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
Authors' conclusion
This study establishes proof of concept for GDF8 inhibition by trevogrumab alone as a generally well tolerated strategy to preserve lean mass during GLP-1 receptor agonist-induced weight loss. Although the addition of ActA inhibition by garetosmab further improved body composition and weight loss, the combination did not have favourable safety and tolerability. Further study is required to understand whether improved body composition during weight loss might preserve physical function and overall metabolic health.
Study context
- Population
- Participants aged 18–80 years with obesity (BMI ≥30 kg/m²) treated with semaglutideenrolled · part A 605 · part B 376
- Participants
- 975 participants
- Comparison
- Semaglutide plus trevogrumab versus semaglutide plus placebo
- Primary endpoint
- Percent change in lean mass, fat mass, and bodyweight from baseline
- Follow-up
- Week 26 (part A) or week 52 (part B)
Methodological detailsmulticentre (60 sites), US-based
- Multicentre (60 sites)
- US-based
Primary result
As reported in the abstract
Part A: semaglutide plus placebo
−6.6%
lean mass change · CI −7.4–-5.7
Part B: semaglutide plus placebo
−7.3%
lean mass change · CI −8.8–-5.8
- Part A: semaglutide plus trevogrumab 200 mg vs Part A: semaglutide plus placebo
- Estimated treatment difference (ETD), lean mass +3.1% (95% CI 1.9–4.3)
- Part A: semaglutide plus trevogrumab 400 mg vs Part A: semaglutide plus placebo
- ETD, lean mass +2.7% (95% CI 1.5–4.0)
- Part A: semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kg vs Part A: semaglutide plus placebo
- ETD, lean mass +4.5% (95% CI 3.1–5.9)
- Part B: semaglutide plus trevogrumab 25 mg vs Part B: semaglutide plus placebo
- ETD, lean mass +1.5% (95% CI −0.3 to 3.3)
- Part B: semaglutide plus trevogrumab 75 mg vs Part B: semaglutide plus placebo
- ETD, lean mass +3.1% (95% CI 1.3–4.9)
Further findings
| Outcome | Values | ETD (CI) | |
|---|---|---|---|
| Change from baseline in fat mass, part APart A: semaglutide plus trevogrumab 400 mgvs Part A: semaglutide plus placeboSignificant | Part A: semaglutide plus placebo −15.6% (CI −17.4–-13.9) | −3.4% (−5.9 to −0.9) | |
| Change from baseline in fat mass, part APart A: semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kgvs Part A: semaglutide plus placeboSignificant | −11.7% (−14.4 to −9.0) | ||
| Percent change in bodyweight, part APart A: semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kgvs Part A: semaglutide plus placeboSignificant | Part A: semaglutide plus placebo −10.6 (CI −11.6–-9.7) | −2.7 (−4.1 to −1.2) | |
| −20−10010Difference (linear scale) |
Change from baseline in fat mass, part A
- No other groups in part A nor any in part B had significantly different changes in fat mass compared with semaglutide plus placebo
Percent change in bodyweight, part A
- No other groups in part A nor any in part B had significantly different changes in bodyweight compared with semaglutide plus placebo
Safety
Safety and tolerability
- Serious adverse events, semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kg
- 14 [9%] of 149
- Treatment discontinuations, semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kg
- 48 [32%] of 149
- Muscle spasms, semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kg group
- 61 [41%] of 149
- Muscle spasms, semaglutide plus trevogrumab 200 mg or 400 mg groups
- 23 [8%] of 299
- Muscle spasms, semaglutide plus placebo groups
- seven [5%] of 151
- Deaths, both in the semaglutide plus trevogrumab 400 mg plus garetosmab 10 mg/kg group; causal association not identified
- Two
- Semaglutide plus trevogrumab (25 mg, 75 mg, 200 mg, or 400 mg) was generally well tolerated with a safety profile similar to semaglutide plus placebo
- Gastrointestinal adverse events were the most commonly reported, with similar incidence across treatment groups
- Most adverse events were mild to moderate in severity
Original publication
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