COURAGE trial - the future of weight loss?
- Georgia McGrath
- 10 hours ago
- 4 min read
Introduction
Glucagon-like peptide 1 (GLP-1) agonists have transformed obesity treatment in recent years. Medications such as semaglutide have become widely used therapies, enabling weight loss that was previously only possible with invasive surgery. Their use continues to grow, with around 1 in 8 US adults reportedly prescribed these in 2025. While efficacious, a significant proportion of weight lost during GLP-1 agonist therapy is attributable to reductions in lean muscle mass. This can be detrimental in later life, increasing the risk of significant falls, frailty and bone fractures. These concerns raise an important question: can the quality of weight loss can be improved, not just the quantity?
The Phase 2 COURAGE trial
The Phase 2 COURAGE trial is investigating whether administering muscle-preserving antibodies (trevogrumab and garetosmab) alongside semaglutide can reduce lean muscle loss during pharmacologically-induced weight loss. The trial is split into two 26-week phases; a weight loss phase and a maintenance phase.
For the weight loss phase, approximately 600 participants with a BMI >30kg/m2 were randomised into four treatment arms:
◦ Semaglutide 2.4mg alone
◦ Semaglutide + low dose trevogrumab (200mg)
◦ Semaglutide + high dose trevogrumab (400mg)
◦ Semaglutide + high dose trevogrumab + garetosmab (10mg/kg) - triplet therapy
After the weight-loss phase, the participant’s change in lean mass, fat mass and body weight were measured and compared. During the maintenance phase, subjects will either receive high dose trevogrumab or a placebo.
Mechanisms of Action
Trevogrumab is a monoclonal antibody that blocks myostatin, a central inhibitor of muscle growth. Garetosmab targets activin A, a cytokine that activates muscle-atrophy pathways and suppresses muscle development. Together, these antibodies act by dampening muscle-wasting signals and supporting muscle preservation and growth. The hypothesis for this trial is that adding these agents alongside semaglutide will enable ongoing fat loss whilst minimising lean muscle mass loss.
The Results
At 26 weeks, the results showed clear differences amongst treatment groups. Semaglutide alone produced an average weight loss of 10.6%, with 33% attributed to lean muscle mass. Combining semaglutide and low-dose trevogrumab produced slightly less overall weight loss (9.9% on average), but a notably lower percentage of this was lean muscle mass (16.8% on average). High-dose trevogrumab and semaglutide resulted in greater overall weight loss at 11.1% on average, but a slightly larger proportion of this was lean muscle mass compared to low-dose trevogrumab (18.1%). Finally, triplet therapy produced the greatest overall weight reduction at 13.4% on average, and appeared to preserve lean muscle mass most effectively, with only 7.4% of weight loss attributed to lean muscle.
Other parameters, including waist circumference, blood pressure, cholesterol, triglycerides and A1C were measured. These all showed marked improvements across the board.
As the study is still ongoing, results from the maintenance phase are not yet available.
Why this matters
Maintaining lean muscle mass is essential for movement, metabolism and overall physiological stability. Decreased muscle mass is associated with reduced balance, strength and mobility, and may also contribute to declines in bone density over time. This can increase the likelihood and severity of falls, leading to physical and psychological impacts such as diminished dependence and confidence. Furthermore, muscle tissue is highly metabolically active, meaning lower muscle mass can reduce overall metabolic rate. This can make it more difficult to maintain weight loss, and in the context of GLP-1 agonists, may contribute to weight regain once treatment ceases.
Study Limitations
Although the initial results of the phase 2 COURAGE trial are promising, several limitations should be considered. Firstly, the study cohort was relatively small, with approximately 600 participants, and limited to 52 weeks. As an early-phase trial, long-term efficacy and safety have not yet been established. Notably, discontinuation rates due to adverse effects were relatively high in the triplet-therapy arm (approximately 28%). This could suggest tolerability issues which may affect real-world adherence. Additionally, body composition was assessed using DXA scanning, which quantifies lean mass but does not directly measure functional outcomes, including physical strength and performance. Further evaluation of these measures will help determine how applicable results could be to real-life functions. Finally, demographic features, such as sex, age and ethnicity have not been disclosed at this time. Their significance therefore cannot be evaluated. These limitations emphasise the need for larger, longer studies to confirm efficacy, safety and meaningful patient-centred outcomes.
What next?
Results from the maintenance phase of this trial, expected at the end of 2026, should provide further insight into the potential of pharmacological lean-mass preservation. Beyond this, larger and longer Phase 3 trials will be necessary to evaluate the long-term safety and efficacy of these combination therapies. Additional research into their effect on measurable outcomes, such as strength, mobility and metabolic health, will help clarify how these therapies may influence real-world physical functions. Comparison of these results with existing muscle-preservation strategies during weight loss, including strength training, will also help define their potential role in clinical practice. Ultimately, only robust confirmatory evidence can determine whether these combination therapies will have a place in future routine obesity management.
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