The investigational antimyostatin drug trevogrumab not only reduced lean mass loss during treatment with semaglutide but it also increased lean mass during rebound weight gain after semaglutide discontinuation, new results from the phase 2 COURAGE study showed.

In addition, a substudy showed that the effects of lean mass preservation were greater in patients with a lower lean mass at baseline.

This trial “established proof-of-concept for the potential of trevogrumab’s role in obesity management, emphasizing not only the magnitude of weight loss but also improvements in body composition quality,” said co-author Julio Rosenstock, MD, a clinical professor of medicine at The University of Texas Southwestern Medical Center in Dallas, presented the findings at the European Association for the Study of Diabetes (EASD) 2026 Annual Meeting.

A key concern surrounding the significant weight loss observed with GLP-1 receptor agonist (RA) treatment is the accompanying loss of lean muscle mass, with potential losses estimated between 15% and 45%, posing risks for sarcopenia, falls, frailty, and other outcomes.

Furthermore, although weight loss with GLP-1 RAs is typically a combination of fat and lean mass, the rapid regaining of weight known to occur when the drugs are discontinued has been shown to consist primarily of fat, resulting in a potentially greater imbalance of fat and lean mass than may have existed prior to treatment.

Trevogrumab is among an array of drugs being investigated to offset those effects through the neutralization of myostatin, a key protein that inhibits the chemical pathways necessary for muscle development.

COURAGE Part A

A total of 975 patients took part in the study; the mean age was 49 years, mean BMI was 36.7, and 64% of participants were women. Lean mass changes throughout the study were assessed using DEXA and skeletal muscle using MRI.

In part A of the study, 599 patients treated with semaglutide (titrated up to 2.4 mg weekly) were randomized to receive additional placebo (n = 151), trevogrumab 200 mg (n = 149), trevogrumab 400 mg (n = 152), or trevogrumab 400 mg plus the activin signaling inhibitor, garetosmab 10 mg/kg (n = 147) over a period of 26 weeks. In a subsequent withdrawal period, patients received either trevogrumab 400 mg or placebo for an additional 26 weeks.

As previously reported, over the first 26 weeks, patients receiving semaglutide plus placebo saw a 6.6% reduction from baseline in lean body mass compared with a loss of just 3.4% with the addition of trevogrumab 200 mg to semaglutide, and a 3.9% lean mass loss observed with the addition of trevogrumab 400 mg.

Overall body weight changes between the three groups were similar over the period (-10.6%, -9.9%, and -11.1% from baseline, respectively).

Of note, although the percentage of reduction specifically in fat mass over the 26 weeks was similar in the placebo and 200 mg group, the reduction in fat was significantly higher in the trevogrumab 400 mg group vs placebo (-19.0% vs -3.4%; P = .01).

The triplet-combination that included the drug garetosmab was associated with an even lower lean mass loss of approximately 2.1%; however, it was also associated with higher serious adverse events, muscle spasms, and discontinuations. Only trevogrumab is being evaluated as research continues.

Lean Mass Changes in Rebound Weight-Gain

To further evaluate the effects of trevogrumab in weight regain upon semaglutide withdrawal, all patients were discontinued from semaglutide at week 27; subsequently, half were treated with trevogrumab 400 mg, and half with placebo for an additional 26 weeks.

The total weight regain occurring after discontinuation through week 52 was similar in the three treatment groups, with total weight loss compared to baseline declining from about 10% at 26 weeks to about 6% at week 52.

However, increases in lean mass after discontinuation were notably higher among those receiving trevogrumab than among those receiving placebo. Those who switched from semaglutide plus placebo in the first 26 weeks had a 48% increase in lean mass with placebo vs a 65% increase with trevogrumab 400 mg after discontinuation over the second 26 weeks.

Among those switching from semaglutide plus trevogrumab 200 mg in the first 26 weeks, the increases in lean mass were 6% with placebo vs 42% with trevogrumab 400 mg, and among those originally in the semaglutide plus trevogrumab 400 mg group, the post-withdrawal lean mass increases were 26% with placebo vs 54% with continued trevogrumab 400 mg.

Percentages of fat mass and body weight in both groups remained below baseline at the end of the 52 weeks.

“In general, we can conclude that the amount of lean mass loss was reduced with trevogrumab during weight loss with semaglutide treatment, and it was almost restored to approximately baseline values after semaglutide was discontinued,” Rosenstock said.

Part B: Lower Trevogrumab Doses

In the second part of the study, 375 patients were treated with semaglutide, escalated to 2.4 mg weekly, and randomized to either additional placebo, trevogrumab 25 mg, or trevogrumab 75 mg for a full 52 weeks.

Those treated with semaglutide and placebo had a mean loss of lean mass compared with baseline of -6.7% at week 26, with the loss increasing to -7.3% at week 52.

The addition of trevogrumab 25 mg to semaglutide was associated with a lower reduction in lean mass of -4.7% at 26 weeks and -5.8% at 52 weeks, representing 29.9% and 20.5% greater lean mass preservation compared with semaglutide alone, respectively.

