Targeting GLP1 receptor for reducing global cardiovascular risk

Abstract

Background

Overweight and obesity are increasingly recognized as major contributors to cardiovascular (CV) and renal dysfunctions, even in the absence of traditional metabolic comorbidities such as dyslipidemia, hypertension, or type 2 diabetes mellitus (T2DM). Recent evidence demonstrates that individuals classified as metabolically healthy obese (body mass index ≥30 kg/m²) remain at elevated risk for atherosclerotic CV disease, and heart failure (HF). This has led to an emerging concept of the cardio-kidney-metabolic (CKM) syndrome, a pathophysiological continuum that underscores the interconnection between metabolic, CV, and renal health.

Main body

Following experimental studies, clinical trials and real world-data, drugs blocking beta adrenergic-receptors (β-ARs), and angiotensin II type 1- receptors (AT1-Rs) have shown their fundamental role in improving CV outcomes. Surprisingly, another class of receptors from the same seven-spanning transmembrane family, the glucagon like peptide 1-receptors (GLP1-Rs) is being considered to regulate similarly CV functions. Pharmacologic agents that bind these receptors (GLP1-RAs) promote substantial weight loss, improve insulin sensitivity, and exert protective effects on CV and renal systems through both peripheral and central mechanisms. At the molecular level, GLP1-RAs enhance pancreatic β-cell survival, reduce inflammation and oxidative stress, and improve endothelial function.

Conclusion

Large clinical trials have demonstrated that GLP1-RAs significantly reduce major adverse CV events (MACE), improve HF outcomes both in preserved and reduced ejection fraction and provide additional benefits in lowering blood pressure, improving lipid profile, and reducing systemic inflammation. Their role is also being explored in emerging areas such as cardio-oncology, where they may counteract chemotherapy-induced cardiotoxicity, and obstructive sleep apnea, while weight-independent effects are yet under investigation. Moreover, preclinical data suggest a potential role for GLP1-RAs in sepsis management, owing to their anti-inflammatory and endothelial-protective properties, although clinical validation is pending. While further studies in extreme conditions, such as microgravity environment yet require investigations, current adoption of GLP1-RAs is playing a central role in preventive and personalized medicine.

Introduction

Seminal works developed by research groups involved in pharmacology, physiology, and molecular biology have highlighted the important role of G-Protein Coupled Receptors (GPCRs) expressed in the heart [1–3]. Drugs targeting many of these GPCRs expressed in the cardiovascular (CV) system are mainstays of clinical treatment for a wide range of pathologies. Until few years ago only 2 families of GPCRs were considered in CV medicine, namely beta-adrenergic receptors β-ARs, and AT1-Rs. β-ARs and AT1-Rs are major GPCRs governing CV homeostasis and disease progression. Dysregulation of these receptors contributes to cardiac hypertrophy, fibrosis, and heart failure (HF). Glucagon-like peptide-1 receptor agonists (GLP1-RAs), originally developed for type 2 diabetes mellitus (T2DM), have emerged as modulators of GPCR signaling, interacting at the molecular level with both β-AR and AT1-Rs pathways [4–7]. Among the family of same seven-spanning transmembrane receptors, GLP1-RAs are primarily coupled to Gs proteins, leading to adenylyl cyclase activation and increased intracellular cyclic AMP (cAMP), a signaling pathway shared with β-ARs [8]. In cardiomyocytes, GPCRs activation enhances cAMP and protein kinase A (PKA) signaling independently of β-ARs stimulation, thereby partially compensating for β-ARs desensitization observed in chronic sympathetic activation and HF [4–12]. At the molecular level, β-ARs signaling is tightly regulated by GPCR kinases (GRKs), particularly GRK2, which promotes receptor phosphorylation, β-arrestin recruitment, and desensitization [1, 6, 10]. GLP1-RAs have been shown to reduce GRK2 expression and activity, preserving β-ARs responsiveness and improving cardiac contractile reserve [7, 8]. Moreover, GLP1-Rs signaling activates β-arrestin–dependent pathways, including ERK1/2 and PI3K/Akt, which overlap with β-arrestin–mediated β-ARs signaling and promote cardiomyocyte survival, mitochondrial integrity, and anti-apoptotic responses [13].

AT1-R mediates the deleterious CV effects of angiotensin II primarily through Gq/11-dependent activation of phospholipase Cβ, intracellular Ca²⁺ mobilization, PKC activation, and oxidative stress [5]. Chronic AT1-R signaling promotes inflammation, fibrosis, and pathological remodeling of the heart and vasculature. GLP1-Rs activation counteracts AT1-Rs signaling at multiple molecular levels. GLP1-RAs attenuate AT1R-induced NADPH oxidase activation and reactive oxygen species (ROS) production, thereby suppressing redox-sensitive kinases and transcription factors involved in hypertrophy and fibrosis [14, 15]. These effects are mediated, in part, by cAMP/PKA-dependent inhibition of PKC and downstream signaling cascades. AT1-Rs also signals through β-arrestin–dependent pathways that activate MAPKs and transactivate receptor tyrosine kinases such as Epidermal Growth Factor Receptor (EGFR), contributing to maladaptive remodeling [5, 16]. GLP1-Rs signaling appears to bias β-arrestin–mediated signaling toward cardioprotective pathways, including Akt and AMPK activation, while limiting pro-fibrotic gene expression [13, 17].

Additionally, GLP-1RAs have been reported to downregulate AT1R expression at both transcriptional and post-translational levels, further reducing angiotensin II–driven CV injury [15, 18]. β-ARs, AT1-Rs, and GLP1-Rs form an interconnected GPCR signaling network sharing second messengers (cAMP, Ca²⁺), GRKs, and β-arrestins as adaptor proteins. Crosstalk among these receptors allows fine regulation of CV signaling under physiological conditions but contributes to disease when chronically dysregulated [6–10]. GLP1-RAs act as network modulators by enhancing beneficial Gs/cAMP signaling, limiting GRK2-mediated β-ARs desensitization, suppressing AT1-Rs driven oxidative stress, and promoting β arrestin–biased cardioprotective pathways. This integrated molecular profile provides a mechanistic basis for the CV benefits observed with GLP1-RAs in clinical outcome trials [7, 19].

To date, increasing evidence are developing about GLP1-RAs. The aim of this review is to GLP1-RAs, in different pathophysiologic settings, such as diabetes mellitus, obesity, heart failure, cardio-oncology, systemic hypertension, sleep apnea, and sepsis, providing data about their selective molecular targets.

