The large number of people with mild to moderate obesity contribute more to its overall public health burdens than the smaller number of people with severe obesity. High-risk, high-efficacy strategies and population strategies focusing on lifestyle and behavioral modifications have failed to address the population burden of disease. An individualized approach is likely to provide the most effective management of this disease for the largest number of patients. This review discusses advances in pharmacologic therapies for obesity with a focus on currently approved drugs and those in later stages of development.
Obesity and its associated conditions, including type 2 diabetes and cardiovascular disease, have reached epidemic proportions. This development is particularly evident in the developed world, where the consequences include substantially increased morbidity, mortality, and cost to the health care system. In a recent meta-analysis of 89 prospective studies, obesity was significantly associated with at least 18 comorbid conditions that can be generally categorized into the following groups: metabolic disorders (including type 2 diabetes mellitus), cardiovascular disease, pulmonary, gastrointestinal (GI) and musculoskeletal complications, and cancer. Studies from the National Health and Nutrition Examination Survey show that approximately one-third of the adult US population has obesity, that nearly 40% of these individuals have metabolic syndrome, and 1 in 7 have type 2 diabetes.
The risks associated with obesity lie on a continuum. According to Geoffrey Rose’s prevention paradox, the large number of people with mild to moderate obesity contribute more to its associated public health burden than the small number of people with more severe forms of this disorder. Nonetheless, severe obesity is more commonly associated with comorbid disorders, and the burden of disease for each individual with severe obesity is disproportionately greater. Specialized treatments for this severely affected population, including GI weight loss surgery (GIWLS), are associated with too much risk to be applied to the broader population with obesity. The challenge in addressing obesity therefore lies in dealing with both sick individuals and a sick population.
Although population-based strategies, focusing on lifestyle and behavioral modifications, provide the greatest public health benefit overall, their long-term efficacy has been limited. The basis for this limitation is much debated, but biologic factors and the physiologic response to a changed environmental milieu play a role.
A graded approach, akin to the management of hypertension, type 2 diabetes, and other chronic diseases seems likely to provide the greatest opportunity for clinical success. This approach, enabled by the development of a spectrum of new therapies, likely enables clinicians to make meaningful progress in the treatment of this epidemic. Potential contributors to this multifaceted approach include changes in diet composition, increased physical activity, and the sequential addition of nutritional, pharmacologic, endoscopic, and minimally invasive surgical therapies as needed.
Recent advances in our understanding of the mechanisms by which Roux-en-Y gastric bypass and other types of GIWLS induce profound, long-term weight loss and improvements in diabetes and other metabolic sequelae of obesity, combined with emerging endoscopic technologies, have opened the door to using endoscopic approaches to reproduce many of the benefits of bariatric surgery and thereby contribute to the effective treatment of obesity and its associated disorders. Early results are encouraging and suggest that endoscopy-based therapies may provide the next major treatment advance in this area. Progress in the development of new pharmacologic agents for obesity has been more limited. Despite extensive research and development efforts, few new pharmacologic agents have made their way into clinical practice for the primary management of obesity during the past 40 years. Of the currently available medications approved for the treatment of obesity, orlistat is the one most recently approved by the US Food and Drug Administration (FDA) for this indication, and it was approved in 1999. The absence of newer agents reflects the modest effectiveness of recently developed weight loss medications, combined with safety profiles that have been considered unacceptable by FDA advisory committees and regulatory staff. The limitations of these agents likely reflect the complexity and redundancy of pathways that regulate energy balance, appetitive drives, nutrient absorption and handling, and energy expenditure. Powerful compensatory mechanisms seem to limit the clinical effects of these single-agent and dual-agent drug therapies. Recognizing these limitations, many clinicians and investigators have suggested the need for a broader array of medications to treat obesity that target different components of the weight regulatory machinery and that can be used in combinations tailored to the needs of different patient subgroups. However, this approach is in the earliest stage of development, and there are few clinically relevant predictors of response to weight loss therapies in individual patient subgroups. This review discusses medications that are currently approved by the FDA for treatment of obesity, along with those that are in the later stages of clinical development.
