Lean Mass Changes With Incretin Therapy Versus Lifestyle Intervention: A Systematic Review and Meta‐Analysis of Randomised Controlled Trials

ABSTRACT Aims To compare lean mass changes between incretin‐based therapies (GLP‐1 receptor agonists and dual GLP‐1/GIP agonists) and intensive lifestyle interventions in adults with overweight or obesity, and to determine whether the proportion of total weight lost as lean mass differs between these treatment modalities. Materials and Methods PubMed, Embase, Cochrane CENTRAL, and Web of Science were searched from inception through 20 January 2026. Randomised controlled trials of semaglutide, tirzepatide, liraglutide or lifestyle interventions reporting body composition outcomes measured by dual‐energy X‐ray absorptiometry or magnetic resonance imaging were included. The co‐primary outcomes were the absolute change in lean mass (kg) and the proportion of total weight loss attributable to lean mass. Data were pooled using random‐effects models. Risk of bias was assessed using Cochrane RoB 2, and certainty of evidence was evaluated using GRADE. Results Twenty randomised controlled trials (RCTs) comprising 15 782 participants met inclusion criteria. Lean mass constituted 25%–39% of total weight lost with incretin agonists: semaglutide (35.2% [95% CI: 31.5–38.9]), tirzepatide (25.4% [22.8–28.0]) and liraglutide (26.8% [23.1–30.5]). Lifestyle interventions showed comparable proportional lean mass loss (26.2% [24.1–28.3]; p = 0.42 for comparison), while lifestyle plus resistance training demonstrated the most favourable profile (17.5% [14.2–20.8]). Heterogeneity was moderate ( I 2 = 68%). No publication bias was detected (Egger's test p = 0.23). Conclusions Lean mass loss during significant weight reduction is substantial, and the proportion of weight lost as lean mass is broadly comparable between incretin‐based pharmacotherapy and lifestyle interventions. Muscle mass can be significantly preserved by integrating resistance training, adequate protein intake, and body composition monitoring into weight‐loss treatment programs.