Diabetes mellitus

T2DM is a complex metabolic disorder strongly associated with obesity, CKD, HF, and an increased risk of morbidity and mortality. As a result, diabetes management has evolved from a purely glucose-focused strategy toward an integrated cardio–reno–metabolic approach. In this setting, GLP1-RAs have revolutionized the management of T2DM through their multifaceted effects on glycemic control, weight reduction, and CV risk mitigation. Their therapeutic efficacy is mediated by a combination of peripheral and central mechanisms, targeting key pathophysiological features of diabetes. GLP1-RAs mimic the endogenous incretin hormone GLP1, which enhances glucose-dependent insulin secretion from pancreatic β cells while suppressing glucagon release from β cells, thereby reducing hyperglycemia. The receptor agonists also delay gastric emptying and promote satiety via central nervous system pathways, contributing to reduced caloric intake and weight loss [20]. At the cellular level, GLP1-Rs activation stimulates cAMP production and downstream signaling cascades, improving β-cell function and survival, reducing apoptosis, and enhancing insulin biosynthesis. Additionally, GLP1-RAs exert anti-inflammatory and anti-oxidative effects that help ameliorate β-cell dysfunction and insulin resistance [21, 22]. Clinically, GLP1-RAs produce significant reductions in glycated hemoglobin, with average decreases ranging from 1.0 to 1.5% points, depending on the agent and dose (Table 1) [26]. They also promote meaningful weight loss, a critical benefit in overweight or obese individuals with T2DM, contributing to improved insulin sensitivity and metabolic control [27, 28] (Fig. 1). Antidiabetic drug classes differ markedly in their mechanisms of action and clinical profiles. Metformin primarily reduces hepatic gluconeogenesis, sodium-glucose cotransporter 2 inhibitors (SGLT2i) lower plasma glucose by promoting urinary glucose excretion and provide CV and renal protection, while insulin therapy effectively controls hyperglycemia but is associated with weight gain and hypoglycemia risk. In contrast, GLP1-RAs enhance glucose-dependent insulin secretion, suppress glucagon release, delay gastric emptying, and promote satiety, resulting in improved glycemic control and clinically meaningful weight loss [29–31]. Robust evidence from randomized controlled trials and meta-analyses demonstrates that GLP1-RAs significantly reduce HbA1c and body weight while conferring CV benefits. In the SURPASS-2 trial, tirzepatide, a dual GIP/GLP-1 receptor agonist (GIP/GLP1-RAs), was superior to once-weekly semaglutide in improving glycemic control and reducing body weight in patients with T2DM [32]. Semaglutide has also shown consistent efficacy and safety in patients with CKD and in those receiving concomitant SGLT2i, as reported in the FLOW trial [33].

Table 1.

GLP1-RAs currently available for clinical use

	Drug	Dose	Dosing regimen	Route of administration
	dulaglutide [23]	0.75 mg	once/week	s.i.
		1.5 mg	once/week	s.i.
		3.0 mg	once/week	s.i.
		4.5 mg	once/week	s.i.
	exenatide [23]	5 mcg	twice/daily	s.i.
		10 mcg	twice/daily	s.i.
	exenatide LAR [23]	2 mg	once/week	s.i.
	Liraglutide [23]	0.6 mg	once/daily	s.i.
GLP1-RAs		1.2 mg	once/daily	s.i.
		1.8 mg	once/daily	s.i.
	lixisenatide [23]	10 mcg	once/daily	s.i.
		20 mcg	once/daily	s.i.
	semaglutide [24]	1.5 mg	once/daily	oral
		4 mg	once/daily	oral
		9 mg	once/daily	oral
	semaglutide (obesity) [24]	0.25 mg	once/week	s.i.
		0.50 mg	once/week	s.i.
		1.0 mg	once/week	s.i.
		1.7 mg	once/week	s.i.
		2.4 mg	once/week	s.i.
		2.5 mg	once/week	s.i.
GIP/GLP1-RAs	Tirzepatide [25]	5 mg	once/week	s.i.
		7.5 mg	once/week	s.i.

Receptor agonists for glucagon-like peptide-1 (GLP1-RA); Glucose-dependent Insulinotropic Polypeptide (GIP); subcutaneous injection (s.i.)

Fig. 1.

Flowchart of management for patients with obesity and other cardiometabolic diseases. Schematic representation of different phenotypes indicating the proper timing of pharmacologic drug implementation with new drugs, namely GLP1-RAs and SGLT2i. Abbreviations: ASCVD, atherosclerotic cardiovascular diseases; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; CV, cardiovascular; RAAS, renin-angiotensin-aldosterone system; GLP1-RAs, glucagon like peptide 1-receptor agonists; SGLT2i. sodium glucose-cotransporter 2 inhibitors

Beyond glycemic control, GLP1-RAs exert pleiotropic effects relevant to CV disease. Systematic reviews and meta-analyses have demonstrated significant reductions in MACE among high-risk patients with T2DM treated with GLP1-RAs [34, 35]. Emerging data further suggest a potential role for GLP-1RAs in HF with preserved ejection fraction (HFpEF), particularly in individuals with obesity, through mechanisms involving improved adiposity, reduced inflammation, and enhanced myocardial and endothelial function [36]. Several large-scale randomized controlled trials have demonstrated that GLP1-RAs not only improve glycemic parameters but also confer CV benefits, including reductions in MACE and improvements in HF outcomes [37]. The dual GLP1/GIP-RAs tirzepatide has shown particularly promising results, combining potent glucose lowering with substantial weight loss and anti-inflammatory effects [38]. Furthermore, GLP1-RAs have favorable effects on blood pressure (BP) control in patients with T2DM and hypertension, likely related to their weight-lowering effects and direct vascular actions [39]. GLP1-RAs are generally well tolerated. The most common side effects are gastrointestinal, including nausea, vomiting, and diarrhea, which typically diminish with continued use. The risk of hypoglycemia is low when GLP1-RAs are used as monotherapy or in combination with agents that do not favor hypoglycemia [20]. GLP1-RAs represent a cornerstone in the contemporary management of T2DM, offering robust glycemic control, weight reduction, and CV protection. Ongoing research continues to elucidate their pleiotropic effects, expanding their therapeutic potential beyond diabetes. Nevertheless, given their combined metabolic, CV, and weight-related benefits, GLP1-RAs represent a key component of contemporary T2DM management, especially in patients with obesity and elevated CV risk (Table 2).

Table 2.

