DXA-measured lean and fat mass differences with incretin-based therapy versus comparators: a meta-analysis of phase 3 trials

Background Glucagon-like peptide-1 (GLP-1) receptor agonists and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists produce substantial weight loss, part of which is lean tissue. We quantified comparator-adjusted differences in dual-energy X-ray absorptiometry (DXA)-measured lean body mass (LBM) and fat mass in phase 3 trials in adults with obesity or type 2 diabetes (T2D). Methods Meta-analysis of phase 3 randomized trials of GLP-1 or dual GIP/GLP-1 receptor agonists versus placebo or an active comparator for ≥ 24 weeks with DXA-derived LBM and fat mass. PubMed, Scopus and Cochrane CENTRAL were searched to 23 March 2026 (updated 4 September 2026) and Web of Science on 6 September 2026. Mean differences (MD) were pooled (REML, Hartung–Knapp–Sidik–Jonkman) separately for placebo-controlled trials in obesity and active-comparator trials in T2D, the five-trial estimate being a secondary summary; leave-one-out and Bayesian sensitivity analyses, Risk of Bias 2.0 and GRADE were applied. Extracted values were independently audited. Results Five trials (569 adults) were included. In the two placebo-controlled obesity trials (semaglutide 2.4 mg, tirzepatide; 68–72 weeks), LBM was 3.43 and 4.40 kg lower than with placebo (pooled MD − 3.95 kg; 95% CI − 10.10 to + 2.19), fat mass 6.99 and 12.30 kg lower. In the three active-comparator T2D trials (semaglutide 1.0 mg, liraglutide 1.8 mg; 26–52 weeks) LBM differences were − 0.78, − 2.82 and − 0.96 kg (pooled MD − 1.53 kg; 95% CI − 4.38 to + 1.32; I² = 73%). The five-trial LBM difference was − 2.49 kg (95% CI − 4.45 to − 0.53; prediction interval − 6.97 to + 2.00 kg) but the interval included zero when any of three trials was omitted; the fat-mass estimate (− 5.29 kg; 95% CI − 10.78 to + 0.21) was compatible with no difference. Certainty was very low. Conclusions All trial-level point estimates favored lower DXA-measured LBM with incretin-based therapy than with the comparator, by 3.4 to 4.4 kg versus placebo at obesity doses and 0.8 to 2.8 kg versus active comparators in T2D, although several trial and both stratum intervals included zero. The comparisons differ in population, drug, dose, comparator and analysis strategy, the pooled difference is fragile, and heterogeneity cannot be explained. DXA lean mass is a composite compartment of unknown functional significance. Trial registration PROSPERO CRD420261323497 (registered 23 March 2026).