GLP-1 lean mass loss has become a major concern in modern obesity treatment. While GLP-1 receptor agonists like semaglutide drive significant fat reduction, emerging data from the Phase 2 COURAGE trial suggests that preserving lean mass may be the next evolution in weight-loss therapy.
Semaglutide alone led to meaningful weight reduction, but about one-third of that loss came from lean mass. When you combine semaglutide with trevogrumab, lean mass decline drops by roughly half, depending on dose. The triplet regimen, which adds garetosmab, further shifts weight loss toward fat mass.
Study Structure and Treatment Groups
You can break the trial into two consecutive 26-week periods:
- Weight-loss phase (Weeks 0–26)
- Weight-maintenance phase (Weeks 26–52)
The 26-week analysis reflects the end of the weight-loss phase. Participants had obesity, defined by a body mass index of at least 30 kg/m².
During the first phase, patients received one of the following:
| Group | Treatment | Sample Size (n) |
|---|---|---|
| Monotherapy | Semaglutide 2.4 mg | 151 |
| Low-dose combo | Semaglutide + Trevogrumab 200 mg | 149 |
| High-dose combo | Semaglutide + Trevogrumab 400 mg | 152 |
| Triplet | Semaglutide + High-dose Trevogrumab + Garetosmab 10 mg/kg | 147 |
You measure lean and fat mass using DXA scanning, while standard scales capture total body weight. Because these methods differ, lean and fat values do not perfectly sum to total body weight.
Lean Mass Outcomes
With semaglutide alone, lean mass declined by 6.5% from baseline, translating to about 3.3 kg, or 33% of total weight loss. This confirms that a substantial fraction of GLP-1–associated weight loss comes from non-fat tissue.
When you add trevogrumab, lean mass loss decreases:
- Low-dose combo: −3.3% (−1.5 kg; 16.8% of total loss)
- High-dose combo: −3.8% (−1.9 kg; 18.1% of total loss)
- Triplet: −2.0% (−0.9 kg; 7.4% of total loss)
These findings show that trevogrumab preserves a meaningful portion of muscle mass during pharmacologic weight reduction. Statistical testing met significance thresholds for primary endpoints, though multiplicity adjustments were not applied.
Fat Mass Reduction
Fat mass decreased across all arms, but the proportion of fat loss improved with combination therapy.
| Group | % Fat Mass Change | Fat Mass Loss (kg) | % of Total Weight Loss from Fat |
|---|---|---|---|
| Semaglutide | −15.7% | −6.7 kg | 67.0% |
| Low-dose combo | −17.3% | −7.6 kg | 83.2% |
| High-dose combo | −19.1% | −8.5 kg | 81.9% |
| Triplet | −27.1% | −11.8 kg | 92.6% |
You see the most pronounced fat reduction in the triplet arm. More than 90% of weight lost in that group came from fat mass.
This shift in composition matters because adipose tissue drives many obesity-related metabolic complications. Increasing the proportion of fat loss while limiting lean tissue decline may improve functional and metabolic outcomes.
Total Body Weight Changes
Total body weight decreased in every group:
- Semaglutide: −10.6%
- Low-dose combo: −9.9%
- High-dose combo: −11.1%
- Triplet: −13.4%
The triplet achieved the largest percentage reduction in overall body weight. However, tolerability and discontinuation patterns also differed among groups.
Metabolic and Cardiometabolic Measures
You observe numerical improvements across treatment arms in several secondary and exploratory endpoints. These include:
- Waist circumference
- Systolic and diastolic blood pressure
- Total cholesterol
- Triglycerides
- Glycated hemoglobin (A1C)
These changes align with established metabolic effects of GLP-1 receptor agonists. The addition of muscle-preserving therapy did not blunt these favorable trends.
The trial did not position these secondary findings as definitive outcomes. Instead, they provide directional support for broader cardiometabolic benefit.
Safety and Tolerability
The semaglutide–trevogrumab combinations were generally tolerated. Adverse events occurring in at least 5% of participants in any group included:
- Muscle spasms
- Nausea
- Constipation
- Fatigue
- Diarrhea
- Headache
- Vomiting
- Gastroesophageal reflux
- Upper respiratory infections
- Nasopharyngitis
- Urinary tract infection
- Influenza
- COVID-19
Most events were mild to moderate in intensity.
You should note that the triplet arm showed a higher rate of treatment discontinuation due to adverse events and tolerability issues. Two deaths occurred in the triplet group: one in a patient with multiple cardiovascular risk factors and one in a patient with prior cardiovascular disease who experienced cardiac arrest. Investigators did not establish a causal link between treatment and these events.
Neither trevogrumab nor garetosmab has received regulatory approval, and authorities have not yet evaluated their safety and efficacy.
