Lean mass loss on GLP-1 drugs, and the myostatin drugs trying to prevent it

Rapid weight loss costs muscle as well as fat. In the DEXA substudy of STEP 1 (140 participants), people on semaglutide lost 15 percent of body weight over 68 weeks, and roughly 40 percent of what they lost was lean mass [1]. In the SURMOUNT-1 DEXA substudy (160 participants), about 25 percent of the weight lost on tirzepatide was lean mass, the same proportion as on placebo [2]. Lean mass on a scan includes water, glycogen, and organ tissue as well as muscle, so these numbers overstate muscle loss, but they are not zero. For an older adult, the trade can mean weaker legs, worse balance, and less reserve in an illness. Two responses exist. The first is behavioral: resistance training and adequate protein while losing weight. In a 2018 meta-analysis of six trials in older adults with obesity, resistance training prevented 93.5 percent of the lean mass loss caused by calorie restriction [3], and a 2016 meta-analysis found older adults on higher-protein diets kept more lean mass during weight loss [4]. The second response is pharmacologic, and it is producing a strange result.

The target

Myostatin is a signal muscle cells release to limit their own growth. Mice with the gene knocked out have individual muscles two to three times normal weight [5], and a child born in 2000 with a loss-of-function mutation in both copies had gross muscle hypertrophy and no detectable myostatin in his blood [6]. That made the pathway an obvious drug target. Blocking it should, in theory, preserve or add muscle. The open question has always been whether the added mass does anything.

What they did: EMBRAZE

Apitegromab is an antibody that blocks myostatin activation. In the Phase 2 EMBRAZE trial, 102 adults with overweight or obesity took tirzepatide (up to 15 mg weekly) for weight loss and were randomized to apitegromab 10 mg/kg every four weeks or placebo for 24 weeks [7]. Both groups lost a similar amount of weight, 12.3 percent with apitegromab and 13.4 percent with placebo [8]. The composition differed. The apitegromab group lost 1.6 kg of lean mass and 8.5 kg of fat; the placebo group lost 3.5 kg of lean mass and 8.0 kg of fat. Lean mass was 14.6 percent of the weight lost on the drug, versus 30.2 percent on placebo, a difference of 1.9 kg (p = 0.001) [7, 8].

What they found

By body composition, the drug did its job. By function, it did not show up. Grip strength and sit-to-stand tests were exploratory endpoints, and neither differed significantly between groups at 24 weeks; the authors also reported no clear improvement in cardiometabolic measures [7]. An extra 1.9 kg of preserved lean mass bought no measurable strength over six months. Possible explanations include the short trial, the relatively young participants, and the gap between DEXA lean mass and actual contractile muscle.

The pattern repeats: bimagrumab

Bimagrumab blocks the activin type II receptors that myostatin and related signals act through. In the Phase 2 BELIEVE trial, 507 adults with obesity were randomized across nine arms for 48 weeks [9]. At 48 weeks, high-dose bimagrumab with semaglutide 2.4 mg produced 17.8 kg of weight loss, versus 14.2 kg on semaglutide alone, 9.3 kg on bimagrumab alone, and 3.3 kg on placebo. About 92 percent of the combination group's loss was fat, against 76 percent for semaglutide alone, and bimagrumab alone raised lean mass by about 2.5 percent while fat fell [9, 10]. The trial's primary endpoint was weight; no functional benefit has been reported. Side effects were higher with bimagrumab: muscle spasms and acne were more common, and 14 to 21 percent of bimagrumab-treated participants stopped for adverse events, versus 3.6 percent on placebo [9].

Earlier bimagrumab trials in muscle disease and in frail older adults tell the same story. A 14-patient pilot in sporadic inclusion body myositis reported more thigh muscle on MRI and a better six-minute walk at 16 weeks [11], but the 52-week RESILIENT trial that followed did not improve six-minute walk distance at any dose [12], and its two-year extension found no mobility benefit either [13]. In 180 adults aged 70 and older with sarcopenia, six months of bimagrumab raised lean mass by 7 percent versus 1 percent on placebo, yet the physical performance score (1.34 versus 1.03 points), gait speed (0.14 versus 0.11 m/s), and six-minute walk (24.6 versus 14.3 m) all improved similarly in both groups, which both received diet advice and a home exercise program [14].