Cardiovascular, heart failure, and renal outcomes in major GLP-1RAs trials

Trial	GLP-1RA	Population	Primary CV outcome (MACE)	Renal outcomes	Strength of evidence
LEADER	Liraglutide	T2DM + high CV risk (81% ASCVD)	HR 0.87 (0.78–0.97) ↓	↓ composite renal outcome (HR 0.78); ↓ new-onset macroalbuminuria	Robust (MACE, renal)
SUSTAIN-6	Semaglutide (s.c.)	T2DM + high CV risk	HR 0.74 (0.58–0.95) ↓	↓ new-onset persistent macroalbuminuria (−36%)	Robust (MACE), renal surrogate
REWIND	Dulaglutide	T2DM, mostly primary prevention	HR 0.88 (0.79–0.99) ↓	↓ composite renal outcome (macroalbuminuria, eGFR decline ≥30%)	Robust (MACE, renal)
PIONEER-6	Oral semaglutide	T2DM + high CV risk	HR 0.79 (0.57–1.11) NI	Exploratory only	CV safety (NI)
EXSCEL	Exenatide	T2DM + CV risk	HR 0.91 (0.83–1.00) NS	↓ albuminuria progression (secondary)	Modest
SELECT	Semaglutide 2.4 mg	Obesity + ASCVD (no T2DM)	HR 0.80 (0.72–0.90) ↓	Not primary endpoint	Robust (MACE, non-T2DM)
STEP-HFpEF	Semaglutide	Obesity + HFpEF	Not powered for MACE	NA	Emerging (HFpEF functional)

ASCVD = atherosclerotic cardiovascular disease; HF = heart failure; HFpEF = heart failure with preserved ejection fraction; HR = hazard ratio; MACE = major adverse cardiovascular events; NI = non-inferiority

CV death reduction in PIONEER-6 is hypothesis-generating due to low event numbers

Obesity

Proper mitochondrial transport function is critical for maintaining a healthy balance between energy expenditure and storage [38]. Dysfunction in these transporters can disrupt metabolic processes and contribute to the development of obesity. Indeed, current investigations into the distinct functions of various mitochondrial transporters and their potential use as therapeutic targets are opening new avenues in the treatment of metabolic diseases such as obesity [40]. GLP1-RAs have emerged as pivotal agents in the management of obesity, acting through multiple mechanisms that contribute to sustained weight loss and metabolic improvements. These agents mimic the incretin hormone GLP1, enhancing glucose-dependent insulin secretion, delaying gastric emptying, and notably reducing appetite and food intake via central nervous system pathways [20]. Body mass index (BMI) has long been used as a simple and widely accessible surrogate measure to classify overweight and obesity in both clinical practice and epidemiological research. Although BMI correlates with total body mass, it fails to discriminate between fat mass and lean mass, as well as to capture the distribution and biological behavior of adipose tissue [37]. As a result, individuals with similar BMI values may exhibit markedly different cardiometabolic risk profiles, highlighting the limitations of BMI as a standalone diagnostic and prognostic tool [40]. Adipose tissue is a heterogeneous and metabolically active organ composed of multiple depots with distinct structural and functional characteristics. Subcutaneous adipose tissue, which represents the largest fat compartment, primarily serves as an energy storage site and is relatively less deleterious from a cardiometabolic standpoint. In contrast, visceral adipose tissue, located within the abdominal cavity and surrounding internal organs, exhibits heightened lipolytic activity, increased inflammatory signaling, and greater endocrine dysfunction [41]. Visceral fat contributes disproportionately to insulin resistance, systemic inflammation, endothelial dysfunction, and myocardial structural remodeling, thereby playing a central role in the pathogenesis of cardiometabolic diseases, including T2DM and HFpEF [42]. Emerging evidence from studies evaluating GLP1-RAs underscores the clinical relevance of adipose tissue quality and distribution over absolute body weight reduction. These therapies preferentially reduce visceral and ectopic fat depots, leading to improvements in cardiometabolic risk that are not fully captured by changes in BMI alone [43]. Consequently, a growing body of literature advocates for a shift beyond BMI toward more refined assessments of adiposity when evaluating obesity-related risk and therapeutic response [37, 43–45]. Obesity is a heterogeneous condition inadequately captured by BMI alone. Contemporary evidence highlights the importance of direct measures of adiposity and ectopic fat in defining cardiometabolic risk. GLP1-RAs, particularly semaglutide across different doses and formulations, have demonstrated substantial and sustained weight loss in non-diabetic individuals with overweight or obesity, accompanied by improvements in cardiometabolic risk markers [46]. These effects extend beyond weight reduction, influencing HF risk, systemic inflammation, and metabolic flexibility [47]. GLP1-RAs and SGLT2i represent two cornerstone pharmacological classes in contemporary cardiometabolic medicine. Beyond glucose lowering, both drug classes exert pleiotropic effects on body weight, CV and renal outcomes, inflammation, and HF phenotypes [48]. Emerging evidence suggests that their combination either pharmacological or pathophysiological may provide additive or synergistic benefits across a spectrum of metabolic diseases, extending to non-diabetic populations; such data are based on the mechanisms and clinical effects of GLP1-RAs (including dual GIP/GLP-1 agonism) and SGLT2i, with particular emphasis on their interactions in patients with T2DM, CKD, obesity, and HFpEF [49]. The therapeutic landscape of T2DM and obesity has evolved substantially with the introduction of GLP1-RAs and SGLT2i. Initially developed as glucose-lowering agents, both classes have demonstrated robust benefits extending beyond glycemic control, reshaping treatment paradigms in CV and renal medicine [33]. Large, randomized trials and mechanistic studies now support their use in patients with and without diabetes, particularly in those with obesity-related cardiometabolic disease, CKD, and HFpEF [13, 36]. The convergence of these two pharmacological strategies raises important questions regarding complementary mechanisms, clinical interactions, and optimal implementation strategies, including insulin de-escalation and personalized metabolic care [30]. GLP1-RAs exert their primary effects through glucose-dependent stimulation of insulin secretion, suppression of glucagon release, and delayed gastric emptying. However, extensive preclinical and clinical evidence demonstrates broader actions involving central appetite regulation, weight reduction driven predominantly by fat mass loss, improvement in endothelial function, and attenuation of systemic inflammation and atherosclerosis [19, 50, 51]. Dual GIP/GLP1-RAs, exemplified by tirzepatide, appears to amplify these effects. In the SURPASS-2 trial, tirzepatide demonstrated superior reductions in HbA1c and body weight compared with semaglutide in patients with T2DM, highlighting the metabolic potency of combined incretin signaling [3, 21]. At physiologic level, GLP1-RAs act in the hypothalamus and brainstem, modulating appetite-regulating neurons, which lead to decreased hunger and increased satiety [27]. This anorectic effect, coupled with improved glycemic control, makes GLP1-RAs particularly effective in overweight and obese patients with or without T2DM. Tirzepatide, has shown enhanced efficacy, bridging glycemic control and CV benefits, underscoring the broad metabolic impact of incretin-based therapies [27, 32]. Clinically, randomized controlled trials have consistently demonstrated significant weight reductions with GLP1-RAs such as semaglutide, liraglutide, and dulaglutide, with weight losses often exceeding 10% of baseline body weight. This weight reduction is associated with improvements in cardiometabolic risk factors, including BP, lipid profile, and inflammatory markers [44]. The administration can occur either through subcutaneous injection or orally (Table 1). Moreover, GLP1-RAs exhibit pleiotropic effects beyond weight loss, such as enhancing cardiac glucose metabolism and improving endothelial function, which are particularly beneficial in obese individuals with concomitant cardiac dysfunction [49]. These vascular and metabolic benefits contribute to the overall reduction in obesity-related morbidity and mortality. Given their multifaceted actions, GLP1-RAs represent a cornerstone in modern obesity management, offering not only effective weight reduction but also improvements in metabolic and CV health, thereby addressing the complex pathophysiology of obesity [43–49].

