FDA Advisors Say Sibutramine's CV Risks Warrant Harsher Restrictions or Withdrawal

Shelley Wood

September 15, 2010

September 15, 2010 (Updated September 16, 2010) (Adelphi, Maryland) — An FDA advisory panel has voted to recommend that the FDA either severely restrict access to the weight-loss drug sibutramine (Meridia, Abbott Laboratories) and add tougher warnings 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.

Dr Sanjay Kaul (Cedars Sinai Heart Institute, Los Angeles, CA) voted for option "D," to recommend withdrawal of the drug.

"This drug has modest weight-loss efficacy; however, there was no subgroup in which a desirable benefit/risk profile was discernible, and I did not see any clinical variable that was identified to optimize the benefit/risk profile," he said, explaining his vote.

Dr Jodi Segal (Johns Hopkins University, Baltimore, MD), voted "C"--to recommend keeping the drug on the market, but with a boxed warning and restricted distribution aimed at limiting its use, with only specially trained physicians able to prescribe it.

"I still hold out hope that a population can be identified where the absolute risk is still low enough that it does make it worthwhile," she said. "And I think that informed patients can make the decision as to what benefits they hope to get out of the drug, and I don't necessarily think that everybody is thinking they are going to have cardiovascular benefit."

Dr David Waters (University of California, San Francisco) disagreed, voting for withdrawal. "I think weight loss is important and it has benefits not related to cardiovascular events, but the average patient that does lose weight is hoping that it does reduce cardiovascular risk or the chances of developing diabetes, and this drug doesn't do that. So in a sense, it's misleading. I don't think that we can characterize a high-risk population and restrict the drug's use to people who won't have risk. I think the risk exceeds the benefit."

Sibutramine was first approved for use as a weight-loss drug in 1997. Dr Dennis Dixon (National Institutes of Health, Bethesda, MD), a statistician, voted for continued marketing, with a boxed label warning physicians about the increased risk for major adverse cardiac events and the need to closely monitor patients' blood pressure and pulse and body weight.

"I think that the benefit [of sibutramine] was established several years ago with the appropriate data, and we didn't see any data today that contradicted that. Nor in my view was there . . . clear evidence that there is harm associated with the use of the drug in low-risk individuals identified in the labeling."

Scrutinizing SCOUT

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 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). Rates of the primary outcome event--nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death--were 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 was split over whether REMS could adequately minimize CV risks with this drug.

Kaul cited the example of cisapride, the gastroprokinetic ultimately voluntarily withdrawn due to its effects on the heart. "That's a classic example of where these kinds of warnings and other REMS strategies did not work," he said. "Labeling changes do not reliably mitigate risk, and elevating warnings to contraindications has an inconsistent track record of improving inappropriate patient selection."

But Dr Peter Gross (Hackensack University Medical Center, NJ), who voted C, countered that, in his mind, the drug could help people lose weight. "I think by limiting the use to the appropriate setting, specially trained physicians can make sure the drug is used appropriately. Strict REMS have minimized inappropriate use for a whole bunch of drugs."

Panel members grappled with a number of issues over the course of the day, including the relative contribution of high blood pressure or high pulse, the majority ultimately concluding that neither of these could be used to identify sibutramine users at higher risk of adverse events. They also were uncomfortable with the idea of using a cutoff of 5% weight loss to determine whether a patient should stay on the drug or not. As several panel members summarized, if it can't be determined for sure who is benefiting from the drug or who is at risk, the benefit of stopping the drug can't be determined.

Several panel members, in response to a question from one of their members, bluntly stated that the drug would not be missed from their "armamentaria" if it were withdrawn--many were not prescribing it, often because the drug, they said, is too expensive. As was repeatedly pointed out during the day's proceedings, most insurers do not cover obesity treatments.

Of note, other noncardiovascular outcomes, such as quality of life or orthopedic benefits, were not studied in SCOUT, something several panel members lamented. But ultimately, the lack of any solid metabolic benefits of taking the drug seemed to sway the panel.

In the words of panel member Dr Lamont Weide (University of Missouri, Kansas City): "This is a unique drug; you can lose weight without getting any of the benefits of doing so."

Many panel members are back at the same tables Thursday to discuss the new drug application for another weight-loss drug, lorcaserin (proposed brand name: Lorqess, Arena Pharmaceuticals).

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