to decrease albuminuria and prevent worsening of nephropathy (59). ACE inhibitors and ARBs have been shown to decrease albuminuria and prevent worsening of nephropathy. including combining RAAS blockers or using very high doses of a single RAAS blocker. A variety of strategies to more aggressively block the RAAS have been studied in kidney disease. namely.54). instructing the patient to hold these medications if they feel that they are becoming dehydrated for any reason.73). Although these drugs can be used safely in patients with renovascular disease.61). ARBs. all of these drugs can reduce kidney function during times of intercurrent illness. and ARBs have been shown to delay the time to dialysis in those with renal dysfunction at baseline (61e64). and these 2 medication classes appear to be equally effective for cardiorenal protection (57. In type 2 diabetes. so their usage and dosage should be reevaluated during periods where kidney function changes. with the combination of albuminuria and low eGFR predicting a very high level of risk (Figure 4) (53. All people with CKD are at risk for cardiovascular (CV) events and should be treated to reduce these risks (see Vascular Protection chapter. in particular when they develop significant intravascular volume contraction due to reduced oral intake or excessive losses due to vomiting or diarrhea. In type 1 diabetes. which can further reduce blood flow into the glomerulus in patients who are volume contracted. which. Nonsteroidal anti-inflammatory drugs cause constriction of the afferent arterioles. RAAS blockade can lead to hyperkalemia. McFarlane et al. In addition. Table 4 Stages of chronic kidney disease . The degree of risk of CV events or progression to ESRD increases as albuminuria levels rise. ACE inhibition has been shown to reduce proteinuria. Sodium bicarbonate (500 to 1300 mg orally twice a day) can also increase urinary potassium excretion. slow progressive loss of glomerular filtration rate and delay the need for dialysis (70. typically when a patient develops intravascular volume contraction (78). Mild-to-moderate hyperkalemia can be managed through dietary counselling. A number of additional medications need to be dose adjusted in patients with renal dysfunction. the ability of angiotensin II to contract the efferent arteriole to support glomerular filtration during these periods. This protective effect has been demonstrated in people with diabetes and hypertension (46) but not in normotensive people with diabetes (47e49). which then stabilizes (79).S132 Table 3 Conditions that can cause transient albuminuria P. / Can J Diabetes 37 (2013) S129eS136 In CKD from causes other than diabetic nephropathy. The progression of renal damage in diabetes can be slowed through intensive glycemic control (38) and optimization of BP (55). Blockers of the RAAS interfere with the kidney’s response to intravascular volume contraction. angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) can reduce the risk of diabetic nephropathy independent of their effect on BP. ACE inhibitors have been shown to reduce progression of diabetic nephropathy in albuminuric normotensive individuals with both type 1 (65e68) and type 2 diabetes (69). These strategies reduce proteinuria but have not been proven to improve patient outcomes in diabetic nephropathy (74e77) and come at a risk of increased acute renal failure. and ARBs have been shown to reduce proteinuria (60). RAAS blockade can precipitate renal failure.71). If hyperkalemia is severe. Progression of diabetic nephropathy can be slowed through the use of an ACE inhibitor or ARB (56). and as eGFR falls. Aggressive RAAS blockade strategies should be restricted to specialized clinics. For these reasons. For these reasons. in particular furosemide. These renalprotective effects also appear to be present in proteinuric individuals with diabetes and normal or near-normal BP. In patients in whom a significant change in creatinine or potassium is seen. eGFR. ACR. McFarlane et al. albumin-to-creatinine ratio. / Can J Diabetes 37 (2013) S129eS136 S133 Figure 3. . estimated glomerular filtration rate.P. Screening for chronic kidney disease (CKD) in people with diabetes. 0 mg/mmol and/or an eGFR<60 mL/min on at least 2 of 3 samples over a 3-month period [Grade D. Consensus] Abbreviations: ACE. Appendix 6 lists some medications commonly used in people with diabetes and how they should be used if kidney dysfunction is present. 11. Ritz E. Consensus]. Hasslacher C. Different patterns of renal damage in type 2 diabetes mellitus: a multicentric study on 393 biopsies. Laffel L. Kidney Int 2004.86)]. Consensus]. multifaceted approach to reduce cardiovascular risk (see Vascular Protection. Clinical epidemiology of cardiovascular disease in chronic renal disease. ACR persistently >60 mg/mmol c. 4. Adults with diabetes and CKD with either hypertension or albuminuria should receive an ACE inhibitor or an ARB to delay progression of CKD [Grade A. glomerular filtration rate. All patients with diabetes and CKD should receive a comprehensive. van den Hoogen HJ. Other Relevant Guidelines Targets for Glycemic Control. Myers BD. People with diabetes on an ACE inhibitor or an ARB should have their serum creatinine and potassium levels checked at baseline and within 1 to 2 weeks of initiation or titration of therapy and during times of acute illness [Grade D. A diagnosis of CKD should be made in patients with a random urine ACR 2. specialist care may be necessary when renal dysfunction is severe. . S100) [Grade A. eGFR<30 mL/min d. S163 Diabetes and Pregnancy. p. Smidt UM.7:930e7. when there are difficulties implementing renal-protective strategies or when there are problems managing the sequelae of renal disease (85). 4. Parfrey PS.36:1071e8. Gambara V.61e65. Reenders K. Bell CM. In adults. Kidney Int 2000. J Am Soc Nephrol 1996. 3. Canadian Organ Replacement Register Annual Report: Treatment of End-Stage Organ Failure in Canada. Canadian Institute for Health Information.3:1458e66. et al. et al. Combination of agents that block the renin-angiotensin-aldosterone system (ACE inhibitor. 5. p. GFR. Am J Kidney Dis 1998.10:169e72. Level 1A (51. cardiovascular mortality. p. Remuzzi G. Mecca G. The course of kidney function in type 2 (non-insulin-dependent) diabetic patients with diabetic nephropathy. Mazzucco G. Heterogeneous nature of renal lesions in type II diabetes. p. DRI) should not be routinely used in the management of diabetes and CKD [Grade A. Unable to achieve target BP (could be referred to any specialist in hypertension) [Grade D. As the use of RAAS blockers during pregnancy has been associated with congenital malformations. Evolution of incipient nephropathy in type 2 diabetes mellitus. S184 Relevant Appendices Appendix 6: Therapeutic Considerations for Renal Impairment Appendix 7: Sick Day Medication List References 1. 7. Rossing K. consideration should be given to their discontinuation prior to conception. Gearin G.69. Am J Kidney Dis 2002.12: 482e7. Bodlaj G. S153 Type 2 Diabetes in Children and Adolescents. The natural course of microalbuminuria in insulin-dependent diabetes: a 10-year prospective study. Chronic. Level 1(89. et al. p.39:713e20. 10. Diabetologia 1993. Chapman RH. CKD. et al. S31 Monitoring Glycemic Control. Tarnow L. Nielsen FS.87. Fortunato M. Abdullah I. Diabetes and its long-term complications in general practice: a survey in a well-defined population.104:771e4. p. 14. Screening should commence at diagnosis of diabetes in individuals with type 2 diabetes and 5 years after diagnosis in adults with type 1 diabetes and repeated yearly thereafter. Wahl P. de Nobel E. Clinical versus histological diagnosis of diabetic nephropathy: is renal biopsy required in type 2 diabetic patients with renal disease? QJM 2011. Bertani T. Gall MA. women with diabetes of childbearing age should avoid pregnancy if drugs from these classes are required (84). Referral to a specialized renal clinic Figure 4. et al. Diabet Med 1995. DRI. albumin-to-creatinine ratio. Ronn B. p.4:859e63. Ottawa. et al. and for ARB use in type 2 diabetes. et al. Fam Pract 1993. ARB. 8. 12.58:1228e37. / Can J Diabetes 37 (2013) S129eS136 medications wishes to become pregnant. Foley RN. Sarnak MJ. Consensus]. Mathiesen ER. 9. Similar risks of nephropathy in patients with type I or type II diabetes mellitus. S35 Pharmacotherapy in Type 1 Diabetes. J Am Soc Nephrol 1993. Weir MR. S56 Pharmacologic Management of Type 2 Diabetes. screening for CKD in diabetes should be conducted using a random urine ACR and a serum creatinine converted into an eGFR [Grade D.88)]. 6. 2. If a woman with diabetes receiving such Most people with CKD and diabetes will not require referral to a specialist in renal disease. Unable to remain on renal-protective therapies due to adverse effects such as hyperkalemia or >30% increase in serum creatinine within 3 months of starting an ACE inhibitor or ARB e. Effect of duration of type I diabetes on the prevalence of stages of diabetic nephropathy defined by urinary albumin/ creatinine ratio. and progression of kidney disease. p. An off-the-shelf help list: a comprehensive catalog of preference scores from published cost-utility analyses. et al. angiotensin-converting enzyme. Storm B. ARB. People with diabetes should be referred to a nephrologist or internist with an expertise in CKD in the following situations: a. Stone PW. 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Nephropathy in type 2 diabetes. Gherardi G. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. Metab Clin Exp 1979. Limitations of creatinine as a filtration marker in glomerulopathic patients. Bakker AJ. Population-based study in Rochester. Diabetic nephropathy as the mode of presentation of diabetes mellitus. et al. Kidney Int 1985. 21. Ann Intern Med 2009. Campbell DJ. Humphrey LL. et al. et al. Ravid M. Wiseman M. Hirata A. N Engl J Med 2000. 42. UK Prospective Diabetes Study Group.151:11e20. 66.21:88e92. Chalmers TC. Bain RP.14:591e3. Sheldon CV. 44. Diabetes Care 1997. The effect of angiotensin-convertingenzyme inhibition on diabetic nephropathy. Wang PH. et al. North American Microalbuminuria Study Group. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001. J Cardiovasc Pharmacol 1999. Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria. Minn Med 1967. Utility of untimed urinary albumin measurements in assessing albuminuria in black NIDDM subjects. Al-Amro SA. Middleton RJ.379:165e80. Ruggenenti P. The urine protein to creatinine ratio as a predictor of 24-hour urine protein excretion in type 1 diabetic patients with nephropathy. Gerstein HC.212:167e9. J Am Soc Nephrol 2009. Pogue J. N Eng J Med 2000. Nat Clin Pract Nephrol 2007. Glickman JL. 60. Gaede P. et al. et al. Giese J. 62. Mathiesen ER. and blood pressure in type 2 diabetes mellitus. 40. Detection of microalbuminuria. 23. Al-Rubeaan KA. Jacobsen P. Chaturvedi N. 34. Shemesh O. et al. Zinman B. et al. Levey AS. Kalil RS. Suzuki H.342:381e9.152:1225e9. Lewis EJ. et al. 55. Viikari JS.22:307e13. 26. Long-term stabilizing effect of angiotensinconverting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. renal impairment. Khawaja R. 27. Longerich LL. Ann Intern Med 1999. Kaar M. Invalidity of simple concentration-based screening tests for early nephropathy due to urinary volumes of diabetic patients. et al. Wang X.118:577e81. Kidney Int 2004. Gruppo Italiano di Studi Epidemiologici in Nefrologia (GISEN). Vedel P. The nephropathy of non-insulindependent diabetes: predictors of outcome relative to diverse patterns of renal injury. de Galan BE. Jerums G. 43. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. The Diabetes Control and Complications (DCCT) Research Group. J Intern Med 1999. N Engl J Med 2004.134:370e9. Sjolie AK.83:164e8.28:830e8. Savin H. 36. Unusual renal complications in diabetes mellitus. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. Eckardt KU. Strippoli GF. 28. 47:1703e20. 70. Gans DJ. Parving HH.352:837e53. 30. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.361:40e51. Diabetologia 1981. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial.348:383e93. Yonsei Med J 1999. Bard M. 33. Maschio G. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. 63. J Okla State Med Assoc 1990. et al. et al. et al. et al. et al. et al. Effect of candesartan on microalbuminuria and albumin excretion rate in diabetes: three randomized trials. The validity of random urine specimen albumin measurement as a screening test for diabetic nephropathy. Viberti GC. 29. Feldman HA. et al. Modification of Diet in Renal Disease Study Group. 64. Barnett AH. Chronic kidney disease. Mogensen CE.53:493e501. Perkovic V. Bouter P. Diabetologia 1984. Andersen S. Kidney Int 2005. Tsukamoto Y. Kadomoto Y. Kidney Int 2000. Schrier RW. Harnett JD. Rossing P. Appropriate blood pressure control in hypertensive and normotensive type 2 diabetes mellitus: a summary of the ABCD trial. 35.17:S153e5. UK Prospective Diabetes Study (UKPDS) Group.8:204e11.23(Suppl 2):B21e9. Am J Kidney Dis 2001.345:870e8. Winaver J. Diabetes Care 2000. Perna A. 87. et al. Hansen HP. Schmieder RE. Brenner BM. 8:290e7. Viberti G. 319:24e5. Lancet 2008. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. ramipril.123:1098e107. Am J Med 1985. Mathiesen ER. Muirhead N. or both. 85. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000. Clase CM. Miyamori I. Circulation 2002. Care and referral of adult patients with reduced kidney function: position paper from the Canadian Society of Nephrology. MicroAlbuminuria Reduction With VALsartan Study Investigators. Gao P. et al. McQueen M. Tobe SW. Major congenital malformations after first-trimester exposure to ACE inhibitors. Levin A. Hypertension 1986.358:580e91. Smith RD. McFarlane et al. Yasuhara S. BMJ 1999. Mendelssohn D. N Engl J Med 2008. Effects of converting enzyme inhibition on split renal function in renovascular hypertension. Aliskiren combined with losartan in type 2 diabetes and nephropathy.351:585e92. ramipril. Hypertension 1986. et al.372:547e53. Effect of a multifactorial intervention on mortality in type 2 diabetes.79:14e23. Franklin SS.S136 P. et al. 75. in people at high vascular risk (the ONTARGET study): a multicentre. et al. 79. 77. Comparison of effects of enalapril plus hydrochlorothiazide versus standard triple therapy on renal function in renovascular hypertension. Takeda Y. McMurray JJV. et al. 354:2443e51. 88. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. renal function. Parving HH. et al. Parving H. 89. Bakris GL.20:893e900. Use of the converting enzyme inhibitor enalapril in renovascular hypertension. double-blind. N Engl J Med 2006. 84. Weir MR. 82. controlled trial. randomised. / Can J Diabetes 37 (2013) S129eS136 83. Managing hyperkalemia caused by inhibitors of the reninangiotensin-aldosterone system. et al. Persson F. 90. N Engl J Med 2012.358:2433e46. Supramaximal dose of candesartan in proteinuric renal disease.160:685e93. Parving HH. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. 76. Clin J Am Soc Nephrol 2006. Lund-Andersen H. Epstein M. Mann JF. Reams GP. 2006. Palmer BF. J Am Soc Nephrol 2009. Cooper WO. Renal outcomes with telmisartan.367:2204e13.1:940e51. 78. Gaddy P. Hernandez-Diaz S. and the renin-angiotensin-aldosterone system. Weinberger M. Selective aldosterone blockade with eplerenone reduces albuminuria in patients with type 2 diabetes. 86. or both in people at high renal risk: results from the ONTARGET and TRANSCEND studies. N Engl J Med 2004. Arbogast PG. Effect on blood pressure. Gaede P. et al. Williams GH. 81.106:672e8. 80. Rene de Cotret P. Circulation 2011. Cardiovascular and renal outcomes with telmisartan. N Engl J Med 2008. Lewis JB. .8: 415e21. Hommel E. Burgess E. Bauer JH. Wheeldon NM. et al. 5). which is also well recognized as a potentially blinding complication of diabetes but currently has no treatment options.1016/j. and none had sight-threatening diabetic retinopathy (9. More recently. In the United Kingdom Prospective Diabetes Study (UKPDS). no person <17 years of age developed proliferative retinopathy or macular edema (14.doi.  Tight glycemic control reduces the onset and progression of sightthreatening diabetic retinopathy. intraretinal hemorrhage. FRCP(UK). Conversely.com Clinical Practice Guidelines Retinopathy Canadian Diabetes Association Clinical Practice Guideline Expert Committee The initial draft of this chapter was prepared by Shelley R. and 3% in people receiving oral antihyperglycemic therapies (2). a form of vascular change detected on 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. limb amputation and visual loss due to diabetic retinopathy are the independent predictors of early death (7). irrespective of age of onset of diabetes. Frank Stockl MD. Higher prevalence rates were noted in First Nations populations in Canada (4.2013.15. ophthalmic screening strategies are intended to detect disease treatable by this modality (8e11). the prevalence of mild nonproliferative retinopathy was 2%. Despite the change in treatment modalities. or “centre-involving” DME has come to describe patients who could benefit from this treatment over laser. Screening Because laser therapy for sight-threatening diabetic retinopathy reduces the risk of blindness. the more general term DME. 14% in people with type 2 diabetes and on insulin therapy. 2) progressive accumulation of blood vessel change that includes microaneurysms. Visual loss is associated with significant morbidity. few patients without retinopathy at diagnosis of diabetes had disease progression to the point of requiring retinal photocoagulation (laser treatment) in the following 3 to 6 years (21). proliferative diabetic retinopathy or clinically significant macular edema (CSME) (8). local intraocular pharmacological therapy and surgery reduce the risk of significant visual loss. and 3) retinal capillary closure. Among individuals with type 1 diabetes.038 . screening programs remain unchanged and consider the differences in incidence and prevalence of retinopathy observed in type 1 and type 2 diabetes. and distinguish between children and adults (Table 1) (12e17).jcjd. FRCSC. respectively (3). fluorescein angiography. Screening intervals for diabetic retinopathy vary according to the individual’s age and type of diabetes. the prevalence rate increases sharply after 5 years’ duration of diabetes in postpubertal individuals with type 1 diabetes (16).20). Definition and Pathogenesis Diabetic retinopathy is clinically defined.3%. Introduction Diabetic retinopathy is the most common cause of new cases of legal blindness in people of working age (1). in people with type 2 diabetes. hip fracture and a 4-fold increase in mortality (6). Macular edema occurs in 11%. Three distinct forms of diabetic retinopathy are described: 1) macular edema. diagnosed and treated based on the extent of retinal vascular disease exclusively. However. FRCSC. sight-threatening retinopathy occurred at a rate of 8.16). Since the introduction of new treatments based on intravitreal (intraocular) injection of pharmacological agents and use of Optical Coherence Tomography (OCT) to quantify macular thickness.  