The blockbuster diabetes and weight loss drug semaglutide (Wegovy, Ozempic, Rybelsus) reduced the relative risk of heart attack, stroke, or cardiovascular deaths by 20 percent in high-risk patients with cardiovascular disease but not diabetes during a large and long randomized, placebo-controlled trial.

That overall risk reduction equates to 15 fewer cardiovascular events per 1,000 patients treated. People on semaglutide in the trial lost an average of 9.5 percent of their body weight, an 8.5 percentage-point drop over those in the placebo group.

The study, which was previewed in an August press release by the drug's maker and trial-runner Novo Nordisk, was published in full Saturday in the New England Journal of Medicine, timed to a presentation of the findings at the American Heart Association conference in Philadelphia.

The results have bolstered excitement over semaglutide, with many saying it advances the drug as a new pharmaceutical weapon in the fight against cardiovascular diseases, in addition to diabetes, obesity, and overweight—shedding any lingering notions of it being merely a lifestyle drug. The trial may sway more insurance providers to cover the drug, which is pricey. Wegovy—sematglutide used for weight loss—has a list price in the US of $1,349 per month. People in the trial were on the drug for an average of around three years, which would carry a price tag of $48,564.

Limitations

The trial has some notable caveats. Perhaps the largest is that while the trial was large, with 17,604 participants, it did not enroll a diverse group of participants. Most were white (84 percent) and male (72 percent).

A requirement for entering the trial was to have established cardiovascular disease and thus be at high risk of an event, such as stroke, heart attack, or cardiovascular-related death. But the participants on the whole did not have their baseline cardiovascular risk factors—like cholesterol levels and blood pressure—under control, which can be done using existing tools such as statins and hypertension drugs. It's possible that the benefits of semaglutide may not have been as positive as they were if these underlying risk factors had been well controlled.

The trial also leaves looming the question of how semaglutide reduced the relative risk of cardiovascular events in patients without diabetes. Was it simply the loss of weight, or was it another action of the drug, which mimics the metabolic hormone Glucagon-like peptide-1 (GLP-1) to increase insulin secretion, slow stomach emptying, and decrease appetite? As two experts from the University of Texas Southwestern Medical Center and the National Institutes of Health wrote in an accompanying editorial in NEJM, "It remains unclear to what degree the trial findings were dependent on weight loss, concomitant reductions in risk factors, or other salutary mechanisms of GLP-1 receptor agonism."

The question is a critical one given that patients who go on the drug do so for an indefinite period, with the potential to regain the lost weight after stopping the drug.

Study details

Of the 17,604 patients enrolled across 41 countries, 8,803 were randomly assigned to receive weekly subcutaneous injections of semaglutide, with 8,801 getting a placebo. The trial ran from October 2018 to March 20221. The patients' mean age was 61, and the mean body mass index was 33, falling in the category of obesity. Side effects, mainly gastrointestinal disorders, led 1,461 patients (16.6 percent) in the semaglutide group and 718 patients (8.2 percent) in the placebo to discontinue their assigned intervention.

The trial primarily looked at a "composite end point" of patients who had a cardiovascular-related death, nonfatal heart attack, or a nonfatal stroke. In the semaglutide group, there were 569 patients (6.5 percent) who had at least one of these events, while there were 701 (8 percent) in the placebo group. This was the only statistically significant finding in the study.

Broken down further, the results indicated a 15 percent relative risk reduction for cardiovascular deaths in those on semaglutide, but this was not statistically significant. There also appeared to be a 28 percent relative risk reduction for heart attack and a 7 percent reduction in risk of stroke, but the statistical significance of these findings was not calculated after deaths failed to meet the statistical threshold.