Development of pharmacological interventions for the treatment of sarcopenia

Introduction

Sarcopenia is a progressive skeletal muscle disorder involving the accelerated loss of muscle mass and function that is associated with functional impairments. Sarcopenia has been recognized as one of the most important geriatric syndromes which may lead to an increased risk of adverse outcomes such as falls, fractures, frailty, disability, and death (1). It commonly occurs as an age-related process in older adults, and can also occur in mid-life in association with a range of secondary factors or conditions (2).

The underlying pathophysiological pathways of sarcopenia have not been fully understood yet. Intrinsic factors such as apoptosis, autophagy, or epigenetic disorders may lead to changes in muscle structure and functional deterioration, while systemic factors such as hormonal changes or chronic inflammation can accelerate these effects. Several molecular mechanisms have been described as causes of sarcopenia that involve different levels of muscle physiology, including the functions of hormones, muscle fiber composition and neuromuscular drive, the potential of myo-satellite cells to differentiate and proliferate, systemic inflammatory pathways and intracellular mechanisms involved in the processes of proteostasis and mitochondrial function (3).

Current recommendations for the treatment of sarcopenia

Due to the importance of sarcopenia in the elderly population, early diagnosis and timely intervention are crucial for improving the prognosis and reducing healthcare costs in patients with sarcopenia. Designing effective treatment strategies is of primary concern. Current recommendations for the prevention and treatment of sarcopenia are still mainly based on the practice of non-pharmacologic therapy, including nutritional and physical interventions (4-6). Daily nutritional supplementation mainly include proteins, amino acids [e.g., essential amino acids, branched-chain amino acids (BCAA)], beta-hydroxy-beta-methylbutyrate (HMB), vitamins (e.g., vitamin D), lipids (e.g., omega-3 fatty acids) and creatine. Resistance exercise, aerobic training, balance training, and their combination are effective physical interventions (4,5,7-9). A systematic review and network meta-analysis on the basis of randomized controlled trials (RCTs) revealed that resistance exercise, whether accompanied by nutritional intervention or not, and the combination of resistance exercise with aerobic exercise and balance training are the most effective interventions to improve the quality of life (8). Adding nutritional supplementations to exercise has a greater effect on physical function measures than exercise alone (8,9). With rapid progress in the field of gut microbiota research, sarcopenia has recently been shown to be closely related to gut microbiota (10-12). Strategies such as probiotics and fecal microbiota transplantation (FMT) have shown potential to be possible therapeutic targets for age-related sarcopenia on the basis of their role in ameliorating the muscle loss (13). However, these studies still lack evidence from clinical trials and have not been recommended by guidelines or consensuses.

In clinical practice, “older adults” may not respond to lifestyle modifications, or be unable to adhere. To this end, effective drugs are needed to prevent the burden of sarcopenia and related outcomes in the aging world. The development of pharmacological agents targeting the biological mechanisms of sarcopenia is promising. Unfortunately, owing to the complex mechanism of sarcopenia, which is not yet clear, most medications are still in the research stage and are not recommended in guidelines. There are currently no specific drugs approved by the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA) for the treatment of sarcopenia.

Current and investigational pharmacological therapy for sarcopenia

Over the years, clinicians, researchers and pharmaceutical companies have tried to explore possible targets and novel medications for sarcopenia. Numerous clinical trials investigating various pharmacological treatments are arising in order to demonstrate their efficacy and safety in combating muscle mass, strength, and functional decline. Significant progress has been made in therapeutic landscape of sarcopenia, particularly with the emergence of activin receptor therapies, represented by selective androgen receptor modulators (SARMs) and myostatin antibodies. These innovations in investigational drugs have shown prospect in clinical trials, offering potential enhancements in muscle mass and strength. In this review, we aim to describe the latest advances in the development of pharmacological agents for sarcopenia and the underlying pathophysiological pathways, and review the findings based on the completed and/or ongoing trials so far. The potential pharmacotherapeutics and relevant signaling pathways are presented in Figure 1.

Figure 1 Relevant signaling pathways associated with sarcopenia and potential pharmacotherapeutics. 4E-BP1, eukaryotic translation initiation factor 4E-binding protein 1; ActRII, activin type 2 receptors; Akt, protein kinase B; AMP, adenosine monophosphate; AMPK, AMP-activated protein kinase; ATP, adenosine triphosphate; DHEA, dehydroepiandrosterone; FOXO, forkhead box protein O; GHSR, growth hormone secretagogue receptor; IGF-1, insulin-like growth factor 1; IKK, IκB kinase; IRS1/2, insulin receptor substrates 1/2; mTOR, mammalian target of rapamycin; MuRF-1, muscle ring-finger protein-1; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; PI3K, phosphoinositide 3-kinase; S6K1, ribosomal protein S6 kinase 1; SARMs, selective androgen receptor modulators; TGF-β, transforming growth factor-β; TNF-α, tumor necrosis factor-α; TSC, tuberous sclerosis complex; ULK1, unc51-like kinase-1.

In order to avoid missing important studies on this topic, we searched PubMed (March 1, 2026) for reviews and studies on the terms of “therapy” OR “medicine” OR “intervention”, combined with “sarcopenia”. We included clinical trials of pharmaceutical treatments, which reported efficacy on at least one component of sarcopenia (muscle mass, muscle strength or physical performance). Since we focused mainly on pharmacological interventions for sarcopenia in this review, studies testing non-pharmacological treatments [e.g., physical activity and daily nutritional supplementations such as vitamin D, leucine, melatonin, omega-3 fatty acids, antioxidants, creatine, HMB, coenzyme Q10 (CoQ10), and probiotics] were not included. Although numerous studies have directly or indirectly confirmed that the use of hormonal steroids such as testosterone, dehydroepiandrosterone (DHEA), growth hormone (GH), and anabolic steroids is a potential treatment for sarcopenia (which are presented in Table S1), we do not discuss these agents in this review due to the adverse effects (AEs) and their limitation in clinical conditions. We also searched for relevant information from clinical trials using the term “sarcopenia” on the website of the International Registry of Clinical Trials (ClinicalTrials.gov, http://www.clinicaltrials.gov).

