The Influence of Glucagon-like Peptide-1 Receptor Agonists and Other Incretin Hormone Agonists on Body Composition

Over the past decade, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a transformative class of pharmacotherapies for obesity and type 2 diabetes mellitus (T2D) [1,2]. Obesity represents a major global health challenge, affecting more than 650 million adults worldwide and contributing substantially to morbidity, mortality, and healthcare costs [3]. Beyond excess adiposity, obesity is characterized by complex alterations in body composition, including the accumulation of visceral and ectopic fat, infiltration of adipose tissue into muscle and liver, and progressive impairment of skeletal muscle quality [4,5]. Large randomized controlled trials (RCTs) have demonstrated that GLP-1 RAs such as liraglutide [6] and semaglutide [7] produce clinically meaningful, durable weight loss and reduction in adipose tissue, especially visceral and ectopic depots alongside improvements in glycaemic control and cardiovascular outcomes. More recently, dual and triple incretin agonists, targeting combinations of GLP-1, glucose-dependent insulinotropic polypeptide (GIP), and glucagon (GCG), have achieved even greater weight reductions in clinical trials, raising the prospect of unprecedented efficacy in medical obesity treatment [8,9,10].

However, the profound reductions in body weight achieved with incretin-based therapies have renewed attention to their effects on body composition. Weight loss achieved through lifestyle or surgical interventions is often accompanied by decreases in both fat mass and lean mass [11], with lean tissue typically accounting for 20–30% of total weight reduction [8]. Loss of skeletal muscle mass may have important implications for metabolic health, functional capacity, and long-term outcomes, particularly in older adults and those with comorbidities. Whether incretin-based therapies preserve, disproportionately reduce, or even improve aspects of lean tissue and muscle quality remains an open and clinically relevant question [12]. Moreover, interindividual variability, methodological heterogeneity in body-composition assessment, and limited data on long-term outcomes complicate interpretation. The addition of lifestyle strategies, such as resistance exercise and protein optimization, may offer opportunities to enhance muscle preservation during pharmacologically induced weight loss [13,14], but rigorous trial evidence remains scarce.

Thus, while the efficacy of incretin-based therapies in achieving weight loss is firmly established, their impact on lean muscle mass remains insufficiently explored [15], underreported, and underrepresented in current clinical guidelines. This gap is particularly important given the aging population, where interventions that preserve muscle health may critically influence long-term outcomes [16].

This review aims to synthesize current knowledge on the influence of GLP-1 RAs and incretin hormone agonists on body composition. We summarized the physiologic actions of GLP-1, GIP and GCG and their association with metabolic disorders. Furthermore, we discussed evidence from preclinical studies on the effect of GLP-1 RAs and co-agonists on body composition parameters, highlighting the pathogenetic mechanisms implicated in this process. Of importance, we emphasized the published RCTs regarding the influence of incretin hormone agonists on body weight, lean muscle mass as well as we pinpointed methodological considerations and potential limitations, thus exploring emerging insights into mechanisms. Lastly, this review considers emerging strategies aimed at mitigating lean mass loss, such as combining incretin-based therapies with structured exercise programs or employing adjunctive anabolic approaches including myostatin/ActRII inhibition, to provide a broader perspective on muscle preservation during pharmacologically induced weight loss.

Skeletal muscle disorders are closely interrelated with key metabolic diseases and comorbidities such as T2D. These conditions share overlapping pathophysiological mechanisms, including insulin resistance, chronic inflammation, oxidative stress, and lipid dysregulation [67]. The prevalence of sarcopenia is significantly higher in T2D patients compared to normoglycemic individuals, reaching up to 29.3% [68]. Likewise, SO is prevalent in about 27% of individuals with T2D [69,70]. Of importance, the association between T2D and muscle disorders is bidirectional [71,72,73]. Sarcopenia can contribute to the onset of T2D by reducing skeletal muscle mass, a major site for insulin-mediated glucose disposal, while sarcopenia is also associated with physical inactivity and frailty, both risk factors for T2D [73,74,75]. Of note, SO may also have a synergistic impact on metabolic deterioration. In T2D, SO has been associated with impaired renal function, macroalbuminuria, cognitive decline, and cardiovascular disease [69,76]. Myosteatosis is also independently linked to insulin resistance and hyperinsulinemia, even after adjusting for total fat and regional adiposity, underscoring its metabolic impact [77]. Recognizing myosteatosis as an early marker of T2D may contribute to the development of novel predictive models for metabolic risk [65,78,79]. These conditions are interrelated and mutually reinforcing excess adiposity impairs mobility and induces chronic inflammation, insulin resistance, and oxidative stress, all of them contributing to accelerated muscle degeneration [57]. Conversely, sarcopenia promotes obesity by reducing physical activity and energy expenditure [57]. Patients with SO exhibit higher risks of cardiometabolic diseases and mortality [59,80], with outcomes generally worse than when either condition occurs on its own [59]. In obese individuals undergoing bariatric surgery, pre-existing myosteatosis may influence the procedure's effectiveness, affecting weight loss outcomes and metabolic improvements [81].

