The Courage Trial

Edited and approved by Stephen C. Rose, PhD, MS

GLP-1 drugs have changed what is possible in obesity treatment. Semaglutide and related medicines can produce weight loss that once required bariatric surgery. But the number on the scale does not tell the whole story. When body weight falls, some of the loss comes from fat and some comes from lean tissue - a category that includes skeletal muscle, organs, connective tissue, water, and glycogen.

That distinction matters most for older adults, people who already have low muscle mass, and anyone losing weight rapidly. Muscle helps control blood glucose, supports balance and mobility, protects bone, and provides a reserve during illness. The ideal obesity treatment would therefore remove large amounts of fat while preserving as much functional muscle as possible.

Regeneron's Phase 2 COURAGE trial is testing a direct attempt to do exactly that: combine semaglutide with trevogrumab, a monoclonal antibody that blocks myostatin, one of the body's natural brakes on muscle growth. An additional trial arm also includes garetosmab, which blocks activin A, a related signal. The early results are genuinely interesting - but they require careful interpretation.

Why GLP-1 Weight Loss Can Include Lean Tissue

Semaglutide reduces appetite and food intake by activating the glucagon-like peptide-1 receptor. In the STEP 1 trial, adults with overweight or obesity lost an average of 14.9% of their body weight over 68 weeks, compared with 2.4% with placebo [1]. Most of that loss was fat, which is the intended outcome. However, rapid energy restriction also reduces the body's need to carry and support its previous mass, and it can lower protein intake and muscle-building signals.

A systematic review of semaglutide studies found that lean mass generally declined along with body weight, although the proportion varied widely across studies [2]. This does not mean semaglutide uniquely destroys muscle. Lean tissue typically falls during substantial weight loss from diet, surgery, or medication. In some people, the percentage of body weight made up of lean tissue actually improves because fat falls faster than lean mass.

Still, the absolute loss can matter. A person who loses 45 pounds and derives one-quarter to one-third of that loss from lean tissue may lose a meaningful amount of tissue that contributes to strength and metabolic health. That concern has created a new goal in obesity medicine: not simply greater weight loss, but higher-quality weight loss.

Myostatin: The Brake on Muscle Growth

Myostatin, also called growth differentiation factor 8 or GDF8, is a signaling protein produced mainly by skeletal muscle. It binds to activin type II receptors and activates pathways that limit muscle-fiber growth. Rare genetic loss of myostatin produces unusually muscular animals and humans, which made the pathway an obvious drug target.

Trevogrumab is a fully human monoclonal antibody designed to bind and neutralize myostatin. The basic idea is simple: semaglutide lowers appetite and body fat, while trevogrumab removes part of the biochemical restraint on muscle. Garetosmab targets activin A, another ligand using overlapping receptor pathways. Blocking both signals might have a stronger effect, but it could also create more adverse effects.

The concept is supported by earlier work. In obese animals undergoing GLP-1-driven weight loss, blocking activin type II receptor signaling preserved or increased lean mass while fat loss continued [3]. In a separate human Phase 2 trial, bimagrumab - an antibody that blocks activin type II receptors rather than myostatin itself - reduced fat mass by 20.5% and increased lean mass by 3.6% over 48 weeks in adults with obesity and type 2 diabetes [4]. These findings established that fat loss and muscle gain do not always have to move in opposite directions.

How the COURAGE Trial Was Designed

COURAGE is a randomized Phase 2 study registered as NCT06299098. It includes adults with obesity and tests semaglutide alone against semaglutide combined with lower-dose or higher-dose trevogrumab, as well as a triplet containing semaglutide, higher-dose trevogrumab, and garetosmab [5]. The study separates treatment into a 26-week weight-loss period and a 26-week weight-maintenance period.

The primary outcomes at week 26 were changes in body weight, fat mass, and lean mass. Body composition was measured by dual-energy X-ray absorptiometry, usually called DXA. That is a practical and widely used method, but it cannot directly tell investigators how much contractile skeletal muscle was preserved or whether participants became stronger. DXA lean mass also includes body water and nonfat tissues outside muscle.

What the 26-Week Results Suggest

The complete week-26 findings were presented at the European Association for the Study of Diabetes meeting in September 2025, but they have not yet appeared as a full peer-reviewed paper. According to Regeneron's official report, semaglutide alone reduced body weight by 10.6%. Participants lost 6.7 kilograms of fat mass and 3.3 kilograms of lean mass; by the company's calculation, lean tissue accounted for 33% of the combined fat-plus-lean loss [6].

Adding trevogrumab approximately halved that lean-mass loss. The lower-dose combination produced a 1.5-kilogram lean-mass decrease, while the higher-dose combination produced a 1.9-kilogram decrease. Fat loss was 7.6 and 8.5 kilograms, respectively. Total weight loss remained similar to semaglutide alone with the lower dose and was slightly greater with the higher dose.

