Pharmacological intervention: Challenges and promising outcomes for fat loss and preservation of lean body mass in the treatment of overweight and type 2 diabetes

Abstract

Treatment with GLP‐1 receptor agonists (GLP‐1 RAs) is effective in reducing body weight in individuals with overweight and type 2 diabetes (T2D). However, measurements indicate that a considerable portion of the weight loss derives from fat‐free mass (FFM), including skeletal muscle, which may compromise metabolic health and physical function. We aimed to evaluate the evidence for the ability of pharmacological interventions to preserve or increase lean body mass (LBM) during weight loss with GLP‐1 RAs, assess their clinical potential and limitations, and identify knowledge gaps requiring further research. A literature review was conducted using PubMed, JAMA, Wiley, ResearchGate, The Royal Danish Library, and ClinicalTrials.gov. Included were preclinical and clinical studies on compounds with documented anabolic effects and established safety profiles. The primary outcomes assessed were changes in LBM, fat mass (FM), physical function, and adverse events. Activin II receptor inhibition with bimagrumab demonstrated significant preservation and increases in LBM, along with FM reduction, in both preclinical and phase 2 studies in individuals with overweight and T2D. Similar effects were observed for myostatin and activin A inhibitors (trevogrumab, garetosmab), latent myostatin inhibitors (apitegromab, SRK‐439), and Selective Androgen Receptor Modulators (enobosarm). Notably, enobosarm also improved physical function. Adverse events were generally mild and reversible; however, long‐term data remain limited. Pharmacological adjunct therapies show potential for improving body composition and physical function during GLP‐1 RA‐induced weight loss. Preliminary findings are promising, but larger, controlled trials are necessary to confirm efficacy and safety before clinical implementation can be considered.

1. INTRODUCTION

The global rise in obesity and type 2 diabetes (T2DM) has intensified the search for effective weight loss strategies. In this context, glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) have emerged as potent treatments for diabetes and obesity ¹ promoting significant weight loss. However, recent research suggests that a substantial portion of the weight loss achieved with these agents may also include a loss of muscle mass. Nevertheless, uncertainty remains regarding this. ²

Drugs originally developed to combat cachexia, muscle degeneration, and aging have been shown to counteract this muscle loss in both mice and humans, ³ and with the advent of a new wave of anti‐obesity medications, new opportunities have arisen in an otherwise underprioritized area of pharmaceutical research. This particularly involves drugs classified as myostatin inhibitors, selective androgen receptor modulators (SARMs), Mas receptor agonists, and selective thyroid hormone receptor‐beta agonists, which may upregulate muscle mass and thereby preserve lean body mass during GLP‐1 RA‐induced weight loss. All of these agents have demonstrated efficacy in preserving lean body mass (LBM ¹ ), and some even indicate improved physical function ⁴ and additional fat mass reduction compared to GLP‐1 RA monotherapy. ⁵ However, none are yet FDA‐approved for combination therapy with weight loss medications, but several promising studies are underway. Until the endpoints of these studies are released, weight loss treatment should be supplemented with exercise and adequate protein intake to prevent lean body mass loss. ⁶

1.1. Changes in body composition associated with GLP‐1 RA treatment

GLP‐1 receptor agonist (GLP‐1 RA) medications stimulate insulin secretion, inhibit glucagon release, and delay gastric emptying, leading to improved glycemic control. In addition, they reduce food intake and increase satiety. ⁷

It is well established that diet‐induced weight loss inevitably leads to some reduction in fat‐free mass, regardless of whether it is achieved through changes in diet or pharmacological treatment. ⁸ When the body is in calorie deficit, energy reserves are mobilized—initially glycogen stores, but over time also fat and muscle protein. Several systematic reviews have shown that a substantial portion of weight loss—up to 31% ² in diet‐induced weight loss—derives from muscle mass, particularly when protein intake is low or physical activity is not maintained. ⁹ , ¹⁰ Therefore, it is crucial to consider strategies to preserve muscle mass during weight loss, especially in clinical settings where pharmacological treatments may potentially intensify this effect.

In several studies investigating GLP‐1 RA treatment as a weight loss strategy, a loss of fat‐free mass (FFM) has been observed. ¹¹ On one hand, multiple studies show that up to 45% of the total weight loss consists of FFM. These include studies of semaglutide 2.4 mg (−45.2% FFM) (STEP‐1), ¹² tirzepatide ³ (−25.3% FFM) (SURMOUNT‐1), ¹³ semaglutide 1.0 mg (−40.3% FFM) (SUSTAIN‐8), ¹⁴ and liraglutide (−15.0% FFM). ¹⁵

On the other hand, a meta‐analysis has found evidence that the loss of fat‐free mass is comparable between treatment and control groups treated with life style changes, ¹⁶ and one study even observed a marked increase in FFM (+14.9%) when physical exercise was added to the treatment regimen. ¹⁷ Additionally, a population‐based study found that lifelong, genetically proxied GLP1R activation—that is, the presence of genetic variants associated with enhanced GLP‐1 receptor signalling—was linked to weight reduction driven predominantly by loss of fat mass rather than lean or muscle mass. This genetic approach serves as a natural experiment mimicking pharmacologic GLP‐1 receptor agonism, providing causal evidence that activation of the GLP‐1 pathway preferentially promotes fat loss, thereby countering concerns about clinically significant muscle wasting. ¹⁸ These results suggest GLP1R agonists may preferentially reduce fat mass compared to muscle mass. However, long‐term genetic effects may not match short‐term drug effects, which is why confirmation from clinical trials is needed. ¹⁹ On the other hand, preclinical research has shown that semaglutide can reduce cardiac muscle mass in human cardiomyocytes, although without any functional impact on cardiac performance. ²⁰ This highlights significant heterogeneity in FFM loss associated with GLP‐1 RA treatment, and the amount of data to support any possible conclusions about the long‐term effects of GLP‐1 RA therapy on body composition and muscle physiology remains insufficient.

One study also points to changes in bone mineral density (BMD) associated with GLP‐1 RA, specifically semaglutide, treatment. ²¹ In this study, a decrease in BMD was observed in the spine, hip, and tibia, along with increased bone resorption. However, it is noteworthy that no changes were detected in the non‐weight‐bearing distal radius, and the observed changes were limited to the weight‐bearing skeleton. This may suggest that the alterations result from adaptation due to reduced mechanical loading because of the semaglutide‐induced weight loss.

