Glucagon-Like Peptide-1 Receptor Agonists in the Prevention of Ischemic Stroke: Therapeutic Potential and Mechanisms

Zhenzong Lin; Zixiao Li; Qian Jia

doi:10.5853/jos.2025.00584

J Stroke > Volume 27(3); 2025 > Article

Lin, Li, and Jia: Glucagon-Like Peptide-1 Receptor Agonists in the Prevention of Ischemic Stroke: Therapeutic Potential and Mechanisms

Review

Journal of Stroke 2025;27(3):289-301.

Published online: September 29, 2025

DOI: https://doi.org/10.5853/jos.2025.00584

Glucagon-Like Peptide-1 Receptor Agonists in the Prevention of Ischemic Stroke: Therapeutic Potential and Mechanisms

Zhenzong Lin¹, Zixiao Li^1,^2,^3,^4,^5,⁶

, Qian Jia^1,²

¹Vascular Neurology, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

²China National Clinical Research Center for Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

³Chinese Institute of Brain Research, Beijing, China

⁴National Center for Healthcare Quality Management in Neurological Diseases, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

⁵Center for Stroke, Beijing Institute for Brain Disorders, Beijing, China

⁶Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, China

Correspondence: Zixiao Li Department of Neurology, Beijing Tiantan Hospital, No. 119, S Fourth Ring W Rd, Fengtai District, Beijing, China, 100070 Tel: +86-13683234256 E-mail: lizixiao2008@hotmail.com

Co-correspondence: Qian Jia Department of Neurology, Beijing Tiantan Hospital, No. 119, S Fourth Ring W Rd, Fengtai District, Beijing, China, 100070 Tel: +86-15810048909 E-mail: jiaqian1616@163.com

Received February 4, 2025 Revised April 4, 2025 Accepted April 8, 2025

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Numerous randomized controlled trials have demonstrated that glucagon-like peptide-1 receptor agonists (GLP-1RAs) can reduce the risk of stroke across various populations, likely because of their effectiveness in lowering the incidence of ischemic stroke events. This review aimed to consolidate recent advancements in clinical research on the role of GLP-1RAs in preventing ischemic stroke and examine the mechanisms involved. GLP-1RAs have been shown to significantly improve several risk factors associated with ischemic stroke, such as elevated body mass index, hyperglycemia, and renal dysfunction, while potentially mitigating hypertension and dyslipidemia. Additionally, GLP-1RAs play a role in modulating the initiation of inflammation, endothelial dysfunction, and vascular inflammation in atherosclerosis, which may contribute to their protective effects against ischemic stroke. Nevertheless, further investigations are required to substantiate the efficacy of GLP-1RAs in ischemic stroke prevention and comprehensively elucidate the underlying mechanisms.

Keywords: Glucagon-like peptide-1 receptor agonists; Hypoglycemic agents; Ischemic stroke; Prevention; Mechanisms

Introduction

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are synthetic analogs of GLP-1 that enhance insulin secretion and sensitivity by inhibiting the action of dipeptidyl peptidase-4 while also suppressing glucagon release and influencing eating behaviors, thereby achieving significant hypoglycemic effects. In randomized controlled trials (RCTs), the glucose-lowering efficacy of GLP-1RAs has been demonstrated to be non-inferior to that of insulin, with a reduced incidence of hypoglycemia [1]. In addition, the cardiovascular benefits of GLP-1RAs have been extensively recognized. Nine cardiovascular outcome trials (CVOTs) in type 2 diabetes mellitus (T2DM) populations, including AMPLITUDE-O [2], EXSCEL [3], Harmony Outcomes [4], REWIND [5], PIONEER 6 [6], ELIXA [7], LEADER [8], SUSTAIN 6 [9], and FREEDOM-CVO [10], revealed that the cardiovascular outcomes of GLP-1RAs were neither inferior nor superior to placebo (Table 1) [2-10]. A meta-analysis of these studies demonstrated a significant reduction in the risk of 3-point major adverse cardiovascular events (MACE-3), including cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction, with a hazard ratio (HR) of 0.86 (95% confidence interval [CI], 0.80 to 0.93) by GLP-1RAs [11]. In light of its cardiovascular benefits, the most recent guidelines from the American Diabetes Association and European Society of Cardiology endorse GLP-1RAs as the preferred treatment option for patients with T2DM who also have atherosclerotic cardiovascular disease (ASCVD) [12,13].

