Trevogrumab Cuts Lean Mass Loss by Half in Semaglutide Phase 2 Trial

Trial Finds Trevogrumab Preserves Muscle During GLP-1 Therapy

In a Phase 2 trial of 975 adults with obesity, adding the investigational antibody trevogrumab to semaglutide cut lean tissue loss by roughly half over 26 weeks. Researchers presented the findings at the annual meeting of the European Association for the Study of Diabetes (EASD) in Milan, Italy, with publication pending in The Lancet. Glucagon-like peptide-1 (GLP-1) receptor agonists lower body weight, but a portion of that reduction regularly comes from muscle rather than fat.

Trevogrumab targets growth differentiation factor 8 (GDF8), a signaling protein also known as myostatin that acts as a natural brake on muscle growth. The study tested whether blocking myostatin could shield skeletal muscle while semaglutide reduced body weight and fat mass. The trial was sponsored by Regeneron, the biotechnology firm developing trevogrumab, and led by Dr. Ofri Mosenzon alongside Dr. Julio Rosenstock of the University of Texas Southwestern Medical Center.

Phase 2 Data Show Lean Mass Spared Across Dosing Arms

Participants enrolled in the two-part study had a body mass index (BMI) of 30 kg/m2 or higher, with an average starting BMI of 36.7 kg/m2 and a mean age of 49 years. Women accounted for 64 percent of the study group. Investigators tracked body composition using dual-energy X-ray absorptiometry (DXA) scans, paired with an exploratory magnetic resonance imaging (MRI) substudy in 76 patients to measure skeletal muscle volume directly.

In part A of the trial, participants on semaglutide plus placebo lost 6.6 percent of their lean mass by week 26. Adding 200 milligrams of trevogrumab limited lean mass loss to 3.4 percent, while a 400-milligram dose resulted in a 3.9 percent loss. A separate arm combining trevogrumab with garetosmab, an antibody targeting activin A, held lean mass loss to 2.1 percent.

Part B tracked lower trevogrumab doses over 52 weeks of semaglutide treatment, where placebo-arm participants lost 7.3 percent of their lean mass. A 25-milligram trevogrumab dose produced a 1.5 percentage-point improvement that was not statistically significant. In contrast, the 75-milligram dose produced a 3.1 percentage-point improvement, which met statistical significance.

Muscle Maintained After Semaglutide Discontinuation

The trial also evaluated what occurs when patients stop taking semaglutide after 26 weeks of treatment. Participants discontinued semaglutide and received either 400 milligrams of trevogrumab alone or a placebo for an additional 26 weeks.

Patients transitioned to placebo ended week 52 with lean mass still 2.4 percent below baseline. Participants receiving trevogrumab alone recovered lean tissue, finishing 0.4 percent above baseline, creating a 2.8 percentage-point difference between the groups. Body weight and fat mass remained below baseline in both groups through week 52.

Safety Profile and Combination Therapy Dropouts

Trevogrumab alone demonstrated an adverse event rate comparable to placebo across all tested doses. Discontinuation rates due to side effects through week 26 were 4.6 percent for semaglutide plus placebo, 5.4 percent for the 200-milligram dose, and 10.6 percent for the 400-milligram dose. Serious adverse event rates remained low across these groups, ranging from 0.7 percent to 1.3 percent.

The combination regimen combining trevogrumab with garetosmab produced a marked rise in tolerability problems. In that group, serious adverse events rose to 9 percent, compared to 0.7 percent in the semaglutide and placebo group. Discontinuations reached 32 percent, indicating that dual inhibition of myostatin and activin A creates tolerability trade-offs that monotherapy avoided.

• Semaglutide plus placebo: 0.7 percent serious adverse events, 4.6 percent discontinuations
• Semaglutide plus trevogrumab 200mg: 0.7 percent serious adverse events, 5.4 percent discontinuations
• Semaglutide plus trevogrumab 400mg: 1.3 percent serious adverse events, 10.6 percent discontinuations
• Semaglutide plus trevogrumab 400mg and garetosmab: 9.0 percent serious adverse events, 32.0 percent discontinuations

What the Research Means for Metabolic Health Management

These data clarify that pharmacological preservation of skeletal muscle during rapid weight reduction is biologically feasible. Preserving lean tissue is relevant because muscle drives glucose clearance, supports resting energy expenditure, and protects physical mobility. However, trevogrumab remains an unapproved investigational drug that is not currently available outside clinical trials.

Individuals currently taking GLP-1 medications must still rely on established lifestyle methods to protect skeletal muscle. Resistance exercise and adequate dietary protein intake remain the primary evidence-supported strategies for maintaining physical function during weight loss. Anyone concerned about loss of muscle strength while using semaglutide should talk to their clinician about structured resistance training and dietary targets.