Summary
A recent medRxiv preprint comparing semaglutide (e.g., Ozempic, Wegovy) and tirzepatide (e.g., Mounjaro, Zepbound) found that people starting tirzepatide experienced modestly greater losses of lean body mass than those starting semaglutide. The study has not yet been peer reviewed.
Study design and main findings
– The analysis included 7,965 people newly prescribed a GLP-1 receptor agonist: 6,196 began semaglutide and 1,769 began tirzepatide.
– Lean body mass was measured before treatment and during follow-up after the first prescription.
– Tirzepatide users lost more lean mass than semaglutide users: about 1.1% greater loss during the first 3 months, rising to around 2% greater loss by 12 months.
– Roughly 10% of tirzepatide users reached a combined threshold of ≥20% total weight loss and ≥5% lean mass loss; about 7% of semaglutide users met those same thresholds.
Context and interpretation
– Lean body mass includes muscle, connective tissue, and other nonfat tissues that support metabolism, strength, and physical function.
– Because tirzepatide tends to produce larger overall weight loss, a greater relative loss of lean mass is biologically plausible: more aggressive weight loss commonly includes some muscle loss as well as fat. As Jeffrey Lee, MD (not involved in the study) explained, faster or larger weight loss increases the likelihood that some of the loss will be muscle rather than only fat.
– The findings are from a preprint and should be interpreted cautiously until peer review and further replication.
Factors associated with greater lean mass loss
– Higher medication doses and longer treatment duration
– Reduced ability or tolerance for exercise while taking the medication
– Pre-existing musculoskeletal conditions or lower baseline muscle mass
Strategies to preserve muscle while taking GLP-1 drugs
– Resistance (strength) training: regular strength exercise is the most effective way to signal the body to retain muscle during calorie deficit.
– Adequate protein intake: meeting protein needs supports muscle maintenance.
– Gradual weight loss and careful dose titration: slower, monitored weight loss tends to spare more lean mass than rapid loss.
– Monitor function and body composition: clinicians and patients can track strength, physical function, and, when available, body composition measures to detect excessive muscle loss early.
Bottom line
Tirzepatide appears to be associated with slightly greater lean body mass loss than semaglutide, likely because it often produces larger overall weight reductions. Patients considering or using GLP-1 medications should prioritize resistance training, sufficient protein intake, and monitored, gradual weight loss to reduce the risk of losing muscle. Discuss individual risks and strategies with a clinician, especially if there are musculoskeletal issues or concerns about strength and function.