Both semaglutide and tirzepatide produce substantial lean body mass (LBM) reductions alongside fat loss, yet this narrative review synthesizing randomized controlled trials and observational data concludes that LBM decline is generally proportional to total weight lost—not a signal of direct drug-induced myotoxicity. Tirzepatide shows a distinct advantage over semaglutide by reducing muscle fat infiltration (intramyocellular lipid), improving skeletal muscle composition beyond the scale reading. Semaglutide's effects on strength and physical performance are more heterogeneous, raising particular concern in older or frail patients at baseline sarcopenia risk.
This finding lands at a critical moment. Tens of millions of adults are now on incretin therapies, and the reflex fear that 'muscle is melting' has generated real clinical anxiety and premature discontinuation. The review's central argument—that proportional LBM loss during energy deficit is metabolically normal, not pathological—is an important corrective, aligning with well-established physiology of caloric restriction. The tirzepatide-versus-semaglutide muscle composition distinction deserves independent replication with gold-standard MRI or CT quantification, not just DEXA.
The practical implication is clear and actionable: protein intake at or above 1.2–1.6 g/kg body weight combined with progressive resistance training should be co-prescribed alongside any GLP-1-based regimen, especially in adults over 60. As a narrative review, this paper cannot establish causality and likely reflects publication bias toward positive metabolic outcomes. Still, it consolidates a working clinical framework where muscle quality—not merely mass—becomes the functional outcome that matters.