1.2. Loss of fat‐free mass and its impact on health

Skeletal muscle mass (SMM) plays a central role in metabolic regulation, particularly in glucose and lipid metabolism. Since skeletal muscle is the primary tissue responsible for postprandial, insulin‐stimulated glucose uptake, it is a key determinant of insulin sensitivity. ²² A reduction in muscle mass impairs glucose metabolism and substantially contributes to insulin resistance, which is a core mechanism in the development of type 2 diabetes (T2D) and cardiovascular disease. Conversely, increased muscle mass is associated with improved insulin sensitivity. ²³ Muscle tissue also contributes to the clearance of free fatty acids from the circulation, thereby preventing fat accumulation in peripheral tissues and organs. ²⁴

In addition to muscle mass, muscle quality ²⁵ is especially critical for both functional capacity and metabolic health. Muscle quality refers to the functional capacity of skeletal muscle relative to its size, encompassing factors such as strength per unit of muscle mass, neuromuscular activation, and tissue composition—including the proportion of contractile elements, intramuscular fat infiltration, and connective tissue content. Unlike muscle mass alone, muscle quality provides a more comprehensive measure of muscle health and functional performance. Poor muscle quality compromises mobility, balance, and the ability to perform daily activities, ²⁶ all of which significantly influence metabolic resilience and the risk of chronic diseases. ²⁷ In one study involving older adults, muscle mass loss was associated with declining strength; however, the rate of decline in muscle strength was typically faster than the concurrent loss of muscle mass in this particular population. This suggests that it is not only the quantity of muscle that affects the physiological health of the musculature—muscle quality also deteriorates with age. ²⁸

The age‐related loss of muscle mass, also known as sarcopenia, ²⁹ results from negative muscular changes that accumulate over a lifetime and is estimated to occur at a rate of approximately 0.6%–1% per year. ³⁰ When compared with the loss of lean body mass observed with semaglutide or tirzepatide treatment—up to 25%–40% of the lost weight over 6–12 months—this represents a minute fraction of the loss associated with pharmacological treatment. The extent of lean mass loss from GLP‐1 RA therapy could thus correspond to several decades' worth of age‐related decline.

Sarcopenia may arise because older individuals require a higher protein intake to maintain the same muscle mass. ³¹ Moreover, sarcopenia is itself a risk factor for falls and thus bone fractures in the elderly, ³² and individuals with diabetes or obesity are already at elevated risk for developing sarcopenia. ³³

GLP‐1 RA treatment, due to the rapid and substantial weight gain followed by treatment discontinuation, is also associated with weight cycling—repeated weight loss followed by weight regain. ³⁴ This mechanism is largely driven by muscle loss (at cessation of medication), which leads to a decline in basal energy expenditure, ³⁵ as muscle tissue consumes significantly more energy than fat tissue. In the short term, no notable adverse effects are observed in body weight, composition, or metabolism. However, with multiple repeated cycles, body composition deteriorates further by favouring fat mass (FM) accumulation and reducing the proportion of FFM. This is because the weight regain in each cycle primarily consists of fat tissue, ³⁶ thereby increasing the FM/FFM ratio. ³⁷ The consequences include greater strain on the cardiovascular system due to fluctuations in blood pressure, heart rate, blood lipid levels, and blood glucose. ³⁸

According to one study, substantial weight loss also affects thermogenic muscular organs such as the heart (−5%), liver (−4%), and kidneys (−6%). ³⁹ The reduction in the mass of these organs further contributes to decreased basal energy expenditure and promotes additional weight cycling. This provides yet another rationale for combining GLP‐1 RAs with muscle‐preserving agents to maintain favourable body composition and mitigate long‐term consequences of weight cycling.

1.3. Consequences of GLP‐1 RA‐induced weight loss

Overall, it is crucial to maintain both muscle mass and muscle quality in order to preserve insulin sensitivity, metabolic flexibility, ⁴⁰ long‐term health, and to counteract weight cycling—particularly in the context of treatments aimed at significant weight loss. The proportion of loss of fat‐free mass (FFM) compared to lean body mass, and thereby the underlying loss of skeletal muscle mass, is especially problematic in older individuals due to age‐related muscle decline, as well as in individuals with sarcopenic obesity who already have low muscle mass. While there is considerable heterogeneity among studies examining GLP‐1 RA‐induced loss of fat‐free mass, these studies have been conducted in various populations with different indications—including both healthy young individuals and elderly patients with comorbidities. This makes it difficult to determine in general whether and how a rapid GLP‐1RA‐induced weight loss leads to muscle loss and affects muscle quality. ² Skeletal muscle mass (SMM) is a highly variable component of FFM and has generally not been specifically quantified in trials and studies, making it premature to rule out potential muscle‐related risks of GLP‐1 RA‐based weight loss treatment. Emerging preclinical evidence indicates that GLP‐1RA‐induced changes in lean mass are not uniform across muscles, and functional consequences may exceed what size reductions suggest. In a mouse model of diet‐induced obesity, semaglutide caused dose‐dependent weight loss with decreases in both fat and lean mass. ⁴¹ Yet muscle atrophy was modest and mainly reflected reversal of high‐fat diet–induced hypertrophy, with mass not falling below lean controls. Strikingly, the fast‐twitch extensor digitorum longus showed an early ~20% decline in force despite minimal atrophy, whereas the slow‐twitch soleus was unaffected. This disproportionate loss of strength indicates a decoupling of muscle size and function, underscoring the need to evaluate both mass and performance when assessing GLP‐1RA therapy. Still, direct translation to humans is limited by species differences, activity levels, and age‐related vulnerabilities. Future research should focus on investigating how muscle quality is affected by GLP‐1 RA treatment and on quantifying and differentiating the individual components of the FFM loss.

Although resistance training and adequate protein intake can effectively counteract lean body mass loss, ¹⁷ , ⁴² adherence to such guidelines is often low, especially among older adults ⁴³ and individuals with severe obesity, ⁴⁴ partly because these populations frequently belong to socioeconomically vulnerable groups. ⁴⁵ This underscores the need for strategies to counteract GLP‐1 RA‐induced muscle loss, such as muscle‐preserving combination therapies with activin and myostatin inhibitors or selective androgen receptor modulators (SARMs).

2. LITERATURE SEARCH

Prior to the literature search, nine pharmacological compounds with the highest clinical and preclinical potential were identified based on the following criteria: ongoing or completed phase 2 trials, documented safety in human studies, promising anabolic effects in previous research, no evidence of terminated or discontinued drug development, as well as upcoming or completed phase 2 trials. The selected compounds were: Bimagrumab, Enobosarm, Trevogrumab, Garetosmab, Apitegromab, SRK‐439, Taldefgrobep alfa, Ruvembri, and TERN‐501.

