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Review ArticleEmerging Role of Dipeptidyl Peptidase-IV (DPP-4) Inhibitor Vildagliptin in the Management of Type 2 Diabetes Sanjay Kalra* Abstract Diabetes mellitus (DM) is one of the most common chronic disorders, with increasing prevalence worldwide. Type 2 diabetes (T2DM), a multifaceted disease involving multiple pathophysiological defects, accounts for nearly 85–95% of total reported cases of DM. Chances of developing T2DM are increased by obesity and physical inactivity and are augmented further with age. Two most important unmet needs associated with the management of T2DM are the lack of lasting efficacy in reducing hyperglycemia and failure to target primary causes. Different classes of Oral Hypoglycemic Agents (OHA’s) with nearly equipotent efficacy are now available targeting the different pathophysiologic factors contributing to T2DM; however, almost all of them are associated with one or the other kind of adverse effect. Several studies have found that certain diabetes drugs may carry increased cardiovascular (CV) risks compared to others. The new approach in management of T2DM based upon the effects of incretin hormones; Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). Vildagliptin is a drug from a new class of medications called dipeptidyl peptidase IV (DPP4) inhibitors. By inhibiting DPP-4, vildagliptin causes an increase in GLP-1, an intestinal hormone that aids in glucose homeostasis and insulin secretion. Vildagliptin has a half-life of about 90 minutes; however, ≥50% of DPP4 inhibition continues for more than 10 hours, allowing for once- or twice-daily dosing. Clinical trials have shown that vildagliptin is effective in significantly lowering glycosylated hemoglobin (HbA1c), fasting plasma glucose, and prandial glucose levels. β-cell function may also be improved. The drug has placebo like tolerability and rate of hypoglycemia events. Vildagliptin expands non-injectable treatment options available for management of T2DM patients, who are poorly controlled with monotherapy. D Introduction iabetes mellitus (DM) is one of the most common chronic disorders attaining epidemic proportions worldwide. The prevalence of diabetes is rapidly rising globally at a distressing rate, affecting both developed and developing countries alike. Worldwide DM is currently estimated to affect 285 million (6.4%) adults aged 20–79 years and this number is projected to increase to 439 million (7.7%) adults by the year 20301. Diabetes Atlas 2009 published by the International Diabetes Federation estimated diabetic population in India to around 50.8 million, which is expected to rise to 87 million by 2030,1 earning India the dubious distinction of being called the “diabetes capital of the world”. Type 2 diabetes (T2DM) accounts for nearly 85–95% of total reported cases of diabetes2. T2DM is a multifaceted disease involving multiple pathophysiological defects, including impaired islet function and insulin resistance, which results in impaired glucose tolerance and inappropriately high fasting hepatic glucose production. Chances of developing T2DM are increased by obesity and physical inactivity and are further augmented with age. for metabolic control of patients with T2DM, but with course of time this approach alone is insufficient to attain glycemic control, calling for introduction anti-hyperglycemic pharmacotherapy. Different classes of Oral Hypoglycemic Agents (OHA’s) are now available that target the different pathophysiologic factors contributing to T2DM:a-glucosidase inhibitors to delay intestinal carbohydrate absorption, biguanides to target hepatic insulin resistance, insulin sensitizers or thiazolidinediones (TZDs) to target adipocyte and muscle insulin resistance and insulin secretagogues or sulfonylureas (SU) to increase pancreatic insulin secretion.6 These compounds have nearly equipotent efficacy; however, almost all of them are associated with one or the other kind of adverse effect.7 An alternative approach based on targeting incretin hormones, founded on better understanding of their potential has in turn led to the development of incretin analogs and incretin enhancers for treatment of T2DM. In this article we will review the pharmacology, clinical efficacy and role of incretin enhancer vildagliptin, a potent and selective inhibitor of dipeptidyl peptidase-4 (DPP-4) in the management of T2DM. Two most important unmet needs associated with the management of T2DM are the lack of lasting efficacy in reducing hyperglycemia and failure to target primary causes. Poor glycemic control accounts for much of the morbidity, mortality and economics associated with T2DM. 3-5 Though Lifestyle modification (Exercise, dietary management) provides the basis Present Treatment Regimes and Cardiovascular Risks In the past, several studies have found that certain diabetes drugs may carry increased cardiovascular (CV) risks compared to others. A recent study of over 90,000 T2DM patients compared the CV effects in individuals treated with either metformin or SU. Consultant Endocrinologist and Diabetologist, Bharti Hospital, Wazir Chand Colony, Kunjpura Road, Karnal, Haryana - 132 001 Received: 02.09.2010; Revised: 01.11.2010; Accepted; 07.12.2010 * © JAPI • april 2011 • VOL. 59 237 28)10 and significant increase in the risk of myocardial infarction (43%).13 The utmost practical