Weight loss alone does not explain lower heart disease risk for those on semaglutide

by European Society of Cardiology

edited by Sadie Harley, reviewed by Robert Egan

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Semaglutide is known to reduce the risk of serious heart disease. However, a new study published in the European Heart Journal suggests that this effect cannot be entirely explained by patients losing weight on the drug.

Researchers examined known risk factors for heart disease, such as body weight and waist circumference, in patients taking part in a clinical trial of semaglutide for overweight and obesity. Although the risk of serious cardiovascular disease was lower for those taking the drug, only half of this reduction could be explained by changes in these risk factors.

The researchers say semaglutide may also be working to reduce heart disease in some other way, meaning it can be considered a way of preventing serious cardiovascular disease, over and above its current use as a weight loss treatment.

The SELECT trial behind the findings

The study is based on patients taking part in a gold-standard clinical trial called SELECT (Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity). Half of the 17,604 patients in the trial were treated with semaglutide, a type of drug called a GLP-1 receptor agonist, and half were given a placebo.

The study was led by Professor Helen Colhoun from the University of Edinburgh, UK. She said, "Several major trials have established that GLP-1 receptor agonists reduce serious cardiovascular disease, primarily in people with type 2 diabetes. SELECT was the first trial to show that these drugs can also lower cardiovascular disease in people who did not have diabetes.

"In this study, we analyzed data from the trial to ascertain whether the reductions in known cardiovascular risk factors that we saw in the trial could fully account for the reduction in heart disease."

Risk factors explain only part

The researchers looked at how factors like body weight, waist circumference and blood pressure changed over two years in people in the trial. They also looked at changes in people's blood tests, including cholesterol, and signs of diabetes, inflammation and kidney function. They compared this information with rates of cardiovascular disease, such as heart attack, stroke or death from cardiovascular disease, in the patients.

Patients who were receiving semaglutide lost weight, their waist measurements decreased and their blood tests improved. However, when researchers looked at all these factors separately and together, they could not fully account for the 20% lower rates of heart disease in patients taking the treatment.

Colhoun said, "Our analyses could not fully ascribe the effects of semaglutide on cardiovascular disease to known risk factors with any certainty. Whether we combine all risk factors together or look at some subsets of the risk factors, no more than half of the reduction in heart disease could be explained by the changes in these risk factors.

"These results suggest that semaglutide should be considered a cardiovascular disease reduction drug and not just a weight loss drug.

"We don't know how else semaglutide could be preventing heart disease, but many other mechanisms have been proposed. These include anti-inflammatory effects not fully captured by the risk factors measured in the trial, and other direct effects on heart muscle or on the lining of blood vessels. We need more research to fully explore other potential mechanisms of how semaglutide reduces cardiovascular disease."

The researchers caution that, even with a large study of this kind, their findings rely on estimates of risk and that the trial included patients being treated during the COVID-19 pandemic, which had an impact on data collection. They also point out that some patients in the trial may have lost weight for reasons other than taking semaglutide, for example, due to frailty, which can increase rather than decrease the risk of serious cardiovascular disease.

Unanswered questions need not delay treatment

In an accompanying editorial, Professor Subodh Verma from the University of Toronto, Canada, and colleagues said, "By all accounts, the remarkable story of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in cardiovascular medicine has been one of serendipity.

"Two years ago, in the European Heart Journal, we wrote that the journey of semaglutide was one such story—a drug born to lower glucose that has become the most versatile weapon against cardiometabolic-, kidney- and obesity-related diseases … If one molecule makes so many things better at once, then the obvious question at the bedside becomes 'How does it work?'

"The conclusion of this paper is appropriately humble. Known risk factor changes could not, with any confidence, explain all of the GLP-1RA effects on major adverse cardiovascular events.

"So, in summary, while the magic of semaglutide and GLP-1RAs on cardiometabolic outcomes is real, our search for the mechanistic underpinnings continues … At the end of the day, mechanistic knowledge is only useful if it sharpens how we deploy these remarkable drugs to save lives. The lack of clear mechanistic understanding should not be a barrier to therapeutic adoption to reduce vascular events."

Publication details

Semaglutide and cardiovascular risk reduction: a mediation analysis of the SELECT trial, European Heart Journal (2026). DOI: 10.1093/eurheartj/ehag524

Journal information: European Heart Journal

Key medical concepts

SemaglutideWeight LossWaist Circumference

Clinical categories

CardiologyEndocrinologyCommon illnesses & PreventionWeight managementClinical pharmacology Provided by European Society of Cardiology Who's behind this story?

Sadie Harley

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Robert Egan

Bachelor's in mathematical biology, Master's in creative writing. Well-traveled with unique perspectives on science and language. Full profile →

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