Heart failure

Chronic inflammation, a critical driver of CV diseases, including atherosclerosis and HF, promotes immune cell recruitment and endothelial dysfunction. It has been demonstrated that G-protein coupled estrogen receptors increase resistance to oxidative damage [52] and exert anti-inflammatory effects by inhibiting the mitogen activated protein kinase (MAPK) pathways [53] reducing cardiac arrhythmias [54]. GLP1-RAs have garnered increasing attention for their cardioprotective effects, extending beyond glycemic control to directly influence HF). Their role is particularly relevant in HFpEF and HFrEF, where metabolic dysregulation and inflammation are key contributors to disease progression. Recent studies emphasize the pleiotropic actions of GLP1-RAs in improving cardiac function and mitigating adverse remodeling. Bonfioli et al. highlighted GLP1-RAs as promising anti-inflammatory agents in HFpEF, noting their capacity to reduce systemic and myocardial inflammation, which is critical in a condition often driven by metabolic syndrome and obesity-related inflammation [55]. By attenuating inflammatory pathways, GLP1-RAs may improve diastolic function and reduce myocardial fibrosis. Furthermore, Taktaz et al. and Fontanella et al. demonstrated that tirzepatide, activates multiple molecular pathways involved in cardioprotection, including improved mitochondrial function, reduced oxidative stress, and enhanced myocardial glucose utilization. These mechanisms contribute to improved cardiac energetics and contractility, which are often impaired in HF setting [27–56]. Harrington et al. discussed the broader CV benefits of GLP1-RAs in patients with obesity and cardiac pathologic conditions, emphasizing weight loss, BP reduction, and improved insulin sensitivity as critical factors that indirectly support HF management. They also noted emerging evidence for direct myocardial effects, such as improved left ventricular function and reduced fibrosis [28]. Moreover, Verma et al. reviewed the cardiometabolic phenotype of HFpEF, underscoring that GLP1-RAs target key metabolic disturbances insulin resistance, obesity, and inflammation that drive HFpEF pathogenesis; this assumption supports the rationale for using GLP1-RAs as adjunct therapies to conventional HF treatments [37]. Turan et al. compared the pleiotropic effects of GLP1-RAs to another medical agent category which has shown protective effects on both heart and kidney, namely SGLT2i; basically, by addressing cardiac glucose intolerance, the authors revealed that GLP1-RAs enhance cardiac glucose uptake and utilization, thereby improving myocardial energy metabolism in HF [49]. This metabolic modulation may translate into better cardiac efficiency and symptomatic relief. Lastly, Natale et al. reviewed semaglutide and other GLP1-RAs in cardiometabolic diseases, highlighting their potential to reduce MACE and improve HF outcomes (Table 2), particularly in selected high-risk populations (Fig. 1) [43]. In summary, GLP1-RAs offer a multifactorial therapeutic approach in HF by modulating inflammation, improving metabolic dysfunction, and enhancing myocardial energetics. Taken together, these effects categorize GLP1-RAs as promising agents in the evolving landscape of HF treatment, warranting further dedicated clinical trials.

