Эволюция агонистов рецепторов глюкагоноподобного пептида-1 в терапии сахарного диабета 2 типа

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

<b>Objective</b> <p>Short-acting GLP-1 receptor agonists (GLP-1 RAs) decelerate gastric emptying more than long-acting GLP-1 RAs. Delayed gastric emptying is a risk factor for gastroesophageal reflux disease. We aimed to measure esophageal reflux and function as well as gastric emptying and acid secretion during treatment with short- (lixisenatide) and long-acting (liraglutide) GLP-1 RAs.</p> <p><b>Research Design and Methods</b></p> <p>57 subjects with type 2 diabetes were randomized to a 10-week treatment with lixisenatide or liraglutide. Changes from baseline in the number of reflux episodes during 24-hour pH registration in the lower esophagus, lower esophagus sphincter pressure, gastric emptying (<sup>13</sup>C-sodium octanoate acid breath test) and gastric acid secretion (<sup>13</sup>C-calcium carbonate breath test) were analyzed.</p> <p><b>Results</b></p> <p>Gastric emptying half-time was delayed by 52 min (16, 88) min with lixisenatide (p = 0.0065) and by 25 min (3, 46) with liraglutide (p = 0.025). There was no difference in the number of reflux episodes (33.7±4.1 vs. 40.1±5.3, p = 0.17) or the extent of gastroesophageal reflux (DeMeester-Score) (35.1±6.7 vs. 39.7±7.5, p = 0.61) with similar results for the individual GLP-1 RAs. No significant changes from baseline in other parameters of esophageal motility and lower esophageal sphincter function were observed. Gastric acidity decreased significantly by -20.7 (-40.6, -0.8) % (p = 0.042) with the GLP-1 RAs.</p> <p><b>Conclusions</b></p> <p>Lixisenatide exerted a more pronounced influence on gastric emptying after breakfast than liraglutide. Neither lixisenatide, nor liraglutide had significant effects on esophageal reflux or motility. Gastric acid secretion appears to be slightly reduced by GLP-1 RAs.</p> <br> <br>

More than 26 million people in the United States have type 2 diabetes mellitus (T2D). Many treatment options exist, but achieving long-term glycemic control in patients with T2D remains challenging. The glucagon-like peptide-1 receptor agonists (GLP-1 RAs) offer a treatment option that improves glycemic control and reduces weight, with a low risk of hypoglycemia. They have emerged as attractive options for the treatment of T2D, and significant advances and developments continue to be published regarding these agents. To identify relevant literature on emerging issues related to GLP-1 RAs, a search of the MEDLINE database was performed. Studies published in English evaluating the safety and efficacy of GLP-1 RAs were analyzed. Because of their advantages and unique mechanism of action, GLP-1 RAs are currently being studied in new clinical areas, including in combination with basal insulin, as adjunctive therapy in type 1 diabetes, and for weight loss. In addition, there are several emerging agents in development. Lixisenatide is a once-daily GLP-1 RA that targets postprandial glucose and may be most useful when added to basal insulin as an alternative to rapid-acting insulin. Albiglutide and dulaglutide are once-weekly GLP-1 RAs that may offer more convenient dosing. The most common adverse effects of all GLP-1 RA agents are gastrointestinal (e.g., nausea, diarrhea, and vomiting), but the rates of occurrence vary among agents. Due to the differences in pharmacokinetics, efficacy, rates of adverse effects, and administration requirements within the GLP-1 RA class, each agent should be evaluated independently. The future of GLP-1 RAs offers broader treatment options for T2D as well as potential in other treatment areas.

