In September 2014, the Food and Drug Administration (FDA) approved the weight loss drug Contrave. It’s a combination of naltrexone and bupropion, an antidepressant, that together work to lower appetite. But bupropion is also linked to high blood pressure and increased heart rate, and two previous weight loss drugs with similar effects on the heart had already been removed from the market. That's why, even though it approved the drug, the FDA required Contrave’s maker, Orexigen, to conduct a trial investigating its possible side effects.
In a study published in JAMA, scientists detail how the release of early results—before the study was completed, and before the results should have been made public—skewed the picture. Early research about Contrave suggested the drug was good for heart health, a message that made its way to the public. The problem, according to the new study, is that as the trial continued, that benefit didn’t hold up. When more data was analyzed, the heart benefit disappeared. In fact, there was almost no significant difference in heart events among the people taking the drug and those taking a placebo.
“Morally and ethically we could not allow that situation to continue,” says lead author Dr. Steven Nissen, chair of cardiovascular medicine at Cleveland Clinic, of his and his colleagues' decision to release all of the available data on the trial. “We didn’t believe that the early data accurately reflected the benefits. And sure enough it turned out not to be reliable evidence of benefit.”
Orexigen did not respond to multiple requests for comment.
The JAMA study sheds light on some of the potential issues wrought by a new approval process adopted by the FDA in recent years. The new process is intended to bring new drugs to market sooner. Normally, accumulating data about side effects like heart attacks, strokes, even death can take five years or more. Now, in order to speed drugs to patients faster, the agency can approve drugs before the full study on its side effects is complete—as long as certain criteria are met. The FDA, the drug maker and the scientists doing the trial must agree on a pre-specified threshold of safety that the drug has to meet. In this case, all parties agreed that the study would have to show that the drug didn't more than double the number of negative heart-related outcomes.
The FDA also requires that trials for approval be blinded, so that researchers and the people in the studies are not aware of whether they are taking the drug or a placebo. Of course, some people at the drug manufacturer and at the FDA are privy to—and are required to keep confidential—the results of a trial before it is final. In Contrave’s case, the early finding that the drug was linked to a 41% lower risk of heart events was shared with more than 100 people. And because the results meant it met that agreed-upon threshold for safety, the FDA approved the drug.
It also requested an entirely new study to continue evaluating the drug’s heart safety and shut down the existing trial.
Given the widespread publicity over the preliminary results that showed benefit, however, doctors began prescribing the drug and many people participating in the trial dropped out so they could get the medication from their own physicians.
Orexigen did not respond to requests from TIME and Takeda Pharmaceuticals, which is partnering with Orexigen on Contrave, did not respond to questions about the heart-related safety issues, but said in a statement: "Takeda was not involved in the decision to disclose the interim data... We remain confident in the therapeutic benefits of Contrave and its importance as a treatment option for chronic weight management as an adjunct to a reduced-calorie diet and increased physical activity."
For now, the question of whether people taking Contrave are exposed to a higher risk of heart events is still unanswered. The only thing for certain is that it doesn’t double the risk of heart events compared to people taking placebo. Orexigen is now funding a new trial that will deliver a more definitive answer on the heart safety of its drug, which Nissen will lead. But it will take another five years, at least.
“We always hope that weight loss drugs would actually help heart disease,” says Nissen. “But it has to be done scientifically and in a rigorous fashion.”