Cardio-oncology

Cardio-oncology addresses the complex interplay between cancer therapies and CV health, as many oncological treatments induce cardiometabolic complications, including HF, arrhythmias [57], vascular dysfunction, and other manifestations of cancer related CV toxicity [58]. Nowadays, the comorbid effect of diabetes can also affect the therapeutic benefits of immune checkpoint inhibitors in patients with advanced oncologic conditions [59]. A comprehensive analysis of the inflammasome and its role in radiation-induced CV could provide valuable insights and establish the basis for innovative therapeutic approaches [60]. Cardio-oncology addresses the complex interplay between cancer therapies and CV health, as many oncological treatments induce cardiometabolic complications, including HF, arrhythmias, vascular dysfunction, and other manifestations of cancer related CV toxicity. Multiple anticancer therapies, including anthracyclines, HER2-targeted agents, vascular endothelial growth factor (VEGF) inhibitors, and immune checkpoint inhibitors, induce endothelial dysfunction, oxidative stress, and neurohormonal activation, thereby promoting hypertension and accelerating CV damage [61]. Hypertension acts synergistically with these mechanisms, exacerbating myocardial injury and adverse remodeling, and is consistently recognized as a modifiable risk factor in current European Society of Cardiology cardio-oncology guidelines [62]. Recent evidence highlights the multifaceted mechanisms by which GLP1-RAs may mitigate cardiotoxicity and improve cardiometabolic outcomes in cancer patients. Fontanella et al. demonstrated that tirzepatide, prevents neurodegeneration through modulation of several molecular pathways, including anti-inflammatory, antioxidant, and mitochondrial function preservation, which are also implicated in CV protection. These pleiotropic effects suggest that GLP1-RAs may confer systemic benefits extending to cardiac tissues subjected to oncologic stressors [56]. Moreover, Quagliariello et al. provide a comprehensive overview of the pathophysiology linking cancer, cardiometabolic dysfunction, and the protective role of GLP1-RAs, by emphasizing that GLP1-RAs improve endothelial function, reduce oxidative stress, and attenuate inflammation, key drivers of cancer therapy-related cardiotoxicity. By enhancing insulin sensitivity and modulating lipid metabolism, GLP1-RAs also counteract metabolic derangements common in cancer patients, such as insulin resistance and dyslipidemia, which exacerbate CV risk [61]. Cardio-oncology has emerged as a critical discipline addressing CV complications induced by anticancer therapies, which frequently involve oxidative stress, inflammation, mitochondrial dysfunction, and maladaptive signaling in cardiomyocytes and vascular cells [44]. Among the molecular pathways implicated, the GLP1-Rs axis and RAS-related signaling networks have gained increasing attention due to their cardioprotective and metabolic regulatory roles [45]. GLP1-Rs is expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells [38]. Upon activation, GLP1-Rs primarily signals through the cAMP/PKA pathway, leading to downstream activation of PI3K/Akt and AMPK. These cascades promote endothelial nitric oxide synthase (eNOS) activation, improve mitochondrial biogenesis, and inhibit apoptotic signaling. In the cardio-oncology setting, GLP1-Rs activation counteracts chemotherapy-induced cardiotoxicity by reducing ROS generation, suppressing NF-κB–mediated inflammatory responses, and preserving calcium homeostasis. In cardio-oncology specifically, direct clinical evidence supporting GLP1-RAs use is limited. Emerging mechanistic and observational data suggest potential cardioprotective effects through metabolic modulation, anti-inflammatory pathways, and mitigation of endothelial dysfunction processes highly relevant in cancer therapy–related CV injury [35]. However, these findings are derived largely from preclinical studies, retrospective cohorts, or extrapolations from non-oncologic populations, limiting causal inference. Furthermore, cancer patients often present with complex metabolic and inflammatory profiles, polypharmacy, and variable nutritional status, raising questions about the generalizability and safety of GLP1-RAs in this setting. Robust prospective, randomized studies in cardio-oncology populations are currently lacking. Importantly, GLP1-RAs appear to exert direct myocardial benefits, including improved cardiac contractility and reduced fibrosis, possibly through intracellular pathways involving cAMP/PKA and nuclear factor erythroid 2–related factor 2 (Nrf2). These pathways block apoptosis induced by chemotherapeutic agents and promote cell survival. Furthermore, GLP1-R stimulation mediates weight loss and BP reduction, with final effects of CV strain improvement and survival in cancer subjects [61]. Collectively, these data suggest that GLP1-RAs hold therapeutic promise in cardio-oncology, offering a dual advantage of metabolic regulation and direct CV protection. However, clinical trials specifically designed to evaluate GLP1-RAs in cancer populations remain limited, necessitating further research to define optimal indications, dosing strategies, and long-term safety profiles in this vulnerable cohort.

Hypertension

In patients with diabetes, levels of seric enzymes in the NAD pathway are elevated and are positively associated with insulin resistance and higher urinary albumin-to-creatinine ratios. Such markers of endothelial damage are also increased in non-diabetic, non-proteinuric hypertensive outpatients and associated with decline of kidney function (Fig. 2) [63]. GLP-1RAs have gained substantial attention for their multifaceted benefits beyond glycemic control, particularly in CV risk management. Among the emerging therapeutic roles above elucidated, pivotal importance is attribute to drugs that can control BP, including GLP1-RAs; in particular, their effect is especially relevant given the high prevalence of hypertension in individuals with obesity and T2DM. Several recent reports emphasize the antihypertensive effects of GLP1-RAs, which appear to be mediated by both direct and indirect mechanisms. Berra et al. highlighted the complementary role of GLP1-RAs alongside SGLT2i in controlling BP in patients with T2DM and arterial hypertension. The authors describe how GLP1-RAs improve endothelial function, promote natriuresis, and reduce sympathetic nervous system activity, collectively contributing to BP reduction [39]. These effects are partly attributable to weight loss and improved insulin sensitivity; however, accumulating evidence suggests additional weight-independent mechanisms [63]. GLP1-R activation promotes natriuresis through inhibition of sodium–hydrogen exchanger activity in the proximal renal tubule and enhances diuresis, contributing to lessen intravascular volume. Moreover, GLP1-RAs may attenuate sympathetic nervous system activity and improve arterial compliance, further supporting BP lowering effects [64]. Jarade et al. reviewed the application of GLP1-based therapies in resistant hypertension among overweight and obese individuals. Their analysis underscored consistent reductions in systolic and diastolic BP across multiple clinical trials, with the degree of reduction correlating partly with weight loss but also involving direct vascular effects. Importantly, GLP1-RAs improve vascular endothelial health by enhancing nitric oxide bioavailability and reducing oxidative stress, thus mitigating arterial stiffness and atherosclerotic progression [50]. Park et al. further elucidated the vascular protective mechanisms of GLP1-RAs, focusing on endothelial modulation; ligands to the GLP1-Rs trigger signaling cascades that enhance endothelial nitric oxide synthase (eNOS) activity, leading to vasodilation and improved arterial compliance, therefore these agents attenuate vascular inflammation and inhibit smooth muscle proliferation, which are critical factors in hypertension pathophysiology and vascular remodeling [51]. Harrington et al. provided a comprehensive update on novel pharmacotherapies for obesity, including GLP1-RAs, emphasizing their role in reducing CV risk through weight loss and direct hemodynamic effects. They highlighted that GLP1-RAs reduce sympathetic overactivity, a key contributor to hypertension in obese patients, and improve cardiac function, thereby offering a dual benefit in managing both obesity-related hypertension and cardiac conditions [28]. Overall, GLP1-RAs represent a promising adjunctive treatment for hypertension, particularly in the context of obesity and metabolic disease. Their BP lowering effects are achieved through a combination of weight loss, natriuretic effects, modulation of autonomic tone, and direct improvement of vascular function. Future studies are warranted to further delineate their long-term impact on hypertension-related outcomes and CV morbidity (Fig. 2).

Fig. 2.

