Obesity and New Pharmaceutical Approaches

AND NEW PHARMACEUTICAL APPROACHESObesity American Council on Science and Health OBESITY AND NEW PHARMACEUTICAL APPROACHES by Steven Marks for the American Council on Science and Health Ruth Kava, Ph.D., R.D. Project Coordinator and Editor February 2009 AMERICAN COUNCIL ON SCIENCE AND HEALTH 1995 Broadway, 2nd Floor, New York, NY 10023-5860 Phone: (212) 362-7044 • Fax: (212) 362-4919 acsh.org •HealthFactsAndFears.com E-mail: [email protected] TH E FOLLOWI NG PEOPLE R EVI EW E D TH I S P U B LICATION. Nigel Bark, M.D. Albert Einstein College of Medicine Thomas G. Baumgartner, Pharm.D., M.Ed., FASHP, BCNSP University of Florida, Gainesville George A. Bray, M.D. Pennington Biomedical Research Center Joseph F. Borzelleca, Ph.D. Medical College of Virginia Jack C. Fisher, M.D. University of California, San Diego Donald A. Henderson, M.D., M.P.H. University of Pittsburgh Medical Center Ruth Kava, Ph.D., R.D. East Carolina University American Council on Science and Health Kathryn Kolasa, Ph.D., R.D., LD/N Gilbert L. Ross, M.D. Harvard Medical School American Council on Science and Health Thomas P. Stossel, M.D. Elizabeth M. Whelan, Sc.D., M.P.H. American Council on Science and Health ACSH accepts unrestricted grants on the condition that it is solely responsible for the conduct of its research and the dissemination of its work to the public. The organization does not perform proprietary research, nor does it accept support from individual corporations for specific research projects. All contributions to ACSH—a publicly funded organization under Section 501(c)(3) of the Internal Revenue Code—are tax deductible. Copyright © 2009 by American Council on Science and Health, Inc. This book may not be reproduced in whole or in part, by mimeograph or any other means, without permission. CONTE NT CHAPTER CHAPTER 1 Executive Summary CHAPTER 2 Introduction CHAPTER 3 What’s Under the Hood: How the Body Regulates the Balance Between Food Intake and Energy Expenditure CHAPTER 4 Current Treatments: How Effective Are They? CHAPTER 5 New Approaches: Putting the Central and Peripheral Mechanisms to Work CHAPTER 6 Central Targets: The Role of the Hypothalamus a. The Serotonin System: A Safer Redux? b. Gut Hormones: Ensuring Fuel for the Short Trip CHAPTER 7 Peripheral Mechanisms: Energy Expenditure a. Metabolism b. Fat Storage CHAPTER 8 Toward the Future CHAPTER 9 Conclusion ACKNOWLEDGMENTS REFERENCES PG 1 2 4 8 10 11 13 15 16 17 18 CHAPTE R Executive Summar y Obesity is a growing problem worldwide, with serious health and qualityof-life implications. Dietary and behavioral changes offer only limited help; although some people benefit from antiobesity drugs, expectations are often unrealistic. The effectiveness of current treatments is limited; for the morbidly obese, surgery is the most effective option, although it is not risk-free. Efforts to foster weight loss are countered by the body’s inherent need to preserve weight. Considerable progress has been made in identifying new means of treating obesity, particularly those that suppress appetite or restrict fat absorption. The extremely complexity of the body’s energy system means that altering one part affects others, as well as other biological systems. The development of new helping patients eat less they eat; thus far, drugs of existing fat stores are development. drugs should focus on and better utilize what that stimulate the use in the early stages of Pharmaceutical agents will not solve the obesity problem by themselves; lifestyle adjustments will likely always be necessary. For the immediate future, the most effective treatment is likely to be a combination of drug and behavioral therapy, along with changes in diet, rest, and exercise. Obesity and New Pharmaceutical Approches / Chapter 1 / 1 CHAPTE R Introduction 2 eral forms of cancer (Cooke 2006). These trends suggest that the current generation of Americans may be the first in the past 200 yeas to have a shorter life expectancy than their parents had, according to physicians at the University of Illinois Medical Center in Chicago (Olshansky 2005). This is hardly the definition of progress. In addition to the health consequences, obesity also entails substantial economic and social costs. An obese worker costs his employer an estimated $2,500 per year in added medical expenses and lost productivity, according to studies from RTI International and the CDC. Overall, business and industry pay a hefty price for obesity:$13 billion a year, estimates the Washington, DC-based National Business Group on Health, a health policy group comprising the nation’s largest corporations (Harper 2007). Obese people themselves are often stigmatized. Documented cases of discrimination extend to employment, education, and healthcare. There have also been suggestions of bias in adoption proceedings, jury selection, housing, and other areas of public life, according to Yale University investigators (Puhl 2001). Obesity is now the nation’s second-biggest public health problem, right after smoking. Although lifestyle changes, The endocrinologist David Ludwig calls his patients, the seven-member G family, “a microcosm of 21st-century America.” One of the parents is overweight and the other is obese, wrote the Harvard Medical School professor and director of the Optimal Weight for Life Clinic (Ludwig 2007). All five of the children are even more severely obese, and although they are still young, they already face the prospect of lives limited by chronic medical problems. One of the youngsters shows the first signs of fatty liver, while another has high blood pressure. Three have marked insulin resistance, the first sign of type-2 