Semaglutide, the active ingredient in Ozempic and Wegovy, reduced the risk of serious cardiovascular events by 20% in overweight and obese people with established cardiovascular disease, according to results from a large randomized presented today at the American Heart Association Scientific Sessions meeting in Philadelphia.

Semaglutide had been previously shown to reduce cardiovascular events by 25% among people with diabetes. But these result from the SELECT trial opens the door to much broader use among the 20 million people in the U.S. with coronary artery disease, most of have overweight or obesity but only 30% of whom have diabetes. Nearly 90% of the people in the 17,604 people enrolled in the study were taking a statin, so semaglutide may be positioned as an add-on therapy to statins that would further lower cardiovascular risk.

The side effect picture from the trial was mixed. The researchers tallied a lower incidence of serious side effects among the people randomized to treatment with semaglutide than among those randomized to placebo (33.4% vs. 36.4%). However, side effects that led to people discontinuing with their treatment were two times more common in the semaglutide group than in the placebo group (16.6% vs. 8.2%), and gastrointestinal disorders (nausea, diarrhea), well-documented drawback of semaglutide, were the most common reason.

The people randomized to semaglutide lost, on average, 9.4% of their body weight. But the researchers and discussants of the findings said there are strong hints of semaglutide having a direct, protective effect against cardiovascular disease, apart from the risk reduction that comes from losing weight.

“I think most of us believe that some of this is weight loss, but I think that oversimplifies a very complex molecule, a complex receptor on multiple tissues, and I don’t think it is as simple as that,” said A. Michael Lincoff, vice chairman for research for the Department of Cardiovascular Medicine at the Cleveland Clinic in Ohio, and the first author of the research article describing the findings that was published in the New England Journal of Medicine simultaneously with Lincoff’s presentation at the AHA meeting

Results from the SELECT trial are likely to be persuasive because it was a large, double-blind, randomized multicenter study. However more than 80% of the participants were white and more than 70% were male, so there are questions about how applicable the results will be to a more diverse population.

To be included in trials, patients had to be age 45 or older, have a BMI of 27 or greater, and have established cardiovascular disease, which for the purposes of this trial was defined as having had a myocardial infarction, previous stroke or symptomatic peripheral arterial disease. The trial was designed to test semaglutide protective among people without diabetes, so people who had been diagnosed with diabetes or hemoglobin A1C (HbA1C) level of 6.5% of higher were excluded.The primary end point was a composite of death from cardiovascular causes, nonfatal myocardial infarction or nonfatal stroke.

In addition to taking statins and having low LDL levels, most (86.2%) of the people enrolled in the study were taking platelet-aggregation inhibitors (aspirin, for example), and almost as many (70.2%) were taking a beta blocker. The mean BMI was 33.3, although 28.5% of the participants were in the overweight range (a BMI less than 30).

The average duration of taking semaglutide or the placebo was 34 months.

Of the 8,803 in the semaglutide group, 569, or 6.5% experienced one of the end points in the composite primary end point compared with 701, or 8%, of the 8,801 in the placebo group. That works out to a 20% difference. Secondary end points also stacked up in favor of semaglutide.

“Twenty percent may not sound like a huge number but that’s what we do in heart disease: We chip away at what is still the largest source of mortality in the world, “ said Lincoff said during a press conference on Friday.

The SELECT trial was funded by Novo Nordisk, which makes and markets Ozempic, the lower-dose version of semaglutide that is approved as a treatment for type 2 diabetes, and Wegovy, the higher dose version approved for weight loss. The trial tested weekly subcutaneous injections of 2.4-mg dose of semaglutide, which is one of the two doses that Wegovy comes in.

Semaglutide is a glucagon-like peptide-1 (GLP-1) inhibitor, a class of drugs that includes tirzepatide, which the FDA approved on Wednesday as a weight loss drug that Eli Lilly is marketing as Zepbound. Sales of GLP-1 inhibitors have skyrocketed as they morphed from being drugs for treatment of type 2 diabetes to also being weight loss drugs.

Although the SELECT trial assessed semaglutide in people who already had cardiovascular disease, Lincoff said most drugs, including statins, that are effective in that circumstance — secondary prevention — are also effective work in primary prevention, which in this context would mean overweight or obese people who didn’t have established cardiovascular disease.

In accompanying editorial in the New England Journal of Medicine, Amit Khera, M.D., at the University of Texas Southwestern Medical Center in Dallas and Tiffany M. Powell-Wiley, M.D., M.P.H., of the National Heart, Lung and Blood Institute and the National Institute on Minority Health and Health Disparities, heralded the SELECT trial as pointing to a welcome treatment option for people at risk of cardiovascular events despite having well-controlled risk factors and very low LDL levels. But they also noted the “significant cost” of GLP-1 inhibitor therapy at the current prices and argued for continuing to address the “upstream underpinnings “of obesity and the downstream effects on the communities that are most vulnerable to experiencing it.