Current Perspectives on GLP-1 Agonists in Contemporary Clinical Practice from Science and Mechanistic Foundations To Optimal Translation

Over the past century, many observations have been made supporting the presence of gastrointestinal (GI) substances that might increase insulin secretion. In 1906, Moore et al. suggested that the duodenal mucosa could potentially release a hormone that acts as an excitant for internal pancreatic secretions [8].

In 1959, the innovation of radioimmunoassay by Berson and Yalow helped quantify insulin secretion in humans [9]. Experiments undertaken in 1964 showed more insulin secretion with oral versus intravenous (IV) glucose administration despite identical glucose concentrations, an effect coined the "Incretin effect" [10].

In 1973, John Brown discovered the glucose-dependent insulinotropic polypeptide (GIP) employing peptide purification and protein sequencing, it was shown to have an incretin effect, increasing Insulin release triggered by glucose intake after oral administration [11]. However, preservation of the incretin effect after GIP removal has been demonstrated in animal GIP immunoneutralization experiments [12]. Studies in humans confirmed the lack of GIP effect on insulin secretion in patients with all DM types [13].

During the early 1970 s, the introduction of recombinant DNA (rDNA) technology enabled more precise protein amino acid sequencing by analyzing the nucleotide sequences of cloned recombinant cyclic DNA (cDNA) derived from messenger RNA (mRNA) [14]. Using this new technology, Habener et al. discovered the amino acid and gene sequences of proglucagon from anglerfish, which contained a stretch of amino acids resembling glucagon [14, 15]. Shortly thereafter, Graeme Bell et al. published the complete structure of mammalian and human proglucagon, which contained two glucagon-like structures called GLP-1 and GLP-2 [16]. However, there was uncertainty regarding the identification of the bioactive isoforms of Glucagon-like peptide 1 (GLP-1) that possessed a true insulinotropic effect.

Svetlana Mojsov first predicted the presence of GLP-1 isoforms [17]. Her subsequent work with Daniel Drucker using radioimmunoassay and chromatography identified a unique pattern of proglucagon-derived peptides in the gastrointestinal tract and pancreas, including more immunoreactive GLP-1 peptides in GI extracts [18]. Subsequent experiments showed that the active forms of GLP-1 were GLP-1(7–36 amide) and GLP-1(7–37) isoforms, increasing cAMP levels, insulin mRNA transcripts, promoting insulin secretion in the pancreases of pigs and rats, respectively [19]. In 1993, Nauck et al. showed that fasting glucose levels were completely normalized by GLP-1 infusion in T2DM patients [20]. This observation led to a study where GLP-1 was given to obese patients with T2DM and showed improved glycemic control with no side effects, establishing a proof-of-concept for GLP-1 agonists, which over time led to their use in the treatment of T2DM patients [21].

GLP-1 receptor agonists have been administered as subcutaneous injections. To overcome a potential barrier among patients favoring an alternative, oral formulations were developed. In 2019, oral semaglutide received approval as the first oral GLP-1 receptor agonist [22]. To improve gastrointestinal absorption, a carrier molecule of sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) was added to its chemical structure to overcome the challenges of peptide degradation and poor membrane permeability [23].

Looking ahead, the future of GLP-1RA delivery is poised to include oral, ultralong-acting injectables, implantable pumps, smart electronic devices, and noninvasive systems like sublingual or transdermal routes. These innovations aim to enhance bioavailability, reduce dosing frequency, and improve patient compliance [24].

GLP-1R gene encodes the glucagon-like peptide 1 receptor, a protein essential for regulating glucose metabolism and promoting insulin secretion. It's a 7-transmembrane protein that functions as a receptor for the GLP-1 hormone. GLP-1R gene expression has been demonstrated in many organs and organ systems, including the heart and cardiovascular system [30].

Transcription events related to the GLP-1R gene involve its activation by GLP-1 or its analogs, initiating a series of intracellular reactions. These reactions include increasing cAMP and intracellular calcium, activation of protein kinase A, and induction of gene transcription [33]. Furthermore, GLP-1R can also become internalized in response to GLP-1 and its analogs, indicating a complex regulatory mechanism that affects gene expression and protein activity [32].