diabetes; four have abnormal cholesterol profiles, and two complain of orthopedic problems. The children all express serious emotional distress, stemming from their obesity. Were the G family unusual, their health problems could be written off as medical curiosities. Unfortunately, families like that of Mr. and Mrs. G and their children are becoming all too common in industrialized nations around the world. Today, about 66% of all Americans are overweight or obese (Ogden 2006). Researchers from the Centers for Disease Control and Prevention (CDC) report that since 1970, the number of overweight children and adolescents between the ages of 6 and 19 years has tripled, meaning that more than 9 million young Americans (or nearly onein-five) are at risk for a wide range of obesity-related problems, including diabetes, hypertension, high cholesterol, coronary artery disease, respiratory problems, sleep apnea, gallbladder disease, osteoarthritis, and sev- Obesity and New Pharmaceutical Approches / Chapter 2 / 2 most notably dietary adjustments and increased physical activity, can help people lose weight and stave off obesity, many find it difficult to comply with such weight-loss regimens. Shedding surplus pounds is frequently a struggle, but for many people, it's a battle they are genetically programmed to lose. (Later on, we’ll learn just why this is so.) For this reason, a great deal of interest – and hope – rests on the potential effectiveness of pharmaceutical therapies for obesity. Americans currently spend more than $33 billion a year on weight-loss treatments (BW 2008), ranging from prescription drugs to diet programs and nutritional supplements. Not all such treatments are credible (see “Buyer Beware” sidebar in Chapter 4), and the results can be disappointing for even those treatments that have value. Nonetheless, the pharmaceutical industry has invested enormous capital in the search for effective and safe weight-loss drugs that target the body’s intricate energy-regulation mechanisms. The research and development continues today. Obesity and New Pharmaceutical Approches / Chapter 2 / 3 CHAPTE R What’s Under the Hood? 3 How the Body Regulates the Balance Between Food Intake and Energy Expenditure What is obesity, biologically speaking? Simply put, obesity is an excessive accumulation of body fat. It can be determined using a variety of means, including underwater weighing, CT scans, and bioelectric impedance analysis, an exam in which a low-voltage electric current is used to determine lean body mass – the more fat a body has, the more resistant it is to the current. Many of these tests are not easy to perform, and some require sophistcated technology. To overcome these limitations, the U.S. Government in the late 1990sbegan to use a simpler, actuarial-based measure of obesity, the “Body Mass Index” (BMI). BMI is the ratio of weight to height (kg/m2, or pounds/in2) (Table 1). People are said to be overweight if they have a BMI between 25 and 29.9 kg/m2; those with a BMI above 30.0 kg/m2 are considered obese. That would be a weight of 175 pounds for a 5 foot 4 inch person. Several caveats are in order when interpreting BMI. The index is an initial warning that an individual might be carrying excess body fat. It is most accurate for people who are generally inactive; for these people, a high BMI is a warning to look more closely for signs of obesity-related diseases. For example, a sedentary individual with a BMI of 31 might want to measure the circumference of his waist to determine if he has excess abdominal fat, a condition associated with an increased risk of metabolic syndrome, diabetes, and cardiovascular disease. Tests of blood glucose (for incipient diabetes) and lipids (for coronary artery disease) also might be ordered. On the other hand, a BMI of 31 in a body builder, tennis player, or other well-trained athlete would not be cause for concern. Excessive body fat is not an issue for people who have increased muscle mass. In other words, BMI is helpful to identify those at risk for serious obesity-related diseases, although its utility as an indicator of health status and risk is limited. (For more on the use of BMI, see, “Are Our Athletes Really Fat?” at www.acsh.org/factsfears/ newsID.517/news_detail.asp.) Obesity is the end result of a long-term imbalance between the amount of energy, or calories, we consume and the amount we use. Eat or drink too much or get too little exercise and the result is the same – an expanding waistline. Perhaps a more useful way to consider the problem of excessive fat is to examine the physiology of weight gain. In this regard, obesity is the end result of a long-term imbalance between the amount of energy, or calories, we consume and the amount we use. Eat or drink too much or get too little exercise and the result is the same – an expanding waistline. However, the two sides of the equation are not quite equal; in fact, many obesity experts now focus their attention on the “energy out” component. Whereas the consumption of high-calorie foods and beverages was once believed to be the primary cause of obesity, the lack of exercise is now understood to be at least as important. As the Harvard cell biologist Bruce Spiegelman says, “The precise contribution of overeating to obesity is unclear. Studying diet in obese patients Obesity and New Pharmaceutical Approches / Chapter 3 / 4 Body Mass Index Table Overweight 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 Normal Obese Extreme Obesity 51 52 53 54 BMI 19 20 21 22 23 Height (inches) Body Weight (pounds) 58 91 96 100 105 110 115 119 124 129 134 138 143 148 153 158 162 167 172 177 181 186 191 196 201 205 210 215 220 224 229 234 239 244 248 253 