Search Results (1,262)

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed type 2 diabetes mellitus (T2DM) and obesity care, with clinical trials demonstrating weight loss exceeding 15%. However, real-world effectiveness lags trial efficacy, largely owing to high discontinuation rates. We characterize the global persistence gap and propose a framework integrating Medical Nutrition Therapy (MNT) to improve adherence. Methods: We conducted a narrative review of real-world evidence from North America, Europe, Asia, and Latin America, synthesized with physiological, nutritional, and behavioral data to distinguish established contributors to discontinuation from strategies that remain partly extrapolated from related populations. Results: Global persistence varies widely: from approximately 75–80% at 12 months in reimbursed T2DM cohorts (Sweden, Denmark) to below 10% in obesity-focused or high out-of-pocket-cost settings (Poland, Colombia), with intermediate rates in the United States and United Kingdom; in several cohorts, persistence falls below 15% by 24 months. The primary drivers are gastrointestinal intolerance and economic barriers. Meal size, dietary composition, and gastric-emptying effects influence gastrointestinal tolerability; inadequate protein intake during rapid weight loss raises concern for lean mass loss. Conclusions: Pharmacotherapy alone is unlikely to sustain long-term obesity management. Narrowing the persistence gap will require an integrated care model in which structured nutritional support—targeting protein intake, micronutrient density, and gastric-sparing feeding—is systematically offered rather than treated as an optional adjunct, while recognizing that most supporting evidence is extrapolated from primary trials in obesity and cardiometabolic disease rather than derived from GLP-1–specific randomized trials. Full article

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists have transformed obesity treatment, producing substantial weight loss during active therapy. However, real-world effectiveness may be limited by gastrointestinal adverse events, reduced dietary intake, fat-free mass loss as part of total weight reduction, and weight regain after discontinuation. Methods: This narrative review synthesizes current pharmacological, nutritional, gastrointestinal, body-composition, and implementation evidence to propose an evidence-informed nutrition-first framework for patients receiving incretin-based therapy for obesity. Results: We translate pharmacologic mechanisms into practical dietary strategies, including protein prioritization, structured meal patterns, hydration and fiber management, symptom-targeted interventions, resistance-training support, and maintenance planning. Because direct trials of structured nutrition interventions in GLP-1RA- or dual incretin-treated populations remain limited, several recommendations are extrapolated from the broader obesity, caloric restriction, body-composition, gastrointestinal, and expert-consensus literature. Conclusions: Integrating structured nutrition care into pharmacotherapy pathways may help address meal-related symptom burden, support protein and fluid adequacy, identify patients at higher nutritional or body-composition risk, and prepare patients for long-term weight-management behaviors. Embedding practical nutrition management within multidisciplinary obesity care may help translate pharmacologic efficacy into durable, patient-centered outcomes. Full article

The global burden of type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD) continues to rise at an alarming pace, with substantial pathophysiological overlap driven by insulin resistance, visceral obesity, and chronic low-grade inflammation. MASLD may progress to metabolic dysfunction-associated steatohepatitis (MASH), with increased risk of cirrhosis and hepatocellular carcinoma. Glucagon-like peptide 1 (GLP-1)-based therapies have transformed the management of T2DM and obesity. They exert pleiotropic effects whose basis remains incompletely understood. Concurrently, Akkermansia muciniphila has emerged as a keystone gut microbiota species with demonstrated hepatoprotective potential in preclinical models of MASLD/MASH. This narrative review positions A. muciniphila simultaneously as a target of GLP-1-mediated microbiome remodeling and as an independent modulator of hepatoprotection in MASLD/MASH. A structured search of PubMed, Scopus, and Web of Science (last searched: 12 April 2026) was conducted using terms related to Akkermansia muciniphila, GLP-1 receptor agonists, MASLD/MASH and T2DM. A total of 174 records were identified. Of these, 148 were excluded due to duplication or non-relevant study design. 26 studies (23 preclinical, 3 clinical) were included in the synthesis, directly addressing A. muciniphila. Preclinical evidence demonstrates that liraglutide, semaglutide, exenatide, and tirzepatide increase A. muciniphila abundance, while A. muciniphila in turn enhances endogenous GLP-1 secretion via the P9/ICAM-2 axis, forming a hypothetical positive feedback loop. A working mechanistic model integrating these bidirectional interactions is proposed, alongside a discussion of current limitations and future research priorities, including microbiome-guided clinical trials in MASLD/MASH populations. Full article

