Muscle loss on GLP-1s: what the EMBRAZE trial found

• 25–40% of total weight loss during incretin-based therapy (GLP-1/GIP drugs) typically comes from lean tissue, not fat, based on literature cited in the EMBRAZE paper.
• In the 24-week EMBRAZE trial (n=102), adding apitegromab to tirzepatide preserved 54.9% more lean mass than tirzepatide plus placebo — an average of 1.9 kg (about 4.2 lbs) less lean mass lost.
• Total weight loss was similar across both arms, suggesting the drug shifted the composition of loss without reducing its amount.
• Adverse event rates were comparable between arms.
• Apitegromab is investigational. It is not FDA-approved and is not available outside of clinical trials.

Lean mass is a broad category that includes skeletal muscle, bone mineral content, organ tissue, and water. When the body loses weight — through caloric restriction or medication — it draws on lean tissue alongside fat.

The concern with significant lean mass loss is not only cosmetic. Skeletal muscle supports physical function, metabolic rate, and long-term mobility. Loss of lean mass during weight loss has been associated with reduced strength and, in older adults, increased frailty risk. The clinical significance of the specific lean mass changes seen in GLP-1 trials is still an active area of research — the question of how much lean mass loss matters, and for whom, is not fully settled.

Apitegromab, developed by Scholar Rock, is a selective inhibitor of myostatin — a protein that suppresses muscle growth. By blocking myostatin, the working hypothesis is that the body may be better positioned to maintain or build lean tissue even during periods of caloric restriction or drug-driven weight loss.

Myostatin inhibitors have been studied in conditions involving significant muscle loss, such as spinal muscular atrophy. The EMBRAZE trial represents the first Phase 2 test of this approach specifically alongside a GLP-1/GIP medication.

EMBRAZE was a randomized, double-blind, placebo-controlled, multicenter Phase 2 trial. It enrolled 102 adults with overweight or obesity. Participants were randomized 1:1 to receive tirzepatide plus apitegromab, or tirzepatide plus placebo, over 24 weeks.

The primary outcome was lean mass change, measured using DEXA scanning.

Key results:

• The apitegromab arm lost an average of 1.9 kg less lean mass than the placebo arm (p=0.001).
• This corresponds to 54.9% preservation of lean mass relative to placebo — or about 4.2 lbs of lean mass retained.
• Total weight loss was similar across both arms: apitegromab did not appear to reduce the overall weight loss effect of tirzepatide.
• Adverse event rates were comparable: 76% of the apitegromab group reported at least one adverse event vs. 71% in the placebo group. Serious adverse events were 2% in each arm.

Results were published in Nature Medicine (doi: 10.1038/s41591-026-04440-4). The trial is registered at ClinicalTrials.gov as NCT06445075.

EMBRAZE was a 24-week, 102-person proof-of-concept study. There is a lot it cannot tell us:

• Duration: Does lean mass preservation hold beyond 24 weeks, and what happens after treatment ends?
• Functional outcomes: Does preserving 1.9 kg of lean mass translate to measurable improvements in strength, mobility, or quality of life? The trial measured lean mass, not function.
• Broader populations: The trial enrolled adults with overweight or obesity. Effects in older adults, people with type 2 diabetes, or those with existing sarcopenia (age-related muscle loss) are unknown.
• Long-term safety: Phase 2 trials are not sized or designed to detect rare adverse events. Longer-term safety data would be needed before this combination could move toward clinical use.

Lean mass loss during GLP-1 therapy is an active research area, and EMBRAZE is one early data point in a larger question. The trial establishes biological plausibility — that myostatin inhibition can alter the composition of weight loss alongside tirzepatide — but it does not establish apitegromab as a standard or recommended add-on therapy.

Phase 3 trials — testing larger populations, longer durations, and clinically meaningful outcomes like strength and function — would be needed before this approach could become a treatment option.

Apitegromab is not available. But the strategies with the strongest current evidence for preserving lean mass during weight loss are:

• Resistance training. Strength exercises consistently show benefits for lean mass preservation during caloric deficit across multiple study populations. This remains the most accessible and evidence-supported option.
• Adequate protein intake. Higher protein intake is associated with less lean mass loss during weight loss. What level is appropriate for you depends on your age, activity level, kidney function, and other factors — your clinician or a registered dietitian can help.

Neither requires waiting for investigational drug results. Both can be discussed at your next appointment.

• Should we track lean mass or body composition, and if so, how?
• What resistance training approach is realistic and safe for my current health status?
• Is a specific protein intake target relevant to my situation?
• Are there clinical trials studying lean mass preservation during GLP-1 therapy that I might qualify for?

• Physical function over time: can you do what you could six months ago? Climbing stairs, carrying items, balance
• Grip strength, if your clinician can measure it — a validated proxy for overall muscle strength
• Body composition if available through your provider — DEXA scanning measures lean mass directly, though it is not routine for all patients

Medical disclaimer: This content is for educational purposes only and is not medical advice. Always consult a licensed healthcare professional before starting, stopping, or changing any treatment.

Sources

• Nature Medicine — EMBRAZE trial: nature.com
• PubMed PMID 42260100: pubmed.ncbi.nlm.nih.gov
• ClinicalTrials.gov NCT06445075: clinicaltrials.gov
• Scholar Rock EMBRAZE results press release: investors.scholarrock.com