concern of SU therapy is associated with two common adverse effects. and glimepiride) are more potent and probably safer than firstgeneration SUs (chlorpropamide. SU ingestion was a factor in 65% of adult cases and 86% of these cases were of patients older than 50 years.21 Ischemic preconditioning in human myocardium relies on KATP channels. acetohexamide and tolazamide) but essentially of equal efficacy. so-called “Incretin Mimetics” and second. slow gastric emptying. typically from 2 to 5 kg and SU associated hypoglycemia affects the elderly with worsening renal function and irregular meal schedules.29-30 This approach was first encapsulated by Holst and Deacon. GLP-1 has also shown to suppress glucagon secretion. respectively.23 However the role of GLP-1 and GIP in glucose regulation is limited because of their short half life. With SU therapy. Rosiglitazone monotherapy was found to be associated with higher risk for any CV event (HR 1.28 Two approaches have been developed to negate this problem and prolong duration of GLP-1 action.26-27 In T2DM patients.19 Case fatality rates of 4%–10% have been reported with SUs. since they are rapidly degraded and inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4).24 Even though cardiotoxic effect of SUs therapy has been debated for long. advanced age and fasting as the major risk factors for the development of hypoglycemia requiring hospitalization.e.11 moreover as add-on rosiglitazone and pioglitazone were associated with comparable CV risk.These researchers found an increased likelihood of death from any cause in the patients treated with SU (24-61% increased risk depending on the specific drug). In T2DM effects of GLP-1 functions are preserved and in contrast GIP secretion remains normal but with reduced insulinotropic effect. reduced incretin effect combined with constant decline in pancreatic β and a-cell function leads to progressive loss of glycemic control. some 10%-20% of people will immediately fail to control their blood glucose levels adequately on the highest recommended dose (Primary failure). 59 . Hypoglycemia secondary to insulin and SU therapy is often associated with 238 serious morbidity. i. may explain the excess CV mortality in these patients. anecdotal evidence has long implicated hypoglycemia as a potential cause of myocardial ischaemia or a cardiac arrhythmia. which is the main cause of death in people with T2DM.17 Seltzer et al in a comprehensive retrospectively review of 1418 cases of severe drug-induced hypoglycemia. Second-generation SUs (glyburide. thereby increasing its concentration as well as its duration of action on target tissue.8 These results reinforced the similar findings of a 2006 study and an earlier 2009 study. As a therapeutic application in T2DM. tolbutamide. studies have provided pathophysiological plausibility as SUs appear to aggravate the hypoxaemic damage to the myocardium in the case of coronary occlusion or artery disease. glipizide. increase the risk of both CV and all-cause mortality. between 6 and 18% of deaths have been attributed to hypoglycemia. so roughly 5% to 10% of people who initially respond to SU therapy will subsequently fail each year (Secondary failure). Also being small molecule DPP-4 © JAPI • april 2011 • VOL. the prolongation of the endogenous GLP-1 and GIP effect produced by DPP-4 inhibition has several advantages compared with conventional therapies and newer GLP-1 analogues. They enhance meal-induced insulin secretion and play an important part in maintenance of normal glucose homeostasis by a process termed as incretin effect.9 Also concerns have been raised about CV risks associated with TZDs. which maintains the physiologic effect of native GLP-1 but is resistant to action of DPP-4. which plays an important role in regulation of coronary blood flow but also protect cardiac cells from ischaemia/reperfusion injury. Specifically. along with an increased risk of congestive heart failure (18-30%). The researchers found higher daily doses of first and second-generation SUs increased mortality risk by more than 200% and 30%-40%. rather than being limited to surrogate markers New Approach in Management of T2DM The new approach in management of T2DM is based upon the effects of incretin hormones. The ACCORD study has reported an increased CV risk and total mortality associated with intensive glucose control. SUs do not always succeed in controlling diabetes.22 with an excess of fatal vascular events being associated with a higher frequency of severe hypoglycemia.25 Furthermore every SU drug needs to be studied individually for its effectiveness and safety vis-à-vis the relevant endpoints for T2DM. cv morbidity and mortality. with about 5% of survivors having permanent neurological impairment.89. However in diabetic patients KATP channel function are already impaired and the long-term inhibition of KATP channels with KATP channel inhibitors like older generation SUs. In addition to this weight gain associated with SUs is also marker of increased CV risk. 95%CI 1. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP). respectively. reduce food intake and body weight.20 Although much attention has been paid to neurologic consequence of SUs induced hypoglycemia but its CV side effect can not be overlooked.12 Unfortunately. One is the development of long-acting stable analogues of GLP-1.18 Hypoglycemia results in significant morbidity and in younger patients with T2DM (aged from 20–49 years). giving rise to hypothesis that reducing degradation of GLP-1 may compensate for its decreased secretion in T2DM. which are increasingly being used to treat T2DM. called “Incretin Enhancers”. gastrointestinal hormones released from β-cells of the islets of Langerhans into the bloodstream primarily in response to meal ingestion.7. who showed that DPP-4 inhibition increases circulating levels of GLP-1 in experimental animals and that the insulinotropic action of exogenously administered GLP-1 is augmented by DPP-4 inhibition. 2.57. weight gain and hypoglycemia.10 SU were the first widely used OHAs and have been available in the United States since 1954 and still remain a cornerstone of T2DM therapy.23 A new study has found that SUs—the mainstay of glucose control in T2DM. 13 Another concern with SUs is their tendency to overwork the pancreas until it eventually “exhaust β-cell function” and is unable to secrete an adequate amount of insulin. This decline in β and a-cell function is evident as progressive loss of glucose-dependent insulin release and as a progression to unregulated glucagon production.14-16 Jennings et al demonstrated that up to 20% of patients taking oral SU agents experience symptoms consistent with hypoglycemia over a 6-month period.31 Later studies demonstrated that the prevention of inactivation of GLP-1 by DPP-4 inhibition markedly increases the active GLP-1 in the circulation. resulting in loss of their insulinotropic activity. About 80% to 90% of people with diabetes are obese and SUs tend to make them gain even more weight. inhibition of DPP-4 using low molecular weight inhibitors which decrease the inactivation of GLP-1. especially the ones with less selectivity. identified SU ingestion. whereas as OD dosage was administered before breakfast. Its molecular weight is around 303.39-41 The drug improves hyperglycemia primarily by prolonging the half-lives of GLP-1 and GIP. Vildagliptin is primarily metabolized in the kidney to inactive cyano and amide metabolites and approximately 85% of the drug is eliminated in the urine (21–23% as the unchanged drug) and 15% into the faeces. was 2.37-38 Vildagliptin has demonstrated the ability to inhibit DPP-4.0–4. The trials were randomised.41 Vildagliptin The DPP-4 inhibitor vildagliptin is approved in the Europe for the treatment of T2DM. DPP-4 inhibition resulting in increased levels of active inhibitors are orally available and relatively free from side effects (Table 1). double-blind. represent a potentially important addition to the oral treatment options currently available for the management of T2DM.5 nmol/L) of DPP-4 inhibition.46 BID dosages where stated were administered at breakfast and dinner. long acting Drug overdose nontoxic Mild CNS side effects Mild nausea and vomiting Commonalities Lower risk of hypoglycemia than insulin Induces satiety and weight loss Improves β-cell function Increases glucose dependent insulin secretion Decreases glucagon secretion Incretin Mimetics N Mixed meal Intestinal release of GLP-1 Lower risk of hypoglycemia than insulin Induces satiety and weight loss Improves β-cell function Increases glucose dependent insulin secretion Decreases glucagon secretion Active GLP-1 Inhibition DPP-4 Inactivation of GLP-1 blocked DPP-4 Inactive GLP-1 Fig.36 This results in improved glycemic control as determined by glycosylated haemoglobin (HbA1c) and fasting plasma glucose (FPG) levels plus an enhancement of pancreatic a-and β-cell function. increase plasma concentrations of intact GLP-1 and GIP. considerably greater reduction in HbA1c levels from baseline was seen with Vildagliptin 50mg (between-group 239 . reaching peak plasma concentrations (Cmax) achieved in a time (tmax) of 1.7 years in the monotherapy trials and 4. phase II trials (n=27939 and 9840). therefore.42 Drug is quickly absorbed after oral administration.42 The mean age of the patients was 53–59 years. a concern Potential for side effects Increased levels of nausea and vomiting N O H Monotherapy In a randomised. 59 N HO Injectable Single known target Higher levels of GLP-1 Longer acting.3 mmol/L in all studies. days–weeks Drug overdose. PPG. 39 Mean baseline HbA1c of patients considered for monotherapy was between 6. however these effects are not thought to be of any clinical significance and drug can be taken © JAPI • april 2011 • VOL. thus enhancing their action on islet cells and promoting glucose-dependent insulin secretion and suppression of inappropriate glucagon secretion. vildagliptin is 1-([(3-hydroxy-1-adamantyl) amino] acetyl)-2-cyano-[S]-pyrrolidine. which is more potent than that reported for another DPP-4 inhibitor. with ability of potentiating the actions of GLP-1 as well as GIP. bodyweight and blood lipids Pharmacologic Overview The effect of vildagliptin in humans is reflected by the 50% inhibitory constant (IC50 4. glimepiride or insulin in treatment-experienced patients.45 with a terminal elimination half life of approximately 3 hours following oral administration.6–6.8–10. It is a potent. placebo or active comparator controlled. with a reversible and competitive mechanism of action (MOA) that binds and forms a complex with DPP-4. Vildagliptin appears to attenuate the decline in glucosedependent β-cell function and improve insulin sensitivity.32-35 Oral DPP-4 inhibitors.43. The therapeutic efficacy of oral vildagliptin once-daily (OD) or twice-daily (BID) has been investigated as monotherapy. Therapeutic Efficacy The unique action of Vildagliptin. irrespective of drug dosage or food intake. in placebo-controlled or active comparator-controlled trials in drug naive patients or in combination with metformin pioglitazone. has encouraged new outlook in treatment and pathobiology of T2DM.43 Plasma concentrations of vildagliptin increase in an approximately dose-dependant manner.7 hours after administration. causing its inhibition.46 The primary efficacy endpoint for all trials was change in HbA1c levels. 