In the SUSTAIN 6, PIONEER 6, and REWIND trials, GLP-1RAs, specifically semaglutide and albiglutide, exhibited potential roles in reducing the risk of stroke [5,6,9]. Similar outcomes were corroborated by two meta-analyses, with HRs of 0.83 (95% CI, 0.76 to 0.92) and relative risks (RR) of 0.85 (95% CI, 0.77 to 0.93) [11,14]. However, few studies have specifically investigated the role of GLP-1RAs in the prevention of ischemic stroke. Therefore, this review aimed to discuss the progress of clinical studies on GLP-1RAs in different populations for the prevention of ischemic stroke and to investigate their potential mechanisms.

Clinical research progress of GLP-1RA in the prevention of ischemic stroke

To search for studies on the role of GLP-1RAs in preventing ischemic stroke in different populations, we searched MEDLINE (via PubMed) using the following major Medical Subject Headings terms and keywords: “ischemic stroke” and “glucagon-like peptide-1 receptor agonist.” As this review was designed to summarize recent clinical and basic research advances in this field, we did not adhere to the methodology of systematic reviews (i.e., PRISMA), which requires rigorous pre-specified inclusion and exclusion of studies (Tables 1 and 2).

Although several RCTs have demonstrated the effects of GLP-1RAs in preventing MACE, a notable paucity of research focusing on their potential role in the prevention of ischemic stroke remains. A post hoc analysis of the REWIND study showed that albiglutide treatment significantly lowered the risk of ischemic stroke among individuals with T2DM and increased the risk of ASCVD (HR 0.75, 95% CI 0.59 to 0.94) [15]. Conversely, a combined analysis of the SUSTAIN 6 and PIONEER 6 trials found that semaglutide did not significantly reduce the risk of ischemic stroke in a similar demographic [16]. This inconsistency may be because the ischemic stroke events were recorded by the investigators solely as secondary outcomes. Therefore, conducting a study in which ischemic stroke is designated as the primary outcome is crucial for comprehensively exploring the role of GLP-1RAs in its prevention.

Various cohort studies have provided valuable insights into the impact of GLP-1RAs on ischemic stroke (Table 2). A retrospective analysis conducted by Lin et al. [17] involving 948,342 patients with T2DM in Taiwan indicated that users of GLP-1RAs had a reduced risk of ischemic stroke compared with those on dipeptidyl peptidase 4 inhibitors (DPP-4i) (HR 0.71, 95% CI 0.52-0.94, P=0.024). This finding is similarly supported by Tan et al. [18], whose study of patients with T2DM and ASCVD in the United States (n=64,971) demonstrated that the risk of ischemic stroke was significantly lower among those treated with GLP-1RAs than among those treated with DPP-4i (HR 0.74, 95% CI 0.63-0.87, P<0.001).

The comparative efficacies of GLP-1RAs and sodium-dependent glucose transporter 2 inhibitors (SGLT2i) in preventing ischemic stroke events remain controversial. A retrospective analysis of 12,375 patients with T2DM in Sweden suggested that GLP-1RAs were associated with a diminished risk of ischemic stroke (HR 0.58, 95% CI 0.38-0.87) [19]. Similar results were reported in a cohort study by Lui et al. [20], which included 5,840 patients with T2DM in Hong Kong (HR 0.65, 95% CI 0.42-0.99, P=0.044). However, studies by Dong et al. [21] and Lin et al. [22] found no significant reduction in ischemic stroke risk with GLP-1RAs compared with SGLT2i among patients with T2DM in Taiwan (HR 0.86, 95% CI 0.65-1.14; HR 0.93, 95% CI 0.81-1.07) involving 26,032 and 287,091 patients, respectively.

Compared with other hypoglycemic agents, GLP-1RAs appear to be associated with a lower incidence of ischemic stroke. Baviera et al. [23] reported that, among 30,399 patients using hypoglycemic agents in Lombardy, GLP-1RAs were associated with a lower risk of ischemic stroke than other classes of drugs, including metformin, sulfonylureas, glinides, thiazolidinediones, acarbose, and DPP-4i (HR 0.72, 95% CI 0.60-0.87). Similarly, a retrospective analysis involving 6,534 patients with T2DM in Taiwan, who did not have comorbid ASCVD but presented with hypertension and lipid metabolism disorders, indicated a relatively low risk of ischemic stroke among GLP-1RA users (HR 0.69, 95% CI 0.47-1.00, P=0.0506) [24]. However, this protective effect was not observed in patients undergoing atrial fibrillation ablation (HR 0.99, 95% CI 0.70-1.42, P=0.97) [25].

