Clinical testing on current weight-loss drugs has been inadequate to determine whether their benefits outweigh the risks of long-term use, according to a literature review by Canadian researchers.
The review, by Dr. Raj S. Padwal and Dr. Sumit R. Majumdar of the University of Alberta, Edmonton, took a close look at the two drugs currently approved by the Food and Drug Administration for the treatment of obesity—orlistat (Xenical) and sibutramine (Meridia)—and at another drug, rimonabant (Acomplia), that has not yet received FDA approval (Lancet 2007;369:71–7).
Although the three drugs all work by different mechanisms, clinical trials show that they tend to result in about the same modest degree of weight loss: an average of 5 kg (11 lbs), or roughly 5% of body weight. They all have side effects, but in general the side effects have been judged to be tolerable.
None of the drugs has been subjected to long-term testing. It's unknown, for example, whether the weight loss induced by these drugs translates to decreases in obesity-related morbidity and mortality. Dr. Padwal and Dr. Majumdar describe this as “a major gap in knowledge.”
It's also unknown whether use of the drugs results in improvements in some of the other consequences of obesity, such as osteoarthritis, gastroesophageal reflux disease, sleep apnea, and reduced quality of life.
Furthermore, the existing clinical trials for orlistat, sibutramine, and rimonabant were all marred by high levels of attrition. In general, 40%–50% of all the patients enrolled in those trials dropped out before the trials were concluded. This makes it difficult to assess the drugs' true levels of efficacy and safety in the general population.
“We think that antiobesity drug trials powered to show clinically important reductions in major obesity-related morbidity and mortality should be required either before these drugs are approved for widespread use or as a condition of ongoing approval,” the authors wrote.
They advanced three justifications for this conclusion. First, drugs that improve secondary end points, such as weight loss, may not in the long run improve more clinically relevant end points, such as cardiovascular morbidity and mortality.
Second, a drug's toxicity may not be apparent on initial release. Rimonabant, for example, appears to decrease hunger by blocking endocannabinoid receptors in the brain. Preliminary data suggest that endocannabinoids may work to prevent stroke, limit the size of myocardial infarctions, and inhibit cancer-cell proliferation. Blocking endocannabinoid receptors on a long-term basis may therefore have unintended negative consequences.
Third, new drugs are expensive, and the enormous potential market for obesity drugs amplifies their cost to society. The lack of proof that these drugs improve overall outcomes makes it difficult to justify those costs.
Bariatric surgery is the only treatment proven to produce consistent and effective long-term weight loss, but Dr. Padwal and Dr. Majumdar described bariatric surgery as “neither a feasible nor desirable population-based treatment for obesity.”
They wrote that although it's important to address all aspects of the environment that encourage obesity, the search for novel drug treatments is both legitimate and necessary.
“However,” they wrote, “in our efforts to fill the therapeutic void” that characterizes contemporary obesity management, “the benefits of obesity pharmacotherapy must outweigh the risks and costs.”