Sibutramine: balanced judgment or prejudice?

Abstract

Sibutramine has been used worldwide as an anti-obesity agent for nearly 15 years. Some concerns were raised because of its combined peripheral and central sympathomimetic effects and potential long-term impact on cardiovascular risk. To evaluate the long-term effect of sibutramine on the incidence of cardiovascular outcomes among high-risk subjects, the SCOUT (Sibutramine Cardiovascular Outcome Trial) was designed as a double-blind, placebo-controlled study in which all subjects would be treated with sibutramine before randomization for a lead-in period of six weeks. The average duration of the SCOUT was 3.4 years. Despite the far lower than expected event rates in each arm of the trial, the risk of a primary outcome event was 16% higher in the sibutramine group compared with the placebo group. Mean blood pressure levels fell in both groups, but not to such low levels in the sibutramine group as they did in the placebo group after randomization (1 to 2 mmHg difference). Four important characteristics of the SCOUT should be considered when interpreting its results. First, for ethical reasons, there was no true placebo group because all subjects were treated with sibutramine during the leadin period to allow the exclusion from randomization of subjects with potentially increased sensitivity to sibutramine appearing as substantial increases in blood pressure or heart rate. The second important limitation of the trial was its reduced statistical power caused by the overall event rate, which was initially only one-third of the expected based on the results of previous cardiovascular studies. All subgroup analyses were therefore handicapped by the overall low event rate. The third feature of the SCOUT, also derived from the low event rate, was the need to progressively recruit patients with the highest possible risk in an attempt to reach the required statistical power for the trial. This resulted in a study population remarkably different from the patients using sibutramine in daily life. The vast majority of participants at the entry of the trial would not meet the treatment criteria specified in the sibutramine label. Fourth, the SCOUT subjects continued to receive therapy for up to six years, regardless of whether they achieved any weight loss or even put on weight. Yet sibutramine has never been recommended as a long-term treatment for patients that did not achieve significant weight loss. Taking all these characteristics into account, the SCOUT results should not be extrapolated to the general population of obese patients using sibutramine in clinical practice. There are no new anti-obesity agents currently available to replace sibutramine. Therefore, if other regulatory agencies decide for the withdrawal of sibutramine, tens of thousands of patients are likely to regain weight and to have their absolute cardiovascular risk significantly incremented as their weight increases. (PsycINFO Database Record (c) 2016 APA, all rights reserved)