The triplet produced the most dramatic body-composition result: 11.8 kilograms of fat loss, only 0.9 kilograms of lean-mass loss, and a 13.4% reduction in body weight. On paper, that looks close to the desired profile - substantially more fat loss with much less lean loss. But the triplet also had a substantially higher discontinuation rate because of tolerability problems and other adverse events. Two deaths occurred in that group; the company reported that it had not identified a causal relationship, but the small and early-stage nature of the trial means safety remains a central question [6].

Preserved Lean Mass Is Not Yet Proven Preserved Muscle Function

The most important caution is that lean mass is not synonymous with healthy, functional muscle. A drug can increase or preserve tissue measured by DXA without improving strength, walking speed, balance, or the ability to perform daily tasks. Myostatin inhibitors have repeatedly increased muscle size in clinical development, but improvements in function have often been smaller or inconsistent [7].

That gap is especially important in obesity. Some lean-mass loss during weight reduction may simply reflect less water, glycogen, connective tissue, or muscle needed to support a lighter body. Conversely, preserving kilograms of lean tissue is not automatically valuable if the tissue does not produce more force or improve physical performance.

Future trials need to measure grip strength, chair-rise performance, walking speed, power, falls, and patient-centered function - not just DXA. They also need longer follow-up. A 26-week result cannot tell us whether the body-composition benefit persists, whether muscle quality improves, or what happens after the antibodies or semaglutide are stopped.

What the Safety Results Mean

The semaglutide-trevogrumab combinations were reported as generally well tolerated. Events occurring in at least 5% of participants in one or more groups included muscle spasms, nausea, constipation, fatigue, diarrhea, headache, vomiting, reflux, and several common infections [6]. Because trevogrumab is experimental, its long-term cardiovascular, metabolic, tendon, and musculoskeletal effects remain uncertain.

The triplet's poorer tolerability is a warning against assuming that stronger pathway blockade is always better. Activin signaling participates in multiple tissues and biological processes. Greater fat loss and lean-mass preservation must ultimately justify any increase in risk, inconvenience, and cost. Neither trevogrumab nor garetosmab is approved for obesity treatment, and these drugs should not be sought from peptide or research-chemical sellers.

What People Using GLP-1 Drugs Should Do Now

The COURAGE trial is not a reason to wait for a muscle-preserving antibody before treating obesity. The health benefits of appropriate GLP-1 therapy can be substantial, and the clinical meaning of medication-associated lean-mass loss remains debated. Strength does not necessarily decline in proportion to DXA lean mass, particularly when mobility and metabolic health improve.

For now, the best-supported protection is less futuristic: progressive resistance training, adequate protein and total nutrition, and a rate of weight loss that does not become unnecessarily aggressive. Reviews of weight-loss interventions consistently identify resistance exercise and sufficient dietary protein as the main tools for limiting muscle loss [8,9]. For older adults or people with frailty, clinicians may also monitor strength, walking performance, protein intake, and body composition rather than relying only on scale weight.

The larger lesson from COURAGE is that obesity treatment is entering a second phase. The first breakthrough was learning how to produce major weight loss with medication. The next challenge is controlling what kind of tissue is lost, preserving physical function, and maintaining the result over years. Trevogrumab offers credible early evidence that pharmacology may eventually help reshape that tradeoff.

But the honest conclusion is narrower than the headlines: the COURAGE combinations preserved more DXA-measured lean mass and increased fat loss over 26 weeks. We do not yet know whether they preserve strength, prevent frailty, improve long-term outcomes, or provide an acceptable safety and cost profile. That is promising science - not finished medicine.

References

1. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021;384:989-1002.
2. Alabduljabbar K, Al-Najim W, le Roux CW. A systematic review of the effect of semaglutide on lean mass: insights from clinical trials. Int J Obes (Lond). 2024.
3. Nunn E, et al. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024;80:101880.
4. Heymsfield SB, Coleman LA, Miller R, et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021;4:e2033457.
5. ClinicalTrials.gov. A Study to Test if Trevogrumab or Trevogrumab With Garetosmab When Taken With Semaglutide Is Safe and Works in Adult Patients With Obesity (COURAGE). NCT06299098.
6. Regeneron Pharmaceuticals. Results from Phase 2 COURAGE Trial Demonstrating Potential to Improve Quality of GLP-1 Receptor Agonist-Induced Weight Loss by Preserving Lean Mass. September 17, 2025. Company-reported conference results; not yet a peer-reviewed full paper.
7. Wagner KR. The elusive promise of myostatin inhibition for muscular dystrophy. Curr Opin Neurol. 2020;33:621-628.
8. McCarthy D, Berg A. Weight Loss Strategies and the Risk of Skeletal Muscle Mass Loss. Nutrients. 2021;13:2473.
9. Mechanick JI, et al. Strategies for minimizing muscle loss during use of incretin-mimetic drugs for treatment of obesity. Obes Rev. 2025.