Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy.
Level 3 - non-randomized controlled study
Non-randomized multi-database active-comparator cohort and self-controlled case-series study
PubMed 39976940 · doi:10.1001/jamaophthalmol.2024.6555
What was done
This retrospective multi-database study across 14 electronic health record and claims databases (OHDSI network) evaluated adults with type 2 diabetes receiving semaglutide, other GLP-1 receptor agonists (dulaglutide, exenatide), or non-GLP-1 medications (empagliflozin, sitagliptin, glipizide) between December 2017 and December 2023. Nonarteritic anterior ischemic optic neuropathy (NAION) was evaluated using both sensitive and specific diagnosis-code definitions. Risk was assessed using propensity score-adjusted Cox proportional hazards models for active-comparator new-user cohorts and conditional Poisson regression for self-controlled case-series (SCCS) analyses, pooled using random-effects meta-analysis.
What was found
The study examined 37.1 million individuals with type 2 diabetes, including 810,390 new semaglutide users. NAION incidence among semaglutide users was 14.5 per 100,000 person-years. In active-comparator analyses using the sensitive definition, semaglutide was not associated with statistically significant risk differences versus empagliflozin (HR 1.44; 95% CI, 0.78–2.68; P = .12), sitagliptin (HR 1.30; 95% CI, 0.56–3.01; P = .27), or glipizide (HR 1.23; 95% CI, 0.66–2.28; P = .25). Using the specific definition, risk was significantly higher only compared to empagliflozin (HR 2.27; 95% CI, 1.16–4.46; P = .02). SCCS analysis showed a modest increased risk of NAION during semaglutide exposure (IRR 1.32; 95% CI, 1.14–1.54; P < .001).
Why it matters
This massive multi-database analysis suggests semaglutide is associated with a modest increase in NAION risk, though the magnitude is substantially smaller than indicated by initial safety reports.
Limits
The study is observational and relies on administrative billing and EHR codes, risking outcome misclassification. Risk estimates varied depending on whether a sensitive or specific NAION definition was applied. Residual confounding by indication, diabetes severity, and glycemic trajectory remains possible.
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