Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy
Authors: Cai Cindy X. , Hribar Michelle , Baxter Sally , Goetz Kerry , Swaminathan Swarup S. , Flowers Alexis , Brown Eric N. , Toy Brian , Xu Benjamin , Chen John , Chen Aiyin , Wang Sophia , Lee Cecilia , Leng Theodore , Ehrlich Joshua R. , Barkmeier Andrew , Armbrust Karen R. , Boland Michael V. , Dorr David , Boyce Danielle , Alshammari Thamir , Swerdel Joel , Suchard Marc A. , Schuemie Martijn , Bu Fan , Sena Anthony G. , Hripcsak George , Nishimura Akihiko , Nagy Paul , Falconer Thomas , DuVall Scott L. , Matheny Michael , Viernes Benjamin , O’Brien William , Zhang Linying , Martin Benjamin , Westlund Erik , Mathioudakis Nestoras , Fan Ruochong , Wilcox Adam , Lai Albert , Stocking Jacqueline C. , Takkouche Sahar , Lee Lok Hin , Xie Yangyiran , Humes Izabelle , McCoy David B. , Adibuzzaman Mohammad , Areaux Raymond G. , Rojas-Carabali William , Brash James , Lee David A. , Weiskopf Nicole G. , Mawn Louise , Agrawal Rupesh , Morgan-Cooper Hannah , Desai Priya , Ryan Patrick B. 
Published: February 2025

Importance

Semaglutide, a glucagonlike peptide-1 receptor agonist (GLP-1RA), has recently been implicated in cases of nonarteritic anterior ischemic optic neuropathy (NAION), raising safety concerns in the treatment of type 2 diabetes (T2D).

Objective

To investigate the potential association between semaglutide and NAION in the Observational Health Data Sciences and Informatics (OHDSI) network.

Design, Setting, and Participants

This was a retrospective study across 14 databases (6 administrative claims and 8 electronic health records). Included were adults with T2D taking semaglutide, other GLP-1RA (dulaglutide, exenatide), or non–GLP-1RA medications (empagliflozin, sitagliptin, glipizide) from December 1, 2017, to December 31, 2023. The incidence proportion and rate of NAION were calculated. Association between semaglutide and NAION was assessed using 2 approaches: an active-comparator cohort design comparing new users of semaglutide with those taking other GLP-1RAs and non–GLP-1RA drugs, and a self-controlled case-series (SCCS) analysis to compare individuals’ risks during exposure and nonexposure periods for each drug. The cohort design used propensity score–adjusted Cox proportional hazards models to estimate hazard ratios (HRs). The SCCS used conditional Poisson regression models to estimate incidence rate ratios (IRRs). Network-wide HR and IRR estimates were generated using a random-effects meta-analysis model.

Exposures

GLP-1RA and non–GLP-1RAs.

Main Outcomes and Measures

NAION under 2 alternative definitions based on diagnosis codes: one more inclusive and sensitive, the other more restrictive and specific.

Results

The study included 37.1 million individuals with T2D, including 810 390 new semaglutide users. Of the 43 620 new users of semaglutide in the Optum’s deidentified Clinformatics Data Mart Database, 24 473 (56%) were aged 50 to 69 years, and 26 699 (61%) were female. The incidence rate of NAION was 14.5 per 100 000 person-years among semaglutide users. The HR for NAION among new users of semaglutide was not different compared with that of the non–GLP-1RAs using the sensitive NAION definition—empagliflozin (HR, 1.44; 95% CI, 0.78-2.68; P = .12), sitagliptin (HR, 1.30; 95% CI, 0.56-3.01; P = .27), and glipizide (HR, 1.23; 95% CI, 0.66-2.28; P = .25). The risk was higher only compared with patients taking empagliflozin (HR, 2.27; 95% CI, 1.16-4.46; P = .02) using the specific definition. SCCS analysis of semaglutide exposure showed an increased risk of NAION (meta-analysis IRR, 1.32; 95% CI, 1.14-1.54; P &amp;lt; .001).

Conclusions and Relevance

Results of this study suggest a modest increase in the risk of NAION among individuals with T2D associated with semaglutide use, smaller than that previously reported, and warranting further investigation into the clinical implications of this association.