FDA:sibutramine's CV risks warrant harsher restrictions or w

[andy]

FDA advisors say sibutramine's CV risks warrant harsher restrictions or withdrawal
September 15, 2010 | Shelley Wood http://www.theheart.org/article/1122267.do
Adelphi, MD - An FDA advisory panel has voted to recommend that the FDA either severely restrict access to the weight-loss drug sibutramine (Meridia, Abbott Laboratories) or pull the plug on it altogether, due to its increased CV risk profile. Only two of the agency's Endocrinologic and Metabolic Drugs Advisory Committee, which spent Wednesday reviewing the results of the Sibutramine Cardiovascular Outcomes Trial (SCOUT), concluded that the drug should remain on the market with a boxed warning only, and no members thought the drug could stay on the market with no labeling changes.

Back in November 2009, the FDA released an "early communication" about the SCOUT trial, launched in 2002, after a preliminary analysis of the data pointed to a higher rate of the primary outcome—heart attack, stroke, resuscitated cardiac arrest, or death—among patients taking sibutramine. In January 2010, the FDA requested that a new contraindication be added to the label, stating that the drug should not be used in patients with a history of CVD. At the same time, the European Medicines Agency recommended a marketing suspension of all drugs containing sibutramine. Full results were published September 3, 2010 in the New England Journal of Medicine.




SCOUT results
SCOUT was a randomized double-blind placebo-controlled trial looking at adverse cardiovascular events in patients taking sibutramine vs placebo. Specifically, the trial randomized 10 744 overweight or obese subjects, aged 55 or older, with preexisting cardiovascular disease, type 2 diabetes mellitus, or both.

During a lead-in period, all patients received sibutramine and achieved a mean weight loss of 2.6 kg. After six weeks, subjects were randomized to receive sibutramine (n=4906) or placebo (n=4898), with mean duration of treatment 3.4 years. After randomization, participants receiving sibutramine achieved and maintained additional weight reduction (mean 1.7 kg). Rate of the primary outcome event—nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death—was higher in the sibutramine group than in the placebo group, 11.4% vs 10.0% (p=0.02). Rates of nonfatal MI (4.1% vs 3.2%, p=0.02) and nonfatal stroke (2.6% vs 1.9%, p=0.03) were also higher in the sibutramine group, while rates of CV death and all-cause death were the same in both groups.





Early in the day, the sponsor reviewed the data and proposed a "risk-management plan" that entailed beefed-up labeling, including a black-box warning to "reinforce" the contraindication for people with a history of CV disease, a risk evaluation and mitigation strategy (REMS) with improved "communication and education tools," and potentially including a restricted dispensing program through a special pharmacy organization.

In their presentations, however, FDA speakers hinted that the sponsor's proposals for mitigating the risks of the drug wouldn't cut it, and during discussions the panel overwhelmingly concluded that despite the weight loss seen with the drug, the cardiovascular risk profile stayed the same or deteriorated, rather than improved as expected.

In the words of one panel member: "This is a unique drug; you can lose weight without getting any of the benefits of doing so."