After weight loss regular exercise rather than GLP-1 weight-loss drug reduces leading cause of heart attack and strokes

Randomised trial finds that maintaining a large weight loss with exercise seems to reduce the development of atherosclerosis (a leading cause of heart attack and strokes), which was not seen with the GLP-1 receptor agonist liraglutide.

2025-09-16

(Press-News.org) Maintaining weight loss with regular exercise rather than the glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide, a drug used to treat type 2 diabetes and obesity, seems to reduce atherosclerosis development in adults with obesity—a leading underlying cause of cardiovascular disease.

The study of adults with obesity but not diabetes is by researchers from the University of Copenhagen, Denmark, and is presented at this year’s Annual Meeting of The European Association for the Study of Diabetes (EASD), Vienna (15-19 Sept).

“Our findings reveal that regular exercise is crucial to helping people living with obesity get the full cardiovascular benefits after a substantial weight loss,” said lead author Dr Rasmus Sandsdal from the University of Copenhagen, Denmark.

Cardiovascular disease is the leading cause of death worldwide and often originates in atherosclerosis, a chronic condition in which inflammation and fat deposits cause arteries to harden and narrow. Over time, plaques can rupture, causing serious complications such as heart attacks and strokes.

Obesity causes chronic low-grade inflammation, which can lead to endothelial dysfunction (a condition in which the blood vessels become unable to contract and relax adequately and the development of atherosclerosis.

Both exercise and GLP-1RAs have been shown to reduce the obesity-associated risk of cardiovascular events like heart failure and heart attacks, but little is known about their impact on the development of atherosclerosis during weight loss maintenance.

To explore this further, Danish researchers conducted a randomised placebo-controlled trial involving 215 adults (aged 18-65 years; 63% female) living with obesity (BMI 32-43 kg/m²) who did not have diabetes or other serious chronic disease at the start of the trial.

Initially, participants were asked to adhere to a low-calorie diet of 800 kcal per day (Cambridge Weight Plan) for 8 weeks. The 195 participants who had lost at least 5% of their body weight (average reduction in body weight of 12%/13.1 kg) were randomly assigned for 1 year to one of four weight maintenance strategies: moderate-to-vigorous-intensity exercise 150 min/week plus placebo; treatment with liraglutide (3.0 mg per day); combination of exercise 150 min/week and liraglutide; or placebo.

Blood levels of inflammatory biomarkers interleukin-6 [IL-6] and interferon-γ [IFN-γ] and biomarkers of endothelial function (intercellular adhesion molecule [ICAM-1], vascular adhesion molecule [VCAM-1], and tissue plasminogen activator [tPA]) were measured at the start of the low-calorie diet, the start of the weight maintenance period, and after one year. Participants also had an ultrasound of the carotid artery to measure intima-media thickness [cIMT].

After the 1-year weight maintenance period, both exercising participants and those undergoing liraglutide treatment maintained weight loss.

Nevertheless, the study found that participants who followed an exercise programme (with or without treatment with liraglutide) had lower levels of inflammatory biomarkers compared with non-exercising participants (with an average IL-6 level 21% lower and an IFN-γ level 27% lower).

Exercising also had a favourable impact on biomarkers of endothelial function (with an average 6% drop in VCAM-1, an 8% drop in ICAM-1, and a 12% decrease in tPA) compared to non-exercising participants, and reduced carotid artery thickness (average -0.024 mm).

Interestingly, no differences were noted in inflammatory or endothelial function biomarkers or carotid artery thickness between participants treated with liraglutide and those not taking the drug.

“Regular exercise seems to confer a protective effect against the development of atherosclerosis in people trying to maintain weight loss. Since both exercise and GLP-1RA treatment were successful at keeping weight off, it seems that exercise plays an important role in mitigating cardiovascular risk factors in a weight-independent manner,” said Dr Sandsdal.

Exercise benefits health in numerous ways, including improving body composition and increasing cardiorespiratory fitness. These benefits collectively contribute to improved cardiometabolic health.

“The most important message from our findings is that, for those trying to maintain weight loss, exercise is crucial in improving long-term health,” said corresponding author Professor Signe Sørensen Torekov from the University of Copenhagen. “Given the substantial societal and economic costs of obesity-related cardiovascular disease, these findings underscore regular exercise as a critical component of weight management and heart health.”

The study had some limitations, including the small sample size and that performing the structured exercise programme outside the support of this trial, in free living conditions, might reduce individual adherence. The researchers note that future research should investigate the combined effects of adherent exercise and newer GLP-1RAs for treatment periods longer than one year.

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