Background: Effective postprandial glycemic regulation is essential for preventing metabolic disorders such as type 2 diabetes. While pharmacological interventions like GLP-1 (Glucagon-Like Peptide-1) receptor agonists are effective, dietary strategies using low-digestible carbohydrates (LDCs) may offer a sustainable and complementary approach. Methods: Two human physiological investigations were conducted to evaluate the acute metabolic responses to allulose, 1-kestose, resistant maltodextrin (RD), and fructo-oligosaccharide powder (FOP), administered both in isolation and in conjunction with a reference meal (RM). Results: In Study 1, all tested LDCs elicited minimal plasma glucose responses when consumed alone. In Study 2, distinct metabolic benefits were observed depending on the type of LDCs. Allulose exhibited the strongest effects, significantly reducing postprandial glucose and insulin levels while increasing plasma GLP-1 concentrations. 1-Kestose exhibited significantly lower plasma glucose and insulin incremental area under the curve (iAUC) compared to RM alone, indicating improved glycemic regulation. RD significantly enhanced subjective satiety between 30 and 180 min post-consumption. These findings highlight that each LDC exerts unique physiological effects. Conclusions: Collectively, these results demonstrate that acute LDCs consumption distinctly regulates metabolic responses, supporting their application as functional ingredients in targeted nutritional strategies for managing glycemic and metabolic health. Full article

Metabolic dysfunction-associated steatotic liver disease (MASLD) is now recognized as the principal hepatic manifestation of obesity and metabolic dysfunction. Its pathogenesis is complex and multifactorial, driven by insulin resistance, low-grade chronic inflammation, oxidative stress, gut microbiota alterations, and abnormalities in lipid metabolism; together, these promote steatosis, lipotoxicity, and progression to fibrosis which can lead to compensated advanced chronic liver disease (cACLD). MASLD is also a multisystem condition closely associated with an increased risk of major adverse cardiovascular events such as myocardial infarction, ischemic stroke, atrial fibrillation, and other extrahepatic complications. In this context, emerging metabolic therapies show significant potential for modifying the natural history of the disease. Glucagon-like peptide (GLP)-1 receptor agonists induce substantial weight loss and improve steatosis and necro-inflammatory activity. Sodium–glucose cotransporter 2 inhibitors (SGLT-2I) reduce glucotoxicity, promote modest weight loss, and lower hepatic fat content by improving insulin sensitivity and inflammatory signaling. Even more promising are dual GLP-1/GIP receptor agonists, which have demonstrated superior efficacy in metabolic control, reducing hepatic steatosis, and potentially modulating fibrotic processes, although definitive histological confirmation is still lacking. Overall, in this review, we discuss the physiopathological mechanisms of MASLD leading to cACLD along with the emerging therapies, such GLP1 receptor agonists, SGLT-2I, and GLP1/GIP which, when combined with structured lifestyle interventions, may attenuate progression toward steatohepatitis (MASH), fibrosis, and, thus, cirrhosis. Full article

Fermentation is widely used to enhance the bioactivity of herbal phytochemicals through microbial bioconversion. Rehmannia glutinosa contains catalpol, an iridoid glycoside with metabolic and immunomodulatory potential; however, its efficacy in the unfermented form is limited. This study investigated whether fermentation enhances catalpol production and improves metabolic and immune-regulating functions via glucagon-like peptide-1 receptor (GLP-1R) signaling. Rehmannia glutinosa extract was fermented under optimized conditions, and catalpol and iridoid precursor levels were quantified to assess bioconversion efficiency. Biological effects were evaluated in intestinal epithelial cells, macrophages, and an Artemia model, focusing on glucose transport, GLP-1 secretion, dipeptidyl peptidase-4 (DPP-4) expression, mucosal defense, and GLP-1R/protein kinase A/cAMP response element-binding protein (PKA/CREB) signaling. Fermentation significantly increased catalpol content while reducing iridoid precursors. The fermented extract suppressed intestinal glucose absorption by downregulating sodium–glucose cotransporter 1 (SGLT1) and glucose transporter 2 (GLUT2). It also enhanced GLP-1 secretion and reduced DPP-4 expression, leading to activation of GLP-1R/PKA/CREB signaling. This activation increased mucin 2 (MUC2) expression and promoted anti-inflammatory. Full article

