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

BACKGROUND: There are few data evaluating the association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and nonarteritic anterior ischemic optic neuropathy (NAION), which constitutes approximately 75% of ischemic optic neuropathy (ION) cases in adults. OBJECTIVE: To estimate the effect of GLP-1RAs versus sodium-glucose cotransporter-2 inhibitors (SGLT2is) and dipeptidyl peptidase-4 inhibitors (DPP4is) on risk for ION. DESIGN: Observational emulation of a target trial. SETTING: Large U.S.-based commercial claims database (January 2017 to December 2022). PARTICIPANTS: Patients aged 18 to 65 years with type 2 diabetes initiating a GLP-1RA, an SGLT2i, or a DPP4i. MEASUREMENTS: The primary outcome was incident ION as a proxy for NAION. Analyses adjusted for more than 80 covariates using inverse probability of treatment weights, and 18-month cumulative incidence and risk differences (RDs) per 10 000 patients were estimated. RESULTS: The 18-month risk for ION was 8.5 versus 5.5 per 10 000 among GLP-1RA users versus SGLT2i users (RD, 3.0 [95% CI, 0.4 to 5.7]) and 7.8 versus 4.2 per 10 000 among GLP-1RA users versus DPP4i users (RD, 3.6 [CI, 1.1 to 6.1]). Corresponding numbers needed to harm were 3333 and 2778, respectively. Among GLP-1RA users, 69 (85.2%) of the 81 ION events occurred in persons older than 50 years and 57 (70.3%) occurred in men. Risk differences were attenuated among metformin monotherapy users (2.0 and 4.1) compared with users of 2 or more diabetes medications (5.7 and 4.0) versus SGLT2is and DPP4is, respectively. Risk differences were higher in men, patients aged 50 years or older, and those with cardiovascular disease or ophthalmic conditions, with minimal differences in women and those younger than 50 years. LIMITATIONS: Diagnostic codes specifically for NAION were lacking. Missing data on key clinical factors (such as body mass index and type 2 diabetes duration) may contribute to residual confounding, leaving uncertainty about whether the observed association is causal. CONCLUSION: Use of GLP-1RAs was associated with higher 18-month risk for ION than use of SGLT2is and DPP4is, although absolute risk remained very low. Observed differences may reflect residual confounding. PRIMARY FUNDING SOURCE: National Institutes of Health.