Laser therapy. Boyd MD. FRCSC KEY MESSAGES  Screening is important for early detection of treatable disease.canadianjournalofdiabetes. a strictly defined form of diabetic macular edema (DME) that relies on the clinical assessment of retinal thickening based on subjective assessment of area and distance from the fovea (the centre of the macula responsible for high-acuity vision). including increased falls.2% (1). Among patients <15 years of age. Sightthreatening diabetic retinopathy includes severe nonproliferative diabetic retinopathy. Filiberto Altomare MD.01. which includes diffuse or focal vascular leakage at the macula. vascular tortuosity and vascular malformation (together known as nonproliferative diabetic retinopathy) that ultimately leads to abnormal vessel growth (proliferative diabetic retinopathy).18.19). PhD. 15% and 4% of these groups. Previous data showed the prevalence rate of proliferative retinopathy to be 23% in people with type 1 diabetes. retinopathy may be present in 21% to 39% of patients soon after clinical diagnosis but is sight-threatening in only about 3% (3.org/10. In the Wisconsin Epidemiology Study of Diabetic Retinopathy 4-year incidence study. with or without so-called hard exudates. The Eye Diseases Prevalence Research Group determined the crude prevalence rate of retinopathy in the adult population with diabetes of the United States to be 40.17.Can J Diabetes 37 (2013) S137eS141 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. Andrew Advani MB ChB. Diabetic retinopathy rarely develops in children with type 1 diabetes <10 years of age regardless of the duration of diabetes (16). the latter of which cannot be applied to the fovea. standard therapy.36).21. there have been no studies comparing various screening intervals in their effectiveness to reduce the risk of vision loss (23). is recommended to slow the development and progression of diabetic retinopathy. pregnancy (with type 1 diabetes). the addition of fenofibrate 160 mg daily to simvastatin was associated with a 40% reduction in the primary outcome of retinopathy progression over 4 years (37). fenofibrate 200 mg daily reduced both the requirement for laser therapy (a prespecified tertiary endpoint) and retinopathy progression among patients with pre-existing retinopathy (46). rapid improvement of glycemia may be associated with transient early worsening of retinopathy.0%. while BP lowering (including use of RAS blockers) reduces retinopathy rates and is an important component of vascular protection. low hemoglobin level. Glycemic control Tight glycemic control. and adjust therapy to reach targets per guidelines*  Screen for other diabetes complications If retinopathy is not present  Type 1 diabetes: rescreen annually  Type 2 diabetes: rescreen every 1e2 years  Review glycemic. In the Renin-Angiotensin System Study (RASS). involving 5231 participants. Thus. In the ACCORD Eye study. nor the angiotensin receptor blocker (ARB). The progression rates of diabetic retinopathy were prospectively evaluated (12. enalapril. While statin-based lipid-lowering therapies are an integral part of vascular protection in diabetes. normoalbuminuric participants with type 1 diabetes. Two studies examined the effect of more aggressive blood glucose lowering (A1C 6. BP control (target BP <150/85 mm Hg.5%) in patients with established type 2 diabetes (duration 6 to 10 years). while in the Action in Diabetes and . Delay of Onset and Progression Risk factors for the development or progression of diabetic retinopathy are longer duration of diabetes. respectively (12).0% and 15. The role of the peroxisome proliferator-activated receptor-alpha agonist. Although a number of trials have examined the effect of reninangiotension system (RAS) blockade on retinopathy progression or development among normotensive patients with diabetes. * See “Other Relevant Guidelines”.13. and in type 2 diabetes individuals it was 0. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study. 3.5%. Although the incidence of sightthreatening diabetic retinopathy in the group without baseline diabetic retinopathy is low (12. BP and lipid control. has been assessed in 2 largescale randomized controlled trials. intensive glycemic control did not significantly reduce development or progression of retinopathy (38). losartan. neither the angiotensin-converting enzyme (ACE) inhibitor.45). In type 1 diabetes. involving 223 normotensive. targeting an A1C 7%. had no diabetic retinopathy. / Can J Diabetes 37 (2013) S137eS141 When to initiate screening  Five years after diagnosis of type 1 diabetes in all individuals 15 years  In all individuals at diagnosis of type 2 diabetes Screening methods  Seven-standard field. but this effect is offset by long-term benefits (39). Programs relying on OCT to evaluate macular edema are under investigation. and adjust therapy to reach targets per guidelines*  Screen for other diabetes complications BP.R.43). active treatment did not show additional benefit vs. evaluated the effect of the angiotension II type 1 ARB candesartan 32 mg daily on the incidence of new retinopathy in patients with type 1 diabetes (DIRECT-Prevent 1) (42) and on the progression of retinopathy in patients with either type 1 diabetes (DIRECT-Protect 1) (42) or type 2 diabetes (DIRECT-Protect 2) (43). stereoscopic-colour fundus photography with interpretation by a trained reader (gold standard)  Direct ophthalmoscopy or indirect slit-lamp funduscopy through dilated pupil  Digital fundus photography If retinopathy is present  Diagnose retinopathy severity and establish appropriate monitoring intervals (1 year)  Treat sight-threatening retinopathy with laser.22). blood pressure. where mean BP was <140/80 mm Hg in both the active intervention and control groups. Lipid-lowering therapy Dyslipidemia is an independent risk factor for retinal hard exudates and CSME in type 1 diabetes (28. among patients with newly diagnosed type 2 diabetes. the incidence in these groups was 0. The Diabetes Control and Complications Trial (DCCT) and the UKPDS demonstrated that intensive glycemic control (A1C 7%) reduced both the development and progression of retinopathy (32e34). fenofibrate. pharmacological or surgical therapy  Review glycemic. the results generally have been conflicting or inconclusive. with the beneficial effects of intensive glycemic control persisting for up to 10 years after completion of the initial trials (35. The ACCORD and ADVANCE studies examined more aggressive BP lowering in patients with established type 2 diabetes. Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) Retinal Measurements study (AdRem).3%. From the study’s control and event rates.13. The UKPDS showed that. The Diabetic Retinopathy Candesartan Trials (DIRECT) program. increased blood pressure (BP).6% and 13. the role of these agents in preventing the development or progression of retinopathy has not been established (34.25e31). intensive glycemic control was associated with a lower rate of retinopathy progression than standard therapy (37). The DIRECT studies did not meet their primary endpoints.S138 Table 1 Screening for retinopathy S. at baseline. BP and lipid control. although there was an overall change toward less severe retinopathy with candesartan (42. had background retinopathy or had mild preproliferative retinopathy. elevated glycated hemoglobin (A1C).22).19.44). In people with type 1 diabetes. proteinuria and severe retinopathy itself (14e17. The Liverpool Diabetic Eye Study reported the 1-year cumulative incidence of sight-threatening diabetic retinopathy in individuals with type 1 or type 2 diabetes who. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Eye study. reduced retinopathy progression independent of BP change (41). Boyd et al. dyslipidemia. the number of patients needed to treat with combination statin and fenofibrate therapy to prevent 1 retinopathy progression event is estimated at 27 over the 4-year period.3%. In both these studies. respectively (13). 5. actual BP 144/82 mm Hg) resulted in a significant reduction in retinopathy progression as well as a decrease in significant visual loss and requirement for laser therapy compared to less control (target BP <180/105 mm Hg. Blood pressure control BP control is an important component of risk factor modification in diabetes and reduces the risk of retinopathy progression. Telemedicine programs relying on fundus photography are widely used in Canada and internationally for the identification and triage of patients with diabetic retinopathy (24). there is insufficient evidence to recommend RAS blockade as primary prevention for retinopathy for all normotensive patients with diabetes. actual mean BP 154/87 mm Hg) (40). intraocular pharmacotherapy is now available. Antiplatelet therapy Systematic review suggests that acetylsalicylic acid (ASA) therapy neither decreases nor increases the incidence or progression of diabetic retinopathy (47).52. respectively. However. in addition to statin therapy. Level 1 (66)]. Steroids are an alternate class of drug evaluated in the treatment of DME. Boyd et al. using an initial loading dose of 3 monthly injections of 0. early vitrectomy was RECOMMENDATIONS 1. Level 1 (15. 5. . unlike ranibizumab.R. 4.49). Thus.58)] and/or pharmacological intervention [Grade A.46)]. treatment with intraocular steroid was associated with increased rates of glaucoma. using monthly ranibizumab. with or without prompt laser. 44% and 39% of patients receiving 0. Visually disabled people should be referred for low-vision evaluation and rehabilitation [Grade D. The interval for follow-up assessments should be tailored to the severity of the retinopathy. In those with no or minimal retinopathy. Laser therapy and/or vitrectomy [Grade A. Laser therapy As determined in the Diabetic Retinopathy Study (DRS) and the Early Treatment Diabetic Retinopathy Study (ETDRS). Two phase III clinical trials investigating the implantation of a long-term drug delivery device containing fluocinolone acetonide met their primary and secondary outcomes (visual acuity and OCT) but showed increased rates of glaucoma and cataract progression compared to sham (55. Two masked phase III clinical trials. Surgical intervention The Diabetic Retinopathy Vitrectomy Study (DRVS) Group evaluated the benefit of early vitrectomy (<6 months) in the treatment of severe vitreous hemorrhage (57) and very severe proliferative diabetic retinopathy (58). People with type 1 diabetes of <20 years’ duration and severe vitreous hemorrhage were more likely to achieve good vision with early vitrectomy compared to conventional management (57). people with diabetes should be treated to achieve optimal control of blood glucose [Grade A. Screening for diabetic retinopathy should be performed by experienced professionals. fenofibrate. However. The risk-to-benefit ratio was considered unacceptable to the United States Food and Drug Administration (FDA) where the treatment was not approved. Level 1 (14. gained 15 letters or more (3 lines) of acuity vs. Consensus].56)] should be used. Level 1A (8. In individuals 15 years of age with type 1 diabetes. Consensus]. intraocular injection of bevacizumab in diabetic retinopathy constitutes off-label use of the drug in Canada.16)].33)] and BP [Grade A. Correspondingly. In the RIDE study. As determined by the ETDRS. the addition of fenofibrate to statin therapy could be considered in patients with type 2 diabetes to slow the progression of established retinopathy. Similar results were obtained by the Diabetic Retinopathy Clinical Research Network using physician-based flexible treatment algorithms rather than a strict prescribed injection schedule (53). likewise showed improvement in the primary and secondary outcome measures of best correct visual acuity and reduction in central macular thickness. screening and evaluation for diabetic retinopathy by an expert professional should be performed at the time of diagnosis of diabetes [Grade A. RISE and RIDE.57. Two-year results are pending. Level 1A (40). blood pressure. with active treatment being associated with an increase in high-density lipoprotein-cholesterol and decrease in serum triglycerides in ACCORD Eye (37) but appearing to be independent of plasma lipid concentrations in FIELD (46).3 or 0. In the RISE trial.5 mg. Level 1 (15. intraocular injection of pharmacological agents and vitreoretinal surgery. and as-needed treatment thereafter. In the RESTORE study. 6.3 or 0. may be used in patients with type 2 diabetes to slow the progression of established retinopathy [Grade A. Patients with sight-threatening diabetic retinopathy should be assessed by a general ophthalmologist or retina specialist [Grade D. this was true when ranibizumab was used as monotherapy or in conjunction with macular photocoagulation. the recommended interval is 1e2 years [Grade A. for type 2 diabetes]. Local (intraocular) pharmacological intervention In the treatment of DME with centre-involving disease.5 mg ranibizumab. With the knowledge that the cytokine vascular endothelial growth factor (VEGF) plays a primary role in the development of DME. In all studies. improved visual acuity compared against sham over the 2 years of study (51). 2 anti-VEGF drugs are now widely used. the BOLT trial. RESTORE. Treatment Treatment modalities for diabetic retinopathy include retinal photocoagulation. By contrast.5 mg ranibizumab. 37% to 43% of ranibizumab-treated patients improved vision by 10 letters or more compared to 16% with standard laser therapy (52). screening and evaluation for retinopathy by an expert professional should be performed annually starting 5 years after the onset of diabetes [Grade A. CVD. Abbreviations: BP. Similarly. Furthermore. focal and/or grid laser treatment to the macula for CSME reduces the incidence of moderate visual loss by 50% (8).18)]. a humanized recombinant anti-VEGF antibody fragment. Long-term follow-up studies to the original laser photocoagulation trials confirm its benefit over several decades (50). 2. 3.25 mg bevacizumab compared to 4% in the control arm (54).S. either in person or through interpretation of retinal photographs taken through dilated pupils [Grade A. the fluocinolone insert has received approval in several European countries. In individuals with type 2 diabetes. laser therapy by panretinal photocoagulation to the retinal periphery reduces severe visual loss and reduces legal blindness by 90% in people with severe nonproliferative or proliferative retinopathy (9e11). Two-year results of a phase III clinical trial. Level 1A (37. cardiovascular disease. Level 1A (32. Though not recommended for CVD prevention or treatment. 33% or 45% of patients gained 15 letters or more at doses of 0.18)] and annually thereafter. 1-year results of a phase III clinical trial. 7. respectively.56).55. demonstrated a gain of at least 15 letters or more in 32% of patients receiving 1. A similar outcome was noted when comparing intraocular injection of bevacizumab (a full-length antibody against VEGF) to macular laser. Intraocular injection of steroid combined with prompt macular laser was as effective as ranibizumab in a single subgroup of patients characterized by previous cataract surgery (53). To prevent the onset and delay the progression of diabetic retinopathy. / Can J Diabetes 37 (2013) S137eS141 S139 mechanism for any beneficial effect of fenofibrate in diabetic retinopathy has not been established. Intravitreal injection with ranibizumab is approved by Health Canada.10. ASA use does not appear to be associated with an increase in risk of vitreous hemorrhage or DME (48. 18% of those in the control arm. as defined by OCT or clinical examination. Level 1A (51. 2. Moss SE. The case for biennial retinopathy screening in children and adolescents. Klein BE. S168 References 1. Sun W. Diabetic macular edema. Metabolic control and progression of retinopathy. such as intraocular pharmacological treatment. Diabetes Care 2005. Broadbent DM. Ophthalmology 1987. 21. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). et al. Agron E. White NH. Management of diabetic retinopathy: a systematic review. et al. Relationship between the severity of retinopathy and progression to photocoagulation in patients with Type 2 diabetes mellitus in the UKPDS (UKPDS 52). Invest Ophthalmol Vis Sci 1998.363:233e44. Fisher MR. Lancet 2003. Int J Circumpolar Health 2004.39:233e52. Arch Ophthalmol 2004. The prevalence of diabetic retinopathy among adults in the United States. Lancet 2008. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. The current status of diabetes care. 30. Vora JP. 34. thus supporting vitrectomy in advanced proliferative diabetic retinopathy (59). Klein R.114: 1079e84.28:617e25. 7. Klein R. et al.168:160e4.89:360e3.122: 552e63. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. Maberley D. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years.61. 3. Diabetes Care 1992. Vora JP. Patel A. Chang A. 42. 41. Moss SE. Whited JD. Kohner EM. Accuracy and reliability of teleophthalmology for diagnosing diabetic retinopathy and macular edema: a review of the literature. . Vu HT. Gardiner R. Broadbent DM. 27.62) and warfarin therapy (63) for persons undergoing ophthalmic surgery does not appear to raise the risk of hemorrhagic complications. Zinman B. Boyd et al. Koushik A. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. The Diabetes Control and Complications Trial Research Group. Keeffe JE. Lancet 1998. UKPDS Group. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Laara E. Diabetes Care 1995. Klein BE. 15. N Engl J Med 2008. Porta M. 14. The Wisconsin epidemiologic study of diabetic retinopathy. Diabetologia 2009. Stratton IM.S140 S. 22. 43. 26. 27. Surgical advances in vitrectomy since the DRVS trials have demonstrated reduced side effects with more consistent favourable visual outcomes. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Moss SE. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Harding SP. Chew EY. / Can J Diabetes 37 (2013) S137eS141 16. Furthermore. 37. Moss SE. 30: diabetic retinopathy at diagnosis of non-insulin-dependent diabetes mellitus and associated risk factors. Moss SE. Incidence of sight-threatening retinopathy in Type 1 diabetes in a systematic screening programme. The Wisconsin epidemiologic study of diabetic retinopathy. Ophthalmology 1989.65). S31 Dyslipidemia. et al. Screening for diabetic retinopathy in James Bay. Klein R. Maguire A. Incidence of sight-threatening retinopathy in patients with type 2 diabetes in the Liverpool Diabetic Eye Study: a cohort study.15:1875e91. Taylor HR. Arch Ophthalmol 1984. 6. Arch Ophthalmol 1989. