The GLP-1 Muscle-Sparing Add-On Race

TL;DR: GLP-1s melt weight fast, but a real slice of it is muscle — often cited around a quarter to 40% of total loss. That “quality of weight loss” gap has become the hottest sub-theme in obesity pharma, and a pack of add-on drugs is now racing to close it. As of 2025, four names lead: bimagrumab (ActRII antibody), apitegromab (anti-myostatin antibody), trevogrumab plus garetosmab (Regeneron’s myostatin/activin double-block), and enobosarm (an oral SARM — not a peptide). All posted encouraging phase 2 data. None is approved for this use yet, and first approvals look like a 2027-2028 story. The lever that already works today is still resistance training plus enough protein.

Every incretin success story has the same asterisk. When semaglutide or tirzepatide works, the scale drops, but body-composition substudies keep showing that a meaningful fraction of what comes off is lean tissue, not fat. That is the setup for what might be the busiest race in metabolic medicine right now: a field of “muscle-sparing” add-ons, each trying to be the drug you stack on your GLP-1 so the weight you lose is almost entirely fat. This is the roundup of who is actually in that race and what their numbers say.

The problem every one of these drugs is chasing

Start with the gap, because it defines the whole category. In the flagship trials, a large minority of GLP-1 weight loss is lean mass. The STEP 1 DXA substudy put semaglutide’s split at roughly 60% fat and 40% lean; SURMOUNT-1 put tirzepatide nearer 75% fat and 25% lean. Newer readouts keep landing in that band — Regeneron’s COURAGE trial confirmed that 33% of semaglutide’s weight loss was lean mass.

Our guide to preventing muscle loss on GLP-1s covers the behavioral side of this — protein, training, pacing. The drugs below attack the same gap from the muscle side of the equation, and the pitch is identical across all of them: keep the appetite-driven weight loss, but bolt on a mechanism that independently defends muscle so the loss skews harder toward fat. Where they differ is how they defend it.

The field, at a glance

Four serious contenders, all in phase 2 for this specific use, all with 2025-era readouts.

Bimagrumab: the antibody that also burns fat

Bimagrumab is the one with the most eye-catching numbers, and we give it a full write-up in our bimagrumab and semaglutide deep dive, so the short version here. In the phase 2 BELIEVE trial, the high-dose bimagrumab-plus-semaglutide combination lost 22.1% of body weight by week 72, and 92.8% of that loss was fat mass, with lean mass falling only 2.9%. Bimagrumab monotherapy actually increased lean mass while still dropping fat.

What makes bimagrumab distinct in this field is that it blocks activin type II receptors (ActRII), the shared docking point for both myostatin and activin A. Because activin signaling also touches fat cells, it does not just spare muscle — it appears to independently mobilize fat, which is why the combination lost more total weight than either drug alone. It is a monoclonal antibody, not a peptide, dosed by intravenous infusion. Full mechanism and the arm-by-arm table live in the dedicated article.

Apitegromab: the precision myostatin play

Scholar Rock’s apitegromab took a narrower aim. Instead of blocking a receptor, it is an antibody that binds the inactive (pro- and latent) forms of myostatin before they get switched on — a more selective way to release the “stop growing” brake on muscle without touching the broader activin system.

The phase 2 EMBRAZE trial read out in June 2025 and hit its mark. Over 24 weeks in 87 adults, adding apitegromab to tirzepatide preserved 54.9% more lean mass than tirzepatide alone — participants retained about 1.9 kg (roughly 1.9 kg) more lean mass, at p=0.001. Crucially, fat loss was essentially unchanged between arms (18.8 vs 8.0 kg), so the quality of the loss shifted: the combination ran an 85% fat / 15% lean split, versus 70% fat / 30% lean on tirzepatide alone.

One nuance worth flagging: apitegromab’s lead indication is spinal muscular atrophy, where it is much further along regulatory-wise. The obesity/muscle-preservation use is the phase 2 program above, heading toward a larger trial rather than an imminent approval.

