Increased Risk of New Onset NAION for Initiators of Semaglutide with Type 2 Diabetes in the U.S. Veterans Health Administration

ImportanceGlucagon-like peptide-1 receptor agonists (GLP-1RAs) are among the safest and most effective medications for diabetes and weight loss and are currently used by millions of individuals worldwide. While their cardiometabolic benefits are well established, emerging observational reports have raised concerns about a potential association between GLP-1 RA use and new-onset non-arteritic anterior ischemic optic neuropathy (NAION). ObjectiveTo emulate a target trial evaluating the risk of NAION associated with initiation of semaglutide, a GLP-1RA, compared with a sodium-glucose cotransporter-2 inhibitor (SGLT2i) as second-line therapy for type 2 diabetes in a nationwide cohort of U.S. Veterans. DesignActive-comparator, new-user, target trial emulation. Marginal cause-specific hazard ratios (HRs) were estimated using overlap weighting to account for confounding. Data analysis was conducted from July 2025 to September 2025. SettingThe Veterans Health Administration (VHA) nationwide health care system between March 1, 2018 and March 1, 2025. ParticipantsU.S. Veterans with a diagnosis of type 2 diabetes who were current metformin users and had no prior exposure to GLP-1RAs or SGLT2is. ExposureInitiation of semaglutide or any SGLT2i. Main Outcome and MeasureIncident NAION, identified using ICD-10 and SNOMED diagnosis codes. ResultsA total of 102,361 Veterans met inclusion criteria, including 11,478 new initiators of semaglutide and 90,883 new initiators of an SGLT2i. Baseline characteristics were well balanced between treatment groups after overlap weighting (mean [SD] age, 60.1 [11.7] years; BMI, 37.8 [6.7] kg/m2; hemoglobin A1c, 7.0% [1.4]; 85.5% male; 61.9% non-Hispanic White; 20.7% Black; 8.1% Hispanic). Over a median follow-up of 2.1 years, 153 total incident NAION events occurred. The incidence rate of NAION was 123 per 100,000 person-years among semaglutide initiators and 67 per 100,000 person-years among SGLT2i initiators. Patients who initiated semaglutide had a 2.33-fold higher risk than patients who initiated SGLT2i (HR, 2.33; 95% CI, 1.54-3.54; P<.001). Conclusions and RelevanceIn this nationwide cohort of U.S. Veterans with type 2 diabetes, patients who initiated semaglutide had over a 2-fold increased risk of NAION compared to patients who initiated SGLT2i.