NEJM: Meridia worsens CV risks; FDA mulls its future

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Patients with a history of cardiovascular (CV) conditions treated with sibutramine (Meridia, Abbott Laboratories) saw an increased risk of MI and nonfatal stroke, but not CV death, according to the results of a study published Sept. 2 in New England Journal of Medicine.

In January, the FDA warned that use of sibutramine, a drug used to curb obesity, could have an increased risk for patients with a history of CV disease. FDA asked Abbott to add several contraindications to the drugs label.

In the current SCOUT (Sibutramine Cardiovascular Outcomes) trial, W. Philip T. James, MD, of the London School of Hygiene and Tropical Medicine, and colleagues set out to examine the long-term effects and CV outcomes the administration of sibutramine had on 10,744 overweight or obese subjects.

The randomized, double-blind, placebo-controlled multicenter trial,conducted between January 2003 and March 2009, enrolled patients who were 55 years or older, had a body mass index of at least 25 and less than 27 and a history of CV disease, type 2 diabetes with at least one additional CV risk.

“In some patients, sibutramine increases blood pressure, pulse rate, or both, owing to its sympathomimetic effects,” the authors wrote. “Sibutramine is not indicated for patients with a history of CV disease; otherwise, treatment with sibutramine is recommended for no more than one to two years in patients who achieve a 5 percent weight loss.”

During the study, the researchers evaluated the long-term effects of the drug along with diet and exercise. Patients were administered 10 mg of sibutramine daily along with diet and exercise advice and the researchers used nonfatal MI, nonfatal stroke, resuscitation after cardiac arrest and CV death as primary outcomes. The mean follow-up period of the study was 3.4 years.

The researchers reported that weight loss during the six-week lead-in period when all patients received sibutramine was 2.6 kg. Subsequently, the patients administered sibutramine experienced further weight loss—a maximum mean weight loss of 1.7 kg at 12 months. The additional weight loss in patients who received placebo was 0.7 kg by month 12.

Of the 10,744 patients, 9,804 were included in the intention-to-treat population. From there, researchers randomized 4,906 patients to receive sibutramine and 4,898 to receive placebo.

According to the results, patients in the sibutramine arm had a 16 percent higher risk of experiencing a primary outcome compared to those in the placebo arm—11.4 percent versus 10 percent, respectively.

Additionally, the rates of MI and stroke were higher in the study arm administered sibutramine compared to placebo. These rates were 4.1 percent versus 3.2 percent, and 2.6 percent versus 1.9 percent, respectively. However, the researchers found no statistically significant differences in CV death between the two study arms, 4.5 percent versus 4.7 percent, respectively.

Adverse event rates (with MI as most common) occurred in 13.6 percent of the patients in the sibutramine group compared to 12.4 percent in the placebo group. These adverse events led to the discontinuation of the study drug.

The researchers reported that serious adverse events occurred in 42.1 percent of the patients administered sibutramine and 40.5 percent taking placebo.

The authors speculated that the increase of event rates in patients administered sibutramine could be linked to “the recognized effect of increased blood pressure on CV outcomes and the combined peripheral and central sympathomimetic effects of sibutramine.

“In the SCOUT trial, event rates in the sibutramine group were lower than expected, and the sibutramine group lost more weight than the placebo group and maintained the weight loss,” the authors wrote.

However, rates of nonfatal MI and stroke were higher in patients administered sibutramine. “On the basis of these results, sibutramine should continue to be excluded from use in patients with pre-existing CV disease,” the authors concluded.

In an accompanying editorial, Gregory D. Curfman, MD, along with his fellow editors from the New England of Journal of Medicine, wrote, “In real-world clinical practice, it can be difficult to reliably identify patients with silent cardiovascular disease who may be placed at risk with sibutramine treatment.

“The SCOUT trial was designed as an efficacy trial to determine whether weight loss with sibutramine would improve CV outcomes. No improvement was observed. Among subjects with pre-existing CV disease, CV outcomes were worse,” Curfman and colleagues wrote.

While drugs such as sibutramine to curb weight loss and obesity are important, Curfman et al wrote, “Given that sibutramine has minimal efficacy for weight loss, no apparent benefit for clinical outcomes, a worrisome CV risk profile, and a plausible mechanism to explain the CV risk, it is difficult to discern a credible rationale for keeping this medication on the market.”

According to Curfman and colleagues, the FDA will meet on Sept. 15, to discuss whether or not the appetite-suppressing drug should continue to be stocked on the shelves.