In recent studies on populations with ischemic stroke, investigators have generally focused on the potential role of GLP-1RAs in the acute phase of ischemic stroke, such as the TEXAIS [26] (NCT03287076), GALLOP (NCT05920889), and ASSET (NCT05630586) studies. These trials sought to explore the neuroprotective effects of GLP-1RAs during acute ischemic stroke but did not specifically address the potential preventative benefits of GLP-1RAs against ischemic stroke. The LAMP study (NCT03948347) focused on evaluating the efficacy of liraglutide in preventing stroke recurrence within 90 days after ischemic stroke, which may enhance our understanding of the role of GLP-1RAs in reducing recurrent strokes. Nonetheless, longer follow-up studies are necessary to comprehensively investigate the role of GLP-1RAs in preventing ischemic stroke. Therefore, we anticipate that future long-term RCTs will provide further insight into the preventive effects of GLP-1RAs on ischemic stroke, yielding valuable evidence for the long-term implications of GLP-1RAs and informing clinical practices in ischemic stroke prevention.

Potential mechanisms of ischemic stroke prevention by GLP-1RA

Atherosclerosis is a major cause of ischemic stroke, and risk factors such as high systolic blood pressure (SBP), high blood glucose levels, lipid metabolism disorders, high body mass index (BMI), and renal insufficiency play important roles in accelerating the process of atherosclerosis. These risk factors promote the development of ischemic stroke, which is partly independent of atherosclerosis. Thus, efficient control of these risk factors and deceleration of atherosclerosis progression are crucial primary and secondary preventive strategies against ischemic stroke [27]. Growing evidence indicates that GLP-1RAs modulate these risk factors and atherosclerotic processes, thereby playing a role in ischemic stroke prevention.

BMI-lowering effect

High BMI is a significant risk factor for ischemic stroke and contributes to approximately 6.2% of the risk of ischemic stroke [28]. GLP-1RAs have been shown to significantly reduce the body weight of patients. A meta-analysis included 132 RCTs showed that GLP-1RAs lead to substantial weight loss in obese individuals compared with placebo (OR 6.33, 95% CI 5.00 to 8.00; mean difference (MD) -5.79, 95% CI -6.34 to -5.25) [29]. Additionally, data from the SELECT study suggest that semaglutide improves the cardiovascular outcomes of obese patients, which is potentially related to weight loss [30].

The weight loss effect of GLP-1RAs is mainly attributed to the regulation of gastric emptying and food intake. In addition to their direct effects on the smooth muscles of the stomach and intestines, GLP-1RAs can also stimulate GLP-1R located on vagal nerve endings, thereby modulating gastric emptying [31]. In addition, GLP-1R-positive (GLP-1R+) neurons in the dorsal vagal complex of the brainstem and in various brain nuclei such as the hypothalamic nuclei, nucleus ambiguus, and amygdala contribute to the regulation of gastric emptying [32,33]. These nuclei also play a role in the limbic reward system, which regulates ingestive behavior and constitutes a complex neural network. Kabahizi et al. [33] delineated the neural circuitry involved in ingestion regulation, which includes GLP-1-expressing neurons in the arcuate nucleus, lateral parabrachial nucleus, paraventricular hypothalamic nucleus, and nucleus tractus solitarius. Subsequent research progressively included the chiasmatic nucleus, amygdala, dorsomedial hypothalamus, lateral hypothalamus, and lateral septum in the regulatory network [34-36]. The hypothalamus secretes hormones that modulate metabolic homeostasis, correlating with the reduction in fat accumulation and the increase in energy expenditure observed with GLP-1RA treatment (Figure 1) [37].

Glucose-lowering effect

A study by Benn et al. [38] showed that an increase of 1 mmol/L in plasma glucose from 5.2 mmol/L corresponds to a 74% increase in the relative risk of ischemic stroke (RR 1.74, 95% CI 1.31-2.18). Several clinical studies confirmed the excellent glucose-lowering ability of GLP1-RAs. A meta-analysis by Yao et al. [1] showed that 15 types of GLP-1RAs significantly lower hemoglobin A1c (HbA1c) and fasting blood glucose levels in users. The glucose-lowering effect of GLP-1RAs is closely correlated with their benefits against MACE. Post hoc mediation analyses from the LEADER and REWIND trials demonstrated that the reduction in HbA1c accounts for 41%-83% of the cardiovascular benefit observed in the LEADER trial and 17%-36% in the REWIND trial, contributing 54% to the prevention of stroke events in the latter [39]. These findings suggest that GLP-1RAs improve the risk of ischemic stroke through their excellent glucose-lowering effects.