258 59 94 99 104 109 114 119 124 128 133 138 143 148 153 158 163 168 173 178 183 188 193 198 203 208 212 217 222 227 232 237 242 247 252 257 262 267 60 97 102 107 112 118 123 128 133 138 143 148 153 158 163 168 174 179 184 189 194 199 204 209 215 220 225 230 235 240 245 250 255 261 266 271 276 61 100 106 111 116 122 127 132 137 143 148 153 158 164 169 174 180 185 190 195 201 206 211 217 222 227 232 238 243 248 254 259 264 269 275 280 285 62 104 109 115 120 126 131 136 142 147 153 158 164 169 175 180 186 191 196 202 207 213 218 224 229 235 240 246 251 256 262 267 273 278 284 289 295 63 107 113 118 124 130 135 141 146 152 158 163 169 175 180 186 191 197 203 208 214 220 225 231 237 242 248 254 259 265 270 278 282 287 293 299 304 64 110 116 122 128 134 140 145 151 157 163 169 174 180 186 192 197 204 209 215 221 227 232 238 244 250 256 262 267 273 279 285 291 296 302 308 314 65 114 120 126 132 138 144 150 156 162 168 174 180 186 192 198 204 210 216 222 228 234 240 246 252 258 264 270 276 282 288 294 300 306 312 318 324 66 118 124 130 136 142 148 155 161 167 173 179 186 192 198 204 210 216 223 229 235 241 247 253 260 266 272 278 284 291 297 303 309 315 322 328 334 67 121 127 134 140 146 153 159 166 172 178 185 191 198 204 211 217 223 230 236 242 249 255 261 268 274 280 287 293 299 306 312 319 325 331 338 344 68 125 131 138 144 151 158 164 171 177 184 190 197 203 210 216 223 230 236 243 249 256 262 269 276 282 289 295 302 308 315 322 328 335 341 348 354 69 128 135 142 149 155 162 169 176 182 189 196 203 209 216 223 230 236 243 250 257 263 270 277 284 291 297 304 311 318 324 331 338 345 351 358 365 Obesity and New Pharmaceutical Approches 70 132 139 146 153 160 167 174 181 188 195 202 209 216 222 229 236 243 250 257 264 271 278 285 292 299 306 313 320 327 334 341 348 355 362 369 376 71 136 143 150 157 165 172 179 186 193 200 208 215 222 229 236 243 250 257 265 272 279 286 293 301 308 315 322 329 338 343 351 358 365 372 379 386 / 72 140 147 154 162 169 177 184 191 199 206 213 221 228 235 242 250 258 265 272 279 287 294 302 309 316 324 331 338 346 353 361 368 375 383 390 397 73 144 151 159 166 174 182 189 197 204 212 219 227 235 242 250 257 265 272 280 288 295 302 310 318 325 333 340 348 355 363 371 378 386 393 401 408 74 148 155 163 171 179 186 194 202 210 218 225 233 241 249 256 264 272 280 287 295 303 311 319 326 334 342 350 358 365 373 381 389 396 404 412 420 Chapter 3 75 152 160 168 176 184 192 200 208 216 224 232 240 248 256 264 272 279 287 295 303 311 319 327 335 343 351 359 367 375 383 391 399 407 415 423 431 76 156 164 172 180 189 197 205 213 221 230 238 246 254 263 271 279 287 295 304 312 320 328 336 344 353 361 369 377 385 394 402 410 418 426 435 443 / Source: Adapted from Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults: The Evidence Report. 5 Although cavemen struggled to find food and constantly teetered on the edge of starvation, contemporary Americans eat – and overeat – for many reasons other than hunger. Humans eat for social purposes and to relieve stress and sometimes for no other reason than that they can. People find it hard to pass by the local convenience store if they feel like enjoying a burrito and fries, and the energy regulatory system is happy to oblige. is confounded by the fact that these patients tend to under-report their food intake by as much as 30%. Overeating can be gauged only in relation to that individual’s energy expenditure (Spiegelman 2007).” This observation means that people who follow a regular exercise regime and do not overeat routinely tend to maintain their weight. However, even small changes in diet or in the amount of physical activity can affect body weight when the changes extend over a long period of time. Under normal conditions, the body’s energy balance is strictly regulated and controlled. Consider that most people consume about 700,000 calories each year; even so, body weight usually does not vary by more than 1 kilogram up or down – about 7,000 calories (3,500 calories = 1 pound). This means the body is able to maintain its fat stores to an accuracy of 99% (Hofbauer 2007). The bad news for those trying to lose weight is that fewer than 20 excess calories a day over the course of a year will put on 1 pound of fat. “That the body can regulate such a small amount of overeating – one cannot measure 20 calories accurately – is a sign of how finely balanced is our energy maintenance system,” said Randy G. Seeley, Ph.D., associate director of the Obesity Research Center at the University of Cincinnati, in a telephone interview. Evolutionary pressures, which required prehistoric man to maintain his energy reserves in the face of a harsh environment and limited food supplies, predispose our bodies to prevent weight loss more strongly than weight gain. Our energy regulatory system contains many redundant mechanisms to keep us from starving.