The Lancet November 11, 2026

Trevogrumab (anti-GDF8) with or without garetosmab (anti-activin A) for prevention of muscle loss during semaglutide-induced weight reduction in people with obesity (COURAGE): a two-part, phase 2, double-blind, placebo-controlled, randomised trial

Ofri Mosenzon, Julio Rosenstock, José G Raya, et al.

Bottom Line

In adults with obesity, adjunctive treatment with the anti-myostatin antibody trevogrumab significantly preserved lean mass during semaglutide-induced weight loss, though dual-inhibition adding garetosmab proved poorly tolerated.

Key Findings

1. In Part A (26 weeks), participants receiving semaglutide plus placebo experienced a 6.6% decrease in lean mass. Concomitant treatment with trevogrumab 200 mg, trevogrumab 400 mg, or trevogrumab 400 mg plus garetosmab significantly mitigated this loss, yielding estimated treatment differences (ETD) of +3.1%, +2.7%, and +4.5%, respectively.

2. Fat mass reduction in the semaglutide plus placebo group was 15.6%. The addition of trevogrumab 400 mg or the combination of trevogrumab plus garetosmab led to significantly greater fat loss, with ETDs of -3.4% and -11.7%, respectively.

3. Semaglutide plus placebo resulted in a 10.6% reduction in bodyweight at 26 weeks. Only the dual-antibody combination (trevogrumab plus garetosmab) drove significant additional weight loss (ETD -2.7%) beyond semaglutide alone.

4. In Part B (52 weeks), lower-dose trevogrumab preserved lean mass over the longer term without meaningfully augmenting total weight loss; the 75 mg dose limited lean mass reduction to 4.2%, compared to 7.3% with semaglutide plus placebo.

5. Although the addition of the activin A inhibitor garetosmab maximized body composition improvements, it lacked a favorable safety and tolerability profile, leading to the discontinuation of this combination.

Study Design

Design

Phase 2 RCT

Double-Blind

Sample

975

Patients

Duration

26 wk (Part A) / 52 wk (Part B)

Median

Setting

60 sites, US

Population Adults aged 18-80 years with obesity (BMI ≥30 kg/m2).

Intervention Part A: Semaglutide (2.4 mg weekly) + trevogrumab (200 or 400 mg) ± garetosmab (10 mg/kg). Part B: Semaglutide + lower-dose trevogrumab (25 or 75 mg).

Comparator Semaglutide + placebo

Outcome Percent change in lean mass, fat mass, and bodyweight from baseline to week 26 (Part A) or week 52 (Part B).

Study Limitations

• The combination involving the activin A inhibitor garetosmab was poorly tolerated, preventing the advancement of the dual-pathway blockade strategy.

• The trial relied on surrogate imaging endpoints (DXA and MRI for body composition); it is unknown whether the observed preservation of lean mass will translate into meaningful improvements in physical function, strength, or metabolic health.

• The study cohort was primarily middle-aged (mean age 49), limiting generalizability regarding the intervention's capacity to prevent functional decline in elderly or baseline-sarcopenic populations.

• Relatively short duration (up to 52 weeks) limits conclusions on the long-term safety profile of chronic myostatin inhibition alongside incretin therapy.

Clinical Significance

The COURAGE trial establishes critical clinical proof-of-concept that pharmacological myostatin (GDF8) inhibition can uncouple fat loss from muscle catabolism during aggressive incretin-induced weight loss. By preventing a significant proportion of the lean mass reduction typically caused by high-dose semaglutide, trevogrumab offers a promising adjunctive therapeutic strategy to improve the 'quality' of weight loss, which is increasingly recognized as vital for mitigating the risk of sarcopenic obesity, particularly in vulnerable aging populations.

Historical Context

The rise of highly effective GLP-1 receptor agonists (e.g., semaglutide, tirzepatide) transformed obesity management but revealed a significant clinical challenge: approximately 25-40% of the rapid weight loss driven by these agents consists of lean tissue, including skeletal muscle. Because sarcopenia heightens the risk of frailty, insulin resistance, and functional decline, the field has pivoted towards optimizing body composition rather than merely maximizing absolute weight loss. Myostatin (GDF8) is a potent negative regulator of skeletal muscle. Although anti-myostatin therapies previously faced translational hurdles in primary muscle-wasting disorders, their use as targeted adjuncts to GLP-1 therapy offers a logical physiological synergy, opening a new frontier in next-generation obesity pharmacotherapy.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why is muscle loss a significant concern during semaglutide-induced weight loss, and how does the mechanism of myostatin (GDF8) make it a logical therapeutic target to counteract this?