Previous studies have suggested that GLP-1RAs induce glycemic control by stimulating GLP-1R in pancreatic β-cells, which in turn activates G-protein signaling, subsequently fostering insulin production and release in a glucose-dependent fashion [40]. However, more recent research has elucidated that the hypoglycemic effects of GLP-1RA are mediated through various mechanisms, encompassing the enhancement of pancreatic β-cell signaling and activity, the augmentation of insulin sensitivity in peripheral tissues, and the regulation of glucagon and growth-inhibitory hormone release. Among these processes, the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) and cyclic adenosine monophosphate pathways play major regulatory roles [41]. Recent studies have revealed the role of the brain in GLP-1RA-induced glucose regulation. Hypothalamic and brainstem GLP-1R+ neurons could mediate the antihyperglycemic effects of GLP-1RA by modulating islet function and insulin sensitivity and altering eating patterns [42,43].

Potential blood pressure-lowering effects

Hypertension is a primary risk factor for ischemic stroke [28]. Although there is a lack of RCTs exploring the antihypertensive effects of GLP-1RAs with blood pressure as the primary endpoint, blood pressure as a secondary endpoint has been shown to be significantly reduced by GLP-1RAs. A recent meta-analysis showed that GLP1-RAs showed excellent SBP-lowering effects, such as exenatide (MD -3.36 mm Hg, 95% CI -3.63 to -3.10), liraglutide (MD -2.61 mm Hg, 95% CI -3.48 to -1.74), dulaglutide (MD -1.46 mm Hg, 95% CI -2.20 to -0.72) [44]. However, the effects of GLP-1RAs on blood pressure and ischemic stroke require further research to provide definitive answers.

The effect of GLP-1RAs on SBP can be partially due to their weight loss effects. However, in addition to its weight-lowering effects, it can promote natriuresis, which may be one of its underlying mechanisms. This could be attributed to the increased secretion and sensitivity of natriuretic peptides induced by GLP-1RAs, promotion of diastolic glomerular smooth muscle and blood flow, and inhibition of tubular sodium-hydrogen channel function [45]. The FLOW study [46] revealed that semaglutide significantly improved the estimated glomerular filtration rate in patients with T2DM combined with chronic kidney disease, suggesting another potential mechanism. However, additional detailed mechanisms need to be determined through further research on FLOW study. Notably, the hypothalamus, an endocrine organ expressing GLP-1R, may also be targeted for blood pressure regulation by GLP-1RAs, particularly its influence on the renin-angiotensin and sympathetic nervous systems [33,45].

Potential lipid metabolism regulation effects

Abnormalities in lipid metabolism play a key role in the occurrence of ischemic stroke, contributing to the pathological manifestations of atherosclerosis, thrombosis, and dislodgement of unstable plaque [47]. Piccirillo et al. [48] reviewed the effects of GLP-1RAs on dyslipidemia, including lowering total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C) and increasing high-density lipoprotein cholesterol, which may be more pronounced than with conventional therapies. In addition, oxidized low-density lipoprotein, a lipoprotein highly associated with the initiation of atherosclerosis and development of ischemic stroke, is significantly reduced by dulaglutide or semaglutide in patients with T2DM combined with ASCVD [49]. A meta-analysis by Yao et al. [1] also showed that semaglutide significantly lower LDL-C (MD -0.16 mmol/L, 95% CI -0.30 to -0.02) and total cholesterol (MD -0.48 mmol/L, -0.84 to -0.11) in patients with T2DM, but no changes were observed in other lipoproteins. Given these inconsistent findings, further studies are required to explore the effects of GLP-1RAs on dyslipidemia in ischemic stroke.

Lipoprotein(a) [Lp(a)], a complex of apolipoprotein(a) and low-density lipoprotein (LDL), exhibits proatherogenic, proinflammatory, and prothrombotic properties, with strong associations between elevated levels and incident and recurrent atherosclerosis-driven ischemic stroke [50-52]. Current first-line lipid-lowering therapies for ischemic stroke (statins and ezetimibe) do not significantly reduce Lp(a) levels or the associated risk of stroke [53]. The potential Lp(a)-lowering effect of GLP-1RAs has attracted our attention. Hachuła et al. [54] reported that dulaglutide reduces Lp(a) levels in patients with T2DM and dyslipidemia. Similarly, Jones et al. [55] found that exenatide significantly decreased the cholesterol content within Lp(a) particles in patients with T2DM who had elevated baseline Lp(a). However, this effect was not observed with liraglutide [56,57]. Similarly, we expect that more studies will be conducted to explore the potential of GLP-1RAs in reducing Lp(a) levels.