We provide a comprehensive overview of the drugs for sarcopenia/sarcopenic patients, as well as the main trials tested for efficacy on at least one component of sarcopenia (muscle mass, muscle strength or physical performance). Drugs currently investigated only in the preclinical phase or early phase 1 are not discussed in this review. We classified these pharmacological agents into the novel medications and conventional drugs for new use. The former mainly refers to SARMs, myostatin antibodies, monoclonal antibodies targeting activin type 2 receptors (ActRII), ghrelin receptor agonists, and growth differentiation factor-15 (GDF-15) antibodies. The latter refers to existing medications such as antidiabetic agents, angiotensin converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs), and anti-inflammatory drugs, etc. We summarize the current and potential treatment options for sarcopenia in Figure 2. As research continues, new medications are emerging that have potential for the treatment of sarcopenia.

Figure 2 Current and potential treatment options for sarcopenia. ACEIs, angiotensin converting enzyme inhibitors; ActRII, activin type 2 receptors; ARBs, angiotensin receptor blockers; HMB, beta-hydroxy-beta-methylbutyrate; mTOR, mammalian target of rapamycin; SARMs, selective androgen receptor modulators.

SARMs

Given the numerous side effects caused by long-term androgen supplementation therapy, SARMs have emerged among researchers. SARMs are a new class of non-steroidal anabolic agents, which can selectively target AR and promote muscle growth. Due to safety concerns, the development of SARMs is aimed at eliminating common androgenic effects on the skin, prostate, and hair, while limiting these effects to specific organs and tissues (14,15). Therefore, SARMs can serve as alternative synthetic metabolic agents for testosterone. The mechanism for separating harmful androgenic activity (e.g., virilization/prostatic hypertrophy) from beneficial anabolic metabolism is still not clear (15). While selective estrogen receptor modulators (SERMs) have been investigated for decades, it has only been recently reported that studies have discovered the molecular mechanisms and biological characteristics of SARMs. Multiple mechanisms are involved in the tissue selective function of SARMs, including tissue-specific expression of metabolic enzymes, coregulators involved in the tissue-selective action of synthetic molecules, distinct signaling pathways underlying the SARMs and testosterone, and other potential mechanisms (15). Most research at present is still in the stage of studying the mechanism of action of SARMs and proving their positive effects on skeletal muscle.

Several representative SARMs have been produced and tested in clinical trials, mainly including enobosarm (GTx-024/Ostarine/MK-2866), MK-0773, GSK2881078, VK5211, and OPK-88004 (LY2452473). We summarize the completed clinical trials of these drugs in Table 1. MK-0773 induced an increase in lean body mass (LBM) in older women with sarcopenia and moderate physical dysfunction, but it did not translate to improvement in strength or function compared with placebo (16). In prostate cancer survivors with androgen deficiency, OPK-88004 was associated with a dose-related increase in whole-body and appendicular lean mass and a significantly greater decrease in percent body fat than placebo (17). Enobosarm, an orally bioavailable nonsteroidal SARM, was found to significantly increase total LBM both in healthy older men and postmenopausal women (18), as well as in patients with cancer-induced muscle wasting (19). The Prevention and treatment Of muscle Wasting in patients with cancER (POWER) trials are designed to discuss the threshold of enobosarm for clinical benefit in patients at risk for muscle wasting in non-small cell lung cancer (NSCLC), but the full results from these studies have not yet been published (20). Recently, GSK2881078 was reported to increase leg strength and LBM in men with chronic obstructive pulmonary disease (COPD) compared with physical training alone (21). GSK2881078 was well tolerated and reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings (21).

While SARMs do indeed avoid issues like prostatic hyperplasia typically associated with androgenic treatments, they can still pose a significant threat to one’s liver and kidney health. There is also a heightened risk of cardiovascular and cerebrovascular issues (e.g., heart failure or stroke), along with the potential for testicular atrophy and infertility in males due to the use of SARMs. Recently, a systematic review including six SARMs (LGD-4033, PF-06260414, GSK2881078, GTx-024, MK-0773 and OPK-88004) found that SARMs are associated with a moderate rate of mild to moderate AEs and a low rate of severe AEs (22).

In summary, SARMs can specify the androgenic effects on certain tissues and organs such as muscles and bones, and are considered alternative anabolic agents to testosterone. These clinical studies mainly focused on evaluating the efficacy and safety of SARMs in improving muscle atrophy and physical function in elderly individuals. However, although SARMs can increase muscle mass in some phase 2 clinical trials, some studies suggest that they do not improve muscle strength or physical function. Therefore, the use of these drugs in clinical practice is controversial, and no consensus has been reached yet. On the other hand, due to high incidence of AEs, researchers are supposed to focus on tissue specificity in order to develop SARMs with higher specificity, better efficacy, and better pharmacokinetics in the future.

Myostatin antibodies or monoclonal antibodies targeting ActRII

Myostatin regulates skeletal muscle growth by inhibiting the proliferation and differentiation of skeletal muscle myo-satellite cells, and reducing myotube diameter by downregulating muscle regulatory factors (23). Owing to its ability to promote muscle atrophy and cachexia, myostatin has been investigated as a promising therapeutic target to counteract muscle mass loss in patients affected by different muscle-wasting conditions (23). Myostatin is a member of the transforming growth factor-β (TGF-β) superfamily. Ubiquitin-proteasome system (UPS)-regulated protein degradation, which is activated by TGF-β and myostatin, is essential for maintaining cellular quality control in muscle (23,24). Upon binding to their receptors, the forkhead box protein O (FOXO) is activated, which increases expression of autophagy-related proteins and E3-ubiquitin ligases called Atrogin-1 and muscle ring-finger protein-1 (MuRF-1) in skeletal muscle, which target proteins and cause their destruction by the proteasomal system (25). Akt also decreases protein degradation via phosphorylation and inhibition of the FOXO family of proteins. As age increases, the elevated levels of ubiquitin binding protein and intramuscular myostatin suggest that UPS may lead to sarcopenia in humans (26). Recently, in a preclinical study, researchers reported that blockade of ActRII signaling with bimagrumab improved body composition and metabolic parameters during weight loss induced by the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide and demonstrated the existence of Akt-independent pathways supporting muscle hypertrophy in the absence of ActRII signaling (27).