Rationale for Muscle Preservation
You already know that GLP-1 receptor agonists produce substantial weight loss. However, they also reduce lean mass, including skeletal muscle.
Muscle plays a key role in:
- Glucose disposal
- Physical function
- Basal metabolic rate
- Long-term weight maintenance
When patients discontinue GLP-1 therapy, they often regain weight. Some data suggest that regained weight may disproportionately consist of fat rather than muscle, which can worsen body composition.
By targeting GDF8 (myostatin) with trevogrumab, you inhibit a pathway that limits muscle growth. Blocking myostatin signaling can support muscle maintenance during caloric deficit. Adding an anti-activin A antibody such as garetosmab may further modulate related pathways, though tolerability remains a concern.
Maintenance Phase Design
After completing 26 weeks of weight loss, participants transition into a second 26-week period.
During this maintenance phase, you receive either:
- High-dose trevogrumab alone
- Placebo
This structure allows investigators to evaluate whether muscle-preserving therapy sustains body composition improvements after active weight loss ends.
The full 52-week outcomes will clarify whether early preservation of lean mass translates into longer-term metabolic or functional benefits.
Broader Development Strategy
You see this program as part of a broader effort to improve the quality of weight reduction. The strategy focuses on shifting outcomes away from indiscriminate tissue loss and toward selective fat reduction.
This approach recognizes obesity as a chronic, multifactorial disease that affects more than one billion people worldwide. While GLP-1 receptor agonists have changed treatment standards, they do not fully address muscle preservation or long-term body composition stability.
In parallel, the company continues to develop therapies targeting obesity-related comorbidities and metabolic complications. These agents may eventually integrate with incretin-based regimens.
Antibody Engineering Platform
Trevogrumab and garetosmab originate from a proprietary antibody discovery platform that uses genetically engineered mice with humanized immune systems. This system generates fully human monoclonal antibodies.
The same platform has produced multiple FDA-approved biologics across immunology, oncology, lipid disorders, and infectious disease. You see this as a validated technology base applied to a new therapeutic area.
The obesity-focused antibodies remain investigational. Ongoing data will determine whether muscle-preserving combinations can complement established incretin therapies without compromising safety.
You now have a clearer view of how the 26-week results reshape expectations around pharmacologic weight loss. The findings shift attention from total kilograms lost to the composition of that loss, with measurable differences across dosing strategies.
Frequently Asked Questions
What outcomes did the Phase 2 COURAGE study measure for GLP-1–based therapy?
You will see that the trial focused on body composition, not just total weight.
The three main measures at 26 weeks included:
- Percent change in lean mass
- Percent change in fat mass
- Percent change in total body weight
Researchers assessed these endpoints at the end of the initial 26‑week weight‑loss phase. The study then continued into a separate 26‑week weight‑maintenance period.
How does trevogrumab compare with semaglutide for weight reduction and muscle preservation?
Semaglutide alone produces meaningful weight loss, but about one‑third of that loss may come from lean tissue.
When you add trevogrumab, an antibody that targets myostatin (GDF8), you reduce the amount of muscle lost during weight reduction. Data from the Phase 2 trial showed that combination therapy helped preserve a substantial portion of lean mass compared with semaglutide alone.
Trevogrumab does not replace semaglutide’s fat‑loss effect. Instead, it aims to improve the quality of weight loss by shifting more of it toward fat rather than muscle.
What side effects were reported with GLP-1–based combinations in the trial?
You can expect side effects similar to those seen with GLP‑1 receptor agonists.
Commonly reported events included:
- Nausea
- Vomiting
- Diarrhea
- Constipation
These effects were generally gastrointestinal and consistent with known semaglutide safety data. No unexpected safety signals were widely reported in interim disclosures.
When will the Phase 3 trevogrumab weight management trial finish?
Regeneron has advanced trevogrumab into Phase 3 development for weight management.
Based on public trial timelines, completion is projected around 2027, depending on enrollment pace and follow‑up duration. Final dates may shift as the study progresses.
How does adding garetosmab to trevogrumab influence results?
You may see garetosmab included as an additional antibody targeting activin A.
In Phase 2 testing, investigators explored whether combining:
- Semaglutide + trevogrumab, and
- Semaglutide + trevogrumab + garetosmab
could further improve body composition. Early findings suggest the dual‑antibody approach may enhance lean mass preservation while maintaining fat reduction, though full comparative data remain under evaluation.
Who qualified for enrollment in the Phase 2 COURAGE weight loss study?
Participants were adults with obesity, defined as a body mass index (BMI) of 30 kg/m² or higher.
You typically needed stable health status appropriate for obesity pharmacotherapy and the ability to complete two 26‑week study periods. Standard exclusion criteria for GLP‑1–based trials, such as certain endocrine or gastrointestinal conditions, likely applied.