Background: Glucagon-like peptide 1 receptor agonists (GLP-1RAs) have shown efficacy for reducing cardiovascular morbidity and mortality in patients with diabetes mellitus (DM), but conflicting evidence exists regarding their impact on cardiac arrhythmias. Whereas some studies suggested a possible association between GLP-1RA use and arrhythmogenesis, other studies suggested decreased association with atrial fibrillation (AF). Overall, large-scale real-world data evaluating risk of AF in association with GLP-1RAs are lacking. Objective: To compare risk of incident AF after initiation of GLP1-RA vs Dipeptidyl peptidase-4 inhibitors (DPP4i), as active comparators, in patients with DM. Methods: This retrospective propensity score-matched cohort study was conducted within the Veterans Health Administration from fiscal years 2006 to 2021. The study included U.S. veterans aged 35 years or older who initiated either GLP1-RA or DPP4i prescriptions. The primary outcome assessed was a composite outcome of atrial fibrillation (AF), defined as a diagnosis of AF/flutter based on administrative codes or undergoing an AF procedure. Results: Out of 116,235 GLP1-RA users and 217,668 DPP4i users, we propensity score-matched 80,948 pairs, on 88 characteristics, including demographics, comorbidities, vital signs, cardiovascular risk score, healthcare utilization, DM control, laboratory investigation, and medications. Composite outcome of AF was similar in GLP-1RA group (4.1%) and DPP4i group (4.3%); odds ratio (OR) 0.96, 95% confidence interval (CI) 0.92-1.01. Secondary analyses stratified by medication use duration showed no significant differences in composite AF risk (P>0.05). Notably, individuals achieving weight loss of 2%, 5%, or 10% of baseline body weight had significantly lower AF incidence, whereas no significant differences were observed in those with no weight loss or weight gain (OR 0.99, 95% CI 0.91-1.07). Conclusions: Use of GLP1-RA in patients with DM was not associated with a decreased risk of AF when compared with the use of DPP4i. In the subgroup analysis, significantly lower AF risk was seen in the GLP-1 RA group who achieved weight loss vs. DPP4i and this highlights weight loss as a potential modifier of cardiovascular outcomes in DM.

Glucagon-like peptide 1 receptor agonists (GLP-1RA) reduce the incidence of major adverse cardiovascular events (MACE) in type 2 diabetes (T2D), although whether benefits extend to both subcutaneous and oral formulations remains unclear. In these meta-analyses, including new data from the Semaglutide cardiOvascular oUtcomes triaL (SOUL) (oral semaglutide) and Evaluate Renal Function with Semaglutide Once Weekly (FLOW) trial, we examined cardiovascular (CV) and kidney benefits and risks of long-acting (defined as having pharmacokinetics sufficient to provide 24-h activity) GLP-1RA in T2D. A systematic review of PubMed was conducted (to 7 February 2025). Randomized placebo-controlled CV and kidney outcomes trials of GLP-1RA with ≥500 individuals with T2D were included. A random-effects model was used to estimate hazard ratios (HRs) for MACE, its components, all-cause mortality, hospitalization for heart failure (HHF), a composite kidney outcome (kidney failure [kidney replacement therapy or persistent estimated glomerular filtration rate [eGFR] <15 mL/min/1.73 m2], sustained ≥50% eGFR decline or nearest equivalent, or kidney-related death), worsening kidney function, and safety outcomes. Across 10 trials (n = 71,351), long-acting GLP-1RA reduced incidence rate of MACE by 14% (HR 0.86 [95% CI 0.81, 0.90]; I2 = 27.6%), HHF by 14% (0.86 [0.79, 0.93]; I2 = 2.1%), and the composite kidney outcome by 17% (0.83 [0.75, 0.92]; I2 = 20.4%) and all-cause mortality by 12% (0.88 [0.82, 0.93]; I2 = 17.5%). A consistent 14% reduction was seen for all MACE components. There was no significant heterogeneity by GLP-1RA administration route (subcutaneous vs. oral). There were no increased risks of severe hypoglycemia, retinopathy, or pancreatic events. Trial-level meta-analyses preclude detailed subgroup analyses and may introduce ecological bias. As a group, long-acting GLP-1RA, including both injectable and oral formulations, reduce incidence of MACE, HHF, and kidney events and all-cause mortality in T2D.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective medications for the treatment of type 2 diabetes and obesity. Pharmacological studies in rodents support an association between the use of GLP-1 RAs and the development of medullary thyroid cancer (MTC) resulting in a black box warning for these agents in patients at risk for this condition. Yet, the association between GLP-1 RAs and non-MTC remains controversial. Excessive worry about unproven thyroid cancer risk might lead to underutilizing GLP-1 RAs in patients who could otherwise experience substantial benefits. Unwarranted concerns about thyroid cancer could lead to unnecessary thyroid cancer screening and harms from overdiagnosis. Summary: The body of evidence assessing the association between GLP-1 RA use and thyroid cancer spans a wide range of methodologies, including basic and translational research investigating biological plausibility; randomized trials assessing clinical efficacy and providing the strongest evidence for causality; observational studies providing real-life outcome evaluation in larger populations but with limited evaluation of covariates or dependable outcome definitions; and pharmacovigilance studies that provide postmarketing assessments of a safety signal but do not address causality. There is biological plausibility supporting an association between GLP-1 RA and MTC in rodents, which is less clear for non-MTC in humans. Clinical evidence from randomized trials and associated meta-analysis suggest thyroid cancer as a rare event making effect estimates imprecise but without conclusive and consistent evidence of increase risk in those receiving GLP-1 RA. Observational studies at higher risk of bias also show low event rates for thyroid cancer, with effect estimates that are inconsistent among different studies. Pharmacovigilance studies consistently show a signal of increased reporting of thyroid cancer in patients treated with GLP-1 RA. Conclusions: Evidence from randomized controlled trials indicates occurrence of thyroid cancer is infrequent in individuals exposed to GLP-1 RA. Observational studies at higher risk of bias yield inconsistent results. Overall there is no conclusive evidence of elevated thyroid cancer risk. These findings can help clinicians when addressing patient's concerns about a potential yet unproven link between GLP-1 RA therapy and thyroid cancer.

