Macro partitioning
GLP-1 receptor agonists (semaglutide) and dual GLP-1/GIP agonists (tirzepatide) cause significant lean mass loss during weight loss, with semaglutide losing approximately 45% of total weight as lean mass and tirzepatide losing 25.7%, posing a specific risk of frailty and fractures in older populations.
If you are taking semaglutide or tirzepatide, be aware that a significant portion of your weight loss (up to 45% for semaglutide) comes from lean mass, not just fat. This is especially risky if you are over 60. Discuss strategies to preserve muscle, such as resistance training or potentially newer combination therapies, with your provider.
Of weight lost with semaglutide, approximately 45% is from lean mass, while with tirzepatide, it is 25%. ... Of the total weight loss with semaglutide approximately 45% was lean mass and for tirzepatide it was 25.7%.
Why this rating
Based on Phase 3 substudies (STEP 1, SURMOUNT 1) using DEXA scans, though the paper notes these are not definitive for bone/muscle separation.
Source
New drugs for the treatment of obesity: do we need approaches to preserve muscle mass?
Donna H. Ryan · Reviews in Endocrine and Metabolic Disorders · 2025
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