The literature search was conducted between March and April 2025 using the databases PubMed, JAMA, Wiley, ResearchGate, and the Royal Danish Library. In addition, ClinicalTrials.gov was utilized to identify relevant ongoing and completed interventional trials. The search strategy employed combinations of the following terms: “obesity,” “type 2 diabetes mellitus,” “treatment,” “body composition,” “fat‐free mass,” “lean body mass,” “GLP‐1 RA,” “preservation,” as well as the name of each compound.

Both human and pre‐clinical (animal‐based) studies were included, and both interventional and experimental study designs were considered. Due to limited available data on certain compounds within overweight and T2D populations, studies involving patients with muscle‐wasting conditions such as sarcopenia and Duchenne muscular dystrophy (DMD) were also included in select cases. Reference lists from relevant articles, reviews, and meta‐analyses were manually screened to identify additional studies.

Inclusion criteria included:

• Published or registered study.

• Quantitative outcome on body composition (LBM/FM) measured by DXA or MRI.

• Any available functional outcomes such as stair climb test or handgrip strength.

• Data on adverse events and safety profile.

Exclusion criteria included:

• Studies without primary data.

• Non‐peer‐reviewed sources.

• Non‐original articles.

• Studies without a control group.

Included articles were reviewed and assessed with a focus on changes in lean body mass (LBM) and fat mass (FM) measured by DXA or MRI, as well as changes in muscle quality and muscle function measured by stair climb performance (power and time) and handgrip strength, where such data were available.

Although the primary inclusion criteria were restricted to peer‐reviewed and original research articles, selected non–peer‐reviewed sources (including conference abstracts, company press releases, and professional meeting summaries) were also considered when they represented the only publicly available information on ongoing or recently completed clinical trials. These sources were included solely to provide timely context regarding investigational pharmacotherapies that have not yet been published in peer‐reviewed form. All such references are clearly marked as grey literature and were interpreted with appropriate caution to avoid overreliance on preliminary or non‐validated data.

3. RESULTS

3.1. ActRIIB inhibition via bimagrumab shows promising results in individuals with overweight

Activin receptor type IIB (ActRIIB) is a key regulator of skeletal muscle growth and serves as a receptor for negative regulators of muscle mass, including myostatin (GDF‐8) and activins (Act‐A). These ligands belong to the transforming growth factor‐beta (TGF‐β) superfamily and inhibit muscle hypertrophy. ⁴⁶ Myostatin prevents excessive muscle growth by binding to ActRIIB and activating the SMAD2/3 signalling pathway, which suppresses muscle protein synthesis and enhances protein degradation.

One of the most extensively studied ActRIIB inhibitors is bimagrumab, a fully human monoclonal antibody that specifically prevents myostatin and activin A from activating ActRIIB. The dual ligand antagonism of both myostatin and activin A is believed to result in a more potent anti‐catabolic and anabolic effect compared to other myostatin inhibitors. By reducing myostatin signaling, ActRIIB inhibitors enhance skeletal muscle growth and improve muscle function. ⁴⁷ Clinical studies have shown that bimagrumab can preserve, and in some cases even increase, lean and fat‐free body mass while simultaneously reducing fat mass—even during weight loss interventions—resulting in a dual beneficial effect in metabolic diseases such as type 2 diabetes and obesity. ⁴⁶

One of the most promising clinical studies on the effect of bimagrumab is Novartis' phase 2 trial in adults with type 2 diabetes and obesity (28 ≤ BMI ≤ 40) followed for a 48‐week period. ⁴⁸ The study was randomized, double‐blind, and placebo‐controlled, in which participants received either bimagrumab 10 mg/kg every 4 weeks for 48 weeks or placebo. The study concluded that patients treated with bimagrumab experienced an average weight loss of 6.5%, primarily consisting of a 20.5% reduction in fat mass (FM), compared to a 0.5% reduction in the placebo group. Simultaneously, lean body mass (LBM) increased by 3.6% in the bimagrumab group, while the placebo group saw a decrease of 0.8%. This contrasts with GLP‐1RA monotherapy, in which a significant portion of weight loss typically includes a substantial loss of fat‐free mass.

Although this study only assessed the effect of bimagrumab as monotherapy and not in combination with a GLP‐1RA, the findings suggest that bimagrumab—and thus ActRIIB inhibition—not only reduces fat mass but can also preserve or potentially increase fat‐free mass during weight loss, distinguishing it from conventional weight loss medications. This supports the potential of ActRIIB inhibition as a strategy to counteract muscle loss while improving body composition during weight reduction. No improvements in physical function were observed in patients in the bimagrumab group compared to placebo, as there was no statistically significant change in hand grip strength measured by dynamometry. As with clinical studies on GLP‐1RAs, this study also cannot exclude the possibility that the increase in LBM consists of, for example, water rather than protein being measured by DXA scanning.

The favourable body composition was accompanied by a 20% increase in insulin sensitivity, ⁴⁸ which was also observed in Garito's 2018 study (see Table 1). Moreover, increased insulin resistance in skeletal muscle is linked to sarcopenic obesity, ⁴⁹ suggesting that the enhanced insulin sensitivity induced by bimagrumab is associated with favourable changes in body composition, implying that the effect is not solely due to ActRIIB inhibition. It should be noted that 84% of participants in the phase 2 trial were treated with metformin alongside bimagrumab, perhaps contributing to some of the effects observed. Bimagrumab was safe and well tolerated, with primarily mild side effects. These include diarrhoea, acne, and muscle spasms. Acne has been suggested to be associated with local production of dihydrotestosterone (DHT), ⁵⁰ , ⁵¹ rather than being a consequence of transiently elevated LH levels, ⁵⁰ as acne was observed in both sexes. However, it should be noted that Garito et al. ⁵⁰ did not measure DHT levels.

TABLE 1.

Overview of clinical and preclinical studies of bimagrumab.

