AIMS: Evidence on the safety of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RA) concerning non-arteritic anterior ischemic optic neuropathy (NAION) is inconclusive, with several studies published to date presenting methodological challenges. We sought to compare the risk of presumed NAION in patients with type 2 diabetes (T2D), initiating a GLP-1RA versus a sodium-glucose cotransporter-2 inhibitor (SGLT2i), using a new-user active comparator cohort study design within a target trial emulation framework.
MATERIALS AND METHODS: Using insurance claims data from three databases (01/2016-08/2024), we identified 482 912 propensity score matched (1:1) pairs of GLP-1RA and SGLT2i adult initiators with T2D and without prior ischemic optic neuropathy (ION) or other optic nerve disorders. NAION was defined as a diagnosis of ION without other causes of optic neuropathy, combined with an ophthalmologist or optometrist visit on the same day. We estimated pooled hazard ratios (HRs) and rate differences (RDs).
RESULTS: Over a median follow-up of 6.7 months on treatment, the risk of incident NAION was higher among initiators of GLP-1RA compared with SGLT2i [HR, 1.85; 95% CI (1.51-2.27); RD, 0.29 (0.19, 0.39) per 1000 person-years]. Results were consistent across subgroups and sensitivity analyses. A meta-analysis of our semaglutide analysis with previously published results also showed an elevated risk, with a HR of 2.78 (1.39-5.56).
CONCLUSIONS: In this large observational study, the initiation of GLP-1RA was associated with an 85% increase in the risk of presumed NAION, compared with the initiation of SGLT2is, though incidence rates and absolute increase in risk were small.
