Clinical trials have revealed concerning patterns of muscle loss associated with GLP-1 agonist medications like semaglutide (Ozempic), with new preclinical research providing deeper insights into the mechanisms behind these effects. The findings highlight the need for comprehensive prevention strategies and further human studies to understand the full implications of these widely prescribed weight-loss medications.
Clinical Evidence of Muscle Loss
Multiple clinical studies have documented significant lean mass reduction in patients using incretin mimetic agents. In the landmark 68-week STEP-1 trial of semaglutide for obesity treatment, patients experienced a 17.3 kg (38 lb) reduction in body weight compared to 2.7 kg (6 lbs) in the placebo group. However, dual-energy X-ray absorptiometry (DXA) scans revealed that patients also lost 6.9 kg (15.1 lb) of total lean mass, versus 1.5 kg (3.3 lb) in the placebo group.
"Overall, 40% of the total weight loss in the semaglutide group was due to a reduction in lean body mass," according to the trial data. This represents a 13.9% loss of lean muscle mass, which experts note is equivalent to roughly 20 years of muscle loss due to aging.
A systematic review evaluating semaglutide's effects on lean body mass across six studies with 1,541 overweight or obese adults found lean mass reductions ranging from 0% to 40% of total weight reductions, with effects particularly evident in larger studies. The authors concluded that while semaglutide affects weight loss primarily through fat mass reduction, "loss in lean mass leads to concerns, especially from larger clinical studies."
New Insights from Preclinical Research
Recent research from the University of Utah has provided new perspectives on how GLP-1 agonists affect body composition. The study found that Ozempic-induced weight loss decreased lean mass by about 10% in mice, but most of this lost weight wasn't from skeletal muscles.
"Most of this lost weight wasn't from skeletal muscles but instead from other tissues like the liver, which shrunk by nearly half," the researchers reported. Dr. Ran Hee Choi, research instructor in nutrition and integrative physiology at University of Utah Health and co-first author on the study, explained that "loss of mass in metabolically active organs, such as the liver, is expected as part of healthy weight loss."
The study revealed that some skeletal muscles did shrink as mice lost weight—on average by about 6%—but this wasn't enough to explain the overall loss in lean mass. Other muscles maintained their size throughout the weight loss process.
Strength vs. Size Discrepancy
Perhaps most concerning was the finding that muscle strength could decline even when muscle size remained unchanged. "When the researchers tested the amount of force the mice's muscles could exert, they found that, for some muscles, strength decreased as the mice lost weight, even when the size of the muscle stayed roughly the same," according to the study results.
Dr. Takuya Karasawa, postdoctoral researcher in the University of Utah Molecular Medicine Program and co-first author, noted that "it's unknown how weight loss drugs affect this balance in people."
Clinical Implications and Risk Factors
The potential for strength loss raises particular concerns for older adults. "A potential loss of strength when taking Ozempic may be of particular concern for adults over the age of 60, who are at higher baseline risk for muscle loss and reduced mobility," researchers warned. As study co-author Funai noted, "The loss of physical function is a strong predictor of not just quality of life but longevity."
Several factors may contribute to muscle loss during Ozempic treatment, including appetite loss, calorie restriction, low protein intake, pre-existing low muscle mass, low physical activity, history of weight cycling, older age, frailty, and type 2 diabetes.
Prevention Strategies
Despite these concerns, proven strategies exist to help maintain muscle strength during GLP-1 agonist treatment. Research has shown that resistance training can be effective in maintaining muscle mass during weight loss in people with obesity or overweight.
Key prevention strategies include:
- Strength training: Regular resistance exercises including weight lifting, resistance bands, leg squats, push-ups, and gym machines
- Adequate protein intake: The Institute of Medicine recommends 0.8 g/kg of body weight per day for healthy adults, with higher amounts suggested for people over 65
- Aerobic exercise: Weight-bearing activities like walking, jogging, stair climbing, or dancing, depending on fitness level and health status
- Proper hydration: Adults should consume 2 to 3 liters of water per day
- Professional guidance: Working with healthcare providers and registered dietitians to optimize nutrition plans
Future Treatment Approaches
New therapeutic approaches are being investigated to address muscle loss concerns. Eli Lilly has announced development of bimagrumab (LY3985863), a monoclonal antibody that binds activin/myostatin type II receptors and blocks ligand binding. In the ongoing BELIEVE Phase 2b study, bimagrumab is being studied alone and in combination with semaglutide in overweight or obese adults.
"The company states that combining these agents may further reduce fat mass while preserving muscle mass and lead to improved outcomes in obesity treatment," according to the development program description.
Need for Additional Research
Researchers emphasize caution in interpreting current findings and stress the need for more comprehensive human studies. "There remains a significant need for validation in humans, especially concerning muscle strength," Karasawa stated.
The University of Utah team noted important limitations in extrapolating mouse study results to humans, as "mice and humans gain and lose weight in different ways." They emphasized that clinical trials should evaluate muscle strength changes not just for current medications but also for future weight-loss drugs in development.
"There are many additional weight loss drugs that are in clinical trials and coming out in the next three to five years," Funai observed. "But with all those clinical trials, if they're interested in measuring lean mass loss, they need to consider physical function."