1 : Vildagliptin (chemical structure is based on the common design for DPP-4 inhibitors: a L-amino acid with a protonable N-terminal primary amine in the P-2 site) exhibits high-affinity.Table 1: Comparison of Incretin Enhancers and Incretin Mimetics32-35 Incretin Enhancers Differences Orally available Multiple targets GLP-1 PK favorable Short vs. with any type of meal. where stated.2–7. reversible.41 gm. sitagliptin (IC50 26 nmol/L).5 hours and Cmax reduced by 19% when drug is administered with a high-fat meal. Structurally. the absolute bioavailability of the drug is 85%.42 FPG baseline means were 8. multicentre studies in patients with T2DM (n =71–780).5–1. placebo-controlled. Mean duration of diabetes. Other endpoints included FPG.5%.2 years in the combination studies. selective and orally active 2nd generation inhibitor of DPP-4. a second member of DPP-IV inhibitor class of drugs. reduce FPG and postprandial glucose (PPG) and suppress plasma glucagon in clinical trials in T2DM patients.43-45 Although the tmax is delayed to 2. and also to enhance the sensitivity of α-cells to glucose. 3 mmol/L after 24 weeks.001 vs.856 and -1. reductions in HbA1c was 1.difference. active-controlled. parallelgroup study evaluated comparative efficacy and tolerability of the vildagliptin (100mg daily.64±0.0-9. randomized. the reductions were 0. as an add-on therapy in T2DM patients inadequately controlled with metformin.6% (95%CI.4%.7% respectively. 6. Prandial glucagon levels decreased by 3.0%) and -1. A pooled analysis of five trials further confirmed that dosages of vildagliptin 50mg BID (n=1138) provides a significant (p<0. double-blind.55-56 Clinical guidelines for the management of T2DM recommend target level of HbA1c to be between 6.54.3±2. The overall population achieving HbA1c levels of <7% ranged from 30% to 46%.h/L (P<0.0%.4±1.004). with a mean between-group difference of –0. following treatment with vildagliptin 50mg.65 Similar results were shown in a 52-week. meeting the predefined statistical criterion for non-inferiority. 25 or 50mg BID treatment significantly reduced HbA1c levels by 0.−0.7%).55 In addition. when added to metformin but without weight gain as associated with pioglitazone therapy. 12 weeks of vildagliptin 10. compared with placebo (all p≤0. SU.7–11. active-controlled study demonstrating noninferiority of vildagliptin in comparison with gliclazide.h/L by glimepiride (n=121).0012) for the whole cohort (baseline HbA1c 8.53 In patients with baseline HbA1c>8%. randomized.8±1.2mg three times daily (TID) (n=192) in reducing HbA1c levels in Japanese patients.66 as comparative agent.6%40) and 100mg (–0.75±0.6–14. as an add-on to metformin.59-68 Out of this Four trial were placebo controlled59-61.5%.52 Also the effect of vildagliptin 50mg OD was shown to be dose-related in the higher baseline group (HbA1c >8%) in two placebo controlled trials.0% from a mean baseline HbA1c of 8. as add on therapy to metformin in T2DM patients inadequately controlled by metformin mono therapy. p<0.49 In the active comparator trials.07% and -0.p<0. data from pooled monotherapy trials57 indicated that 65% of vildagliptin recipients achieved an HbA1c reduction of >0.001).66 Addition of Vildagliptin 50mg OD or BID to existing oral therapy or insulin therapy produced significantly greater reduction in HbA1c baseline levels as compared to placebo. vildagliptin 50mg OD significantly reduced HbA1c. plasma FPG and 2-hour PPG levels were significantly reduced with all vildagliptin dosages. 12 weeks vildagliptin 50mg BID (n=188) was shown to be more effective than Voglibose 0.4%39) daily. the reduction from baseline mean HbA1c levels with vildagliptin 50mg BID in drug-naive T2DM patients was non-inferior to that with acarbose 300mg/ day50 or rosiglitazone 8mg OD.46%. © JAPI • april 2011 • VOL.255 mmol/L and -1.6 pmol. FPG and PPG and improved β-cell function without weight gain or hypoglycemia. 11 events).7% after 24 weeks. In T2DM patients Vildagliptin achieved greater glycemic control as compared with placebo.0mmol/L respectively.8%.68 to −0. p=0. This established that vildagliptin 50mg significantly improves postprandial alpha-cell function when compared to SU glimepiride.7 vs.9 years and mean HbA1c and FPG levels at baseline ranging between 6.1 pmol. Result from study showed that Vildagliptin as add-on to metformin had similar efficacy as that of glimepiride.056 and -0. improving HbA1c by -0. with between-group difference of 7. TZDs and insulin treatment and in initial combination with pioglitazone. to reduce risk of CV complications. with prime objective of demonstrating non-inferiority of vildagliptin vs. 28.5-10% and 8.5% and 7. 