Abstract / Summary
Incretin-based pharmacotherapies produce substantial weight loss, but their comparative effects on lean tissue remain incompletely characterized.We systematically reviewed randomized controlled trials in adults with overweight, obesity, and/or type 2 diabetes.The prospectively registered primary outcome was the between-group difference in relative percentage change from baseline in total lean body mass measured by dual-energy X-ray absorptiometry (DXA) at 48 to <80 weeks; absolute DXA change in kilograms was the key secondary outcome.The auditable record-level dataset comprised 6,526 imported records from PubMed and ClinicalTrials.gov;after the removal of 250 within-PubMed duplicates, 6,276 records were screened, and 52 trial families met review-level eligibility.Three direct contrasts had defensible precision for the registered primary outcome: pooled tirzepatide versus placebo, -8.3 percentage points (95% confidence interval {CI}: -10.6 to -6.1); semaglutide 1.0 mg versus placebo, -3.81 (-6.57 to -1.06); and semaglutide 2.4 mg versus placebo, -6.06 (-8.79 to -3.33).Because the two BELIEVE semaglutide contrasts shared a placebo group and their joint covariance was unavailable, they were not treated as independent edges in a single dose-specific network meta-analysis (NMA).Separate placebo-anchored sensitivity comparisons of pooled tirzepatide versus semaglutide were -4.49percentage points (95% CI: -8.05 to -0.93) for semaglutide 1.0 mg and -2.24 (-5.78 to 1.30) for semaglutide 2.4 mg; both were graded very low confidence.For the key secondary absolute DXA outcome, mean differences versus placebo were -3.43 kg (95% CI: -4.74 to -2.13) for semaglutide 2.4 mg, -4.40 kg (-5.60 to -3.20) for pooled tirzepatide, and -5.90 kg (-7.28 to -4.52) for mazdutide 9 mg.DXAderived lean mass is not synonymous with skeletal-muscle mass or function, and these reductions should not by themselves be interpreted as evidence of sarcopenia or clinically harmful muscle loss.Randomized evidence therefore supports measurable lean-mass loss during incretin-associated weight reduction, but sparse network geometry, heterogeneous estimands, selected body-composition substudies, and incomplete reporting preclude a reliable comparative treatment ranking.