What the scan does not measure

A DEXA scan reports lean mass, which includes water and connective tissue along with contractile muscle. Strength depends on fiber quality, nervous system recruitment, and tendons, none of which the scan reports. Across every myostatin-pathway trial published so far, the drug has added or preserved mass on the scan without improving a functional endpoint such as chair stands, gait speed, grip strength, or walk distance. For patients losing weight now, resistance training and protein have functional evidence behind them [3, 4]. A muscle drug will have earned a place when it improves one of those functional measures in a trial designed to detect it.

Sources

1. Wilding JPH, Batterham RL, Calanna S, et al. Impact of semaglutide on body composition in adults with overweight or obesity: exploratory analysis of the STEP 1 study. J Endocr Soc. 2021;5(Suppl 1):A16-A17. https://doi.org/10.1210/jendso/bvab048.030
2. Look M, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study of adults with obesity or overweight. Diabetes Obes Metab. 2025;27:2720. https://doi.org/10.1111/dom.16275
3. Sardeli AV, Komatsu TR, Mori MA, Gáspari AF, Chacon-Mikahil MPT. Resistance training prevents muscle loss induced by caloric restriction in obese elderly individuals: a systematic review and meta-analysis. Nutrients. 2018;10(4):423. https://doi.org/10.3390/nu10040423
4. Kim JE, O'Connor LE, Sands LP, Slebodnik MB, Campbell WW. Effects of dietary protein intake on body composition changes after weight loss in older adults: a systematic review and meta-analysis. Nutr Rev. 2016;74(3):210-224. https://doi.org/10.1093/nutrit/nuv065
5. McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83-90. https://doi.org/10.1038/387083a0
6. Schuelke M, Wagner KR, Stolz LE, et al. Myostatin mutation associated with gross muscle hypertrophy in a child. N Engl J Med. 2004;350(26):2682-2688.
7. Pratley RE, et al. Apitegromab with tirzepatide for preservation of lean mass during weight loss (EMBRAZE): a randomized phase 2 trial. Nat Med. 2026. https://doi.org/10.1038/s41591-026-04440-4
8. Scholar Rock. Scholar Rock reports positive Phase 2 EMBRAZE trial results demonstrating statistically significant preservation of lean mass with apitegromab during tirzepatide-induced weight loss. Press release, June 18, 2025. https://www.businesswire.com/news/home/20250618254394/en/
9. Heymsfield SB, Aronne LJ, Montgomery P, et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial (BELIEVE). Nat Med. 2026. https://doi.org/10.1038/s41591-026-04204-0
10. Pennington Biomedical Research Center. Combination GLP-1 therapy shows fat mass loss while preserving lean mass in adults with obesity. Press release, March 2026. https://www.pbrc.edu/news/media/2026/semaglutide_and_bimagrumab.aspx
11. Amato AA, Sivakumar K, Goyal N, et al. Treatment of sporadic inclusion body myositis with bimagrumab. Neurology. 2014;83(24):2239-2246. https://doi.org/10.1212/WNL.0000000000001070
12. Hanna MG, Badrising UA, Benveniste O, et al. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019;18(9):834-844. https://doi.org/10.1016/S1474-4422(19)30200-5
13. Amato AA, Hanna MG, Machado PM, et al. Efficacy and safety of bimagrumab in sporadic inclusion body myositis: long-term extension of RESILIENT. Neurology. 2021;96(12):e1595-e1607. https://doi.org/10.1212/WNL.0000000000011626
14. Rooks D, Swan T, Goswami B, et al. Bimagrumab vs optimized standard of care for treatment of sarcopenia in community-dwelling older adults: a randomized clinical trial. JAMA Netw Open. 2020;3(10):e2020836. https://doi.org/10.1001/jamanetworkopen.2020.20836