Author	Status	Population, dosing and outcome	Results	Side effects
Heymsfield et al. 48	Phase 2	Adults with T2D and BMI 28–40; bimagrumab 10 mg/kg every 4 weeks for 48 weeks Outcome: safety and efficacy	LBM increased (+3.6%) and FM decreased notably (−20.5%); improved glycemic control. ↓ FSH and urate; ↑ CK (reversible). No improvement in physical function. 84% received metformin in treatment arm	Diarrhoea, muscle spasms, acne
Rooks et al., 52	Phase 1	Elderly with sarcopenia; 700 mg bimagrumab every 4 weeks for 28 weeks Outcome: muscle strength and function	LBM increased (+2.0 kg) and FM decreased (−4.0 kg). No clinically significant improvement in physical function between treatment groups	Diarrhoea, muscle spasms, falls
Garito et al. 50	Phase 1	Insulin‐resistant adults, avg. BMI 29.3; single dose of 30 mg/kg bimagrumab. Outcome: insulin resistance and body composition	LBM (+2.7%); FM (−7.9%); insulin sensitivity (+21.8%). No change in body weight. No increase in CK	Acne, myalgia, muscle spasms, diarrhoea
Rooks et al. 53	Phase 2	Elderly with sarcopenia and impaired mobility; 30 mg/kg on Day 1 and 57; followed 24 weeks. Outcome: TMV, body composition, 6MWD	Gradual increase in TMV; LBM progressed parabolically (max +6.0%). Improvements in 6MWD and grip. Strength observed	Diarrhoea, muscle spasms, acne
Rooks et al., 52	Phase 1	Healthy and overweight elderly; single dose bimagrumab; followed 12–20 weeks. Outcome: safety, PK, tolerability	Safe and tolerable. LBM and TMV; FM. No change in muscle strength	Diarrhoea, muscle spasms, rash, URI
Rooks et al. 53	Phase 1	Healthy young men with limb immobilization; single 30 mg/kg dose after cast removal. Outcome: TMV and thigh tissue composition	Accelerated TMV recovery. No improvement in knee extension strength vs. placebo. ↓ IMAT volume 2 weeks post‐treatment	Acne, muscle spasms
Petricoul et al., 54	Phase 1	Healthy elderly >70 y/o, BMI 18–34; 7 dosing groups; followed 48 weeks. Outcome: safety, PK, PD	Absolute bioavailability ~40%. LBM increased (4–6%) except in Group 7; FM decreased (2–3 kg). Upper respiratory infections observed in bolus SC groups (Groups 5–7). Safe and tolerable	Diarrhoea, muscle spasms
Garito et al. 50	Phase 1	Healthy adults; single 10 mg/kg dose on Days 1 and 29; followed 20 weeks. Outcome: effect on HPG and HPA axes	Reversible FSH (−42.1 IU/L) and LH (+2.1 IU/L) after 8 weeks. Changes in LBM (+1.59 kg) and FM (−0.97 kg). GnRH stimulation test positive. DHT was not measured despite presence of acne	Muscle spasms, acne, back pain
Nunn et al. 5	In vivo	Diet‐induced obese mice; semaglutide 120 μg/kg, bimagrumab 30 mg/kg or both. Outcome: efficacy	Bimagrumab increased LBM (+8%), semaglutide lowered LBM (−10%). Combination preserved LBM completely and led to loss in FM (−70%). Muscle preservation in tibialis anterior, soleus, and gastrocnemius. Improved VO₂‐max with combination	No report
BELIEVE Study (Heymsfield et al. 55 )	Phase 2	Adults with obesity; either BMI >30 or BMI >27 and at least one obesity related comorbidity. Bimagrumab 30 mg/kg or 2.4 mg semaglutide or both; followed 48 weeks. Outcome: safety and efficacy	Combination therapy reduced BW (−22.1%) and LBM (−2.6%). Semaglutide alone decreased BW (−15.7%) and LM (−7.9%). Bimagrumab alone decreased BW (−10.8%) and increased LBM (+2.3%). Waist circumference (surrogate VAT marker) reduced by 22 cm	Diarrhoea, muscle spasms, acne, headache

Abbreviations: 6MWD, 6 min walking distance; BW, body weight; CK, creatine kinase; DHT, dihydrotestosterone; FSH, follicle‐stimulating hormone; IMAT, intermuscular adipose tissue; LH, luteinizing hormone; PD, pharmacodynamics; PK, pharmacokinetics; TMV, thigh muscle volume; URI, upper respiratory infection.

Among the more interesting side effects is a reversible reduction in follicle‐stimulating hormone (FSH), which has been observed across most studies. ⁴⁸ , ⁵⁰ , ⁵³ However, it remains uncertain whether this has any impact on, for instance, fertility.

In a preclinical study, ⁵ bimagrumab was investigated in diet‐induced obese mice. The mice were treated for 14 days with either semaglutide (120 μg/kg), bimagrumab (20 mg/kg), a combination of both, or placebo. The study showed that mice treated with semaglutide alone or in combination with bimagrumab lost over 25% of their body weight. Fat mass was reduced by 50% with semaglutide alone and by 30% with bimagrumab alone. The combination therapy produced the greatest effect, resulting in a 70% reduction in fat mass. Semaglutide monotherapy reduced lean body mass (LBM) by 10%, whereas bimagrumab monotherapy increased LBM by 8%. Combination treatment with semaglutide and bimagrumab completely preserved lean body mass, with no change observed compared to the control group. These findings suggest that ActRIIB inhibition via bimagrumab administration can counteract muscle loss during GLP‐1RA therapy while maintaining the efficacy of weight reduction.

The combination of ActRIIB inhibitors and GLP‐1RAs represents a promising therapeutic strategy aimed at achieving weight loss without concurrent muscle loss—or potentially even enabling muscle gain. Preliminary preclinical and clinical studies have shown encouraging results, including consistent increases in LBM with bimagrumab monotherapy ⁴⁸ , ⁵⁰ and full preservation of LBM with semaglutide co‐treatment in mice, ⁵ indicating that ActRIIB inhibition may counteract GLP‐1RA‐induced muscle mass deterioration.

Early results from the phase 2b, randomized, double‐blind, placebo‐controlled BELIEVE trial assessed the efficacy and safety of bimagrumab, semaglutide, and their combination in adults with obesity over 48 weeks. Participants receiving high‐dose combination therapy with bimagrumab (30 mg/kg) and semaglutide (2.4 mg) achieved the greatest reductions in body weight, with a mean loss of 24.2 kg (−20.2% from baseline) compared with 16.5 kg (−14.8%) for semaglutide alone and −10.8% for bimagrumab alone. Fat mass reduction with combination therapy was substantial, representing 92.8% of total weight loss, and was accompanied by relative preservation of lean mass (−2.6% vs. −7.9% with semaglutide alone), while bimagrumab monotherapy increased lean mass by 2%–2.5%. These findings indicate that the addition of bimagrumab to semaglutide attenuates the lean mass loss observed with GLP‐1 receptor agonist monotherapy. Adverse events were consistent with well‐known profiles of the individual agents. In conclusion, high‐dose bimagrumab–semaglutide combination therapy produced superior, predominantly fat‐driven weight loss with preservation of lean mass compared with either agent alone. ⁵⁵ , ⁵⁶ , ⁵⁷

Future studies of antibodies targeting ActRIIB should focus on establishing their efficacy and safety in humans, as well as exploring the potential of co‐administration with a GLP‐1RA. Several such studies are already underway, primarily aiming to investigate co‐administration strategies. In addition, a larger trial investigating tirzepatide/bimagrumab combination therapy is currently enrolling both overweight individuals ⁵⁸ and overweight individuals with type 2 diabetes (Table 2). ⁵⁹

TABLE 2.