Current criteria for use of pharmacologic therapies for obesity
Current recommendations for the pharmacologic treatment of obesity limit those therapies to patients with a body mass index (calculated as weight in kilograms divided by the square of height in meters) greater than 30 kg/m 2 or greater than 27 kg/m 2 with significant obesity comorbidities who have previously failed behavioral and lifestyle approaches alone.
The standard FDA benchmark for clinical efficacy of antiobesity drugs has been a loss of initial body weight that is 5% more than that produced by placebo treatment in the same study. However, in clinical practice the most common criterion has been a 1.8-kg (4-pound) weight loss per month for at least 3 months. Maintaining this weight loss after the first 3 months is used as an indication for continued treatment. Although FDA approval and marketing of antiobesity medications is limited to 3 to 24 months, experienced clinicians recognize that for long-term effectiveness, pharmacotherapy needs to be continued indefinitely. These physicians often continue demonstrably effective weight loss medications for as along as they remain effective and well tolerated. The maximal weight loss effects of these drugs are usually observed within the first 6 to 12 months of use, with diminishing additional benefit thereafter. Some regain of the lost weight in the long-term can be expected, although the magnitude of both the initial weight loss and subsequent weight regain varies widely among patients. When these medications induce weight loss, their cessation is almost always associated with rapid regain of the lost weight.
Pharmacologic therapies for obesity
Medications for the treatment of obesity can be conveniently classified into 4 groups: (1) those that act directly on the GI tract, (2) those that alter gut-brain signaling, (3) those that act directly on the central nervous system (CNS), and (4) formulations that include combinations of different agents.
Pharmacologic therapies for obesity
Medications for the treatment of obesity can be conveniently classified into 4 groups: (1) those that act directly on the GI tract, (2) those that alter gut-brain signaling, (3) those that act directly on the central nervous system (CNS), and (4) formulations that include combinations of different agents.
Medications that act directly within the GI tract
Pancreatic Lipase Inhibitors
Inhibitors of pancreatic and intestinal lipases cause decreased hydrolysis of ingested triglycerides to absorbable fatty acids and monoacylglycerols, thus inducing malabsorption of calorie dense fats. Orlistat is a pancreatic and intestinal lipase inhibitor currently approved by the FDA for the treatment of obesity. It is sold in 2 versions, one available by prescription at a dose of 120 mg 3 times per day (Xenical) and one available over the counter at a reduced dose of 60 mg 3 times per day (Alli). The efficacy of orlistat (120 mg 3 times a day) in reducing weight has been reported in multiple studies, with weight loss averaging 3% to 7% beyond that observed with placebo treatment. This modest weight loss has been shown to be associated with improvement in lipids, insulin resistance, and blood pressure. After long-term treatment of up to 4 years, some weight regain has been observed, although orlistat continued to show significantly greater efficacy than placebo. Potential side effects of orlistat include flatulence, steatorrhea, fecal incontinence, increased stool frequency, oily rectal discharge, and malabsorption and deficiency of 1 or more fat-soluble vitamins (vitamins A, D, E, and K). In patients receiving chronic orlistat therapy, routine supplementation with a preparation containing these vitamins is advisable. Vitamin D levels should be measured both before and during orlistat therapy, with deficiencies corrected by vigorous supplementation. The recent identification of 13 cases of severe liver injury in patients taking orlistat has generated concern about potential liver toxicity from this agent, and the FDA has added a warning about potential hepatic complications to the labeling. A second lipase inhibitor, cetilistat, is undergoing phase 3 clinical evaluation. The effectiveness of this agent is reputed to be similar to that of orlistat, but early studies suggest that cetilistat is associated with fewer GI side effects.
