Trevogrumab (anti-myostatin) can help preserve lean mass during and after semaglutide-induced weight loss
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New research presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy, Sept. 28–Oct. 2, and in press at The Lancet shows that trevogrumab, which inhibits a protein that negatively regulates muscle mass, can reduce lean mass loss during semaglutide treatment by 50% compared with semaglutide and placebo.
The study is by Dr. Ofri Mosenzon of Regeneron in Tarrytown, New York; Dr. Julio Rosenstock of the University of Texas Southwestern Medical Center in Dallas; and colleagues. Regeneron, the manufacturer of trevogrumab, sponsored the study.
Rapid weight loss induced by glucagon-like peptide-1 receptor agonists (GLP-1 RAs) is accompanied by pronounced muscle loss. Growth differentiation factor 8 (GDF8), also known as myostatin, is a negative regulator of muscle mass. The researchers explored how antibodies blocking GDF8 (trevogrumab, Trevo) and ActA (garetosmab, Gar) affect semaglutide-induced weight and muscle loss.
The Phase II study was conducted as a two-part trial in participants with obesity (BMI ≥30 kg/m2). In part A, participants treated for 26 weeks with semaglutide (Sema) were randomized to receive concomitant treatment with placebo (Sema+Pbo), high doses of Trevo (Sema+Trevo200mg; Sema+Trevo400mg), or both Trevo and Gar (Sema+Trevo400mg+Gar10mg/kg). Part A also included a subsequent Sema withdrawal period, during which participants received Trevo400mg or placebo for an additional 26 weeks.
Participants in part B were treated with Sema for 52 weeks and randomized to receive concomitant treatment with placebo (Sema+placebo) or lower doses of Trevo (Sema+Trevo25mg; Sema+Trevo75mg). The primary endpoints were percentage changes in lean mass (LM), fat mass (FM) and body weight (BW) from baseline to week 26 (part A; n=599) or week 52 (part B; n=376). An exploratory MRI substudy (n=76) assessed muscle volume in part B.
A total of 975 participants were enrolled. The mean age was 49 years, and the mean BMI was 36.7 kg/m2; 64% (627/975) were female. Lean mass was assessed using dual-energy X-ray absorptiometry (DXA), and skeletal muscle was assessed using magnetic resonance imaging (MRI). MRI directly measured skeletal muscle volume, isolating the effect on muscle specifically rather than lean mass more broadly.
Part A confirmed a substantial decrease in LM in the Sema+Pbo group at week 26 (-6.6%). Adding trevogrumab reduced that loss by roughly half, to about 3.4% with the 200mg dose and 3.9% with the 400mg dose. The combination with garetosmab reduced it further, to about 2.1%.
At the end of the initial 26-week treatment period, all participants discontinued Sema and were randomized to Trevo400mg or Pbo for an additional 26 weeks. Among those who were originally treated with semaglutide and switched to Pbo for the final 26 weeks, the mean percentage change in LM from baseline at week 52 was -2.4%, still below baseline.
Those who switched to Trevo400mg had a mean percentage change from baseline of +0.4%—a difference of 2.8 percentage points between the trevogrumab and placebo groups. FM and BW remained below baseline in both groups.
In part B, the percentage change in LM from baseline to week 52 was -7.3% for Sema+Pbo. The LM ETD for Sema+Trevo25mg versus Sema+Pbo was +1.5%, which was not statistically significant. It was +3.1% for Sema+Trevo75mg, which was statistically significant.
Sema+Trevo25mg/75mg/200mg/400mg was generally well tolerated, with a safety profile comparable to Sema+Pbo. Sema+Trevo400mg+Gar10mg/kg had a substantially higher incidence of serious adverse events and treatment discontinuations than the other part A arms. Rates of serious adverse events and treatment discontinuations, respectively, through each part's primary endpoint were:
Part A (weeks 0–26)
For Sema+Pbo, the rates were 0.7% (1/151) and 4.6% (7/151). For Sema+Trevo 200mg, they were 0.7% (1/148) and 5.4% (8/148). For Sema+Trevo 400mg, they were 1.3% (2/151) and 10.6% (16/151). For Sema+Trevo 400mg+Gar 10mg/kg, they were 9% (14/149) and 32% (48/149).
Part B (week 52)
For Sema+Pbo, the rates were 5.3% (4/76) and 15.8% (12/76). For Sema+Trevo 25mg, they were 1.4% (2/150) and 6.8% (10/150). For Sema+Trevo 75mg, they were 3.3% (5/150) and 10.5% (16/150).
Although the incidence of the most commonly reported adverse events was generally comparable across treatment arms, muscle spasms occurred more frequently in the Sema+Trevo400mg+Gar10mg/kg arm (41%, 61/149) than in the Sema+Trevo200mg/400mg arms (8%, 23/299) and Sema+Pbo arm (5%, 7/151). Most of these events were mild to moderate. Two deaths occurred during the study, both in the Sema+Trevo400mg+Gar10mg/kg arm; a causal association between treatment and the deaths has not been identified.
In the MRI substudy of part B, which evaluated thigh muscle volume, Trevo co-treatment reduced muscle loss by 69%–72% compared with Sema+Pbo. Trevogrumab attenuated lean mass loss by ~50%, as measured by DXA, and muscle volume loss by ~70%, as measured by MRI, compared with Sema alone.
The authors note that although the combination of trevogrumab and garetosmab provided numerically greater lean mass preservation than trevogrumab alone, it was not well tolerated because of the high adverse event rate, including muscle spasms, in the garetosmab group.
Trevogrumab alone showed greater preservation of lean mass than has been reported with GLP-1 RA combined with moderate-to-vigorous-intensity exercise, though differences in trial design preclude direct comparison. Individuals meeting the imaging component of the sarcopenia definition for low lean mass were older on average than those who did not (53 years versus 46 years).
They presumably had a greater need for muscle preservation, experienced greater lean mass loss with semaglutide treatment and had numerically greater preservation with trevogrumab co-treatment. In this subgroup, trevogrumab performed as well as the combination with garetosmab.
Concerns have been raised about the composition of weight people may regain if they stop GLP-1 RA treatment—and whether it could be mostly fat with little lean mass. The authors say, "Treatment with Trevo following cessation of GLP-1 RA during the subsequent period of weight regain suggests that Trevo has the potential to help regain the lean mass loss that occurred during weight loss."
They conclude, "These findings strengthen evidence supporting selective myostatin inhibition as an adjunct to GLP-1 RA therapy to improve body composition during pharmacological weight loss with an acceptable safety profile. These results suggest that obesity treatment may be further optimized by considering not only the magnitude of weight loss but also lean mass and skeletal muscle preservation.
"Whether preservation of muscle during intentional weight loss translates into long-term improvements in physical function, metabolic health, and clinical outcomes, particularly in high-risk individuals vulnerable to functional decline, requires further investigation."
Publication details
The Lancet (2026)
Journal information: The Lancet
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Citation: Trevogrumab (anti-myostatin) can help preserve lean mass during and after semaglutide-induced weight loss (2026, September 30) retrieved 1 October 2026 from https://medicalxpress.com/news/2026-09-trevogrumab-anti-myostatin-mass-semaglutide.html This document is subject to copyright. Apart from any fair dealing for the purpose of private study or research, no part may be reproduced without the written permission. The content is provided for information purposes only.