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years.R. Klein BE. The relationship between hemoglobin levels and diabetic retinopathy. et al. Bethel MA. with significantly improved visual outcome. Holman RR. Klein BE.298:902e16. Diabetes Care 1990.94:1389e400. BMJ 1998.126:1707e15. Klein R. Br J Ophthalmol 2005. Klein R.28:509e13. Klein BE. Paul SK. The Wisconsin epidemiologic study of diabetic retinopathy. The Wisconsin epidemiologic study of diabetic retinopathy. et al. O’Colmain BJ.372:1385e93. et al. Wong TY. Epidemiology of proliferative diabetic retinopathy. Arch Ophthalmol 1989. 13. enhanced magnification.107:244e9. IX. Klein R. X. Aldington SJ. Photocoagulation for diabetic macular edema. 31. Ferris 3rd FL. Ophthalmology 1984. Group AS. Early Treatment Diabetic Retinopathy Study report number 1.103:1796e806. It is worth noting that the use of perioperative ASA (49. 29. Younis N. Moss SE.13:34e40. Diabetes Technol Ther 2006. Effect of pregnancy on progression of diabetic retinopathy. Keinanen-Kiukaanniemi S. Arch Ophthalmol 1985. 12. Moss SE.20:758e65. 24.361:195e200. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. p.102:520e6. Gillies MC.18:631e7. 40. Klein BE. Arch Ophthalmol 2008. p. II.63:277e85. et al. Group AES. et al. Early Treatment Diabetic Retinopathy Study Research Group. Klein BE. Ophthalmology 1998.91:1464e74. et al. Most notably. et al. United Kingdom Prospective Diabetes Study. 39. 10-year follow-up of intensive glucose control in type 2 diabetes.50:153e8. Trans Am Ophthalmol Soc 1996. Diabetic nonproliferative retinal lesions. Ontario: a cost-effectiveness analysis. Impact of unilateral and bilateral vision loss on quality of life.52:2027e36. The incidence of macular edema. Moss SE. et al. Chew EY.372: 1394e402. IV. Cusick M. Aldington SJ. Diabet Med 2001. Klein R. it is important to encourage patients with even moderate visual loss to seek assistance from community services that provide spectacle correction. await long-term follow-up but already demonstrate both preservation and recovery of vision in persons with DME. local and surgical treatments of diabetic eye disease.269:1290e1.317:703e13. The Diabetes in Early Pregnancy Study. Maberley D. CMAJ 2003. Overall. N Engl J Med 2009. Mohamed Q. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XVII. Other Relevant Guidelines Targets for Glycemic Control. et al. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. long-term follow-up to early laser studies confirm their sustained efficacy in preserving vision (50). III. Davis MD.359:1577e89. 38. JAMA 2007.116: 297e303. 9. Despite these successes. Mauer M. Kaur H. J Clin Epidemiol 1997. Meleth AD.105:1801e15. S153 Type 2 Diabetes in Children and Adolescents. et al. 19. Arch Ophthalmol 1998. 35. Lancet 2008. the last few years have seen significant advances in systemic. Ferris F. Moss SE. Diabetes C. Younis N. Cleary PA. Stratton IM.361: 190e1. The Diabetes Control and Complications Trial Research Group. 10. Moss SE. p. Klein BE. VII. How effective are treatments for diabetic retinopathy? JAMA 1993. 23. Lancet 2003. Arch Ophthalmol 1998. these advances have expanded surgical indications to include vitrectomy for diffuse macular edema with or without vitreomacular traction (60). Leske MC. Klein R. et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. et al.96: 1501e10.23:1084e91. Hay D. Early photocoagulation in patients with either type I or type II diabetes. p. Risk factors for high-risk proliferative diabetic retinopathy and severe visual loss: Early Treatment Diabetic Retinopathy Study Report #18. N Engl J Med 1993. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is less than 30 years. 20. associated with higher chance of visual recovery in people with either type 1 or 2 diabetes with very severe proliferative diabetic retinopathy (58).107: 237e43. Qiao Q. 36. 28. Klein R. 17. S117 Type 1 Diabetes in Children and Adolescents. et al. Diabet Med 2003. Renal and retinal effects of enalapril and losartan in type 1 diabetes. vision aids and measures to encourage independence and ongoing quality of life (64. Complications Trial Research Group. Effects of blood pressure lowering and intensive glucose control on the incidence and progression of retinopathy in patients with type 2 diabetes mellitus: a randomised controlled trial. 25. et al. Diabetes Care 2005.94:505e37. Klein BE. Chaturvedi N. Effects of medical therapies on retinopathy progression in type 2 diabetes. 18. XI. Beulens JW. McCarty CA. Cruickshanks KJ. Ophthalmology 1978. Ferris 3rd FL. Kohner EM. Klein R. National Institute of Child Health and Human Development Diabetes in Early Pregnancy Study. New therapies.329:977e86. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised. Four-year incidence and progression of diabetic retinopathy when age at diagnosis is 30 years or more. et al. Klein BE. Sjolie AK. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of diabetic retinopathy study findings. Walker H. Klein R. et al. Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Chew EY. Gangnon RE.352: 837e53. Vingerling JR. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. 4. p. placebo-controlled trials. UK Prospective Diabetes Study (UKPDS) Group. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. Klein R. et al. UK Prospective Diabetes Study Group. Klein R. The 14-year incidence and progression of diabetic retinopathy and associated risk factors in type 1 diabetes.116:874e86.361:40e51. Arch Ophthalmol 1996.102:527e32. Klein ML. 5. Mills JL. Cusumano J. S163 Diabetes and Pregnancy.8:102e11. Arch Ophthalmol 1984. Cruess A. Chan A. et al. 8.85:82e106. p. S110 Treatment of Hypertension. 32. diabetic retinopathy screening and eye-care in British Columbia’s First Nations Communities. N Engl J Med 2010. Diabetes Care 2000. et al. Porta M. Metzger BE. Screening interval for retinopathy in type 2 diabetes. 11. Kempen JH. 33.18:178e84. 20:532e8. et al. Nathan DM. 50. Durrington PN. Ip M. et al. et al. Bandello F. Remaley NA. Mitchell P. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Lancet 2007. et al. Optical treatment of residual vision in diabetic retinopathy. Qin H. Sculpher MJ. 54. Early Treatment Diabetic Retinopathy Study report no.8: 371e7. Diabetes 2004. 52. Ophthalmology 2011. Cahill MT.132:760e76. Results of a randomized trialeDiabetic Retinopathy Vitrectomy Study Report 3. et al.118:626e35. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema.118:609e14. Aiello LP. Fouryear results of a randomized trial: Diabetic Retinopathy Vitrectomy Study Report 5. Summanen PA. 62. Long-term benefit of sustaineddelivery fluocinolone acetonide vitreous inserts for diabetic macular edema. Pearson A.S. 51. Csaky KG.95:1307e20. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter. A 2-year prospective randomized controlled trial of intravitreal bevacizumab or laser therapy (BOLT) in the management of diabetic macular edema.43:491e507. Flynn Jr HW. Lancet 2004. S141 55. Curr Opin Ophthalmol 2009. et al. A systematic review. 58. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision.98(5 Suppl):757e65. Ferguson BA. 63. Vitrectomy in the management of diabetic retinopathy. 66. ETDRS report number 8. Klein ML. Chew EY. Arch Ophthalmol 2012. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebocontrolled trial. et al. Endocrinol Metab Clin North Am 2002. Clar C. Ophthalmology 2011.31: 1983e7. Colhoun HM.110: 1683e9. controlled clinical trial. Rajendram R. Betteridge DJ. Ophthalmology 2011. Anticoagulation and clinically significant postoperative vitreous hemorrhage in diabetic vitrectomy.R. Early Treatment Diabetic Retinopathy Study Research Group. Chew EY. Ranibizumab for diabetic macular edema: results from 2 phase iii randomized trials: RISE and RIDE. Am J Ophthalmol 2001. Albert SG. Chew EY.31:779e93.113:52e5. Expanded 2-year follow-up of ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Wong JS. Ophthalmology 2011. Nguyen QD. 64. 20. 61. Mitchell P. Ophthalmology 2003. 46. 56.118:615e25. Smiddy WE. Fraser-Bell S. Buxton MJ. The Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. 59. Comstock TL. Aspirin in diabetic retinopathy. Kaines A. El-Asrar AM. et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial.118:1580e7. Miljanovic B. Brown DM. Richter B. .101:84e8. Schmidt-Erfurth U.130:972e9. Mahmoud TH.364:685e96. Ferris 3rd FL. 57. 65. Systemic considerations in the management of diabetic retinopathy. Al-Mezaine HS. Changing paradigms in the treatment of diabetic retinopathy. Results after lens extraction in patients with diabetic retinopathy: early treatment diabetic retinopathy study report number 25. Murphy RP. The long-term effects of laser photocoagulation treatment in patients with diabetic retinopathy: the early treatment diabetic retinopathy follow-up study. Arch Ophthalmol 1995. Keech AC.370:1687e97. Surv Ophthalmol 1999. Pearson PA. Glynn RJ. Arch Ophthalmol 1999. Marcus DM. Ola MS. Campochiaro PA. 47. Bressler NM. Ophthalmology 1991. Bergerhoff K. Diabet Med 1991. / Can J Diabetes 37 (2013) S137eS141 44. Ophthalmology 1988. randomized. et al. Elman MJ. Retina 2011.19:175e7. A prospective study of serum lipids and risk of diabetic macular edema in type 1 diabetes.53: 2883e92. Ophthalmology 2012. Brown DM. Boyd et al. et al. Ophthalmology 1994. et al. Benson WE. 45. 49. et al. 48. Fonda GE. et al. 53.108:958e64. Effects of aspirin treatment on diabetic retinopathy. Arch Ophthalmol 1990. Bernbaum M.119:789e801. 60.117:1600e6. Screening for treatable diabetic retinopathy: a comparison of different methods. Referring patients with diabetes and vision loss for rehabilitation: who is responsible? Diabetes Care 1996. Brown JS. the benefits of intensive insulin treatment persist for over a decade for the primary prevention of neuropathy (19).  Intensive glycemic control is effective for the primary prevention or secondary intervention of neuropathy in people with type 1 diabetes. In individuals with significant early progressive symptoms of neuropathy or in whom a clinical suspicion of nondiabetic neuropathy exists. particularly carpal tunnel syndrome. While clinical neuropathy is uncommon in people with type 1 diabetes within the first 5 years after the onset of diabetes.47). the neuropathic pain associated with symptomatic disease is frequently bothersome and often limits physical activity. lower blood glucose levels are associated with a reduced frequency of neuropathy (7. Furthermore.canadianjournalofdiabetes. Both somatic and autonomic neuropathies may occur and may require referral to a specialist experienced in managing the affected body system. Cory Toth MD.18). high body mass index.53). which depends on the degree of foot insensitivity (5). Although not all patients with neuropathy have motor or sensory symptoms.com Clinical Practice Guidelines Neuropathy Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Vera Bril MD. up to 50% of children with type 1 diabetes will have subclinical polyneuropathy (2). tolerance. Opioids are effective for PDN (41e45) and are used mostly when other treatments fail. perform reasonably well for the identification of neuropathy and prediction of its future onset. Additionally. elevated triglycerides. There are insufficient comparative studies to recommend which oral medication should be used first. Other effective therapeutic options include topical nitrate sprays (46. the management necessary to achieve improved glycemic control and the prevention of neuropathyrelated sequelae (11). Methods for using the monofilament or tuning fork to detect diabetic neuropathy are explained in Appendix 8 (12. Management of Neuropathy Intensive glycemic control is effective for the primary prevention and secondary intervention of neuropathy in people with type 1 diabetes (8. smoking and hypertension (4).20). lower blood glucose levels are associated with a reduced frequency of neuropathy.8). smoking and hypertension are risk factors for neuropathy. patients with neuropathy utilize more health resources than those without this complication (9). elevated triglycerides.01. Risk factors for neuropathy include elevated blood glucose levels.Can J Diabetes 37 (2013) S142eS144 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.doi. The surgical release of distal lower limb nerves is not recommended due to lack of evidence supporting efficacy (54) and the possible complications of foot and ankle surgery in patients with diabetes.17.039 .2013. In fact. such as the monofilament and vibration perception tests for neuropathy. An important observation is that few patients have complete relief of painful symptoms with any treatment. quality of life and work productivity (7. high body mass index.13. is common in people with diabetes and can be difficult to diagnose (10). dose escalation and diversion (21). Multiple treatments are available for the management of neuropathic pain.16). topical capsaicin (48e52) and transcutaneous electrical nerve stimulation (52. Details are listed in Table 1. and amputation are important and costly sequelae of diabetic neuropathy (6). Mononeuropathy. although most practitioners advise against the use of opioids for PDN due to the potential for dependency. In those with type 2 diabetes. Introduction Detectable sensorimotor polyneuropathy will develop within 10 years of the onset of diabetes in 40% to 50% of people with type 1 or type 2 diabetes (1). Screening for Peripheral Neuropathy Screening for neuropathy can be performed rapidly and reliably using the 10-g Semmes-Weinstein monofilament or the 128-Hz tuning fork (12e16). Anticonvulsants (22e30) and antidepressants (31e40) are most often used as first-line therapy. Foot ulceration. The underdiagnosis of neuropathy is a fundamental problem in the primary care of people with diabetes and impedes the benefits of early identification.jcjd.org/10. FRCPC. and that a 30% to 50% reduction in baseline pain is considered to be a clinically meaningful response. FRCPC. referral for additional neurological evaluation is indicated. MPH. However.  In people with type 2 diabetes. and detailed evidence-based guidelines on the treatment of painful diabetic neuropathy (PDN) have been published (21). Bruce Perkins MD.  Simple physical examination screening tests.1016/j. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. effective treatment with capsaicin involves short-term pain that limits its acceptability and generalizability in clinical practice. people with type 2 diabetes may have neuropathy at the time of diagnosis (3). No other disease-modifying treatments are currently available. FRCPC KEY MESSAGES  Elevated blood glucose levels. Level 2 (41. Most studies failed to achieve Grade A. 2 times a day. Although subclinical autonomic neuropathic manifestations are common. Diabetes Care 2001.05 $56. The diagnosis of symptomatic autonomic neuropathy is based on the exclusion of specific cardiovascular.51) Capsaicin cream (48. Boyko EJ. S31 RECOMMENDATIONS 1.37. once daily. annual screening should commence after 5 years’ postpubertal duration of diabetes [Grade D. Level 1 (24. Niskanen L.49) Transcutaneous electrical nerve stimulation (53. S153 Type 2 Diabetes in Children and Adolescents. 4. Vascular risk factors and diabetic neuropathy. 6. Lower extremity foot ulcers and amputations in diabetes. dose adjustments for renal and hepatic dysfunction are not shown here. Level 2 (31. Partanen J.7:305e10.17). Breddy JL. Anticonvulsants (pregabalin [Grade A. Anglin RE. Pain Med 2011. et al. Optimal doses are the lowest doses required for maximum efficacy without significant side effects. N Engl J Med 2005. 2. and nephropathy in a populationbased cohort: the Rochester Diabetic Neuropathy Study. Topical nitrate spray [Grade B. p.43e45. Reiber GE.08 $62. Level 2 (46. The prediction of diabetic neuropathic foot ulceration using vibration perception thresholds. Level 1. Bril et al. y Denotes that this drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy. et al.47. Singleton JR.16)]. . In: Diabetes in America. National Institute of Diabetes and Digestive and Kidney Diseases. 5. productivity. 10. / Can J Diabetes 37 (2013) S142eS144 Table 1 Treatment options for the management of painful diabetic peripheral neuropathy Suggested starting dose Anticonvulsants Gabapentiny (23. 3. Simple screening tests for peripheral neuropathy in the diabetes clinic. p.30) Valproatey (27. Consensus]. Opioid analgesics (tapentadol ER. Level 1 (13. et al.90 $132. 8. screening for peripheral neuropathy should begin at diagnosis of diabetes and occur annually thereafter. Dyck PJ.29)]. Level 2 (23. 12. In people with type 1 diabetes.40) Venlafaxiney (37) Opioids Dextromethorphan (41) Morphine sustained release (55) Oxycodone ER (43) Tapentadol ER Tramadol (44) Others Topical nitrate sprays (46. Screening for peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament or loss of sensitivity to vibration at the dorsum of the great toe [Grade A. et al. Zinman B.y valproatey [Grade B. Physicians should refer to the most current edition of the Compendium of Pharmaceuticals and Specialties (Canadian Pharmacists Association.43: 817e24.333:89e94. Foot Care. Olaleye D.36 $14. Chaturvedi N. Lehtinen J. The following agents may be used alone or in combination for relief of painful peripheral neuropathy: a.075% cream applied 3e4 times per day d May titrate slowly up to 600 mg po qid May titrate slowly up to 300 mg po bid May titrate slowly up to 500 mg po bid May titrate slowly up to 100 mg po qhs May titrate to 60 mg po OD May titrate slowly up to 150 mg po bid May May May May May titrate titrate titrate titrate titrate slowly slowly slowly slowly slowly up up up up up to to to to to 200 mg po qid 60 mg po bid 40 mg po bid 250 mg po bid 50 mg po qid May titrate slowly up to 30 mg spray to legs bid May titrate to 5e6 times per day d 60 mg/day 5e6 applications per day d bid. Perkins BA. but research in this field remains active.32. Level 2 (20).24:1448e53. Young MJ.32) Duloxetine (35. A longitudinal assessment of painful diabetic peripheral neuropathy on health status. gabapentin.17:557e60. Does this patient with diabetes have largefiber peripheral neuropathy? JAMA 2010. Pediatr Diabetes 2006.V. Level 1A (8.37 $19. Diabetes Care 1994.28) Antidepressants Amitriptyliney (31. The Diabetes Control and Complications Trial Research Group. National Institutes of Health. venlafaxiney) [Grade B. Comparison of conventional and non-invasive techniques for the early identification of diabetic neuropathy in children and adolescents with type 1 diabetes. MD: National Diabetes Data Group. Bromberg MB. Bril V. Neurology 1993.55)]) b. Other Relevant Guidelines Targets for Glycemic Control. retinopathy. 3. S145 Type 1 Diabetes in Children and Adolescents. 2. OD.28. Smith AG. Antidepressants (amitriptyline. A prospective study. gastrointestinal or genitourinary manifestations through assessment by a specialist in the affected system.329:977e86. Karnes JL.55 $101. 13.24:250e6. Joshi AV. p.51)] Footnote: y Denotes that this drug is not currently approved by Health Canada for the management of neuropathic pain associated with diabetic peripheral neuropathy.35. The prevalence by staged severity of various types of diabetic neuropathy. 