VIENNA — Exercise to maintain weight loss reduced atherosclerosis progression and improved cardiovascular biomarkers, while GLP-1 therapy alone didn’t, according to a randomized trial in people with obesity but without diabetes.

After losing weight by diet alone, participants who followed an exercise program, with or without liraglutide, had lower levels of inflammatory biomarkers and endothelial dysfunction compared with participants who didn’t exercise at 1 year of weight maintenance. Both groups maintained their weight loss, but only those who exercised showed cardiovascular benefit.

“Our findings reveal that regular exercise is crucial to helping people living with obesity get the full cardiovascular benefits after substantial weight loss,” said lead investigator Rasmus Sandsdal, MD, from the University of Copenhagen, Copenhagen, Denmark. “We saw no change in artery lining thickness and the investigated inflammatory biomarkers and markers of endothelial dysfunction in patients who took liraglutide for weight maintenance, so [the benefits] seemed linked to exercise.”

The study results were presented at European Association for the Study of Diabetes Annual Meeting (EASD) 2025 Annual Meeting.

Sandsdal’s senior colleague, Signe Sørensen Torekov, PhD, professor of clinical translational metabolism in the Department of Biomedical Sciences at the University of Copenhagen, further discussed the findings in a separate session that addressed weight maintenance as well as the balance between associated fat loss and muscle loss.

“What we want is healthy weight loss, primarily fat mass, with lean mass preserved or even increased,” remarked Torekov. “One proven way to achieve this is through structured exercise after weight loss. In our studies, participants who exercised not only reduced fat mass but also increased lean mass, leading to healthier long-term outcomes.”

Effect of Exercise on Atherosclerosis Markers

The researchers aimed to evaluate the effects of exercise or liraglutide during weight-loss maintenance on biomarkers of low-grade inflammation and endothelial dysfunction, both of which can lead to atherosclerosis. While GLP-1 receptor agonists have been shown to reduce inflammation and major adverse cardiac events, the question was whether those benefits extend to weight maintenance via medication and/or exercise after diet-induced loss.

Data were drawn from a randomized placebo-controlled trial which included 215 adults (aged 18-65 years; 63% women) living with obesity (BMI, 32-43) who did not have diabetes or other serious chronic disease at the start of the trial (initially published in The New England Journal of Medicine, 2021).

Having followed an 800 kcal/d diet (Cambridge Weight Plan) for 8 weeks, 195 of the participants who had lost at least 5% of their body weight (mean reduction in body weight of 12% or 13.1 kg) were randomly assigned to one of the four weight maintenance strategies for a duration of 1 year: moderate-to-vigorous-intensity exercise 150 min/wk (for example, spinning) plus placebo; treatment with liraglutide (3.0 mg/d) alone; a combination of exercise and liraglutide; or placebo.

Levels of circulating biomarkers of inflammation (interleukin-6 [IL-6] and interferon-gamma [IFN-gamma]) and endothelial dysfunction (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1[VCAM-1], and tissue plasminogen activator [tPA]) were measured. Ultrasound-assessed carotid intima-media thickness (cIMT) during the weight maintenance period was also assessed.

Over the year, all groups maintained initial weight loss, while those on combined exercise and liraglutide lost additional weight.

Exercisers also had lower inflammatory biomarkers — IL-6 decreased by 21% (95% CI, -34 to -10) and IFN-gamma by 27% ( -46 to -1) — than nonexercisers. Endothelial function was also improved in people who exercised vs those who did not, with a mean drop of 6% in VCAM-1 (95% CI, 0.88-1.00), an 8% drop in ICAM-1 (95% CI, 0.84-1.00), and a 12% decrease in tPA. cIMT was also reduced by a mean of -0.024 mm.

“It was only those people who exercised who had a clinically relevant reduction in carotid intima-media thickness, and that reduction may be mediated by exercise-induced reductions in pro-inflammatory and atherosclerotic biomarkers,” concluded Torekov.

This degree of reduction is associated with around a 24% lower risk for cardiovascular disease, she added. “This reduction was not seen with liraglutide.”

Differing Effects on Body Composition

Weight loss is not just about losing weight; it is about sustaining a healthy weight throughout life, stressed Torekov. However, “the moment weight is reduced, appetite increases, sedentary tendencies rise, and our cells become more energy-efficient, lowering energy expenditure,” she explained. “All these mechanisms push the body to regain weight. So the real challenge is not the weight loss itself, but how to preserve it.”

Despite similar effects on BMI, exercise and liraglutide differed in how they influenced body composition. Exercise preserved or increased lean mass and bone mass, while liraglutide led mainly to fat loss. The combination produced twice as much fat loss as liraglutide alone, with modest lean mass gains.

Sandsdal cautioned that with drug-induced weight loss, “we need to consider the quality of the loss.” Loss of lean mass and bone may outweigh benefits in older adults or those with osteopenia if not countered by exercise.

Torekov noted that hip bone loss seen with liraglutide alone was prevented when exercise was added. She also emphasized the feasibility of the intervention. In one of our trials, people averaged just 2 hours of high-intensity exercise per week — mostly spinning — for over a year, she said. “That modest time commitment was enough to deliver measurable benefits to body composition and weight maintenance.”

Her team is now studying how to preserve weight loss after semaglutide in young people with early-onset obesity. “The driver of long-term success is not just the medication but the integration of exercise into daily life,” she concluded.

Understanding Lean Mass Loss

Niels Jessen, PhD, head of Research and professor of clinical pharmacology at the Steno Diabetes Center Aarhus, Aarhus, Denmark, who moderated the second session, said the next frontier in weight-loss drugs is not just about how much weight patients lose, but where they lose it.

With drugs, “we’re now nearing the 30% weight loss seen with bariatric surgery. Now the challenge is to fine-tune that loss — keeping muscle while shedding fat. It’s not just the muscle fibers, but the role of the cellular composition of the muscles and receptors expressed in these various cells that are important.”

Jessen explained the importance of another presentation in the same session by Marco Sandri, MD, University of Padova, Padua, Italy, who leads a research group on signaling pathways that control protein homeostasis in muscles.Using human serum from patients with cancer who have experienced extreme muscle loss, Sandri investigated signaling pathways and how they changed during weight loss that included muscle loss.

“Sandri’s models are incredibly useful in helping us understand how muscle loss happens during overall weight loss within the clinical field of obesity diabetes,”said Jessen.

“He combines muscle cells and neuron cells in vitro and this is what we need to test the effects of overall weight loss on muscle mass. We can’t do this in animals because these pathways are species-specific,” Jessen explained.

“These in vitro models are incredibly important to understanding the effects on different tissues of human weight loss and lead the way into a new era of tailored weight loss because the current GLP-1 drugs do not target muscles.”

There are new drugs in development including those that are both a GLP-1 receptor agonist and an amylin receptor agonist or molecules that target the myostatin axis, for example.

However, he added, some of these are inhibitory receptors, and some are stimulating receptors, and “we can’t really predict exactly what is happening.”

“It’s really important that we get the basic knowledge on board, and this is what Marco Sandri brings to our understanding.”

The study was supported by the Novo Nordisk Foundation, Danish Diabetes and Endocrine Academy (DDEA), and Novo Nordisk A/S (study medication). Sandsdal reported receiving a PhD scholarship from the DDEA. Torekov reported receiving honoraria and consulting roles with Merck, Ferring, and Novo Nordisk, as well as research funding from Novo Nordisk and Embla. Jessen declared no financial disclosures.