Glucagon-like peptide-1 receptor agonists and muscle health: potential role in sarcopenia prevention and treatment

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as a cornerstone therapy for weight loss and glycemic control in type 2 diabetes mellitus and obesity. Moreover, robust cardiometabolic benefits and favorable safety profiles have positioned GLP-1RAs at the forefront of modern obesity pharmacotherapy. However, findings from large-scale trials (eg, SUSTAIN, STEP, SURPASS) have raised concerns that a significant proportion of the weight loss achieved with GLP-1RA treatment may derive from lean body mass-particularly skeletal muscle-which could be detrimental in populations already at risk for sarcopenia. However, emerging preclinical evidence suggests that GLP-1RAs may directly and indirectly influence skeletal muscle through anti-inflammatory, antioxidant, and mitochondrial-supportive mechanisms. These include modulation of key signaling pathways such as PI3K/Akt/mammalian target of rapamycin (mTOR) and AMP-activated protein kinase-PGC-1α, suppression of proteolytic activity, and promotion of myogenic differentiation. In experimental models of aging, sarcopenic obesity, and chronic disease, GLP-1RAs have shown muscle-preserving properties. Nevertheless, the balance between adipose tissue reduction and lean mass preservation remains incompletely understood in clinical settings. This review examines the existing experimental and clinical evidence and identify critical research directions to determine whether GLP-1RAs confer overall benefit or carry unintended risks for skeletal muscle integrity in the context of weight loss.