Diabetic peripheral neuropathy (DPN) remains a leading cause of disability in diabetes, yet current care is largely symptomatic and does not directly address early neurovascular-immune pathology. This narrative review synthesizes clinical, redox, vascular, and immunological evidence into a peripheral nerve neurovascular unit (PNVU)/blood–nerve barrier (BNB)-centered framework for DPN. First, the review outlines the diagnostic and translational endpoint landscape of DPN, emphasizing that commonly used clinical, neurophysiological, small-fiber, and imaging-based tools capture important disease domains but do not directly assess early BNB dysfunction. It then reviews the anatomical and functional basis of the PNVU and BNB, including endoneurial microvascular endothelial cells, pericytes, basement membrane components, immune cells, and tight-junction proteins. Next, it discusses how chronic hyperglycemia and dyslipidemia drive metabolic-to-vascular coupling, redox imbalance, antioxidant defense failure, advanced glycation end products (AGEs), receptor for AGEs (RAGE), and nuclear factor-κB (NF-κB) signaling, endothelial activation, leukocyte recruitment, macrophage polarization, and junctional disassembly, culminating in increased BNB permeability and exposure of peripheral nerves to pro-inflammatory and neurotoxic mediators. Finally, it evaluates incretin-based therapies—including glucagon-like peptide-1 receptor agonists (GLP-1RAs), dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors, DPP-4is), and emerging multi-agonists—as potential modulators of oxidative and inflammatory stress within this framework. Although semaglutide and related agents show mechanistic plausibility and preclinical promise, direct evidence for incretin-mediated BNB stabilization in human DPN remains limited. By reframing DPN as a redox-driven neurovascular-immune disorder, this review highlights barrier-focused biomarkers, translational endpoints, and hypothesis-generating therapeutic opportunities that require clinical validation. Full article

Rheumatoid arthritis (RA) is a chronic inflammatory disorder associated with a substantially increased risk of cardiovascular (CV) disease, driven by both persistent systemic inflammation and a high burden of traditional cardiometabolic risk factors. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs), licensed for type 2 diabetes mellitus and obesity, have attracted attention for their broader metabolic and cardiovascular benefits, raising the question of their potential role in RA. This scoping review summarizes current evidence on the impact of GLP-1RAs on RA disease activity, CV comorbidities, and the underlying immuno-metabolic mechanisms. Experimental studies suggest that GLP-1RAs could modulate key inflammatory pathways in synovial cells, reducing pro-inflammatory cytokine production, oxidative stress, and tissue-degrading enzymes, while improving mitochondrial function. Although clinical data remains limited, observational studies report improvements in disease activity, inflammatory markers, and pain in patients with RA treated with GLP-1RAs in addition to immunosuppressive treatment. Extensive evidence from randomized trials in metabolic populations demonstrates that GLP-1RAs improve glycemic control, induce significant weight loss, and reduce modestly but consistently blood pressure and atherogenic lipids, ultimately lowering major CV events and mortality. Although this evidence cannot be directly translated to RA populations, early real-world data specific to the disease suggest similar favorable trends, including reductions in cardiometabolic risk factors and thromboembolic events. Taken together, these findings suggest that GLP-1RAs may offer dual benefits in RA by addressing both metabolic dysfunction and inflammation. However, the current evidence base is heterogeneous and largely non-randomized, underscoring the need for dedicated trials. Full article

Heart failure (HF) remains associated with high morbidity and mortality, with heart failure with preserved ejection fraction (HFpEF) becoming increasingly prevalent and therapeutically challenging despite advances in pharmacological and rehabilitative care. Beyond their glucose-lowering effects, glucagon-like peptide-1 receptor agonists (GLP-1RAs) confer cardiometabolic benefits and may serve as effective adjuncts to cardiac rehabilitation (CR), particularly in obese patients with HFpEF. Obesity plays a central role in the pathophysiology of HFpEF, and GLP-1RAs promote weight loss, reduce insulin resistance and leptin signaling, and improve hemodynamic and metabolic abnormalities associated with HFpEF. Accumulating evidence suggests that the benefits of GLP-1RAs are phenotype-specific and more pronounced in patients with HFpEF than in patients with HF with reduced ejection fraction. Current clinical guidelines recommend GLP-1RAs for patients who have type 2 diabetes mellitus and established cardiovascular (CV) disease or are at high CV risk, with recent updates recognizing their potential benefits in patients with HFpEF and obesity. Cardiac rehabilitation, delivered through multidisciplinary programs, remains a cornerstone of HF management. Although caloric restriction and aerobic exercise can be beneficial in patients with HFpEF and obesity, these interventions alone are often insufficient. Sarcopenia is common in older patients with HFpEF and contributes to adverse outcomes, underscoring the importance of incorporating resistance training into CR programs. The most frequent adverse effects of GLP-1RAs are gastrointestinal events, which are generally mild to moderate but may lead to treatment discontinuation in some patients. Future studies should investigate the potential synergistic effects of GLP-1RAs and CR, clarify their long-term safety and efficacy in HF populations, and define their role beyond obese HFpEF phenotypes. Full article