MASLD is deeply associated with metabolic dysfunctions, including insulin resistance, obesity, and T2D [82]. The prevalence of myosteatosis in MASLD patients is estimated at approximately 27.6%, significantly higher than in healthy adults [83,84]. Sarcopenia and myosteatosis are more prevalent in patients with advanced liver disease [84]. However, myosteatosis often develops independently and prior to sarcopenia, suggesting its potential utility as an earlier and more sensitive biomarker [63,85]. Importantly, severe myosteatosis—not sarcopenia—has been specifically linked to early stages of metabolic dysfunction–associated steatohepatitis (MASH), suggesting its utility as a novel biomarker for disease progression and fibrosis risk [86]. Both sarcopenia and myosteatosis are associated with increased MASLD severity and mortality [63,84,85]. Central obesity combined with low muscle mass are associated with a higher prevalence of MASLD [87], while they were considered as significant independent predictors of cardiovascular disease (CVD) and may serve as useful tools for 10-year CVD risk stratification in MASLD patients [87]. These muscle abnormalities are strongly associated with increased frailty, complications, and mortality [88]. Identifying them early, particularly through advanced imaging and validated biomarkers, may facilitate better risk stratification, disease management, and therapeutic intervention. Further research is essential to unravel the complex interplay between muscle health and metabolic dysfunction. A deeper understanding of shared mechanisms could pave the way for novel predictive tools and improve clinical outcomes through integrated metabolic-muscular care strategies [64].

Evidence based on experimental preclinical models (Figure 4).

Preclinical studies indicate that GLP-1RAs and co-agonists exert complex and sometimes divergent effects on skeletal muscle composition and function, reflecting the involvement of multiple and distinct pathophysiological mechanisms (Table 2).

In murine models, semaglutide elicited an increase in the cross-sectional area of tibialis anterior and gastrocnemius fibres, accompanied by an overall decline in total muscle weight. These findings suggest a disproportionate preservation of myofibre integrity relative to total lean mass, indicative of adaptive hypertrophic remodelling under GLP-1 receptor activation [89,90]. Co-administration with the activin receptor type II (ActRII) inhibitor bimagrumab preserved fibre morphology, implying that ActRII blockade may synergize with GLP-1RAs to mitigate lean mass loss [91]. In diet-induced obesity (DIO) models, both liraglutide and semaglutide reduced relative lower limb muscle weight compared with chow-fed controls but attenuated high-fat-diet–induced atrophy, improving fibre organization, contractility, and resistance to lipotoxic infiltration [92]. Beyond these structural effects, GLP-1RAs enhanced muscle microvascular perfusion and capillary recruitment by improving nutrient and insulin delivery to myocytes, which may support muscle energy metabolism and limit proteolytic stress [93]. Semaglutide-treated rats showed marked reductions in adiposity while maintaining lean tissue, whereas vehicle-treated controls accumulated fat and lost muscle mass. These findings support a dual mechanism by which GLP-1RAs preferentially mobilize adipose stores while partially preserving skeletal muscle integrity [92,94].