Overview of upcoming studies involving bimagrumab.

Study ID	Population	Treatment	Objective	Status
NCT05933499 (2025)	Overweight adults	Bimagrumab	Effect of bimagrumab on body composition, insulin sensitivity, and bone compared to semaglutide	Not yet recruiting
NCT06890611 (2025)	Healthy adults	Bimagrumab/tirzepatide	Safety and efficacy	Recruiting
NCT06643728 (2025)	Overweight adults	Bimagrumab/tirzepatide	Safety and efficacy	Recruiting
NCT06901349 (2025)	Adults with T2D and overweight	Bimagrumab/tirzepatide	Safety and efficacy	Not yet recruiting

3.2. Synergy between garetosmab and trevogrumab enhances lean body mass

Garetosmab and trevogrumab are both monoclonal antibodies targeting members of the TGF‐β superfamily, modulating signalling pathways involved in muscle and fat metabolism. Garetosmab targets activin A, a cytokine that signals via activin receptors and activates SMAD2/3‐dependent transcriptional pathways, leading to inhibition of muscle growth and promotion of fibrogenesis and inflammation. ¹ , ⁶⁰ By blocking activin A, garetosmab inhibits this signalling, thereby promoting muscle hypertrophy while reducing inflammation and fibrosis.

Trevogrumab inhibits myostatin. Inhibition of myostatin results in increased muscle protein synthesis and muscle mass. The combination of garetosmab and trevogrumab produces a synergistic effect, ⁶¹ as both signaling pathways are inhibited concurrently, resulting in more pronounced increases in muscle volume and lean body mass, as well as reductions in fat mass. Together, they exhibit a dual‐antagonist mechanism of action similar to that of bimagrumab. Both agents represent targeted biological therapies with potential for the treatment of muscle‐wasting diseases and metabolic disorders.

Garetosmab has been evaluated in a randomized, placebo‐controlled, double‐blinded phase 1 trial, ⁶⁰ in which older women received doses of 0.3, 1, 3, or 10 mg/kg garetosmab. The treatment was safe and well tolerated, with the most common adverse events being headache, gastrointestinal symptoms, and “nervous system disorders,” all of which were resolved by the end of the study. An increase in circulating activin A levels was observed, indicating target engagement by garetosmab. One case of anti‐drug antibody (ADA) development was reported.

A preclinical study ⁶² concluded that trevogrumab‐treated mice exhibited increased muscle hypertrophy and strength, measured by weight increases of up to 25% in the gastrocnemius and 19.8% in the tibialis anterior muscles. Additionally, increased muscle fibre diameter was observed, though without changes in fibre type or fibre number. Several groups of mice were included in the study. Trevogrumab counteracted muscle atrophy in immobilized mice, with a 4.0% increase in gastrocnemius mass compared to non‐immobilized, placebo‐treated mice. Furthermore, in dexamethasone‐induced atrophic mice, trevogrumab prevented muscle wasting and shortened the recovery period in aged mice subjected to 2 weeks of hindlimb suspension.

According to a randomized, placebo‐controlled, double‐blind phase 2 study in patients with sarcopenia, ⁶³ participants were treated with 300 mg trevogrumab every 4 weeks for a total of 12 weeks. The treatment resulted in a 1.8% and 2.3% increase in total LBM after 12 and 20 weeks, respectively, compared to placebo. Additionally, reductions of 5.0% and 9.6% in total and android fat mass, respectively, were observed after 20 weeks compared to placebo. However, no statistically significant clinical improvements in muscle strength were reported, as measured by handgrip strength and leg and chest press.

A preclinical study in non‐human primates ⁶⁴ , ⁶⁵ evaluated the effects of the myostatin inhibitors trevogrumab and garetosmab in combination with the GLP‐1 receptor agonist semaglutide on body composition. After 20 weeks of treatment, primates receiving semaglutide alone experienced a 2.5% loss in LBM, indicating that GLP‐1RA‐induced weight loss in this case also involved loss of muscle mass. Treatment of primates with co‐administration of trevogrumab (anti‐MSTN) and garetosmab (anti‐ActA) not only prevented muscle loss but led to a ~8.7%increase in LBM and a ~34.5% loss in fat mass. The effect on body composition was even more pronounced with the addition of semaglutide. Furthermore, co‐administration of semaglutide with trevogrumab/garetosmab led to more favorable changes in body composition, nearly doubling fat mass reduction (49.6% vs. 25.1% with semaglutide alone) accompanied by a 6.2% increase in lean body mass.

These findings suggest that concurrent inhibition of myostatin and activin A with trevogrumab and garetosmab synergistically mitigates GLP‐1RA–induced loss of lean body mass, not only preventing LBM decline but promoting increases, while simultaneously enhancing fat mass reduction and thereby improving the overall quality of weight loss.

In a separate phase 1 study, ⁶¹ healthy men and postmenopausal women were treated with trevogrumab, garetosmab, a combination of both, or placebo, using both single‐ and multiple‐dose regimens. Following a single dose, thigh muscle volume (TMV) increased by 7.7% with combination therapy compared to a 4.4% increase with trevogrumab alone. Android and visceral fat mass decreased by 4.6% and 6.7%, respectively, under combination therapy. In the multiple‐dose arm, a transient increase in TMV was observed alongside a sustained reduction in android and visceral fat by 14.3% and 20.1%, respectively. No safety concerns were reported. The combination of trevogrumab and garetosmab demonstrated dose‐dependent, more‐than‐additive improvements in muscle mass and fat reduction, indicating a synergistic interaction between the two agents.

Interim 26‐week results from the phase 2 COURAGE trial ⁶⁶ showed clear combination‐dependent effects of semaglutide, trevogrumab (anti‐myostatin), and garetosmab (anti‐activin A). While semaglutide alone reduced both fat (−15.7%) and lean mass (−6.5%), adding trevogrumab substantially attenuated lean mass loss (−3.3% to −3.8%) and enhanced fat reduction (up to −19.1%) in adults with obesity (BMI ≥30). The triple combination achieved the most favorable body composition profile (−27.1% fat, −2.0% lean), highlighting a pharmacologically synergistic preservation of muscle alongside amplified fat loss. However, these data remain interim and short‐term, with final results expected in 2026.

Future studies are underway to evaluate the efficacy and safety of combined administration of garetosmab and trevogrumab with the GLP‐1RA semaglutide in overweight individuals, focusing on weight loss, fat reduction, and body composition outcomes. ⁶⁷ Recruitment for this trial has been completed.

