The use of semaglutide (Ozempic) was tied to a risk of nonarteritic anterior ischemic optic neuropathy (NAION) in adults with type 2 diabetes, according to a retrospective study.

In this review of 37.1 million patients, the incidence rate of NAION among semaglutide users was 14.5 and 8.7 per 100,000 person-years using the sensitive and specific NAION definitions, respectively, reported Cindy X. Cai, MD, MS, of Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore, and colleagues in JAMA Ophthalmologyopens in a new tab or window.

The risk for NAION, which can cause sudden vision loss, using the sensitive definition — which required one ischemic optic neuropathy diagnosis code — was not different among new semaglutide users compared with users of the GLP-1 receptor agonist dulaglutide (Trulicity), the SGLT2 inhibitor empagliflozin (Jardiance), the DPP-4 inhibitor sitagliptin (Januvia), and the sulfonylurea glipizide.

For the specific definition, which required a second confirmatory ischemic optic neuropathy diagnosis code within 90 days, the risk was higher only compared with empagliflozin (HR 2.27, 95% CI 1.16-4.46, P=0.02).

In a self-controlled case-series analysis, which assessed individuals’ risk during exposure and non-exposure periods for each drug, there was an increased NAION incidence rate associated with semaglutide exposure using both the sensitive definition (incidence rate ratio [IRR] 1.32, 95% CI 1.14-1.54, P<0.001) and the specific definition (IRR 1.50, 95% CI 1.26-1.79, P<0.001).

“We identified a small increased risk of NAION among patients with [type 2 diabetes] who were exposed to semaglutide, smaller than that previously reported,” Cai and team concluded. “In the absence of a known mechanism for this association, we urge clinicians to weigh the concern for an increased risk of a rare but potentially blinding eye condition with the many therapeutic benefits of semaglutide.”

“Truthfully, we weren’t sure what we would find going into this study,” Cai told , noting that a previous study “identified an increased risk for NAIONopens in a new tab or window with semaglutide but another paperopens in a new tab or window … did not identify an increased risk. Not being sure one way or the other was why we ran the study.”

In an accompanying commentaryopens in a new tab or window, Joseph F. Rizzo III, MD, of Massachusetts Eye and Ear, and Jimena Tatiana Hathaway, MD, MPH, of the Harvard T.H. Chan School of Public Health, both in Boston, noted that these findings can help “calibrate one’s understanding of the degree of the risk” for NAION.

In the study that previously showed an increased riskopens in a new tab or window, Rizzo and Hathaway reported a 4.28-fold higher risk for NAION among patients taking semaglutide compared with those taking a non-GLP-1 receptor agonist. Of note, those prescribed semaglutide for overweight or obesity (Wegovy) had a 7.64-fold higher risk for NAION. All patients were diagnosed by neuro-ophthalmologists.

“Although our study might have overestimated the risk, the [current] study might have underestimated the risk given the higher likelihood of misdiagnosis by non-neuro-ophthalmologists,” they pointed out.

“At the least, patients taking semaglutide should be made aware of the apparent risk of NAION, the magnitude of that risk, and the existence of studies that do not consistently identify an increased risk,” they wrote. However, “patients should not stop taking semaglutide on this account alone, especially given potential increases in morbidity from conditions that are well controlled by semaglutide, potential adverse effects of hyperglycemia caused by abrupt cessation of treatment, and the seemingly low absolute risk of NAION.”

Cai agreed, highlighting the many benefits of semaglutide, including glucose management, weight loss, and cardiovascular and kidney protectionopens in a new tab or window.

For this study, Cai and team used data from 14 databases (six administrative claims databases and eight electronic health records). Of the 37.1 million patients with type 2 diabetes, 810,390 were new semaglutide users, 326,282 were treated with dulaglutide, 25,936 with exenatide (Byetta, Bydureon), 715,802 with empagliflozin, 493,563 with sitagliptin, and 832,295 with glipizide.

Of the 43,620 new users of semaglutide in Optum’s de-identified Clinformatics Data Mart Database, 56% were ages 50 to 69, 61% were women, and 66% were white.

The authors noted that some of the databases did not include patients older than 65, which may have led to missing cases of NAION, since it often affects an older population.