Upon nutrient ingestion enteroendocrine L-cells secrete GLP-1, which has a crucial role in glucose metabolism regulation via enhancing insulin secretion and inhibiting glucagon release. The evolutionary advantage of this system is to ensure efficient nutrient utilization and energy storage, which are critical for survival during periods of food scarcity [34, 35].

The cardiovascular effects of GLP-1 can be seen as an extension of its role in maintaining metabolic homeostasis. By improving cardiovascular function, GLP-1 helps to ensure that nutrients and oxygen are efficiently delivered to tissues, which is essential for overall metabolic health [36].

The biological and physiological interface between the gastrointestinal (GI) tract and the cardiovascular system can be explained from an embryological perspective by examining the co-development of these systems during organogenesis.

During embryogenesis, the heart and the GI tract develop in proximity and share common signaling pathways and structural components. The heart originates from the mesoderm, while the GI tract arises from the endoderm. The interaction between these germ layers is crucial for the proper development of both systems.

Research has shown that the endoderm has a significant role in heart morphogenesis. For example, the endoderm provides essential paracrine signals that influence cardiac specification and differentiation. This is evident in the co-development of heart and digestive system tissues within human induced pluripotent stem cell (iPSC)-derived organoids, where the presence of endodermal tissue promotes the maturation of cardiac tissues [37].

In addition, the serosal mesothelium, which covers the gut, is a major source of gut vasculature smooth muscle cells. This mesothelium undergoes epithelial-mesenchymal transition (EMT) and plays a role vascular smooth muscle cells development, highlighting a conserved mechanism in blood vessel development for coelomic organs, including the heart and gut [38].

During heart tube assembly, the endoderm mechanical role is critical as it contracts, pulling the heart fields towards the midline to facilitate heart tube formation. This mechanical interaction underscores the importance of the endoderm in guiding the morphogenesis of the heart [39].

The gut-heart axis involves bidirectional communication where gut microbiota and their metabolites, such as short-chain fatty acids (SCFAs) and trimethylamine-N-oxide (TMAO), influence cardiovascular health. SCFAs have protective cardiovascular effects, while TMAO and lipopolysaccharides (LPS) from gut dysbiosis exacerbate cardiovascular diseases by promoting inflammation and endothelial dysfunction [40].

Vasoactive Intestinal Peptide (VIP), another gut-derived peptide, acts as a potent vasodilator and has positive inotropic effects on the heart. It increases coronary blood flow and reduces vascular resistance, contributing to improved cardiac function and protection against ischemic injury [41].

These interactions highlight the complex and integrated role of gut-derived peptides in modulating cardiovascular function, emphasizing the therapeutic potential of targeting these pathways in cardiovascular diseases as captured below under gaps and new areas of investigation.

Over the past thirty years, researchers have made significant strides in understanding the gut-derived hormones impact on cardiovascular health. Among these hormones, GLP-1 has emerged as a pivotal role in cardiovascular disease and health.

GLP-1R agonists exert their cardiovascular effects through multiple pathways.

GLP-1 exerts positive inotropic and chronotropic effects on the heart. By enhancing myocardial contractility, GLP-1 contributes to efficient cardiac function [42].

GLP-1 maintains left ventricular integrity through both direct and indirect mechanisms. It contributes to cardiac functional and structural well-being. These effects particularly are relevant in preventing adverse remodeling and heart failure progression [43].

GLP-1 activates pro-survival kinases within cardiac cells. These kinases promote cell survival, potentially protecting against ischemic injury and oxidative stress. Furthermore, GLP-1 enhances energy utilization, optimizing cardiac metabolism [44].

Induced human regulatory T cells (iTregs) express a functional GLP-1R, which increases intracellular cAMP levels upon stimulation with a GLP-1R agonist. This suggests that GLP-1R signaling in iTregs may mediate GLP-1R agonists anti-inflammatory effects [45]. A subset of CD8 T cells also express GLP-1R when exhausted. These GLP-1R-positive CD8 T cells has a role in the alloimmune response, and their signaling through GLP-1R acts as a negative costimulatory mechanism. This signaling can prolong allograft survival and mitigate alloimmune responses [46].

