Considerations Regarding Association of Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy

To the Editor Hathaway et al reported on a relatively high 36-month cumulative incidence of nonarteritic anterior ischemic optic neuropathy (NAION), 8.9% (95% CI, 4.5%-13.1%), among a cohort of semaglutide users (n = 169) with evidence of type 2 diabetes who received care in a neuro-ophthalmology clinic at an academic medical center. Most NAION cases were observed in the first year. In August 2022, the US Food and Drug Administration used its Sentinel System—a multisite, national electronic health care data network that then contained more than 65 million unique patients with commercial or Medicare insurance—to monitor potential adverse effects among semaglutide users with evidence of diabetes. New users of semaglutide were matched 1:1 to new users of sitagliptin (a dipeptidyl peptidase 4 inhibitor, another class of antidiabetes drugs that were also included in the comparison group in the study by Hathaway et al) using propensity scores, including a high-dimensional propensity score (hdPS) sensitivity analysis to account for underlying disease severity. With more than 134 000 matched pairs identified, data were collected on event frequency in the first 6 months after treatment initiation for up to 83 000 International Statistical Classification of Diseases, Tenth Revision, Clinical Modification nonpregnancy and noncancer diagnosis codes and analyzed for imbalances in outcome occurrence using tree-based scan statistics. The primary pharmacovigilance analysis observed 17 and 13 new cases of ischemic optic neuropathy (code H47.01*) in the ambulatory care setting among semaglutide and sitagliptin users, respectively, where a new case was defined as the first in 400 days. The hdPS sensitivity analysis yielded 15 and 12 cases, respectively. The incidence among semaglutide users was 12.7 (95% CI, 7.9-20.4) cases per 100 000 persons, whereas the incidence among sitagliptin users was 9.7 (95% CI, 5.6-21.8) cases per 100 000 persons. These observed cumulative incidences are consistent with previous literature noting that NAION occurs at a rate of 2 to 10 cases per 100 000 persons among a general population. The incidence risk difference of H47.01* was 3 (95% CI, 0-19) cases per 100 000 users (calculated as 17 cases per 134 009 persons minus 13 cases per 134 009 persons). H47.01* may possibly overestimate potential NAION cases, but validation studies have found reasonable performance (positive predictive value, 74.5%-86.8%).

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