Mechanisms of available weight-loss medications


Weight-management medications facilitate weight loss by means of several mechanisms. Orlistat acts by preventing the breakdown of dietary fat in the gastrointestinal tract, reducing gastrointestinal absorption of food energy (Table 1 and Table 2). Weight loss with orlistat (60 or 120 mg, taken 3 times daily 1 hour before each meal) is approximately 3% greater than that with placebo.11,15Because the drug’s actions are limited to the gastrointestinal tract, adverse events with orlistat are gastrointestinal in nature. The agent is generally safe, with very rare cases of liver injury reported.15Patients should take a multivitamin to ensure adequate levels of fat-soluble vitamins.

Centrally acting weight-management medications include phentermine (HCl or resin; FDA-approved for short-term use), lorcaserin, the combination phentermine HCl/topiramate extended-release, and the most recently approved medication naltrexone HCI and bupropion HCI extended-release tablets (Table 1 and Table 2).11,15,16These agents are thought to act on the brain pathways that regulate appetite to reduce food intake.3,16-20


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Liraglutide, also in development, is an injectable analogue of a hormone produced by the stomach, glucagon-like peptide-1 (GLP-1), which has central and peripheral actions that include reduced appetite.3,11,15Safety and efficacy data are currently based on phase-3 clinical trials of at least 1 year in duration that included dietary and exercise advice for all participants, including those on placebo.20-30Liraglutide produced dose-dependent, placebo-subtracted weight loss of 4% to 6%.29,30Responses to medication varied substantially, and dropout rates of approximately 30% to 50% were observed in clinical trials. The efficacy, tolerability, and safety of this medication will likely vary widely among individual patients in clinical practice.

Phentermine is the most commonly prescribed weight-management medication in the United States and is labeled as a schedule-IV drug by the Drug Enforcement Administration (DEA). Few long-term efficacy data are available. Weight loss with phentermine appears to be dose-related.11,15,31

Lorcaserin is a selective serotonin (5-HT2C) receptor agonist designed to selectively stimulate the serotonergic 2C receptor to promote increased satiety in the hypothalamus and to have limited effect upon the 2B receptor. Because of the greater selectivity to the brain, as opposed to the heart, clinical trials did not support a significant increase in cardiac valvulopathy, as was observed with previous nonselective serotonergic agents, such as fenfluramine.21,22,32-34

The combination of phentermine HCl (approved for short-term obesity treatment since 1959) and topiramate extended-release (an anticonvulsant associated with weight loss) is administered as a fixed dose available in 4 dose combinations. The dose is titrated over 2 weeks until the maintenance dose of 7.5 mg of phentermine and 46 mg of topiramate is achieved, with the potential to increase the dose to a maximum of 15 mg of phentermine and 92 mg of topiramate if weight loss is insufficient.18In clinical studies, phentermine/topiramate produced dose-dependent, placebo-subtracted weight loss of 4% to 12%, depending on the analysis population.18,20,23

The newest weight-management medication, approved in September 2014, contains an opioid-receptor antagonist (naltrexone) and an antidepressant (bupropion). The effectiveness of this combination was evaluated in multiple clinical trials that included approximately 4,500 obese and overweight patients with and without significant weight-related comorbidities.

All patients received medication for 1 year and participated in lifestyle interventions consisting of a reduced-calorie diet and regular physical activity. In clinical trials, 42% of patients without diabetes mellitus treated with the naltrexone/bupropion combination lost at least 5% of their body weight. Results from another clinical trial that enrolled patients with type 2 diabetes showed that these patients had an average weight loss of 2% over treatment with placebo at 1 year.25-28

The most common adverse effects with centrally acting weight-management medications (Table 2)generally reflect their mechanism of action, and many of these effects resolve with continued use. Adverse events with liraglutide are consistent with GLP-1 receptor activation (Table 2).29,30