Proinflammatory cytokine expression in the myocardium has been shown to be reduced by GLP-1R agonists, which directly protects the heart against oxidative stress and inflammation. These combined effects on immune cells and direct myocardial protection underscore the multifaceted cardioprotective benefits of GLP-1R agonists [47].

Evidence suggests that inflammation in organs such as the liver, kidneys, and heart can be reduced by GLP-1R agonists [48]. In addition, by minimizing inflammation and preventing apoptosis they have a cellular protective role in the nervous and cardiovascular systems [49]. GLP-1R agonists regulate various molecular pro-inflammatory mediators, including oxidative stress, cytokine production, immune cell recruitment, glucotoxicity, and lipotoxicity ([50]). Employing preclinical, ex vivo, in vivo, and in vitro model systems investigators determined that GLP-1 agonists exert anti-inflammatory and immune modulating effects through their effects on macrophages (reduced interleukin [IL] 1β, IL-6, tumor necrosis factor [TNF]α, and C-X-C motif chemokine ligand [CXCL]), T and B lymphocytes (reduced cluster of differentiation [CD] 4 cells), monocytes (increased IL-10), mononuclear cells (decreased monocyte chemoattractant protein [MCP]−1, cell death protein [PD],, CD4 and CD8 T cells) [51 –55].

Shiraki and colleagues determined that GLP-1 agonists anti-inflammatory effect were particularly robust on vascular endothelial cells [56]. GLP-1 agonists has protective effects against inflammation and oxidative stress on human endothelial cells, including those injured by inflammatory mediators like tumor necrosis factor (TNF)-α [57]. The inhibition of protein kinase C (PKC), NADPH oxidase, and NF-ҡB signaling exhibited anti-oxidative and anti-inflammatory effects in endothelial cells, accompanied by the upregulation of protective anti-oxidative enzymes [57]. Favorable effects were also demonstrated by Krasner and colleagues [58].

Atherosclerosis, a chronic inflammatory disorder of the arterial wall, involves several key contributors to its initiation and progression that can be favorably altered or attenuated by GLP-1 agonists. Low density lipoprotein (LDL) cholesterol (C) and oxidized (ox) LDL are involved in atherogenesis, including the initial stage of endothelial cell injury and inflammation. GLP-1 agonists reduce LDL-C and ameliorate ox-LDL's proinflammatory injurious effects on vascular endothelial cells that include monocyte binding [59]. Yue and colleagues showed that the GLP-1 agonist, liraglutide, reduced the transcriptional factor KLF2 and the rescued ox-LDL induced reduction of mitogen-activated protein kinase (MAPK) kinase extracellular signal regulated kinase 5 (ERK5) phosphorylation, and blockage of ERK5 activity on KLF2 expression [60]. Liraglutide also reduced endothelial tight junction protein barriers, ameliorated ox-LDL induced endothelial monolayer permeability, and inhibited ox-LDL induced expression of vascular adhesion molecules (E-selectin and vascular cell adhesion molecule- 1), preventing ox-LDL induced monocyte adhesion to endothelial cells [57].

GLP-1R are present in human coronary artery endothelial cells [61]. There is interest in GLP-1 agonists and their ability to either reduce atherosclerotic plaque burden or the potential for plaque disruption- recognized as a proximate cause of arterial thrombotic events. There are supportive clinical trials in T2DM patients of GLP-1 agonist mediated reduction in plaque burden, size and composition [62].

Despite a growing body of work, the precise mechanism(s) whereby GLP-1R agonists achieve anti-atherogenic effects is an area of much needed investigation.

GLP-1 agonists exert vasodilatory properties in several vascular beds, ranging from the aorta to the coronary, mesenteric and renal arteries. The mechanism(s) represents a combination of direct and indirect effects on smooth muscle and endothelial cells. Selley and colleagues reported that GLP-1 associated vasodilation was mediated through the glucagon receptor [63]. Koska et al. found that increased postprandial endothelial function (EF) was independent of reductions in plasma glucose and triglycerides. The GLP-1 agonist, exenatide, increased fasting EF via endothelial nitric oxide (NO) synthase (eNOS) activation, nitric oxide (NO) production in endothelial cells, induced dose-dependent vasorelaxation, and reduced high-glucose or lipid-induced endothelial dysfunction in arterioles ex vivo [64].

