In part B, 376 participants took semaglutide for a full 52 weeks, combined with either placebo or lower trevogrumab doses of 25 mg or 75 mg. The main endpoints were percentage changes in lean mass, fat mass, and body weight. Lean mass was measured with dual-energy X-ray absorptiometry (DXA), a scanning technique that separates bone, fat, and lean tissue. A smaller MRI substudy of 76 participants in part B directly measured thigh muscle volume, isolating the effect on muscle itself.

What the researchers found

Part A confirmed substantial lean mass loss in the semaglutide-plus-placebo group: participants lost 6.6% of their lean mass over 26 weeks. Adding trevogrumab cut that loss roughly in half, to 3.4% with the 200 mg dose and 3.9% with the 400 mg dose. The four-drug combination performed even better, limiting lean mass loss to about 2.1%.

The withdrawal phase produced a striking result. Participants who stopped semaglutide and switched to placebo remained below their starting lean mass at week 52, at –2.4%. Those who switched to trevogrumab 400 mg ended at +0.4% — above baseline — a gap of 2.8 percentage points. Fat mass and body weight stayed below baseline in both groups. This matters because clinicians have worried that weight regained after stopping a GLP-1 drug may be mostly fat, not muscle.

In part B, the semaglutide-plus-placebo group lost 7.3% of lean mass over 52 weeks. Trevogrumab at 25 mg provided a modest, not statistically significant benefit of 1.5 percentage points. The 75 mg dose provided a statistically significant 3.1-percentage-point benefit.

The MRI substudy showed an even larger effect on muscle itself: trevogrumab reduced thigh muscle volume loss by 69% to 72% compared with semaglutide alone.

Safety, and a caution on the combination

Trevogrumab alone at all doses tested was generally well tolerated, with a safety profile comparable to placebo. The combination with garetosmab was not. In part A, 9% of participants on semaglutide plus trevogrumab 400 mg plus garetosmab experienced serious adverse events (14 of 149), and 32% discontinued treatment (48 of 149). Comparable rates for the semaglutide-plus-placebo group were 0.7% and 4.6%.

Muscle spasms clustered in the garetosmab arm, affecting 41% of those participants (61 of 149), versus 8% in the trevogrumab arms and 5% in the placebo arm. Most events were mild to moderate. Two deaths occurred during the study, both in the garetosmab combination arm; the researchers state that no causal association between treatment and the deaths has been identified.

Because of this tolerability problem, the authors conclude that although the combination preserved more lean mass numerically than trevogrumab alone, it was not a viable option.

Context and caveats

The researchers note that trevogrumab alone preserved more lean mass than has been reported for GLP-1 RA treatment combined with moderate-to-vigorous exercise, though differences in trial design preclude direct comparison. Participants who met the imaging criterion for sarcopenia — age-related low muscle mass — were older on average (53 versus 46 years) and appeared to both lose more lean mass on semaglutide and gain more protection from trevogrumab.

"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," the authors say.

They add: "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."

Still, these are Phase II results, and key questions remain open. Whether preserving muscle during intentional weight loss improves long-term physical function, metabolic health, and clinical outcomes — particularly in high-risk people vulnerable to functional decline — "requires further investigation," the authors write. Larger and longer trials will be needed before trevogrumab could reach clinical practice.