409e28. oxycodone ER. Ottawa. due to a <80% completion rate (21). Eaton SE. every bedtime. People with diabetes should be treated with intensified glycemic control to prevent the onset and progression of neuropathy [Grade A. 1995. Perkins BA. Nelson D. Ontario. p.47. Veves A. Grade B. N Engl J Med 1995. The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. Tesfaye S. Olaleye D.92 $138.25:565e9. smaller starting doses and slower titration schedules may be indicated. Kratz KM.14 d 300 mg bid 75 mg bid 250 mg bid 10 mg qhs 30 mg OD 37.12:118e26. 11. for type 1 diabetes.352:341e50. 9. et al. qid. N Engl J Med 1993. Cappelleri JC.55)] d.y duloxetine.30 $1. Although required for some agents.39)] c. and health care utilization and cost. Smith DG. Diabetes Care 2005. S163 Relevant Appendix Appendix 8: Rapid Screening for Diabetic Neuropathy References 1. qhs.56) Suggested titration if tolerated Suggested maximal tolerated dose 3. 2nd ed. for type 2 diabetes]. Diabetes Care 2001. 7. The treatment of autonomic neuropathy is based primarily on expert opinion. 4.55) Pregabalin (24e26. tramadol) [Grade B. Hunt DL. Kennedy L.16 $4.81 $8. In people with type 2 diabetes. et al.600 mg/day 600 mg/day 1500 mg/day 150 mg/day 120 mg/day 300 mg/day 960 180 160 500 400 mg/day mg/day mg/day mg/day mg/day S143 Estimated monthly cost for starting dose $36.27. daCosta DiBonaventura M. Adams C. et al. Mah JK. 4 times a day.303:1526e32.28:1480e1.84 $12. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. Diabetes Care 2002. Kanji JN. symptomatic involvement is infrequent. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Herman WH. Dose ranges are for adults and are taken from published trials.5 mg bid 100 mg qid 15 mg bid 10 mg bid 100 mg bid 50 mg qid 30 mg spray to legs qhs 0. p. Underdiagnosis of peripheral neuropathy in type 2 diabetes. Bethesda. Canada) for product monographs and complete prescribing information. Carpal tunnel syndrome in patients with diabetic polyneuropathy. flexible-dose. 46. Sodium valproate for painful diabetic neuropathy: a randomized double-blind placebo-controlled study.50: 1842e6. Sodium valproate in the management of painful neuropathy in type 2 diabetes: a randomized placebo controlled study. 37. Identifying diabetic patients at high risk for lower-extremity amputation in a primary health care setting. Neurology 1987. et al. randomized multicenter trial comparing duloxetine with placebo in the management of diabetic peripheral neuropathic pain. Britz A. and the American Academy of Physical Medicine and Rehabilitation. Neurology 2004.22:241e5. Neurology 2006. et al. 28. Prediction of incident diabetic neuropathy using the monofilament exam: a 4-year prospective study. Pain 2004. et al. Shapiro DY.311:1047e52. Neurology 2006. Nakao K.21:1322e5. Sharma P. Richter RW.151:2225e9.77:161e7. Hotta N. 44. Yasuda H. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Lu Y.352:1324e34. double-blind.25:1699e703. Booher S. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal. 15. 54. Neurology 2003. Rawat N. 41. et al. et al. Diabetes Care 2002. placebo in patients with painful diabetic neuropathy. Krusinski PB. Kincaid J. Max MB. 43. Jain N. placebo-controlled trial.28: 109e16. 14.33:1090e6. Baba M. Raskin J. Pain Med 2005. Opfer-Gehrking TL. et al. Yuen KC. Agrawal RP. Pritchett YL. Lewis GA. Low PA. Sharma U. Portenoy R.6:253e60. Diabetes Care 2000. Controlled study with long-term follow-up. Edwards KR. Pain 2005. Diabetes Care 2011. placebo-controlled trial. et al. et al. double-blind.63:2104e10. et al. Topical capsaicin in painful diabetic neuropathy. et al.e1-21.230:101e8. et al. Pain 2004. Diabetes Care 2010. Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind. Evidence-based guideline: treatment of painful diabetic neuropathy: report of the American Academy of Neurology. Kochar DK. Gooch C. 23.110:628e38. et al. 26. Efficacy and safety of pregabalin for treating neuropathic pain associated with diabetic peripheral neuropathy: a 14 week. 50.352: 837e53. Neurology 2011. Kumar D. et al. Tandan R. Raskin J. 34. Perkins BA. 97:33e8. Albers JW. 53. The effect of intensive diabetes therapy on the development and progression of neuropathy. Anticonvulsant drugs for management of pain: a systematic review. 352. Herman WH. Harati Y. A prospective evaluation of simple screening criteria. et al. a randomized. Jadad AR. Kochar DK. Choudhary R. Schafer SC. Agrawal RP. Diabetes Care 1992. Park KM.66:1805e8. Vermigli C. et al.280:1831e6. Anesthesiology 2002. Kadiroglu AK. Stolusky T. Lesser H. Neurology 1998. 36.37: 589e96. 33. Etropolski M. A double-blind. Carroll D. J Palliat Med 2006. Bailey JM. Muir J. et al. and fluoxetine on pain in diabetic neuropathy. et al. crossover clinical trial. Gilron I. J Intern Med 1991. 27. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. gabapentin. the American Association of Neuromuscular and Electrodiagnostic Medicine. et al. Olaleye D.326:1250e6. How should peripheral neuropathy be assessed in people with diabetes in primary care? A population-based comparison of four measures. Effectiveness of frequency-modulated electromagnetic neural stimulation in the treatment of painful diabetic neuropathy.106:248e52. Rayman G. White PF. Bhansali A. amitriptyline. et al. 17. Effectiveness of electrotherapy and amitriptyline for symptomatic relief. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. 25.6:346e56. Satoh J. Backonja M. Gohdes DM. Sharma U. 29. et al. Goldstein DJ. BMJ 1995. N Engl J Med 2005.67:1411e20. Cheng Y.15:1386e9. Agrawal RP. 51. Dyck PJ. 16. 47. Management of diabetic neuropathy by sodium valproate and glyceryl trinitrate spray: a prospective double-blind randomized placebo-controlled study. Rosenstock J. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabetes mellitus: a randomized controlled trial. Lynch SA. Morphine. Hota D. Kaur H. Wang F. Portenoy RK. et al. 22. 32. Rowbotham MC. Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind. Alvaro MS. Tu D. Diabetes Res Clin Pract 2009. Duloxetine vs. Neurology 1997. placebo-controlled trial. UK Prospective Diabetes Study (UKPDS) Group. JAMA 1998. Gilron I. Conti M. J Diabetes Complicat 2008. Practice advisory: utility of surgical decompression for treatment of diabetic neuropathy: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Wong K. 31.83:371e8. et al. Swenson M.A multicenter. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Goli V. . / Can J Diabetes 37 (2013) S142eS144 35. Sang CN. QJM 2004.9:29e40. Treatment of painful diabetic neuropathy with topical capsaicin. J Pain 2005. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double.122:561e8. Pop-Busui R. Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Double-blind. Richards P. et al. Arch Intern Med 1991. et al. Diabet Med 2003. 15:8e14. Hamza MA. double-blind. Goswami J. Culnane M. N Engl J Med 1992.3:345e52. J Diabetes Investig 2011.27:151e62. et al. 49. Diabetologia 2005. Chaudhry V. et al. 55.23:365e70. The effect of venlafaxine HCl on painful peripheral diabetic neuropathy in patients with type 2 diabetes mellitus. Nelson KA.34:818e22. Guan Y. England J. vehicle-controlled study. Griffin SJ. Robinovitz E. placebo-controlled study. 24. placebo-controlled study of the application of capsaicin cream in chronic distal painful polyneuropathy. et al. Diabet Med 2011. Superiority of duloxetine to placebo in improving diabetic neuropathic pain: results of a randomized controlled trial in Japan. et al. Pain 1995. placebo-controlled trial. et al.48:817e23. Max MB. Bril V. McQuay H. Rathmann W. 39. 56. Acta Neurol Scand 2002. Schwartz S. et al. The Diabetes Control and Complications Trial Research Group. 52. Bosi E. Orszag A. CMRO 2011.96:1053e61. Intensified conventional insulin treatment retards the microvascular complications of insulin-dependent diabetes mellitus (IDDM): the Stockholm Diabetes Intervention Study (SDIS) after 5 years.2:132e9.33:1549e54. Glyceryl trinitrate spray in the management of painful diabetic neuropathy: a randomized double blind placebo controlled cross-over study. 20. A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain. Berglund B. Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Diabetes Care 2010. 45. 30. Stevens JC. et al. placebo-controlled study conducted in China. Bril et al. Baker NR.S144 V. 40. Smith TR.48:1212e8. Effects of desipramine.20:368e74. The Capsaicin Study Group. Franklin GM. Percutaneous electrical nerve stimulation: a novel analgesic therapy for diabetic neuropathic pain. 42.62:163e8. Wernicke JF. LaMoreau L. Reichard P. 38. or their combination for neuropathic pain.116:109e18. Sit D. Pritchett YL. Diabetes Care 1998. Tuchman M. Duloxetine versus routine care in the longterm management of diabetic peripheral neuropathic pain. Rahman M. Relief of painful diabetic peripheral neuropathy with pregabalin: a randomized. Efficacy of pregabalin for peripheral neuropathic pain: results of an 8-week.60: 927e34. et al. Craig WF.33:159e66. LaMoreaux L. double-blind. Agarwal RP. 19. et al. Clin Ther 2011. Rith-Najarian SJ. Gimbel JS. Lancet 1998. 21. et al. 48.blind placebo-controlled crossover study. et al. Kayabasi H. Diabetes Care 1992. randomized. Ding X. Jain S. D’Souza DN. Diabetic peripheral neuropathy. Beydoun A. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). 18.110:697e706. Ann Intern Med 1995. Julka IS. et al. Controlled-release oxycodone for pain in diabetic neuropathy: a randomized controlled trial. Kunz NR. Diabetes Res Clin Pract 2007. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy. Detke MJ. Yagihashi S. et al. 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. caution is still necessary with MRA and CTA in persons with renal dysfunction. offloading of high-pressure areas.1016/j. Plain radiographs have low sensitivity and specificity in differentiating osteomyelitis from Charcot changes. therefore. lower-extremity vascular status and local wound care. John M.  Antibiotic therapy is not generally required for neuropathic foot ulcerations that show no evidence of infection. therefore. the University of Texas Diabetic Wound Classification System has been validated as a predictor of serious outcomes in patients with diabetes with foot ulcers (Table 1) (13. Loss of sensation over the distal plantar surface to the 10-g Semmes Weinstein monofilament is a significant and independent predictor of future foot ulceration and the possibility of lower-extremity amputation (12). Gadolinium-based contrast agents used in MRA have been associated with the development of nephrogenic systemic fibrosis in individuals with poor renal function (23. Of these. it may underestimate the degree of peripheral arterial obstruction in some individuals with diabetes partly due to medial arterial wall calcification in lower-extremity arteries (18). In those persons with diabetes with foot ulcers. For those persons in whom lower-limb ischemia is suspected. although no single .Can J Diabetes 37 (2013) S145eS149 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www.  The management of foot ulceration in people with diabetes requires an interdisciplinary approach that addresses glycemic control. infection. However.com Clinical Practice Guidelines Foot Care Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Keith Bowering MD. The injection of intravenous radiocontrast dye also must be used in CTA.040 In persons with diabetes with underlying ischemia.29). and. FACP. Although the ABI is a readily available and easy-to-perform technique. In addition. microvascular complications.14). Measurement of systolic toe pressure by PPG may be more accurate in determining the presence of arterial disease in this population (19). In populations with diabetes. Magnetic resonance imaging (MRI) of the foot may help clarify this differential diagnosis. Risk Assessment Characteristics that have been shown to confer a risk of foot ulceration in persons with diabetes include peripheral neuropathy.8). limited joint mobility.01. FRCPC. Advanced magnetic resonance angiography (MRA) and computed tomographic angiography (CTA) do not require arterial access and. that early and aggressive treatment be undertaken. a number of wound classification systems have been developed to provide objective assessment of severity. if they do occur.jcjd.org/10. individuals with peripheral neuropathy and peripheral arterial disease (PAD) are predisposed to foot ulceration and infection. caution should be exercised (as with the use of intra-arterial iodinated contrast) in persons with renal insufficiency so as to avoid precipitating acute renal failure. structural deformity. intra-arterial digital subtraction contrast arteriography has provided the most definitive assessment of PAD but may precipitate renal failure in individuals with higher degrees of renal insufficiency. Noninvasive assessments for PAD in diabetes include the use of the ankle-brachial blood pressure index (ABI). Therefore. have gained popularity as reliable alternatives to iodinated contrast studies due to their less invasive approaches (20e22). the distribution of PAD is greater in the arterial tree below the knee than is seen in those without diabetes (15). transcutaneous oximetry (tcPO2) and Doppler arterial flow studies (16. Although amputation rates for people with diabetes have decreased in the past decade. Embil MD. which ultimately may lead to lower-extremity amputation (4e6). The foot examination should include the assessment of skin temperature since increased warmth is the first indicator of inflammation in an insensate foot and also may be the first sign of acute Charcot neuroarthropathy resulting from the loss of protective sensation in the foot (25e27). FACP KEY MESSAGES  Foot problems are a major cause of morbidity and mortality in people with diabetes and contribute to increased healthcare costs. it is essential that every effort possible be made to prevent foot problems. The clinical and radiological differentiation between an acute Charcot foot and a foot infection can be very challenging (30). previous ulceration or amputation. which is indicative of arterial pulse flow in the arterioles of the respective area). Introduction Foot complications are a major cause of morbidity and mortality in persons with diabetes and contribute to increased healthcare utilization and costs (1e3). an acute Charcot foot may be associated with erythema and swelling. they remain exceedingly high compared to nondiabetic populations (7.24). high glycated hemoglobin (A1C) levels and onychomycosis (9e11). FRCPC.doi.canadianjournalofdiabetes. determination of systolic toe pressure by photoplethysmography (PPG) (PPG assesses the intensity of light reflected from the skin surface and the red cells below.17).2013. with overall clinical characteristics very similar to cellulitis (28. PAD. including regular foot examination and evaluation of amputation risk. There is also insufficient evidence to make any recommendation about the role of negative pressure wound therapy (NPWT) in the routine management of neuropathic wounds. in nonischemic wounds. however. the majority of the agents available for use are selected for their antibacterial spectrum (66.S146 K. Table 2 summarizes the different antimicrobial choices for the empiric management of foot infections in persons with diabetes. Embil / Can J Diabetes 37 (2013) S145eS149 Table 1 University of Texas Diabetic Wound Classification System (13) radiological investigation to date has proven to be completely definitive (31). Where bony foot deformities prevent the fitting of appropriate footwear and/or offloading of pressure-related ulcers. Management and Preventative Care The prevention of amputations has involved the use of various preventative measures.34). leading to polymicrobial infections (66. suffered from methodological problems. with subsequent antibiotic selection tailored to the sensitivity results of cultured specimens. With time and the presence of devitalized tissue. Specific recommendations about dressing types cannot be made as there is insufficient evidence to support the use of one variety versus another. the concepts that are generally accepted as the essentials of good wound care include the provision of an optimal wound environment.71). thereby reducing the quality of the evidence to support their use (33.39). the management of foot ulceration should address glycemic control. Although very effective in healing noninfected. Uncontrolled diabetes can result in immunopathy with a blunted cellular response to infection. These therapies may be considered if other conventional options already have been explored (53). Generally. Streptococcus pyogenes (group A streptococcus) and Streptococcus agalactiae (group B streptococcus). Certain subpopulations with diabetes on insulin therapy have poorer outcomes after revascularization than those on oral anithyperglycemic therapy. patient education. Endovascular techniques with angioplasty and stenting in infrainguinal arteries are also effective in limb salvage. This is best achieved with an interdisciplinary approach (36. Removable and irremovable cast walkers and total contact casting have demonstrated efficacy as pressure-reducing devices in plantar surface ulcers (54e56). lowerextremity vascular status and local wound care (35). There are insufficient data to support the use of specific dressing types or antimicrobial dressings in the routine management of diabetic foot wounds (40e48). There is. perhaps reflecting a greater association of comorbidities (75. J. duration and follow-up. With the exception of only a small number of antimicrobial agents that do have a specific indication for the treatment of diabetic foot infections. Data are limited and caution is advised in interpreting these findings (74). but these studies have been limited in sample size. Infection may complicate foot ulcers and may progress rapidly to become limb and/or life threatening (65). and early detection and treatment of diabetic foot ulcers (32). pressure relief/offloading.67). however. Other adjunctive measures for wound healing. consultation with a surgeon skilled in foot surgery may be considered to address the deformity (58e60). in a total contact cast or removable walker device until excessive foot temperatures return to normal (61). Treatment of the acute Charcot foot requires immobilization of the foot. regular debridement of nonviable tissue (38. Deep infections require prompt surgical debridement in addition to appropriate antibiotic therapy (73). wound dressings that maintain a moist wound environment should be selected. further studies are necessary to fully evaluate the use of these agents and other medical therapies in the routine treatment of Charcot arthropathy (62e64). are unreliable in determining the bacterial pathogens involved (68e70). Bowering. When infections first begin.76). In general.37). have been studied in diabetic foot ulcer management. In medically suitable individuals with PAD. Initial antibiotic therapy is typically empiric and may be broad spectrum. some evidence to support NPWT as a postoperative intervention after extensive debridement (49e52). the most frequently encountered pathogens include Staphylococcus aureus. in some studies. regular callus debridement. total contact casting requires careful individual selection and personnel trained specifically in its application due to its potential for complications (57). professionally fitted therapeutic footwear to reduce plantar pressure and accommodate foot deformities. Up to 50% of patients with diabetes who have a significant limb infection may not have systemic signs of fever or leukocytosis at presentation (72). Granulocyte colonystimulating factors have been used as adjunctive therapy in infected diabetic wounds and.78). gram-negative and anaerobic pathogens also can play a role in the process.M. such as topical growth factors and dermal substitutes. . Although bisphosphonate therapy has been considered for the management of Charcot arthropathy. unfortunately. nonischemic plantar surface neuropathic ulcers. were found to reduce the need for surgical intervention. as opposed to deeper tissues obtained by debridement. infection. Many of the studies conducted to assess interventions designed to reduce the occurrence of and heal diabetic foot ulcers have. distal limb revascularization has potential benefit in long-term limb salvage. although the long-term results are inferior in the population with diabetes compared to those without diabetes (77. pressure offloading from the ulcer site and. Specimens for culture from the surface of wounds. Pressure offloading may be achieved with temporary footwear until the ulcer heals and the character of the foot stabilizes. typically for several months. TMP-SMX.K.M. Diabetic foot infections. methicillin-resistant Staphylococcus aureus. Embil / Can J Diabetes 37 (2013) S145eS149 Table 2 Empiric antimicrobial therapy for infection in the diabetic foot S147 MRSA. J. Printed in China: McGraw-Hill. Bowering. John J. Ross. Trepman E. Editors: Sylvia C. Dressler. Brotman. 