Reduced absorption and increased consumption of celiac particles coupled with the regulation of lipoprotein transformation may be the mechanisms by which GLP-1RAs improve lipid metabolism [48]. Zhang et al. [58] and Zobel et al. [59] also found that GLP-1RAs (exenatide and liraglutide) significantly reduced ceramide, sphingomyelin, lysophosphatidylcholine, and lysophosphatidylethanolamine levels in patients with T2DM, which are associated with metabolic abnormalities and insulin resistance in patients. In addition, GLP-1RAs may ameliorate lipid metabolism dysfunction by regulating the fractional catabolism of lipids and secretion of PCSK9 in the liver [48,60]. Moreover, the ongoing ESSENCE (NCT04822181) trial [61] may help reveal the function of semaglutide in hepatic lipid metabolism. The role of the brain within the vagal gut-brain-hepatic axis has been implicated in the regulation of lipoproteins by GLP-1RAs [62].

Atherosclerotic regulation effects

In addition to ameliorating the above risk factors for ischemic stroke, GLP-1RAs also directly influence the process of atherosclerosis, which could contribute to the prevention of ischemic stroke. However, the role of GLP-1RAs in ameliorating atherosclerosis has not been consistently reported. Studies by Rizzo et al. [63], Zhang et al. [64], and Patti et al. [65] found that liraglutide and exenatide significantly reduced carotid intima-media thickness, suggesting a potential inhibitory effect of GLP-1RAs on atherosclerotic progression. This view is further supported by Heinsen et al. [66], who identified a stabilizing effect of liraglutide on atherosclerotic plaques. Nevertheless, Koska et al. [67] and Ölmestig et al. [68] found no evidence that exenatide ameliorates atheromatous plaques. These differences may arise from the varying study populations, drug types, dosages, frequencies, and outcome assessment metrics. Therefore, to further elucidate the effects of GLP-1RAs on atherosclerosis, more comprehensive, long-term RCTs are required, and standardized assessment criteria and metrics should be developed.

Although the ameliorative effects of GLP-1RAs on atherosclerosis have not been consistently established, several clinical and preclinical studies have shown that GLP-1RAs directly target the pathological processes of atherosclerosis, including atherosclerosis initiation, endothelial dysfunction, and vascular inflammation.

Recent studies have shown that GLP-1RAs inhibit the NLRP3 and TLR inflammatory pathways and significantly modulate inflammatory mediators in circulation, in which GLP-1R+ neurons in the hypothalamus and brainstem play an important role [69-71]. In addition, GLP-1RAs inhibit monocyte activation and macrophage M1 differentiation, attenuating the activation of circulating inflammatory cells during atherosclerosis, which may be associated with an increased release of lipocalin (Figure 2) [72,73].

In terms of endothelial dysfunction, GLP-1RAs target the regulation of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and downstream endothelial nitric oxide synthase/nitric oxide pathways, thereby ameliorating endothelial cell disorders during atherosclerosis [74,75]. GLP-1RAs also reduce peroxynitrite levels and decrease oxidative stress and mitochondrial dysfunction in endothelial cells, thereby regulating apoptosis and autophagy processes [70,76].

Previous studies have also shown that GLP-1RAs ameliorate intramural inflammation in atherosclerotic arteries, although a comprehensive consensus has yet to be reached. In rodents, semaglutide reduced aortic wall inflammation levels and macrophage activity, which is correlated with GLP-1RAs-induced reductions in intraplaque macrophage infiltration and M2 phenotypic transformation [77,78]. In addition, GLP-1RAs ameliorate abnormal smooth muscle cell (SMC) migration, differentiation, and apoptosis and reduce SMC-induced inflammatory responses [79]. However, the studies by Ripa et al. [80] and Jensen et al. [81] do not support the idea that liraglutide reduces the level of arterial inflammation in patients with T2DM, which could be because the assessment of arterial inflammation is contingent on positron emission tomography/computed tomography, which lacks specificity in the examination of atherosclerotic inflammation within the vessel wall.

Renal dysfunction ameliorative effect

Chronic renal dysfunction is an independent risk factor for ischemic stroke [28]. Recent studies have highlighted the renoprotective effects of GLP-1RAs, including AMPLITUDE-O, REWIND, SUSTAIN 6, PIONEER 6, and SELECT, demonstrating the potential kidney-protective properties of GLP-1RA (efpeglenatide, dulaglutide, and semaglutide) in individuals with heightened cardiovascular risk combined with T2DM or obesity [2,5,6,9,82]. The FLOW study demonstrated that semaglutide improved renal function (HR 0.76, 95% CI 0.66 to 0.88) for the first time [46]. These findings suggest that GLP-1RAs prevent ischemic stroke by improving renal function.

