This article is educational and summarizes published research and news reports. It is not medical advice. Retatrutide, EloraTZP, CagriSema, and trevogrumab are investigational and not FDA-approved. Talk to your prescriber before making any medication decisions.
The 30-second answer
When you lose weight on any program, including GLP-1 medications like Wegovy or Zepbound, some of that weight comes from lean mass, not just fat. Lean mass includes muscle, which matters for strength, metabolism, balance, and healthy aging.
Drugmakers are now testing medications that could be taken alongside a GLP-1 to protect muscle. The newest data, presented at the European Association for the Study of Diabetes meeting in Milan, show one of these medications, trevogrumab, substantially reduced lean mass loss over a full year. It is a meaningful step, though still years from your pharmacy.
Why muscle loss on GLP-1s matters
GLP-1 medications have transformed weight loss, but Regeneron's release noted that "the quality of GLP-1 receptor agonist-induced weight loss can be negatively affected because these agents can cause profound muscle loss" (Regeneron).
Some lean mass loss is expected and normal with any significant weight loss, because a smaller body needs less supporting tissue. The concern is greatest for:
- Older adults, who naturally lose muscle with age and face higher fall and frailty risk.
- People with sarcopenia, a condition of low muscle mass and strength.
- Anyone losing weight very quickly, since the COURAGE trial found the greatest lean mass loss happened during the first six months, when weight loss was fastest.
Boaz Hirshberg, MD, of Regeneron said muscle loss is "an increasing concern – particularly for people with sarcopenia, older adults and others where frailty is a real concern."
Trevogrumab: the COURAGE trial
Trevogrumab is an antibody that blocks myostatin (also called GDF8), a natural protein that limits muscle growth. Blocking it is meant to let muscle hold on during weight loss.
| Detail | COURAGE Phase 2 trial |
|---|---|
| Who | Adults with obesity (BMI 30 or higher) |
| Comparison | Semaglutide 2.4 mg alone vs. semaglutide plus trevogrumab 25 mg or 75 mg |
| Duration | 52 weeks (primary endpoint) |
| Measurements | DXA scans for lean mass, MRI substudy for thigh muscle volume |
| Status | Presented at EASD 2026; in press at The Lancet |
Source: Regeneron press release.
Lean mass results (DXA)
| Group | Lean mass change at 26 weeks | Lean mass change at 52 weeks | Lean mass preserved at 52 weeks |
|---|---|---|---|
| Semaglutide alone | −6.7% | −7.3% | — |
| + Trevogrumab 25 mg | −4.7% | −5.8% | 20.5% |
| + Trevogrumab 75 mg | −3.3% | −4.2% | 42.5% |
Preservation is relative to semaglutide alone. At 26 weeks, the 75 mg dose preserved 50.7% of lean mass that would otherwise have been lost (Regeneron).
Muscle volume results (MRI)
In the MRI substudy, which measured thigh muscle volume directly, lower-dose trevogrumab preserved almost 70% of the muscle that would have been lost on semaglutide alone. At 52 weeks, the 25 mg dose preserved 71.8% and the 75 mg dose 68.9%.
Lead investigator Julio Rosenstock, MD, of UT Southwestern Medical Center said the results were "sustained through a full year of treatment" and "further validated by MRI measurements of muscle volume."
What trevogrumab did not do
- It did not add weight loss. Lower-dose trevogrumab did not meaningfully change total weight loss compared with semaglutide alone. Its job is to change the composition of what is lost, not the amount.
- It did not prevent all lean mass loss. Even with the best dose, participants still lost about 4% of lean mass over a year.
Safety
Lower doses were generally well tolerated. About 77% of trevogrumab participants had at least one side effect, compared with 82% in the comparison group, with nausea, constipation, diarrhea, and vomiting the most common. Those are typical semaglutide side effects. A separate arm of the trial, which combined trevogrumab with another muscle-targeting antibody called garetosmab, was reported to have notably higher side-effect rates (Reuters).
Who might benefit most
A pre-specified analysis looked at participants who already had low lean mass at the start, using the Foundation for the National Institutes of Health definition of sarcopenia. They lost more lean mass on semaglutide alone and saw numerically more preservation when trevogrumab was added. Regeneron is now planning a Phase 2 trial in older adults with obesity and reduced muscle mass or strength.
Northwestern's RNA therapy (early research)
A separate study took a very different approach. Instead of blocking a muscle-limiting protein, Northwestern University scientists targeted fat itself (Northwestern).
The experimental therapy is a small strand of RNA that silences a gene called ZFP423. That gene acts as a brake on white fat's ability to turn into "beige" fat, which burns energy by producing heat. With the brake released, mice burned more calories.
| Mouse results | RNA therapy + semaglutide | Semaglutide alone |
|---|---|---|
| Lean mass lost | 5.5% | About 10% |
| Body fat at end of treatment | 4 grams | Nearly 8 grams |
The combination also improved glucose tolerance and other measures of metabolic health. Senior author Dr. Joseph Bass said, "We have identified, for the first time, an RNA therapy that promotes thermogenesis and, when combined with the GLP-1 drug semaglutide, helps preserve lean muscle mass." The work was published in the Proceedings of the National Academy of Sciences and developed with Ionis Pharmaceuticals.