Targets of GLP1-RAs through the human body. Six main organs and tissues affected by agonists that bind the GLP1-R. Red arrows report reduction in physiologic functions, blue arrows are related to increased metabolic activities. Abbreviations: GLP1-R, glucagon like peptide 1-receptor

Sleep apnea

Obstructive sleep apnea (OSA) is a highly prevalent and underdiagnosed condition, particularly among individuals with overweight or obesity. It is characterized by recurrent upper airway collapse during sleep, resulting in intermittent hypoxia, sleep fragmentation, and increased sympathetic activity. These pathophysiological changes contribute to cardiometabolic complications and poor quality of life. Weight loss remains a cornerstone of OSA management, and recent interest has focused on the potential of GLP1-RAs to address both obesity and OSA simultaneously [65]. GLP1-RAs, such as liraglutide and semaglutide, have demonstrated significant efficacy in reducing body weight, which is a primary driver of OSA severity. Weight loss achieved through GLP1-RAs reduces peripharyngeal fat deposition, improves upper airway mechanics, and lowers pharyngeal collapsibility during sleep. Clinical trials and meta-analyses have shown that GLP1-RA therapy can lead to meaningful reductions in body weight (approximately 10–11 kg) and BMI, accompanied by improvements in apnea–hypopnea index (AHI) and other respiratory parameters [66]. Beyond weight loss, potential mechanisms by which GLP1-RAs may benefit patients with OSA include modulation of systemic inflammation, improved insulin sensitivity, and attenuation of oxidative stress. These pleiotropic effects could reduce upper airway edema, stabilize ventilatory control, and improve CV risk factors commonly associated with OSA. Additionally, GLP1-Rs are expressed in the brainstem and hypothalamus, suggesting possible direct central effects on respiratory control [51]. A recent narrative review highlighted the emerging evidence supporting GLP1-RAs as an adjunctive therapy for OSA in patients with obesity, noting improvements in both objective (e.g., AHI) and subjective (e.g., daytime sleepiness) outcomes, although most data derive from studies involving liraglutide [26]. Furthermore, GLP1-RAs have shown favorable effects on resistant hypertension, a common comorbidity in OSA, providing additional cardiometabolic benefits [50]. However, important limitations must be acknowledged. Most existing studies are small, of short duration, and focus primarily on liraglutide, leaving uncertainty regarding the comparative effectiveness of newer agents such as semaglutide or tirzepatide in OSA. The degree to which GLP1-RAs improve OSA independent of weight loss remains unclear. Moreover, GLP1-RAs may be less effective in non-obese OSA phenotypes or cases driven by structural upper airway abnormalities. Gastrointestinal side effects and cost may also limit long-term adherence in clinical practice. In conclusion, GLP1-RAs represent a promising therapeutic strategy in the management of OSA, particularly in patients with comorbid obesity. Their dual impact on weight reduction and metabolic health, combined with preliminary evidence of direct respiratory benefits, supports further investigation through well-powered randomized trials focusing on long-term OSA outcomes.

Sepsis

G-protein coupled receptors of the vasoactive intestinal peptide (VPAC) are localized on immune-competent cells and on other mesenchymal and endothelial tissues in humans. For the anti-inflammatory signaling, VPAC1 has been identified as the most important receptor, and showed a dynamic response in granulocytes, monocytes and lymphocytes after administration of systemic low doses of LPS to healthy humans [67]. GLP1-RAs, originally developed for the management of T2DM, have gained interest for their pleiotropic effects beyond glycemic control, including anti-inflammatory, cytoprotective, and endothelial-stabilizing properties. Emerging preclinical evidence suggests that activation of the protective signaling downstream GLP1-Rs activation may offer therapeutic benefits in the context of sepsis, a condition characterized by a dysregulated host response to infection, systemic inflammation, endothelial dysfunction, and multi-organ injury. GLP1-Rs is expressed in various non-pancreatic tissues implicated in sepsis pathophysiology, including the lung, kidney, vasculature, heart, and immune cells such as macrophages and lymphocytes. This widespread receptor distribution provides the anatomical basis for the potential systemic effects of GLP1-RAs in sepsis. Mechanistically, GLP1-R signaling exerts anti-inflammatory actions by suppressing NF-κB activation, reducing the expression of pro-inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β), and inhibiting the NLRP3 inflammasome. Additionally, GLP1-RAs modulate the cAMP/PKA signaling pathway, which may dampen macrophage activation and reduce reactive oxygen species production. These pathways converge to attenuate the exaggerated inflammatory response seen in sepsis [68]. A growing body of preclinical data supports the protective role of GLP1-RAs in models of sepsis-induced organ injury, particularly acute lung injury (ALI). In a murine model of lipopolysaccharide (LPS)-induced ALI, dulaglutide reduced lung inflammation, neutrophil infiltration, and apoptosis, while suppressing STAT3 phosphorylation and NLRP3 activation [69]. Similarly, liraglutide pretreatment was shown to attenuate ALI and vascular leakage in polymicrobial sepsis and pneumonia-induced models, in part through preservation of alveolar epithelial barrier integrity and enhancement of surfactant production. In vitro, liraglutide also mitigated LPS-induced disruption of tight junctions in human lung microvascular endothelial cells, restoring barrier function through inhibition of Rho/NF-κB signaling [70]. Beyond the pulmonary system, GLP1-RAs may exert protective effects in other organs frequently compromised during sepsis. Experimental studies have suggested renoprotective and cardioprotective effects following activation of the GLP1-Rs via anti-apoptotic and anti-inflammatory mechanisms, although direct evidence in septic models remains limited [64]. Importantly, GLP1-RAs offer the advantage of modulating glucose metabolism in a glucose-dependent manner, which may reduce the risk of hypoglycemia in critically ill patients a known limitation of intensive insulin therapy in sepsis. Despite these promising findings, several caveats must be considered. The majority of evidence to date derives from animal studies employing prophylactic or early administration of GLP1-RAs, which may not accurately reflect clinical scenarios in human sepsis. Additionally, the dual role of inflammation in sepsis as both a driver of injury and a mediator of host defense necessitates caution, as excessive immunosuppression could impair pathogen clearance. Furthermore, there is a paucity of clinical data regarding the safety, dosing, and efficacy of GLP1-RAs in septic patients; on the other hand, potential side effects, including gastrointestinal disturbances and hemodynamic instability, warrant further investigation in critically ill populations. In summary, GLP1-RAs represent a promising therapeutic strategy in sepsis, acting through immunomodulatory, cytoprotective, and endothelial-stabilizing mechanisms. While preclinical data are encouraging, translational studies and clinical trials are urgently needed to determine the therapeutic potential, safety profile, and optimal use of GLP-1RAs in the management of sepsis.