Improvement in renal function by GLP-1RAs may directly affect the kidney beyond the benefit of its effects on body weight, blood glucose, and blood pressure. Recent studies have found that GLP-1RAs can regulate the transcription of renal endothelial cells, proximal tubular cells, and podocytes while modulating the expression of receptors for advanced glycosylation end products, thereby reducing inflammatory damage to the kidneys [83]. Additionally, GLP-1RAs are crucial in managing oxidative stress and autophagy in renal epithelial cells [83,84]. In addition to their direct action on renal tissues, GLP-1RAs may also modulate the activity of the renin-angiotensin system, the overactivation of which is thought to be a major cause of chronic kidney disease [85]. However, our understanding of GLP-1RAs in the kidney remains limited. The ongoing REMODEL study (NCT04865770) is expected to shed further light on the potential renal implications of semaglutide.

Intracerebral effects

GLP-1RAs have multiple targets in the brain and modulate several risk factors associated with ischemic stroke. In recent studies, GLP-1RAs have been found to exert excellent neuroprotective effects against several neurodegenerative diseases [41]. Nevertheless, there is a lack of studies investigating the neuroprotective effects of GLP-1RAs in the prevention of ischemic stroke. Previous studies have shown that GLP-1RAs may play a protective role in the acute phase of stroke by promoting angiogenesis, enhancing neuronal tolerance to hypoxia, inhibiting neuroinflammation and oxidative stress, and reversing excitotoxicity in neurons [86]. However, these studies did not elucidate the mechanisms underlying the prevention of ischemic stroke. In preclinical studies, the establishment of ischemic stroke models usually relies on the abrupt blockage of blood flow to the brain of the animal, in which the occurrence of ischemic stroke events seems inevitable [87]. Therefore, there is a need for studies examining GLP-1RAs in various ischemic stroke models, such as photothrombotic and endothelin-1 models, that exhibit the disease process, to enhance our understanding of the role of GLP-1RAs in preventing ischemic stroke [88]. We look forward to further progress in this field of research.

Conclusions

This article reviews the current status of clinical studies on GLP-1RAs for preventing ischemic stroke. Evidence suggests that GLP-1RAs have excellent preventive effects against MACE, including ischemic stroke, in populations with T2DM and obesity. The ability of GLP-1RAs to prevent ischemic stroke may be related to their effects on hypoglycemia, weight loss, and improvement of renal function, as well as to their potential antihypertensive and lipid-metabolism-regulating functions. In addition, direct targeting of GLP-1RAs in the pathological process of atherosclerosis may contribute to its preventative role in ischemic stroke.

Although our study highlights the potential role of GLP-1RAs in ischemic stroke prevention, it has some limitations. Current clinical studies examining the preventive effect of GLP-1RAs on ischemic stroke are mainly based on post hoc analyses of CVOTs or cohort studies, which may introduce bias in the findings. Furthermore, studies focusing on the prevention of recurrent ischemic stroke using GLP-1RAs are scarce. In addition, although we have proposed potential mechanisms for ischemic stroke prevention by GLP-1RAs, the interactions and relationships between these mechanisms and the onset of ischemic stroke have not been conclusively demonstrated. Hence, to investigate the role of GLP-1RAs in the prevention of ischemic stroke and the underlying mechanisms, more in-depth studies are needed. In addition, GLP-1R+ neurons in the brain exhibit significant modulation upon GLP-1RA treatment, which may be a key target for ischemic stroke prevention. Indeed, many studies have demonstrated that GLP-1RAs ameliorate a series of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease [41]. However, studies on the neuroprotective mechanisms of GLP-1RAs in the prevention of ischemic stroke are lacking. In addition, the expression pattern of GLP-1R in the brain and whether different structural GLP-1RAs can cross the blood-brain barrier remain unclear. We expect that more studies will be conducted in the future to explore the long-term neuroprotective effects of GLP-1RAs in ischemic stroke and provide a deeper clinical understanding and potential therapeutic strategies.