GLP-1R agonists effect(s) on vascular smooth muscle cells are equally important to those on endothelial cells with several favorable responses being reported, including enhanced differentiation, attenuated response to reactive oxygen species, reduced vascular remodeling through improved mitochondrial activity and dynamics, and the prevention of aberrant migration [65].

GLP-1R agonists has shown to reduce the effects of several atherosclerotic cardiovascular disease (ASCVD) metabolic risk factors including diabetes mellitus, hyperlipidemia, overweight and obesity, and hepatic steatosis [68].

Essential hypertension is ubiquitous worldwide and contributes substantially to cardiovascular disease-associated morbidity and mortality. GLP-1 agonists exert anti-hypertensive effects compared to placebo [69], reducing systolic blood pressure by 2–3 mmHg. There are several mechanisms that include vasodilation, natriuresis, and decreased sympathetic activity [70].

In the central nervous system, GLP-1Rs are highly expressed in regions involved in metabolic regulation, appetite, and autonomic control. Key sites include the hypothalamic nuclei (arcuate, paraventricular, dorsomedial), area postrema, nucleus of the solitary tract (NTS), dorsal motor nucleus of the vagus nerve, amygdala, lateral septum, hippocampus, and cortex. These receptors are present on both neuronal cell bodies and axonal projections and are found in GABAergic and glutamatergic neurons depending on the region [71].

In the peripheral nervous system, GLP-1Rs are expressed on vagal afferent neurons, enteric neurons, dorsal root ganglia, and nerves innervating metabolically active tissues such as adipose tissue and the gastrointestinal tract. Vagal neurons are a major site for peripheral GLP-1 action, mediating gut-brain communication for the regulation of feeding, gastric emptying, and glucose metabolism [72]. GLP-1Rs are also present on Schwann cells and sensory, motor, and enteric neurons, implicating them in peripheral neuropathy and metabolic disease modulation [73]. GLP-1Rs agonists exert neuro-humoral actions by stimulating insulin secretion and suppressing glucagon release in a glucose-dependent manner, delaying gastric emptying, and reducing appetite via central nervous system pathways. These agents act on GLP-1Rs distributed in pancreatic, gastrointestinal, cardiovascular, hepatic, and neural tissues, mediating both peripheral and central effects.

Neuro-humoral actions include modulation of hypothalamic appetite centers, leading to increased satiety and reduced caloric intake, as well as slowing of gastric emptying, which further contributes to appetite suppression and glycemic control [74]. GLP-1R agonists also demonstrate neuroprotective effects, including reduction of neuroinflammation, oxidative stress, and neuronal apoptosis, with emerging evidence for benefit in neurodegenerative diseases such as Parkinson's and Alzheimer's disease [75, 76].

Vascular aging, marked by structural and functional changes in the vascular wall, is a hallmark of the aging and is strongly linked to cardiovascular mortality and age-related vascular disorders development [77]. Aging is a diverse and multifaceted process as different organs within an individual undergo distinct aging trajectories influenced by genetic, environmental, and lifestyle factors [78].

Vascular aging involves several key components that contribute to the decline in vascular health over time. Arteries and veins lose their elasticity, leading to increased vascular stiffness, which can result in higher blood pressure and a higher risk of cardiovascular diseases. Additionally, vascular endothelium becomes less effective at regulating blood flow and preventing clot formation, leading to endothelial dysfunction, increasing the risk of atherosclerosis, thrombosis, and other vascular diseases. An imbalance between the reactive oxygen species (ROS) production and the body's detoxification ability cause oxidative stress, damaging cells and tissues and contributing to vascular aging. Chronic low-grade inflammation also has a major role in vascular aging, potentially leading to various age-related diseases, including cardiovascular diseases.

Other important determinants of vascular aging include genes that are predisposed to lipid and metabolic conditions, epigenetic modifications, psychosocial stress, and environmental exposures to pollutants [77, 79].

