GLP-1 receptor agonists—drugs like semaglutide/Ozempic®/Wegovy® and tirzepatide/Mounjaro®/Zepbound®—are an ongoing medical revolution, helping people lose substantial weight, manage diabetes, and much more. The one potentially worrisome downside to all of that rapid weight loss is the loss of lean mass. We were early to highlight this potential risk, and also to discuss the nuances of this effect.
While some online personalities are exaggerating the magnitude and effects of the loss of lean mass on these drugs, the risk of losing too much muscle and bone during rapid weight loss is very real, regardless of whether it is achieved via GLP-1-RAs or diet and a lot of cardio. It is therefore imperative that people using these medications use the best tools in the toolkit—resistance training and a higher-protein diet—to hold onto as much lean mass as possible when losing weight with them.
But adherence to resistance training is low: just 30.2% of Americans meet the CDC guideline of performing resistance training two or more times a week, and 57.8% do none at all.1 Many people intensely dislike exercise or lack motivation; injuries can make it difficult for people to exercise; and even able-bodied and highly motivated people can find the financial and logistical barriers to keeping up a consistent resistance training program insurmountable—and our Medicine 2.0 healthcare system is ill-equipped to support and motivate patients.
Recognizing these barriers, the biotech industry is working on an alternative approach: drugs that would counter the risk of muscle loss by stimulating muscle growth—or at least minimizing muscle loss—in people taking GLP-1-RAs.2 If successful, such drugs might find expanded uses in countering muscle loss due to cancer, aging, or disease, keeping people independent and able to do the things they love.
But as these drugs wend their way through clinical trials, a mystery is emerging—or rather, re-emerging, as this movie is a remake. Multiple drugs are showing that they can add lean mass to people’s frame, or slow down the rate at which it is lost on GLP-1-RAs—and yet some of the most prominent fail to deliver commensurate benefits in strength.
A muscle-might mismatch
This June, we got the results of a Phase II trial with apitegromab, one of the latest of such drugs.3 Like many candidate muscle-building drugs, it works by inhibiting signaling by myostatin, a signaling factor produced and released by muscle cells that inhibits muscle growth. Myostatin made a huge splash in bodybuilding circles starting in the late 1990s, as cases were reported of mice,4 cattle,5,6 and even human children7 with cartoonishly large muscles resulting not from special training, but from mutations that disabled their myostatin.
These myostatin mutants were taken as proof-of-concept for drugs that effectively inhibit it, which ought to increase a person’s lean mass—or preserve it during weight loss. Inevitably, these findings led to a black market of purported myostatin-blocking peptides;8 the fact that such peptides have neither disrupted the market for anabolic steroids and “recreational” testosterone nor captured a substantial slice of the current boom in grey-market peptides speaks negative volumes on their efficacy. Relative to nebulous claims of ‘energy’ (SS-31) or whether your elbows feel better (BPC 157), sustained muscle hypertrophy is little influenced by placebo effects.
In the meantime, researchers have developed multiple approaches to target the myostatin pathway at multiple points and with multiple approaches, largely without success.9 Apitegromab is the latest approach to the myostatin problem: an antibody that binds to a precursor to myostatin and a latent (inactive) form of it. This prevents the release of active, mature myostatin and its subsequent binding to its receptor on the muscle surface. Animal studies support its potential: a mouse version of apitegromab caused a 19% surge in the mass of mice’s major calf muscles, and allowed them to generate 16–18% more isometric muscle force.10 The results were even more impressive in the EDL muscle (which runs from the outside of the knee to the top of the foot), where mouse apitegromab increased muscle weight by 34% and increased maximal force production by 20–29%.10
Apitegromab was originally developed to treat spinal muscular atrophy (SMA), a congenital muscle disorder. It showed preliminary signs of efficacy in early-stage clinical trials,11 but its Phase III trial results were ambiguous: While it met its primary endpoint, which was an improvement on a motor function scale in all patients combined, the results in patients on the higher dose (20 mg/kg) did not reach statistical significance versus placebo (least-squares mean difference of 1.4 points (95% CI −0.34 to 3.13; P=.11), while the lower dose (10 mg/kg ) showed a larger effect (2.2-point difference, nominal p =.0121), dragging up the overall result.12 This is the opposite of what you’d expect from a dose-response perspective. Having met its primary outcome, however, FDA approved it for SMA.13
