Though GLP-1 drugs drive major weight loss, researchers warn they may fall short in improving heart and lung fitness. Protecting muscle mass may be key to unlocking their full health potential.
Widely used GLP-1 medications are highly effective at promoting significant weight loss, but new research from the University of Virginia suggests they may fall short in enhancing heart and lung performance, which are critical for maintaining long-term health.
According to the researchers, these drugs offer well-documented advantages for individuals with obesity, type 2 diabetes, and heart failure. These benefits include better blood sugar regulation, improved short-term heart and kidney function, and increased survival rates.
However, the experts note that to achieve the full cardiovascular and respiratory gains typically associated with weight loss, patients might also need structured exercise plans or additional strategies like nutritional supplements or supportive medications.
“Some patients literally told me that they felt that they were losing muscle or muscle was slipping away from them while they were on these medications,” said researcher Zhenqi Liu, MD, Professor of Medicine and James M. Moss Professor of Diabetes at the University of Virginia School of Medicine and former chief of UVA Health’s Division of Endocrinology and Metabolism. “This is a serious concern. Muscle, especially axial muscle, is essential for posture, physical function, and overall well-being. Losing lean body mass can increase the risk of cardiovascular disease, all-cause mortalit,y and diminished quality of life. We need to make sure that patients prescribed these medications aren’t already at risk for malnutrition or low muscle mass.”
About GLP-1 Drugs
While GLP-1 drugs help people lose fat, this comes with loss of fat-free mass, of which muscle makes up 40% to 50%. In fact, fat-free mass lost accounts for 25-40% of the total pounds lost, while age-related declines in fat-free mass are only 8% per decade.
Liu and his collaborators, graduate student Nathan R. Weeldreyer and Siddhartha S. Angadi, PhD, Associate Professor of Kinesiology at UVA’s School of Education and Human Development, wanted to better understand the potential long-term consequences of this muscle loss, so they reviewed available data on the drugs’ effects on cardiorespiratory fitness, or CRF.
CRF (or VO2max) is a measure of how well the body can use oxygen during exercise. It is a handy way for doctors to assess how well the heart, lungs, muscles, and blood vessels work together, and it is used to predict all-cause and cardiovascular mortality (risk of death).
Patients with obesity often have low CRF. In some cases, this is because the person lacks muscle mass; in others, a person may have enough muscle, but the quality of that muscle is compromised by fat that has penetrated it.
“Cardiorespiratory fitness is a potent predictor of all-cause and cardiovascular mortality risk across a range of populations, including obesity, diabetes, and heart failure,” said Angadi, a cardiovascular exercise physiologist with UVA’s Department of Kinesiology. “In a recent study by our group that examined mortality outcomes from almost 400,000 individuals across the world, we found that CRF was far superior to overweight or obesity status for predicting the risk of death. In fact, once CRF was factored in, body weight failed to predict the risk of mortality. This is why it’s so important to understand the effects of this new class of drugs on it.”
In their review of the available medical literature, the researchers found that GLP-1 drugs improve certain measures of heart function, yet those improvements don’t translate into significant improvements in VO2max.
Some small studies, they note, have suggested that exercise can help improve VO2max for patients taking GLP-1 drugs, but these had poor controls and larger, well-designed studies are needed to bear that out.
Ensuring Healthy Weight Loss
The researchers ultimately conclude that GLP-1 drugs “significantly reduce body weight and adiposity, along with a substantial FFM [fat-free mass] loss, but with no clear evidence of CRF enhancement.” They remain concerned that this could take a toll on patients’ metabolic health, healthspan/frailty, and overall longevity. They are urging additional research to better understand the effects of the drugs and ensure patients get the best possible outcomes.
They note, however, that there are promising signs that we may be able to develop medications to help, such as a monoclonal antibody already in the pipeline that may be able to offset lean-muscle loss.
“This is an area of active research, and we are hopeful that better solutions are coming soon,” Liu said. “But for now it is important that patients prescribed GLP-1 drugs have conversations with their healthcare providers about strategies to preserve muscle mass. The American Diabetes Association recommends screening for malnutrition and low muscle mass risk before starting these medications and promoting adequate protein intake and regular exercise throughout treatment.”
“Finally,” Angadi added, “exercise training during GLP1 therapy remains to be assessed in its ability to preserve or improve VO2max during GLP1 therapy.”
Reference: “Incretin Receptor Agonism, Fat-free Mass, and Cardiorespiratory Fitness: A Narrative Review” by Zhenqi Liu, Nathan R Weeldreyer and Siddhartha S Angadi, 9 June 2025, The Journal of Clinical Endocrinology & Metabolism.
DOI: 10.1210/clinem/dgaf335
The work was supported by the National Institutes of Health, grants R01DK124344 and R01DK125330.
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