Semaglutide, the active ingredient in the GLP-1 medications Wegovy and Ozempic, is used for weight management and type 2 diabetes. Research has also shown that, for some people at high risk of heart disease, semaglutide can reduce the risk of heart attack, stroke and cardiovascular death.
But scientists still don't completely understand why.
A new analysis of the large SELECT clinical trial found that weight loss and improvements in other familiar heart risk factors couldn't fully explain the cardiovascular benefits seen among people taking semaglutide. That doesn't prove the medication protects the heart independently of weight loss. Instead, researchers say other changes in the body may also be involved.
The study, published in the European Heart Journal, looked more closely at results from SELECT, a randomized clinical trial involving 17,604 adults ages 45 and older. Participants had overweight or obesity and already had cardiovascular disease, but they did not have diabetes.
The trial was funded by Novo Nordisk, which manufactures semaglutide. The company participated in the study's design, data collection, analysis and interpretation, as well as preparation and review of the manuscript. Several authors are Novo Nordisk employees and shareholders, while other researchers reported financial relationships with Novo Nordisk and other pharmaceutical companies.
In the original trial, half of the participants were assigned to receive a weekly 2.4-milligram dose of semaglutide and half received a placebo. Over the course of the study, 6.5% of people in the semaglutide group experienced a heart attack, stroke or cardiovascular death, compared with 8% in the placebo group. That amounted to a 20% lower relative risk among those assigned to semaglutide.
The new analysis tried to answer what sounds like a fairly straightforward question: Was that benefit mostly because people taking semaglutide lost weight?
Researchers looked at changes in weight and waist size, along with blood pressure, cholesterol, blood sugar, inflammation and kidney health. Semaglutide improved all of them.
But those changes didn't provide a clear explanation for the full cardiovascular benefit.
“Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty,” study leader Helen Colhoun, a professor at the University of Edinburgh, said in a news release.
Weight loss, in particular, didn't emerge as a simple answer. Researchers tried to estimate how much of the cardiovascular benefit could be linked to changes in weight and other health measures, but the results came with too much uncertainty to draw firm conclusions.
That's important because the study shouldn't be read as showing that weight loss doesn't matter for heart health. Nor does it prove that semaglutide has a separate, direct effect on the heart.
Instead, the researchers were unable to confidently explain the cardiovascular benefit using the changes they measured.
“We don’t know how else semaglutide could be preventing heart disease,” Colhoun said in the news release.
Scientists have proposed several possibilities, including changes involving inflammation and blood vessels. But those ideas remain under investigation, and this study wasn't able to pinpoint another explanation.
There are also important limits to what these findings mean for people taking GLP-1 medications.
SELECT studied a specific group: adults ages 45 and older who already had cardiovascular disease and had overweight or obesity. People with diabetes were not included. The findings therefore don't show that everyone taking semaglutide for weight management can expect the same reduction in cardiovascular risk.
The new analysis has limitations of its own. SELECT was designed to test whether semaglutide reduced serious cardiovascular events, not specifically to determine exactly how it did so. The researchers describe this follow-up analysis as exploratory and caution that it cannot prove which changes caused the cardiovascular benefit.
What the original trial established is much clearer: Semaglutide reduced serious cardiovascular events among the high-risk adults studied. What researchers still don't know is exactly why.
As GLP-1 medications become a larger part of weight and metabolic health care, understanding those effects could help researchers better understand what these medications are doing beyond the weight loss people can see.