Popular Weight Loss Drugs Like Ozempic May Cause Major Muscle Loss Without Boosting Fitness, Study Warns

GLP-1 drugs like semaglutide and tirzepatide may cause 25–40% of weight loss to come from lean muscle.

CHARLOTTESVILLE, Va. — Weight loss medications like Ozempic and Wegovy have become household names, promising dramatic results for millions struggling with obesity. But new research out of the University of Virginia reveals a troubling side effect that could undermine long-term health: these drugs may be destroying muscle mass and failing to improve the heart and lung fitness that’s crucial for staying alive.

The study, published in The Journal of Clinical Endocrinology & Metabolism, found that popular GLP-1 receptor agonists — including semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound) — cause people to lose substantial amounts of muscle alongside fat. Even more concerning, despite their proven cardiovascular benefits, these medications appear to do little for cardiorespiratory fitness, a key predictor of mortality.

The researchers found that approximately 25% to 40% of weight loss from these drugs comes from fat-free mass (which includes muscle), at rates that far exceed normal aging. While healthy adults typically lose about 0.8% of their muscle mass each year due to aging, people taking these weight loss drugs can lose muscle much faster. In major clinical trials, participants lost anywhere from 25% to 40% of their total weight from muscle rather than fat alone.

Why GLP-1 Drugs Don’t Improve Heart and Lung Fitness

The research reveals a puzzling contradiction in modern obesity treatment. While these medications have revolutionized weight management and shown remarkable success in reducing heart attacks and strokes, they’re not delivering the fitness improvements doctors would expect from such dramatic weight loss.

Cardiorespiratory fitness — essentially how well the heart, lungs, and muscles work together during exercise — is one of the strongest predictors of mortality risk. People with poor fitness have much higher chances of dying from any cause, regardless of their weight. Typically, losing substantial amounts of weight should improve this fitness level, but the new research suggests these drugs aren’t delivering that benefit.

The study’s authors analyzed multiple clinical trials involving thousands of participants taking various GLP-1 medications. Across nearly every study examined, participants either saw no improvement in their peak oxygen consumption (a gold standard measure of fitness) or showed only modest gains that could be attributed to factors other than the medication itself.

How Weight Loss Drugs Like Ozempic and Mounjaro Trigger Muscle Loss

The muscle loss stems from several factors related to how these medications work. GLP-1 drugs dramatically reduce appetite, leading to severe caloric restriction that can trigger the body to break down muscle tissue for energy. During periods of low food intake, the body increases muscle protein breakdown while decreasing muscle protein synthesis, essentially breaking down muscle to meet its energy needs.

Many people taking these medications also experience fatigue and gastrointestinal side effects that reduce their physical activity levels. Less movement means less stimulus for the body to maintain muscle mass, creating a cycle of muscle loss.

The researchers noted that prolonged caloric restriction also impacts cardiac protein balance, reducing synthesis while sparing degradation. This could explain why some studies found reductions in stroke volume (the amount of blood the heart pumps with each beat) in people taking these medications.

Exercise Training Shows Promise for Preserving Muscle

The study identified a potential solution: combining these medications with exercise training. Small trials that included structured exercise programs alongside GLP-1 treatment showed promising results for maintaining muscle mass and improving fitness levels.

In one study of people taking tirzepatide with exercise training, participants not only preserved more muscle mass but also showed improvements in fitness when measured per kilogram of muscle tissue. Another trial combining liraglutide with exercise demonstrated similar benefits compared to medication alone.

The authors concluded that “concomitant exercise training may be able to offset potential reductions” in cardiorespiratory fitness and muscle loss for people taking these drugs.

Exercise programs that showed benefits typically included both aerobic exercise and resistance training, though the optimal combination, intensity, and duration remain unclear. The studies were small and some lacked proper control groups, so larger trials are needed to confirm results.

What This Means for Patients Taking GLP-1 Weight Loss Medications

The muscle loss has serious implications for the millions of Americans taking these medications. Muscle mass helps regulate blood sugar, supports bone health, and maintains metabolic rate. Losing substantial muscle could potentially diminish some of the long-term health benefits these medications provide.

For older adults and people who already have low muscle mass before starting treatment, the risks may be particularly concerning. These populations could face higher risk for frailty, falls, and functional decline if muscle loss accelerates.

Pharmaceutical companies are already exploring solutions. Some researchers are investigating combining GLP-1 medications with other drugs that specifically preserve muscle mass, such as bimagrumab, an antibody that blocks signals telling muscles to break down.

The study authors emphasized that their results shouldn’t discourage people from using these medications when appropriate. The cardiovascular and metabolic benefits of GLP-1 drugs are well-established and important. Rather, the research highlights the importance of comprehensive treatment approaches that address the whole person, not just the number on the scale. For now, that strategy appears to center on one tried-and-true intervention: regular exercise.

Disclaimer: This article summarizes findings from a narrative review published in The Journal of Clinical Endocrinology & Metabolism. The authors analyzed existing studies and did not conduct new clinical trials. While the review highlights concerning trends in fat-free mass loss and fitness stagnation, it does not suggest that GLP-1 drugs are unsafe or ineffective. These medications remain valuable tools in treating obesity and type 2 diabetes, especially when prescribed under medical supervision. Patients should not stop or alter their medication without consulting a licensed healthcare provider. The information presented here is for educational purposes only and is not a substitute for professional medical advice.