Regulation of glucose metabolism in microgravity

There is a lack of knowledge about human physiology regulation, including glucose metabolism, in extreme settings such as space exploration. When astronauts live in a hostile environment during long-duration space flights, they experience microgravity-associated adaptations that span through the whole body. It has been suggested that microgravity causes subclinical diabetogenic changes, such as insulin secretion and sensitivity alterations, decreased glucose tolerance and increased plasma glucose [71]. However, few reports are available mainly on ocular and cognitive changes. To this regard, a short-acting GLP1-RAs, exenatide, has been used in a phase 2 randomized controlled trial for preventing brain fluid accumulation which causes increased intracranial pressure and optic nerve oedema in neuro ocular syndrome [72]. There is an increasing evidence that exposure to microgravity, whether during actual spaceflight or in groundbased analogues, leads to significant perturbations in glucose regulation and insulin action. Human and animal studies documented alterations in insulin secretion, insulin sensitivity, and glucose tolerance associated with spaceflight and simulated weightlessness. Early astronaut data from the Space Shuttle mission show changes in Cpeptide excretion suggestive of altered insulin dynamics in microgravity, accompanied by nitrogen balance shifts which are indicative of metabolic stress and development of insulin resistance [73]. Groundbased analogues, such as hindlimb unloading and bedrest models, further demonstrate glucose intolerance and peripheral insulin resistance, with impaired glucose disposal and dysregulated signaling in muscle and liver tissues under simulated microgravity [59]. In rodent models, simulated weightlessness induces insulin resistance in both peripheral tissues and the central nervous system, implicating disrupted Akt phosphorylation and increased negative regulation of insulin signaling pathways [74]. At the molecular level, spaceflight alters insulin and estrogen signaling pathways in multiple tissues, including inhibition of hepatic insulin receptor pathways, further supporting systemic metabolic dysregulation [75, 76]. Given these metabolic challenges, pharmacological countermeasures have been explored primarily in terrestrial metabolic disease, but their translation to spaceflight physiology is still emerging [77]. Traditional glucoselowering therapies, including exogenous insulin and secretagogues, effectively reduce hyperglycemia, but inducing risks in terms of hypoglycemia, thus requiring intensive monitoring limitations in the constrained environment of space missions. Insulin sensitizers like metformin may also have tolerability issues and uncertain effects on muscle metabolism in microgravity. Experimental echocardiography in rats undergoing cardiac stress show indeed a detrimental role of Ca²⁺ influx into cardiomyocytes [78]. GLP1-RAs have gained attention, due to their glucoregulatory and cardiometabolic benefits demonstrated in numerous clinical and preclinical studies on Earth. GLP1-RAs enhance glucosedependent insulin secretion and suppress inappropriate glucagon release, reducing hyperglycemia while minimizing hypoglycemia risk. Large clinical trials and metaanalyses confirm that GLP1-RAs significantly improve glycemic control, promote weight loss, reduce visceral adiposity, and favorably modify body composition, with preservation of lean mass relative to fat loss. Beyond classical glycemic effects, GLP1-RAs have been associated with enhancements in mitochondrial morphology and dynamics in skeletal muscle models, thus suggesting potential benefits for muscle energy metabolism independent of weight loss [73, 76]. Mechanistic hypotheses also propose that GLP1-RAs may activate energysensing pathways such as AMPK, aligning with known countermeasures against metabolic stress and potentially counteracting microgravityinduced impairments in substrate utilization and energy homeostasis. As compared to other pharmacological strategies, GLP1-RAs offer several theoretical advantages in the context of spaceflight: their glucosedependent action reduces hypoglycemia risk; longacting formulations decrease dosing frequency; and ancillary benefits on CV risk factors, appetite regulation, and energy balance may address multiple facets of microgravityinduced metabolic dysregulation. Nonetheless, direct experimental evidence of GLP1-RA efficacy in microgravity or analog models remains lacking, and dedicated studies are needed to evaluate their impact on insulin signaling, muscle metabolism, and systemic energy homeostasis under conditions of altered gravitational loading.

In conclusion, the growing body of evidence on microgravityinduced glucose metabolic disruption underscores a clear need for effective countermeasures. GLP1-RAs, with their multifaceted metabolic actions and relative safety profile, represent a promising pharmacological strategy. Future research should give priority to controlled studies in simulated and actual microgravity, in order to directly assess the utility of GLP1-RAs, compare them with conventional therapies, and elucidate underlying molecular mechanisms potentially leading to optimized metabolic management for longduration space missions. Further studies on GLP1-RAs will be therefore critical for assessing together microgravity, hyperglycemia, and persistent low-grade inflammation [79].

Combination strategies

GLP1-RAs exert their primary effects through glucose-dependent stimulation of insulin secretion, suppression of glucagon release, and delayed gastric emptying. Dual GIP/GLP1-RAs, exemplified by tirzepatide, appears to amplify these effects. In the SURPASS-2 trial, tirzepatide demonstrated superior reductions in HbA1c and body weight compared with semaglutide in patients with T2DM, highlighting the metabolic potency of combined incretin signaling [23, 32]. SGLT2i reduce renal glucose reabsorption, inducing glycosuria, osmotic diuresis, and natriuresis. Beyond glucose lowering, these agents improve CV and renal outcomes through hemodynamic unloading, reductions in intraglomerular pressure, modulation of myocardial energetics, and anti-inflammatory and antifibrotic effects [16]. Importantly, many of these benefits are largely independent of glycemic control, providing a strong rationale for their use in non-diabetic populations, particularly in HF and CKD [21]. GLP1-RAs and SGLT2i act on complementary metabolic and CV pathways. While GLP1-RAs predominantly influence appetite regulation, weight loss, insulin secretion, and atherosclerotic risk, SGLT2i primarily target renal hemodynamics, volume status, and HF risk [30, 33, 36]. Evidence from the FLOW trial indicates that semaglutide confers renal and cardiometabolic benefits regardless of concomitant SGLT2i use in patients with T2DM and CKD, supporting an additive rather than redundant therapeutic effect [33]. Implementation studies further suggest that GLP1-RAs, when combined with SGLT2i, facilitate insulin de-escalation while maintaining glycemic control and reducing hypoglycemia risk [30]. Multiple systematic reviews and meta-analyses have demonstrated that GLP1-RAs significantly MACE in patients with high-risk T2DM [23–25, 34, 41, 65, 80]. Mechanistic insights suggest that these benefits are mediated through improvements in endothelial function, lipid metabolism, inflammation, and plaque stability [34]. HFpEF is increasingly recognized as a metabolic disease closely linked to obesity and insulin resistance. While SGLT2i provide robust reductions in heart failure hospitalization, emerging evidence suggests that GLP1-RAs may further improve HFpEF-related symptoms by reducing body weight, epicardial adiposity, and systemic inflammation [33]. Observational data indicate potential incremental benefits of GLP-1 RAs in patients with HFpEF already receiving SGLT2i. Obesity is a heterogeneous condition inadequately captured by BMI alone. Contemporary evidence highlights the importance of direct measures of adiposity and ectopic fat in defining cardiometabolic risk. GLP1-RAs, particularly semaglutide across different doses and formulations, have demonstrated substantial and sustained weight loss in non-diabetic individuals with overweight or obesity, accompanied by improvements in cardiometabolic risk markers [30]. These effects extend beyond weight reduction, influencing heart failure risk, systemic inflammation, and metabolic flexibility [33]. The expanding evidence base supports a shift from glucose-centric to pathophysiology-driven treatment strategies. Selection of GLP1-RAs, SGLT2i, or their combination should be guided by dominant disease phenotypes, including obesity, CV risk, CKD, and heart failure, rather than diabetes status alone. Future research should focus on optimal sequencing and combination strategies, identification of responder phenotypes, and integration of direct adiposity measures into routine clinical practice.