3.3. Apitegromab, SRK‐439, and Taldefgrobep Alfa: Drugs with other indications now investigated as obesity adjunct therapies

Apitegromab, another myostatin antagonist, is currently being evaluated in the phase 2 EMBRAZE proof‐of‐concept trial. ⁶⁸ The study aims to assess the safety, efficacy, and pharmacokinetics of apitegromab when used as adjunctive therapy to GLP‐1 receptor agonist treatment (semaglutide or tirzepatide) in individuals with overweight or obesity without diabetes. Previous evidence has demonstrated improved motor function in late‐onset Type 2 and Type 3 spinal muscular atrophy in younger individuals. ⁶⁹ Notably, the adverse event profile appears more favorable compared to other myostatin inhibitors, with primarily headache, pyrexia, upper respiratory tract infection, and coughing reported. ⁷⁰ This may be due to the fact that, unlike bimagrumab, trevogrumab, and garetosmab—which inhibit active myostatin and activin A—apitegromab specifically targets the latent form of myostatin, ⁷¹ resulting in greater specificity and reduced cross‐reactivity within the TGF‐β superfamily. ⁷²

Another promising compound is SRK‐439, an investigational myostatin‐specific inhibitor that, like apitegromab, selectively inhibits latent myostatin the inactive pro‐form requiring extracellular activation to bind ActRII receptors, but is being developed specifically for obesity. A preclinical study ¹⁹ demonstrated that the compound, administered in combination with metformin—which stimulates the release of GLP‐1—increased LBM relative to baseline. In young diet‐induced obese mice, SRK‐439 monotherapy increased LBM by 32.7% from baseline compared to 16.7% in placebo‐treated mice. Similar results were observed upon combination with metformin (31.6% vs. 15.1%). SRK‐439 treatment also protected obese mice from muscle loss during semaglutide treatment. ¹⁹ Importantly, SRK‐439 attenuated the rebound in fat mass following semaglutide discontinuation. Mice treated with semaglutide + SRK‐439 had 18.0% body fat compared to 28.7% in mice treated with semaglutide alone. These findings support the potential of selective myostatin inhibitors like SRK‐439 to preserve muscle mass during pharmacologically induced weight loss, which could be advantageous in combination with GLP‐1RA therapy. However, no clinical trials are currently ongoing or planned for SRK‐439.

Taldefgrobep alfa is an anti‐myostatin adnectin, that binds the myostatin ligand with high affinity, preventing its activation of ActRIIA/B receptors. Unlike receptor‐blocking antibodies such as bimagrumab, it acts with greater ligand specificity, selectively targeting myostatin and the myostatin receptor complex (ActRIIB), thereby preventing activation of the Smad2/3 signalling pathway. ⁷³ This design may provide more focused myostatin inhibition with reduced off‐target effects. In a phase 1b/2 trial involving ambulatory boys with Duchenne muscular dystrophy (DMD), treatment led to a 1.75% increase in LBM over 24 weeks, compared to a 1.38% decrease in the placebo group. At 168 weeks post hoc, patients continuously treated with taldefgrobep alfa exhibited a 5.6% increase in LBM from baseline, compared to 2.0% in the placebo group. The contractile cross‐sectional area (CSA) of the right thigh muscle increased by 5.45% with treatment, compared to a 0.79% decrease in the placebo group at Week 24. However, no direct functional improvements were observed. ⁷³ The NSAA score, used to evaluate disease progression and treatment response in ambulatory DMD patients, ⁷⁴ was assessed in a separate phase 2/3 trial. Although modest muscle growth was observed (modelled to equate to approximately 1 point of improvement in NSAA), the predefined threshold of 1.5 points was not met, and no meaningful functional change was demonstrated. ⁷³ Taldefgrobep alfa was well tolerated, with the most common adverse events being upper respiratory tract infections, rash, and elevated CK levels. Non‐neutralizing anti‐drug antibodies (ADAs) were observed.

However, taldefgrobep alfa may be useful in antiobesity therapy. Early results from the RESILIENT phase 3 trial, which investigated efficacy and safety in patients with spinal muscular atrophy (SMA), demonstrated consistent increases in LBM, bone density, favorable fat mass changes, and clinically meaningful improvements in motor function. ⁷⁵ These outcomes may also be relevant to patients with sarcopenic obesity, who similarly experience muscle atrophy—though not due to motor neuron degeneration. ⁷⁶ Biohaven, the pharmaceutical company behind taldefgrobep alfa, aims to transition into clinical trials in individuals with obesity as soon as possible.

3.4. Myostatin inhibitors are not the only candidates

Looking in another direction, additional drug classes may also help preserve muscle mass during weight loss. In a preclinical study involving obese mice, the combination of TERN‐501, a selective thyroid hormone receptor beta (THR‐β) agonist, and semaglutide resulted in significantly greater weight loss compared to semaglutide alone. ⁷⁷ Specifically, the combination treatment led to greater total weight loss (26% vs. 33%), a more pronounced reduction in fat mass (11.8 vs. 15.2 g), and notably, without any further loss of fat‐free mass. These findings suggest that TERN‐501 may serve as an effective adjunct to GLP‐1RA therapy by enhancing weight loss, promoting fat reduction, and preserving lean mass.

Ruvembri (BIO101) is a pharmaceutical formulation of 20‐hydroxyecdysone (20E), a naturally occurring plant‐derived steroid that activates the MAS receptor. It promotes protein synthesis in muscle tissue, supports myotube formation, and contributes to muscle hypertrophy, making it a potential candidate for the treatment of age‐related sarcopenia. ⁷⁸ In preclinical studies involving adult and aged mice, BIO101 treatment resulted in significantly improved muscle strength, coordination, and running capacity. Histological analysis revealed increased muscle fibre thickness and a higher number of nuclei per fibre, indicating activation of satellite cells and enhanced muscle regeneration. ⁷⁹

A phase 1 study concluded that BIO101 has a favorable safety profile, with adverse events primarily being mild to moderate, including gastrointestinal symptoms and musculoskeletal pain—especially in the back. Additionally, reductions in creatine kinase (CK) levels were observed, suggesting a potential muscle‐protective effect. ⁷⁸

In the phase 2b SARA‐INT trial, older adults diagnosed with sarcopenia were treated with either 175 mg or 350 mg BIO101 twice daily or placebo for 6–9 months. ⁸⁰ The primary endpoint was the change in 400‐m gait speed. In the full analysis set, a nonsignificant trend toward improvement was noted; however, in the per‐protocol population, a significant improvement of 0.09 m/s was observed in the 350 mg group, approaching the clinically relevant threshold of 0.1 m/s. Subgroup analyses showed a greater effect among high‐risk participants, including individuals with low baseline gait speed, obesity, or impaired chair rise ability. Measurements of LBM and fat mass were conducted, but the results were not highlighted; however, data available on ClinicalTrials.gov revealed no significant changes in LBM (+0.343 kg with 350 mg BIO101) compared to placebo.

