Glucagon-like peptide-1 receptor agonists and muscle: interpreting lean mass changes in clinical care

Skeletal muscle supports mobility and metabolic reserve. Low muscle reserve is common in obesity, type 2 diabetes mellitus (T2DM), and metabolicassociated steatotic liver disease, where myosteatosis and insulin resistance are linked to poorer strength and physical performance. Glucagon-like peptide-1 receptor agonists (GLP1RAs) improve weight and glycemic control, but body composition studies often report reductions in measured lean mass alongside fat mass loss. Interpretation is complicated because lean mass and fat free mass are not direct measures of contractile muscle and are sensitive to hydration and measurement modality, particularly with dual-energy Xray absorptiometry and bioelectrical impedance analysis. A network meta-analysis of 22 randomized trials (n=2258) reported mean reductions of 3.55 kg in body weight, 2.95 kg in fat mass, and 0.86 kg in lean mass, with lean tissue contributing about onequarter of total weight loss. A recent metaanalysis of 38 studies (n=1735) found smaller muscle changes in T2DM (mean reduction: 0.74 kg) than in populations without T2DM (mean reduction: 1.41 kg). In addition, imaging cohorts involving computed tomography show modest declines in muscle area and attenuation after semaglutide. More recently, SEMALEAN study reported 13% weight loss and 19% fat mass loss at 12 months, with early lean mass decline followed by stability, and improved handgrip strength. Clinical decisions should prioritize function over lean mass alone and pair GLP1RA therapy with resistance training and adequate protein intake, with closer monitoring in older adults and other highrisk phenotypes.