Recent studies have focused on developing specific monoclonal antibodies targeting myostatin, such as landogrozumab (28-30), trevogrumab (NCT01963598), and apitegromab (31,32), targeting activin A garetosmab (NCT06299098), or targeting ActRII such as bimagrumab (33-37). The completed RCTs are summarized in Table 2. In a randomized phase 2 trial, landogrozumab (LY2495655), an anti-myostatin antibody, increased LBM and improved functional measures of muscle power, including climbing time (4-step and 12-step tests), chair rise with arms, and fast gait speed, respectively −0.46 s (P=0.093), −1.28 s (P=0.011), −4.15 s (P=0.054), and 0.05 m/s (P=0.088) in older weak fallers (29). However, LY2495655 failed to confer clinical benefit in patients with pancreatic cancer (28). Trevogrumab (REGN1033/SAR391786) is another myostatin monoclonal antibody, which was originally developed for treating sarcopenia (NCT01963598). However, the trial was completed in 2015 but the results have not yet been published. Apitegromab (SRK-015) is a novel myostatin antagonist, which has been verified in children and young adults with spinal muscular atrophy, demonstrating improved motor function with a generally well-tolerated safety profile (31,32). Notably, the safety profile of apitegromab appears more favorable compared to other myostatin inhibitors, with pyrexia, nasopharyngitis, cough, vomiting, upper respiratory tract infection, and headache most frequently reported (31). This may be due to the fact that, unlike landogrozumab and trevogrumab, apitegromab specifically targets the latent form of myostatin, resulting in greater specificity and reduced cross-reactivity within the TGF-β superfamily (38,39). A recent phase 2 trial is currently being evaluated in patients with overweight or obesity (NCT06445075). The efficacy and safety of apitegromab have not been evaluated in elderly individuals with sarcopenia, which becomes a promising direction. Garetosmab promotes muscle hypertrophy while reducing inflammation and fibrosis by targeting activin A. Recently, a clinical trial (NCT06299098) is ongoing, aiming to test if trevogrumab or trevogrumab with garetosmab when taken with semaglutide is safe and how well they work in adults with obesity for weight loss, fat loss, and lean mass preservation. The results of combination therapy are worth looking forward to.

Bimagrumab (BYM338) is the most extensively tested blocker of ActRII. Bimagrumab treatment over 16 weeks increased muscle mass and strength in older adults with sarcopenia and improved mobility, regarding gait speed (mean 0.15 m/s, P=0.009) and 6-minute walk distance (mean 82 m, P=0.022) in those with slow walking speed, based on findings from the phase 2 trial (37). In another study, bimagrumab increased LBM in patients with sarcopenia compared with placebo 6% (95% CI: 4% to 7%), but no significant difference in physical function was found (35). The results were analogous in a trial among patients with COPD and low muscle mass (36). Similarly, no functional benefit was observed in recovery of mobility or lower extremity function, regarding habitual gait speed and short-term physical capacity battery (SPPB) scores in older patients recovering from hip fracture surgery compared with placebo (33). In patients who were overweight or obese and had type 2 diabetes (T2DM), bimagrumab treatment led to a significant loss of body fat mass, a gain in LBM, and metabolic improvements (34). The dual effects of bimagrumab on fat mass decrease and LBM increase make it a potential treatment option for sarcopenic obesity.

Furthermore, a novel myostatin-specific antibody, GYM329, has been found to increase muscle strength in three different mouse models with muscle disease via “sweeping antibody technology”, resulting in superior muscle strength-improvement effects compared with those of conventional anti-myostatin agents (40). The superior efficacy and sweeping capability of GYM329 need to be verified in clinical trials. We do not discuss domagrozumab (PF-06252616) in this review because of its poor treatment effect on increasing muscle volume in its main indication, Duchenne muscular dystrophy (41).

Overall, the majority of antibodies targeting myostatin or inhibiting negative muscle regulators through ActRII have not shown significant improvements in muscle function in clinical trials, although they bear a good capacity to increase LBM. Additionally, although most myostatin antibodies and ActRII blockers are generally well tolerated, the prevalence of AEs such as capillary dilation, epistaxis, acne and diarrhea has been a significant factor in limiting the progression of these therapies.

Ghrelin and ghrelin receptor agonists

Ghrelin is the endogenous ligand for the GH secretagogue receptor (GHSR). The activation of this receptor by ghrelin or ghrelin mimetics stimulates GH secretion and exhibits anabolic properties. Ghrelin promotes protein synthesis by activating the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway and mitochondrial biogenesis and inhibiting the production of inflammatory factors (14). The activation of GHSR can increase appetite, as well as lean and adipose body weight in humans.

In clinical practice, patients with cachexia usually have sarcopenia, and cachexia is also one of the major causes of declines in muscle mass and physical function. In recent years, the impact of ghrelin on appetite in individuals with cancer cachexia has been investigated. Despite the potential benefits of ghrelin in clinical settings, its short half-life of only 30 minutes and the need for subcutaneous injections limit its practical use. However, there is a promising alternative in the form of ibutamoren mesylate (MK-0677). This potent compound acts as a GH secretagogue mimetic, effectively binding to the ghrelin receptor and triggering the release of GH. Unlike ghrelin, MK-0677 can be taken orally, making it a more convenient option for patients. In a phase 2 trial, compared to placebo, MK-0677 increased the stair climbing power, gait speed, and levels of insulin-like growth factor 1 (IGF-1), and tended to lead to fewer falls in patients who had recently experienced a hip fracture (42). However, it failed to improve several other functional performance measures and the trial was terminated early because of a safety signal of congestive heart failure (42).