Special considerations in selected patients’ subgroups

Considering the possible common adverse effects, it is also necessary to pay attention to potential secondary side effects.

Heart-rate increase and cardiovascular implications

GLP1-RAs induce a modest increase in heart rate, typically 2–4 beats per minute, likely mediated by autonomic modulation and direct sinoatrial node effects. While such increments are generally well tolerated in most patients, their clinical implications in HF or ischemic heart disease require consideration: i) small increases in heart rate could theoretically exacerbate diastolic filling impairment or increase myocardial oxygen demand. However, large CVOTs (LEADER, SUSTAIN-6, REWIND) did not demonstrate increased HF hospitalization attributable to GLP1-RAs neither in HFrEF nor in HFpEF [36]; ii) post-marketing data did not indicate significant increase in arrhythmic events or myocardial infarction, although caution and individualized monitoring are recommended in patients with advanced conduction disease or unstable ischemia. Therefore, the modest heart-rate elevation should be balanced against the proven MACE reduction and renal benefits, while for high-risk patients, baseline ECG assessment and periodic monitoring are reasonable.

Gastrointestinal and pancreatic risks, and retinopathy

GLP1-RAs slow gallbladder emptying and may increase the risk of gallstone formation. Clinical vigilance is advised for patients presenting with abdominal pain or biliary symptoms. Rare cases of pancreatitis have been reported; patients should be advised to report persistent abdominal pain. Routine imaging is not indicated without symptoms. Rapid improvement in glycemic control with GLP1-RAs may transiently worsen diabetic retinopathy, particularly in patients with pre-existing proliferative or severe non-proliferative retinopathy. Eye examinations before and during therapy are recommended in high-risk individuals. These adverse effects are infrequent and manageable with careful monitoring, education, and dose titration.

Considerations in frail, sarcopenic, or obese patients

GLP1-RAs induce weight loss, which is beneficial for obesity-related cardiometabolic risk. However, in frail or sarcopenic patients, aggressive weight loss may: reduce lean mass disproportionately relative to fat mass; worsen functional status, strength, and exercise tolerance, potentially aggravate HFpEF, where lean mass preservation is crucial for diastolic filling and exercise capacity. The clinical strategy could be to monitor body composition and functional status, prioritize gradual weight reduction and resistance exercise to preserve skeletal muscle, individualize therapy in elderly or frail patients, balancing glycemic, CV, and renal benefits against functional risks.

Conclusion

Over the past decade, GPCRs have emerged as central regulators of CV and metabolic homeostasis. Within this framework, GLP1-R and its agonists have gained recognition as powerful modulators of an interconnected GPCR signaling network involving β-ARs and the renin–angiotensin system. Accumulating molecular and clinical evidence indicates that GLP1-RAs should no longer be regarded solely as glucose-lowering agents, but rather as pleiotropic network modulators capable of restoring maladaptive GPCR signaling through coordinated effects on cAMP/PKA pathways, β arrestin biased signaling, GRK2 regulation, oxidative stress attenuation, and mitochondrial and endothelial protection. Clinically, GLP1-RAs have transformed the management of T2DM and obesity, consistently demonstrating robust efficacy in improving glycemic control, inducing clinically meaningful and sustained weight loss, and reducing MACE. Importantly, these benefits extend beyond traditional diabetic populations, with growing evidence supporting their role in heart failure particularly HFpEF, systemic hypertension, obstructive sleep apnea, and CKD. These observations reinforce a shift from a glucose-centric treatment paradigm toward a pathophysiology-driven, cardio–reno–metabolic approach. Emerging and nontraditional clinical settings, including cardio-oncology, sepsis, and metabolic dysregulation associated with microgravity, further highlight the broad biological relevance of GLP1-Rs signaling. In these contexts, the anti-inflammatory, cytoprotective, endothelial-stabilizing, and metabolic effects of GLP1-RAs offer compelling mechanistic rationale for therapeutic benefit. However, current evidence in these domains remains largely preclinical or observational, underscoring the need for dedicated prospective and randomized clinical trials to define efficacy, safety, and optimal clinical implementation. An important theme arising from this review is the complementary and potentially synergistic interaction between GLP1-RAs and SGLT2i. Acting on distinct yet converging metabolic, hemodynamic, and inflammatory pathways, these drug classes collectively address the multifactorial nature of cardiometabolic disease. Their combined use is particularly relevant in patients with obesity, HFpEF, and CKD, and supports a treatment strategy guided by dominant disease phenotypes rather than diabetes status alone. Despite their favorable benefit–risk profile, GLP1-RAs require thoughtful clinical application. Modest heart rate increases, gastrointestinal effects, gallbladder disease, and the potential for lean mass loss in frail or sarcopenic individuals warrant individualized monitoring and patient selection. Future research should focus on identifying responder phenotypes, refining combination and sequencing strategies, integrating direct measures of adiposity and body composition into routine practice, and elucidating long-term effects across diverse clinical populations.

In summary, GLP1-RAs represent one of the most impactful therapeutic advances in modern medicine, bridging metabolic, CV, renal, and systemic disease domains. Continued translational research and carefully designed clinical trials will be essential to fully harness their potential and to establish personalized, mechanism-based strategies for the management of complex chronic diseases.

Authors contributions

Conceptualization, A.C., F.M., C.M.; writing—original draft preparation, A.C., F.M., A.P., and S.C.; writing—review and editing, A.C., F.M.; supervision, A.C. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Data availaiblity

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable. This study did not involve human participants or animals.

Consent for publication

Not applicable.

Competing interest

The authors declare that they have no competing interests.