At the metabolic level, GLP-1RAs modulate substrate utilization within skeletal muscle. Liraglutide increased acetyl-CoA availability and enhanced de novo fatty acid synthesis in DIO models while suppressing glycolysis and amino acid catabolism, thereby reflecting a shift toward lipid-based energy metabolism and altered mitochondrial substrate preference [95]. GLP-1RA treatment also promotes mitochondrial biogenesis and remodelling, increasing mitochondrial density, citrate-synthase activity, and oxidative phosphorylation efficiency [96]. This shift toward oxidative metabolism is often accompanied by fibre-type remodelling, with enrichment of type I (oxidative) fibres and improved endurance capacity in GLP-1 overexpression models [97]. Transcriptomic profiling corroborates this metabolic reprogramming: RNA sequencing of gastrocnemius muscle from GLP-1 overexpression models revealed differential expression of over 700 genes enriched in AMPK phosphorylation, phosphoinositide 3-kinase (PI3K–Akt), cAMP-mediated signalling, calcium homeostasis, tricarboxylic acid cycle (TCA) cycle, phospholipase D metabolism, and chemokine signalling pathways [95,97]. Collectively, these changes indicate that GLP-1RAs activate integrated anabolic and metabolic signalling networks that contribute to muscle functional preservation [97].

At the cellular level, GLP-1RAs directly stimulate myogenesis and suppress proteolytic and inflammatory cascades. In C2C12 myoblasts, liraglutide promoted differentiation via a cAMP–PKA–dependent cascade involving PI3K/Akt, p38 MAPK, and ERK pathways. This was accompanied by upregulation of the myogenic transcription factors MyoD, myogenin, and CREB, key regulators of hypertrophy, repair, and regeneration [98]. In parallel, GLP-1RAs downregulated atrogenes such as Atrogin-1 and MuRF-1, thereby limiting ubiquitin–proteasome-mediated protein degradation [99]. In denervation-induced atrophy models, liraglutide preserved myotube morphology and reduced proteolysis, though this protection was attenuated by concurrent glucocorticoid exposure [98]. Furthermore, GLP-1RAs attenuated intramuscular inflammation by reducing Tumour necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-1β expression, and enhanced antioxidant defences via SIRT1 activation and increased superoxide dismutase activity [99]. Collectively, these data suggest that GLP-1RAs support skeletal muscle health through systemic fat reduction, direct pro-myogenic signalling, and metabolic reprogramming that enhances mitochondrial efficiency and contractile capacity [97,98,99].

The therapeutic landscape of obesity and T2D has been profoundly transformed by the emergence of incretin-based pharmacotherapies, particularly GLP-1 RAs and, more recently, dual and triple agonists targeting GLP-1, GIP, and GCG receptors. While the metabolic benefits of these agents, especially their potent effects on glycaemic control and body weight are well established, their impact on body composition, and specifically on lean body mass, remains a topic of considerable scientific and clinical interest. A key concern in pharmacological weight reduction is the potential loss of fat-free mass, which includes skeletal muscle, a critical determinant of insulin sensitivity, physical function, and metabolic health, as we previously highlighted in experimental models. In individuals with obesity or sarcopenia-prone phenotypes (e.g., older adults, patients with T2D), disproportionate lean mass loss during treatment may lead to impaired glucose utilization, frailty, and adverse cardiovascular outcomes.

We encompassed all the published RCTs (Table 3) that have assessed the impact of GLP-1 RAs as well as double/triple agonists on body composition. The included RCTs utilized a range of body composition assessment methods—most commonly dual-energy X-ray absorptiometry (DXA), followed by bioelectrical impedance analysis (BIA) and, in fewer cases, magnetic resonance imaging (MRI). Across these 22 RCTs, interventions ranged from short-term (8 weeks) to long-term (up to 72 weeks), as did study populations, including individuals with obesity, T2D, prediabetes and NAFLD/MASLD, with sample sizes from 15 to 371 participants. The majority focused on liraglutide (in doses ranging from 0.6 to 3.0 mg/day), with others evaluating semaglutide, exenatide, and tirzepatide.