“Our bodies were not designed to restrict our intake of food but to help us survive,” Dr. Seeley added. Although cavemen struggled to find food and constantly teetered on the edge Figure 1. Nerve signals from adipose tissue and gastrointestinal organs such as the stomach and intestines influence appetite and satiation (feelings of fullness) via central and peripheral mechanisms. All of these signals are integrated in the hypothalamus. Fat-cell signals are primarily responsible for the long-term regulation of hunger, while messages from the organs such as the stomach and intestines control immediate energy needs and satiety. Adapted from Hofbauer KG, Nicholson JR, and Boss O. Obesity and New Pharmaceutical Approches / Chapter 3 / 6 AREAS OF INVESTIGATION AREAS OF CURRENT RESEARCH Leptin Melanocortin system Serotonin system Loracaserin Melanin-concentrating hormone Cannabinoid receptors Zimulti* Gut hormones Peptide YY Cholecystokinin Ghrelin Synthetic GLP-1 Uncoupling proteins Adipokines Adiponectin DRUGS NOW IN USE Central (appetite, satiation, metabolism) Meridia Sympatomimetics Phentermine Phendimetrazie Benzphetamine Glucophage and Sandostatin† Peripheral (metabolism, energy use, fatnstorage) Xenical Alli (OTC) * Currently in final clinical studies prior to FDA review † Used for treatment of adolescent obesity, although not approved for that indication of starvation, contemporary Americans eat – and overeat – for many reasons other than hunger. Humans eat for social purposes and to relieve stress and sometimes for no other reason than that they can. People find it hard to pass by the local convenience store if they feel like enjoying a burrito and fries, and the energy regulatory system is happy to oblige. In other words, getting fat is easy for most people, but losing weight can be a major struggle. The relationship between energy intake (i.e., food consumption), energy expenditure (i.e., body functions, such as heart beat and breathing, and physical activity), and weight is often expressed as “calories in” versus “calories out.” Too many calories consumed and too few calories burned off can lead to overweight, and in time, obesity. This simple equation explains why understanding the connection between energy intake and expenditure is so important. The balance between the two is regulated by a host of complex biological processes that involve two basic types of mechanisms – the “central” and “peripheral.” Central mechanisms include neuronal systems in the brain that monitor caloric intake and use and respond to signals from the body that contain information about energy stores and availability, much as a warehouse manager keeps track of inventory. Peripheral mechanisms include hormonal signals from the gastrointestinal tract, as well as from fat cells to such organs as the liver and pancreas, skeletal muscle, and even disease-fighting immune cells that carry out various metabolic (biochemical) functions important to energy regulation (Hofbauer 2007) (see Figure 1). These are the orders the warehouse must fill, sometimes immediately and other times later in the day. Here is how the two mechanisms work. First, feelings of hunger cause one to fix a sandwich or grab an apple. Eating triggers the process of digestion, and then signals emanating from the stomach tell the brain you are satisfied and have had enough to eat. The brain gathers this information, along with other neuronal and hormonal data relating to the body’s overall energy status, to produce a coordinated response to the change in the nutritional state. In this respect, the role of the hypothalamus, the part of the brain that regulates homeostasis (stability), is critical, says Richard Palmiter, Ph.D., professor of biochemistry at the University of Washington and an obesity investigator at the Howard Hughes Medical Institute (personal communication). Ongoing obesity drug research has targeted both central and peripheral mechanisms in the search for safe and effective treatments (Table 2). This research investigates strategies to reduce food intake by altering appetite, feelings of satiety (i.e., fullness or satisfaction), and fat absorption, and to elevate energy expenditure by boosting metabolism. Obesity and New Pharmaceutical Approches / Chapter 3 / 7 CHAPTE R Current Treatments: How Effective Are They? 4 The Food and Drug Administration (FDA) has approved three drugs for the long-term treatment of obesity, Meridia (sibutramine), Xenical (orlistat), and Alli, an over-the-counter (OTC) version of Xenica. Each primarily addresses one of the two mechanisms described above. Centrally acting Meridia blocks the action of several important chemicals involved mainly in promoting hunger and, to a lesser degree, food intake. In the clinical trials of Meridia, patients lost about 3% to 4% of their body weight, most of which occurred during the first six months of treatment. Continued use of the drug helped maintain the weight loss. Patients also experienced reductions in triglyceride levels and increases in good (HDL) cholesterol, which could help prevent the development of metabolic syndrome, diabetes, and heart disease. However, this benefit was counterbalanced by a slight increase in blood pressure and heart rate. As a result, for patients with hypertension or who have had an excessively rapid heart beat in the past, the use of Meridia may require regular monitoring. The drug did not affect bad (LDL) cholesterol. In contrast, Xenical and Alli work on the gastrointestinal system, where they prevent the absorption of fat. People using these drugs lose about the same amount of weight as those taking Meridia. Ongoing treatment also appears to keep the weight off. Unfortunately, Xenical and Alli may have some socially disturbing side effects that stem from their special mechanism of action: the fat that is not absorbed remains in the gut, where it can contribute to flatulence and the need for frequent bowel movements, which can be difficult to control. These gastrointestinal difficulties usually occur at the beginning of treatment and tend to diminish over time, especially when fat intake is reduced. A fourth drug, Zimulti/Accomplia (rimonabant), is in late clinical development and should also be noted. Researchers were prompted to study the effects of Zimulti and sister drugs on appetite suppression because cannabis (the active ingredient in marijuana) has long been known to promote feelings of hunger, the so-called “munchies.” This BUYER BEWARE The shelves of grocery stores and pharmacies are stocked floor to ceiling with