2012. trimethoprim-sulfamethoxazole. . McKean. Ginsberg. Jeffrey S. Daniel D. * Modified and used with permission from Embil JM. In: Principles and Practice of Hospital Medicine. Daniel J. 100:65e86. et al. Louis. Faglia E. Boulton AJ. Individuals who develop a foot ulcer should be managed by a multidisciplinary healthcare team with expertise in the management of foot ulcers to prevent recurrent foot ulcers and amputation [Grade C. International Working Group on the Diabetic Foot (IWGDF) Editorial Board.14: 8e11. 32. Oyibo SO. Chalmers N. Morrison WB. Desgranges P. Peripheral arterial disease in diabetic and nondiabetic patients: a comparison of severity and outcome. Jude EB. et al. Diabet Med 2009.301:415e24. et al. Embil JM. evaluation for neuropathy and PAD. Lavery LA. J. Venermo M. 12. Differential diagnosis of pedal osteomyelitis and diabetic neuroarthropathy: MR imaging. Prediction of diabetic foot ulcer occurrence using commonly available clinical information. 6. Harding KG. BMC Health Serv Res 2003. consequences and costs of diabetes-related lower extremity amputations complicating type 2 diabetes: the Freemantle Diabetes Study. Oyibo SO. Level 3 (38)]. Winell K. Clerici G. Morrison WB. 19. Frykberg RG. Diabetes Care 2005. Schaper NC. p.g. Practical guidelines on the Hyperbaric oxygen therapy (HBOT) is not considered part of the routine management of persons with neuropathic/neuroischemic foot ulcerations with or without underlying infection. Higgins KR. A clinical practical guideline (2006 revision).33:2598e603.24:84e8. Carrino JA. 28. 18. p. Causal pathways for incident lowerextremity ulcers in patients with diabetes from two settings. 11. 8. J Vasc Surg 2011. Predicting foot ulcers in patients with diabetes: a systematic review and meta-analysis. Fagrell B. Feng Y. et al. Boulton AJ. PAD. Zgonis T. et al. Price P.22:157e62. Semin Musculoskelet Radiol 2005. peripheral arterial disease. Gadolinium-enhanced MR angiography as first-line preoperative imaging in high-risk patients with lower limb ischemia. 3. granulocyte colony-stimulating factors. Kleijnen J. O’Brien JA. Trepman E.35:822e7.82. Lapeyre M. Ikonen TS. Albert SF. Bruce DG. Level 4 (1)]. Relationship of limited joint mobility to abnormal foot pressures and diabetic foot ulceration. S142 Relevant Appendices Appendix 9: Diabetes and Foot Care: A Patient’s Checklist Appendix 10: Diabetic Foot Ulcers: Essentials of Management References 1. Cost of managing complications resulting from type 2 diabetes mellitus in Canada. Diabetes Care 2006. Preventing diabetic foot ulcer recurrence in high-risk patients: use of temperature monitoring as a self-assessment tool. et al. Gabrielli L.92: 210e20. Boyko EJ. Diabet Med 2005. Caro JJ. Fernando DJ. 2002-2006. In carefully selected persons with nonhealing foot ulcerations for whom all possible interventions have been attempted. Hartemann-Heurtier A.31:1679e85. Bipat S. AJR Am J Roentgenol 2005. 29. Diabetes Care 2001. professionally fitted footwear and early referrals to a healthcare professional trained in foot care management if foot complications occur [Grade C. Armstrong DG. Diabetes Care 1999. 25. Davis TM. Jude EB. The Seattle Diabetic Foot Study. Masson EA. Reiber GE. Level 4 (53.238:622e31. In people with diabetes. 7. ulcerations and evidence of infection [Grade D. Nephrogenic fibrosing dermopathy associated with exposure to gadolinium-containing contrast agentseSt. Met R. Assessment of critical limb ischemia in patients with diabetes: comparison of MR angiography and digital subtraction angiography. with endorsement by the American Association of Clinical Endocrinologists. HBOT may be considered as an adjunctive therapy (79e81).5:577e81. American Association of Clinical Endocrinologists. Other Relevant Guidelines Targets for Glycemic Control. Williams DT. 5. foot examinations by healthcare providers should be an integral component of diabetes management to identify persons at risk for ulceration and lower-extremity amputation [Grade C. 23. The ankle-brachial index and the diabetic foot: a troublesome marriage. Nelson KM. Level 3 (33. such as topical growth factors. SCAR (SCreening for ARteriopathy) Study Group.22: 1036e42. Pedersen M. Vileikyte L. Diabetes Care 1991.26: 391e6. 20. 30. Sund R.25:770e7. Armstrong DG. Boyko EJ. Ahroni JH. 17. Massaad D. evidencebased criteria for the selection of persons with diabetes who have foot problems and who may benefit from HBOT do not exist. Kobeiter H. Neuropathic arthropathy of the foot with and without superimposed osteomyelitis: MR imaging characteristics. 56:137e41.21:855e9. 24. The Semmes Weinstein monofilament examination is a significant predictor of the risk of foot ulceration and amputation in patients with diabetes mellitus. et al. infection. range of motion of ankles and toe joints. 27. 31. Diabetes Care 2009. Lanctot DR. Sumpio BE.53:220e6. American College of Foot and Ankle Surgeons. Level 4 (1)]. J Am Podiatr Med Assoc 2002.30:14e20. Diabetes Care 1999. Screening for peripheral arterial disease by means of the anklebrachial index in newly diagnosed type 2 diabetic patients. 13. et al.22:147e51. Aerden D. Bauer E. Diabetes Care 2010. 16. et al. structural abnormalities (e. hyperbaric oxygen therapy. Brillet PY. bony deformities). A comparison of two diabetic foot ulcer classification systems: the Wagner and the University of Texas wound classification systems. Diabetes Care 1999. et al. Ahroni JH. Level 3 (36)]. Norman PE.34:317e21. Armstrong DG. but they may be considered in nonhealing. Diabetes Care 2007. The contribution of depth. 2. Bowering. RECOMMENDATIONS 1. Boyko EJ.45(5 suppl):S1e66. Abbreviations: HBOT. Inkster M. et al. . et al. Ledermann HP. 4. von Kemp K. Marchetti R.12)] and should be performed at least annually and at more frequent intervals in those at high risk [Grade D.80)]. Jacqueminet S. and ischemia to risk of amputation. Radiology 2006. skin temperature. Ann Vasc Surg 2011. Fewer major amputations among individuals with diabetes in Finland in 1997-2007: a population-based study. Crawford F. 9. Caravaggi C. General principles of wound management involve the provision of a moist wound environment. et al. Transcutaneous oxygen tension and toe blood pressure as predictors for outcome of diabetic foot ulcers. Diabetes Care 1998. J Vasc Interv Radiol 2003. Predictors.M. 22. J Rehabil Res Dev 1997. 26. J Foot Ankle Surg 2006. debridement of nonviable tissue (nonischemic wounds) and offloading of pressure areas [Grade B. Lavery LA. nonischemic wounds when all other options have been exhausted [Grade D. There is currently insufficient evidence to recommend any specific dressing type for diabetic foot ulcers [Grade C. Long-term prognosis of diabetic patients with critical limb ischemia: a population-based cohort study. Faglia E.83)]. Evidence is currently lacking to support the routine use of adjunctive wound-healing therapies. Currently. An evaluation of the efficacy of methods used in screening for lower-limb arterial disease in diabetes. 15.29: 1202. 14. Fahey T. Hudson JR.S148 K.3:7. Missouri. Legemate DA. Stensel V. Yu GV. Apelqvist J.22:1310e4. 10. Nat Rev Endocrinol 2009. Armstrong DG. Kalani M.14:1139e45. Diabetologia 2006. S31 Neuropathy. Tarawneh I. Ahmadi ME. et al. Brismar K. Fosse S. dermal substitutes or HBOT in diabetic foot ulcers. Level 3 (5. American Diabetes Association. JAMA 2009. Diabetes Care 2001. Veves A. MMWR Morb Mortal Wkly Rep 2007. Patrick AR. Tassart M. Assessment by healthcare providers should include the assessment of skin changes. Centers for Disease Control and Prevention (CDC). QJM 2007. et al.74. Davis WA. Evaluation and treatment of stage 0 Charcot’s neuroarthropathy of the foot and ankle.24:1433e7. 2. Comprehensive foot examination and risk assessment: a report of the task force of the foot care interest group of the American Diabetes Association.9: 272e83. Monitoring healing of acute Charcot’s arthropathy with infrared dermal thermometry. 5.28: 2206e10.185:1641e50. Harkless LB. Embil / Can J Diabetes 37 (2013) S145eS149 3. 21. A case of diabetic Charcot arthropathy of the foot and ankle. A prospective study of risk factors for diabetic foot ulcer. Lavery LA. et al.25:881e3. People at high risk of foot ulceration and amputation should receive foot care education (including counselling to avoid foot trauma). Incidence and characteristics of lower limb amputations in people with diabetes. van Houtum WH.49:2634e41. J Magn Reson Imaging 2007. Level 3 (40)]. Safety update on the possible causal relationship between gadolinium-containing MRI agents and nephrogenic systemic fibrosis. Bakker K. Diabetic foot disorders. et al. Validation of a diabetic wound classification system. Schlösser FJ. Diagnostic performance of computed tomography angiography in peripheral arterial disease: a systematic review and meta-analysis. Vayssairat M. 4. callus pattern. Diabetes Care 2008. Topical silver for treating infected wounds. Freyer D.183:61e4. 48. S149 33. Bisphosphonates in the treatment of Charcot neuroarthropathy: a double-blind randomised controlled trial. Huijberts MS. Gregor S. Vinik A.44:2032e7. Wound dressings in diabetic foot disease. Cochrane Database Syst Rev 2004. et al.3:CD006810. GMS Health Technol Assess 2010. Fagher K. Williams DT. Sumpio BE.39(suppl 2):S100e3. The importance of growth factors for the treatment of chronic wounds in the case of diabetic foot ulcers. Sleegers R. Bergin SM. Armstrong DG.6:Doc12. 78. Diabetes Care 2011. Insulin use is associated with poor limb salvage and survival in diabetic patients with chronic limb ischemia. Ottawa. Singh N.21:705e9. Swab cultures accurately identify bacterial pathogens in diabetic foot wounds not involving bone.143:189e96. 2010.1:CD005486. Giurini JM.1:CD003556. McCabe CJ. et al. Canadian Diabetes Association Technical Review: the diabetic foot and hyperbaric oxygen therapy. Diabetes Care 2006. Br J Surg 2001. Bus SA. Six-month treatment with alendronate in acute Charcot neuroarthropathy: a randomized controlled trial. 12. diagnosis and treatment. Tan JS. A metaanalysis. Jonushaite A. Hackney LA. Sheldon TA. Beltrand E. 40. July 7. Isildak M. 2013. et al. Katzman P.29:1288e93. Single-stage surgical treatment of noninfected diabetic foot ulcers. Canadian Agency for Drugs and Technologies in Health. 2013. Trepman E. 68.51:1178e89. Preventing foot ulcers in patients with diabetes. Silver Dressings for the Treatment of Patients with Infected Wounds: A Review of Clinical and CostEffectiveness. Dargis V.33:998e1003. Sauerland S. et al. Hammarlund C. Cochrane Database Syst Rev 2007. Majid M. doi:10. Pantelejeva O.ca/media/pdf/ l0193_silver_dressings_htis-2. 51. Can aggressive treatment of diabetic foot infections reduce the need for above-ankle amputation? Clin Infect Dis 1996. Kriegsman DM.42:57e62. editor. J Vasc Surg 2007.pdf.28:243e7. Diabetes Care 2005. Kansal N. 67. et al. Selby PL.22:692e5. 66. Negative Pressure Therapy for Patients Infected Wounds: A Review of the Clinical and Cost Effectiveness Evidence and Recommendations for Use. 35. Lipsky BA. 50. Systematic review of antimicrobial agents used for chronic wounds. Off-loading the diabetic foot wound: a randomized clinical trial. July 14. Canada: Canadian Pharmacists Association. Elective surgery of the diabetic foot. Armstrong DG. Armstrong DG.3:CD006478. Buchberger B.cadth. Topical silver for preventing wound infection.293:217e28. Miranda-Palma B. Vos CG. 63. 70. Cullum NA. et al. Beuker B. Karakaya J. et al. Total contact casting of the diabetic foot in daily practice: a prospective follow-up study. Westerbos SJ.52:314e22. J.23:286e91. Dressings and topical agents for surgical wounds healing by secondary intention. de Lalla F. Conrad MF. Löndahl M. 59. Topical negative pressure for treating chronic wounds. Wunderlich RP. The effectiveness of footwear and offloading interventions to prevent and heal foot ulcers and reduce plantar pressure in diabetes: a systematic review. Hamdan AD. 49. et al. 83. Pearson RL. Clin Infect Dis 2004. 39. Jude EB.31:633e58. Harlan A. Gürlek A. Armstrong DG.109:601e9. JAMA 2005. .3205/hta000090. 46. Dolan AM. Friedman NM. Mengoli C. Armstrong DG. Pomposelli FB. 2011. Benefits of a multidisciplinary approach in the management of recurrent diabetic foot ulceration in Lithuania: a prospective study. Galimanis A. Accuracy of cultures of material from swabbing of the superficial aspect of the wound and needle biopsy in the preoperative assessment of osteomyelitis. What is the role of hyperbaric oxygen in the management of diabetic foot disease? Curr Diabetes Rep 2011.22:1428e31.2:CD003554. 54. Cruciani M. Diabetes Care 2010. Bowering. 65. Diabetes Care 1999. A systematic review of the effectiveness of interventions to enhance the healing of chronic ulcers of the foot in diabetes. Cochrane Database Syst Rev 2010. Burgess J. Surgical or endovascular revascularization in patients with critical limb ischemia: influence of diabetes mellitus on clinical outcome. Nabuurs-Franssen MH. Abularrage CJ. Vermeulen H. et al. Long-term outcomes of diabetic patients undergoing endovascular infrainguinal interventions. Löndahl M. Vermeulen H. Berlin JA. Endocrinol Metab Clin North Am 2002. van Hattem JM. 2010. Cochrane Database Syst Rev 2006.3:CD001898. Hazelton-Miller C. Ekoé JM. Patient education for preventing diabetic foot ulceration: a systematic review.24(suppl 1): S181e7. Lavery LA. pdf. Lipsky BA. Diabetologia 2001. Rosenblum BI. 52. 61. 74. 41. Lindsley L. 71. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Hilton JR. Diabetes Metab 2010. 82. Aydin K. Ubbink DT. Webster MW. Diabetes Care 1999. Katz IA. Senneville E. Boldur I. 62. 72. Hinchliffe RJ. Diabetes Metab Res Rev 2008. Nader ND. Negative pressure wound therapy after partial diabetic foot amputation: a multicentre.36:251e5. et al. 37.26:46e63. 47. 80. 64. Negative pressure wound therapy: a vacuum of evidence? Arch Surg 2008. Dosluoglu HH. Diabet Med 1998. et al. et al. 75. Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: concordance with ulcer swab cultures. Pinzur MS. Fonseca V. Ubbink DT. Foot Ankle Int 1997. 45. Apelqvist J. Diabetes Care 2001. Clin Infect Dis 2006. Peters A. Healing of diabetic neuropathic foot ulcers receiving standard treatment.24:1019e22.30: 411e21. Charcot’s foot: newest findings on its pathophysiology. Ubbink DT. 58. Räkel A. 38. Vermeulen H. Debridement of diabetic foot ulcers. Cochrane Database Syst Rev 2009. 55.24(suppl 1):S162e80. Maegele M. Effect of extensive debridement and treatment on the healing of diabetic foot ulcers. Donohoe D. 81. Evans D. Drugs 2007. et al. 77. Huot C. Stenström A. Embil / Can J Diabetes 37 (2013) S145eS149 management and prevention of the diabetic foot: based upon the International Consensus on the Diabetic Foot (2007). Miller GA. 57. Risk factors for foot infections in individuals with diabetes. Canadian Agency for Drugs and Technologies in Health. 69. Lavery LA. Edwards J.366:1704e10. 56. Perry CR. O’Meara SM. Lipsky BA. et al. Diabetes Care 2005. et al.23:348e59. Lall P.ca/media/pdf/l0194_negative_pressure_therapy_htis-2. Storm-Versloot MN. 79. 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A decade of experience with dorsalis pedis artery bypass: analysis of outcome in more than 1000 cases. Endocrine 2010. Diabet Med 2006. Diabetes Care 2005.28:1214e5. et al. Nilsson A.M. Embil JM. Evaluation of removable and irremovable cast walkers in the healing of diabetic foot wounds: a randomized controlled trial.cadth. Can J Diabetes 2006. et al. Lipsky BA. Golder S. Available at: http://www. 42. Kantor J.20:783e92.11: 285e93. Hyperbaric oxygen therapy facilitates healing of chronic foot ulcers in patients with diabetes. Therapeutic Choices. 44. J Vasc Surg 2010. Valk GD.88:4e21. Stapley S. et al. Clin Podiatr Med Surg 2003.34:1041e6. Diabetes Metab Res Rev 2008. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections.24(suppl 1):S119e44. Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections.38:87e92. Clin Infect Dis 2012. Optimizing antimicrobial therapy in diabetic foot infections. Diabetic Ulcer Study Group.67:195e214. 6th ed. Slater RA. Eneroth M. Pitocco D. Paragas LK. 43. Silver based wound dressings and topical agents for treating diabetic foot ulcers.73:745e9. Wraight P. Nguyen HC. Caputo S. Evaluation of a diabetic foot screening and protection programme. Ubbink D.28:555e9. J Vasc Surg 2010. Sayner LR. Diabet Med 2004. Diehm N.28:551e4. Nihal A. et al. Wu S. 73. Lavery LA. Diabetic infection.37:307e15. Accessed March 1. Systematic review of antimicrobial treatments for diabetic foot ulcers. 