More specifically, in Astrup et al. [105] study, liraglutide 3.0 mg led to a total weight loss of approximately 8.0 kg over 20 weeks, with 1.5 kg attributable to lean mass loss, representing ~18% of total weight lost. Consistently, in the studies of Silver et al. [112] and Kadouh et al. [118] administration of liraglutide 1.8–3.0 mg over short durations (14–16 weeks) was examined. Both studies reported modest lean mass reductions (~1.1–1.2 kg), with relative preservation of lean mass when combined with behavioural support. In contrast, Neeland et al. [6] observed a greater lean mass reduction (2.3 kg) over 49 weeks, also using liraglutide 3.0 mg, however accompanied by a larger fat mass loss (~6.2 kg). Interestingly, two other studies [119,120] reported similar lean mass losses (~1.8–2.0 kg) using liraglutide 3.0 mg over 16 to 48 weeks. These data suggest that longer intervention durations may lead to more significant absolute lean mass reductions, possibly attributed to greater body weight reduction, although the proportion of lean-to-fat loss remains relatively stable.

Studies using semaglutide, by Blundell et al. [121] and McCrimmon et al. [122] reported lean mass losses of 1.3–1.7 kg over 12 to 52 weeks. In both trials, participants experienced >10% total weight loss, and lean mass comprised approximately 20–25% of this reduction. Similarly, another RCT [123] demonstrated a 3.4 kg lean mass decrease in a longer treatment period of 68 weeks using semaglutide 2.4 mg, again reflecting 25% of the 13.3 kg total weight loss, confirming the observation that a longer treatment duration may lead to greater lean mass loss. Although exenatide was less frequently studied, two independent RCTs have provided data regarding anthropometric parameters. In Yin et al. [115] and Bunck et al. [124] studies, lean mass loss ranged from 0.9 to 1.6 kg over treatment periods of 16 to 48 weeks. These studies involved patients with T2D and demonstrated that lean mass preservation was similar to that seen with newer agents, though total weight loss was more modest. We shall point out that although absolute reductions in lean mass tend to increase with the magnitude of total weight loss [125,131], the relative proportion of lean tissue loss remains largely stable—typically representing 20–30% of total body weight reduction across trials. This pattern indicates that GLP-RAs primarily mobilize adipose depots rather than inducing disproportionate skeletal muscle catabolism. Nevertheless, maintaining muscle quality and function remains a clinical priority, particularly in older or metabolically vulnerable populations.

In terms of dual agonists, tirzepatide was evaluated in Heise et al. [116] and Jastreboff et al. [125] studies. In the SURMOUNT-1 trial [125] weight loss approached 22.5% of baseline body weight, with lean mass reduction comprising 26% of the total loss. The average lean mass loss in these studies ranged from 1.9 to 2.8 kg, consistent with the greater potency of tirzepatide in driving overall weight loss.

Importantly, data regarding objective measures of muscle strength, function or performance are scarce [132], limiting interpretation regarding the clinical relevance of body composition changes. Of importance, a recent post hoc analysis of a multicentre open-label RCT (SURPASS-3), where 246 individuals with T2D received either tirzepatide or insulin glargine [127] assessed the use of GLP-1 RA on muscle composition in patients with T2D, overweight and obesity. Tirzepatide treatment was associated with significant reductions in muscle fat infiltration (by 4.4%) and muscle volume, whereas treatment with insulin degludec was associated with a small but significant increase in muscle volume, and no significant changes in muscle fat infiltration. These observations with tirzepatide occurred in the context of significant bodyweight reduction, indicating a qualitative improvement in muscle composition. This finding is of particular interest given the anabolic suppression and intramyocellular lipid accumulation frequently observed in T2D. Consistently, Pandey et al. conducted a pre-specified secondary analysis of a previously published RCT [6] that assessed the treatment with liraglutide 3 mg vs. placebo for 40 weeks on 128 obese female patients without baseline T2D. This study [132] showed that compared to placebo, liraglutide reduced both thigh muscle fat by 7.8% from baseline and adverse muscle composition, defined as high muscle fat and low muscle mass, compared to placebo group.

To this end, an ongoing open-label RCT [133] is assessing the effect of semaglutide in physical function and body composition on older (>65 years) adults with overweight and insulin resistance and similar data on this direction are much awaited. Another prospective study showed that even though treatment with semaglutide in T2D patients resulted in decreased weight, fat mass index and visceral adipose tissue, it preserved muscle strength and muscle quality index after six months compared to baseline [134]. It is of importance to acknowledge that since T2D is a well-recognized risk factor for muscle loss, it is conceivable to assume that by improving glycaemic control and reducing glucotoxicity, GLP-1RAs may indirectly protect skeletal muscle integrity [135]. Moreover, these agents appear to reduce ectopic lipid accumulation within muscle tissue, thereby improving both muscle quantity and quality [136]. GLP-1RAs also promote muscle anabolism through mechanisms involving enhanced vascular perfusion, increased glucose uptake, and activation of the AMP-activated protein kinase (AMPK) pathway, which together stimulate protein synthesis and inhibit proteolytic processes [136,137].

