Top PubMed Studies on GLP-1 Drugs and Muscle / Lean Mass Loss (2026)

This pre-specified DEXA substudy of SURMOUNT-1 reported body-composition outcomes for 160 of the 2,539 randomized participants. At week 72, tirzepatide reduced total fat mass roughly 33-34% and lean mass roughly 10-11% from baseline, with the fat-to-lean ratio of weight lost approximately 75/25 — meaning about one quarter of lost weight was lean tissue. Visceral adipose tissue dropped roughly 40%. Bone mineral density was preserved. This is the largest randomized DEXA dataset on tirzepatide and provides the canonical reference for the muscle-loss question on Zepbound.

PMID 39996356 ↗NCT04184622 ↗DOI 10.1111/dom.16275 ↗

Coskun and colleagues reported the body-composition substudy of the phase 2 retatrutide trial in adults with type 2 diabetes. At week 36, retatrutide reduced total fat mass dose-dependently with the highest dose producing fat-mass losses substantially greater than lean-mass losses. Lean mass fell roughly 8-12% of the total weight lost — proportionally similar to tirzepatide and semaglutide. Visceral and hepatic fat dropped sharply. Hand-grip strength and physical function were not the primary endpoints, leaving the functional question open, but the fat-preferential pattern matches what SURMOUNT-1 showed for tirzepatide.

PMID 40609566 ↗DOI 10.1016/S2213-8587(25)00092-0 ↗

Although designed as an alcohol-use-disorder trial, the Hendershot 2025 JAMA Psychiatry semaglutide RCT (48 adults, 9 weeks) included DEXA body-composition assessment as an exploratory endpoint, and the small but well-controlled signal it produced has been widely cited as supportive of the broader GLP-1 lean-mass story. Participants on semaglutide lost about 5% of body weight with a fat-to-lean ratio similar to longer obesity trials. The short duration and small sample limit definitive conclusions, but the pattern aligns with the SURMOUNT-1 and retatrutide substudies.

PMID 39937469 ↗DOI 10.1001/jamapsychiatry.2024.4789 ↗

The Lundgren 2021 NEJM trial is the gold-standard randomized comparison of GLP-1 therapy versus exercise versus the combination for weight-loss maintenance. After an 8-week low-calorie-diet run-in, 195 adults were randomized to liraglutide 3.0 mg, supervised exercise, both, or placebo for 52 weeks. The combination arm lost the most weight and preserved the most lean mass — fat-mass loss roughly doubled while lean-mass loss was attenuated compared with liraglutide alone. Established the empirical case that resistance and aerobic exercise during GLP-1 therapy meaningfully shift the fat-to-lean ratio of weight lost.

PMID 33951361 ↗NCT04122716 ↗DOI 10.1056/NEJMoa2028198 ↗

This post-treatment follow-up of the Lundgren 2021 NEJM trial assessed what happens after the supervised exercise and liraglutide are stopped. One year off-treatment, the exercise-alone group maintained the largest share of fat-mass reduction and lean-mass preservation, while the liraglutide-alone group regained the most weight and the combination group fell in between. The finding reframes the muscle-mass debate: discontinuation of pharmacotherapy reverses the favorable body-composition pattern unless exercise habits are sustained. Reinforces the chronic-disease framing of obesity treatment.

PMID 38544798 ↗NCT04122716 ↗DOI 10.1016/j.eclinm.2024.102475 ↗

The Locatelli 2024 Diabetes Care narrative review synthesized the body-composition data across GLP-1 and dual-agonist obesity trials and laid out the rationale for combining incretin therapy with resistance exercise. The review estimates that 25-40% of weight lost on a GLP-1 is lean mass — comparable to diet-induced weight loss but with absolute losses larger because total weight loss is larger. The authors argue that resistance training during pharmacotherapy is the most evidence-supported mitigation strategy and call for dedicated RCTs powered for functional muscle outcomes.

PMID 38687506 ↗DOI 10.2337/dci23-0100 ↗

The Karakasis 2025 Metabolism network meta-analysis pooled body-composition outcomes from RCTs of liraglutide, semaglutide, tirzepatide, and retatrutide. Across the included trials, GLP-1 and co-agonist therapy produced large fat-mass reductions with smaller absolute lean-mass reductions, and the fat-to-lean ratio of weight lost was comparable to diet-induced weight loss. Tirzepatide and retatrutide showed the most favorable ratios. The authors caution that DEXA conflates fat-free mass with skeletal muscle, and that no included trial measured muscle function as a primary endpoint.

PMID 39719170 ↗DOI 10.1016/j.metabol.2024.156113 ↗

The Neeland 2024 Diabetes Obesity and Metabolism review distinguished between adaptive lean-mass loss — proportional to fat-mass loss and physiologically expected — and maladaptive lean-mass loss, which would compromise function and cardiometabolic health. The authors concluded that current GLP-1 trial data falls into the adaptive pattern, with lean-mass percentage of total weight lost similar to historical diet trials. Mitigation strategies discussed include high protein intake (1.2-1.6 g/kg/day), resistance training, slower titration in older adults, and emerging activin-receptor or myostatin-targeting agents.

PMID 38937282 ↗DOI 10.1111/dom.15728 ↗

The Linge 2024 Circulation perspective argued that the alarm over GLP-1 muscle loss has outpaced the evidence. Pooling MRI and DEXA data across STEP, SURMOUNT, and SURPASS substudies, the authors showed thigh-muscle-fat infiltration improves and visceral fat falls disproportionately compared with skeletal muscle volume. The accompanying lean-mass reduction tracks fat-mass reduction proportionally — the expected physiologic response. The piece called for functional outcomes (grip strength, gait speed, lean-mass-for-height index) in future obesity trials rather than DEXA fat-free mass alone.

PMID 39401279 ↗DOI 10.1161/CIRCULATIONAHA.124.067676 ↗

The Nunn 2024 Molecular Metabolism paper provided the mechanistic rationale for combining GLP-1 therapy with activin-receptor blockade — the strategy underlying Eli Lilly bimagrumab and similar muscle-preservation agents in development. In diet-induced obese mice, semaglutide plus an activin-type-II-receptor antibody produced greater fat loss than semaglutide alone while fully preserving skeletal muscle mass. The translational version of this combination is now in phase 2/3 obesity trials and represents the most-watched muscle-preservation strategy for the GLP-1 era. Preclinical only — human RCT data pending.

PMID 38218536 ↗DOI 10.1016/j.molmet.2024.101880 ↗