Semaglutide associated with Nonarteritic Anterior Ischemic Optic Neuropathy: JAMA

Semaglutide (Ozempic; Novo Nordisk) was approved by the US Food and Drug Administration (FDA) in December 2017 to treat type 2 diabetes (T2D) and in December 2022 to treat obesity (typically at higher doses, as Wegovy [Novo Nordisk]). Weekly new-to-brand prescriptions in the United States of these and other glucagon-like peptide receptor agonist (GLP-1 RA) drugs increased by approximately 60% from 2021 to 2023.

In major medical centers, neuro-ophthalmologists are most likely to evaluate suspected cases of NAION. This study was designed to capitalize on this expertise by characterizing the risk of NAION among individuals using semaglutide within a neuro-ophthalmology practice at a single academic center.

In a retrospective matched cohort study using data from a centralized data registry of patients evaluated by neuro-ophthalmologists at 1 academic institution from December 1, 2017, through November 30, 2023, a search for International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code H47.01 (ischemic optic neuropathy) and text search yielded 16 827 patients with no history of NAION. Propensity matching was used to assess whether prescribed semaglutide was associated with NAION in patients with type 2 diabetes (T2D) or overweight/obesity, in each case accounting for covarying factors (sex, age, systemic hypertension, T2D, obstructive sleep apnea, obesity, hyperlipidemia, and coronary artery disease) and contraindications for use of semaglutide. The cumulative incidence of NAION was determined with the Kaplan-Meier method and a Cox proportional hazards regression model adjusted for potential confounding comorbidities. Data were analyzed from December 1, 2017, through November 30, 2023.

Among 16 827 patients, 710 had T2D (194 prescribed semaglutide; 516 prescribed non–GLP-1 RA antidiabetic medications; median [IQR] age, 59 [49-68] years; 369 [52%] female) and 979 were overweight or obese (361 prescribed semaglutide; 618 prescribed non–GLP-1 RA weight-loss medications; median [IQR] age, 47 [32-59] years; 708 [72%] female).

In the population with T2D, 17 NAION events occurred in patients prescribed semaglutide vs 6 in the non–GLP-1 RA antidiabetes cohort.

The cumulative incidence of NAION for the semaglutide and non–GLP-1 RA cohorts over 36 months was 8.9% (95% CI, 4.5%-13.1%) and 1.8% (95% CI, 0%-3.5%), respectively.

A Cox proportional hazards regression model showed higher risk of NAION for patients receiving semaglutide (hazard ratio [HR], 4.28; 95% CI, 1.62-11.29); P < .001).

In the population of patients who were overweight or obese, 20 NAION events occurred in the prescribed semaglutide cohort vs 3 in the non–GLP-1 RA cohort.

The cumulative incidence of NAION for the semaglutide vs non–GLP-1 RA cohorts over 36 months was 6.7% (95% CI, 3.6%-9.7%) and 0.8% (95% CI, 0%-1.8%), respectively.

A Cox proportional hazards regression model showed a higher risk of NAION for patients prescribed semaglutide (HR, 7.64; 95% CI, 2.21-26.36; P < .001).

This study is the first to report an association between semaglutide and NAION, although the design of study did not enable query into a causal relationship between the two. The best approaches to confirm, refute, or refine findings would be to conduct a much larger, retrospective, multicenter population-based cohort study; a prospective, randomized clinical study; or a postmarket analysis of all GLP-1 RA drugs. A risk inherent in larger studies, however, is the standard use of ICD-10 diagnostic codes given that there is no ICD-10 code for NAION. The most specific code relevant to NAION is the broader category of ischemic optic neuropathy. SThe manual review of records for this study revealed that 40% of cases coded as ischemic optic neuropathy were not actually NAION but rather arteritic ischemic optic neuropathy from giant cell arteritis (which is commonly managed by neuro-ophthalmologists) or other forms of ischemic or nonischemic optic neuropathies.Manual review is not practical for extremely large databases, and the lack of a specific ICD-10 code for NAION (as identified by Hamedani et al31) would be a severe hindrance for any large study. Emerging algorithms would improve the accuracy of diagnostic coding in larger studies but would not attain the precision of a manual review and might not provide sufficient accuracy to establish a statistical association between use of a drug and occurrence of a relatively uncommon disorder like NAION.

Source: Jimena Tatiana Hathaway, MD, MPH; Madhura P. Shah, BS; David B. Hathaway, MD; JAMA Ophthalmol. doi:10.1001/jamaophthalmol.2024.2296