Anamorelin (RC-1291) is a newly discovered oral analog of ghrelin and GH secretagogue that has been shown to increase body weight and anabolic hormone levels in healthy volunteers (43) and is being investigated for its ability to treat cancer cachexia. In 2013, Garcia et al. (44) reported that anamorelin significantly increased body weight, the levels of IGF-1 and insulin-like growth factor-binding protein 3 (IGFBP-3), and patient-reported symptoms, including appetite in individuals with cancer cachexia. Researchers have also evaluated the effects of anamorelin on body composition, strength, quality of life, and biochemical markers in patients with cancer accompanied by anorexia and cachexia based on an integrated analysis of two RCTs, which revealed a favorable clinical response profile (45). However, anamorelin significantly increased LBM, but not handgrip strength in patients with advanced NSCLC (46,47). Recently, a systematic review and meta-analysis pooled the results of five RCTs and reported significant increases in body weight, LBM, fat mass, IGF-1, and IGFBP-3 in patients with cancer who received anamorelin as a treatment for cachexia (48). There was a significant increase in appetite in the 100 mg/day group compared to the non-users. Additionally, a phase 1 RCT has been carried out to evaluate the impact of a daily dosage of 100 mg of anamorelin on the overall muscle mass of individuals diagnosed with both sarcopenia and osteopenia. As of now, the results of this trial are eagerly anticipated as they have not been made public yet. The trial, registered under the code NCT04021706, holds promise for shedding light on the effectiveness of anamorelin in addressing these conditions. Capromorelin is another oral GH secretagogue. Compared with placebo, capromorelin improved LBM, tandem walk, and stair climb in healthy older participants at risk for functional decline (49).

Due to limited effective treatment measures for patients with cachexia and unmet medical needs, ghrelin receptor agonists may become potential therapeutic agents for cancer patients. However, anamorelin currently faces core challenges in clinical application. Key functional indicators have not met expectations; that is, corresponding improvements in patient muscle function have not been observed, which is the most significant limitation of anamorelin. In addition, based on the disconnect between therapeutic efficacy and functional improvement mentioned above, regulatory agencies in various countries have made different decisions. Anamorelin has been approved in Japan for the treatment of cachexia in patients with specific cancers such as NSCLC, gastric cancer, etc. However, due to a lack of convincing evidence in improving physical function, it has not yet been approved in the United States and the European Union. To overcome existing limitations, future research should shift from monotherapy to more comprehensive intervention strategies, such as the combination therapy of anamorelin and GLP-1 receptor agonists (GLP-1RAs). In addition, future applications should not be limited to late-stage diseases. It is recommended to start using anamorelin at an earlier stage, such as the “pre-cachexia” phase of cancer cachexia, to achieve early intervention and comprehensive management.

Antidiabetic agents

There is growing evidence that anti-diabetic drugs may increase muscle mass and improve function in patients with T2DM. Antidiabetic agents include metformin, thiazolidinedione, sodium/glucose cotransporter 2 (SGLT2) inhibitors, dipeptidyl peptidase-4 (DPP4) inhibitors, and GLP-1 receptor agonists. Clinical trials of antidiabetic agents for the treatment of sarcopenia on ClinicalTrials.gov are presented in Table S2.

The potential of metformin for treating sarcopenia has been explored for years. Multiple pathways by which metformin might exert beneficial effects on age-related pathophysiology, particularly on mechanisms relevant to energy utilization and skeletal muscle function, have been identified (50). In a multicenter RCT, metformin induced an increase in AMP-activated protein kinase (AMPK) signaling and a trend toward blunted increases in mTORC1 signaling, leading to negative impacts on muscle hypertrophy in response to progressive resistance exercise in older adults (51). In another trial, metformin significantly improved usual gait speed but did not improve the EuroQol-5 Dimension (EQ-5D) index score, handgrip strength, or myostatin serum level (52). In older adults with prediabetes, long-term metformin treatment did not result in an increase in LBM (NCT01804049). The researchers published the preliminary results on ClinicalTrials.gov, but we are unable to obtain the final research data and conclusions elsewhere. In the study published recently, metformin did not improve 4-m walk speed and was poorly tolerated in older people with probable sarcopenia and prefrailty or frailty (53). In total, the evidence regarding the effects of metformin on muscle is contradictory. Furthermore, loss of appetite, risk of malnutrition and weight loss, vitamin B12 deficiency, and lactic acidosis are the most common side effects, which may bring the elderly significant risks. Thus, further studies are needed to clarify whether the benefits of metformin outweigh its risks and AEs.

Thiazolidinediones are agonists of peroxisome proliferator-activated receptor gamma (PPARγ), which can improve insulin sensitivity and change fat metabolism. In recent years, thiazolidinediones have been reported to potentially have an anabolic effect, mainly due to its potential role in reducing the intracellular lipid content in cardiomyocytes and improving fatty acid metabolism in skeletal muscle (54). In 2011, pioglitazone was found to increase visceral fat loss but not reduce skeletal muscle loss in overweight/obese older men undergoing hypocaloric weight loss (55). Nevertheless, in another trial, pioglitazone potentiated the effect of resistance training on muscle power in older women but not in men (56). The mechanisms underlying the gender differences in this effect remain to be clarified. Pioglitazone significantly improved whole-body aerobic capacity and skeletal muscle energy metabolism in patients with metabolic syndrome, and the beneficial effect might be in part through improved fatty acid metabolism in skeletal muscle (57). In summary, the available data are limited to clarify the potential positive effects of thiazolidinediones on muscle.