24.3839 In one of the dose-finding study in Japanese patients (n=291).58 240 Combination Therapy The mean age of enrolled patients across all combination trial was 54–60 years with a mean BMI of 31–33 kg/m2. with superior Gastrointestinal (GI) tolerability.h/L by vildagliptin (n=137) and increased by 3. monotherapy with vildagliptin 25mg BID (n=70) was well tolerated and significantly improved glycemic control in comparison to placebo (n=28). But noninferiority of vildagliptin 50mg BID when compared to acarbose 300 mg/day in reducing FPG levels was not established after 24 weeks of treatment.2% (p=0.92% respectively (p<0.6±0.07% respectively. Vildagliptin was as effective as metformin. placebo) from baseline levels of 7. This study established that the Vildagliptin is an effective and well-tolerated treatment option in elderly patients with T2DM.05) reduction of 1.001). 59 .001).43%39 and –0.64 Another trial evaluated non-inferiority of vildagliptin vis-à-vis glimepiride in reducing HbA1c levels as add-on to metformin over the period of 2 years.2%.555 mmol/L with vildagliptin 50mg OD.1% with vildagliptin 50mg BID and 1. multicentre.8% vs.7pmol.52 Vildagliptin has been evaluated in randomized. double-blind trials as add-on therapy to metformin.53%. 0. Vildagliptin and metformin were administered as separate agents in all the trials.6% and 0. moreover vildagliptin did not induce weight gain. Associated improvements in β-cell function were also observed with vildagliptin 25mg.08 mmol/L from a mean baseline FPG of 10. mean duration of T2DM 4. than with vildagliptin 50mg BID though it significantly reduced FPG levels from baseline.50 In study of diet-treated T2DM subjects.52.) T2DM patients. Between-group difference in adjusted mean change in HbA1c from baseline to endpoint was -0.0% vs. Similar proportion of patients reached HbA1c <7.63 and one each had pioglitazone63 and TZDs65 and two had glimepiride64. Similarly. Data from the pooled analysis of vildagliptin 50mg BID (n=1135) indicated a significant (p<0.48 Furthermore decrease in mean FPG levels after 24 week treatment with vildagliptin 50mg BID were -0. Also the number of AEs were similar in both groups but the number of SAEs was higher in the gliclazide group (8.7%.62 In a comparative trial evaluating effect of vildagliptin 50mg BID to glimepiride up to 6mg OD on prandial glucagon levels. with more patient on vildagliptin therapy reaching target (HbA1c<7%) without hypoglycemia when compared to glimepiride (36. In a 52 week study conducted to evaluate efficacy and tolerability of vildagliptin 50mg OD in 306 drug-naïve T2DM patients with mild hyperglycemia.05) reduction of 1. but the total number of hypoglycemic events were lower in the vildagliptin group (6 vs.001) amid this vildagliptin provided a significantly greater response rate in achieving HbA1c levels of ≤6. whereas in patients with baseline HbA1c ≤8%.2% for subjects with baseline HbA1c of 8. n=169) and metformin (titrated to 1500mg daily. showing similar improvement in glycemic control as metformin. metformin in HbA1c reduction.5%. n=166) in drug-naïve elderly (≥65 yrs. A doubleblind.51 after 24 weeks of treatment.47 Furthermore. which were significantly greater compared to placebo. 59 pioglitazone60 and glimepiride61 therapy and was as effective as pioglitazone (noninferiority established).67% and 0.–0. but with markedly reduced hypoglycemia risk and no weight gain.7% with metformin 2000mg/day.004) after 12 weeks treatment.50.5% compared with voglibose (50.57 However in active comparator trials reduction in baseline FPG were significantly greater with rosiglitazone51 or metformin54 (both p=0. in T2DM patients with inadequately controlled HbA1c (7-10%).9 vs. p=0. glimepiride as add-on therapy in patients inadequately controlled on metformin monotherapy (HbA1c 6. The results of this meta-analysis established that vildagliptin was not associated with an increased risk of adjudicated CCV events in a T2DM population.6% [95% CI –1. 95% CI=0. USA (USFDA) guidance. 95% (CI)=0. 2.0. cough. 1. In an extension of the vildagliptin plus insulin trial60 the reduction in HbA1c seen with vildagliptin at 24th week was sustained at week 52.76 241 .57±0. 55. levels when added to metformin. This metaanalysis by Schweizer et al and colleagues. double-blind.8%)59 or glimepiride (21.05). 65.166) or active and placebo comparators (n=6. when evaluated as add-on therapy to pioglitazone.4%).3% vs. The majority of reported adverse events (AEs) were of mild to moderate severity and transient in nature53-54. 95% CI=0.59–1. there is little evidence that vildagliptin or other DPP-4 inhibitors are associated with significant hepatic risk.662 for Vildagliptin 50mg BID.1%) was noninferior to pioglitazone 30mg OD (-1. 44.24) and those with higher CCV risk (RR=0. to evaluate CCV safety of vildagliptin.11% (95%CI:-0. 1.70 Galiant trial compared efficacy and tolerability of vildagliptin 100mg with TZDs (agent and dose at the investigators discretion) as add on therapy to stable dose of metformin (≥1000 mg/day). rosiglitazone and insulin with or without matching placebo) and 26–69% of vildagliptin plus active comparator (metformin. In vildagliptin plus insulin trial. 