Early results with rimonabant, the first of several projected drugs from its class (the cannabinoid-receptor blockers), created high expectations a few years ago when clinical studies showed that it produced significant weight loss, resulted in improved success with smoking cessation, and produced favorable changes in triglyceride, HDL cholesterol, and CRP levels. However, in 2006 the FDA declined to approve the drug because of concerns that it produced psychological side effects (principally depression). This decision was in distinct contrast to the one taken by the European Medicines Evaluation Agency, which approved the drug after concluding that rimonabant's benefits outweighed its risks, at least in patients without a history of major depression.
American doctors and patients favoring approval of rimonabant therefore anxiously awaited the results of the STRADIVARIUS trial, which were published in the Journal of the American Medical Association. STRADIVARIUS enrolled 839 patients with abdominal obesity (including patients with a history of psychiatric problems) and randomized them to rimonabant vs. placebo. After 18 months, patients on rimonabant lost roughly 10 more pounds and 2 more inches from their waists, and had significantly improved HDL and triglyceride levels, than patients on placebo. However, the volume of their atherosclerotic plaques (that is, the amount of hardening of the arteries, which was the primary endpoint of the study) was not significantly improved over the placebo group. Furthermore, patients on rimonabant had a significantly higher incidence of psychiatric effects, mainly depression and suicidal ideation (thinking about suicide).
While at least two other randomized trials with the drug are ongoing, this study may prove to be the final nail in the coffin for rimonabant in the United States.
DrRich Comments:
Those Americans who have been anxiously awaiting rimonabant, and who may wonder even now why the FDA would refrain from approving a drug that produces significant improvements in weight loss and smoking cessation (and that also significantly improves lipid and inflammation profiles), should keep two things in mind.
First, remember Vytorin, which was approved by the FDA on the basis of its unquestioned ability to produce favorable changes in lipid levels. But when the ENHANCE trial failed to demonstrate a reduction in atherosclerotic plaques with Vytorin (similar to the findings in STRADIVARIUS with rimonabant), the subsequent firestorm of vituperation heaped upon the drug makers, the FDA, and physicians (for having pushed this drug on an unsuspecting public), leading to congressional hearings and (likely) lawsuits, has been notable -- and noted.
Second, in contrast to Vytorin, which is expensive but doesn't have other remarkable side effects, rimonabant produces significant psychiatric toxicity and increases the risk of suicide.
So don't be angry with the FDA. We have successfully beaten the FDA into a cautious position by our outcry over their premature release of Vytorin (and Vioxx and Avandia ). To swing the pendulum back in the other direction, we'll have to express our public indignation over not having access to certain drugs we really want, and loudly accuse the FDA of being overcautious (mainly to protect themselves or the Medicare budget), and then instigate congressional hearings over same. We haven't done that yet, but if history is an indicator, we will.
Source:
Nissen SE, Nicholls SJ, Wolski K, et al. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease. The STRADIVARIUS randomized controlled trial. JAMA 2008; 299: 1547-1560.