A systematic review in effects of glucagon-like peptide-1 (GLP-1) mono-agonists on functional connectivity: Target engagement and rationale for the development in mental disorders

Cardiovascular Effects and Tolerability of GLP-1 Receptor Agonists: A Systematic Review and Meta-Analysis of 99,599 Patients.

Randomized clinical trials have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) cause significant weight loss and reduce cardiovascular events in patients with type 2 diabetes (T2D). Black patients have a disproportionate burden of obesity and cardiovascular disease and have a higher rate of cardiovascular-related mortality. Racial and ethnic disparities in health outcomes are largely attributable to the pervasiveness of structural racism, and patients who are marginalized by racism have less access to novel therapeutics. To evaluate GLP-1 RA uptake among a commercially insured population of patients with T2D; identify associations of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use; and specifically examine its use among the subgroup of patients with atherosclerotic cardiovascular disease (ASCVD) because of the known benefit of GLP-1 RA use for this population. This was a retrospective cohort analysis using data from OptumInsight Clinformatics Data Mart of commercially insured adult patients with T2D (with or without ASCVD) in the US. Data from October 1, 2015, to June 31, 2019, were included, and the analyses were performed in July 2020. We estimated multivariable logistic regression models to identify the association of race, ethnicity, sex, and socioeconomic status with GLP-1 RA use. A prescription for a GLP-1 RA. Of the 1 180 260 patients with T2D (median [IQR] age, 69 [59-76] years; 50.3% female; 57.7% White), 90 934 (7.7%) were treated with GLP-1 RA during the study period. From 2015 to 2019, the percentage of T2D patients treated with an GLP-1 RA increased from 3.2% to 10.7%. Among patients with T2D and ASCVD, use also increased but remained low (2.8%-9.4%). In multivariable analyses, lower rates of GLP-1 RA use were found among Asian (aOR, 0.59; 95% CI, 0.56-0.62), Black (adjusted odds ratio [aOR] 0.81; 95% CI, 0.79-0.83), and Hispanic (aOR, 0.91; 95% CI, 0.88-0.93) patients with T2D. Female sex (aOR, 1.22; 95% CI, 1.20-1.24) and higher zip code-linked median household incomes (>$100 000 [OR, 1.13; 95% CI, 1.11-1.16] and $50 000-$99 999 [OR, 1.07; 95% CI, 1.05-1.09] vs <$50 000) were associated with higher GLP-1 RA use. These results were similar to those found among patients with ASCVD. In this cohort study of US patients with T2D, GLP-1 RA use increased, but remained low overall for treatment of T2D, particularly among patients with ASCVD who are likely to derive the most benefit. Asian, Black, and Hispanic patients and those with low income were less likely to receive treatment with a GLP-1 RA. Strategies to lower barriers to GLP-1 RA use, such as lower cost, are needed to prevent the widening of well-documented inequities in cardiovascular disease outcomes in the US.