95% CI=0. but a greater proportion of patients reached this target without hypoglycemia in the vildagliptin group (50.1.67 In a 52 week interim analysis of large randomized. these cases resolved on treatment and overall no increased risk of hepatic events was reported. examining the efficacy and safety of vildagliptin vs. However reduction in baseline FPG levels compared to placebo.3%) rosiglitazone 8 mg/day (64. Between the groups difference was -0. pioglitazone 30 mg/day (50.5% CI. p<0. vildagliptin showed greater lowering of adjusted mean HbA1c levels in the older patients.4. 0. after 24 weeks of treatment. establishing the non-inferiority of vildagliptin (p=0. AEs were reported by 55–70% of vildagliptin recipients. nasopharyngitis.78. 59–74% of placebo recipients. Although cases of ALT elevations with concomitant increase in bilirubin have been reported recently for sitagliptin. 95% CI=0.02% and -0.8% vs 12%)63 (all p < 0. 0. 1. –0. The tolerability profile of oral vildagliptin has been reviewed previously.393). and increased sweating. 1. which act by increasing plasma levels of active GLP-1. 34–75% of active comparator recipients (metformin. 61.with rare treatment related discontinuations.7% or 36. the safety profile of any new OHA is of utmost importance for treatment of chronic and progressive disease like T2DM. where the drug was used either alone or in combination with other therapies.14 for 50 mg BID). hepatitis-C infection and pancreatitis and these complications could be aggravated by drug treatment. However in comparator trial of Vildagliptin 50mg BID daily. The RRs for both vildagliptin regimens were <1 (RR=0. The pooled monotherapy data showed that frequency of AEs in patients with normal renal function compared to patients with mild renal impairment did not differ significantly in recipients of vildagliptin 50 mg OD (54. drug failed to establish the noninferiority to pioglitazone 30mg OD in reducing mean FPG. the reduction in mean baseline HbA1c with Vildagliptin 50mg BID (-0. pioglitazone.60 glimepiride61 or insulin69 was not significant.9% vs.02%) and -0. pioglitazone and insulin) recipients.53% (0.01). p=0. twice daily (BID) (n = 6.2% or 24. placebo –0.9.4% vs.87. over the past couple of years.8% vs.60. 59 Hepatic Safety Profile To date. Subsequently alongside efficacy. dizziness.44% (0.57-62 © JAPI • april 2011 • VOL.11 for 50 mg OD and RR=0.04%). 46 The most common AEs reported in patients receiving vildagliptin during clinical trials included headache.43 which were –0. 48%) or placebo (63. Mean change from baseline HbA1c (7. demonstrating non-inferiority of vildagliptin (97. Vildagliptin 50mg OD or BID showed significantly greater reduction in baseline FPG levels as add on therapy to metformin when compared with placebo59 at 24th week.37. constipation.001]) unlike patients aged <65 years (–0.88. may actually exert cardio-protective effects. including among those at most risk. vildagliptin 50 mg BID (60. The mean change in HbA1c from baseline was -0.68±0.663 for Vildagliptin 50mg OD and –0.3. showed that vildagliptin does not lead to an increase in CCV events in a T2DM population.860 and –0.62 Safety and Tolerability of Vildagliptin T2DM itself is characterized by increased risk of organ specific complications like CV disease. subgroup analysis showed that patient age was an important factor in achieving glycemic control.1%). Patients received either a 50-mg dose of vildagliptin once daily (OD) (n = 1.84. Patients aged >65 years had a significant lowering of adjusted mean HbA1c levels (between-group difference vildagliptin 50mg BID vs. 0.63 When added to metformin.02%) with vildagliptin and glimepiride respectively.001) after 3 months of treatment.69 Similarly in combination with glimepiride.19).71 There is considerable preclinical evidence that DPP-4 inhibitors.03% in vildagliptin and TZD group respectively.73-74 It is well known that hypoglycemia is associated with increased CCV risk and as discussed in this article DPP-4 inhibitor vildagliptin has been associated with reduced incidence and severity of hypoglycemia.061).16%). multicentre study. USFDA has issued guidance for industry with recommendations for methodology to show that a new therapy does not cause any unacceptable increase in CV risk.5%).62 The mean HbA1c of <7% was achieved in considerably more recipients of vildagliptin 50mg OD or BID than placebo recipients when administered as adjuvant therapy to pioglitazone (28.04.060 and –0.46 drug as monotherapy or in combination was well tolerated for periods up to 52 weeks. 57.0±0.1% [95% CI –0.68 Cardio and Cerebrovascular Safety Cardiovascular and cerebrovascular (CCV) events are highly prevalent co-morbidities of T2DM.3% vs. the link between OHAs and CV disease has been a area of concern with some of new compounds have unexpectedly been linked with excess CV AEs.62.2%).3%) at week 52 endpoint was -0.73).5.02%.361])61 and this effect was sustained in extension trial at week 52. males (RR=0.3%. Similar results were seen across all subgroups including elderly patients (RR=1.72 also limited human studies that are available have suggested that GLP-1 may improve CV function.9±0.4% vs 14.51.5%).63 A study conducted as per Food and Drug Administration.62.17% and -0.75 pooled the data from 25 phase III vildagliptin trials lasting from 12 weeks to over 2 years.59 –0.5-8. 0.001). 