Medications that alter signaling within the gut-brain axis
GLP-1 Agonists
Within the mucosa of the small intestine, specialized enteroendocrine cells release peptides that promote satiety and enhance insulin secretion in response to luminal and circulating nutrients and hormones. Those peptides that enhance insulin secretion in response to nutrient ingestion have been given the name incretins. These peptides exert their effects through interaction with specific receptors on neighboring intestinal epithelial cells, vagal and spinal neurons innervating the gut, or cells in other parts of the body accessed through the portal or peripheral bloodstream. Among these gut-derived peptides, glucagon-like peptide-1 (GLP-1) is the best characterized and currently the most advanced and promising target for antiobesity drug development. GLP-1 is secreted by enteroendocrine L cells in response to luminal nutrients (primarily glucose and other carbohydrates), bile acids, and neural stimulation. These cells are located throughout the small intestine and colon, with highest concentrations in the ileum and proximal colon. Sweet-tasting compounds are among the best-known stimulants of L-cell GLP-1 secretion; these compounds (including sugars) act by binding to specific cell-surface G protein-coupled receptors that activate gustducin-mediated intracellular signaling to stimulate GLP-1 secretion. GLP-1 also stimulates insulin secretion in a glucose-dependent manner, inhibits pancreatic glucagon secretion, and has cytoprotective and regenerative actions on pancreatic β cells. It promotes satiety and inhibits food intake, actions that have been associated with demonstrable weight loss. Some studies have also suggested that GLP-1 improves insulin sensitivity.
Exenatide (Byetta), a GLP-1 agonist administered twice daily as a subcutaneous injection at doses of 5 to 10 μg per injection, is currently approved by the FDA for the treatment of type 2 diabetes. Nausea is the most commonly reported side effect. A longer-acting (once-weekly) formulation called Exenatide LAR is undergoing phase 3 clinical evaluation. Liraglutide (Victoza) is a GLP-1 analogue with a longer half-life than exenatide that is also approved by the FDA for the treatment of type 2 diabetes. Its longer half-life allows for once-daily subcutaneous administration at doses between 0.6 and 1.8 mg depending on the glycemic response. A recent, 20-week, double-blind, placebo-controlled, multicenter European trial of liraglutide with an open-label orlistat arm and an 84-week extension open-label follow-up treatment showed superiority of liraglutide over both placebo and orlistat (mean weight loss with various liraglutide doses ranged from 4.8 to 7.2 kg vs 4.1 kg with orlistat and 2.8 kg with placebo). Nausea and vomiting were more common in the liraglutide group, but these symptoms rarely resulted in treatment discontinuation. In this study, liraglutide was also found to improve insulin resistance and prediabetes. However, despite these encouraging results, GLP-1 analogues are not yet approved by the FDA for the treatment of obesity per se. Nonetheless, they are gaining increasing off-label use for this indication, particularly in patients with type 2 diabetes, prediabetes, or other insulin resistance syndromes.
Amylin Analogues
Amylin is a 37-amino acid peptide secreted by the pancreatic β cells primarily in response to meals that augments the effectiveness of insulin in regulating blood glucose. The amylin analogue pramlintide (Symlin) is approved by the FDA as an adjunct to insulin therapy for the treatment of type 2 diabetes. It is administered subcutaneously at a dose of 60 to 120 μg, 2 to 3 times daily before major meals. Pramlintide has been shown to produce more weight loss than exenatide, but side effects, including hypoglycemia, nausea, and vomiting, have limited its off-label use for the treatment of obesity. Clinical studies of pramlintide for the treatment of obesity are ongoing. Early results suggest that there is particular promise in combination therapy with both pramlintide with metreleptin, a synthetic leptin analogue. In this combination, pramlintide seems to enhance leptin responsiveness, and metreleptin is believed to prevent the metabolic adaptation and counterregulatory physiology induced by weight loss generally. In a recent 20-week, phase 2 clinical trial, pramlintide-metreleptin therapy generated an average weight loss of 12.7%.
Related posts:
Obesity Overview: Epidemiology, Health and Financial Impact, and Guidelines for Qualification for Surgical Therapy
Presurgical Evaluation and Postoperative Care for the Bariatric Patient
Medical Management of Postsurgical Complications: The Bariatric Surgeon’s Perspective
Management of Acute Postoperative Hemorrhage in the Bariatric Patient
Accessing the Pancreatobiliary Limb and ERCP in the Bariatric Patient
Management of Postsurgical Leaks in the Bariatric Patient
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
