Faculty Peer Reviewed
Despite the high prevalence of obesity1 and its associated morbidity2 and mortality 3,4, it represents one of the most difficult chronic conditions to treat. Barriers include a metabolically toxic environment, a history of ill-fated weight-loss regimens, and a general view of obesity as primarily a social, not a medical problem. 5 Deep down, the belief that obesity really is the result of gluttony and sloth probably persists. However, as we learn more about the physiology of energy balance, appetite regulation, and peripheral signaling mechanisms, obesity is increasingly regarded in the same light as other chronic medical conditions, such as hypertension or diabetes, and equally deserving of medical attention.
Theoretically, obesity can be treated in four different ways: (1) reduction of calorie intake through decreased appetite or (2) decreased nutrient absorption, (3) increase in energy expenditure, and (4) direct removal of fat. 6 These targets can be achieved through changes in diet and lifestyle, medication, surgery, or some combination of the above. All overweight and obese patients should follow a reduced-calorie diet and increase their physical activity, whether or not they choose to pursue adjunctive medication or surgery. 7 Medications used for obesity treatment, including those still under development, aim to reduce calorie absorption or decrease appetite.
The FDA has approved two drugs for the induction and long-term maintenance of weight loss. Sibutramine (Meridia) reduces appetite by inhibiting the reuptake of norepinephrine and serotonin in the central nervous system. The other approved medication, orlistat (Xenical, Alli), blocks peripheral absorption of calories in the form of fat by inhibiting pancreatic lipase in the gastrointestinal tract. Both drugs have demonstrated safety and efficacy in inducing weight loss of up to 8-10%. 8,9 However, patients often regain the weight upon discontinuation of the medications and no long-term safety or efficacy data currently exist for either drug beyond two years. Furthermore, undesirable side effects, lack of a dramatic weight-loss response, and the persistence of obesity on an individual and population scale continue to spur the development of other weight-loss treatments.
The selective cannabinoid-1 receptor antagonist rimonabant initially promised to deliver superior results to sibutramine and orlistat, particularly with regard to improvements in HDL, triglycerides, and glucose tolerance. Rimonabant reduces appetite and results in a 4.7 kg weight loss over one year compared to placebo. Although rimonabant initially received approval in Europe, in October 2008 the European Medicines Agency withdrew marketing authorization due to the emergence of anxiety, depression, and suicidality in patients with no prior history of psychiatric illness. The Food and Drug Administration has not approved rimonabant for use in the United States due to similar safety concerns. 10
Lorcaserin, an anorectic selective serotonin 2C receptor agonist, is currently undergoing phase III clinical trials. It differs from the earlier nonselective serotonin agonists, fenfluramine and dexfenfluramine, in that it exerts minimal activity against the serotonin 2B receptors implicated in the pathogenesis of heart valve damage. In a randomized double-blind placebo-controlled study, healthy obese patients receiving 10 mg of lorcaserin twice daily lost an average of 3.1 kg over 12 weeks while maintaining their usual diet and exercise habits. No significant valvular changes were detected by echocardiogram. The most common adverse effects were headache, nausea, and dizziness. 11
Another medication undergoing phase III trials is cetilistat, which induces weight loss by inhibiting pancreatic lipases and thereby decreasing the absorption of dietary fat. Although it works by a mechanism similar to orlistat, evidence suggests that cetilistat produces fewer gastrointestinal side effects. Participants receiving 60 mg, 120 mg, or 240 mg of cetilistat three times daily, in conjunction with a reduced-calorie diet, lost 3.3 kg, 3.5 kg, and 4.1 kg, respectively, over the course of 12 weeks. Participants on cetilistat did report more adverse effects than participants on placebo, including increased defecation, soft or oily stools, abdominal pain, and flatulence, but these symptoms were generally mild, occurred on only one occasion, and did not appear to be dose-dependent. Fecal incontinence, flatus with discharge, and oily spotting occurred only rarely. 12