34. Diabetes Metab Res Rev 2008. et al. Cochrane Database Syst Rev 2010. Change in amputation predictors in diabetic foot disease: effect of multidisciplinary approach. Ruotolo V. Plast Reconstr Surg 2002. Arad Y. Apelqvist J. 60. Goossens A. with both positive and negative studies (28. International Index of Erectile Function (37.01. a condition that can impair sensory feedback from the penis. In spite of the overwhelming amount of data linking ED and diabetes. such as some antihypertensives and antidepressants. Introduction Erectile dysfunction (ED) affects approximately 34% to 45% of men with diabetes and has been demonstrated to negatively impact quality of life among those affected across all age strata. KEY MESSAGES  Erectile dysfunction (ED) affects approximately 34% to 45% of adult men with diabetes. hypertension. Organic causes of ED include microvascular and macrovascular disease.38) or Sexual Health Inventory for Men (39)) have been shown to be both sensitive and specific in determining the presence of ED and providing a means of assessing response to therapy.18). Diabetic retinopathy has been shown to correlate with the presence of ED (8. while bioavailable testosterone is recognized as the gold standard for biochemistry confirmation. with a low reported side effect profile. duration of diabetes.2013.17. Men with diabetes and ED should be further investigated for hypogonadism. Those with ED should be investigated for hypogonadism. the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) showed that intensive glycemic control was effective for primary prevention of and secondary intervention for neuropathy.jcjd. where treatment of nonresponders to PDE5 inhibitors with testosterone replacement is successful in roughly 50% of individuals. FRCSC. ED is a side effect of many drugs commonly prescribed to men with diabetes. cigarette smoking. and should be offered as first-line therapy to men with diabetes wishing treatment for ED. and neuropathy. The Androgen Deficiency in Aging Males (ADAM) instrument is the most widely accepted screening questionnaire. leading to reduced erectile function (41e43).34. glycemic control and ED. dyslipidemia. a recent report describes 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. Interestingly.041 Treatment While no randomized clinical trials have demonstrated that interventions that improve glycemic control also reduce the incidence and progression of ED.  All adult men with diabetes should be regularly screened for ED with a sexual function history. and should be .Can J Diabetes 37 (2013) S150eS152 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. androgen deficiency states (16) and cardiovascular (CV) disease (8. with a greater likelihood among men with diabetes that their ED is permanent (1). Based on these conflicting data. Furthermore. In addition. multiple studies have reported men with diabetes having higher rates of hypogonadism (16. risk factors include increasing age. with upward of 50% of men having ED by year 6 after diagnosis (3). studies indicate that 40% of men with diabetes >60 years of age have complete ED (4e12).31e34). Among the population with diabetes. total testosterone is an acceptable alternative if bioavailable testosterone is unavailable or unaffordable (40). They have been reported to have a major impact on erectile function and quality of life.10. Validated questionnaires (e.44e46). phosphodiesterase type 5 (PDE5) inhibitors appear to be less effective in hypogonadal states (32.doi. In fact.g.29). In addition. has been demonstrated to negatively impact quality of life among those affected across all age strata and may be the earliest sign of cardiovascular disease. FRCPC a correlation between glycemic control and testosterone levels (35). poor glycemic control.com Clinical Practice Guidelines Erectile Dysfunction Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Gerald Brock MD. The current mainstay of treatment for ED is therapy with PDE5 inhibitors. and.  The current mainstay of therapy is phosphodiesterase type 5 inhibitors. Screening for ED in men with type 2 diabetes should begin at diagnosis of diabetes.28). Recent reports describe up to one-third of newly diagnosed men with diabetes have ED at presentation (2).10. this remains a subject often neglected by clinicians treating the population with diabetes (30).org/10. The current data are controversial as it relates to diet. Recent studies have reported that alteration of the cyclic guanosine monophosphate (cGMP(/nitric acid (NO) pathway among men with diabetes with impaired vascular relaxation is related to endothelial dysfunction (13e15). Screening All adult men with diabetes should be regularly screened for ED with a sexual function history. ED as a marker of potential CV events has been reported by numerous investigators (19e26). psychological or situational factors may cause or contribute to ED. They have been shown to have major impacts on erectile function and quality of life. Importantly. ED has been shown to be significantly associated with all-cause mortality and CV events (27. a prudent physician should encourage tight glycemic control as a potential factor in maintaining erectile function (28). Compared with the general population.canadianjournalofdiabetes.1016/j.36). William Harper MD. Diabetes Care 1996. J Clin Endocrinol Metab 2004.G. Consensus]. et al. Peiró C. among PDE5 inhibitor failure patients. Am J Cardiol 1988. Rubin A. intracorporal injection therapy with prostaglandin E1 [PGE1] alone or in combination with papaverine and phentolamine [triple therapy].46:285e90. Christov VG. et al.6-di-t-butyl4-((dimethyl-4-methoxyphenylsilyl) methyloxy)phenol). Alexopoulou O. Effects of age on complications in adult onset diabetes. if there are no contraindications to its use.34)]. to premature or retarded ejaculation. may impact lower urinary tract symptoms and has the potential for endothelial benefits (55). Fernández A. et al. Level 4 (16. and may improve efficacy with lower rates of side effects. Adherence to Mediterranean diet and erectile dysfunction in men with type 2 diabetes. Int J Clin Pract 2007. They range in scope from retrograde ejaculation. J Sex Med 2010. Rosenthal M. Jamart J. Subclinical coronary artery atherosclerosis in patients with erectile dysfunction. 32. Hatzichristou DG. Aversa A. clinical features and treatment. Prevalence of self-reported erectile dysfunction in people with long-term IDDM. Aging Male 2003. et al. Diabetes Metab 2001. Kahn CB. Fisher W. J Am Geriatr Soc 1989. Association of type and duration of diabetes with erectile dysfunction in a large cohort of men.166:201e6. Level 2 (53. 18. Enhanced thromboxane receptormediated responses and impaired endothelium-dependent relaxation in human corpus cavernosum from diabetic impotent men: role of protein kinase C activity. 11. erectile dysfunction.27(suppl 1):I8e13. Bruzziches R. 2. Identifying patients with type 2 diabetes with a higher likelihood of erectile dysfunction: the role of the interaction between clinical and psychological factors.32.6:1e7. 24. 2. Eardley I.37:838e42. W. Maiorino MI. Erectile dysfunction and lower androgenicity in type 1 diabetic patients. visceral obesity and partial androgen deficiency. et al. Diabetologia 1984. J Am Coll Cardiol 2005. Erectile dysfunction and mortality.89: 5462e8. Montague DK.18:279e83. 4. et al. attitudes and treatment-seeking patterns in men with erectile dysfunction. Expert Rev Cardiovasc Ther 2006. Al-Hunayan A. 12. Acta Diabetol 2009.58).17(suppl 1):S19e24. Ratti C. 27. J Pharmacol Exp Ther 2006. 21. Referral to a specialist in ED should be considered for eugonadal men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated [Grade D. Diabetes exacerbates the functional deficiency of NO/cGMP pathway associated with erectile dysfunction in human corpus cavernosum and penile arteries. Dhindsa S. should be offered as first-line therapy to men with diabetes and ED in either an ondemand [Grade A. 26. Men with diabetes and ejaculatory dysfunction who are interested in fertility should be referred to a healthcare professional experienced in the treatment of ejaculatory dysfunction [Grade D. Int J Impot Res 2000. 23. Level 1A (47-53)] or scheduled-use [Grade B. Al-Mutar M. How often do we ask about erectile dysfunction in the diabetes review clinic? Development of a neuropathy screening tool. Ejaculatory Disorders Ejaculatory disorders are a common disorder of sexual function in men with diabetes. Thompson IM. Kehinde EO.29:589e92. Bellastella G. 8. Erectile dysfunction in general medicine practice: prevalence and clinical correlates. Cuevas P. AC3056 (2. 30. Franciosi M.54). Prescott RJ. J Urol 2003. et al. Referral to a specialist in ED should be offered to men who do not respond to PDE5 inhibitors or for whom the use of PDE5 inhibitors is contraindicated. Kaouache M. Prediction of coronary heart disease by erectile dysfunction in men referred for nuclear stress testing. The prevalence of erectile dysfunction in the primary care setting: importance of risk factors for diabetes and vascular disease. J Sex Med 2010. Heart disease risk factors predict erectile dysfunction 25 years later (the Rancho Bernardo Study). The prevalence and predictors of erectile dysfunction in men with newly diagnosed with type 2 diabetes mellitus. 16. Harper / Can J Diabetes 37 (2013) S150eS152 S151 offered as first-line therapy to men with diabetes wishing treatment for ED (47e52). et al. Chronic sildenafil in men with diabetes and erectile dysfunction. 13. 22. Diabetes 1974. Billups KL. Their recognition as an important component in sexual quality of life makes inquiry about ejaculatory function important. 6. Additionally. et al. Angulo J. et al. Sethi M. All adult men with diabetes should be regularly screened for ED with a sexual function history [Grade D. 5. occurring in 32e67% of that population (61). Expert Opin Drug Metab Toxicol 2007. Campbell IW. De Berardis G. Urology 1987.46:1503e6.31. Interestingly.6:373e87. Cuevas P. Wu FC.169: 1422e8. or intraurethral therapy using PGE1) or third-line therapy (penile prosthesis) may be considered for these men (60).23:306e9.57. 19. et al. Clin Cardiol 2004. Boneva Z. S184 . men with diabetes appear to have lower rates of side effects with PDE5 inhibitors than the general population. Naliboff BD.27:329e36. Hu FB. Grover SA. usually secondary to autonomic neuropathy with incomplete closure of the bladder neck during ejaculation. The multinational Men’s Attitudes to Life Events and Sexuality study: the influence of diabetes on self-reported erectile function. Other Relevant Guidelines Screening for the Presence of Coronary Artery Disease. 14. 3. Araujo AB. Impotence and diabetes mellitus. et al. 4. PDE5. Goodman PJ.7:1911e7.12:41e5. 29. Lowensteyn I. et al. phosphodiesterase type 5. Angulo J. Lipscomb D. McCulloch DK. Maiter D. et al. Men with diabetes and ED should be investigated for hypogonadism [Grade D. Erectile dysfunction and subsequent cardiovascular disease. Diabetes Care 2002.168:498e500. Sexual dysfunction in the diabetic patient with hypertension. References 1. Giovannucci E. et al.6:2445e54. Tangen CM. 15. 5. et al. Abbreviations: ED. et al. Erectile dysfunction as an early sign of cardiovascular disease. Bacon CG. Pellegrini F. A PDE5 inhibitor. Martin LM. 10. p. 31. Kolodny RC. 25:1458e63.3:451e64. J Sex Med 2009. Ganz P. Testosterone supplementation in men with type 2 diabetes. Brock. reverses erectile dysfunction in diabetic rats and improves NO-mediated responses in penile tissue from diabetic men.99:130e4. Erectile dysfunction in men with diabetes mellitus. Am J Cardiol 2005. Impotence and its medical and psychosocial correlates: results of the Massachusetts Male Aging Study. Consensus].61:27He33H. et al. JAMA 1958. use of a vacuum constriction device may salvage a significant percentage of erectile function and should be considered (56).26:437e40. Cardiovascular risk stratification and cardiovascular risk factors associated with erectile dysfunction: assessing cardiovascular risk in men with erectile dysfunction.96:3Me7M. Feldman HA. Evidence for scheduled daily therapy is effective within the population with diabetes and ED (53.54)] dosing regimen. 9. Frequent occurrence of hypogonadotropichypogonadism in type 2 diabetes. The natural history of impotence in diabetic men.g. Chiurlia E. Giugliano F. Barrett-Connor E. 3. BJU Int 2007. This is believed to be a result of altered vasomotor tone or other factors (59). Goldstein HH. RECOMMENDATIONS 1.19:135e41. Diabetologia 1980. Zemel P. J Sex Med 2009. Rosen RC. Erectile dysfunction and coronary atherothrombosis in diabetic patients: pathophysiology. Maatman TJ. Contraindications for the use of PDE5 inhibitors include unstable angina or untreated cardiac ischemia and concomitant use of nitrates (3.61:1446e53.319:783e9. 7(2 pt 1):758e68. Boyanov MA. Goldstein I. Angulo J. Gazzaruso C. et al. Lee KE. vacuum constriction devices. 17. p. Min JK. Prabhakar S. McCulloch DK. Int J Impot Res 2005. Chew KK. Klein R. The prevalence of diabetic impotence. et al. 20. Arch Intern Med 2006. et al. González-Corrochano R. S105 Diabetes in the Elderly. Earle CM. Sexual dysfunction in diabetic men.4:173e80. Grant PS. Vitale C. Travison TG. Consensus]. Second-line therapies (e. Okwuosa TM. The novel antioxidant. Cuevas P. Stuckey BG.166:213e9. Arch Intern Med 2006. Babbott D. JAMA 2005. Barrett-Connor E.151:54e61. Williams KA.294:2996e3002. J Urol 1994. D’Amico R. 28. 7. 25. et al. Klein BEK. Young RJ. et al. Wagner G. Mulcahy JJ. et al. 55. Lue TF. . BJU Int 2005. Athanasopoulos A. Bella A.122:561e8. Briganti A. Rajfer J. Pattern of endocrinal changes in patients with sexual dysfunction. safety and patient satisfaction outcomes of the AMS 700CX inflatable penile prosthesis: results of a long-term multicenter study. The impact of daily sildenafil on levels of soluble molecular markers of endothelial function in plasma in patients with erectile dysfunction. 58. The evolving role of testosterone in the treatment of erectile dysfunction. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Rubio-Aurioles E. et al. J Sex Med 2006. et al. et al. Young JM. The effects of intensive glycemic control on neuropathy in the VA Cooperative Study on Type II Diabetes Mellitus (VA CSDM).96:257e80. Sayed HM. Am J Cardiol 2000. Likelihood of tadalafil-associated adverse events in integrated multiclinical trial database: classification tree analysis in men with erectile dysfunction. The Diabetes Control and Complications Trial Research Group. Moncada I. et al.60:1378e85. 39. J Urol 2000. 88:152e9. Auerbach S. Giannitsas K. Denne J. Hermann. et al. 44:1296e301. Ramanathan R. Impact of diabetes mellitus on the severity of erectile dysfunction and response to treatment: analysis of data from tadalafil clinical trials. Valiquette L. Goldstein I. et al. Glina S. et al. Abraira C.73:756e61.25:2159e64. Buvat J. Carson CC. et al. Isidro ML. Gallina A. 35. Diabetologia 2001. et al. W. 10:155e60. Selam J-L. Shabsigh R. 57. 38. 50. a new phosphodiesterase type 5 inhibitor.86:175e81. Urology 1997. 25:138e46. Nat Clin Pract Urol 2005. 59. et al. Efficacy of tadalafil once daily in men with diabetes mellitus and erectile dysfunction. 44. 54. Randomized study of testosterone gel as adjunctive therapy to sildenafil in hypogonadal men with erectile dysfunction who do not respond to sildenafil alone. 41. Hatzichristou D. Rosen RC. Fischer J. 48. Harper / Can J Diabetes 37 (2013) S150eS152 47. 33. Urology 2009. El-Sakka AI. Prospective correlation between the International Index of Erectile Function (IIEF) and Sexual Health Inventory for Men (SHIM): implications for calculating a derived SHIM for clinical use. Sildenafil for treatment of erectile dysfunction in men with diabetes: a randomized controlled trial. Kalinchenko SY. Boulton AJM. Sildenafil citrate for the treatment of erectile dysfunction in men with type II diabetes mellitus. Int J Clin Pract 2006. Aversa A. N Engl J Med 1993. Goldstein I. Chun S. J Sex Med 2007. 42. 51.S152 G. Ann Intern Med 1995. Sáenz de Tejada I. Int J Clin Pract 2006. Cappelleri JC.164:376e80. Urology 1999. Konstantinopoulos A. 53. Diagnostic evaluation of the erectile function domain of the International Index of Erectile Function. Oral testosterone undecanoate reverses erectile dysfunction associated with diabetes mellitus in patients failing on sildenafil citrate therapy alone. Tayeb KA. 52. 60. et al. Vardenafil Study Group. Combination of vacuum erection device and PDE5 inhibitors as salvage therapy in PDE5 inhibitor nonresponders with erectile dysfunction. et al.26:777e83. Brock G. Sweeney M. J Diabetes Complications 1990. Postgrad Med 2012. On-Demand Regimen Evaluation (SURE) study in 14 European countries. J Sex Med 2005. JAMA 1999. Kaufman JM. Emanuele NV. Diabetologia 2004. Drug insight: oral phosphodiesterase type 5 inhibitors for erectile dysfunction.4:1334e44. Rao S. Androgen pattern in patients with type 2 diabetes-associated erectile dysfunction: impact of metabolic control. Diabetes Care 2002. Smith MD. 43. 49. et al.352: 837e53. The effect of intensive diabetes therapy on the development and progression of neuropathy. Rosen RC.4:269e75. 40. Azad N. in the treatment of erectile dysfunction in men with diabetes: a multicenter double-blind placebo-controlled fixed-dose study.13:307e13. et al. 36. 46. Morales A. Govier FE. et al. Rajfer J.6:2561e7. Salonia A. Fredriksson W. 34. Rendell MS. Hassoba HM. et al. Bailen J. Gontcharov NP. Drory Y. Fonseca V. Mulhall J. First-dose success with vardenafil in men with erectile dysfunction and associated comorbidities: RELY-I. A practical guide to diagnosis. Expert Opin Pharmacother 2009. Shabsigh R. Seftel A. Knight JR. Efficacy.172: 658e63. 56. Kozlov GI. Can Urol Assoc J 2010. Anglin G. Montorsi F. Lancet 1998. Phosphodiesterase type 5 inhibitors for erectile dysfunction.60:1087e92. 37. DeBusk R. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. J Urol 2004. et al. Wicker PA. The Diabetes Control and Complications Trial Research Group. UK Prospective Diabetes Study (UKPDS) Group.49:822e30. Brock. Diabetes Care 2003. Vardenafil. Canguven O.47:1914e23.2:551e8. Urology 2009. El-Sakka AI. et al. management and treatment of testosterone deficiency for Canadian physicians.3:512e20. Aging Male 2003.2:239e47. Effects of tadalafil on erectile dysfunction in men with diabetes.6:94e9. Riley A. The International Index of Erectile Function (IIEF): a multidimensional scale for assessment of erectile dysfunction. Carson CC. 45. Diabet Med 2008. et al. Gambla M. Efficacy and safety of two dosing regimens of tadalafil and patterns of sexual activity in men with diabetes mellitus and erectile dysfunction: Scheduled Use vs.329:977e86. 281:421e6. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of the Princeton Consensus Panel. Steidle C. 61. Sexual dysfunction in men with type 2 diabetes.74:552e9. 