However, the possible adverse effects of GLP-1RAs in patients with ischemic stroke should be carefully considered in future studies. Among the 10 CVOTs of GLP-1RAs included in this study, only the SELECT trial explicitly defined BMI thresholds (≥27 kg/m²). However, the mean BMI values in other trials consistently fell within the obese range, suggesting limited generalizability of these safety findings to populations with ischemic stroke [2-10,30]. Notably, obesity ranks only as the ninth most common risk factor for ischemic stroke, and population-based cohorts have reported lower mean BMIs than the above studies, particularly in Asian populations [28,89,90]. In the above CVOTs, gastrointestinal adverse effects were the most frequent cause of treatment discontinuation and patient suffering, which was mainly attributed to delayed gastric emptying. Whether this effect is exacerbated in populations with low or normal BMI remains unclear. However, patients with ischemic stroke often experience immobility or concomitant gastrointestinal dysfunction, which may exacerbate these adverse effects in clinical practice [91]. In addition, concerns regarding the risk of hypoglycemia in lean populations merit consideration. Current evidence suggests that GLP-1RAs have a low hypoglycemic risk unless combined with insulin or sulfonylureas because their mechanism of regulating insulin and glucagon secretion is glucose-dependent. In non-diabetic obese populations, Moiz et al. [92] reported no increase in the risk of hypoglycemia with 12 GLP-1RAs. However, individuals with obesity may have a lower risk of hypoglycemia than those with low BMI [93]. Thus, careful glycemic monitoring is essential in future trials involving frail patients with ischemic stroke. Finally, the potential for GLP-1RA-induced weight loss to exacerbate age-related muscle loss in elderly stroke survivors warrants further investigation. Linge et al. [94] suggested that the effects of GLP-1RAs on skeletal muscle are adaptive; that is, they maintain or minimally affect the physiological response to muscle health or function. However, the risk of muscle loss needs to be further evaluated in populations with ischemic stroke, especially in older adult patients and those with debilitation. Limited by the indications for the use of GLP-1RAs, the current evidence on GLP-1RA safety in populations with ischemic stroke is limited. We expect that subsequent studies will further expand our understanding of this drug in different populations.

Notes

Funding statement

This study was funded by the Ministry of Science and Technology of the People’s Republic of China (2022YFC2504902 and 2023YFA1801200) and the National Natural Science Foundation of China (82171270, 81801152, and 92046016).

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Conceptualization: Zixiao Li, QJ. Study design: Zixiao Li, QJ. Methodology: Zixiao Li, Zhenzong Lin. Data collection: QJ, Zhenzong Lin. Investigation: Zhenzong Lin. Statistical analysis: Zhenzong Lin. Writing—original draft: Zhenzong Lin. Writing—review & editing: Zixiao Li, QJ. Funding acquisition: Zixiao Li, QJ. Approval of final manuscript: all authors.

Acknowledgments

We acknowledge BioRender for providing the platform for the production of the figures in this article (Created in BioRender. L, Z. [2025] https://BioRender.com/sebp8yf; https://BioRender.com/fpyp5pr).

Figure 1.

Central-peripheral regulatory network for GLP-1RA-mediated regulation of feeding and metabolism. GLP-1RAs, glucagon-like peptide-1 receptor agonists; PUT, putamen; AMG, amygdala; NAc, nucleus accumben; VTA, ventral tegmental area; LS, lateral septum; LH, lateral hypothalamus; PVN, paraventricular nucleus; ARC, arcuate nucleus; DMH, dorsomedial hypothalamus; BNST, bed nucleus of the stria terminalis; VLM, ventrolateral medulla; PBN, parabrachial nucleus; DMV, dorsal motor nucleus of the vagus; NTS, nucleus tractus solitarius; AP, area postrema (Created in BioRender; https://BioRender.com/sebp8yf).

Figure 2.

GLP-1RAs regulate multiple pathological processes in atherosclerosis. GLP-1RAs, glucagon-like peptide-1 receptor agonists; LDL, low-density lipoprotein; IFN-γ, interferon-γ; TNF-α, tumor necrosis factor-α; MCP-1, monocyte chemoattractant protein-1; IL-10, interleukin-10; TGF-β, transforming growth factor-β (Created in BioRender; https://BioRender.com/fpyp5pr).

Table 1.

