Muscle loss with weight loss – is there a drug for it?

10th June 2024, A/Prof Chee L Khoo

muscle weakness

There will always be a certain degree of fat free mass (i.e. muscle) loss with any weight loss. While the makers of the GLP1/GIP agonists will tell you that overall, there is more fat loss than muscle loss, it is still a concern for the long term health of patients who lose muscles which may not be restored. This puts them at severe risk of sarcopenia as they get older. Many already have a certain degree of sarcopenia. Interestingly, there are a couple of drugs in the pipeline in Phase 2/3 trials which may preserve or even rebuild muscles.

There are a number of drugs in various stages of development but two drug classes are in the final stages of their clinical trials that have the potential in preserving if not rebuilding muscle mass. They attack the problem from separate angles – one tries to build more muscles while the other tries to slow down the loss of muscles. Incidentally, with muscle preservation we might see better fat loss and better biochemical parameters. It is hoped that this might also mean preservation of muscle strength. You will recall when we looked at sarcopenia, we highlighted that the new definition of sarcopenia is more about muscle function and strength rather than mass.

Selective androgen receptor modulators

Anabolic androgenic steroids have long been used to address muscle loss but their unwanted virilising effects in women, prostatic stimulation in men and potential adverse cardiovascular effects limits their use in reversing muscle loss. In addition, there are issues of hepatotoxicity and adverse lipid effects.

Selective androgen receptor modulators (SARMs) selectively activate the androgen receptor in specific tissues. They are called modulators rather than stimulators because of their variable effect on androgen receptors – they can be fully or mildly agonistic or fully antagonistic depending on the dosage and the tissue in question. They are (supposedly) selective in which tissues they work on. In theory, they promote muscle and bone growth with hopes of minimal androgenic effects. No SARMs have yet to be approved for clinical use but they have been widely used in the sporting world. SARMs were banned by the World Anti-Doping Agency (WADA) in 2008.

The most widely studied of the SARMs is oral enobosarm, first identified in 2004 and has been studied in at least 25 pre-clinical trials for cancer and non-cancerous conditions. Enobosarm led to significant improvements in lean body mass (LBM) and physical function in healthy postmenopausal women and elderly men (1). Enobosarm is also explored in patients with various cancers – non-small-cell lung cancer (NSCLC), colorectal cancer, non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, or breast cancer (2).

Two phase 3 trials, POWER 1 and POWER 2 are designed to assess the efficacy and safety of enobosarm for the prevention and treatment of muscle wasting in patients undergoing first-line chemotherapy for NSCLC has completed (3). They reported an increase in lean body mass at day 84 and 147 but have yet to report on effect on muscle function.

There are a number of other companies conducting studies on other SARMS – GSK 2881078 (GSK), GLPG-0492 (Galapagos), Ligandrol (Viking Therapeutics) and BMS-564929 (Bristol-Myers-Squipb) to name a few (4). They are mainly in Phase 1/2 trials.

The SARMs are not as selective as they claimed to be. While the traditional androgens are plagued by hepatotoxicity, some of the SARMs have some alteration in liver enzymes. Further, none of the trials have incorporated resistance exercise and protein intake into their intervention.

Enobosarm is now under development for preserving muscle loss with GLP1-RA. In particular, it is currently in a phase 2b clinical trial for use with semaglutide in people who are at risk for muscle atrophy and weakness (NCT06282458) (5).

Inhibitors of myostatin

Myostatin is secreted by myocytes and acts on muscle cells to inhibit muscle growth. Myostatin act by binding to activin receptor type IIA (ActRIIA) and IIB (ActRIIB) to inhibit muscle growth. Myostatin expression is decreased in physically active individuals while obesity is linked to having a higher level myostatin [6]. Muscle hypertrophy is enhanced by the blockade of both receptor subtypes, ActRIIA and ActRIIB with muscle mass increase approximately 2-fold that seen with myostatin inhibition alone (7).

Bimagrumab is a human monoclonal antibody developed to treat pathological muscle loss and weakness. It binds to and inhibits both ActRIIA and ActRIIB. It was first explored as therapy for patients with inclusion body myositis (8). A randomised controlled Phase 2b trial demonstrated safety but failed to demonstrate efficacy (6-minute-walking-distance). It has since been explored in primary and secondary sarcopenia:

  • A single dose of bimagrumab accelerated the recovery of thigh muscle volume and reversal of accumulated intermuscular adipose tissue following 2 weeks in a joint-immobilising cast compared with placebo (9).
  • Bimagrubmab improved the 6-min walk test in 244 participants aged 68 years old on average (10)
  • In older adults with sarcopenia who had 6 months of adequate nutrition and light exercise, bimagrumab increased lean body mass, decreased fat body mass and improved physical performance but the numbers did not reach statistical significance (11)
  • In adult patients aged ≥60 years undergoing surgery for hip fracture, bimagrumab treatment for 24 weeks resulted in significant increases in lean body mass but no functional benefit was observed in recovery of mobility or lower extremity function compared with placebo (12)
  • In a phase 2b randomised controlled trial, 75 adults with type 2 diabetes, BMI 28 – 40, and HbA1c levels between 6.5% – 10.0%, bimagrumab led to significant loss of fat mass, gain in lean mass and metabolic improvements (reduction of HbA1c by up to 0.75%) (13)

Scholar Rock will evaluate the effect of apitegromab, an inhibitor of the precursor of myostatin, promyostatin, on preservation of lean muscle mass as an adjunctive therapy in overweight and obese adults that are taking a GLP1-RA. Trial data is expected in mid-2025 (14).

