Across incretin-based therapies — GLP-1 receptor agonists and dual GLP-1/GIP agonists like semaglutide and tirzepatide — weight loss is predominantly fat-driven, yet synthesized clinical and real-world data indicate that roughly 25–39% of total weight lost over 36–72 weeks reflects lean body mass (LBM) reduction. In patients with cardiovascular-kidney-metabolic (CKM) syndrome, where sarcopenia already independently elevates all-cause, cardiovascular, and non-cardiovascular mortality and accelerates disease staging, this lean-mass erosion represents a clinically meaningful but largely unmeasured hazard.
The broader context makes this finding pressing. GLP-1 agonists are now prescribed at extraordinary scale across cardiometabolic indications, yet most pivotal trials — SURMOUNT, STEP, FLOW — were not designed to track muscle mass, strength, or functional trajectories as primary endpoints. The 25–39% LBM figure aligns with what has historically been observed in caloric-restriction weight loss without resistance training, suggesting the mechanism may be dietary-restriction-mediated rather than drug-specific — but that distinction remains unresolved. For older adults, individuals with chronic kidney disease, or those already experiencing protein-energy wasting, even modest LBM loss can tip functional thresholds, increasing fall risk and frailty. This review's call for systematic muscle-health monitoring is clinically warranted and practically urgent. The field needs standardized body-composition endpoints in incretin trials, not as afterthoughts. Until then, clinicians prescribing these agents to high-risk CKM populations should proactively pair therapy with resistance exercise and adequate protein intake.