58.7%50. vildagliptin was not associated with an increased risk of having severely elevated liver enzymes (AST/ALT ≥10 x ULN.53.49.90 and 0.32-35 As a result of their diverse mechanism of action.The meta-analyses conducted by Kothny W et al and colleagues. the skin and in patients with impaired renal function has been discussed in detail in metaanalysis by Ligueros-Saylan M and colleagues. the pancreas.61 In combination with metformin. More notably. p<0. nausea.56 vs. In addition to this.81 pooled safety data from 24 phase 2 and 3 double-blind controlled clinical trials. a number of new medications have been approved by USFDA for treatment of diabetes. regimens complicatedness. dyspepsia and flatulence with metformin than with vildagliptin.4%53 in metformin. no events with pioglitazone).5% vs.51 pioglitazone. The results from this meta-analysis showed that the greater proportion of vildagliptin recipients had mild elevations in liver enzymes versus comparator recipients (ALT/AST levels >= 3 x upper limit of normal [ULN]). no other recently approved medications are orally administrable. vildagliptin 50mg BID resulted in a significant (p<0. but patient resistance and fear of needle.1% reductions) have been observed in patients receiving vildagliptin. time and cost are main barriers to patient non-compliance to these therapies.78 GLP-1 agonists such as exenatide79 and DPP-4 inhibitor sitagliptin80 have been associated with some cases of acute pancreatitis. Unlike many other antihyperglycemic medications.49. Two patients experienced severe elevations in liver enzymes attributable to vildagliptin treatment.78. The frequency of reported GI AEs with metformin 2000 mg daily were twice than that of recipients of 242 vildagliptin 50mg BID (43. The safety of vildagliptin versus comparators on the liver. respectively).51. with sustained reductions to clinically significant levels for up to 2 years. as cholelithiasis. the occurrence of cardiac AEs (including arrhythmias and conduction abnormalities) and hypertension with vildagliptin was comparable to placebo and also less than with metformin. The availability and accessibility of a new class of therapeutic agents is key to lessen burden of T2DM. ranging from the IGT population to patients with advanced disease on insulin.57 The occurrence of GI-related AEs in acarbose recipients was more than twice than that in vildagliptin recipients (25.4–1. In the new group of drugs orally administered DPP-4 inhibitor vildagliptin proves to be a very efficacious drug for improving glycemic control in a wide range of T2DM patients. Ligueros-Saylan M et al. All the same.53-54 Hypoglycemic events were rare (≤3. when compared to placebo plus metformin recipients. However with exception of inhaled insulin. With aim of assessing whether treatment with the DPP-4 inhibitor vildagliptin is associated with an increased risk of pancreatitis. a SU or a TZDs. 21. the immune system. as change in bodyweight associated with vildagliptin treatment is neutral or modest in nature and not significantly different from placebo.43 Existing data indicates that HbA1c lowering potential of Vildagliptin is in range of TZDs and acarbose. thereby reducing associated microvascular and vascular co-morbidities. Nor was vildagliptin associated with an increased risk of hepatic AEs. no hypoglycemic events were observed.83 Role of Vildagliptin in T2DM Therapy The primary aim of T2DM therapy is a prompt and sustained lowering of elevated glucose levels. modest reductions in HbA1c values (0.82 Hypoglycemia The incidence of hypoglycemia reported by vildagliptin monotherapy were low and similar to that with metformin or rosiglitazone.4% vs. (≤0.50 In three trials. oral inhibitor of DPP-4 vildagliptin improves glycemic control in patients with T2DM through physiological mechanisms that result in an attenuation of β-cell decline and thus restoration of the incretin effect.8%.001).6%) in all combination therapy trials.54.022).59 Gastrointestinal (GI) AEs The incidence of GI AEs reported with vildagliptin 50mg is comparable to placebo and is much less than in metformin or acarbose treated patients.04% in rosiglitazone and 0% in placebo56 recipients). abdominal pain. T2DM is a disease associated with a progressive decline in β-cell function.8%).49 Bodyweight The DPP-4 inhibitor vildagliptin appear to be bodyweight neutral. 60 Moreover. 60. or AST/ALT ≥3 x ULN and bilirubin ≥2x ULN). The result from this meta-analysis established that there was no evidence of an increased risk of pancreatitis related AEs following treatment with vildagliptin at the marketed doses of 50mg OD and BID relative to the all comparators group. The odds ratio for pancreatitis-related AEs was <1 for vildagliptin 50mg OD and BID (OR = 0. 0.53.53 This resulted in 3-4 times higher incidence of diarrhoea.77 pooled the safety data from 36 phase 2 and 3 clinical trials to investigate hepatic safety profile vildagliptin. vildagliptin treatment was not associated with the weight loss that is coupled with some other antidiabetic agents.56-62 However there was a tell apart difference in weight neutral effect of vildagliptin to weight gain effect of rosiglitazone. inconvenience. when used in combination with insulin.57. Despite the fact that injectable therapies like insulin and exenatide are effective treatments. Pancreatic Safety Profile As mentioned earlier T2DM has also been associated with increased risk of pancreatitis. Vildagliptin is indicated as second-line therapy as part of an oral combination therapy regimen in T2DM patients whose hyperglycemia is poorly controlled by monotherapy with metformin. Since a small number of these hepatic