medwireNews: Study findings suggest an increased risk for nonarteritic anterior ischemic optic neuropathy (NAION) with semaglutide treatment in people with type 2 diabetes, but not as great as previously reported.
Compared with other glucagon-like peptide (GLP)-1 receptor agonists and non-GLP-1 receptor agonists, new users of semaglutide had an increased risk for NAION compared with new users of the non-GLP-1 receptor agonist empagliflozin, but only when a specific, restrictive, definition of NAION was used, whereby two confirmatory ION diagnostic codes within 90 days were needed rather than just one.
There was also evidence, however, of an increased risk for NAION when semaglutide exposure versus no exposure was assessed in a self-controlled case series, irrespective of the definition used.
“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,” say the study authors in JAMA Ophthalmology.
After a previous single center study reported a 4.28-fold increase in the risk for NAION with semaglutide versus non-GLP-1 receptor agonists, Cindy Cai (Johns Hopkins School of Medicine, Baltimore, Maryland, USA) and colleagues analyzed 14 Observational Health Data Sciences and Informatics databases to clarify the potential association.
The study included 37.1 million individuals with type 2 diabetes, including 810,390 new semaglutide users, 326,282 new dulaglutide users, 25,936 new exenatide users, 715,802 new empagliflozin users, 493,563 new sitagliptin users, and 832,295 new glipizide users.
In a related comment, Joseph Rizzo (Harvard Medical School, Boston, Massachusetts, USA) and Jimena Hathaway (Harvard TH Chan School of Public Health, Boston, USA) observe that “[t]he sheer volume of data provide an opportunity to explore an uncommon event like NAION.” In a representative database, Optum’s deidentified Clinformatics Data Mart Database, 56% of the 43,620 new users of semaglutide were aged 50 to 69 years, and 61% were women.
Among new users of semaglutide, the incidence rate of NAION was 14.5 per 100,000 person–years using the sensitive one diagnostic code definition, which was shown to have a high sensitivity but lower positive predictive value than the two code definition (73 vs 33% and 71 vs 88%, respectively). Based on the latter definition, the NAION incidence rate was calculated to be 8.7 per 100,000 person–years.
In an active-comparator cohort analysis, using the sensitive definition for NAION the risk among semaglutide-treated individuals was not significantly different to that among patients using the GLP-1 receptor agonist dulaglutide, nor the non GLP-1 receptor agonists empagliflozin, sitagliptin, and glipizide. With the specific definition, the risk was significantly increased compared with empagliflozin, at a hazard ratio of 2.27, but not compared with the other treatments.
In a self-controlled case series analysis, the risk for NAION was significantly increased when 38,650 patients were taking semaglutide, with an incidence rate ratio (IRR) of 1.32 for the sensitive definition and 1.50 for the specific definition, compared with when they were not. For other GLP-1 receptor agonists, there was a significantly increased risk associated with exposure to exenatide in 36,132 patients but only for the specific definition (IRR=1.62) and there was no association with exposure to dulaglutide in 25,751 patients. “These nuanced findings might suggest that the potential association is not a class-wide effect,” note Rizzo and Hathaway.
Cai et al acknowledge that they were not able to distinguish between incident and prevalent cases of NAION, or access granular ophthalmic data, and say that “[a]dditional studies that incorporate ophthalmic risk factors or examine dose-dependent effects [...] are needed to investigate a potential causal relationship between semaglutide and NAION.”
Rizzo and Hathaway recommend that “patients should not stop taking semaglutide based on this account alone.” However, they “advise added caution for patients taking semaglutide or those who are considering starting this medication if they have experienced visual loss from any cause.”
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JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2024.6555
JAMA Ophthalmol 2025; doi:10.1001/jamaophthalmol.2025.0005