Dapagliflozin, empagliflozin, and canagliflozin are highly selective inhibitors of SGLT2 that can reduce hyperglycemia and weight in patients with T2DM by increasing urinary glucose excretion. Since their weight loss effects are not as strong as GLP-1RAs in the following text, the effects of lipolysis and fatty acid oxidation may be beneficial to muscle, especially in obese sarcopenia. Studies have reported significant decreases in adipose tissue mass and fat tissue index with stable lean tissue parameters and without muscle mass reduction in patients treated with SGLT2 inhibitors (58-60). However, SGLT2 inhibitor treatment with dapagliflozin was found to reduce fat mass as well as lean tissue mass in patients with T2DM (61). In the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) study, empagliflozin increased grip strength in Japanese subjects with T2DM (62). More clinical trials are needed to determine the benefits of SGLT-2 inhibitors for patients, particularly in individuals with sarcopenia or sarcopenic obesity and without diabetes mellitus. Moreover, dehydration, postural hypotension, and increased risk of falls are the most important side effects for the elderly, which may lead to serious adverse outcomes.

GLP-1 is a hormone that plays a crucial role in regulating insulin secretion from the pancreas in both healthy individuals and those with diabetes. GLP-1 is released from the gut in response to the ingestion of oral carbohydrates and works to stimulate pancreatic cells, triggering the release of insulin. GLP-1RAs potentially affect muscle health through improving the functions of endothelium, reducing the expression of myostatin and inflammatory factors (50). GLP-1 infusion markedly enhanced postprandial microvascular perfusion and further stimulated muscle protein metabolism, during a postprandial insulin hyperaminoacidaemic clamp (63). Researchers have also detected the activation of the Akt-mTOR signaling, and the results were similar between the groups. Recently, intravenous GLP-1 treatment has been demonstrated to play a significant role in increasing skeletal muscle microvascular blood flow (64). The positive impact of GLP-1 in improving overall glycemic control by increasing insulin levels is clear, especially when insulin levels are maintained at levels seen in the fed state. This underscores the importance of GLP-1 as a viable target for therapeutic interventions (64). Pemvidutide, a dual receptor agonist targeting both GLP-1 and glucagon receptors, has recently been reported to have an apparent capacity to preserve LBM during weight reduction (65). However, clinical trials studying the effect of the GLP-1 analogue liraglutide treatment in patients with T2DM did not improve physical performance or endurance (66). Gastrointestinal intolerance (nausea, vomiting, diarrhea), weight loss, increased risk of malnutrition and dehydration, injection site reactions, nasopharyngitis are the most common side effects (14,67). Furthermore, the loss of LBM and skeletal muscle associated with weight loss induced by GLP-1RAs warrant attention. The rapid and significant decline in muscle mass places certain patient populations already predisposed to sarcopenia at higher risk for muscle loss and adverse events (67). Thus, the use of GLP-1RAs requires adequate protein intake in older adults when they have already lost the muscle reserve.

The DPP4 inhibitors have been shown to have hypoglycemic effects through increasing GLP-1 and glucose-dependent insulinotropic polypeptide levels, leading to increased insulin and C-peptide levels, decreased glucagon levels, and improved oral glucose tolerance (68). Compared with the sulfonylurea group, the DPP4 inhibitors were associated with better sarcopenic parameters (fat-free mass, skeletal muscle mass, and related indices, muscle strength, and gait speed) (68). The study also revealed that these sarcopenic parameters were correlated with GLP-1 area under the curve values. Studies investigating the clinical effects of DPP4 inhibitors on sarcopenia are thus far lacking.

Despite the potential risk of hypoglycemia, antidiabetic therapy may still be considered for individuals with sarcopenia to benefit from its muscle-building properties. However, it is important to note that T2DM is a complex and diverse disease, making it challenging to pinpoint whether T2DM itself or its associated medications play a larger role in the development of sarcopenia. Most of the clinical trials evaluating the effects of antidiabetic agents on muscle were conducted in T2DM patients. Thus, the current evidence is insufficient to form recommendations for these populations.

ACEIs or ARBs

Some preclinical studies and observational data suggest that classical renin-angiotensin system (RAS) inhibitors, including ACEIs and ARBs, may improve physical function in older adults through direct and indirect effects on skeletal muscles (69). In addition, ACEIs can enhance the insulin function of peripheral tissues, thereby improving the uptake of glucose by skeletal muscles (70). Perindopril has been reported to improve exercise capacity in functionally impaired older adults, equivalent to that reported after 6 months of exercise training (71). Recently, a pilot study showed that the use of losartan was associated with improvements in the serum concentrations of molecular markers of frailty, knee strength, and frailty scores in prefrail older adults (72). However, other studies have reported no significant benefits or support for the use of RAS inhibitors. Studies have reported that perindopril or losartan has no additive effect on skeletal muscle or physical function in response to exercise training (73,74). Moreover, perindopril had no effects on improving physical performance or muscle mass in these individuals with sarcopenia (75), or improving postural sway in older adults at high risk of falls (76). A systematic review and meta-analysis evaluated the use of ACEIs or ARBs in older people and included eight trials, with no trials specifically targeting populations with sarcopenia (77). However, no significant effect was observed on endurance outcomes, strength outcomes or the short physical performance batteries (77). Moreover, among the elderly population, hyperkalemia, acute kidney injury, and angioedema are particularly important side effects that need to be paid attention to.

Overall, current research does not support the use of ACEIs or ARBs as sole treatments for enhancing skeletal muscle function and structure in elderly individuals, regardless of whether they have been diagnosed with sarcopenia. While these medications are generally deemed safe and well-received in clinical settings, their primary benefits lie in improving cardiovascular health rather than physical performance.

mTOR inhibitors

The mTOR pathway is critical to multiple ageing processes, especially through the regulation of autophagy. Two complexes, mTORC1 and mTORC2, both include mTOR as their common catalytic subunit, but each has unique biochemical components and distinct functions (78,79). mTORC1 promotes and controls protein synthesis and mTORC2 regulates cell survival and metabolism (78). The mTOR pathway is recognized as a key modulator of ageing and age-related disease. Chronically increased mTORC1 activity inhibits autophagy, resulting in age-related muscle degradation and atrophy (80). Tuberous sclerosis complex (TSC) 1–2 can be phosphorylated by Akt, which leads to mTORC1 activation. mTORC1 triggers translation and protein synthesis through activation of the downstream ribosomal protein S6 kinase 1 (S6K1) and inhibition of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) (79). Inhibition of the mTOR pathway extends lifespan in model organisms and confers protection against a growing list of age-related pathologies (81). In animal studies, partial inhibition of mTORC1 may delay the progression of sarcopenia by regulating multiple age-associated downstream pathways, indicating that mTORC1 is an effective target for treating sarcopenia (82).