various and sundry dietary aids, including vitamins, minerals, herbs and botanicals, and other substances such as enzymes, amino acids, glandulars, and metabolites. Some carry the labels “natural” and “clinically proven.” Others guarantee dramatic weight-loss results. Don’t believe a word of it. Snake oil is still snake oil, even when wrapped in fancy packaging. Alli is the only FDA-approved, over-the-counter treatment for obesity. This means its prescription version, Xenical, has met rigorous standards for safety and effectiveness. The difference between Alli and Xenical relates to dose – Alli is half as potent (60 mg) as Xenical (120 mg) and therefore deemed safe for consumer use without a doctor’s order. In contrast, other weight-reducing aids have not undergone human clinical testing. Under current law, these products are categorized as “dietary supplements” (i.e., foods); as such, they can be sold without proof of efficacy. Dietary supplements can be also harmful. The active ingredients may interact with common prescription medications or analgesics such as Tylenol or aspirin, raising the risk of a serious side effect. Even sorbitol, the sweetener used in sugarless gum, can cause severe diarrhea and bowel problems if over-consumed (Bauditz 2008). (Before taking any dietary supplement, review the ingredients with a doctor or pharmacist.) The bottom-line on miracle weight-loss pills: if the claim sounds too good to be true, it probably is. Obesity and New Pharmaceutical Approches / Chapter 4 / 8 drug blocks a class of receptors in the brain that respond to cannabis (cannabinoid receptors), which, in theory, should reduce the desire to overeat. In clinical trials, weight loss achieved with Zimulti had positive effects on a number of risk factors for heart disease, including cholesterol and triglyceride levels and insulin resistance. Blood pressure was not affected, which was surprising in light of the fact that patients taking Zimulti also lost about 3% to 5% of their weight and therefore should have experienced a reduction in blood pressure. Nearly 20 Current obesity drugs offer only modest benefits. Moreover, combining Xenical and Meridia does not have an additive effect – the weight loss remains the same. The lack of robust results puts patients and physicians in a quandary. Patients are often disappointed to discover that the drugs will help them lose only about 3% to 4% of their body weight. countries around the world have approved this medication for use. However, in 2007, the FDA rejected Zimulti because of the risk of psychiatric side effects, including depression, anxiety, and loss of sleep. The manufacturer plans to conduct additional studies and then resubmit Zimulti for approval. In addition to Meridia, Xenical, and Alli, which are designed and approved for chronic therapy, the FDA also has approved several other drugs for short-term use. Phentermine, phendimetrazine, and benzphetamine all belong to a drug class known as sympathomimetics. These medications act as appetite suppressants by mimicking the hormones adrenaline or noradrenaline. The sympathomimetics commonly prescribed for the treatment of obesity can serve as helpful adjuncts to a regimen of diet and exercise. Because these drugs can be habit-forming and may cause serious side effects, including high blood pressure, agitation, depression, and even psychoses, physicians limit their use to two to three weeks. (See “The Serotonin System: A Safer Redux” section in Chapter 6.) The sympathomimetics are not recommended for children and adolescents because of the potential for abuse and adverse events. Current obesity drugs offer only modest benefits. Moreover, combining Xenical and Meridia does not have an additive effect – the weight loss remains the same. The lack of robust results puts patients and physicians in a quandary. Patients are often disappointed to discover that the drugs will help them lose only about 3% to 4% of their body weight. A 1997 study examined patient expectations for obesity drugs and produced startling results. Obese patients indicated that they hoped to lose from 31% to 38% of their weight. Twenty-five percent was deemed acceptable, and 17% was rated as disappointing (Foster 1997). These findings suggest that obesity doctors may have a difficult time managing their patients’ expectations for drug therapy. “It’s true that it has been difficult to develop scientifically rational treatments that produce the kind of weight loss that people want,” says Dr. Seeley. “As things now stand, our treatments aren’t even effective enough to be disappointing!” More important, maintaining even the modest reduction in weight requires life-long treatment. “There is a common misconception that any effective obesity drug can be used for a limited time – until the desired weight loss is achieved – and then stopped,” says Rudolph Leibel, MD, professor of molecular genetics at Columbia University and co-director of the Naomi Berrie Diabetes Center, in an interview. “In this respect, treating obesity is no different from treating hypertension or high cholesterol. Any successful drug or combination of drugs will probably have to be taken indefinitely.” The hope is that, in the future, doctors will have a wider range of drug therapies that they will be able to use selectively on the patients best able to benefit from them. That remains the objective of current pharmaceutical research and development. Obesity and New Pharmaceutical Approches / Chapter 4 / 9 CHAPTE R New Approaches: 5 Putting the Central and Peripheral Mechanisms to Use One possible reason for the marginal utility of current drugs, some pharmaceutical researchers believe, is that the body’s most important