The new generation of incretin-based therapies are potent anti-obesity medications (AOMs) that offer the first non-surgical treatment for 936 million patients globally suffering from being overweight or obese[1]. However, clinical data suggest that incretin-mimetics could cause a disproportionate decrease in lean body mass (LBM) [2, 3], raising a concern for deterioration of skeletal muscle and acceleration of sarcopenic obesity[4]. Unfortunately, muscle mass and function are not routinely assessed in obesity studies and original data on the matter remains sparse. In this work, we conducted various pre-clinical studies and a proof-of-concept clinical trial to examine how skeletal muscle is affected by AOMs. We found that in mice with diet-induced obesity (DIO), incretin-based therapies result predominantly in a substantial decrease in fat mass alongside a small but significant decrease in LBM. Among the lean tissues, the decrease in liver mass exceeded the change in muscle mass robustly. While absolute muscle mass did decrease, relative muscle mass (i.e., the muscle mass to body weight (BW) ratio) improved significantly. Similarly, we found that absolute muscle strength decreased mildly but increased relative to the BW of mice. The relative preservation of muscle was also associated with marked improvement in running performance. Additionally, during a scenario of extreme muscle wasting (i.e., immobilization), DIO mice on incretin-based therapies did not experience more muscle loss than calorie-matched, pair-fed mice. Finally, in our clinical proof-of-concept trial, patients on AOMs significantly decreased BW, which was accompanied by a mild decrease in absolute LBM but an improvement in relative LBM. Muscle function as indicated by maximum voluntary contraction (MVC) did not decrease. Overall, these data suggest that in middle-aged obese mice and men, incretin-based therapies do cause a mild decrease in absolute muscle mass and strength that is offset by a more pronounced decrease in fat and liver mass, resulting in an improved muscle to BW ratio, function, and mobility.

HTL previously worked for Boehringer Ingelheim (2023-2024) and served as a consultant for Almac Discovery and Actimed Therapeutics. PMT's research contributing to this manuscript was conducted at the University of Pennsylvania while serving as a faculty member (2017-2025). PMT is currently an employee of Eli Lilly and Company; however, the research contributing to this manuscript, as well as the discussion and viewpoints expressed, are not affiliated with, nor endorsed by, Eli Lilly and Company. PMT is acting on their own in the preparation and submission of this manuscript. KB is a co-founder of SinewUS, a tendon loading company and has consulted for food companies such as PepsiCo, Ynsect, Advanced Muscle Technologies, GelTor, Evergrain, and Digestiva.

NCT05606471

NKG was supported by the UC Davis T32 in Pharmacology (T32 GM144303). PMT and EN were supported by the National Institute of Diabetes and Digestive and Kidney Diseases (DK139663). CMTH was supported by the National Institute of Diabetes and Digestive and Kidney Diseases U2C/TL1 LAUNCH program (DK139565).

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

University of Nottingham Faculty of Medicine and Health Sciences Research Ethics Committee (FMHS REC). Approval was obtained prior to recruitment of the first patient to the study. The proof-of-concept clinical trial prospectively received ethical approval from local authorities (East of England, Essex Research Ethics Committee) and was later registered on clinicaltrials.gov (NCT05606471)

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All data produced in the present study are available upon reasonable request to the authors.