•GLP-1 Receptor Agonists: Weighing the Costs, Losing the Gains?

Unexpected side effect of GLP-1RAs

Semaglutide (Ozempic, Wegovy) and Tirzepatide (Mounjaro) have transformed the treatment of type 2 diabetes and obesity. These GLP-1 receptor agonists (GLP-1RAs) are highly effective for weight loss. But here’s the catch: they may also cause a significant loss of muscle mass, not just fat.

GLP-1 Receptor Agonists and Lean Mass Loss

Emerging research shows that 30–40% of the weight lost while using GLP-1RAs comes from lean mass, i.e., muscle, not fat. This is especially concerning for older adults or those already at risk for muscle loss.

This is concerning, as muscle mass plays a critical role in maintaining metabolic health, physical function, and overall quality of life. In addition, lean muscle mass plays an important role in fat loss, by burning fat.  The plateauing of weight loss for patients taking GLP-1RAs is in part attributed to this loss of lean mass.

Weight loss, especially following treatment with GLP-1 receptor agonists is associated with not only loss of fat, but also loss of muscle, i.e., loss of lean mass. Adapted from (https://upload.wikimedia.org/wikipedia/commons/6/61/1025_Atrophy.png) 

The loss of lean mass in patients taking the GLP1 class of drugs is likely multifactorial:

• Reduced caloric intake may contribute, as the body breaks down muscle tissue for energy when in a calorie deficit.

• Hormonal changes induced by GLP-1 agonists could directly influence muscle protein synthesis and breakdown.

  
  

The net result is a loss of muscle tissue, which might offset some of the metabolic benefits gained from fat loss and potentially increase the risk of frailty, especially in older adults.

Myostatin Inhibition as a Protective Strategy

The future may lie in combining fat-burning drugs like Ozempic with muscle-preserving therapies.

Several pharmaceutical and biotech companies are running clinical trials combining GLP-1 therapies with myostatin inhibitors to test this approach—not just in obesity, but in serious diseases like Duchenne muscular dystrophy and spinal muscular atrophy.

Myostatin is a myokine that negatively regulates muscle growth. Myostatin functions by binding to activin receptors on muscle cells, suppressing satellite cell activation and protein synthesis pathways. In animal models and early human studies, inhibition of myostatin induces significant increases in muscle mass and strength.

Antibodies that bind myostatin or block its access to its receptor prevent the ability of myostatin to decrease muscle mass.

Loss of myostatin function can be so profound that it can create "super" humans and animals. Naturally occurring or laboratory generated genetic loss of myostatin leads to animals with substantially greater muscle mass. 

Combining GLP-1RAs with myostatin inhibitors may make it possible to achieve the best of both worlds: substantial fat loss without sacrificing lean mass.

If animal studies and early clinical trials are any indication, we are not far off.