3.5. Enobosarm shows promise for improved physical function with a favourable side effect profile

Selective androgen receptor modulators (SARMs) represent a promising strategy for preserving muscle mass during pharmacologically induced weight loss. In contrast to traditional anabolic steroids, which are associated with systemic side effects ⁸¹ —particularly cardiovascular ⁸² and testicular risks—SARMs bind selectively to androgen receptors in muscle and bone tissue. This selectivity is due to their unique molecular structure, which allows activation of anabolic signaling pathways without overstimulating other tissues.

The drug functions by binding with high affinity to the androgen receptor (AR) in tissues such as skeletal muscle, bone, liver, and prostate. When enobosarm binds to AR in muscle and bone, the receptor is activated and the complex translocates into the cell nucleus, where it binds to specific DNA sequences known as androgen response elements (AREs). This promotes the transcription of genes involved in protein synthesis, satellite cell activation and maturation, and muscle fiber hypertrophy. ⁸³ Additionally, SARMs inhibit muscle degradation by reducing the activity of protein‐degrading systems including the ubiquitin‐proteasome pathway and the myostatin signaling pathway. This results in muscle hypertrophy, improved muscle function, and potentially a protective effect against age‐related sarcopenia. In bone tissue, enobosarm can enhance osteoblast activity and help maintain bone mineral density, making it a relevant candidate for the treatment of osteoporosis. ⁸⁴

The biopharmaceutical company Veru Inc. recently completed the Phase 2b QUALITY study, which investigated the effect of enobosarm in patients over 60 years of age with overweight or obesity receiving semaglutide for weight loss. In this 28‐week double‐blinded, placebo‐controlled trial, patients were randomized to receive either 3 or 6 mg of enobosarm or placebo in combination with semaglutide. The primary endpoint was the change in total lean body mass after 16 weeks, while secondary endpoints included changes in fat mass, total body weight, and physical function. ⁴

The results showed that patients who received enobosarm in combination with semaglutide lost 71% less lean body mass compared to those receiving semaglutide alone, suggesting that SARM treatment may be an effective strategy for preserving muscle mass during GLP‐1 RA treatment. At the same time, patients in the enobosarm/semaglutide group lost 27% more fat mass than those in the placebo/semaglutide group, without a significant difference in total weight loss in kilograms. ⁴ Overall, this indicates a more favorable change in body composition.

In addition to preserving muscle mass, enobosarm was associated with improved physical function. The study reported a significant decrease in the proportion of patients experiencing a ≥10% decline in stair‐climb strength, from 42.6% in the placebo/semaglutide group to 19.4% in the enobosarm/semaglutide group. This supports the hypothesis that SARM treatment may not only preserve muscle mass but also prevent functional decline, which is particularly of interest for older patients with already reduced skeletal muscle mass.

Overall, these findings suggest that combination therapy with SARMs and GLP‐1RAs (semaglutide or tirzepatide) may preserve lean body mass and bone strength without compromising fat loss.

Several other clinical studies on enobosarm support its effect on lean body mass preservation. In a phase 2 trial involving elderly men and postmenopausal women treated with 3 mg enobosarm, a significant increase in LBM (+1.246 kg) and a reduction in fat mass (−0.322 kg) were observed, without a change in total body weight (+0.9 kg). ⁸⁵ Additionally, patients demonstrated improved muscle function, as shown by a statistically significant increase in stair‐climb power compared to placebo (+16% vs. 7%), along with improved stair‐climb speed.

In patients with advanced cancer, a significant increase in LBM has likewise been reported. A phase 2 clinical trial showed increases in LBM of +1.5 kg and +1.0 kg for 1 and 3 mg enobosarm respectively, with no clear dose dependency. ⁸⁶ Clinically meaningful improvements in muscle function were also observed in stair‐climb power for 1 and 3 mg enobosarm (+18.0% and 21.7%, respectively) compared to placebo (+4.7%).

Enobosarm had a favourable safety profile in both studies. The most common adverse events were mild and included fatigue, nausea, headache, and muscle spasms, as well as reversible suppression of LH, FSH, and testosterone, with no significant clinical consequences. Enobosarm thereby offers a targeted and safe approach to improving muscle mass and function in patients with sarcopenia, cancer‐associated weight loss, or osteoporosis, while posing a low risk of developing hormonal side effects due to its tissue selectivity, which contrasts with conventional androgen therapies.

4. DISCUSSION

The preclinical and clinical studies generally indicate that GLP‐1RA treatment is associated with a significant loss of muscle mass, which may have clinical implications for metabolic health and physical function. However, clinical studies on ActRIIB inhibitors, myostatin inhibitors, THR‐β agonists, Mas receptor agonists, and SARMs have demonstrated that these therapies can preserve—or even increase—fat‐free mass during weight loss, while simultaneously promoting fat reduction. Preclinical findings further support the notion that combination therapies may improve body composition and help mitigate the loss of functional muscle mass. At present, however, it is impossible to determine the long‐term prospects for these muscle‐preserving pharmacological agents.

ActRIIB inhibition using bimagrumab demonstrated convincing ability to counteract the loss of fat‐free mass during weight reduction in both human and preclinical studies. Clinical data from overweight individuals with type 2 diabetes showed a 3.6% increase in LBM, alongside a greater than 20% reduction in fat mass, as well as improved glycemic control ⁴⁸ and studies in mice showed that combination therapy with semaglutide and bimagrumab led to a 70% reduction in fat mass without any loss of fat‐free mass. ⁵ Furthermore, results from the BELIEVE Phase 2b trial show a superior reduction in body weight and preservation of lean mass, when combining semaglutide and bimagrumab compared to the effects of monotherapy with each drug. ⁵⁷ Human studies combining bimagrumab with tirzepatide and trevorgrumab/garetosmab with semaglutide are currently ongoing but not yet completed. Notably, bimagrumab shows dual antagonism of both myostatin and activin A, which may underpin its potent anabolic effects.

Other agents—such as garetosmab, trevogrumab, apitegromab, and SRK‐439—have shown varying degrees of muscle preservation, although often with limited clinical relevance or uncertain safety profiles. However, interim findings from the phase 2 COURAGE trial ⁶⁶ indicate that co‐administration of semaglutide with trevogrumab and garetosmab produces combination‐dependent, synergistic effects on body composition, markedly enhancing fat loss while preserving lean mass compared with semaglutide monotherapy. Taldefgrobep alfa did not yield meaningful improvements in functional outcomes among DMD patients; however, new studies in individuals with obesity are currently in the pipeline. In addition, data suggest that not only myostatin inhibitors, but also agents from other pharmacological classes—such as selective thyroid hormone receptor beta (THR‐β) agonists like TERN‐501—may contribute to muscle preservation and further fat loss, particularly in combination with GLP‐1 RAs.

