PubMed17 Apr 2026Annals of internal medicine● 7/10i Effect of Incretin-Based and Nonpharmacologic Weight Loss on Body Composition : A Systematic Review.
Batsis JA, Gavras A, Gross DC, Cheever CR, Da Silva BR et al.
Incretin-based therapies caused muscle-related losses that exceeded expected benchmarks in two-thirds of studies, with a median 34.9% of total weight loss coming from muscle-based tissue rather than the expected 25% threshold. Systematic review of 36 randomized controlled trials with median 71 participants and 26-week duration across liraglutide, semaglutide, tirzepatide, and dulaglutide. This quantifies a clinically important side effect profile that has received limited systematic evaluation despite widespread prescribing of these agents for weight management. The analysis was limited by heterogeneous measurement methods that prevented meta-analysis.
Strategic Signal
Medical affairs teams will face intensified safety questions from endocrinologists and obesity specialists about muscle preservation strategies, potentially driving combination approaches with resistance training protocols or anabolic agents. Regulatory agencies may require more comprehensive body composition endpoints in future obesity trials, following the pattern established for osteoporosis drugs where bone density became mandatory. Competitive messaging will likely shift toward muscle-sparing profiles, with companies potentially developing companion diagnostics or co-therapies to address this limitation.
Original Abstract
BACKGROUND: Incretin-based therapies induce substantial weight loss and are widely prescribed; disproportionate losses in fat-free mass (FFM) and skeletal muscle are a concern. PURPOSE: To evaluate body composition changes associated with incretin therapies in adults with obesity. DATA SOURCES: Scopus, Embase (Elsevier), PubMed (National Institutes of Health, National Library of Medicine), CINAHL, PsycINFO (EBSCOhost), and ClinicalTrials.gov from January 2003 to February 2026. STUDY SELECTION: English-language randomized controlled trials reporting body composition outcomes of liraglutide, semaglutide, tirzepatide, or dulaglutide therapy in adults (aged ≥18 years). DATA EXTRACTION: Primary outcomes included changes in fat mass, FFM, lean soft tissue (LST), muscle-related indices, and visceral adiposity measured by bioelectrical impedance analysis (BIA), dual-energy x-ray absorptiometry (DXA), computed tomography (CT), or magnetic resonance imaging (MRI). Prespecified benchmarks were applied to contextualize expected muscle-related losses (about 25% of total weight loss for FFM or LST derived from BIA or DXA, and about 15% for skeletal muscle measured by CT or MRI). DATA SYNTHESIS: Among 8102 titles and abstracts, 36 primary studies met criteria (median duration, 26 weeks; median of 71 participants); 41.7% were at low risk of bias and 10 (27.8%) prespecified body composition as a primary outcome. Mean participant age ranged from 20 to 63.7 years and mean body mass index from 27.9 to 41.6 kg/m2. Weight loss was consistently larger in the incretin intervention groups than in placebo or lifestyle intervention comparators and was consistently accompanied by reductions in total fat mass and visceral adiposity. The degree of muscle-based losses varied widely; no study reported objective physical function outcomes. Within the incretin groups across agents and measurement methods, the median proportion of total weight loss attributable to reductions in muscle-based indices was 34.9% (IQR, 19.0% to 48.2%), with 68% exceeding the benchmark of about 25%; among studies using BIA or DXA, the median was about 34.9% (IQR, 17.0% to 46.9%) of total weight loss, with 65% exceeding the 25% benchmark, and in studies using CT or MRI, the median was about 35.8% (IQR, 29.8% to 50.4%), all exceeding the 15% benchmark. In contrast, the 14 studies reporting weight loss in the lifestyle or placebo comparator groups accounted for a median weight loss of -2.4% (IQR, -4.4% to 1.0%), 50% of which exceeded the respective benchmark. LIMITATION: Heterogeneous body composition methods and reporting precluded meta-analysis. CONCLUSION: Loss of muscle-related indices exceeded prespecified benchmarks in two thirds of incretin-based interventions and half of nonpharmacologic interventions that produced weight loss. Future trials are needed to better understand mechanisms underlying these changes and their clinical implications. PRIMARY FUNDING SOURCE: None. (Open Science Framework: https://doi.org/10.17605/OSF.IO/S3A5E).