Diabetic macular edema and GLP-1 receptor agonist use: a systematic review and meta-analysis.
This systematic review and meta-analysis examined whether glucagon-like peptide-1 receptor agonists (GLP-1RAs) — medications commonly used for type 2 diabetes and obesity — are associated with an increased risk of diabetic macular edema (DME). Researchers searched five major databases through October 2025 and ultimately included 13 retrospective cohort studies (published 2021–2025) drawn from large real-world databases, all involving patients with diabetes who did not have DME at baseline. Using random-effects models, the study found that the pooled incidence proportion of new-onset DME among GLP-1RA users was approximately 14%. Compared with mixed antihyperglycemic therapies, GLP-1RA use was not significantly associated with increased DME risk (HR: 0.81, 95% CI: 0.52–1.26). GLP-1RAs were associated with a higher relative risk of DME compared to SGLT-2 inhibitors (HR: 1.50, 95% CI: 1.17–1.94), but not compared to DPP-4 inhibitors. The authors rated the overall certainty of evidence as very low, citing high statistical heterogeneity (I² = 99.8%), reliance on retrospective observational designs with inherent confounding risks, and variability across database sources. The study concluded that current evidence does not support a clear overall increased DME risk with GLP-1RA use but called for prospective studies to better characterize comparative retinal safety.
Why this grade: Although this is a meta-analysis of human data, all 13 included studies were retrospective observational cohorts with very low GRADE-rated certainty of evidence, extreme heterogeneity (I²=99.8%), and inherent confounding limitations that preclude strong causal conclusions.
Background Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are widely used for type II diabetes and obesity because of their cardiometabolic benefits. However, concerns regarding potential ocular adverse effects, particularly diabetic macular edema (DME), have prompted the need to clarify their retinal safety. Methods A systematic review and meta-analysis study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-analysis of Observational Studies in Epidemiology statements (PROSPERO registration: CRD420251176164). MEDLINE (Ovid), EMBASE (Ovid), CENTRAL (Ovid), Web of Science, and PubMed were searched from inception to October 24, 2025. Randomized trials and observational cohort or case-control studies, including individuals with diabetes without baseline DME and exposed to GLP-1RAs were eligible. Two reviewers independently screened studies, extracted data, and assessed risk of bias using ROBINS-I. Certainty of evidence was evaluated using Grading of Recommendations, Assessment, Development, and Evaluation. Random-effects models were used to pool incidence proportions and hazard ratios (HRs). Results Thirteen retrospective cohort studies (2021-2025) using large real-world databases were included. Across 6 studies, the pooled proportion of incident DME among GLP-1RA users was 0.14 (95% CI: 0.07-0.23; I² = 99.8%). Compared with mixed antihyperglycemic therapies, GLP-1RA use was not associated with increased DME risk (pooled HR: 0.81, 95% CI: 0.52-1.26). GLP-1RAs were associated with a higher relative risk of DME compared with sodium-glucose cotransporter-2 inhibitors (HR: 1.50, 95% CI: 1.17-1.94) but not compared with dipeptidyl peptidase-4 inhibitors (HR: 0.90, 95% CI: 0.69-1.19). Evidence certainty was very low. Conclusion Current low-certainty observational evidence does not support an overall increased risk of DME with GLP-1RA use. Prospective studies are needed to clarify comparative retinal safety.
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