54:346e51. J Sex Med 2009. Sayed HM. aggressive attempts should be made to reach the recommended glycemic targets outlined in Table 1. This section addresses those areas of type 1 diabetes management that are specific to children. more Introduction Diabetes mellitus is the most common endocrine disease and one of the most common chronic conditions in children. ongoing care and psychosocial support to a diabetes team with pediatric expertise.2). However. substance use. are being increasingly recognized in children and should be considered when clinical presentation is atypical for type 1 diabetes.1016/j. nutrition therapy. including genetic defects of beta cell function. Beth Mitchell PhD.Can J Diabetes 37 (2013) S153eS162 Contents lists available at SciVerse ScienceDirect Canadian Journal of Diabetes journal homepage: www. Insulin Therapy Insulin therapy is the mainstay of medical management of type 1 diabetes.01. FRCPC. Cpsych. including the child’s age. and prevention. The honeymoon period. but few have been studied specifically in children with new-onset diabetes. clinical judgement is required to determine which children can reasonably and safely achieve these targets. sick-day management and prevention of diabetic ketoacidosis (DKA). the term “child” or “children” is used for individuals 0 to 18 years of age. socioeconomic factors.canadianjournalofdiabetes. Regardless of the insulin regimen used.org/10. FRCPC.jcjd. Healthcare providers should regularly initiate discussions with children and their families about 1499-2671/$ e see front matter Ó 2013 Canadian Diabetes Association http://dx. Anticipatory guidance and lifestyle counselling should be part of routine care.  Children should be referred for diabetes education. duration of diabetes. while other studies have found chronic hyperglycemia in young children to be associated with poorer cognitive performance (7e10). MSc. family lifestyle. Education Children with new-onset type 1 diabetes and their families require intensive diabetes education by an interdisciplinary pediatric diabetes healthcare (DHC) team to provide them with the necessary skills and knowledge to manage this disease. and the term “adolescent” for those 13 to 18 years of age. FRCPC KEY MESSAGES  Suspicion of diabetes in a child should lead to immediate confirmation of the diagnosis and initiation of treatment to reduce the likelihood of diabetic ketoacidosis (DKA). Young age at diabetes onset (<7 years of age) has been associated with poorer cognitive function in many studies (6). school.  Management of pediatric DKA differs from DKA in adults because of the increased risk for cerebral edema. obtaining a driver’s license and career choices. patient. The choice of insulin regimen depends on many factors. exercise. upon school entry. Outpatient education for children with new-onset diabetes has been shown to be less expensive than inpatient education and associated with similar or slightly better outcomes when appropriate resources are available (3). beginning high school). Episodes of severe hypoglycemia have been associated with poorer cognitive function in some follow-up studies. such as maturity-onset diabetes of the young.2013. all children should be treated to meet glycemic targets. blood glucose (BG) and ketone testing. which can last up to 2 years after diagnosis. with consideration given to individual risk factors. was associated with improved metabolic control (11). developmental and emotional needs of children and their families necessitate specialized care to ensure the best long-term outcomes (1. and physician preferences.042 . and treatment of hypoglycemia. Type 2 diabetes and other types of diabetes. and consistent target setting by the diabetes team.5 units/kg/day). detection. and family. especially during critical developmental transitions (e. Céline Huot MD. psychological issues.doi. is characterized by good glycemic control and low insulin requirements (<0. Danièle Pacaud MD. dosage adjustment.5). Glycemic Targets As improved metabolic control reduces both the onset and progression of diabetes-related complications in adults and adolescents with type 1 diabetes (4. diabetes camp. A variety of insulin regimens can be used. Analysis from a large multicentre observational study found that knowledge of glycemic targets by patients and parents. The complex physical. At the end of this period.g. Children with new-onset diabetes who present with DKA require a short period of hospitalization to stabilize the associated metabolic derangements and to initiate insulin therapy. Note: Unless otherwise specified. Pediatric protocols should be used. Education topics must include insulin action and administration. Treatment goals and strategies must be tailored to each child.com Clinical Practice Guidelines Type 1 Diabetes in Children and Adolescents Canadian Diabetes Association Clinical Practice Guidelines Expert Committee The initial draft of this chapter was prepared by Diane Wherrett MD. 33). Significant risk of hypoglycemia often necessitates less stringent glycemic goals. Benefit correlated with duration of sensor use. A Cochrane review found that CSII gave slightly improved metabolic control over basal-bolus therapy (15). A1C 6. * Postprandial monitoring is rarely done in young children except for those on pump therapy for whom targets are not available. milk and alternatives. Nutrition All children with type 1 diabetes should receive counselling from a registered dietitian experienced in pediatric diabetes.0 Fasting/preprandial PG (mmol/L) 6.S154 D.0%) to identify potential causative Table 2 Examples of carbohydrate for treatment of mild-to-moderate hypoglycemia Patient weight Amount of carbohydrate Carbohydrate source Glucose tablet (4 g) Dextrose tablet (3 g) Apple or orange juice. A careful multidisciplinary assessment should be undertaken for every child with chronic poor metabolic control (e.13). Two large population-based observational studies have not found improved A1C in patients using basal-bolus therapy or CSII when compared to those using NPH and rapid-acting bolus analogues (21.0 Two-hour postprandial PG* (mmol/L) d Considerations Caution is required to minimize hypoglycemia because of the potential association between severe hypoglycemia and later cognitive impairment. PG. Factors responsible for this deterioration include adolescent adjustment issues. and meat and alternatives). A1C >10. sweet beverage (cocktails) <15 kg 5g 1 2 40 mL 15e30 kg 10 g 2 or 3 3 85 mL >30 kg 15 g 4 5 125 mL . A dose of 10 mg per year of age (minimum dose 20 mg.27). Nutrition therapy should be individualized (based on the child’s nutritional needs. This involves consuming a variety of foods from the 4 food groups (grain products. which was much lower in children and adolescents.e. Subcutaneous continuous glucose sensors allow detection of asymptomatic hypoglycemia and hyperglycemia.5 7. the use of mini-doses of glucagon has been shown to be useful in the home management of mild or impending hypoglycemia associated with inability or refusal to take oral carbohydrate. Hypoglycemia Hypoglycemia is a major obstacle for children with type 1 diabetes and can affect their ability to achieve glycemic targets. but the respective roles of hypoglycemia and hyperglycemia in their development are still questioned (6. Children with diabetes should follow a healthy diet as recommended for children without diabetes in Eating Well with Canada’s Food Guide (25). but the use of insulin to carbohydrate ratios is not required. vegetables and fruits. with an additional doubled dose given if the BG has not increased in 20 minutes (32. treatment must be individualized (30). psychosocial distress. intentional insulin omission and physiological insulin resistance. y In adolescents in whom it can be safely achieved. Appropriate for most adolescents. As such. Appropriate matching of insulin to carbohydrate content may allow increased flexibility and improved glycemic control (26. Children with early-onset diabetes are at greatest risk for disruption of cognitive function and neuropsychological skills.0 d 5.29).0 4.0 4. In children.g. Frequent use of continuous glucose monitoring in a clinical care setting may reduce episodes of hypoglycemia (31).0e7.0 mmol/L). intensive management may be required to continue meeting glycemic targets. Basal-bolus therapy has resulted in improved control over traditional twice daily NPH and rapid-acting bolus analogue therapy in some but not all studies (12. Glucose Monitoring Self-monitoring of BG is an essential part of management of type 1 diabetes (23). See Table 2 for treatment of mild-to-moderate hypoglycemia.0e10. ability and interest) and must ensure normal growth and development without compromising glycemic control. CSII is safe and effective and can be initiated at any age (14). Features suggestive of eating disorders and of celiac disease should be systematically sought out (28).0e10.0e6. The effect of protein and fat on glucose absorption must also be considered. Consider target of <8. detemir and glargine. Severe hypoglycemia should be treated with pediatric doses of intravenous (IV) dextrose in the hospital setting or glucagon in the home setting.y 6e12 13e18 7. CSII. insulin pump therapy).22). Most. resulted in improved control over basal-bolus therapy alone (17). Some clinic-based studies of CSII in school-aged children and adolescents have shown a significant reduction in glycated hemoglobin (A1C) with reduced hypoglycemia 12 to 24 months after initiation of CSII when compared to pre-CSII levels (16). eating habits.5% if excessive hypoglycemia occurs Targets should be graduated to the child’s age. Individualization of insulin therapy to reach A1C targets.0% if excessive hypoglycemia occurs. There is no evidence in children that 1 insulin regimen or mode of administration is superior to another for resolving nonsevere hypoglycemia. fasting/preprandial PG 4. with use of a continuous glucose sensor. minimize hypoglycemia and optimize quality of life is indicated.18e20). lifestyle. glycated hemoglobin. Two methods of intensive diabetes management have been used: basal-bolus regimens (long-acting basal insulin analogues and rapid-acting bolus insulin analogues) and continuous subcutaneous insulin infusion (CSII.0%. particularly for younger children. plasma glucose. / Can J Diabetes 37 (2013) S153eS162 Table 1 Recommended glycemic targets for children and adolescents with type 1 diabetes Age (years) <6 A1C (%) <8. maximum dose 150 mg) is effective at treating and preventing hypoglycemia. have demonstrated improved fasting BG levels and fewer episodes of nocturnal hypoglycemia with a reduction in A1C (12. consider aiming toward normal PG range (i.0e10.0 mmol/L and 2-hour postprandial PG 5.0 A1C. but not all. This plan should be evaluated regularly and at least annually. Chronic Poor Metabolic Control Diabetes control may worsen during adolescence. Wherrett et al. pediatric studies of the long-acting basal insulin analogues. regular soft drink. Consider target of <8. Use has resulted in improved diabetes control with less hypoglycemia in some studies.0e8. There is no evidence that 1 form of nutrition therapy is superior to another in attaining ageappropriate glycemic targets. A randomized controlled trial did not show improved control in children and adolescents but did in adults (24). anxiety. The risks increase exponentially during adolescence (70. behavioural intervention and family support (42.71). / Can J Diabetes 37 (2013) S153eS162 S155 factors. Research has demonstrated that while parental psychological issues may distort perceptions of the child’s diabetes control (81). requiring parental knowledge of sick-day management and increased attention during periods of illness. in adolescents. children on insulin pumps or long-acting basal insulin analogues. intravenous. Psychological/psychiatric risks Children and adolescents with diabetes have significant risks for psychological problems. DKA results from failing to take insulin or poor sick-day management. Table 3 Risk factors for cerebral edema          Younger age (<5 years) New-onset diabetes High initial serum urea Low initial partial pressure of arterial carbon dioxide (pCO2) Rapid administration of hypotonic fluids IV bolus of insulin Early IV insulin infusion (within first hour of administration of fluids) Failure of serum sodium to rise during treatment Use of bicarbonate IV.0% of pediatric cases are complicated by cerebral edema (CE) (46). For this reason. The frequency of DKA in established diabetes can be decreased with education. such as depression and eating disorders. is associated with worse metabolic control (65). including depression. A bolus of insulin prior to infusion is not recommended since it does not offer faster resolution of acidosis (53. the probability of psychological problems increases (80). Psychological Issues For children. Risk is increased in children with poor metabolic control or previous episodes of DKA.D. DKA DKA occurs in 15% to 67% of children with new-onset diabetes and at a frequency of 1 to 10 episodes per 100 patient years in those with established diabetes (36). DKA can be prevented through earlier recognition and initiation of insulin therapy. consequently. Eating disorders should be suspected in those adolescent and young adult females who are unable to achieve and maintain metabolic targets.54) and may contribute to CE (55). Maternal anxiety and depression are associated with poor diabetes control in younger adolescents and with reduced positive effect and motivation in older teens (86). strategies are required to prevent the development of DKA (37). Smoking Prevention and Cessation Smoking is a significant risk factor for both macrovascular and microvascular complications of diabetes (64) and. Unplanned pregnancies should be avoided.35). Use of bedside criteria may allow earlier identification of patients who require treatment for CE (56). Furthermore. several factors are associated with increased risk (Table 3) (48e52). Long-lasting immunogenicity to influenza vaccination has been shown to be adequate in these children (63). eating disorders and externalizing disorders (67e69). In new-onset diabetes. Smoking prevention should be emphasized throughout childhood and adolescence. In contrast. negative medical outcomes (76e79). . Immunization Historically. As DKA is the leading cause of morbidity and mortality in children with diabetes. Management of DKA While most cases of DKA are corrected without event. especially when insulin omission is suspected. as glycemic control worsens. family and coping issues show a modest reduction in A1C with reduced rates of hospital admission (34. often. Recent evidence suggests early insulin administration (within the first hour of fluid replacement) may increase the risk for CE (52). national guidelines have recommended influenza and pneumococcal immunization for children with type 1 diabetes (58e60). Although the cause of CE is still unknown. DKA should be managed according to published protocols for management of pediatric DKA (Figure 1) (57).47). Multipronged interventions that target emotional. Conversely. Studies have shown that psychological disorders predict poor diabetes management and control (72e75) and. Eating disorders Ten percent of adolescent females with type 1 diabetes meet the Diagnostic and Statistical Manual of Mental Disorders (4th Edition) criteria for eating disorders compared to 4% of their age-matched peers without diabetes (87).43). Currently. children with psychiatric disorders and those with difficult family circumstances (39e41). CE has rarely been reported in adults (39. Wherrett et al. Special caution should be exercised in young children with DKA and new-onset diabetes or a greater degree of acidosis and extracellular fluid volume depletion because of the increased risk of CE. Public awareness campaigns about the early signs of diabetes have significantly reduced the frequency of DKA in new-onset diabetes (38). as pregnancy in adolescent females with type 1 diabetes with suboptimal metabolic control may result in higher risks of maternal and fetal complications than in older women with type 1 diabetes who are already at increased risk compared to the general population (66). The presence of psychological symptoms and diabetes problems in children and adolescents are often strongly affected by caregiver/ family distress. as well as access to 24-hour telephone services for parents of children with diabetes (44. there is a need to identify psychological disorders associated with diabetes and to intervene early to minimize the impact over the course of development. However. peripubertal and adolescent girls. eating disorders are associated with poor metabolic control and earlier onset and more rapid progression of microvascular complications (88). 0.45). It is important to identify individuals with eating disorders because different management strategies are required to optimize metabolic control and prevent microvascular complications (87e89). which is associated with significant morbidity (21% to 35%) and mortality (21% to 24%) (47).62). and particularly adolescents. In children with established diabetes. they are related to poor psychological adjustment and diabetes control (82e85). Contraception and Sexual Health Counselling Adolescents with diabetes should receive regular counselling about sexual health and contraception. parents may choose to immunize their children. there is no evidence supporting increased morbidity or mortality from influenza or pneumococcus in children with type 1 diabetes (61. the management of type 1 diabetes can be complicated by illness.7% to 3. and to identify and address barriers to improved control. Daneman D. Wolfsdorf J. Given the prevalence of psychological issues. 