Long-term use of the weight loss drug sibutramine was not associated with an increased risk of death; however, the drug was associated with a significantly increased risk of nonfatal myocardial infarctions and strokes among overweight and obese people with preexisting cardiovascular conditions, based on data from the Sibutramine Cardiovascular Outcomes (SCOUT) trial.
The rate of nonfatal MIs associated with sibutramine was increased by 28% and the rate of nonfatal stroke was increased by 36%, compared with placebo in the randomized, double-blind multicenter study, which was conducted in Europe, Central and South America, and Australia from January 2003 through March 2009 (N. Engl. J. Med. 2010 Sept. 1;363:905-17).
Abbott Laboratories, which has marketed the drug in the United States as Meridia since its approval in 1997, funded SCOUT. Sibutramine is a norepinephrine and serotonin reuptake inhibitor that induces satiety and is known to be associated with modest increases in blood pressure and resting pulse rates.
The results indicate sibutramine “should continue to be excluded from use in patients with pre-existing cardiovascular disease,” concluded Dr. W. Philip T. James of the London School of Hygiene and Tropical Medicine, and the other authors of the study.
In an accompanying editorial, titled “Sibutramine – Another Flawed Diet Pill,” Dr. Gregory Curfman and his coauthors wrote that this 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 of new cardiovascular events.” While this was a “defensible interpretation” of the data, they pointed out that marketing of sibutramine in the European Union was withdrawn in January 2010 based on early results of SCOUT (N. Engl. J. Med. 2010 Sept. 1;363:972-4).
The SCOUT results will be reviewed at a September 15 meeting of the Food and Drug Administration’s Endocrinologic and Metabolic Drugs Advisory Panel.
While noting the need for safe and effective weight loss medications, the authors of the editorial stated: “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.”
The study compared the primary outcome – nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest, or cardiovascular death – in about 9,000 obese or overweight men and women. All were randomized to receive placebo or 10 mg/day of sibutramine after both groups had received sibutramine as part of a weight management program for 6 weeks. Study participants were aged 51-88 years (mean age, 63 years) and had preexisting cardiovascular disease, type 2 diabetes, or both. During the initial 6-week phase, the mean weight loss was 2.6 kg. Those who stayed on sibutramine lost a mean of another 1.7 kg after 1 year (for a total of 4.3 kg, or 9.5 pounds), while those on placebo had a mean weight gain of 0.7 kg.
Over a mean 3.4 years of treatment, the rate of the primary outcome was 11.4% among those on sibutramine, compared with 10% among those on placebo, an increased risk of 16% that was statistically significant. There were no significant differences in the cardiovascular death rates and the rate of death from any cause (a secondary outcome) among those on sibutramine, compared with those on placebo.
The nonfatal MI rate in the sibutramine-treated patients was 4.1%, compared with 3.2% in the placebo group, and the rate of nonfatal stroke was 2.6% among those on sibutramine, compared with 1.9% among those on placebo. The rate of resuscitation after cardiac arrest was 0.2% or less in the two groups.
The risk of nonfatal events was increased among sibutramine users with preexisting cardiovascular disease and with cardiovascular disease and type 2 diabetes. Risk was not increased among those with type 2 diabetes alone. The increase in nonfatal events might be caused by the “recognized effect of increased blood pressure on cardiovascular outcomes, and the combined peripheral and central sympathomimetic effects” of the drug, the authors wrote.
During the initial 6 weeks, when all patients were receiving sibutramine, systolic blood pressure dropped by a mean of 4.7 mm Hg and diastolic blood pressure dropped by a mean of 1.7 mm Hg. These values remained below the initial measurements in both groups during the remainder of the study, but were “consistently higher” among those on sibutramine, with mean differences of 1 mm Hg-2 mm Hg.
The mean pulse rate among those on sibutramine was also “consistently higher” than among those on placebo, with mean differences of 2.2 to 3.7 beats per minute.