And recently, the company reported results from the Phase II EMBRAZE trial, testing apitegromab’s ability to help people hold on to lean mass while losing weight on tirzepatide.3 In EMBRAZE, 102 overweight or obese people were randomized 1:1 to receive either apitegromab or placebo on top of tirzepatide for weight loss for 24 weeks. Both groups lost a similar amount of body weight (roughly 12 kg, or 26 pounds), but what they lost was very different: people on apitegromab lost 1.6 kg (80% confidence interval (CI) 0.8−2.3) of lean mass and 8.5 kg (7.4−9.6) of fat, versus 3.5 kg (2.8−4.1) of lean mass and 8.0 kg (7.0−9.0 of fat in the placebo.3 Thus, only 14.6% (10.5−18.7%) of the weight lost on tirzepatide plus apitegromab was lean mass, versus twice that proportion (30.2% (26.4−33.9%)) on tirzepatide plus placebo. Looking at it from the opposite side, about 85% of the total weight loss among people who received apitegromab was fat, versus just roughly 70% of the weight in those who received placebo.3
At the end of the 24 weeks, the investigators withdrew both apitegromab and tirzepatide and observed the volunteers for an additional 8 weeks. As you would expect, people in both groups began regaining weight—but surprisingly, both groups regained lean mass more quickly than fat.3 That’s a counterintuitive pattern, but it has precedents: this general pattern was previously observed with semaglutide14 and liraglutide, an older GLP-1-RA.15
And there was another surprise in the results. Having held onto an extra four and a half pounds of lean mass, you would think that the apitegromab group would hold onto a corresponding amount of extra strength. But it’s not clear that they did. Study participants ran through two strength tests before and after the study: repetitive sit-to-stand tests (like a bodyweight squat) and grip strength. At the end of the 24 weeks of the trial proper, the tirzepatide-plus-apitegromab group was able to do an average of 2.4 (standard deviation (SD) 3.0) more sit-to-stand reps, while the tirzepatide-plus-placebo group gained a very similar 2.2 (SD 2.5) more reps.3
The apitegromab group also didn’t hold onto any more grip strength: on average, they gained 0.9 (SD 6.9) kg of squeezing force, while the tirzepatide-plus-placebo group lost an average of 0.3 (SD 8.5) kg.3 The headline numbers are in opposite directions, but they weren’t statistically significantly different (p ≈ 0.72), and you can see from the standard deviation that there was enormous variability around the mean effect. And to put those numbers in context, we’re talking about a nominal difference in changes of about one kilogram of grip strength,3 whereas the median grip strength for people the same age as those in the trial is over 38 kg.16
The bimagrumab bust
As already alluded, this isn’t the first time an agent that targets the myostatin pathway has been reported to increase lean mass (or prevent its loss) without clearly resulting in an associated strength gain. A prominent example of this is bimagrumab, a monoclonal antibody originally developed by Novartis. Bimagrumab targets ActRIIs, the receptors to which myostatin binds to send its muscle-limiting signal. When bimagrumab binds to these receptors, it blocks myostatin and other ligands from binding to them, which ought to lead to muscle mass gains.
Like apitegromab, bimagrumab was originally developed to treat rare muscle diseases including sporadic inclusion body myositis (sIBM),17 a poorly-understood disease of aging muscle loss that involves inflammation and aggregated beta-amyloid, a protein better known for its role in Alzheimer’s disease. sIBM made particular sense as a first indication, since a key protein that transmits the myostatin signal downstream of ActRII is hyperactivated in sIBM relative to other muscle-wasting diseases.
A preliminary clinical trial seemed to go well: When tested for 16 weeks in 14 people with sIBM, bimagrumab led to significant increases in thigh muscle volume on MRI—the gold standard for measuring muscle—and a 14.6% greater 6-minute walking test (6MWT) (p = 0.008) compared with placebo. And in a subsequent one-year Phase IIb trial in 105 subjects with sIBM, patients on the higher two of three doses of bimagrumab gained more lean mass than people on placebo (a 5.8% difference in the highest-dose group, p<0·0001). However, in this larger, longer trial, there was no difference in 6MWT or in the risk of falls relative to placebo.18
The same pattern occurred when Novartis trialed bimagrumab in sarcopenia, the loss of muscle mass and strength as a result of aging processes. An initial trial found that bimagrumab increased muscle volume, and in a subgroup analysis, the subjects with the slowest walking speeds improved on their 6MWT.19 Although other researchers cast some doubt on the trial,20 Novartis followed up with a late-stage trial of bimagrumab in people over the age of 70 who met the clinical criteria for sarcopenia. The investigators worked to maximize the chances for muscle gain in all subjects: both bimagrumab and placebo groups received protein and vitamin D supplements, dietary counseling every two weeks, and a home-based exercise routine.