Background: The dual agonism of glucagon-like peptide-1 receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) becomes a groundbreaking treatment for type 2 diabetes (T2D) that achieves robust glycemic control and maintains body weight. It also induces potential risk reduction in diabetic retinopathy (DR), Alzheimer disease (AD), and heart diseases including coronary artery disease (CAD) in treated T2D patients. To date, the molecular basis underpinning the remarkable causal treatment effects and synergy of the dual agonism of GLP-1R and GIPR on risk reduction in T2D, CAD, DR and AD has not been systematically investigated. Methods: To elucidate the treatment effects and potential synergy of dual GLP-1R/GIPR agonism on risk reduction in T2D, CAD, DR and AD while minimizing the impact of confounders, we used a robust cis-Mendelian randomization (cis-MR) with a principal component-based generalized method of moments (PC-GMM) where blood-based glycated hemoglobin (HbA1c), high- and low-density lipoprotein cholesterol (HDL-c, LDL-c), and BMI were used as mediating biomarkers. Results: Our cis-MR analyses confirmed a synergistic causal protective effect of dual GLP-1R/GIPR agonism on T2D via HbA1c reduction [OR = 0.17; 95% CI = (0.11, 0.26); p = 3.68 × 10⁻¹⁷] which is more significant than either GLP-1R agonism or GIPR agonism alone. Similarly, the causal protective effect of dual GLP-1R/GIPR agonism via HbA1c reduction was also significant for DR [OR = 0.20; 95% CI = (0.11, 0.36); p = 9.22 × 10⁻⁸]. Further, our multivariate cis-MR (or cis-MVMR) analyses revealed that after adjusting for HbA1c, a synergistic protective effect on DR via a reduction in LDL-c is significant in dual GLP-1R/GIPR agonism [OR = 0.57; 95% CI = (0.29, 0.94)], while the protective effect on DR of LDL-c reduction is non-significant in either GLP-1R agonism or GIPR agonism alone. Also, after adjusting for HbA1c, the multivariate cis-MR results showed significant protective effects on AD via a reduction in LDL-c in GLP-1R/GIPR agonism [OR = 0.44; 95% CI = (0.25, 0.81)]. Importantly, the multivariate cis-MR results also revealed that dual GLP-1R/GIPR agonism has significant protective effects on CAD via both a reduction in BMI [OR = 0.46; 95% CI = (0.28, 0.75)] and an improvement in HDL [OR = 0.59; 95% CI = (0.39, 0.90)]. This is in support of the hypothesis that dual GLP-1R/GIPR agonism has a synergistic protective effect on CAD that is stronger than that of GLP-1R agonism alone, which yielded a non-significant causal effect for both HDL and BMI, and GIPR agonism alone also yielded a non-significant causal effect for HDL when adjusted for BMI. Conclusions: These novel findings have significant implications for repurposing dual incretin agonism in terms of diabetic drugs to serve as a unifying, precision prevention strategy against CAD, DR and AD as leading drivers of mortality and morbidity in diabetic patients. Full article