Several mini clinical trials have investigated the effects of acute rapamycin ingestion on skeletal muscle protein synthesis. Short-term rapamycin administration only impaired protein synthesis in human skeletal muscle mTORC1 signaling, which occurs in response to resistance training or increased amino acid availability (83). Compared with the control, rapamycin treatment failed to alter post-absorptive muscle protein metabolism, mTORC1 signaling, and markers of autophagy (83). Two clinical trials (NCT05414292 and ACTRN12624000790549) are currently underway, using rapamycin to improve the intracellular environment of aging muscles and stimulating muscle growth through exercise to achieve a “1+1>2” effect. The results of these trials have not yet been published.

Overall, there is a scarcity of clinical trials assessing the effectiveness and safety of rapamycin in preserving muscle health and combating sarcopenia in humans. Although the initial efficacy is encouraging, the application of rapamycin faces significant challenges. Side effects are the main concern: as an immunosuppressant, rapamycin may increase the risk of infection, affect glucose and lipid metabolism, change the blood system, and cause oral ulcers and other side effects. Future research will focus on how to maximize its efficacy and avoid risks. Moreover, given the risk of side effects from daily administration, researchers are actively exploring low-dose intermittent dosing or developing more precise next-generation mTORC1 inhibitors to achieve precise regulation of the pathway.

Anti-inflammatory drugs

Chronic low-grade inflammation (also known as “inflammatory aging”) is not only the core driving factor for the occurrence and development of sarcopenia, but also forms a complex vicious cycle between the two. Higher levels of systemic proinflammatory markers such as tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), and C-reactive protein (CRP) are significantly correlated with lower muscle strength and muscle mass (84). Increases of reactive oxygen species (ROS) and these proinflammatory cytokines may result in muscular breakdown through upregulating calpain-mediated degradation (85). Inflammation and mitochondrial damage-associated molecular patterns (mDAMPs) could synergistically contribute to sarcopenia; for example, mDAMPs can trigger NF-κB signaling, thus increasing the expression of IL-6 and TNF-α (86,87). The NF-κB pathway has been reported to play an important role in regulating immune response, inflammation, and muscle atrophy, and may therefore affect the occurrence and development of sarcopenia (88). Activation of the NF-κB pathway, which sequentially stimulates the IKK complex, inhibits skeletal myogenesis and muscle regeneration and promotes muscle protein breakdown through multiple mechanisms (including autophagy, ubiquitination and satellite cell function impairments) involving either increased muscle-specific protein degradation or decreased synthesis (89-91). For example, the E3 ubiquitin ligases atrogin-1/MAFbx and MuRF-1 are upregulated during active muscle wasting, and target MyoD, calcineurin, eIF3f and myofibrillar proteins for proteolysis (92,93). Activated NF-κB also reduces muscle formation through MyoD transcription and increases muscle proteolysis (91). Thus, strategies aimed at targeting proinflammatory cytokines or the NF-κB pathway represent potential therapeutic strategies to mitigate the effects of sarcopenia.

A prospective small-sample cohort study reported that the anti-TNF agent infliximab reversed inflammatory sarcopenia in patients with Crohn’s disease with acute disease flares (94). In a phase 2 trial, isomyosamine (MYMD-1), an oral TNF-α inhibitor, was found to significantly reduce the levels of TNF-α, IL-6 and sTNFR1 in patients with chronic inflammation caused by sarcopenia or frailty (NCT05283486). Another phase 2 clinical trial (NCT06942182) launched in 2025 is evaluating the safety and efficacy of isomyosamine in elderly patients with sarcopenia after fractures, with the primary endpoint being changes in SPPB scores. In in vivo experiments, indoxyl sulfate (IS) accumulation in muscle cells and subsequent superoxide production and the up-regulation of inflammatory cytokines such as TNF-α and IL-6, and TGF-β induce muscle wasting through myostatin and Atrogin-1 (95). AST-120, the oral adsorbent of IS, was found to reduce the accumulation of IS in organs, including skeletal muscles (96). However, in a clinical trial, the addition of AST-120 to standard treatment failed to significantly affect gait speed in patients with chronic kidney disease (97).

Anti-inflammatory treatment could reduce muscle wasting and improve physical function by controlling chronic systemic low-grade inflammation. However, anti-inflammatory therapy may interfere with muscle repair function, and clinical trials still lack large-scale high-quality evidence. At present, researchers are dedicated to developing more precise and safe anti-inflammatory drugs, striving to find a balance between “anti-inflammatory” and “repair promoting”.

MAS receptor activator

In recent years, the activation of the pathway of non-classical RAS on skeletal muscles has become a novel therapeutic target (14). Sarconeos (BIO101) is an oral small molecule, which has been shown to activate the MAS receptor, a key component of the RAS in muscle cells, increase protein synthesis, and improve muscle function in preclinical studies (98). In a phase 1 study, BIO101 exhibited a good safety and pharmacokinetic profile, which led to the selection of doses for the subsequent interventional phase 2 clinical trials in age-related sarcopenia (SARA-INT) and phase 3 in COVID-19 (COVA) (99,100). In the SARA-INT trial, BIO101 at the highest dose resulted in a clinically meaningful improvement in the 400-Meter Walk Test (400MWT). This effect is close to the minimal clinically important difference (MCID) in sarcopenia (0.1 m/s) which is known to be associated with a reduction in mobility disability and mortality in older individuals (https://www.biophytis.com/en/october-04-2021). Biophytis has filed with the FDA for authorization to initiate SARA-31 phase 3 study in sarcopenia, based on the promising results from the previous SARA-INT phase 2b study and discussions with health authorities (https://www.biophytis.com/en/press-releases/press-releases-2023/3).

