Clinical Context
As semaglutide prescriptions have surged for diabetes and obesity management, pharmacovigilance signals have emerged regarding potential ocular side effects. Nonarteritic anterior ischemic optic neuropathy (NAION) is a sudden, painless vision loss caused by infarction of the optic nerve head. It’s the most common cause of acute optic neuropathy in adults over 50 and typically leaves permanent visual field defects in the affected eye. There is no proven treatment.
NAION occurs when blood flow to the optic nerve head becomes insufficient, often in patients with crowded optic disc anatomy (“disc at risk”) combined with cardiovascular risk factors like hypertension, diabetes, hyperlipidemia, and sleep apnea. The mechanism is thought to involve nocturnal hypotension or other hemodynamic stresses that compromise already-marginal perfusion.
An earlier case series from Massachusetts Eye and Ear reported an association between GLP-1 receptor agonists and NAION, prompting concern. This large Danish registry study systematically examined whether semaglutide use increases NAION risk compared to non-use in a national cohort of over 400,000 patients with type 2 diabetes.
Study Summary (PICO Framework)
Summary:
In patients with type 2 diabetes in Denmark, once-weekly semaglutide exposure was associated with doubled five-year risk of nonarteritic anterior ischemic optic neuropathy (NAION) (HR 2.19) compared to non-exposure to semaglutide, though the absolute risk remains low and causality is not established.
| PICO | Description |
|---|---|
| Population | 424,152 persons with type 2 diabetes in Denmark (106,454 semaglutide-exposed, 317,698 unexposed). |
| Intervention | Semaglutide prescription (once-weekly formulation). |
| Comparison | No semaglutide exposure; sensitivity analyses included SGLT2 inhibitor users. |
| Outcome | Adjusted hazard ratio for NAION: 2.19 (p<0.001). Median time to NAION onset: 22.2 months after semaglutide initiation. |
Clinical Pearls
1. The relative risk increase is substantial, but absolute risk remains low. NAION is rare, with an estimated incidence of 2-10 per 100,000 annually in the general population. Even a doubling of risk in semaglutide users translates to a small absolute increase. For individual patient counseling, the absolute risk matters more than the relative risk.
2. This is an association, not proven causation. Registry studies cannot establish causality. Patients prescribed semaglutide may differ systematically from non-users in ways not captured by the data (e.g., more severe diabetes, higher cardiovascular risk). The study adjusted for confounders, but residual confounding is possible.
3. No clear mechanism has been identified. Proposed mechanisms include rapid improvement in glycemic control (similar to early worsening of diabetic retinopathy with intensive glucose lowering), hemodynamic effects from weight loss, or direct GLP-1 receptor effects on ocular vasculature. None are proven.
4. The median onset time of 22 months is notable. This suggests the risk is not immediate and may accumulate with continued use. It also complicates surveillance—patients would need long-term monitoring to detect this rare complication.
Practical Application
For most patients, benefits likely outweigh this risk. Semaglutide’s cardiovascular and metabolic benefits are well-established through randomized trials (SUSTAIN, PIONEER, SELECT). A rare, non-fatal ocular complication should be weighed against these substantial benefits. For most patients with type 2 diabetes or obesity, semaglutide remains an appropriate treatment option.
Consider individual risk factors: Patients with known “disc at risk” anatomy (small, crowded optic disc), prior NAION in the fellow eye, or multiple cardiovascular risk factors may warrant additional discussion. There is no validated tool to predict NAION risk, but awareness of the association allows informed consent.
Counsel patients to report visual symptoms: Advise patients to report any sudden, painless vision loss, visual field defects, or dimming of vision immediately. While NAION has no proven treatment, prompt evaluation is important to rule out other treatable causes and to document the event.
Do not routinely obtain baseline ophthalmology exams: Given the rarity of NAION, routine screening before semaglutide initiation is not warranted. However, patients with pre-existing optic nerve disease or prior NAION should have the risk-benefit discussion documented.
How This Study Fits Into the Broader Evidence
The initial signal came from a 2024 case-control study from Massachusetts Eye and Ear, which found a higher proportion of GLP-1 RA users among NAION cases compared to controls. This Danish registry study provides population-level data supporting the association, though with the inherent limitations of observational research.
The FDA has not issued formal warnings about NAION and semaglutide, and the drug’s labeling does not currently include this risk. The manufacturer (Novo Nordisk) has stated that clinical trials did not show a causal relationship. However, NAION is too rare to be reliably detected in typical clinical trials.
This finding parallels other rapid glycemic improvement concerns. Intensive insulin therapy in the DCCT trial transiently worsened diabetic retinopathy, suggesting that rapid metabolic changes can stress ocular microvasculature. Whether a similar mechanism applies to NAION with GLP-1 RAs is speculative.
Limitations to Consider
The study relied on registry diagnoses, which may have misclassification. Important confounders including smoking status, BMI, blood pressure control, and ophthalmic examination findings were not available. Prescription data doesn’t confirm actual medication adherence. The study cannot establish causality—only association. Results from Denmark may not generalize to other populations.
Bottom Line
This large Danish registry study found that semaglutide use was associated with approximately doubled risk of nonarteritic anterior ischemic optic neuropathy over five years. While concerning, the absolute risk remains low, and causality is not established. For most patients, semaglutide’s substantial metabolic and cardiovascular benefits likely outweigh this potential risk. Clinicians should include this information in risk-benefit discussions, particularly for patients with pre-existing optic nerve disease, and counsel patients to report any sudden visual changes promptly.
Source: Grauslund, J., et al. “Once-weekly semaglutide doubles the five-year risk of nonarteritic anterior ischemic optic neuropathy in a Danish cohort of 424,152 persons with type 2 diabetes.” International Journal of Retina and Vitreous, 2024;10:97. Read article here.