Combination medications currently undergoing phase III trials include phentermine plus topiramate (Qnexa) and naltrexone plus bupropion (Contrave). Phentermine reduces appetite by inhibiting reuptake of norepinephrine, thus suppressing appetite, and has FDA approval for the short-term treatment of obesity. Topiramate is an antiepileptic noted to have weight-loss effects. In a 24-week randomized double-blind placebo-controlled study, the combination of phentermine and topiramate induced 11.4 kg weight loss compared to 5.3 kg and 6.6 kg weight loss for phentermine or topiramate alone.13 The other combination regimen, naltrexone and bupropion, theoretically works by promoting hypothalamic proopiomelanocortin (POMC) activity, thereby reducing appetite and increasing energy expenditure while minimizing autoinhibition by endogenous beta-endorphins. Phase II trials demonstrated that participants receiving either a 16 mg or 32 mg dose of combined naltrexone and bupropion lost approximately 5.4% of their initial body weight over 24 weeks. In comparison, the placebo- treated group lost only 0.8% over the same time period. 14
Despite the significant weight-loss observed in clinical trials, the medications are unlikely to produce such dramatic results in real clinical practice for several reasons. Participants in many of the trials were able to follow a reduced-calorie diet. 8,12-14 Even without specifically prescribed dietary changes, participants may be motivated to initiate changes on their own because of their enrollment in a clinical trial. In contrast, patients offered medication in practice are often unable to sustain a reduced-calorie diet for any length of time. Participants in clinical trials also receive much more frequent follow-up and support for weight-loss efforts compared to the average clinic patient. The high attrition rate15 and lack of long-term follow-up limit the strength of the findings in many of the studies. Most trials specifically excluded patients with pre-existing cardiovascular disease8,9,11-14, but many obese patients in clinical practice already have coronary artery disease, congestive heart failure, or a history of myocardial infarction. As a final note, most insurance companies, including Medicare and Medicaid, do not cover prescription drug costs for weight loss medications, forcing patients to pay as much as $140 per month for the FDA-approved drugs sibutramine and orlistat.
Obesity represents the second leading cause of preventable death in this country4 and an effective treatment has the potential to save millions of lives. Just a 10% reduction in weight has a major beneficial impact on cardiovascular risk factors alone. 16 The currently approved medications and those in phase III trials have demonstrated efficacy in producing weight loss of this magnitude, but obesity and its associated health complications remain widely prevalent in clinical practice. Truly effective treatment strategies will need to target multiple physiologic pathways, in addition to multiple aspects of our social environment. Hopefully in the near future we will be able to lift this great weight from the shoulders of this country and the rest of the world.
Arlene Chung is a fourth year medical student at NYU School of Medicine and a copy editor for Clinical Correlations.
Peer reviewed by Michelle McMacken, MD Assistant Professor, Division of General Internal Medicine
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- Poirier P, Giles TD, Bray GA, et al. Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation. 2006;113:898-918.
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- Sjostrom L, Rissanen A, Andersen T, et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet. 1998;352(9123):167-172.
- Idelevich E, Kirch W, Schindler C. Current pharmacotherapeutic concepts for the treatment of obesity in adults. Ther Adv Cardiovasc Dis. 2009;3(1)75-90.
- Smith SR, Prosser WA, Donahue DJ, et al. Lorcaserin (APD356), a selective 5-HT(2C) agonist, reduces body weight in obese men and women. Obesity (Silver Spring). 2009;17(3):494-503.
- Kopelman P, Bryson A, Hickling R, et al. Cetilistat (ATL-962), a novel lipase inhibitor: a 12-week randomized, placebo-controlled study of weight reduction in obese patients. Int J Obes. 2007;31:494-499.
- Gadde KM, Kolotkin RL, Peterson CA, Day WW. Changes in weight and quality of life in obese adults treated with topiramate plus phentermine. North American Association for the Study of Obesity: The Obesity Society Annual Scientific Meeting, 2007. Poster presentation.
- Greenway FL, Fujioka K, Gupta AK, et al. A double-blind, placebo-, bupropion- and naltrexone-controlled study of the efficacy and safety of three doses of naltrexone-bupropion SR combination therapy in obesity: Effects on total and visceral adipose tissue and CV risk markers. North American Association for the Study of Obesity: The Obesity Society Annual Scientific Meeting, 2007. Poster presentation.
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