Beyond weight loss: a narrative review of tirzepatide's impact on muscle and lean mass in people with overweight and obesity.

Tirzepatide, a dual glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, has demonstrated substantial efficacy for weight loss in individuals with overweight and obesity. However, the extent to which this weight reduction affects lean mass remains unclear. This review evaluates current evidence on the impact of tirzepatide on body composition, with a particular focus on changes in lean mass and its proxy measures. A structured literature search identified ten studies, including randomized controlled trials, observational studies and modelling analyses, encompassing diverse populations with and without type 2 diabetes mellitus. Across studies, tirzepatide consistently produced large, dose-dependent reductions in body weight. These reductions were predominantly attributable to fat mass, although decreases in lean mass, fat-free mass or skeletal muscle mass were observed in all studies. The proportion of total weight loss attributable to lean mass generally ranged from 10% to 30%, broadly aligning with expected physiological responses to weight loss. However, substantial heterogeneity in study design, population characteristics, and body composition assessment methods limits the ability to draw definitive conclusions. Most studies relied on indirect measures such as bioelectrical impedance analysis, with limited use of dual-energy X-ray absorptiometry. Importantly, functional outcomes were not assessed, and the clinical significance of observed lean mass reductions remains uncertain. Overall, tirzepatide appears to promote preferential fat loss, though some loss of lean mass occurs. Strategies such as resistance training and adequate protein intake may help mitigate potential adverse effects on muscle mass during treatment.