BackgroundThe rising prevalence of obesity and type 2 diabetes mellitus (T2DM) among patients undergoing total joint arthroplasty (TJA) presents a significant clinical challenge, increasing the risk of postoperative complications. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a potential perioperative optimization strategy, but their impact on TJA outcomes remains debated. This systematic review was conducted to synthesize the evidence on the risks and benefits of GLP-1 RA use in adult patients undergoing primary TJA—specifically, total hip arthroplasty (THA), total knee arthroplasty (TKA), and total shoulder arthroplasty (TSA).MethodsA systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The PubMed, Scopus, and Web of Science databases were searched from their inception to June 16, 2025, for studies comparing postoperative outcomes in adult patients undergoing primary total joint arthroplasty (TJA) and using GLP-1 RAs versus a control group. Data on study characteristics, patient demographics, and postoperative outcomes were extracted. Due to significant heterogeneity and overlap in data sources, a narrative synthesis rather than meta-analysis of the findings was conducted. Study quality was assessed using the Newcastle–Ottawa Scale (NOS).ResultsFifteen retrospective cohort studies involving an aggregate total of 318,143 patients (114,365 THA, 125,505 TKA, 78,273 TSA) were included, with 56,132 receiving GLP-1 RAs. In THA and TKA, GLP-1 RAs use was associated with a reduced risk of periprosthetic joint infection (PJI) (e.g., 1.6% vs. 2.9% at 2 years for THA) and lower 90-day readmission rates (e.g., 1.1% vs. 2.0% for TKA and 1.6% vs. 2.0% for THA). When analyzed by exposure timing, the reduced PJI risk was most consistent in studies that defined GLP-1 RA use in the immediate perioperative period. Reported mean length of stay (LOS) was generally similar or slightly shorter among GLP-1 RA users compared to controls. Multiple studies reported either a reduction or no significant difference in the risk of 90-day emergency department visits. The short-term revision rates and dislocations were infrequent and did not differ significantly between groups in most of the included studies. In the TSA, evidence was inconsistent, with reduced odds of 90-day surgical site infection (SSI) (OR 0.25) in one study; however, no clear trend was observed. Gastrointestinal side effects and conflicting systemic risks were noted across procedures.ConclusionCurrent observational data suggest that perioperative GLP-1 RA use in patients undergoing total hip or knee arthroplasty is not associated with a consistent increase in short-term revision rates and may be associated with a reduced risk of postoperative infection. Evidence regarding TSA remains inconclusive. However, given the retrospective nature of the evidence, substantial overlap in data sources, heterogeneity in exposure definitions, and short-term follow-up, these findings should be considered hypothesis-generating. Future prospective, randomized controlled trials with standardized exposure definitions and longer follow-up are required to confirm these associations and establish causality.Supplementary InformationThe online version contains supplementary material available at 10.1186/s42836-026-00375-w.

GLP-1 (Glucagon like Peptide-1) receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, Exenatide, was approved in the year 2000, other agents with a longer duration of action that do not require twice-daily dosing are now being developed. Indeed, Liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, a once-weekly extended-release formulation of Exenatide (Exenatide ER) was approved in 2011 and now more recently Semaglutide, an oral GLP 1 receptor agonist was approved for medical use in the United States in September 2019 and in the European Union in April 2020. The importance of GLP-1 itself and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the GLP-1 receptor agonists (Exenatide ER, Liraglutide, Lixisenatide, Albiglutide, Taspoglutide and Semaglutide) is provided and their mechanism of action, efficacy in terms of glycaemic control, weight loss and tolerability are reviewed. Keywords: GLP1 receptor agonist; Liraglutide; Exenatide ER; Lixisenatide; Semaglutide

Studies have shown that glucagon-like peptide-1 receptor agonists (GLP-1 RAs) provide lung benefits beyond glycemic control, including reduced risks of lung malignancy, pulmonary infection and chronic obstructive pulmonary disease exacerbations. A retrospective cohort study with a new-user and active-comparator design was conducted using the TriNetX US Network. Adults (≥ 18 years) with Type 2 diabetes mellitus (T2DM) (n = 3,389,059) from January 1, 2005, to December 31, 2020, were identified. Two cohorts of new GLP-1 RA (n = 201,153) and new dipeptidyl peptidase-4 inhibitor (DPP4i) (n = 323,114) users were created. Propensity score matching was used to create comparable cohorts. The primary outcome was lung cancer, while other pulmonary conditions were secondary outcomes over a 10-year follow-up. Through 1:1 propensity score matching, two balanced cohorts of GLP-1 RA and DPP4i (n = 158,224) users were created. GLP-1 RA users had a significantly lower risk of lung cancer than did DPP4i users (hazard ratios [HR] 0.86; 95% confidence interval [CI] 0.80–0.94). Reduced risk of influenza and pneumonia (HR 0.94; 95% CI 0.92–0.96) and pulmonary fibrosis (HR 0.92; 95% CI 0.87–0.98) were also noted in GLP-1 RA users. Our findings indicate that GLP-1 RAs may lower the risks of lung cancer, pulmonary fibrosis, and respiratory infections, meriting further prospective study.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-19657-5.