regulators of weight remain to be characterized. The available therapies only address those mechanisms that fine-tune the energy balance. As one investigator commented, “There are lots of new targets under evaluation, and we hope that some of them may turn out to be much more effective than the current drugs. We may not have found the right targets yet, but we’re still looking.” BARIATRIC SURGERY A WAY TO BYPASS GASTRIC BYPASS? At present, the most dramatic obesity treatment is surgery. Many severely obese patients who undergo bariatic surgery (gastric bypass), for instance, maintain a significant weight loss of 45 to 60 pounds or more for periods of at least a decade. However, surgery is highly invasive and not without risks; as Dr. Randy Seeley of the University of Cincinnati pointed out, high rates of rehospitalizations and post-operative complications can be associated with these procedures. For this reason, techniques such as gastric bypass or banding usually are reserved for the most serious cases – people with a BMI >40 or with a lower score and other coexisting health problems such as heart disease or diabetes. Interestingly, scientists from University College in London recently identified two proteins – P2Y1 and P2Y11 – that control relaxation of the gut (BBC News 2008). By blocking the P2Y11 receptor, which directs slow relaxation, a drug could theoretically help control stomach volume in a manner not unlike gastric banding. Much research will need to be carried out before this provocative concept can be proven, but if successful, it could prove to be a way to achieve to the benefits of these surgical interventions without incurring the risks. Obesity and New Pharmaceutical Approches / Chapter 5 / 10 CHAPTE R Central Targets: 6 The Role of the Hypothalamus As noted above, the hypothalamus serves as the central caretaker of energy homeostasis. Our understanding of the myriad pathways involved in this process took a giant leap forward in 1994 when a hormone called leptin was identified. Hormones are signaling agents produced by various tissues in the body. Scientists discovered that leptin is released from fat cells to inform the brain about the state of the body’s energy supply. We now know that leptin circulates in the blood to the hypothalamus, providing information about the number and size of adipose (fat) cells in the body – the greater the amount of body fat, the more leptin a person produces, the greater the amount of body fat. In theory, administration of leptin to obese people would signal the brain that fat stores were abundant, thereby reducing food intake. However, early studies using a genetically engineered form of the hormone proved to be disappointing: daily injections of leptin helped only a small percentage of obese subjects lose weight. This finding led researchers to hypothesize that many patients are resistant to leptin. At present, obesity researchers are investigating techniques to overcome this resistance. Other hormones that signal the hypothalamus and may prove useful in the regulation of food intake and energy expenditure include those in the melanocortin system. The central melanocortin system is arguably the most important neuronal pathway involved in the regulation of energy homeostasis; it also is active in a wide array of other processes, including erectile function, blood pressure, and steroid production. Although obesity research on melanocortin pharmaceuticals continues, progress has been stymied by the fact that the these drugs also produce undesirable effects on the other biological activities, altering blood pressure and causing unwanted erections, for example. In addition, there are several different kinds of melanocortin receptors, two of which are abundant in the brain, and it is not entirely clear what the role of each one is. Thus, it is not yet known whether it will be possible to target melanocortin receptors in a way that reduces food intake without causing cardiovascular or sexual side effects. Various approaches to solve this problem are now being explored. The Serotonin System: A Safer Redux? Another central mechanism currently under investigation involves the serotonin system. This neurotransmitter helps control appetite – when serotonin levels are low, people feel hungry. Preventing the re-uptake of serotonin in the brain – keeping levels high, in other words – is the means by which such antidepressants as Paxil and Prozac work, and this approach also may help control weight. The first such serotonin re-uptake blocker, fenfluramine, was used along with the appetite suppressant phentermine in the mid-1990s as a popular anti-obesity regimen. Early in 1996, the FDA approved an updated version of fenfluramine known as Redux, and it, too, was combined with phentermine. Eighteen months later, both serotonin drugs were suddenly withdrawn from the market following reports of heart valve problems. Despite this setback, the concept of altering serotonin levels to dampen appetite remains valid. A new product, lorcaserin, which targets a different receptor in the serotonin system than Redux, Obesity and New Pharmaceutical Approches / Chapter 6 / 11 is now undergoing clinical trials, as is tesofensine, a compound that inhibits serotonin, noradrenaline, and dopamine. In addition to the serotonin system, another central mechanism that could help lower appetite involves melanin-concentrating hormone (MCH). This hormone is produced by neurons in the hypothalamus and acts on specific receptors in the brain that control our desire for food. Several different MCH drugs are also now in the early stages of development. Gut Hormones: Ensuring Fuel for the Short Trip Signals from fat cells (such