Of importance, in a prospective 6-month study by Peralta-Reich et al. [126], 200 adults with overweight or obesity were treated with either semaglutide or tirzepatide alongside structured resistance training and dietary protein guidance. Over six months, total weight loss averaged 11–13%, yet lean mass loss was limited to approximately 0.63 kg in women and 1.0 kg in men, equating to less than 10% of total weight. Moreover, a recent study in individuals with prediabetes and obesity demonstrated that treatment with tirzepatide does not adversely affect physical function; however, combined resistance and aerobic exercise produced superior improvement in muscle strength compared to tirzepatide on its own [138], underscoring the need for further investigation into integrated therapeutic approaches. These findings underscore the potential of lifestyle co-interventions to mitigate muscle catabolism during pharmacologically induced weight loss, a strategy that may be more effective in younger individuals.

In line with this objective, the EMBRAZE Phase 2 trial investigated the combination of tirzepatide with apitegromab, a highly selective myostatin inhibitor (NCT06445075). While tirzepatide monotherapy was associated with lean mass losses comprising up to 30% of total weight loss, the addition of apitegromab resulted in the preservation of approximately 1.9 kg of lean mass, effectively reducing muscle loss by over 50%. Although still in early development, such combinatorial strategies represent a novel frontier in mitigating the catabolic effects of intense pharmacologic weight reduction. Further developments include the REDEFINE 1 and 2 trials, which evaluated the dual agonist cagrilintide, a long-acting analogue of amylin, with semaglutide (CagriSema) in over 3400 participants [129]. While detailed body composition data are pending, the trials reported unprecedented total weight reductions approaching 20.4%. Given the magnitude of this effect, the forthcoming analysis of lean mass dynamics will be pivotal in assessing the overall metabolic benefit of this therapy. Similarly, phase III data from mazdutide, a GLP-1/glucagon dual agonist, demonstrated significant total weight loss in a dose-dependent manner in Chinese population with overweight or obesity [130]. However, lean mass outcomes remain to be reported.

The available evidence undoubtfully suggest that GLP-1 RAs and newer dual or triple incretin agonists deliver profound and sustained weight loss [123,125]. However, their specific effects on lean and fat mass as well as muscle strength and function remain incompletely characterized. Of importance, the research on these effects faces some limitations. A first limitation is the heterogeneity of measurement techniques across studies. Trials employ different modalities, namely DXA, bioelectrical impedance analysis, CT or MRI, often with different analytic approaches and reporting metrics. Some report absolute lean-mass change in kilograms, others use percentages or relative contribution to total weight loss, while hydration adjustments are seldom performed. These methodological differences make cross-trial comparison challenging and contribute to the uncertainty about the magnitude of lean-mass change. Furthermore, the almost exclusive reliance on body-composition surrogates without parallel assessment of functional endpoints. Lean-mass decline does not necessarily equate to a clinically meaningful loss of muscle strength or performance, yet very few trials incorporated measures such as grip strength and gait speed [127,132], a fact largely attributed to the lack of relevant data. However, this is a great filed for ongoing and future research [134]. Another point of concern is that the follow-up in most studies ranges from 24 to 72 weeks, leaving open questions about the extended long-term trajectory of lean mass during chronic therapy or following discontinuation. However, a consistent pattern indicates that longer durations of pharmacotherapy are associated with greater overall weight loss, accompanied by proportionally larger reductions in lean mass. Moreover, the influence of dietary factors, lifestyle parameters and medication other than weight lowering or anti-T2D, has not be adjusted for, and consequently potential biases may be hindered. In addition, trial populations have varied widely, encompassing individuals with and without T2D, different baseline of muscle dysregulations and adiposity levels, and broad age ranges. This heterogeneity raises the possibility that effects on lean mass may differ substantially across subgroups such as older adults, women, or those with pre-existing sarcopenia. Lastly, some studies had a relatively small sample size and therefore the statistical power may not be adequate to distinguish a difference between the experimental and control group.