enzyme elevations were reported on vildagliptin as well. approximately five times as many patients withdrew because of AEs following treatment with metformin when compared with vildagliptin (4. one hypoglycemia event each was reported from vildagliptin 50mg OD and BID recipient57 and one recipient of vildagliptin 50mg BID experienced three hypoglycemic events (vs. indicating no increased risk relative to all comparators. Both cases were asymptomatic and resolved upon discontinuation of treatment. In the last couple of years.p < 0. to investigate its association with pancreatitis-related AEs.3%. liver enzyme monitoring after initiation of therapy is prudent and consistent with the vildagliptin product information.53 Also incidence of GI AEs was considerably lower in vildagliptin 50mg OD plus metformin (≥1500 mg/day) recipients (p=0. DPP-4 inhibitor such as © JAPI • april 2011 • VOL. ≤0. 12. When used as monotherapy or in combination with metformin or insulin.7% vs.60 in phase 3 comparator trial.However.001) reduction in the frequency of hypoglycemic events compared with placebo. hypertrygliceridaemia associated with disease are acknowledged risk factors for acute pancreatitis. 59 . It has the potential to significantly change the clinical management of diabetes and can be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM. Also in other combination trials. Bloomgaren Z. Combining drug with existing medications with complementary MOA. AEs associated with Vildagliptin were generally of mild to moderate severity and transient in nature. presents it to be an effective and safe antihyperglycemic agent. 15.com/ articles/diabetesdefinitions/sulfo nylureas/print/ 14.27:17-20. in type 2 diabetic patients receiving rosiglitazone. vildagliptin as add-on therapy to insulin. Efficacy of glyburide in diabetics poorly controlled on first-generation oral hypoglycemics. 12. FPG.http://www. all countries of European Union (in combination with metformin. 10..3:339. metformin. Ohkubo Y.12:203-208. Disclosures Dr. pioglitazone. Huang WF. Sulfonylureas.14:801-812. Araki E et al. vildagliptin enlarges the treatment options © JAPI • april 2011 • VOL. As add-on therapy to metformin. Oral antihyperglycemia therapy for type 2 diabetes: scientific review.. Diabetes Res Clin Pract 1995. BMJ 2009. Nevertheless. Kilo C. the recommended dose of vildagliptin is 50mg OD administered in the morning. who are poorly controlled with monotherapy. vildagliptin has been shown to reduce HbA1c. Clin Ther 1992. CMAJ 2005. Ward JD. since from a pathogenic point of view combining metformin principally targeting insulin resistance with vildagliptin primarily targeting the β-cell is a rational approach. JAMA 1999. Glyburide versus glipizide in the treatment of patients with noninsulin-dependent diabetes mellitus. Schneider J. Frighi V. Diabetes Res Clin Pract 2010.. These effects contribute to the efficacy of vildagliptin to improve glycemic control as well as to its low hypoglycemic potential. UK Prospective Diabetes Study (UKPDS) Group. N Engl J Med 2007. Acknowledgments Dr. although long-term studies will be required to demonstrate this and to rightly position vildagliptin vis-à-vis to other antihyperglycemic agents. Wilson RM.84 The effect of improving postprandial glycemia provides a good alternative for the up till now limited therapeutic options of affecting postprandial glycemia excursion. Koro CE. Cohen KL.281:2005–2012.28:103-17. PPG and prandial glucagon secretion and improve β-cell function. 17. Symptomatic hypoglycemia in NIDDM patients treated with oral hypoglycemic agents. Jovanovic L. administered as one dose each of 50mg in morning and evening. with a AEs event profile similar to placebo. Robert S. randomized study of glimepiride in patients with type 2 diabetes mellitus for whom diet therapy is unsuccessful. Bowlin SJ. pioglitazone or a SU. Harris S. 4.46:145-54. Meenan A. Glycemic control from 1988 to 2000 among U. vildagliptin provided better glycemic control than placebo57 and in an active comparator noninferiority trial. SUs and TZDs) for the treatment of T2D. there is a continuous advance in disease state of patient.59 glimepiride61 and pioglitazone58 provided more effective glycemic control than placebo.000 patients using the National Health Insurance database in Taiwan. The risk of developing coronary artery disease or congestive heart failure. The preliminary evidence of beneficial effects of Vildagliptin. Wen YW. 243 . member of the novel class of DPP-4 inhibitors. Vildagliptin is currently approved in Latin America. both as monotherapy and in combination with other antidiabetic therapies.available for management of T2DM patients. Inzucchi SE. Sicree RA.356:2457-71. and overall mortality. Zimmerman BR. it was shown to be as effective as pioglitazone60.32:675-90. Fedder DO.87:4-14. 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. Vildagliptin’s unique MOA permits a number of combination regimens for effective control of glucose levels. New Delhi. or sulfonylureas: a retrospective analysis. the risk of hypoglycemia was not aggravated.. International Diabetes Federation. Holman RR. A placebo controlled. Wolski K. J Clin Pharmacol 1998. In clinical studies of T2DM patients. When used in dual combination with a SU. Global estimates of the prevalence of diabetes for 2010 and 2030. 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