The reductions in the 75 mg group compared with baseline were only -3.3% and -4.2%, respectively, representing a 50.7% and 42.5% greater lean mass preservation compared with semaglutide alone, respectively.

The findings in part B, which replicated the findings with higher doses, indicate that “lean mass loss with trevogrumab was maintained for a full year,” Rosenstock said.

Importantly, a subgroup analysis of patients shown on imaging to have a lower lean mass definition of sarcopenia at baseline had greater reductions in lean mass with semaglutide treatment, and numerically greater preservation associated with trevogrumab cotreatment.

“We found that people with the lowest lean mass at baseline had equal to or more preservation of lean mass with the cotreatment with trevogrumab,” Rosenstock reported.

Safety, Muscle Spasms

Combinations of semaglutide and trevogrumab were generally well tolerated at all doses of trevogrumab, with side effects comparable to semaglutide alone.

Aside from the triple-combination arm that was discontinued, the highest rates of serious adverse events in part A of the trial were observed in the semaglutide plus trevogrumab 400 mg arm (1.3%, with 10.6% discontinuing treatment). In part B of the trial, rates of serious adverse events were with 3.3%, with 10.5% discontinuing, in the semaglutide plus trevogrumab 75 mg arm.

Importantly, the addition of trevogrumab was not associated with any significant differences in metabolic measures, including triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or A1c.

“There has been concern [regarding lipids] with these types of medications, [but] it’s good to see that lean mass preservation with trevogrumab was not associated with significant changes in metabolic parameters,” Rosenstock noted.

Muscle spasms, which occurred in about 5% of patients receiving semaglutide alone, were higher in the treatment combinations, at a rate of 6.1% in the trevogrumab plus semaglutide 200 mg arm, 9.3% in the trevogrumab plus semaglutide 400 mg group, and 9.2% in the trevogrumab plus semaglutide 75 mg group, with a lower rate of 2.7% with the trevogrumab 25 mg dose.

“Trevogrumab plus semaglutide at all doses studied was generally well tolerated, but there was an increase in muscle spasms in all trevogrumab arms except for the 25-mg dose,” Rosenstock said.

What Happens to Function?

Commenting on the study as a discussant in the session, Caterina Conte, MD, PhD, of San Raffaele Roma University of Rome in Rome, Italy, called the results, particularly involving the lean mass differences following semaglutide discontinuation, “reassuring,” but noted that the broader functional implications of lean mass require further investigation.

“I think the most important question is what happens to function, because we know that loss of lean mass is not necessarily associated with a reduction in function,” Conte explained. 

“For example, we have data from bariatric surgery where we see an absolute decline in lean mass and skeletal muscle, but overall, the function is preserved.”

Furthermore, in an analysis of the STEP-UP trial of patients with obesity who lost lean muscle mass on semaglutide, even at the highest dose (7.2 mg) over 72 weeks, no changes were observed in the number of endurance repetitions patients could perform, despite reductions in lean mass volume.

“What happens to muscle function is what really matters in the daily life of people,” Conte said.

Other key questions include what the optional duration of therapy would be with trevogrumab, how much lean mass needs to be preserved to optimize health, metabolic, functional outcomes, “and determining which people would benefit the most from the therapy,” she said.

“But I think [these results] are very encouraging and reassuring,” Conte said.

Consider Long-Term and Age-Related Changes

Further commenting on the research, Kaberi Dasgupta, MD, MSc, a professor of medicine and director of the Division of General Internal Medicine at McGill University in Montréal, Quebec, Canada, noted the need to consider the longer term and age-related changes that occur in lean muscle mass.

“While this interesting new agent reduced muscle mass loss, it did not prevent it,” she told Medscape Medical News. “It may not be sufficient to look at muscle strength and function in the short term.”

While peak bone and muscle mass and function are developed at a younger age, “in older age, there is a marked decline in both, [and] it is difficult if not impossible to really build higher muscle mass in older age,” Dasgupta explained.

What might be most protective “is a higher peak muscle mass when you are younger, [therefore] declining from a higher point when you are older,” she said.

Dasgupta noted that in her RESET for Remission trial, also presented at the meeting and published concurrently in The Lancet, a low energy diet and supervised resistance and aerobic training to prevent muscle loss “worked.”

“All of the weight loss was fat,” she said.

The study was sponsored by Regeneron. Rosenstock’s disclosures included consulting and/or other relationships with Applied Therapeutics, Biomea Fusion, Corcept, Eccogene, Eli Lilly, Ferring, Hanmi Pharmaceutical, Novo Nordisk, OraMD, Regor Therapeutics Group, Roche, Sanofi, Structure Therapeutics, and Terns Pharmaceuticals. Conte’s disclosures included receiving speaker and consultancy fees from Novo Nordisk, Eli Lilly, and AstraZeneca. Dasgupta reported receiving current or prior operating grants as principal investigator from the Canadian Institutes of Health Research, Diabetes Canada, The Heart & Stroke Foundation of Canada, The Lawson Foundation, the Medavie Foundation, and the Fonds de recherche du Québec.