Everyone is searching for the magic pill that still lets them eat excessively and lead sedentary lives. In the past decade, there have been a number of drug products on the market that either produce minimal to no long-term results or proved to have serious adverse effects. The only branded pharmaceutical compounds on the market have two distinct mechanisms:
• Hunger suppression – Sibutramine increases the feeling of satiety by increasing the level of neurotransmitters, such as serotonin. Sold under the Meridia brand, the product has shown 3%-5% body weight loss. Byetta suppresses hunger and can show weight loss, although anecdotal data suggests that weight loss is transient and widespread.
• Fat absorption reduction – Orlistat, marketed under the Xenical and alli (over-the-counter) brands, inhibits lipase, which is an enzyme that breaks down and digests fat in the gut. When taken with meals it prevents 25%-30% of dietary fat from being absorbed. Patients on average see a 3% body weight loss.
It is widely recognized that the FDA very carefully and conservatively reviews the risk/benefit profile all new weight loss drugs in development. While drugs must prove that they are effective by inducing clinically meaningful weight loss to FDA standards, they must also show very clean safety and tolerability profiles. The FDA came under heavy criticism in the late 1990s for allowing the approval of Redux (dexfenfluramine) which was eventually found to cause heart valve damage and even death in patients. Redux was part of the notorious Fen-Phen combination (Redux + phentermine) that was very popular and widely used in the mid-1990s due to strong weight loss, often over 10%. The FDA was also very conservative and strict in reviewing Sanofi-Aventis’ drug Rimonabant in the mid-2000s. Rimonabant was a first-in-class endocannabinoid drug which was approved in Europe, but delayed in the US by FDA over neuropsychiatric side effect concerns. The FDA never granted approval due to these concerns, and the drug was eventually recalled in Europe due to these same issues.
The standards by which a drug proves clinically meaningful weight loss are very clear. The drug must induces 5% mean placebo-adjusted weight loss or induce 5% body weight loss in at least 35% of drug patients (which must be about double the rate for placebo). Drugs only need to meet one of these hurdles to show approvable efficacy. FDA safety standards for safety are less rigid but the agency has acknowledged that the risk/benefit analysis is more fluid. Should a drug cause strong weight loss and proven benefit in heart health and diabetes, certain tolerability and/or safety signals may be acceptable as long as they are not severe. Additionally, the FDA requires that Phase 3 pivotal trials include at least 1,500 randomized to drug for one year of therapy in order to establish a large enough amount safety data to ensure adequate review and analysis.