Type 2 diabetes mellitus (T2D) is associated with an increased burden of neuropsychiatric disorders, including cognitive decline, affective disorders, and substance use disorders. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), developed for glycemic control and weight reduction, have been hypothesized to confer neuroprotective and psychotropic benefits via central and peripheral mechanisms. However, evidence across individual studies remains inconsistent. We conducted a systematic review and meta-analysis (PROSPERO CRD420251025534) of randomized controlled trials (RCTs) and observational studies assessing the effect of GLP-1 RAs on neuropsychiatric outcomes. Searches were performed in MEDLINE, SCOPUS, CENTRAL, and Web of Science up to 30th October 2025. Eligible comparators included placebo, standard care, or alternative glucose-lowering agents. Data were synthesized using random-effects models, and risk of bias was assessed using RoB2 and ROBINS-I. Evidence certainty was graded using GRADE methodology. From 10,037 records, 82 studies were included. GLP-1 RAs were associated with a reduced risk of idiopathic Parkinson's disease (PD) (pooled HR 0.70, 95% CI: 0.53-0.92, I2 = 38%) but no improvements in motor symptoms in established PD (MDS-UPDRS Part III off-medication: mean difference -3.29, 95% CI: -7.84, 1.26, I2 = 80%). No consistent improvements in non-motor symptoms, quality of life, or dyskinesia scores were seen. GLP-1 RAs were associated with a reduced risk of cannabis use disorder (pooled HR 0.55, 95% CI: 0.39-0.77, I2 = 71%) but showed no significant effect on opioid use disorder (pooled HR 0.61, 95% CI: 0.24-1.52, I2 = 91%). Liraglutide reduced binge frequency in binge eating disorder (mean difference -1.28, 95% CI: -1.67, -0.89, I2 = 53%) compared to placebo. In observational studies versus non-user controls, GLP-1 RA use was associated with a lower reported risk of suicidality (pooled OR 0.34, 95% CI: 0.18-0.63, I2 = 99%), but no such association was seen with Semaglutide alone (pooled OR 0.71, 95% CI: 0.29-1.73, I2 = 99%), active-comparator studies (pooled HR 0.96, 95% CI: 0.81-1.15, I2=0%) or RCTs (pooled RR 1.13, 95% CI: 0.53-2.41, I2=0%). No associations were observed for depression or anxiety. For dementia, findings were mixed: no benefit versus SGLT2 inhibitors (pooled RR 1.07, 95% CI: 0.73-1.56, I2 = 78%), but there was a reduced risk of Alzheimer's disease when compared to unmatched or non-exposed controls (pooled RR 0.37, 95% CI: 0.14-0.96, I2 = 98%). Certainty of evidence ranged from moderate to very low. Current evidence, largely of low to very low certainty, suggests potential selective neuropsychiatric associations of GLP-1 RAs, particularly in Parkinson's disease risk reduction and binge eating disorder. Benefits for dementia risk reduction were observed primarily in comparisons with non-exposed or DPP4i, whereas no advantage was seen versus other active comparators, such as SGLT2 inhibitors. Our findings should be interpreted as hypothesis-generating due to significant heterogeneity and wide confidence intervals, indicating imprecision. Longer-term studies with neuropsychiatric outcomes as the primary endpoint are required.