as leptin) seem to be responsible for maintaining the body’s long-term energy supply. In contrast, neural and hormonal messages from the gastrointestinal system contain information about the status of immediately available energy stores. Important gut hormones include appetite suppressants such as peptide YY and cholecystokinin (CCK), as well as appetite stimulants such as ghrelin. Another gut hormone that helps reduce the desire for food in diabetic patients is synthetic glucagon-like peptide 1 (GLP-1). The first GLP-1 activator, Byetta, is now available, and others are in the final stages of clinical development. These medications, which produce weight loss in many diabetics, are under consideration as anti-obesity therapies. One difficulty facing scientists working on the design of a practicable peptide YY obesity therapy is the chemical composition of the hormone itself: its complex structure makes a pill formulation difficult, if not impossible, to create. Consequently, a nasal spray is being studied, although this route may reduce the drug’s potential effectiveness. In addition, some patients in clinical studies developed nausea and vomiting, raising concerns about the potential safety of this approach. Those working on a ghrelin blocker face a different obstacle. Although such a drug could help obese people cut their appetite, the treatment would have to be given any time a person wanted to eat, a potentially costly and inconvenient approach. Thus, notwithstanding the intriguing hypotheses underlying the research on gut hormones, the viability of these concepts still must be proven in the lab and clinic. Obesity and New Pharmaceutical Approches / Chapter 6 / 12 CHAPTE R Peripheral Mechanisms: Energy Expenditure 7 Uncoupling proteins (UCPs) are specialized substances contained within the inner layer of mitochondria, the cell powerhouse that helps the body produce energy. Investigations in animals show that increasing levels of UCPs raises body temperature. Figure 2. Adipose tissue is an important hormonal, or endocrine, organ that influences other parts of the body. It releases a variety of factors, such as leptin; adiponectin; RPB4 and TNF-alpha, which affect insulin resistance; and angiopoietins, which help regulate blood supply. A mix of hormonal and neural signals to fat cells controls the expression of these factors. More complete discussion of these processes is contained in the text. Adapted from Hofbauer KG, Nicholson JR, and Boss O. Obesity and New Pharmaceutical Approches / Chapter 7 / 13 Unfortunately, early human studies have not been successful, as mitochondria-rich brown fat cells, which express UCP1 and play an important role in temperature regulation in animals, disappear in humans after birth. Ongoing studies are attempting to find triggers of brown fat/UCP1 in adults, as well as other genes involved in energy use. The promise of this science is so great that Dr. Spiegelman at Harvard has written that he is “betting” this line of research will lead to treatments that have a noticeable effect on obesity (Spiegelman 2007). Fat Storage Tinkering with the body’s fat storage system could be a productive way to reduce fat supplies. Two strategies under consideration involve techniques to reduce adipose cell growth and promote cell death. One possible way to induce these favorable changes in fat cells would be to limit their blood supply via adipokines called angiopoietins. Although theoretically reasonable, this concept may be impractical: it may be difficult to develop a drug that could selectively target the appropriate fat cells and not cause other cells, such as those in the liver, to compensate by storing the additional calories. In that case, a patient could run the risk of developing the very health problems (e.g., metabolic syndrome, diabetes, or heart disease) the treatment was designed to avoid. Moreover, too few fat cells themselves can cause serious diseases, such as liposystrophy, in certain individuals. The research on fat storage therapies is continuing. What does all of this drug research mean for those who are seriously overweight or obese? On one hand, much recent progress has been made in identifying new mechanisms involved in energy homeostasis, and these remain promising avenues of drug research and development. On the other, the body’s energy system is extremely complex; altering one part leads to compensatory changes in another, not to mention the possible deleterious effects such alterations may have on other biological processes. Developing new drug treatments for obesity is a more complicated matter than it might appear at first glance. “Treating obesity is different from treating cancer,” Dr. Seeley indicates. “The body doesn’t want a tumor. However, it has been evolutionarily programmed to hold onto stored calories. Trying to take a finely designed system and upend it so that obese people lose weight is counterintuitive. Our bodies simply were not built that way. It’s hard to fool biology, although we continue to try.” “Treating obesity is different from treating cancer,” Dr. Seeley indicates. “The body doesn’t want a tumor. However, it has been evolutionarily programmed to hold onto stored calories. Trying to take a finely designed system and upend it so that obese people lose weight is counterintuitive. Our bodies simply were not built that way. It’s hard to fool biology, although we continue to try.” Metabolism Contrary to popular perception, fat is more than lumpy tissue that makes the wearing of horizontal stripes a dicey matter. We now know that adipose tissue is metabolically active, and its cells are key sources of certain cell messengers, called adipokines, which are essential to