Key Response

Semaglutide induces rapid weight loss, up to 40 percent of which can be lean muscle, increasing the risk of sarcopenia and metabolic rebound. Myostatin is a member of the TGF-beta superfamily that acts as a negative regulator of skeletal muscle growth. Inhibiting it with trevogrumab releases this physiological brake, promoting muscle preservation during a catabolic state.

Resident

Given that dual inhibition with garetosmab (anti-activin A) was poorly tolerated, what specific clinical parameters and adverse events should clinicians monitor when patients are treated with therapies targeting the TGF-beta superfamily?

Key Response

Activin A inhibition has historically been associated with mucocutaneous bleeding and telangiectasias due to its role in vascular stability. Residents must recognize that combining novel biologicals requires vigilant monitoring for off-target vascular adverse events, steering clinical management toward the safer monotherapy.

Fellow

While trevogrumab preserves lean mass during semaglutide therapy, how should we evaluate the clinical relevance of this preserved tissue regarding muscle quality, functional capacity, and long-term metabolic homeostasis?

Key Response

Preserving lean mass does not automatically equate to preserved muscle strength or metabolic function. Fellows must consider whether anti-myostatin therapy prevents functional sarcopenia and whether this translates to improved sustained insulin sensitivity or prevention of weight regain once GLP-1 RA therapy is tapered.

Attending

As we move toward adjunctive biologic therapies to preserve lean mass during incretin-based weight loss, how does this alter our overall paradigm of obesity management, and which specific patient populations stand to benefit the most?

Key Response

The addition of anti-myostatin therapy shifts the focus from absolute BMI reduction to optimizing body composition. This is highly relevant for older adults at risk for osteosarcopenic obesity and post-menopausal women, where semaglutide-induced sarcopenia could precipitate irreversible frailty.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

In designing a trial to evaluate the preservation of lean mass during profound pharmacologic weight loss, what are the methodological limitations of using DEXA as a primary endpoint, and how can future trial designs better distinguish between skeletal muscle versus water or fibrotic tissue?

Key Response

DEXA cannot reliably differentiate between functional skeletal muscle, intramuscular water, and fibrotic tissue, which is critical when evaluating an anti-myostatin agent. Future research must incorporate MRI-based fat-free muscle fraction analysis and functional endpoints like CPET to validate the tissue quality.

Journal Editor

The trial notes that dual inhibition with garetosmab was poorly tolerated. As a reviewer, how would you scrutinize the impact of differential dropout rates and unblinding risks due to adverse events on the internal validity and intention-to-treat analysis of the trial?

Key Response

High rates of unique adverse events in the dual-inhibition arm likely lead to informative censoring and functional unblinding. Reviewers must rigorously assess whether the missing data mechanisms were appropriately handled via tipping point analyses and if the toxicity profile skewed the efficacy signal.

Guideline Committee

Current obesity management guidelines prioritize lifestyle modifications like resistance training to prevent muscle loss during anti-obesity medication use. Based on the COURAGE trial results, what level of evidence and long-term safety data would be required to update guidelines to recommend pharmacologic muscle preservation over or alongside standard lifestyle interventions?

Key Response

While Phase 2 data is promising, current AACE and AHA guidelines mandate lifestyle interventions as first-line for preserving lean mass. A guideline committee would require Phase 3 data demonstrating functional superiority, cost-effectiveness, and long-term safety over structured exercise before recommending expensive adjunctive biologics.

Clinical Landscape

Noteworthy Related Trials

2021

STEP 1 Trial

n = 1,961 · NEJM

Tested

Semaglutide 2.4 mg weekly

Population

Adults with overweight or obesity without diabetes

Comparator

Placebo

Endpoint

Percentage change in body weight at week 68

Key result: Semaglutide 2.4 mg led to a 14.9 percent reduction in body weight compared to 2.4 percent with placebo.

2021

Bimagrumab Phase 2 Trial

n = 75 · JAMA Netw Open

Tested

Bimagrumab 10 mg/kg intravenously every 4 weeks

Population

Adults with type 2 diabetes and overweight or obesity

Comparator

Placebo

Endpoint

Change in total body fat mass at week 48

Key result: Bimagrumab resulted in a 20.5 percent decrease in fat mass and a 3.6 percent increase in lean mass.

2022

SURMOUNT-1 Trial

n = 2,539 · NEJM

Tested

Tirzepatide up to 15 mg weekly

Population

Adults with obesity or overweight without diabetes

Comparator

Placebo

Endpoint

Percentage change in body weight at week 72

Key result: Tirzepatide resulted in up to a 20.9 percent average body weight reduction.

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