The mechanism of MAS receptor activator is novel, as it does not involve hormone pathways, thus avoiding the hormone-related side effects that may be caused by traditional synthetic metabolic drugs such as steroids. Compared to other medications, the side effects of BIO101 are relatively mild, such as back pain and gastrointestinal symptoms. BIO101 is recognized to be one of the most promising drug options for sarcopenia due to its improvement in muscle functions. With the launch of phase 3 clinical trials worldwide, we are expected to see breakthrough progress in this field in the coming years.

GDF-15 monoclonal antibody

GDF-15 is a cytokine of the glial cell line-derived neurotrophic factor family within the TGF-β superfamily. Research has found a significant association between elevated circulating GDF-15 levels and loss of body weight, skeletal muscle and adipose tissue in patients with cancer-associated cachexia, muscle wasting and sarcopenia (101-103). It is considered a key mediator of muscle atrophy. The development of GDF-15 monoclonal antibody ponsegromab (PF-06946860) is one of the most groundbreaking advances in the field of sarcopenia treatment. Ponsegromab is delivered subcutaneously and binds to circulating GDF-15, thereby preventing its interaction with the glial cell-derived neurotrophic factor family receptor α-like (GFRAL) (104), which tends to block the catabolic action of GDF-15 and reduce systemic inflammation. A recent phase 2 trial has shown that ponsegromab-mediated inhibition of GDF-15 resulted in a reduction in cachexia symptoms and increases in body weight, appetite, overall activity, and skeletal muscle mass as compared with placebo in patients with cancer cachexia and an elevated circulating GDF-15 level (105). These findings support the potential therapeutic relevance of targeting GDF-15 in the management of cachexia. As for safety, all ponsegromab doses (100–400 mg) were considered to be safe and had a side-effect profile similar to that of placebo (105). In another phase 2 study of a GDF-15 agonist MBL949 in patients with obesity, gastrointestinal symptoms, nausea, and vomiting were the most frequently reported dose-related AEs (respectively 71% and 39%) (106). Therefore, given the encouraging results of efficacy and satisfactory safety in patients with cachexia-associated muscle wasting, GDF-15 targeted therapy also has great potential in sarcopenia. Future research may validate its role in a larger target population.

Other pharmaceuticals

Other pharmaceuticals for the treatment of sarcopenia include stem cell transplantation, β-adrenoceptor antagonists, levothyroxine, allopurinol, melatonin, cetylpyridinium, oxytocin nasal spray, and potassium citrate. Clinical trials of these pharmaceuticals for the treatment of sarcopenia on ClinicalTrials.gov are presented in Table S3.

Over the past years, the emergence of advanced therapeutic strategies, including stem cell therapy, gene therapy and exosome therapy, represents a paradigm shift in sarcopenia treatment. Significant progress has been made in interpreting the complex associations between muscle stem cells and the occurrence of sarcopenia (107). Muscle-derived stem cells (MDSCs) and satellite cells are the most commonly studied stem cell populations from skeletal muscle, and the latter are adult stem cells that maintain tissue homeostasis and repair damage to preserve skeletal muscle integrity (107). Several studies have shown that changes in the number and function of stem cells can trigger sarcopenia, which in turn leads to adverse influences on stem cells due to the altered internal environment in muscle (107). Unfortunately, the pilot study of mesenchymal stem cells as novel therapies for age-related frailty was withdrawn because of insufficient funding (NCT05284604). Moreover, it is notable that stem cell therapy has several limitations, most importantly ethics and rejection, and production is also a prominent aspect (108). A better understanding of the roles of stem cells in muscle will facilitate the development of novel treatment approaches for sarcopenia involving stem cells. Gene therapy is reported to be another promising treatment for sarcopenia, as multiple preclinical studies have demonstrated its role in improving muscle mass or function (14,109,110). A phase 1/2a, open-label, non-randomized study designed to evaluate the safety and tolerability of intramuscular AAV9-Follistatin gene therapy in adults with age-related muscle decline is recently on the initial recruiting stage (NCT07443826). Exosome-mediated therapy is another recently emerging novel technology rapidly developed in skeletal muscle diseases. Exosomes have been shown to be able to stimulate muscle regeneration and promote muscle protein synthesis through regulating satellite cell behavior and modulating angiogenesis via non-coding RNAs and pro-angiogenic miRNAs (111-113). Research on the application of exosomes in sarcopenia treatment is still evolving. Thus, it is very important to apply these innovative technologies to patients with sarcopenia to confirm their possible therapeutic application.

Some studies have tested and verified the novel use of older medicines, such as oxytocin, allopurinol, and levothyroxine, for treating sarcopenia. In older people with impaired physical performance, allopurinol improved the 6-min walk distance but not the primary outcome post-exercise phosphocreatine (PCr) recovery rate (114). The trial suggested that antioxidant strategies to improve muscle function in older adults may need to be targeted at subgroups with high baseline oxidative stress. Compared with placebo, intranasal oxytocin led to a significant increase in LBM with a trend toward decreasing fat mass, and a significantly reduced plasma low-density lipoprotein cholesterol (115). This proof-of-concept study indicated that oxytocin might be useful for the treatment of sarcopenic obesity in older adults and may also provide additional cardiovascular benefits. An ancillary analysis of two RCTs revealed that thyroid hormone therapy did not affect muscle function, strength or mass in older individuals with subclinical hypothyroidism (NCT04354896 and NCT01660126) (116). Trials evaluating other agents such as allopurinol (NCT01550107), melatonin (NCT03784495), and cetylpyridinium chloride (NCT02575235), did not report the associated results for unknown reasons.

As mentioned above, microbial therapy also has potential. HB05P, an oral pasteurized Akkermansia muciniphila sourced from the breast milk of healthy Korean women, has recently been shown as a promising postbiotic due to the significant improvements in muscle health compared to the placebo group (117). Moreover, it’s noteworthy that the selective neutralizing Ab against RANKL, which is a widely used anti-osteoporosis drug, has shown potential in reducing sarcopenia progression through improving muscle strength and insulin sensitivity (118).

