Glucagon-like Peptide-1 Receptor Agonists and Risk for Anterior Ischemic Optic Neuropathy

BACKGROUND: There are concerns about a possible link between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and nonarteritic anterior ischemic optic neuropathy (NAION). OBJECTIVE: To examine whether use of GLP-1RAs increases risk for AION, which predominantly comprises NAION. DESIGN: Nationwide, register-based, cohort study. SETTING: Sweden, 2013 to 2024. PATIENTS: Initiators of GLP-1RAs compared with initiators of sodium-glucose cotransporter-2 (SGLT-2) inhibitors. MEASUREMENTS: Anterior ischemic optic neuropathy in the national patient register. Adjusted risk differences (RDs) and risk ratios (RRs) were estimated using propensity score weighting. RESULTS: Median follow-up was 1.6 years (IQR, 0.7 to 3.1 years) for GLP-1RA users and 1.5 years (IQR, 0.7 to 2.9 years) for SGLT-2 inhibitor users. Sixty-two of 107 518 GLP-1RA users and 64 of 185 898 SGLT-2 inhibitor users experienced AION. Risks were 0.04% versus 0.02% (RD, 0.02% [95% CI, 0.00% to 0.03%]; RR, 1.93 [CI, 1.00 to 3.73]) at 1 year and 0.12% versus 0.07% (RD, 0.05% [CI, 0.00% to 0.10%]; RR, 1.69 [CI, 0.95 to 3.01]) at 5 years. The differences were substantially attenuated in analyses restricted to patients receiving metformin at baseline (1 year: RD, 0.01% [CI, -0.01% to 0.02%]; RR, 1.40 [CI, 0.64 to 3.05]; 3 years: RD, 0.01% [CI, -0.02% to 0.04%]; RR, 1.24 [CI, 0.68 to 2.26]; 5 years: RD, 0.02% [CI, -0.04% to 0.08%]; RR, 1.23 [CI, 0.65 to 2.33]). LIMITATION: Few outcome events, unmeasured confounding, and limited generalizability to GLP-1RA users without diabetes. CONCLUSION: The relative risk for AION was higher with GLP-1RA use compared with SGLT-2 inhibitor use in type 2 diabetes. However, absolute risks were small, and the RDs were substantially reduced in analyses restricted to patients receiving metformin to better account for confounding by diabetes severity, suggesting observed increases in risk may reflect residual confounding. PRIMARY FUNDING SOURCE: Karolinska Institutet, Swedish Society of Medicine, Swedish Research Council, and Region Stockholm.