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Use of the GLP-1 receptor agonist semaglutide (Ozempic, Wegovy) may be linked with an increased risk of the second most common form of optic neuropathy, a retrospective study suggested.

Over a mean follow-up of nearly 3 years, patients with diabetes on semaglutide had more than a fourfold higher risk for developing nonarteritic anterior ischemic optic neuropathy (NAION) compared with patients not on a GLP-1 agonist (HR 4.28, 95% CI 1.62-11.29, P<0.001), reported Joseph Rizzo III, MD, of Massachusetts Eye and Ear and Harvard Medical School in Boston, and colleagues.

Those prescribed semaglutide for overweight or obesity had an over sevenfold higher risk for NAION (HR 7.64, 95% CI 2.21-26.36, P<0.001), a significant cause of blindness, they wrote in .

Over 3 years, the cumulative incidence of NAION were 8.9% and 6.7% in the two semaglutide groups, respectively, versus 1.8% and 0.8% for the non-GLP-1 groups.

"Despite evidence of neuroprotective properties, expression of the GLP-1 receptor in the human optic nerve and GLP-1 [receptor agonist] RA-induced enhanced sympathetic nervous system activity might influence optic nerve head perfusion and potentially increase the risk of NAION," suggested Rizzo and co-authors.

As with any drug, they said, "therapeutic benefits are inseparable from adverse effects," and prior research has linked semaglutide with higher risks of retinopathy exacerbation, progression of proliferative retinopathy, and new-onset macular edema. But this is the first time semaglutide has been linked to NAION, according to the researchers.

In an , Susan Mollan, MBcHB, of the University Hospitals Birmingham NHS Foundation Trust in England, posed the question: "Could rapid normalization of the cardiometabolic system by GLP-1 RAs be the cause rather than a direct adverse effect of the drug?"

"It has long been observed that tight glycemic control can worsen diabetic retinopathy in the short term in some, however, this is outweighed by the long-term systemic benefits," she wrote, adding that any potential NAION risk shouldn't deter the appropriate use of GLP-1 agonists for diabetes or obesity at this time.

"This evidence mandates (1) further data-driven research to confirm or refute the strength of this association; (2) mechanistic studies to determine biological plausibility; and (3) clear dialogue with our endocrinology and primary care physician colleagues," said Mollan.

The researchers agreed, suggesting the "best approaches to confirm, refute, or refine our 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."

The matched cohort study from Rizzo's team used data from 16,827 neuro-ophthalmic patients at Massachusetts Eye and Ear from December 2017 to November 2023 who had no NAION diagnosis before December 2017.

Of the 710 patients with type 2 diabetes (median 59 years; 52% female), 194 were on semaglutide and 516 were on a non-GLP-1 antidiabetic (e.g., insulin, metformin, sulfonylureas, α-glucosidase inhibitors, thiazolidinediones, DPP-4 inhibitors, SGLT2 inhibitors).

Among the 979 patients with overweight or obesity (median 47 years; 72% female), 361 were on semaglutide and 618 were prescribed a non-GLP-1 weight-loss medication (e.g., bupropion, naltrexone, orlistat, topiramate, phentermine, setmelanotide).

A 1:2 propensity score-matched analysis showed 17 NAION events (10%) with semaglutide compared with six (3%) with the non-GLP-1 medications among the group with type 2 diabetes and 20 events (8%) versus three (1%), respectively, for the group with overweight/obesity.

NAION cases were derived from electronic health records listing the ICD-10 code for ischemic optic neuropathy plus a text search with the terms "NAION" or "nonarteritic anterior ischemic optic neuropathy" as there is no specific ICD-10 code for NAION. This could make sifting through extremely large databases difficult in future studies, noted Rizzo and colleagues.

Limitations to the findings included that researchers could not assess whether all patients took the drugs as prescribed, the cohorts were composed of relatively small percentages of non-white patients, and since their specialized care center sees a large proportion of the region's NAION cases, these findings may not be fully generalizable to other settings.

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