With the Food and Drug Administration (FDA) still under fire for failing to monitor the safety of a popular diabetes drug after it hit the market, researchers have released a new study revealing potentially dangerous risks of another widely prescribed medication: the weight-loss drug Meridia (sibutramine).
The report, published on Wednesday in the New England Journal of Medicine (NEJM), found that among nearly 10,000 overweight or obese patients, those who used Meridia had a 16% greater risk of having a heart attack or stroke over an average 3.4 years than patients taking a placebo. None of the events were fatal, but the finding was especially worrisome since the trial included only patients with a previous history of heart disease or diabetes, or both, which put them at high risk of a second event. Being overweight, they were also already at a higher risk of heart-related health problems.
The study was commissioned by the European Union's European Medical Agency, after initial studies of Meridia users, conducted prior to 2002, found that the drug raised blood pressure and pulse rates, both well known risk factors for heart disease. When Meridia, which suppresses appetite by regulating the brain chemicals serotonin and norepinephrine, was approved for use in the U.S. in 1997, the FDA included a warning about these risks on the label.
The new trial did not address the question of whether such heart risks would outweigh the weight-loss benefit for people without a history of heart disease. But Dr. Gregory Curfman, executive editor of the NEJM, who wrote an editorial accompanying the study with several colleagues, says the risks are significant for all patients, according to the evidence. "With sibutramine we have a risk-benefit picture that is not favorable," he says. "In my opinion, it's time for regulatory action on the drug."
That may come after Sept. 15, when an FDA advisory committee is scheduled to meet to review the latest data on Meridia's safety and to decide whether it should remain on the market. In January, the European Medical Agency recommended banning the medication from its member nations, based on preliminary results from the current trial. The agency's experts noted that the weight loss seen among Meridia users about 9 lb. over the course of the study did not justify the potential health risks associated with the drug. And given the patients' heightened risk of heart problems, the 9-lb. loss was clearly not sufficient to reduce the risk of any weight-related health issues.
The study's authors disagree with that interpretation, however, noting that the elevated risks were limited to those with a history of heart disease. Among patients with diabetes but no history of heart attack or stroke, the authors say, there was no increase in heart problems compared with the control group. In fact, in additional data gathered since the paper was submitted, they say there is evidence that this group of Meridia takers actually lowered their risk of heart events. "What I am saying is that we have got to have some perspective," says lead author Dr. Philip James of the London School of Hygiene and Tropical Medicine. "I am saying we should not give this drug to people with a history of heart attack or stroke. But the best evidence we have at the moment is that among people who followed the prescription recommendations, not only do they not appear to have any greater risk of heart events, but they seem to have substantial benefit as well."
That perspective will likely be the subject of intense debate among the FDA's advisory committee members. "Nobody got better, and some people got worse, and the amount of weight loss wasn't that much," says Curfman. "With that profile, we have a lot of difficulty seeing what the argument would be for keeping the drug on the market."
Dr. Steve Nissen, a cardiologist at the Cleveland Clinic Foundation who has been a vocal critic of recent FDA handling of drug safety concerns, agrees. "We've got a drug here that shows little benefit a few pounds of weight loss and we trade that for a 28% increased risk of heart attack and 36% increased risk of stroke. For a modest amount of weight loss, what are the health outcome benefits?"
That's the question that the FDA will have to answer once again. Commissioner Margaret Hamburg is still weighing similar evidence regarding the diabetes drug Avandia, or rosiglitazone. An advisory committee recommended in July that the drug remain on the market with restrictions on its use, despite strong evidence that users were at increased risk of heart events. Experts in favor of keeping Avandia available to consumers argued that diabetes patients had few other options for controlling blood sugar, and that the evidence was not conclusive about Avandia's harms. Hamburg has yet to decide whether to follow the committee's advice or pull the medication from the market. She may have another tough decision on her hands with Meridia.