Controversial Study Evaluating Cardiovascular Safety Of Anti-Obesity Drug Is Inconclusive

The cardiovascular safety of the anti-obesity drug naltrexone-bupropion (Contrave) remains inconclusive following publication of the final results for the prematurely terminated LIGHT outcomes study.

The LIGHT trial, directed by the Cleveland Clinic Center for Cardiovascular Research, was published today in the Journal of the American Medical Association (JAMA).

The LIGHT Trial randomly assigned nearly 9,000 overweight or obese patients to receive Contrave or placebo, along with lifestyle counseling on weight loss.

A major cardiovascular event occurred in 102 patients (2.3 percent) who received placebo and 90 patients (2 percent) who received naltrexone-bupropion. However, due to the premature termination of the study, this was only 50 percent of the planned number of cardiovascular events, which limits the ability of the study’s authors to confirm the cardiovascular safety of Contrave.

The study, led by Steven Nissen, M.D., chair of the Department of Cardiovascular Medicine at Cleveland Clinic, concluded that the LIGHT study confirmed that Contrave did not double the number of adverse cardiovascular outcomes (including heart, stroke or death). However, the study could not establish whether the drug increased these events by greater than 40 percent, which was the design goal of the study.

The trial was halted on the recommendation of the study’s executive steering committee after the original commercial sponsor of the trial inappropriately released preliminary findings in a patent filing. These results were obtained from a confidential early analysis that was intended to be used only for a regulatory filing with the FDA to allow initial marketing of the drug. Although the FDA approved Contrave in September 2014, the agency concluded that the breach of confidentiality prevented the trial from reliably reaching its goal of determining whether the drug increased cardiovascular events by 40 percent or less.

The patent filing claimed a cardiovascular benefit for Contrave, which the executive committee considered an unreliable conclusion. Subsequently, the committee released additional data, which did not show a benefit, to make certain that patients and providers were not administering the drug based on incomplete information suggesting a heart benefit.

In the JAMA manuscript, the authors write, “The events leading to termination of the study serve as a valuable reminder of the importance of maintaining confidentiality during ongoing trials. Premature release of interim data can result in inappropriate pre-judgment about the benefits or risks of the studied therapy and make completion of the trial highly problematic.”

Because of the failure to complete the LIGHT Trial, the FDA has required a new cardiovascular safety trial for Contrave. This trial, known as the CONVENE Study, is now underway, and is also being directed by Dr. Nissen and Cleveland Clinic, but results will not be available for three to four years.