Exenatide, a first-generation GLP-1 agonist, mitigated vascular aging induced by a high-fat diet in ApoE-/- mice by regulating inflammation and oxidative stress responses [55]. It also lessened ischemia-reperfusion injury induced endothelial dysfunction in humans through the activation of K ATP channels [80].

GLP-1 receptor activation increases DNA repair by enhancement of apurinic/apyrimidinic endonuclease 1 (APE1) expression [81]. Additionally, GLP-1 mitigates H2O2-induced senescence, regulates the antioxidant defense system, reduces cellular senescence, and DNA damage triggered by recurring oxidative stress [82].

GLP-1 agonists reduce cardiovascular events through several mechanisms previously summarized to include improved glycemic control, weight loss, lowering blood pressure, lipid lowering, reduced atherogenesis, attenuated vascular inflammation, improved endothelial cell function, vasodilation, and direct cardiovascular protective effects [88, 89]. The direct cardiovascular effects represent a combination of platelet inhibition, augmented fibrinolytic responses, and attenuated thrombogenesis that collectively address not only the prothrombotic phenotypes of DM mellitus, obesity, and chronic kidney disease but a novel prevention approach beyond traditional risk factors for myocardial infarction, ischemic stroke, and cardiovascular death [90, 91].

The diverse and interconnected mechanisms of action of GLP-1 receptor agonists—spanning cardiac, vascular, endothelial, platelet, and broad intracellular signaling pathways—establish a robust scientific foundation and a clear roadmap for their investigation, clinical trial design, and therapeutic use in medicine. These agents exert beneficial effects on myocardial contractility, vascular tone, endothelial integrity, and platelet aggregation, while also modulating inflammation, oxidative stress, and metabolic homeostasis at the cellular and molecular levels. Their ability to engage in multiple organ systems through biologically conserved pathways has not only validated their initial use in glycemic control but also catalyzed their expansion into cardiovascular, renal, and metabolic domains. The depth and breadth of mechanistic insight continue to inspire new research directions and clinical applications, fueling enthusiasm for broader use and the realization of additional therapeutic benefits across diverse patient populations.

The health benefits of GLP-1R agonists are most pronounced within the first year of treatment, with significant improvements in glycated hemoglobin (HbA1c), body mass index (BMI), and cardiovascular outcomes. A retrospective study showed that HbA1c improved significantly during the first year of treatment and this effect was maintained over four years, although the benefits plateaued after the first year. The cardiovascular benefits, including reductions in MACE and stroke, also accumulate over time, with the most substantial gains observed within the first 24 to 36 months of treatment [124, 125].

GLP-1R agonists have rapidly evolved from glucose-lowering agents for T2DM to multifaceted therapeutics with FDA- and EMA-approved indications for obesity, cardiovascular disease, chronic kidney disease, diabetic nephropathy, and sleep apnea. However, significant gaps remain in translating these benefits into optimal patient care and population health [144]. These include limited long-term safety data across diverse populations, insufficient understanding of mechanisms in neuropsychiatric and oncologic contexts, and suboptimal communication between clinicians and patients. Moreover, disparities in access and coverage, particularly for oral formulations and newer agents, hinder equitable implementation. Targeted research addressing these gaps, especially in real-world effectiveness, risk stratification, and health equity, will be essential to fully realize the population-level potential of GLP-1R agonists.

Grounded in current scientific understanding, established mechanisms of action, and emerging clinical data, we recognize a broad spectrum of medical conditions and critical domains that warrant further exploration and targeted investigation to fully realize the therapeutic potential of GLP-1R agonists.

