Popular GLP-1 weight loss drugs such as semaglutide may help patients shed pounds, but they fall short in improving a vital long-term health metric: cardiorespiratory fitness (CRF), according to a new review from University of Virginia Health researchers.
This missing benefit could have serious consequences for heart health, muscle function, and longevity, especially in people already at risk for frailty or malnutrition.
Muscle loss: the hidden cost of rapid weight loss
GLP-1 receptor agonists (GLP-1RAs) and dual GLP-1/GIP receptor agonists have transformed obesity treatment by triggering significant fat loss. But they also reduce fat-free mass (FFM)—including muscle—at a rate far exceeding typical aging. In fact, 25% to 40% of the total weight lost with these drugs comes from FFM, while natural aging reduces FFM by just 8% per decade.
“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 Dr. Zhenqi Liu of UVA’s School of Medicine. “This is a serious concern.”
Why cardiorespiratory fitness matters more than weight
CRF, measured by VO2max, reflects how well the heart, lungs, and muscles work together to use oxygen during exercise. Low CRF is a better predictor of death than body weight alone—especially in people with obesity, diabetes, or heart failure.
Despite modest improvements in heart function, Liu and his co-authors found no consistent evidence that GLP-1 drugs improve VO2max. This suggests that weight loss alone doesn’t guarantee improved metabolic or cardiovascular fitness.
Key findings from the review
- GLP-1 drugs lead to significant weight and fat loss.
- 25–40% of the lost weight is lean mass, including muscle.
- There’s no clear improvement in cardiorespiratory fitness.
- Low CRF is strongly linked to early mortality, independent of weight.
- Exercise and nutrition may be needed to counteract muscle loss.
Research gaps and future directions
Co-author Siddhartha S. Angadi, a cardiovascular physiologist, noted that CRF “was far superior to overweight or obesity status for predicting the risk of death.” Yet, few clinical trials have assessed how GLP-1 drugs interact with exercise training. Some early studies suggest combining these drugs with physical activity might help—but more rigorous trials are needed.
The team urges healthcare providers to evaluate patients’ muscle mass and nutrition status before prescribing GLP-1 therapy. Screening for malnutrition and encouraging adequate protein intake and regular exercise could help preserve muscle and maximize health gains.
Looking ahead: can medicine fix the muscle gap?
While no solution exists yet, Liu’s team points to promising efforts to develop medications that could help preserve lean mass—such as monoclonal antibodies now in development. “This is an area of active research, and we are hopeful that better solutions are coming soon,” Liu said.
Journal: The Journal of Clinical Endocrinology & Metabolism
DOI: 10.1210/clinem/dgaf335
Published: June 9, 2025
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