Trevogrumab and garetosmab: Regeneron’s double-block

Regeneron entered with a combination-within-a-combination. Its COURAGE trial paired semaglutide with trevogrumab (an anti-myostatin/GDF8 antibody), with or without garetosmab (an anti-activin A antibody), presented as a late-breaker at EASD in September 2025.

The 26-week results confirmed the now-familiar baseline — 33% of semaglutide’s weight loss was lean mass — and showed that adding trevogrumab prevented about half of that lean-mass loss. The interesting part was the triple stack: layering garetosmab on top enhanced fat reduction by 27.3% over semaglutide alone while preserving more than 80% of lean body mass. That mirrors the bimagrumab logic — hit activin A as well as myostatin and you get an extra fat-loss kick, not just muscle defense — but does it by combining two separate antibodies instead of one dual-blocker.

Enobosarm: the oral outsider (and not a peptide)

Enobosarm is the odd one out, and worth being precise about. Veru’s candidate is a selective androgen receptor modulator (SARM) — a small oral molecule that stimulates the androgen receptor in muscle. It is not a peptide, not an antibody, and not a myostatin drug. Different class entirely, taken as a daily pill rather than an injection.

Its phase 2b QUALITY study added enobosarm to semaglutide (Wegovy). Across the group, enobosarm cut lean-mass loss by 71% versus placebo at 16 weeks (p=0.002); at the 3 mg dose that advanced to phase 3, lean mass was essentially fully preserved (p<0.001), and 99% of the weight lost was fat. A 12-week maintenance extension added a second selling point that none of the antibodies have shown yet: after semaglutide was stopped, the 3 mg dose reduced body-weight regain by 46% and prevented fat regain, where the placebo group regained 43% of what it had lost. That regain angle ties directly into our guide on stopping GLP-1s without regaining weight. Veru has since had a productive FDA meeting and is moving 3 mg into a phase 3 program.

The mechanistic map: three different bets

Strip away the trial names and the field sorts into three classes, each making a different wager on how to keep muscle.

• Myostatin/activin pathway inhibitors — the antibody-heavy majority. Bimagrumab (blocks the ActRII receptor), apitegromab (mops up latent myostatin), trevogrumab (blocks myostatin/GDF8), and garetosmab (blocks activin A) all release the same molecular brake on muscle growth, just at different points in the pathway. Follistatin sits conceptually next door as the body’s own myostatin sponge, which is why it draws so much research interest — see our follistatin-344 explainer.
• SARMs — enobosarm, alone in its lane. It drives muscle through the androgen receptor rather than by lifting the myostatin brake, and it is oral. Different mechanism, different molecule class, different route.
• The DIY reality — worth naming, because it is where most self-directed experimentation actually happens. None of the drugs above are available for this use, so people reach for what they can get: resistance training and protein first, and sometimes muscle-oriented research peptides like the IGF-1 variants or follistatin analogues. These are far less studied for the GLP-1 muscle problem specifically, and none has trial data resembling the readouts above.

Here is the cleanest cross-agent view — the lean share of total weight lost, where lower means the loss skewed more toward fat. Read it as a rough field map, not a head-to-head: these come from separate trials with different GLP-1s, doses, and durations.

The spread is real, but so is the caveat baked into the caption: a 16-week SARM readout and a 72-week antibody readout are not the same experiment, and the enobosarm 3 mg figure comes from the arm that performed best. The honest takeaway is directional — every one of these agents shifted the composition of weight loss toward fat, and the pathway drugs and the SARM both cleared the bar in phase 2.

The honest state of play

Here is where the forward-looking excitement has to meet the calendar. Every drug in this roundup is a phase 2 result. Bimagrumab’s BELIEVE, apitegromab’s EMBRAZE, Regeneron’s COURAGE, and enobosarm’s QUALITY are all proof-of-concept tiers — randomized, DXA-measured, genuinely encouraging, but one rung below the phase 3 programs that produced the GLP-1 approvals themselves. None is approved for muscle preservation during weight loss. The phase 3 trials are only now spinning up, which puts realistic first approvals somewhere around 2027-2028, assuming the effects hold at larger scale and longer duration.

