Effect of Incretin-Based and Nonpharmacologic Weight Loss on Body Composition : A Systematic Review.
Level 1 - systematic review of randomized trials
Systematic review of randomized controlled trials
PubMed 41996180 · doi:10.7326/ANNALS-25-00478
What was done
A systematic review of six databases and ClinicalTrials.gov (January 2003 to February 2026) evaluated randomized controlled trials assessing body composition changes from incretin therapies (liraglutide, semaglutide, tirzepatide, or dulaglutide) in adults with obesity. Outcomes included changes in fat mass, fat-free mass (FFM), lean soft tissue (LST), skeletal muscle, and visceral adiposity measured by bioelectrical impedance analysis (BIA), dual-energy x-ray absorptiometry (DXA), CT, or MRI. Prespecified benchmarks for expected muscle-related loss were set at approximately 25% of total weight loss for FFM or LST (BIA or DXA) and approximately 15% for skeletal muscle (CT or MRI).
What was found
The review included 35 primary RCTs (median duration 26 weeks; median of 78 participants; mean participant age 20 to 63.7 years; mean BMI 27.9 to 41.6 kg/m²). Only 42.9% were at low risk of bias, and 10 (28.6%) prespecified body composition as a primary outcome. Across all incretin arms, the median proportion of total weight loss attributable to reductions in muscle-based indices was 28.3% (IQR, 15.9% to 39.9%), with 65% exceeding the 25% benchmark. For BIA or DXA, median muscle-related loss was approximately 29% of weight loss (IQR, 16.6% to 43.1%; 67% exceeded benchmark); for CT or MRI, median loss was 25.3% (IQR, 16.7% to 27.2%; two thirds exceeded benchmark). In 13 comparator groups with weight loss (median weight change -2.5%), 38% exceeded benchmarks. Heterogeneity precluded meta-analysis.
Why it matters
This review demonstrates that lean and muscle tissue loss during incretin therapy frequently exceeds standard benchmark proportions. It underscores the need to determine whether these body composition shifts impair functional capacity or long-term metabolic health.
Limits
Substantial heterogeneity in body composition assessment methods and reporting precluded meta-analysis. Fewer than half of included studies (42.9%) were at low risk of bias, and only 28.6% prespecified body composition as a primary endpoint. Trials were relatively small (median sample size 78) and short (median duration 26 weeks), and none measured objective physical function outcomes.
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- partial During aggressive caloric restriction or bariatric surgery without resistance training or high protein intake, approximately 40% of the weight lost is muscle.