Despite being administered the same lifestyle regimen, subjects in the bimagrumab group gained more muscle in their arms and legs than subjects in the placebo group with a placebo: 7% and 1%, respectively. But once again, bimagrumab failed to significantly improve any of the measures of muscle function and mobility relative to placebo.21
Similar decouplings appeared in clinical trials in healthy young men22 and older adults who had suffered a hip fracture.23 Novartis then funded a trial to test if bimagrumab would improve body composition and blood sugar management in overweight and obese adults with type 2 diabetes. The trial was successful on those outcomes,24 but, surprisingly, Novartis decided that obesity was not a strategic priority and shelved the antibody.25
But some of Novartis’ employees—including Lloyd Klickstein, a two-time guest on The Drive—felt differently, and in 2021, they established Versanis Bio, a small Oakland, California biotech startup that licensed the rights for US$70 M, just in time to meet a new opportunity: the GLP-1-RA revolution, and the concerns about lean mass loss. In 2023, after a positive initial study, Eli Lilly acquired Versanis—and with it, bimagrumab—for US$1.92 billion.
In their latest trial,26 507 adults who were either obese or overweight with at least one obesity-associated complication other than diabetes were randomized to receive one of two doses of bimagrumab, one of two doses of semaglutide plus placebo, or one of two doses each of bimagrumab and semaglutide.
People on high-dose bimagrumab had lost 9.3 kg; those who had received higher-dose semaglutide plus placebo lost 14.2 kg; and people on high-dose combination therapy lost 17.8 kg—versus just 3.3 kg in the all-placebo group. But the larger difference was in where the weight loss came from. One hundred percent of the weight loss in the bimagrumab-only group came from fat. By contrast, about 28% of the weight loss in the semaglutide-plus-placebo groups came from lean body mass. And in all four combinations of bimagrumab plus semaglutide, less than 10% of the weight lost was lean mass.26
But once again, it was a different story for functional measures. There was a trend toward an increase in grip strength in the bimagrumab-only groups, but it was not significantly different from the high-dose semaglutide groups—and there was not even a trend in the combination therapy groups, despite the significant differences in retained lean mass. There were no differences at all between groups on the 36-Item Short Form Health Survey (SF-36) Physical Functioning score. And while the volunteers on the highest dose of bimagrumab in combination with semaglutide did show a statistically significant improvement relative to placebo on another self-reported physical function test (Impact of Weight on Quality of Life-Lite Clinical Trials Version (IWQOL-Lite-CT) Physical Function score), the scores in these groups were similar to those of people on higher-dose semaglutide alone, and no dose of bimagrumab alone improved scores.26
More weak outcomes
Apitegromab and bimagrumab are not alone: multiple candidate therapies that inhibit some node in the myostatin pathway, using a variety of targeting strategies, demonstrated efficacy in animal models and advanced into randomized, double-blind, placebo-controlled trials for Duchenne muscular dystrophy and other muscle-wasting diseases. Not all of them even increased muscle mass, and none of them improved physical function.27
And closer to the longevity medicine space, there are other paradoxical findings. Muscle mass and strength decline with age even in people who perform resistance training, and you might wonder if an age-related rise in myostatin might explain it. But in men, myostatin levels behave oppositely to what you would expect: myostatin levels progressively rise with age up to about age 57, during most of which time period lean mass is flat, but then they decline thereafter, during the time when muscle mass clearly also falls.28 Even more paradoxically, fitter, more active, and non-frail nursing home residents have higher myostatin levels than their less-fit peers—and levels increase rather than decrease after a physical exercise program.29
Myostatin isn’t the only example of this phenomenon, either. A 1990 study with human growth hormone (hGH) for example, showed that men gained lean mass while losing fat.30 A wave of widespread use by would-be longevity medicine providers ensued.31 When similar protocols were tested in larger controlled trials, the effect on lean mass was confirmed—but with only two exceptions (small trials with 1432 and 1033 total participants, respectively—and the former was a split decision), trial after trial failed to find an effect on strength or functional outcomes.34-38 In one trial, for instance, there were no statistically or clinically significant differences between the hGH-treated groups and placebo in knee extension or flexion strength, grip strength, or VO2max.38
How can this be?
The decoupling of lean mass gains from strength in these studies is a mystery. One possible explanation would be that although these agents increase lean mass, they might not be increasing muscle, since “lean mass” includes not only muscle, but internal organs, skin, bone, hydration, and other things in the body other than adipose tissue. This seems to be at play in the case of hGH: studies found hGH had no effect on direct measurements of muscle cross-sectional area37,39,40 and was reported to increase the percentage of Type II fibers in one small trial,40 but had no effect in another.39
This doesn’t seem likely to be the issue with bimagrumab, however: several studies specifically looked at muscle volume using MRI, and confirmed that it does increase the amount of actual muscle.18,19,22 No completed human trial of apitegromab has done this yet: EMBRAZE used DEXA-derived lean mass, whose limitations we’ve already alluded to, and others have relied on functional assessments. Muscle MRI is planned for the Phase II FORGE trial (NCT07435129) in a form of muscular dystrophy, but we aren’t expecting results from FORGE until the end of 2028.
