GLP-1RAs Cut Adiposity, But High-Dose Liraglutide, Semaglutide, Tirzepatide Decrease Lean Mass

The global prevalence of overweight and obesity, often co-occurring with Type 2 Diabetes (T2D), necessitates effective therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as powerful tools for weight management and glycemic control. While their efficacy in reducing overall body weight is well-established, a critical gap remains in understanding their comparative effects on specific body composition metrics, particularly the preservation of lean muscle mass versus fat loss. This network meta-analysis addresses this by directly comparing individual GLP-1RAs on various fat and lean tissue parameters.

Researchers conducted a systematic review and frequentist network meta-analysis of 43 unique randomized controlled trials (RCTs) involving 3379 participants. The search spanned six electronic databases and grey literature up to November 3, 2025, identifying studies on individual GLP-1RAs in adults with overweight or obesity, with or without T2D. Primary outcomes included changes in total body fat (%), fat mass (kg), visceral adipose tissue (VAT) area (cm²), subcutaneous adipose tissue (SAT) area (cm²), liver fat content (%), total lean tissue (%), and lean mass (kg). A random-effects model was used, reporting standardized mean differences (SMDs), with evidence certainty assessed via Confidence in Network Meta-Analysis.

The analysis of 43 RCTs comparing 17 different GLP-1RA interventions/dosages against control groups revealed significant improvements in adiposity. Subcutaneously administered GLP-1RAs were more efficacious than control in decreasing total body fat, fat mass, VAT, SAT, and liver fat from baseline. No significant differences were observed for changes in total lean tissue. However, specific high-dose GLP-1RAs demonstrated unfavorable effects on lean mass:

Liraglutide 1.8 mg/day, semaglutide 1.0 mg-weekly, and tirzepatide 15 mg-weekly significantly decreased lean mass from baseline, with SMDs ranging from -1.09 to -0.50.

These findings highlight a dose-dependent impact on lean mass, particularly with higher therapeutic doses of these agents, despite their overall benefits in reducing excess adiposity.