There is also an open question the trials have only started to touch: preserving lean mass is not automatically the same as preserving function and bone. Enobosarm’s stair-climb-power signal is a promising hint, and bone density during rapid weight loss is its own emerging concern — see our note on GLP-1s and bone density — but strength and skeletal outcomes are where the next round of data will really be judged.

So the mellow, honest conclusion is the same one that opened the article. The muscle-sparing add-on race is one of the most interesting things happening in obesity pharma, and the 2025 readouts are legitimately good. But the lever that is proven and available right now is not in a vial you are waiting on — it is resistance training two to three times a week and enough protein to support it. The drugs are coming. The training works today. If GI side effects are what is keeping food and protein down, our side-effect management guide is the practical companion while the pipeline matures.

Frequently asked questions

Which muscle-preservation drug is winning the GLP-1 add-on race?

There is no crowned winner yet — all four leaders are phase 2. On raw quality-of-loss numbers, bimagrumab and enobosarm posted the most dramatic shifts (fat made up roughly 93% and 99% of weight lost in their top arms), while apitegromab and trevogrumab showed clear, statistically significant lean-mass preservation. But these came from separate trials with different GLP-1s and durations, so cross-comparisons are directional, not definitive. The real ranking waits on phase 3.

Are any of these approved to take with a GLP-1 yet?

No. Bimagrumab, apitegromab, trevogrumab, garetosmab, and enobosarm are all in clinical development for muscle preservation during weight loss, none of them approved for that use. Phase 3 programs are beginning, which points to realistic first approvals around 2027-2028 if the phase 2 effects hold up in larger, longer trials.

Is enobosarm a peptide?

No — this is a common mix-up. Enobosarm is a selective androgen receptor modulator (SARM), a small oral molecule that works through the androgen receptor. It is not a peptide, not an antibody, and does not act on the myostatin pathway the way bimagrumab, apitegromab, and trevogrumab do. It is also taken as a daily pill rather than injected.

How is apitegromab different from bimagrumab?

Both target the myostatin/activin brake on muscle, but at different points. Apitegromab is a highly selective antibody that binds inactive myostatin before it is switched on, leaving the wider activin system alone. Bimagrumab blocks the ActRII receptor itself, the shared docking site for myostatin and activin A — a broader block that also appears to independently drive fat loss, which is why bimagrumab’s combination lost more total weight while apitegromab’s kept fat loss roughly unchanged and simply improved its composition.

What can I actually do about muscle loss on a GLP-1 today?

The proven, available lever is resistance training two to three times weekly plus adequate protein (commonly cited around 1.2-1.6 g/kg/day) — the specifics are in our preventing muscle loss on GLP-1s guide. The pharmacological add-ons in this article are not available for this use yet, so training and protein remain the strategy with the strongest evidence behind it right now.

References

1. Heymsfield SB, et al. Bimagrumab plus semaglutide alone or in combination for the treatment of obesity: a randomized phase 2 trial (BELIEVE). Nature Medicine. 2026. doi:10.1038/s41591-026-04204-0.
2. Scholar Rock, Inc. Scholar Rock Reports Positive Phase 2 EMBRAZE Trial Results Demonstrating Statistically Significant Preservation of Lean Mass with Apitegromab During Tirzepatide-Induced Weight Loss. Press release, June 2025.
3. Apitegromab for lean mass preservation during tirzepatide-induced weight loss: a randomized, double-blind, placebo-controlled phase 2 trial. Nature Medicine. 2026. doi:10.1038/s41591-026-04440-4.
4. 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, Presented at EASD. Press release, September 2025.
5. Veru Inc. Veru Reports Positive Results from Phase 2b QUALITY and Maintenance Extension Study: Enobosarm Reduced Body Weight Regain, Prevented Fat Regain, and Preserved Lean Mass After Semaglutide Discontinuation. Press release, June 2025.
6. Look M, et al. Body composition changes during weight reduction with tirzepatide in the SURMOUNT-1 study. Diabetes, Obesity and Metabolism. 2025. doi:10.1111/dom.16275.

For research and educational use only. This article summarises published literature and is not medical advice or a personal dosing recommendation.