Patients had a mean BMI of 34–37 in those studies, and a mean age of 45–55. Overall, they lost 9–12 pounds, or about 5% of baseline weight, though there was a trend toward a plateauing and then weight increase at the 2-year mark. In RIO-Lipids, patients taking the 20-mg dose saw an increase in HDL cholesterol of about 8% and a decrease in triglycerides of 12%.
Neither the panel nor the FDA questioned Zimulti's effectiveness; instead, safety was the big concern.
Sanofi classified rimonabant as a selective and neutral antagonist of the cannabinoid-1 receptor. But some panelists questioned whether some of the psychiatric and neurologic side effects with Zimulti might indicate that it was acting as an inverse agonist on the endocannabinoid system, meaning the drug would lock the receptors into inactivity and lead to negative consequences.
The FDA estimated that the relative risk for psychiatric adverse events in patients taking Zimulti in the four trials was 1.9, compared with placebo, and for neurologic adverse events the relative risk was 1.7. Four completed suicides have been reported for all of the company's completed and ongoing trials, said Dr. Amy G. Egan of the FDA's division of metabolic and endocrine products.
Because of the high drop-out rate seen in the trials–32%–49% in the first year, and 23%–58% in the second year–the relative risk may be underestimated, said Dr. Egan.
Zimulti appeared to double the risk of psychiatric adverse events, increased a variety of neurologic events, and increased nausea and vomiting, said Dr. Egan, adding that many of the risks “appear to be more pronounced in diabetics.”
The depression-obesity interrelationship gave pause to Dr. Sidney Wolfe, director of Public Citizen's Health Research Group. “The evidence for increased suicidality and depression is of particular concern for a drug targeted towards the obese, a population that has been shown to have a significantly higher incidence of depression,” he told the advisory committee.