Another candidate, Enobosarm—a selective androgen receptor modulator (SARM)—distinguishes itself through a favourable side‐effect profile and a targeted anabolic effect without the hormonal side effects typically associated with agents like testosterone. These findings support the notion that tissue‐specific signalling may be key to the development of future safe treatments for muscle loss. This is exemplified in Veru Inc.'s Phase 2b QUALITY study, ⁴ which reported a 71% reduction in LBM loss compared to the semaglutide/placebo group, as well as a decrease in the proportion of patients experiencing deteriorated stair‐climb performance (42.6% in the placebo/semaglutide group vs. 19.4% in the enobosarm/semaglutide group). This suggests improved physical function in overweight patients and represents the first of such findings in this specific population.

Overall, the results indicate that pharmacological intervention—both alone and in combination with GLP‐1 therapy—can yield significant improvements in body composition, particularly through LBM preservation and fat reduction. At the same time, the data underlines the need for larger and more standardized human Phase 2 and 3 trials before concrete clinical conclusions can be drawn.

For the monoclonal antibodies, cases of non‐neutralizing anti‐drug antibodies (ADA) have been observed, although without any reported impact on efficacy. All agents that have undergone human testing have been identified as safe and well tolerated.

Adequate protein intake and physical exercise are major factors in preserving muscle mass during treatment with GLP‐1 receptor agonists (GLP‐1 RAs) or other incretin‐mimetic agents. ¹¹ , ⁸⁷ If protein intake, physical activity, and resistance training are maintained throughout a weight loss intervention, the prospect for maintaining muscle mass and physical function is favourable. ⁸

Proper nutrition is essential for preserving muscle mass, particularly under caloric restriction associated with the treatment of overweight and obesity. Current guidelines recommend individualized nutritional counselling and medical nutrition therapy. ⁸⁸ Protein intake should be closely monitored, as many patients do not achieve adequate levels when treated with appetite‐suppressing medications. Recommendations range from 0.8 g/kg for adults ⁸⁹ to 1.2–1.5 g/kg for older individuals. ⁹⁰ The quality of protein—including its essential amino acid content and digestibility—is likewise important for stimulating muscle protein synthesis. ⁹¹

Data from NHANES suggest that over 40% of American adults have insufficient protein intake, making this a critical issue to address during pharmacological weight loss, which typically reduces calorie intake by 16%–39%, primarily through downregulation of appetite. ⁹² If patients struggle to meet their protein requirements through diet alone, oral nutritional supplements may be an effective solution. These provide protein, energy, and micronutrients and are supported by clinical research. ⁹³ Current studies are investigating the role of oral supplements in supporting muscle health in individuals with overweight, but results are not yet conclusive, ⁹² and research in this area remains limited. Additionally, improved communication between dietitians and patients is essential, as it currently appears to be a challenge. ⁹⁴ Achieving this could increase adherence to weight loss treatment and help prevent inadequate nutritional intake.

Another strategy for preserving muscle mass during GLP‐1 RA therapy is exercise. Clinical evidence from a study on maintenance therapy combining physical exercise, caloric restriction via liraglutide treatment, or both in combination supports this approach. ¹⁷ The combination treatment led to improvements in LBM and a significant reduction in fat mass compared to liraglutide alone, while LBM gains were greater with exercise alone than with the combination therapy—further supporting the LBM‐depleting effect of GLP‐1 RA treatment. Additionally, lower resting heart rate and improved cardiorespiratory function were observed in the group that included exercise compared to liraglutide alone.

Multiple systematic reviews and meta‐analyses support the addition of resistance training as an effective method to prevent negative changes in muscle mass during caloric deficit associated with weight loss treatment. ⁸⁸ , ⁹⁵ Many clinical studies further emphasize the benefits of resistance training under caloric restriction in individuals with overweight and type 2 diabetes. ⁹⁶ , ⁹⁷ , ⁹⁸

5. CURRENT CHALLENGES AND LIMITATIONS

Despite the promising results, several of the included studies raise methodological concerns. For example, it is noted that results from preclinical studies in mice treated with a myostatin inhibitor may not necessarily be generalizable to humans due to significant inter‐species differences regarding myostatin physiology. Mice exhibit up to 20 times higher levels of myostatin compared to humans, ⁹⁹ which suggests reduced translational efficacy of MSTN inhibitors in clinical contexts.

On the other hand, there is evidence of a direct association between elevated myostatin levels, obesity, insulin resistance, and both type 1 and type 2 diabetes in humans, ⁹⁹ further supporting the rationale for targeting myostatin in weight loss treatments.

Additionally, measurement methods for muscle mass vary, and there remains no consensus in the field on whether lean body mass is the most appropriate primary endpoint. ⁸⁰ Some researchers instead advocate for more functional outcomes, such as muscle strength or D3 creatine dilution assay, particularly in older individuals experiencing recent declines in mobility. ¹⁰⁰ Future studies should therefore utilize alternative assessment methods that address and include the functional capacity associated with changes in muscle mass, as changes in LBM alone may appear diffuse and lack sufficient clinical relevance.

However, the major limitation for the investigated pharmacological agents remains the lack of clinical data from larger human trials. Several of these compounds are still in preclinical or phase 1 clinical stages—such as SRK‐439 and ruvembri. Although preclinical studies in obese mice and primates treated with a GLP‐1 RA and a muscle‐preserving agent demonstrate evidence of synergistic muscle preservation and fat loss and only two completed human drug trials—BELIEVE (bimagrumab) and QUALITY (enobosarm)—testing a muscle‐preserving agent in combination with a GLP‐1 RA, which reported superior reductions in body weight and improved lean mass retention compared with monotherapy, the current evidence remains limited and short‐term. Consequently, the long‐term efficacy and safety of such combination strategies cannot yet be confidently extrapolated to human patients. There is therefore a need for studies systematically evaluating the combination therapy with GLP‐1 receptor agonists.

CONFLICT OF INTEREST STATEMENT

VA: no conflicts. JJH: scientific advisory panels and/or speaker/consultant for several companies including Novo Nordisk, Eli Lilly, MSD. He is co‐founder and owns stock in Antag Therapeutics.

Aimelet V, Holst JJ. Pharmacological intervention: Challenges and promising outcomes for fat loss and preservation of lean body mass in the treatment of overweight and type 2 diabetes. Diabetes Obes Metab. 2026;28(2):803‐816. doi: 10.1111/dom.70229

DATA AVAILABILITY STATEMENT

No new data presented.