Disclosure: F.R. Mateo: None. G. Ajenaghughrure: None. G. Polanco: None. K. Rahima: None. A. Vanaparthi: None. A. Mishra: None. S. Kishore: None. F. Ajayi: None. H. Baloch: None.Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) impacts millions worldwide, creating complex health challenges. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a therapeutic option for this metabolic disorder, extending beyond glycemic control and potentially positively impacting multiple systems. Objectives: We sought to investigate the clinical impacts of GLP-1 on MASLD, highlighting its potential to address systemic metabolic dysfunctions and cardiovascular outcomes. Methods: This prospective case-control study utilized data from the TriNetX federated health research network, which comprises electronic health records from 104 healthcare organizations. Adult patients (aged 18-99 years) diagnosed with hyperlipidemia, MASLD, and heart failure were included. Cohort 1 consisted of 6,573 patients treated with glucagon-like peptide-1 (GLP-1) receptor agonists, while Cohort 2 included 24,697 patients who did not receive GLP-1 receptor agonists. Propensity score matching was applied to balance baseline characteristics, resulting in 6,310 matched patients in each cohort. Outcomes were evaluated over a 5-year period following the index event, defined as the first occurrence of the inclusion criteria. Kaplan-Meier survival analysis, hazard ratios (HRs) with 95% confidence intervals (CIs), and log-rank tests were used to compare the cohort outcomes. Results: Cohorts mean age was 71 (SD 11), 50.02% females and 74.08% white. Patients on GLP-1 receptor agonists had a significantly lower risk of mortality (HR 0.511; 95% CI 0.473-0.552; p < 0.001), acute hepatic failure (HR 0.649; 95% CI(0.552, 0.762); p < 0.001), stroke (HR 0.875; 95% CI (0.777, 0.986); p < 0.028), Myocardial infarction (HR 0.753; 95% CI 0.686-0.826; p < 0.001), cardiogenic shock (HR 0.690; 95% CI 0.564-0.844; p < 0.001), cardiac arrest (HR 0.580; 95% CI 0.475-0.709; p < 0.001), peripheral vascular disease (HR 0.825; 95% CI (0.750, 0.906); p < 0.001) and acute kidney failure (HR 0.757; 95% CI 0.757; p < 0.001). Conclusion: These findings indicate that GLP-1 receptor agonists significantly reduce the risk of mortality, cardiovascular events, and other systemic complications in patients with MASLD, hyperlipidemia, and heart failure, with favorable effects across multiple outcomes. This highlights their potential as a multifaceted therapeutic intervention for this high-risk population.Presentation: Saturday, July 12, 2025

ObjectivesPrevious studies have shown conflicting results on the relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and diabetic retinopathy (DR). This systematic review and meta-analysis aimed to clarify the association between GLP-1 receptor agonists use and the development or progression of DR.MethodsA comprehensive search of MEDLINE (via OVID and PubMed), Embase, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov was conducted from inception to March 2025. We included randomized controlled trials (RCTs) and observational studies reporting on the association between GLP-1 receptor agonists and DR. Screening, data extraction, and quality appraisal were performed independently and in duplicate. We assessed study quality using the Cochrane risk-of-bias tool for RCTs and the Newcastle-Ottawa Scale for observational studies. Meta-analysis was conducted using Stata 17, following PRISMA and MOOSE guidelines.ResultsThe search identified 6,922 studies. Of these, 39 articles (24 RCTs and 15 observational studies) met the inclusion criteria and 23 were included in the meta-analysis. The pooled analysis showed that GLP-1 receptor agonists were not significantly associated with the risk of DR compared with comparators (pooled RR = 1.00, 95% CI 0.71–1.43). Subgroup analyses by study design yielded similar non-significant results, with a pooled RR of 0.91 (95% CI 0.73–1.14) for randomized controlled trials and 2.09 (95% CI 0.47–9.19) for observational studies. After excluding studies with a high risk of bias, the pooled estimate remained non-significant (RR = 1.06, 95% CI 0.67–1.67), supporting the robustness of the overall findings. The association remained non-significant when restricted to larger studies (>500 participants; RR = 1.13, 95% CI 0.70–1.84).ConclusionIn conclusions, this systematic review found no significant association between GLP-1 receptor agonists and DR risk, though a non-significant trend toward lower risk was observed in randomized trials. Given the limited number of long-term studies, the current evidence remains inconclusive. Future studies with longer follow-up period are warranted to clarify the long-term ocular safety of GLP-1 receptor agonists.Systematic review registrationhttps://www.crd.york.ac.uk/PROSPERO/view/CRD420251007882.