The investigational weight-loss combination of naltrexone standard release and bupropion standard release (Contrave) reduces the predicted 10-year risk of cardiovascular events, an analysis of four phase III trials showed.…
According to Robert Chilton, DO, of the University of Texas Health Science Center at San Antonio, using an average of six major risk prediction models, one year of treatment with the combination in low-risk overweight and obese patients reduced the absolute 10-year risk of cardiovascular events by 0.17%, compared with a reduction of 0.05% with placebo (P<0.05). Significant reductions were also seen with the combination in the predicted 10-year risk of coronary heart disease, MI, and congestive heart failure relative to placebo (P<0.01 for all), he reported at the Obesity Society meeting here. The findings, he said, provide confidence that the drug combination will show a benefit in an upcoming cardiovascular outcomes trial.
Naltrexone/bupropion has been shown in randomized trials to be effective in getting overweight and obese patients to lose weight compared with placebo.
The FDA, however, went against the recommendations of one of its advisory committees and did not approve the combination because of concerns about increases in blood pressure in patients taking the active treatment. The agency told the maker of the drug, Orexigen, that it would need to conduct a cardiovascular outcomes trial to ease doubts about safety before the drug could be approved.
Initially, Orexigen was hesitant to conduct such a trial and said it would no longer seek approval for the combination in the U.S., saying the requested trial “is unprecedented and would generate significantly more information than is necessary or feasible.”
The company continued meeting with the FDA, however, and said in a Sept. 20 statement that the design requirements for a cardiovascular outcomes trial “are reasonable and feasible and provide the certainty required to reinitiate development of Contrave.”
The proposed trial would enroll a population of overweight and obese individuals with an estimated annual risk of major cardiovascular events of 1 to 1.5%.
According to Orexigen, the FDA said that the drug could be approved if an interim analysis of the trial excludes any unacceptable cardiovascular risk.
“Both FDA and Orexigen estimate that such a study would require approximately 87 total events by the interim analysis to enable resubmission of the New Drug Application for approval,” according to a statement from the company. “Orexigen estimates that the entire study would require fewer than 10,000 patients and less than two years from study start to the interim analysis.”
The trial is expected to start in the first half of 2012.
According to Chilton, he and his colleagues planned to look at the effect of treatment with naltrexone/bupropion on the predicted 10-year risk of cardiovascular events even before the company submitted data to the FDA for consideration.
The analysis reported at the meeting pooled data on 3,363 patients who participated in the phase III Contrave Obesity Research program, which included four randomized, placebo-controlled trials lasting 56 weeks. Patients on active treatment received 32 mg naltrexone SR/360 mg bupropion SR.
The researchers estimated the change in 10-year risk of cardiovascular events after one year of treatment using six established risk prediction tools — the Framingham, Fremantle, QRisk2, Reynolds, SCORE, and U.K. Prospective Diabetes Study scores.
The patient population had a low cardiovascular risk at baseline. The mean age was about 46, the mean body mass index was 36 kg/m2, and 12 to 13% had type 2 diabetes.
Averaging the six risk scores together, the predicted 10-year cardiovascular risk at baseline was 5.8% in the drug group and 5.6% in the placebo group.
As seen previously, there was significantly greater weight loss in the active treatment group after one year (7% versus 2.3%, P<0.001).
Using all six of the risk scores, the predicted 10-year risk of cardiovascular disease events dropped to a greater extent with active treatment than with placebo after one year in the overall population, as well as in patients with type 2 diabetes and those without the disease.
There was no significant effect on the predicted risk of ischemic heart disease, cardiovascular mortality, or stroke.
Chilton said that the findings suggest that a cardiovascular outcomes trial will show that the drug combination is safe.
“In a year, we do show risk benefits for cardiovascular reduction in events, so the drug would be something worthwhile,” he said, adding that he would prefer having his patients lose weight without drugs.
- Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal.
- Note that this study demonstrates that weight loss with combination naltrexone/bupropion was associated with improved 10-year risk for overall CV disease, CHD, MI, and CHF as measured by published risk equations.
- Point out that confirmation that reduced CV risk is actually associated with improved outcomes will require a prospective trial.
Chilton R, et al “Naltrexone SR/bupropion SR combination therapy improves predicted 10-year risk of cardiovascular disease, coronary heart disease, myocardial infarction, and congestive heart failure” OBESITY 2011; Abstract 598-P.