From Medscape Medical News
Laurie Barclay, MD
September 1, 2010 — Subjects with preexisting cardiovascular conditions who are given long-term sibutramine treatment have an increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality, according to the results of a randomized, double-blind, controlled trial reported in the September 2 issue of the New England Journal of Medicine.
"The long-term effects of sibutramine treatment on the rates of cardiovascular events and cardiovascular death among subjects at high cardiovascular risk have not been established," write W. Philip T. James, MD, DSc, from the London School of Hygiene and Tropical Medicine in London, United Kingdom, and colleagues from the Sibutramine Cardiovascular Outcomes (SCOUT) Investigators.
"...Sibutramine is not indicated for patients with a history of cardiovascular disease; otherwise, treatment with sibutramine is recommended for no more than 1 to 2 years in patients who achieve a 5% weight loss. The ...SCOUT trial evaluated the long-term effects of sibutramine treatment combined with diet and exercise on the rates of cardiovascular events and cardiovascular death among subjects who were at high cardiovascular risk."
The study population consisted of 10,744 overweight or obese subjects 55 years or older with preexisting cardiovascular disease, type 2 diabetes mellitus, or both. During a 6-week, single-blind, lead-in period, all participants received sibutramine and took part in a weight management program. Subsequently, 9804 subjects were randomly assigned to receive sibutramine (n = 4906) or placebo (n = 4898), with mean treatment duration of 3.4 years. The main study outcome was the time from randomization to the first occurrence of a primary outcome event, defined as nonfatal myocardial infarction, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death.
During the lead-in period, mean weight loss was 2.6 kg. After randomization, participants receiving sibutramine achieved and maintained additional weight reduction (mean, 1.7 kg). Although both groups had a decline in mean blood pressure, the placebo group had greater reductions than the sibutramine group (mean difference, 1.2/1.4 mm Hg).
For the sibutramine group, the risk for a primary outcome event was 11.4% vs 10.0% in the placebo group (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.03 - 1.31; P = .02). Nonfatal myocardial infarction occurred in 4.1% of the sibutramine group and in 3.2% of the placebo group (HR, 1.28; 95% CI, 1.04 - 1.57; P = .02). For nonfatal stroke, rates were 2.6% and 1.9%, respectively (HR, 1.36; 95% CI, 1.04 - 1.77; P = .03). Rates of cardiovascular death and all-cause mortality were not increased.
"Subjects with preexisting cardiovascular conditions who were receiving long-term sibutramine treatment had an increased risk for nonfatal myocardial infarction and nonfatal stroke but not of cardiovascular death or death from any cause," the study authors write.
Study Limitations
Limitations of this study include lower overall event rate than originally anticipated, causing reduced statistical power; lack of a true placebo group receiving no treatment at all; and selective recruitment of high-risk subjects. In addition, subjects in the SCOUT trial continued to receive therapy for up to 6 years, regardless of achieved weight loss, which could have altered the risk-benefit ratio of sibutramine.
"Despite these limitations, the trial allowed us to assess the effect of intentional modest weight loss with sibutramine on the risks of cardiovascular events and death with the usual intention-to-treat approach among patients at high cardiovascular risk," the study authors conclude. "On the basis of these results, sibutramine should continue to be excluded from use in patients with preexisting cardiovascular disease."
Editorial: Disagrees With Study Conclusion
In an accompanying editorial, Gregory D. Curfman, MD, and colleagues disagree with the SCOUT investigators' conclusion that no changes are indicated in the clinical use of sibutramine, which they say should continue to be limited to persons without preexisting cardiovascular disease.
"The investigators' conclusion is based on a narrow interpretation of the SCOUT data, in which only the patients with preexisting cardiovascular disease had an increase in the risk for new cardiovascular events," Dr. Curfman and colleagues write.
"The FDA advisory committee will now take up the matter," they conclude. "We surely need safe and effective medications to help overweight and obese patients lose weight and improve their long-term health. But given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome cardiovascular risk profile, and a plausible mechanism to explain the cardiovascular risk, it is difficult to discern a credible rationale for keeping this medication on the market."
Abbott supported this study and employs 3 of the study authors. Some of the study authors have disclosed various financial relationships with Abbott Laboratories, Pfizer (Australia), Servier Laboratories, Eisai Pharmaceuticals, iNova Pharmaceuticals, Eli Lilly, Wiley-Blackwell, GlaxoSmithKline, Sanofi-Aventis, Weight Watchers, Allergan, Aché Laboratórios Farmacêuticos, Roche, Novo Nordisk, Ajinomoto, Merck, Johnson & Johnson, Vivus, Covidien, Boehringer Ingelheim, Arena, NeuroSearch, and/or AstraZeneca–Bristol-Myers Squibb. Disclosure forms provided by the editorialists are available on the NEJM Web site .
N Engl J Med. 2010;363:905-917, 972-974.
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