Incretin-based therapies, particularly glucagon-like peptide-1 receptor agonists (GLP-1 RAs), have emerged as potentially promising therapeutic agents for improving ovarian function, especially in women with polycystic ovary syndrome (PCOS) and obesity-related reproductive dysfunction. This comprehensive review synthesizes evidence from 30 highly relevant studies examining the mechanisms of action, clinical outcomes, and safety profile of incretin therapies on ovarian function. The evidence suggests that GLP-1 RAs may exert beneficial effects through multiple molecular pathways, including FOXO1 signaling, modulation of steroidogenesis, and enhancement of insulin sensitivity, although most mechanistic data derive from animal models and in vitro studies without validation in human ovarian tissue. Clinical outcomes from randomized controlled trials and meta-analyses show improvements in menstrual regularity, hormonal profiles, and spontaneous conception rates, though evidence certainty is limited by small sample sizes, short duration, high heterogeneity, and restriction to overweight/obese populations. While preliminary safety data regarding inadvertent early pregnancy exposure are reassuring, animal studies suggest potential dose-dependent risks that warrant careful consideration. Importantly, GLP-1 RAs are not currently approved or guideline-recommended for fertility restoration, and substantial uncertainty remains regarding long-term reproductive safety, optimal patient selection, and clinical guidelines. This review provides a balanced synthesis of current evidence and identifies critical gaps requiring further investigation before routine clinical use can be recommended. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is highly prevalent in patients with type 2 diabetes (T2D) and is associated with increased cardiovascular risk. However, the relative contribution of traditional cardiometabolic risk factors (CMRFs), hepatic fibrosis markers, and antidiabetic therapies to atherosclerosis remains unclear. Methods: We conducted a cross-sectional study including 46 patients with T2D and MASLD. Atherosclerotic cardiovascular disease (ASCVD) was defined as the presence of carotid atheromatosis, stroke, peripheral arterial disease, or ischemic heart disease, as assessed by imaging-based parameters. Clinical, metabolic, and treatment-related variables were analyzed, including age, Hemoglobin A1c (HbA1c), lipid profile, hepatic fibrosis indices such as Fibrosis-4 index (FIB-4), and antidiabetic therapies (sodium–glucose cotransporter-2 inhibitors (SGLT2is), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and insulin). Multivariable regression models and receiver operating characteristic (ROC) curve analyses were used to evaluate associations and discriminative performance. Results: Traditional CMRFs were more strongly associated with ASCVD than hepatic fibrosis markers or antidiabetic therapies. Age was associated with ASCVD in several exploratory models, although this association was attenuated in the fully adjusted model. HbA1c showed the highest discriminative performance (AUC 0.77), indicating that chronic glycemic exposure is a major determinant of vascular disease in this cohort. In contrast, FIB-4 was not associated with ASCVD and did not improve model performance. Antidiabetic therapies, including SGLT2i and GLP-1 RAs, were not independently associated with ASCVD. Insulin therapy was more frequent among patients with ASCVD, but was not independently associated after adjustment. Conclusions: In patients with T2D and MASLD, ASCVD appears to be associated with traditional CMRFs, particularly chronic glycemic exposure, rather than hepatic fibrosis markers or treatment status. These findings highlight the central role of metabolic control in cardiovascular risk and suggest that the contribution of liver-related markers and therapeutic interventions may be more relevant in longitudinal settings. Full article

Semaglutide represents a unique therapeutic option for patients with type 2 diabetes mellitus (T2DM), being the first and currently only glucagon-like peptide-1 receptor agonist (GLP-1RA) available in both subcutaneous and oral formulations. This study aimed to compare the effectiveness of oral versus subcutaneous (sc) semaglutide on metabolic parameters and cardiovascular risk factors in T2DM patients. This is a retrospective real-world study including adult patients with T2DM taking oral or sc semaglutide followed at the ASUGI Diabetes Center. We analyzed data from 434 patients (median age 70 years, diabetes duration 13 years), treated with oral (n = 232) or sc (n = 202) semaglutide. The oral formulation had a higher discontinuation rate. Among these patients, 130 patients in the oral group and 145 in the sc group had an 18-month follow-up. When comparing these groups, patients taking sc semaglutide had a significantly higher baseline BMI. However, multivariate linear regression models suggested that both formulations were comparably effective in reducing HbA1c and BMI, with baseline values being the primary predictors of response. To address BMI imbalances, propensity score matching was performed, identifying 55 matched pairs. Both oral and sc semaglutide reduced HbA1c and BMI and there were no significant differences in the median change in HbA1c and BMI between groups. Interestingly, oral semaglutide was associated with a significantly greater reduction in diastolic blood pressure compared to the sc formulation. Furthermore, concomitant therapy with SGLT2 inhibitors significantly enhanced the reduction in total and LDL cholesterol. Oral and subcutaneous semaglutide show comparable effectiveness in lowering HbA1c and BMI in a real-world setting. Full article

Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), originally developed for the treatment of type 2 diabetes (T2D), are increasingly used for the management of overweight and obesity in children and adolescents. However, the impact of concomitant lifestyle interventions, which vary in scope, structure, and intensity, remains unclear. Methods: A systematic search of PubMed, Scopus, and ClinicalTrials.gov was conducted from April to December 2025 (last update: 12 December 2025), in accordance with the PRISMA 2020 statement. Randomized and observational studies including patients aged 6–19 years with overweight or obesity, with or without T2D, treated with GLP-1 RAs or dual GIP/GLP-1 agonists, were included. Anthropometric outcomes, metabolic parameters, and the scope and structure of concomitant nutritional and behavioral interventions were assessed. Results: Fifteen studies (12 interventional [RCT/non-RCT] and 3 observational), including 1448 participants, were analyzed: liraglutide (n = 6), exenatide (n = 5), semaglutide (n = 1), dulaglutide (n = 1), tirzepatide (n = 1), and lixisenatide (n = 1). Intervention duration ranged from 6 to 68 weeks. Reported BMI reductions varied across studies and pharmacological agents, with semaglutide trials reporting reductions of up to −16.1%. Lifestyle interventions were heterogeneously reported, ranging from general dietary advice to structured, multidisciplinary programs including nutritional counseling, physical activity, and behavioral or family support. Due to heterogeneity in study design and reporting, the independent contribution of lifestyle interventions could not be determined. Conclusions: Available evidence suggests that GLP-1 RAs may represent an effective therapeutic option for children and adolescents with obesity and metabolic disorders. However, available evidence is largely derived from studies incorporating inconsistently reported lifestyle interventions, limiting the ability to disentangle pharmacological and lifestyle effects. Standardized reporting and studies specifically designed to assess their independent and combined effects are needed. Future research should standardize the reporting of lifestyle protocols (e.g., using TIDieR), incorporate validated measures of eating behavior, food preferences, and dietary intake, and use designs (e.g., factorial or stratified randomization of lifestyle intensity) that allow for the pharmacological and behavioral contributions to be quantified separately. This review highlights a critical and previously underexplored methodological gap regarding the structure and reporting of lifestyle co-interventions in pediatric GLP-1 trials. Full article

Background: Asymptomatic intracranial atherosclerotic arterial stenosis (ICAS) is an underrecognized entity for which vascular risk-factor optimization is the primary management strategy, with no current indication for routine antiplatelet therapy or endovascular intervention for primary stroke prevention. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) reduce major adverse cardiovascular events, including stroke, in high-risk cardiometabolic populations, but their association with outcomes in asymptomatic ICAS is yet to be evaluated. The present study aims to evaluate the association between GLP-1RA use and cerebrovascular outcomes in adults with asymptomatic ICAS. Materials and Methods: We used the TriNetX US Collaborative Network (71 healthcare organizations) to identify adults (≥18 years) with ICAS between 1 January 2016 and 31 December 2025, and excluded patients with prior cerebral infarction, intracranial hemorrhage, or cerebrovascular ischemic syndromes. Exposure was defined as initiation of any GLP-1 receptor agonist (lixisenatide, semaglutide, liraglutide, tirzepatide, dulaglutide) during the 6 months before or on the date of index ICAS diagnosis. Outcomes were assessed at 1 year, and included ischemic stroke, all-cause mortality, and a composite of ischemic stroke or mortality. Propensity-score matching (1:1) was performed, including demographics, vascular risk factors, comorbidities, antithrombotics, lipid/diabetes therapies, and cardiometabolic laboratory/physiologic measures. Results: Before matching, 1746 GLP-1RA users and 71,792 non-users met inclusion criteria; after matching, 1728 patients remained in each cohort. GLP-1RA use was associated with lower 1-year risk of ischemic stroke (4.40% vs. 6.10%; hazard ratio [HR] 0.70, 95% CI 0.52–0.95; p = 0.044), lower all-cause mortality (3.40% vs. 9.40%; HR 0.35, 95% CI 0.26–0.47; p < 0.001), and lower composite outcome risk (7.50% vs. 15.00%; HR 0.48, 95% CI 0.39–0.59; p < 0.001). Notably, these associations were observed despite matching for HbA1c, LDL cholesterol, BMI, and systolic blood pressure, suggesting potential effects beyond measured cardiometabolic risk profiles. Conclusions: In this large, propensity-matched cohort of adults with a-ICAS, GLP-1RA use was associated with lower ischemic stroke, all-cause mortality, and composite outcome at 1 year. These findings are hypothesis-generating and require further prospective studies to confirm this observation. Full article