Greater lean-body-mass decline with tirzepatide than semaglutide in routine care, revealed by body-composition digital phenotyping

GLP-1 receptor agonists induce substantial weight loss, but their effects on lean body mass (LBM) remain incompletely understood. We analyzed 670,422 first-time semaglutide or tirzepatide users using an EHR-linked, LLM-enabled body-composition phenotyping pipeline; 7965 had paired pre- and post-treatment measurements over 12 months. Tirzepatide was associated with greater relative LBM loss than semaglutide, with a 12-month difference of −2.1 percentage points (95% CI −3.8 to −0.3). This difference disappeared after adjustment for concurrent weight change (−0.1, 95% CI −1.6 to 1.4), and LBM accounted for approximately 20% of weight lost with either agent. The exploratory Depletive GLP-1 phenotype (>20% total body weight loss with >5% LBM loss) was more common with tirzepatide (10.3% vs 6.7%, P < 0.001), whereas the Prime phenotype (<5% LBM loss with >10% total body weight loss) occurred similarly (11.8% vs 12.3%, P = 0.66). Reduced exercise tolerance was documented 7.2 and 11.1 percentage points more often in semaglutide- and tirzepatide-treated patients with greater LBM loss, respectively. In this observational study, LBM loss scaled with the depth of weight loss on both agents and varied widely between patients, supporting prospective evaluation of body-composition outcomes alongside weight loss in incretin-based therapy.