Cardiovascular-Kidney-Metabolic (CKM) Syndrome, as defined by the AHA, is a systemic disorder characterized by pathophysiological interactions among metabolic risk factors (such as obesity, insulin resistance, dyslipidemia, and hypertension), chronic kidney disease (CKD), and the cardiovascular system, leading to multiorgan dysfunction and a high rate of adverse cardiovascular outcomes [145]. The syndrome encompasses both individuals at risk for ASCVD due to the presence of metabolic risk factors or CKD, and those with established CVD complicated by metabolic or kidney dysfunction [146]. Recent U.S. data indicate that approximately 90% of adults meet criteria for a CKM stage, with higher prevalence in older adults and in men, and a projected further increase due to the ongoing epidemics of obesity and diabetes [147].Primary cardiovascular disease prevention is an important area of investigation. Although a prior cohort study did not show a statistically significant reduction in major cardiovascular events among patients with no previous history of cardiovascular disease [148], a meta-analysis of eight clinical trials evaluating the effect of GLP-1R agonists on cardiovascular outcomes reported a 14% reduction in major adverse cardiovascular events, with no significant heterogeneity across GLP-1R agonists or subgroups, including patients with or without previous cardiovascular disease [149]. The ACC recommends GLP-1R agonists for cardiovascular risk reduction in patients with T2DM and established ASCVD [114]. This benefit is also supported by trials such as LEADER, SUSTAIN-6, and EXSCEL, in which the reduction in MACE was significant among those with established ASCVD. The REWIND trial with dulaglutide included many patients without established ASCVD and demonstrated a consistent reduction in MACE, supporting a role in primary prevention, although the effect size was modest. The SOUL and FLOW trials further support these findings for oral semaglutide. Importantly, the cardiovascular benefit appears to be independent of glycemic control and is observed across subgroups defined by age, sex, and BMI [113, 150]. However, not all agents in the class are equivalent; short-acting agents such as lixisenatide and exenatide have not demonstrated cardiovascular benefit [151]. The variability in benefit within and across agents in the GLP-1R agonist class remains an important area of investigation.Metabolic dysfunction–associated steatohepatitis (MASH). GLP-1R agonists are known to have beneficial effects in this large and steadily growing patient population, primarily through their effects on weight loss and insulin secretion, although emerging evidence suggests direct hepatic effects as well [152, 153]. Because MASH is a significant risk factor for cardiovascular disease and events, this remains an important area for future investigation [154].Microvascular disease and microvascular dysfunction. The known microvascular diseases and disorders encompass a broad spectrum of conditions affecting small blood vessels (arterioles, capillaries, and venules) across multiple organ systems. The most well-established microvascular diseases and disorders include diabetic microvascular complications, small cerebral vessel disease, renal microvascular disease, pulmonary microvascular disease, systemic autoimmune microvascular disorders, and hereditary microangiopathies [155 –158].

GLP-1RAs attenuate pathological processes such as oxidative stress and inflammation and improve endothelial function—both central to microvascular injury in diabetes and related conditions. These agents enhance nitric oxide (NO) production and endothelial nitric oxide synthase (eNOS) phosphorylation, leading to vasodilation and increased microvascular perfusion in both diabetic and non-diabetic individuals [159, 160].

GLP-1R agonists increase microvascular recruitment and blood flow in skeletal and cardiac muscle, even in the presence of insulin resistance, which may improve tissue oxygenation and metabolic responses [161]. In animal models, GLP-1R agonists prevent capillary rarefaction and microvascular barrier dysfunction and reduce apoptosis and reactive oxygen species in microvascular endothelial cells, contributing to improved organ function and reduced progression of microvascular complications [162].

Clinical trials have shown that GLP-1R agonists increase microvascular blood volume and flow in cardiac muscle, and these effects are preserved in obese individuals with vascular insulin resistance. In addition, systematic reviews and meta-analyses of randomized controlled trials report improvements in cardiac systolic and diastolic function in patients with type 2 diabetes, as well as reductions in infarct size after myocardial infarction [163].

