Real-World Study Compares Lean Mass Changes in Semaglutide and Tirzepatide Users
Recent findings from Nature Health Sciences indicate that popular weight-loss medications lead to reductions in lean body mass alongside fat loss, with tirzepatide showing greater relative decreases due to more substantial overall weight reduction.
🔬ResearchPhoto: Nature Health Sciences
Key points
- Real-world study analyzed over 670,000 first-time semaglutide or tirzepatide users.
- Lean body mass accounted for roughly 20% of total weight lost on both medications.
- Tirzepatide showed greater relative LBM loss due to deeper overall weight reduction.
A recent observational study published in npj Exercise Medicine and Health evaluated the real-world body-composition changes among 670,422 first-time users of semaglutide or tirzepatide. By utilizing an electronic health record-linked phenotyping pipeline, researchers assessed paired pre- and post-treatment measurements over a 12-month period to understand how these popular incretin-based therapies impact lean body mass (LBM).
The investigation revealed that tirzepatide was initially linked to a greater relative reduction in lean body mass compared to semaglutide, with a 12-month difference of minus 2.1 percentage points. However, this discrepancy largely vanished after researchers adjusted for concurrent total weight change. For both medications, lean body mass accounted for approximately one-fifth of the total weight lost. The authors emphasize that lean body mass encompasses body water and non-muscle tissue alongside muscle, meaning these figures do not exclusively represent skeletal muscle loss.
Because this was an observational study relying on routine clinical records, the findings carry inherent limitations, including potential variability in patient adherence, measurement timing, and baseline health characteristics. Furthermore, reduced exercise tolerance was noted more frequently in patients who experienced greater lean tissue reductions.
What to know: Both semaglutide and tirzepatide prompt mixed-tissue weight loss, reducing both fat and lean mass in real-world settings. Patients considering or currently taking these medications should consult a healthcare provider for personalized medical advice regarding nutrition, exercise, and long-term metabolic health.
Source Nature Health Sciences — nature.com/articles/s44437-026-00025-y ↗
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