Current challenges of pharmacological treatments for sarcopenia

As mentioned above, although many new treatments for sarcopenia have been explored over the past few decades, the development of most drugs is still in its infancy. The understanding of sarcopenia’s mechanisms underlying most of these drugs remains largely elusive. Currently, no pharmacological agents have been approved. In 2022, the International Conference on Frailty and Sarcopenia Research (ICFSR) Task Force released a report on the development of drugs for sarcopenia and frailty outlining the challenges currently faced, which noted that the lack of treatment options was caused mainly by the paradigm of standalone/single diseases traditionally adopted in medicine (119). Moreover, most studies lack reports of long-term safety outcomes such as mortality, mainly due to insufficient follow-up periods (e.g., 12–24 weeks). Indeed, the long-term safety of drugs still needs to be verified, which is also one of the challenges in current clinical trials.

The complexity of age-related disorders makes the study of pharmacological interventions more challenging, and various experiments acting on a single potential pathway for sarcopenia may yield conflicting results (14). By targeting multiple mechanistic pathways concurrently, healthcare professionals can optimize treatment outcomes and improve life quality for individuals affected by sarcopenia. The combination treatment may lead to a promising therapeutic strategy aimed at achieving weight loss without concurrent muscle loss. For example, GLP-1RA semaglutide combined with ActRII blocker bimagrumab, is a cutting-edge combination strategy of “muscle increase” and “fat reduction”, mainly for obese or T2DM patients with sarcopenia (120). Similarly, the combination of myostatin antibody trevogrumab and activin A inhibitor garetosmab was recently implemented with promising results, which led to dose-dependent, additive increases in muscle mass and reductions in fat mass, highlighting its potential for improving body composition (121). The currently ongoing phase 2 RCT (NCT06299098) comparing trevogrumab and trevogrumab/garetosmab taken with semaglutide is expected to be completed in mid-2026 and the results are worth looking forward to. A recently completed phase 2 study to evaluate the effects on total LBM of apitegromab as an adjunctive therapy to a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist tirzepatide in subjects with overweight or obesity is also worth promising (NCT06445075). Consequently, novel combination therapies seem necessary to elicit an effective treatment for sarcopenia.

The design of clinical trials for treatment of sarcopenia faces multiple bottlenecks. Firstly, despite advances in pharmaceutical research, many experimental medications have shown effects on simply enhancing muscle mass without significantly enhancing strength and physical performance, facing the translational problem of “increasing muscle without increasing strength”. In most of the recent guidelines, “muscle strength” has been deemed as the center of sarcopenia instead of “muscle mass” because strength decline may precede mass loss and can better predict adverse outcomes (2,7). Recently, the Asian Working Group for Sarcopenia (AWGS) 2025 has constructed for the first time a conceptual framework centered on “muscle health promotion”, which highlights the importance of physical function as an outcome indicator for sarcopenia (6). Thus, there is an urgent need for a paradigm shift from “quantity” to “quality”. Secondly, in recent years, only a few clinical trials have focused on sarcopenic patients, while most studies have been conducted in different clinical older populations (e.g., men with hypogonadism or osteoporosis), and their efficacy has been tested separately on the components of sarcopenia. Moreover, there are over 15 definitions of sarcopenia worldwide at present, and the lack of unified diagnostic criteria makes it difficult for regulatory agencies to establish it as a drug indication. Thirdly, risk of serious AEs is definitely another large concern. Although some preclinical studies have made important discoveries, some results have not yet been translated into humans or validated in large-scale studies (119). Some of these drugs are challenging for patients to tolerate due to the adverse reactions they may cause. Therefore, they have mostly stagnated in phase 2 clinical trials and few have entered phase 3 clinical trials. At the same time, due to the large target population and extremely high safety standards required by regulatory requirements, a large scale of clinical trials is required.

In 2016, an expert working group was convened under the auspices of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and formulated consensus recommendations for the conduct of clinical trials for drugs to prevent or treat sarcopenia (122). In 2020, the expert working group provided an update of the previous recommendations on specific aspects of trial design in accordance with the available evidence in order to improve the methodological robustness and comparability of clinical trials (123). The standardization of design and results would advance this field through better comparative studies, including conducting individual patient-data meta-analyses and different pro-myogenic therapies. Collaborations among academic investigators, the government, FDA, the pharmaceutical industry, patients, and professional societies are needed to optimize the design of clinical trials to evaluate the efficacy of function-promoting pharmacological agents.

Conclusions

Although many new studies have explored the effective treatments of sarcopenia over the past few decades, currently, the interventions are still restricted to nutritional supplementation and resistance exercise. There are still no approved drugs for the treatment of sarcopenia. As previously discussed, sarcopenia is a debilitating condition that arises from a complex interplay of different physiological mechanisms. It’s still difficult to elucidate the clinical function and value of the pathways in the treatment of sarcopenia, which is one of the main reasons for the failure to find an effective pharmacotherapy. Moreover, the diagnosis of sarcopenia is still under review, which is also a major limitation that hampers the development of pharmacological treatments. In this review, we present future directions of the potential pharmacotherapeutic candidates for sarcopenia with the latest knowledge and research by reviewing the underlying pathophysiological pathways involved in the clinical trials. Large-scale studies are needed to verify the efficacy and safety of these agents. Only by conducting thorough research and gaining a comprehensive understanding of the underlying causes of sarcopenia can we open up new possibilities for treatment. This review highlights the need to bridge the gap between mechanism and functional benefit, and calls for future research to prioritize translationally robust, patient-centered endpoints in the development of pharmacotherapies for sarcopenia.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://atm.amegroups.com/article/view/10.21037/atm-2025-1-184/prf

Funding: This work was supported by the Health Commission of Sichuan Province, China (Chuan Jian Yan 2025-103).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-2025-1-184/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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