Weight regain

Oh no!

Adaptive alterations of gut hormone (e.g. ghrelin, leptin) are implicated in weight regain, thus complicating hypocaloric dietary interventions. Another major reason for weight regain is the loss of muscle with weight loss. In the STEP-1 clinical trial for semaglutide, up to 40% of weight loss was due to lean mass loss [15].

In mice experiments, combined ActRII blockade with bimagrumab and GLP-1 receptor agonism with semaglutide leads to improved body composition during weight loss and is associated with improved serum markers of metabolic health compared with semaglutide alone (16). Thus, it is not surprising that a phase 2 study to assess the efficacy of bimagrumab alone or in addition to semaglutide to assess efficacy and safety in overweight or obese men and women is in progress (NCT05616013) (17). It is due to complete in 12 months’ time (June 2025). In July 2023, Eli Lilly purchased Versanis, the company that was developing bimagrumab.

In summary, weight loss comes with some degree of muscle loss. With the newer GLP1/GIP agonists, the weight loss can be substantial and hence, the muscle loss can also be substantial as well. We now have a number of drug classes in development which may mitigate against muscle loss. So far, there are promising preliminary data suggesting the preservation of muscle mass but preservation of muscle function is yet to be reported. Reassuringly, the newer trials are incorporating exercise and protein intake into the interventions which might produce improvement in muscle function as well as muscle mass.


  1. Dalton JT, Barnette KG, Bohl CE, Hancock ML, Rodriguez D, Dodson ST, et al. The selective androgen receptor modulator GTx-024 (enobosarm) improves lean bodymass and physical function in healthy elderlymen and postmenopausalwomen: results of a double-blind, placebo-controlled phase II trial. J Cachex Sarcopenia Muscle. 2011;2(3):153–61
  2. Dobs AS, Boccia RV, Croot CC, Gabrail NY, Dalton JT, Hancock ML, et al. Effects of enobosarm on muscle wasting and physical function in patients with cancer: a double-blind, randomised controlled phase 2 trial. Lancet Oncol. 2013;14(4):335–45.
  3. Crawford J, Prado CM, Johnston MA, Gralla RJ, Taylor RP, Hancock ML, Dalton JT. Study Design and Rationale for the Phase 3 Clinical Development Program of Enobosarm, a Selective Androgen Receptor Modulator, for the Prevention and Treatment of Muscle Wasting in Cancer Patients (POWER Trials). Curr Oncol Rep. 2016 Jun;18(6):37
  4. Fonseca GWPD, Dworatzek E, Ebner N, Von Haehling S. Selective androgen receptor modulators (SARMs) as pharmacological treatment for muscle wasting in ongoing clinical trials. Expert Opin Investig Drugs. 2020 Aug;29(8):881-891.
  6. Catalán V, Frühbeck G, Gómez-Ambrosi J (2018-01-01), del Moral AM, Aguilera García CM (eds.), “Chapter 8 – Inflammatory and Oxidative Stress Markers in Skeletal Muscle of Obese Subjects”, Obesity, Academic Press, pp. 163–189
  7. Morvan  F, Rondeau  JM, Zou  C,  et al.  Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy.   Proc Natl Acad Sci U S A. 2017;114(47):12448-12453
  8. Hanna MG, Badrising UA, Benveniste O, et al, RESILIENT Study Group. Safety and efficacy of intravenous bimagrumab in inclusion body myositis (RESILIENT): a randomised, double-blind, placebo-controlled phase 2b trial. Lancet Neurol. 2019 Sep;18(9):834-844.  
  9. Rooks DS, Laurent D, Praestgaard J, Rasmussen S, Bartlett M, Tankó LB. Effect of bimagrumab on thigh muscle volume and composition in men with casting-induced atrophy. J Cachexia Sarcopenia Muscle. 2017 Oct;8(5):727-734. doi: 10.1002/jcsm.12205. Epub 2017 Sep 14.
  10. Spitz RW, Dankel SJ, Bell ZW, Wong V, Abe T, Kang M, Loenneke JP. Blocking the activin IIB receptor with bimagrumab (BYM338) increases walking performance: A meta-analysis. Geriatr Gerontol Int. 2021 Oct;21(10):939-943.
  11. Rooks D, Swan T, Goswami B, et al. Bimagrumab vs Optimized Standard of Care for Treatment of Sarcopenia in Community-Dwelling Older Adults: A Randomized Clinical Trial. JAMA Netw Open. 2020 Oct 1;3(10):e2020836.
  12. Hofbauer LC, Witvrouw R, Varga Z, et al. Bimagrumab to improve recovery after hip fracture in older adults: a multicentre, double-blind, randomised, parallel-group, placebo-controlled, phase 2a/b trial. Lancet Healthy Longev. 2021 May;2(5):e263-e274.
  13. Heymsfield SB, Coleman LA, Miller R, et al. Effect of Bimagrumab vs Placebo on Body Fat Mass Among Adults With Type 2 Diabetes and Obesity: A Phase 2 Randomized Clinical Trial. JAMA Netw Open. 2021;4(1):e2033457
  15. Wilding J.P.H., Batterham R.L., Calanna S., Davies M., Van Gaal L.F., Lingvay I., et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med. 2021;384(11):989–1002. doi: 10.1056/NEJMoa2032183
  16. Nunn E, Jaiswal N, Gavin M, Uehara K, Stefkovich M, Drareni K, Calhoun R, Lee M, Holman CD, Baur JA, Seale P, Titchenell PM. Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism. Mol Metab. 2024 Feb;80:101880.