The next thing to say is that the disconnect between muscle mass and function on agents that inhibit parts of the myostatin pathways goes even further back than the human clinical trials. In an early study, researchers knocked out the myostatin gene in mice, producing rodents with the expected Hulk-like proportions—but no increase in maximum muscular force production.41 The result was that the myostatin knockout mice effectively had weaker muscles when measured as force per unit of cross-sectional area than wild-type controls. Previous studies in mice with a model form of muscular dystrophy 42 similarly found increased muscle mass, but that the muscles were disproportionately weak, and the same thing happened in a study of a myostatin inhibitor antibody in wild-type mice.43
To date, no one has resolved this paradox, though many non-exclusive hypotheses have been put forward. One is that inhibiting the activin-myostatin pathway increases the amount of some component of muscle volume other than the contractile units that actually allow our muscles to produce force.41 Another suggestion is that the tremendous growth induced by these approaches might somehow disrupt the proper alignment of the muscle fibers with the tendon and bone, impairing its ability to efficiently pull on the limb in which it’s inserted.41
Or perhaps the rapid gain in muscle mass is not coupled with enough of the necessary “wiring” of neuromuscular junctions to allow a person (or a mouse) to fire their target muscles.44,45,46 The extra muscle might grow so fast that it doesn’t develop an adequate blood supply,47 or might somehow develop fibrosis (dysfunctional connective tissue) that masquerades as muscle and impairs its function.48
It’s also possible that some of the disconnect is related to myostatin’s role in development. In the developing animal, muscle fibers lengthen as part of the animal’s growth and when scientists take the myostatin brakes off, they lengthen even more.49 But in adulthood, we are only able to add on more protein to existing fibers with fixed lengths, so adult humans may not be able to capture something important about myostatin pathway inhibition—or strong suppression might even cause dysfunctional changes when imposed outside of its developmental role.
None of these hypotheses have been adequately tested, and some are pure speculation. What seems clear is that while drugs that work through the activin-myostatin pathway add lean mass, the strength gains are lagging. That doesn’t make them useless—the extra fat loss is valuable on its own, and the reserve of lean mass can be crucial to survive and recover from illness or injury, during which disease processes and bedrest often conspire to melt away lean tissue. But they don’t deliver what’s most important about muscle: Strength.
That doesn’t mean we should give up on any possibility of a useful muscle-booster for GLP-1-RA users. Last year, biotech company Veru Inc. announced the results of a Phase IIb trial with their resurrected drug enobosarm as a muscle-sparing add-on to semaglutide.50 Enobosarm is a selective androgen receptor modulator (SARM), meaning that it is a non-steroid molecule that binds to the same receptors as steroids, but is intended to reduce the side-effects of true steroids by selectively targeting androgen receptors in muscle and bone while sparing receptors in other places like the prostate and sebaceous glands.
Enobosarm has a long and torturous history of failed development (as well as a long history on the black market as an anabolic steroid alternative), but the initial results of this trial for this indication look favorable. Subjects who received enobosarm rather than placebo on top of semaglutide lost a statistically indistinguishable amount of total weight, but lost 71% less lean body mass but 27% more fat mass, according to the company press release.50 And unlike with apitegromab or bimagrumab, this lean mass preservation was accompanied by strength benefits: 42.6% of people in the placebo-plus-semaglutide group suffered a decline in their stair-climb strength of at least 10%, versus less than half as many (19.4%) in the enobosarm-plus-semaglutide group.50 And a previous trial, outside of the weight loss realm, found that enobosarm increased stair-climb power compared to placebo (+16% versus 7%), along with moderate increases in lean body mass, reductions in fat mass, and better stair-climb speed.51
Whatever underlies the decoupling of lean mass gains or preservation with apitegromab, bimagrumab, and others in their family, and whatever the fate of enobosarm as a muscle-sparing adjuvant for GLP-1-RA users, the most important intervention for building strong muscles will remain resistance training. Resistance training also strengthens tendon and bone, which bimagrumab and apitegromab do not. And it improves metabolic health, possibly independent of the muscle gain.52 Muscle strength is more closely associated with risk of mortality than lean body mass53 or muscle volume.54 And whether you’re on a muscle-building drug or not, expressing strength is not just a matter of muscle mass, but of the learned skill of controlling that muscle, built one rep at a time.
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Veru Announces Positive Topline Data from Phase 2b QUALITY Clinical Study: Enobosarm Preserved Lean Mass in Patients Receiving WEGOVY® (Semaglutide) for Weight Reduction. Veru Inc. Accessed September 24, 2026. https://ir.verupharma.com/news-events/press-releases/detail/225/veru-announces-positive-topline-data-from-phase-2b-quality
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