Direct clinical trial evidence that GLP-1R agonists reduce symptoms and clinical events specifically in patients with coronary microvascular dysfunction is limited. Most cardiovascular outcome trials and meta-analyses have focused on broader populations with type 2 diabetes and established cardiovascular disease, rather than on patients with isolated coronary microvascular dysfunction [164]. Given the prevalence of coronary microvascular dysfunction, further investigation into the effects of GLP-1R agonists is warranted.5Combination Therapies: in addition to dual or triple GLP-1R agonist therapy and GLP-1R agonist and gastrointestinal peptide (GIP) therapy [165, 166], nterest has emerged in the combined use of cagrilintide—a long-acting amylin analogue that, as monotherapy, produces clinically meaningful weight loss and is well tolerated—with a GLP-1R agonist. Coadministration of cagrilintide and semaglutide (CagriSema) at 2.4 mg each, once weekly, provides substantial benefits for patients with overweight, obesity, or T2DM. The combination yields greater weight loss than either agent alone, with mean reductions in body weight of approximately 20.4% over 68 weeks in non-diabetic adults and 13.7% in those with type 2 diabetes—far exceeding placebo and monotherapy arms. Cardiovascular benefits include significant reductions in systolic and diastolic blood pressure (mean systolic reduction of − 9.9 mm Hg in non-diabetic adults and − 6.5 mm Hg in those with diabetes), improved lipid profiles, and lower C-reactive protein levels, all of which are relevant for cardiovascular risk reduction. Additionally, glycemic control is markedly improved, with a higher proportion of patients achieving normoglycemia or HbA1c ≤ 6.5% [167, 168].6Maintaining muscle mass while losing weight. GLP-1R agonists consistently cause a reduction in muscle mass (usually measured as lean mass or fat-free mass) as part of their overall weight-loss effect. The magnitude of muscle mass loss varies by agent, population, and study methodology, but typically comprises 15–40% of total weight lost, with most studies reporting 15–30%. The time course of muscle mass loss generally parallels the rate of weight loss, with the most rapid changes occurring in the first 3–4 months of treatment, particularly with higher-dose agents such as semaglutide and tirzepatide. There is variability across drugs [169 –172].

Loss of muscle mass can be minimized or prevented through several key strategies, including structured resistance or strength training, ensuring adequate dietary protein intake, and incorporating regular exercise. A slower, more moderate pace of weight loss, along with careful attention to nutritional status, is particularly important for older adults or individuals at risk for sarcopenia [173].

Adjunctive therapies such as bimagrumab and myostatin inhibitors are currently under investigation. These agents block the activin type II receptors (ActRIIA and ActRIIB), which are key mediators of muscle catabolism through the myostatin and activin A signaling pathways. GLP-1R agonists increase signaling through ActRIIA/B via myostatin and activin A [174]. Bimagrumab is a monoclonal antibody that binds to both ActRIIA and ActRIIB, preventing myostatin and activin A from activating these receptors. This blockade inhibits the downstream Smad2/3 pathway—which otherwise promotes muscle protein degradation and atrophy—and instead promotes muscle hypertrophy and differentiation [175]. Dual blockade of both ActRIIA and ActRIIB is necessary for maximal anabolic response and muscle preservation, as single-receptor inhibition is insufficient. In preclinical models, co-administration of bimagrumab or dual myostatin/activin A inhibitors with GLP-1R agonists preserves or increases muscle mass while enhancing fat loss, resulting in improved body composition and metabolic outcomes compared with GLP-1R agonist monotherapy [176]. This effect is mediated by both Akt-dependent and Akt-independent pathways, supporting muscle growth even during caloric deficit [177].

To fully realize the transformative potential of GLP-1R agonists in both individualized care and public health, a concerted effort is needed from clinicians, researchers, regulators, and industry stakeholders [144]. Clinicians are uniquely positioned to identify patient-specific needs and integrate GLP-1R agonists into personalized treatment plans, especially for those with T2DM, obesity, and related metabolic conditions. Their role in educating patients, monitoring outcomes, and advocating for equitable access is critical. Researchers must continue to explore the multifaceted effects of GLP-1R agonists across organ systems, investigate long-term safety and efficacy, and uncover genetic and environmental factors that influence therapeutic response. Regulators can accelerate access by embracing regulatory reliance and convergence, streamlining approval processes, and fostering trust through transparent and collaborative frameworks. Industry stakeholders must prioritize affordability and sustainability, expanding production and distribution models that serve underserved populations. This includes investing in generic manufacturing, supporting localized supply chains, and aligning innovation with equity goals. They should listen carefully to both the clinical and scientific communities and support investigations in new and emerging areas. Together, these groups can close existing gaps in accessibility and ensure that GLP-1R agonists are not only available but also effectively and optimally utilized to improve health outcomes across diverse communities.