The afore-mentioned limitations highlight several key research priorities. Evidence indicates that lean-mass losses accompany weight reduction with GLP-1-based therapies, and meta-analyses suggest that lean mass typically accounts for approximately 20–30% of total weight loss, though the proportion varies across trials [123]. It is essential to clarify whether these reductions are merely proportional to overall weight loss or reflect direct drug-specific effects on muscle metabolism, as recent preclinical experimental studies also suggest that GLP-1RAs may positively influence muscle lipid distribution, muscle fibre content [97,98,99], and muscle fibre size [136,137]. Establishing the clinical significance of lean-mass loss is important for both optimal regulation of T2D and for its potential contribution to functional impairment or increased frailty in older or multimorbid patients [119] who may be on incretin-like treatment even for decades. Consistently, this is equally important in MASLD, where long-term alterations in muscle quantity and quality may influence hepatic steatosis progression, insulin sensitivity, and overall metabolic resilience. Comparative studies are needed to define how newer dual and triple agonists affect lean mass relative to traditional GLP-1 monotherapy, given their ability to induce substantially greater weight loss [125,139]. Furthermore, mechanistic investigations should determine whether changes in lean mass are solely a by-product of caloric deficit or whether incretin and glucagon signalling pathways directly modulate muscle proteostasis, mitochondrial function, or intramuscular fat infiltration. Furthermore, emerging data derived from preclinical and clinical studies suggest that the incorporation of resistance training, protein optimization, or adjunctive anabolic therapies can substantially attenuate lean tissue loss [140,141]. Consistently, while the next generation of agents such as CagriSema and mazdutide may achieve superior overall weight loss, their impact on muscle mass must be closely monitored to ensure comprehensive metabolic health and physical resilience. Lastly, the scarcity of comparative data currently prevents a direct comparison between GLP-1 RAs and other approved pharmacotherapies for obesity, including orlistat, phentermine, and topiramate. For clinical practice, these findings emphasize the importance of multimodal treatment plans that integrate pharmacotherapy with exercise and nutritional support, particularly in vulnerable populations.

Incretin-based pharmacotherapies have transformed the management of obesity and other metabolic comorbidities, delivering clinically meaningful and durable weight loss. However, their effects on lean and fat mass remain insufficiently defined. While GLP-1 RAs and dual/triple agonists inevitably induce some degree of lean mass reduction, this is generally proportional to fat mass loss. Current evidence is limited by methodological heterogeneity, short follow-up, and a lack of functional assessments, leaving uncertainty about the true clinical impact of lean-mass changes.

Future research must address these limitations by implementing standardized and validated methodologies for body-composition assessment, incorporating objective measures of muscle strength and physical performance, and extending longitudinal follow-up to capture long-term trajectories. Rigorous comparative trials of GLP-1RAs, dual GIP/GLP-1 agonists, and emerging triple agonists are warranted to determine whether observed differences in body-composition outcomes are compound-specific or simply proportional to the degree of weight reduction. In parallel, mechanistic studies are needed to elucidate whether these incretin-based therapies exert direct anabolic or catabolic effects on skeletal muscle metabolism independent of caloric restriction. Moreover, future investigations should distinctly evaluate their impact on sarcopenia, SO and myosteatosis to delineate differential effects on muscle quantity, quality, and functional integrity.

Ultimately, designing future trials with muscle health as a central endpoint will be essential. This includes evaluating synergistic strategies that combine pharmacotherapy with resistance exercise, nutritional optimization, or anabolic interventions, particularly in vulnerable populations such as older adults or individuals with SO. Future research should focus on standardizing body composition assessments, evaluating long-term functional outcomes and exploring combinations of metabolic and muscle-targeted therapies. The preservation of lean mass should be considered not merely a secondary endpoint but a primary goal in the pursuit of safe and sustainable weight loss. Only with this comprehensive approach can the full benefits of incretin-based therapies be realized, ensuring that reductions in adiposity do not come at the expense of functional capacity or long-term health.