2007. along with depressive symptoms (94. / Can J Diabetes 37 (2013) S153eS162 Figure 1. along with their families.8:28-43. there is .95).92). Wherrett et al. electrocardiogram. BG. have been shown to improve mental health (67. Pediatr Diabetes. In addition. Diabetic ketoacidosis. subcutaneous. Prevention and intervention Children and adolescents with diabetes. PG. for the International Society for Pediatric and Adolescent Diabetes. Craig ME. Immediate assessment and management of diabetic ketoacidosis (DKA) in children. including overall well-being and perceived quality of life (93). blood glucose. ICU. intravenous. ECG. et al. screening in this area can be seen as equally important as screening for microvascular complications in children and adolescents with diabetes (91). intensive care unit. should be screened throughout their development for psychological disorders (90). IV. Psychological interventions with children and adolescents. Adapted with permission from 57. plasma glucose. SC.S156 D. as well as families. The risk for AITD during the first decade of diabetes is directly related to the presence or absence of thyroid antibodies at diabetes diagnosis (100). or  Digital fundus photography  Question and examine for symptoms of numbness. pain. A first morning urine albumin to creatinine ratio (ACR) has high sensitivity and specificity for the detection of microalbuminuria (110. / Can J Diabetes 37 (2013) S153eS162 Table 4 Recommendations for screening for comorbid conditions in children with type 1 diabetes Condition Autoimmune thyroid disease Addison’s disease Celiac disease Indications for screening All children with type 1 diabetes Positive thyroid antibodies. thyroid symptoms or goiter Unexplained recurrent hypoglycemia and decreasing insulin requirements Recurrent gastrointestinal symptoms. Hypothyroidism is most likely to develop in girls at puberty (101). high-density lipoprotein cholesterol. Thus. Early detection and treatment of hypothyroidism will prevent growth failure and symptoms of hypothyroidism (Table 4). triglycerides. fatigue. some studies have demonstrated that psychological interventions can increase both diabetes treatment adherence and glycemic control. Wherrett et al. or  Direct ophthalmoscopy or indirect slit-lamp funduscopy through dilated pupil. anemia. overnight or 24-hour split urine collections for albumin excretion rate  Repeated sampling should be done every 3e4 months over a 12-month period to demonstrate persistence  Standard field. but in 60% to 70% of these children the disease is asymptomatic (silent celiac disease).96). followed by timed. family history of hyperlipidemia or premature cardiovascular disease  Screen all children with type 1 diabetes at least twice a year Dyslipidemia Hypertension  Use appropriate cuff size ACR. poor linear growth. as well as skin sensation. Celiac disease Celiac disease can be identified in 4% to 9% of children with type 1 diabetes (99). Although screening with a random ACR is associated with greater compliance than with a first morning sample. universal screening for and treatment of asymptomatic celiac disease remains controversial (Table 4).D. Most importantly. if abnormal.5 mg/mmol) Table 5 Screening for diabetes complications.or long-term health risks (106) or that a gluten-free diet improves health in these individuals (107). thyroid-stimulating hormone. Comorbid Conditions Autoimmune thyroid disease Clinical autoimmune thyroid disease (AITD) occurs in 15% to 30% of individuals with type 1 diabetes (99). There is good evidence that treatment of classic or atypical celiac disease with a gluten-free diet improves intestinal and extraintestinal symptoms (104) and prevents the long-term sequelae of untreated classic celiac disease (105). Children with type 1 diabetes are at increased risk for classic or atypical celiac disease during the first 10 years of diabetes (103). stereoscopic colour fundus photography with interpretation by a trained reader (gold standard). Addison’s disease Addison’s disease is rare. Hyperthyroidism also occurs more frequently in association with type 1 diabetes than in the general population. calculated low-density lipoprotein cholesterol Retinopathy Neuropathy  Yearly screening commencing at 15 years of age with duration of type 1 diabetes >5 years  Screening interval can increase to 2 years if good glycemic control. albumin to creatinine ratio. its specificity may be compromised in adolescents due to their higher frequency of exercise-induced proteinuria and benign postural proteinuria. . even in those with type 1 diabetes (102). some evidence that psychosocial interventions can positively affect glycemic control (34. Nephropathy Prepubertal children and those in the first five years of diabetes should be considered at very low risk for microalbuminuria (108. Abnormal random ACRs (>2.92. unexplained frequent hypoglycemia or poor metabolic control Screening test Serum TSH level þ thyroperoxidase antibodies Serum TSH level þ thyroperoxidase antibodies 8 AM serum cortisol þ serum sodium and potassium Tissue transglutaminase þ immunoglobulin A levels Frequency S157 At diagnosis and every 2 years thereafter Every 6e12 months As clinically indicated As clinically indicated TSH. light touch and ankle reflexes  Fasting total cholesterol. there is no evidence that untreated asymptomatic celiac disease is associated with short. However. poor weight gain. Diabetes Complications There are important age-related considerations regarding surveillance for diabetes complications and interpretation of investigations (Table 5). dyslipidemia and hypertension in children with type 1 diabetes Complication Nephropathy Indications and intervals for screening  Yearly screening commencing at 12 years of age in those with duration of type 1 diabetes >5 years Screening method  First morning (preferred) or random ACR  Abnormal ACR requires confirmation at least 1 month later with a first morning ACR and. duration of diabetes <10 years and no retinopathy at initial assessment  Postpubertal adolescents with poor metabolic control should be screened yearly after 5 years’ duration of type 1 diabetes  Delay screening after diabetes diagnosis until metabolic control has stabilized  Screen at 12 and 17 years of age  <12 years of age: screen only those with body mass index >95th percentile.111).109). vibration sense.98). Targeted screening is required in those with unexplained recurrent hypoglycemia and decreasing insulin requirements (Table 4). cramps and paraesthesia. as well as psychosocial functioning (97. Consensus].135)]. 7. Treatment is indicated only for those adolescents with persistent microalbuminuria. Between 25% and 65% of young adults have no medical follow-up during the transition from pediatric to adult diabetes care services (130. Level 2 (19). Organized transition services may decrease the rate of loss of follow-up (132. Glycemic targets should be graduated with age (see Table 1):  Children <6 years of age should aim for an A1C <8. 5. Those with no follow-up are more likely to experience hospitalization for DKA during this period. obesity and/or family history of premature CVD (124). persistence of abnormalities is an inconsistent finding (120). One short-term randomized controlled trial in adolescents demonstrated that angiotensin-converting enzyme (ACE) inhibitors were effective in reducing microalbuminuria compared to placebo (114). treatment of adolescents with persistent microalbuminuria is based on the effectiveness of treatments in adults with type 1 diabetes (115). Glycemic targets 4. In pubertal children without diabetes but with familial hypercholesterolemia. the likelihood of transient or intermittent microalbuminuria is higher during the early peripubertal years (109). Statin therapy has only rarely been studied specifically in children with diabetes. Individuals with transient or intermittent microalbuminuria may be at increased risk of progression to overt nephropathy (113). However. for adolescents. If these goals are not being met. Furthermore.123). provided that appropriate personnel and daily communication with the DHC are available [Grade B. . However. Insulin therapy should be assessed at each clinical encounter to ensure it still enables the child to meet A1C targets.117).131). All children with diabetes should have access to an experienced pediatric DHC team and specialized care starting at diagnosis [Grade D. Dyslipidemia screening should be targeted at those >12 years of age and younger children with specific risk factors for dyslipidemia. hypertension. Consensus for younger children]. Insulin therapy 6. With the exception of intensifying diabetes management to achieve and maintain glycemic targets.g. Consensus]. and treatment options may include the following:  Increased frequency of injections [Grade D. The exceptions are those with longer duration of disease.g. Children with new-onset diabetes should be started on at least 2 daily injections of bolus insulin (e.0% [Grade D. Consensus. Level 1A (5)]. monitoring and contact with diabetes team) should be used [Grade A. adolescents should receive care from a specialized program aimed at creating a wellprepared and supported transition to adult care that includes a transition coordinator. / Can J Diabetes 37 (2013) S153eS162 require confirmation with a first morning ACR or timed urine overnight collection (112). Abnormal screening results require confirmation and follow-up to demonstrate persistent abnormalities. Children with persistently poor glycemic control (e. Level 4 (1)]. there are no long-term intervention studies assessing the effectiveness of ACE inhibitors or angiotensin II receptor antagonists in delaying progression to overt nephropathy in adolescents with microalbuminuria. the role of ambulatory BP monitoring in routine care remains uncertain. Level 3 (132. Neuropathy When present. and support and education. Retinopathy Retinopathy is rare in prepubertal children with type 1 diabetes and in postpubertal adolescents with good metabolic control (116. While prospective nerve conduction studies and autonomic neuropathy assessment studies have demonstrated increased prevalence of abnormalities over time (119). A1C >10%) should be assessed by a specialized pediatric diabetes team for a comprehensive interdisciplinary assessment and referred for psychosocial support as indicated [Grade D.  Children 6e12 years of age should aim for a target A1C 7.g. 3. Transition to Adult Care The change of physician or DHC team can have a major impact on disease management and metabolic control in the person with diabetes (129). Children with new-onset type 1 diabetes who are medically stable should receive their initial education and management in an outpatient setting. Consensus]. Microalbuminuria is rare in prepubertal children. intermediateacting insulin or long-acting basal insulin analogue) [Grade D. Level 1A (3)]. These abnormalities may be predictive of future microalbuminuria (127). an intensified diabetes management approach (including increased education. microvascular complications or other cardiovascular disease (CVD) risk factors. Consensus]. RECOMMENDATIONS Delivery of care 1. Children with type 1 diabetes and confirmed hypertension should be treated according to the guidelines for children without diabetes (128). Twenty-four-hour ambulatory blood pressure (BP) monitoring has been used to exclude white coat hypertension and to identify loss of diurnal systolic rhythm (nondippers) with nocturnal hypertension in some normotensive adolescents with type 1 diabetes (127). Wherrett et al. minimizes the risk of hypoglycemia and allows flexibility in carbohydrate intake. no other treatment modality has been studied in children and adolescents. Hypertension Up to 16% of adolescents with type 1 diabetes have hypertension (126).5% [Grade D. Therefore. Consensus].133)]. 2. patient reminders. including smoking.35. Grade D. statin therapy is safe and effective at lowering LDL-C levels and attenuating progression of surrogate markers for future vascular disease (125). Level 4 (134)]. and there is no evidence linking specific low-density lipoprotein cholesterol (LDL-C) cutoffs in children with diabetes with long-term outcomes. Level 3 (136)]. for younger children]. daily schedule and activities [Grade D.  Change to continuous subcutaneous insulin infusion therapy [Grade C. with or without a joint pediatric and adult clinic [Grade C. To ensure ongoing and adequate diabetes care. Dyslipidemia Most children with type 1 diabetes should be considered at low risk for vascular disease associated with dyslipidemia (122.  Adolescents should aim for the same glycemic targets as adults [Grade A. Caution should be used to minimize hypoglycemia because of the potential association in this age group between severe hypoglycemia and later cognitive impairment [Grade D.  Change in the type of basal and/or bolus insulin [Grade B. Vibration and monofilament testing have suboptimal sensitivity and specificity in adolescents (121). Level 1A (34.S158 D. Intensive family and individualized psychological interventions aimed at improving glycemic control should be considered to improve chronically poor metabolic control [Grade A.133). Grade D. short-acting bolus insulin or rapid-acting bolus insulin analogues) combined with basal insulin (e. Level 1(4) for adolescents. Consensus]. neuropathy is mostly subclinical in children (118). regardless of the duration of diabetes or metabolic control (108). Consensus]. Consensus]. Consensus]. Waugh N. as this may contribute to cerebral edema [Grade D. Consensus]. duration of diabetes <10 years and no significant retinopathy (as determined by an expert professional) [Grade D. the dyslipidemia should be treated per lipid guidelines for adults with diabetes [Grade D. Children and adolescents with diabetes. severe hypoglycemia in an unconscious child >5 years of age should be treated with 1 mg glucagon subcutaneously or intramuscularly. starting 5 years after the onset of diabetes [Grade D. Consensus]. including weight loss if overweight [Grade D.1 units/kg/h [Grade D. von SS. Routine screening for dyslipidemia should begin at 12 years of age. Consensus]. rapid administration of hypotonic fluids should be avoided [Grade D. 24.0e17. In children in DKA.5 mg glucagon should be given. Children 12 years with persistent microalbuminuria should be treated per adult guidelines (see Chronic Kidney Disease chapter. pain. Influenza immunization should be offered to children with diabetes as a way to prevent an intercurrent illness that could complicate diabetes management [Grade D. Diabetic ketoacidosis (DKA) 11. Consensus]. Level 4 (108. teachers) about the early symptoms of diabetes [Grade C. Clar C. treatment should be initiated based on recommendations for children without diabetes [Grade D. should be available for families of children with diabetes. thyroid symptoms or goiter [Grade D.5 mg/mmol) should not be diagnosed in children 12 years unless it is persistent. diabetes healthcare. Level 3 (44)]. 25. Children with type 1 diabetes and symptoms of classic or atypical celiac disease (see Table 4) should undergo celiac screening [Grade D. Level 4 (32)]. Consensus] and. 27. Tynan WD. Adolescent females with type 1 diabetes should receive counselling on contraception and sexual health in order to prevent unplanned pregnancy [Grade D. Consensus]. S129) [Grade D.2:CD004099. Formal smoking prevention and cessation counselling should be part of diabetes management for children with diabetes [Grade D. albumin to creatinine ratio.109)] and should be referred to an expert in mental health and/or psychosocial issues for intervention when required (Grade D. there should be immediate consultation with a centre with expertise in pediatric diabetes [Grade D. 3. 2. 12. Consensus]. Level 4 (48)].0 mmol/L. 29. Consensus]. intravenous. ACR. the insulin infusion rate should be maintained until the plasma anion gap normalizes. Consensus). More frequent screening is indicated in the presence of positive thyroid antibodies. IV insulin bolus should not be given. 26. The episode should be discussed with the diabetes healthcare team as soon as possible and consideration given to reducing insulin doses for the next 24 hours to prevent further severe hypoglycemia [Grade D. and examined for skin sensation. Dextrose 0. BP. 9. 14. Circulatory compromise should be treated with only enough isotonic fluids to correct circulatory inadequacy [Grade D. should be screened regularly for psychosocial or psychological disorders [Grade D. Glasgow AM. Wherrett et al. In children in DKA. 13. dieting. Children with type 1 diabetes who have thyroid antibodies should be considered high risk for autoimmune thyroid disease [Grade C. Children with type 1 diabetes should be screened at diabetes diagnosis with repeat screening every 2 years using a serum thyroidstimulating hormone and thyroid peroxidase antibodies [Grade D. Level 4 (105)]. 32. IV. glycated hemoglobin. Children 12 years should be screened for microalbuminuria with a first morning urine ACR (preferred) [Grade B. Level 4 (138)]. In the home situation. vibration sense. 18. Consensus]. Pediatrics 1991. All children with type 1 diabetes should be screened for hypertension at least twice annually [Grade D.to 4-month intervals over a 6. 31. . be treated with a gluten-free diet to improve symptoms [Grade D. 23.g. Abnormal results should be confirmed [Grade B. 30. the use of mini-doses of glucagon (10 mg per year of age with minimum dose 20 mg and maximum dose 150 mg) should be considered in the home management of mild or impending hypoglycemia associated with inability or refusal to take oral carbohydrate [Grade D. DKA in children should be treated according to pediatric-specific protocols [Grade D. Screening for microalbuminuria should be performed annually. / Can J Diabetes 37 (2013) S153eS162 S159 Hypoglycemia 8. overnight urine collection for albumin excretion rate [Grade D. Consensus]. Children with type 1 diabetes and BP readings persistently above the 95th percentile for age should receive lifestyle counselling. Routine hospital admission versus out-patient or home care in children at diagnosis of type 1 diabetes mellitus. Consensus]. IV glucose should be started to prevent hypoglycemia [Grade D. Mobile diabetes education and care: intervention for children and young people with Type 1 diabetes in rural areas of northern Germany. Microalbuminuria (ACR >2. an IV infusion of short-acting insulin should be used at an initial dose of 0. administration of sodium bicarbonate should be avoided except in extreme circulatory compromise. Readmissions of children with diabetes mellitus to a children’s hospital. et al. Postpubertal children with type 1 diabetes of >5 years’ duration and poor metabolic control should be questioned about symptoms of numbness. Hager S. with repeat screening after 5 years [Grade D.D. If BP remains elevated. Level 4 (52)]. Muller-Godeffroy E. Consensus]. To prevent DKA in children with diabetes:  Targeted public awareness campaigns should be considered to educate parents and other caregivers (e. light touch and ankle reflexes [Grade D. Consensus]. as well as 24-hour telephone services [Grade C. Level 4 (53)]. If appropriate expertise/facilities are not available locally. 28. Level 4 (139)]. Level 3 (43)]. et al.  Comprehensive education and support services [Grade C. 21. screening and evaluation for retinopathy by an expert professional should be performed annually. Once plasma glucose reaches 14. Consensus]. Diabet Med 2006. blood pressure. cramps and paresthesia. DHC. 16. if confirmed. Restoration of extracellular fluid volume should be extended over a 48-hour period with regular reassessments of fluid deficits [Grade D. In children in DKA. Level 4 (104)] and prevent the long-term sequelae of untreated classic celiac disease [Grade D. Consensus]. Consensus]. along with their families. Abbreviations: A1C. Thomas S. Level 2 (111)] or a random ACR [Grade D.23:122e7. 19. p.to 12-month period [Grade D. References 1.5e1 g/kg should be given over 1e3 minutes to treat severe hypoglycemia with unconsciousness when IV access is available [Grade D. Comorbid conditions and other complications 22. Parents should be informed that the need for screening and treatment of asymptomatic (silent) celiac disease is controversial [Grade D. In children in DKA. Cochrane Database Syst Rev 2006. as demonstrated by 2 consecutive first morning ACR or timed collections obtained at 3. Level 3 (42)]. Consensus]. Consensus]. 10. Consensus]. Cons