many of the body’s most important functions, including those in the brain, liver, skeletal muscles, pancreas, and the immune system (see Figure 2). Research has shown that obese people have low levels of one of those messengers, a protein called adiponectin, which is important to the development of insulin resistance, a pre-diabetic condition in which body cells fail to respond to insulin and thus are unable to process or store glucose. In addition to blocking cannabinoid receptors, Zimulti also stimulates the production of adiponectin; so do such diabetes drugs as Avandia and Actos. Scientists are now working on a range of potential chemical approaches to reduce insulin resistance, including drugs that may increase adiponectin or target other adipokines that affect metabolism. Obesity and New Pharmaceutical Approches / Chapter 7 / 14 CHAPTE R Toward the Future 8 Despite the physiological mechanisms that are activated during periods of restrictive dieting to reduce the body’s metabolic rate, there are signs that the development of drugs to produce a persistent change in metabolic rate may be possible. Alteration of such control mechanisms could provide a novel strategy for drug developers that could work hand in hand with other techniques to multiply the long-term effect of treatment. Indeed, such an integrated approach, which is known as systems biology, has already proven useful in the treatment of blood pressure and heart function. Using systems biology for weight loss would require identifying the most promising mechanisms involved in energy maintenance and moving drug discovery toward those compounds that could best affect it. “Our growing understanding of the physiology and molecular biology of obesity hopefully will identify new pathways and constituent molecules that will be ‘drugable,’ generating a group of agents that can be used in combination to address relevant aspects of both energy intake and expenditure,” says Dr. Leibel. Having a compendium of potential drug therapies that address both sides of the energy equation will enable physicians to address obesity in a more systematic fashion. Indeed, this approach may have just produced its first . Analyzing liver and fat tissue samples from mice, scientists from Merck and Rosetta Inpharmatics have identified a complex of core gene groups implicated in the onset of obesity, diabetes, and heart disease (Telegraph 2008). Three new genes, called Lpl, Pmp1l, and Lactb, appear to play an important role in the onset of obesity. A second Merck research team, working together with the Icelandic group Decode Genetics, and the National University in Reykjavik, Iceland, found a corresponding gene network in obese humans. According to one of the lead researchers, Eric Schadt, the fatty tissue of obese individuals displays a typical pattern of genetic expression that is not visible by blood-based diagnostic tools, which may explain why this gene complex was unknown until now. “These studies strongly support the theory that common diseases such as obesity result from genetic and environmental disturbances in entire networks of genes rather than in a handful of genes,” Dr. Schadt says. “If diseases like obesity are the result of complex networks of genes, the accurate reconstruction of these networks will be critical to identifying the best therapeutic targets.” Alas, even a fully stocked medicine chest of complementary anti-obesity drugs may not do the trick for some people. As noted above, people eat for a variety of behavioral and social reasons, and the only way to achieve lasting weight loss is to alter lifestyle, by reducing the amount of food we eat and drink, and increasing the exercise we get. Addressing a chronic condition such as obesity will require a battery of approaches, including behavioral counseling, drug treatment, and changes in lifestyle, to achieve lasting results. Short-term starvation, fitness programs, or even drug therapy alone, simply will not do the trick. “The goal of drug discovery and development is to give physicians a bevy of different drugs so they can rationally prescribe the best treatment for each individual patient,” Dr. Seeley says. “Obesity is a serious dilemma for the public, but over time, we hope to be able give patients a fighting chance.” Obesity and New Pharmaceutical Approches / Chapter 8 / 15 CHAPTE R Conclusion 9 Obesity is a growing public health problem with serious medical and qualityof-life implications. Although several drug treatments are available, their usefulness is limited, at best, and patients are often disappointed in the results. Nevertheless, obesity is a condition rife with therapeutic possibilities. Our knowledge of the mechanisms involved in energy homeostasis has grown enormously in the past decade, providing obesity researchers inside and outside the pharmaceutical industry with many potential drug targets to test. Although the future introduction of a magic pill that will help obese people shed fifty or one hundred pounds painlessly and safely is highly unlikely, a combination of multiple drugs, behavioral therapy, and lifestyle changes should enable patients and their doctors to address the many health and quality-of-life issues associated with this intractable condition. Obesity and New Pharmaceutical Approches / Chapter 9 / 16 ACKNOWLE DG M E NTS In preparing the sections on anti-obesity drug research and development, I benefited immensely from the excellent reviews written by Karl G. Hofbauer, Janet R. Nicholson, and Olivier Boss (Ann Rev Pharmacol Toxicol. 2007;47:565-92) and Dunstan Cooke and Steve Bloom (Nature Rev. 2006;6:919-31). All of the errors are my own. 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