Important: this was a mouse study. Northwestern scientists are now testing similar RNA therapies in human cells. Many promising mouse results do not carry over to people, so treat this as early-stage science.
Where the muscle-preservation field is heading
| Approach | Example | Stage |
|---|---|---|
| Block myostatin to protect muscle | Trevogrumab (Regeneron) | Phase 2 complete; older-adult trial planned |
| Turn on fat burning to shift what is lost | ZFP423-silencing RNA (Northwestern / Ionis) | Animal studies |
| Diet and exercise | Protein targets, resistance training | Proven and available now |
Retatrutide may add another twist. Experts at EASD noted that the full TRIUMPH-2 results did not include body composition data, and the glucagon component of retatrutide could affect muscle in either direction. TRIUMPH-3 includes DEXA scans to answer that question. See our TRIUMPH-2 breakdown.
Why lean mass is not the same as muscle
You will see two different terms in muscle research, and they are not interchangeable:
- Lean mass (measured by DXA scans) includes everything that is not fat or bone: muscle, organs, water, and connective tissue. Some lean mass loss during weight loss reflects organs and fluids adapting to a smaller body, which is normal.
- Muscle volume (measured by MRI) looks at skeletal muscle directly, in this case the thigh.
That is why the COURAGE MRI results are notable. They suggest that trevogrumab's effect was not just on water or other lean tissue but on actual muscle. In the semaglutide-only group, fat-free thigh muscle volume fell by an average of 1.03 units over a year on MRI, compared with 0.29 to 0.32 in the trevogrumab groups, or roughly a third as much (Regeneron).
What researchers still need to show is whether preserved muscle translates into better strength, mobility, and long-term health, especially in older adults. That is what Regeneron's planned trial in older adults is designed to explore.
Who should pay the most attention to muscle
Everyone on a GLP-1 benefits from protecting muscle, but some people have more at stake:
- Adults over 60, who are already losing muscle naturally each year.
- People who lose weight very fast, since COURAGE found lean mass loss was steepest during the fastest phase of weight loss.
- People eating very little because of strong appetite suppression. If you are regularly under your protein target, muscle is at risk.
- People who are sedentary or have joint problems that limit exercise.
- Anyone on higher-efficacy medications. As next-generation options like retatrutide and EloraTZP push average weight loss above 20%, the muscle question gets bigger.
If you fit one of these groups, talk to your prescriber about a body composition baseline and consider working with a dietitian or trainer familiar with GLP-1 care.
What you can do today
You do not need to wait for a new medication to protect your muscle. The tools that work right now are simple, if not always easy:
1. Hit your protein target
Many people on GLP-1s eat so little that protein falls short. A common evidence-based target during weight loss is 1.2 to 1.6 grams of protein per kilogram of body weight per day, adjusted for your situation. Use our protein needs calculator to find your number, and see our protein strategy guide for practical ways to get there with a small appetite.
2. Lift something, two to three times a week
Resistance training is the strongest signal you can give your body to keep muscle. Bands, bodyweight exercises, and dumbbells all count. Our GLP-1 muscle loss prevention guide includes a beginner-friendly plan.
3. Pay attention to the first six months
The COURAGE data showed the steepest lean mass loss happened early, when weight came off fastest. That is the window to be most consistent with protein and training.
4. Track more than the scale
Waist measurements, strength in the gym, and how your clothes fit tell you more about body composition than weight alone. If you have access, a DXA scan can give a precise baseline.
Frequently asked questions
Do GLP-1 medications cause muscle loss?
Some lean mass loss happens with any significant weight loss, including on GLP-1s. In the COURAGE trial, people on semaglutide alone lost 6.7% of lean mass at 26 weeks and 7.3% at 52 weeks.
What is trevogrumab?
Trevogrumab is an investigational Regeneron antibody that blocks myostatin (GDF8), a protein that limits muscle growth. In COURAGE, adding it to semaglutide reduced lean mass loss by up to about half.
Is trevogrumab available?
No. It has not been evaluated by any regulatory authority. Regeneron is planning another Phase 2 trial in older adults with obesity and low muscle mass or strength.
How can I protect muscle on a GLP-1 now?
Prioritize protein (often 1.2 to 1.6 g per kg of body weight daily during weight loss), do resistance training two to three times a week, and be most consistent during the first six months, when muscle loss is fastest.
Does trevogrumab increase weight loss?
No. Lower-dose trevogrumab did not meaningfully change total weight loss. Its effect is on the composition of weight lost, preserving more muscle.
The bottom line
Muscle-preserving medications are moving from theory to real data, and trevogrumab's one-year results are encouraging. They are still years from approval. In the meantime, protein and strength training remain the most effective, accessible way to make sure the weight you lose is mostly fat.
Sources
- Regeneron: Phase 2 COURAGE trial results (October 1, 2026)
- Reuters: Regeneron drug halves muscle loss with semaglutide
- Northwestern University: RNA therapy may help preserve muscle during GLP-1 weight loss
Educational content written by Rolando Valenzuela, founder of GLPTree. Not medical advice. Talk to your prescriber before starting, stopping, or switching any medication.