Sibutramine and Cardiovascular Events: The SCOUT Trial Weighs In

Published - Written by John Staples

Obesity, it has been wryly noted, is a large and growing worldwide problem, and one with hefty consequences: Type 2 diabetes mellitus, cardiovascular disease, osteoarthritis, cancer, and death are just some of the long-term complications associated with excess weight.  Despite the billions of dollars spent on weight-loss products each year, achieving and sustaining weight loss is notoriously difficult.  Does it matter how those pounds are shed?

In this week’s issue of the journal, the SCOUT trial investigators report on a randomized, double-blind, placebo-controlled trial examining the effects of sibutramine (MeridiaTM) on cardiovascular outcomes in 10,744 high-risk overweight and obese patients.  Performed in 16 countries, this trial enrolled patients with a history of cardiovascular disease and/or type 2 diabetes mellitus with at least one other cardiovascular risk factor.  To assess for early hypertension and tachycardia that would make continued sibutramine use inadvisable, all subjects underwent a 6-week single-blind lead-in period, and were subsequently randomized in a double-blind fashion to continue receiving sibutramine or to receive placebo.  All subjects received individualized diet and exercise advice and optimal medical management of their other cardiovascular risk factors.

Given the known efficacy of sibutramine in inducing weight loss, was it able to reduce cardiovascular events?  The results were surprising.  As expected, sibutramine achieved a 2.4kg greater one-year weight loss than placebo.  But after a mean treatment duration of 3.4 years, the sibutramine group had an unexpected increase in the incidence of the primary outcome, a composite of nonfatal myocardial infarction, nonfatal stroke, resuscitated cardiac arrest, and cardiovascular death (11.4% for the sibutramine group versus 10.0% for the control group, p=0.015).  This effect was driven primarily by increases in nonfatal myocardial infarction and nonfatal stroke, and was only demonstrable for patients with a history of cardiovascular disease.

As Drs. Curfman, Morrissey, and Drazen note in an accompanying editorial, this is not the first appetite suppressant to come under scrutiny:  Fenfluramine, dexfenfluramine, and phenylpropanolamine were all removed from the market once information about rare but serious adverse events became apparent after initial FDA approval.

“The results of the SCOUT trial re-emphasize the importance of obtaining reliable data on meaningful outcomes,” says Curfman, “For patients similar to those in this trial, appreciably increasing their cardiovascular risk in order to achieve a modest weight loss is difficult to justify.”

The editorialists note that the FDA advisory committee will meet on September 15 to weigh the risks and benefits of sibutramine, and to determine if it should be subject to new regulatory action – and the SCOUT trial just might tip the scales.