Cardiovascular outcome trials of GLP-1RAs

Study	Population	Intervention	Primary	Results, HR (95% CI)
Study	Population	Intervention	Primary	Primary outcome	Stroke^*	Ischemic stroke
ELIXA [7]	T2DM, with MI or unstable angina within the previous 180 days	Lixisenatide, subcutaneous, 20 μg, daily	MACE-4	1.02 (0.89-1.17)	1.12 (0.79-1.58)	NA
LEADER [8]	T2DM, high cardiovascular risk	Liraglutide, subcutaneous, 1.8 mg, daily	MACE-3	0.87 (0.78-0.97)	1.12 (0.79-1.58)	NA
SUSTAIN 6 [9]	T2DM, high cardiovascular risk	Semaglutide, subcutaneous, 0.5 mg or 1.0 mg, weekly	MACE-3	0.74 (0.58-0.95)	0.61 (0.38-0.99)	0.72 (0.47-1.08)^†
PIONEER 6 [6]	T2DM, high cardiovascular risk	Semaglutide, oral, 14 mg, daily	MACE-3	0.79 (0.57-1.11)	0.74 (0.35-1.57)
EXSCEL [3]	T2DM	Exenatide, subcutaneous,	MACE-3	0.91 (0.83-1.00)	0.85 (0.70-1.03)	NA
Harmony Outcomes [4]	T2DM, CVD	Albiglutide, subcutaneous, 30-50 mg, weekly	MACE-3	0.78 (0.68-0.90)	0.86 (0.66-1.14)	NA
REWIND [5]	T2DM, high cardiovascular risk	Dulaglutide, subcutaneous, 1.5 mg, weekly	MACE-3	0.88 (0.79-0.99)	0.76 (0.62-0.94)	0.75 (0.59-0.94)
AMPLITUDE-O [2]	T2DM, high cardiovascular risk	Efpeglenatide, subcutaneous, 4 or 6 mg, weekly	MACE-3	0.73 (0.58-0.92)	0.74 (0.47-1.17)	NA
FREEDOM-CVO [10]	T2DM, ASCVD or high ASCVD risk	Lixisenatide, continuous subcutaneous infusion, 20 μg, daily	MACE-4	1.21 (0.90-1.63)	1.00 (0.56-1.79)	NA
SELECT [30]	Obesity, CVD, without T2DM	Semaglutide, subcutaneous, 2.4 mg, weekly	MACE-3	0.80 (0.72-0.90)	0.93 (0.74-1.15)	NA

GLP-1RAs, glucagon-like peptide-1 receptor agonists; T2DM, type 2 diabetes mellitus; MI, myocardial infarction; CVD, cardiovascular disease; ASCVD, atherosclerotic cardiovascular disease; MACE-3, cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction; MACE-4, MACE-3+ unstable angina; CVD, cardiovascular disease; HR, hazard ratio; CI, confidence interval; NA, no post hoc analysis.

^* Stroke: total stroke or nonfatal stroke according to the data provided in the study;

^† Derived from a combined post hoc analysis of SUSTAIN 6 and PIONEER 6.

Table 2.

Clinical study of GLP-1RA for the prevention of ischemic stroke

Study	Population	Number of participants	Exposure	Control	Ischemic stroke risk HR (95% CI)
Lin et al. [17] (2021)	T2DM	948,342	GLP-1RAs	DPP-4i	0.71 (0.52-0.94)
Baviera et al. [23] (2021)	Patient with AHA	30,399 (Lombardy)	GLP-1RAs	Other AHA (but no SGLT2i)	0.72 (0.60-0.87)
Baviera et al. [23] (2021)	Patient with AHA	15,818 (Apulia)	GLP-1RAs	Other AHA (but no SGLT2i)	1.01 (0.76-1.33)
Yang et al. [24] (2022)	T2DM without ASCVD, but with dyslipidemia or hypertension	6,534	GLP-1RAs	Non-GLP-1RAs	0.69 (0.47-1.00)
Lin et al. [22] (2022)	DM	287,091	GLP-1RAs	SGLT2i	0.93 (0.81-1.07)
Fu et al. [19] (2022)	T2DM	12,375	SGLT2i	GLP-1RAs	1.71 (1.14-2.59)
Dong et al. [21] (2022)	T2DM	26,032	GLP-1RAs	SGLT2i	0.86 (0.65-1.14)
Tan et al. [18] (2023)	T2DM and ASCVD	64,971	GLP-1RAs	DPP-4i	0.74 (0.63-0.87)
Lui et al. [20] (2023)	T2DM	5,840	SGLT2i	GLP-1RAs	1.53 (1.01-2.33)
Satti et al. [25] (2024)	AF ablation	3,250	GLP-1RAs	Non-GLP-1RAs	0.99 (0.70-1.42)

GLP-1RAs, glucagon-like peptide-1 receptor agonists; T2DM, type 2 diabetes mellitus; AHA, antihyperglycemic agents; DPP-4i, dipeptidyl peptidase 4 inhibitor; SGLT2i, sodium-dependent glucose transporter 2 inhibitor; ASCVD, atherosclerotic cardiovascular disease; AF, atrial fibrillation; HR, hazard ratio; CI, confidence interval.

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