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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as transformative agents in the management of type 2 diabetes mellitus and obesity [1,2]. Among them, semaglutide and tirzepatide have gained particular attention for its metabolic benefits and widespread uptake across clinical settings [1-3].
However, as prescribing rates soar, a new concern has emerged: could semaglutide increase the risk of non-arteritic anterior ischemic optic neuropathy (NAION)?
Understanding NAION
NAION is the most common acute optic neuropathy in individuals over 50 years of age [4]. It is thought to arise from hypoperfusion of the optic nerve head. Vision loss is typically painless, sudden, and often irreversible. Primary risk factors include small optic discs (‘disc-at-risk’), diabetes, hypertension, and obstructive sleep apnoea [4-5].
A potential pharmacologic trigger for NAION carries serious implications given (a) the severity of vision loss in this devastating condition and (b) the rapidly expanding population using GLP-1 RAs. Even a small, relative risk increase could translate into significant morbidity at the population level. While case reports and early observational data have suggested a possible association, the evidence base – and how we are interpreting it – is rapidly evolving.
What does the latest evidence suggest?
Concern over semaglutide’s potential link to NAION gained momentum after a single-centre study from the Massachusetts Eye and Ear Infirmary. Hathaway, et al. reviewed six years of neuro-ophthalmology records and found a markedly increased risk of NAION in semaglutide users compared to matched controls – with hazard ratios (HRs) over four in patients with diabetes and over seven in those prescribed semaglutide for obesity [6]. Though retrospective and limited to one centre, the study’s rigorous design and large effect sizes catalysed broader investigation. Several large-scale studies followed.
Hsu, et al. analysed data from over 3.3 million patients in the TriNetX network [7]. They found no increased NAION risk at short-term follow-up (one, three, six or 12 months), but a significant rise in risk at 2–4 years, with HRs between 2.05–2.44. Limitations included a lack of data on diabetes duration, retinopathy, and confirmed optic disc features.
Grauslund, et al., using Danish national data, found a similar pattern: semaglutide use was associated with more than double the five-year risk of NAION (adjusted HR 2.19) [8]. Sensitivity analyses excluding patients with diabetic retinopathy or prior GLP-1 RA use supported the finding. While the absolute risk of NAION remained low, the authors noted the implications given semaglutide’s widespread use.
In contrast, other studies have found no significant association. Abbass, et al. conducted a large, matched cohort study using TriNetX, evaluating over 120,000 patients with type 2 diabetes and 58,000 overweight patients prescribed semaglutide [9]. Across all groups, they found no increased five-year risk of NAION or ischemic optic neuropathy. Similarly, Klonoff, et al. conducted seven real-world cohort analyses across institutional and national datasets; while early signals were observed, they disappeared after adjusting for comorbidities and healthcare utilisation [10].
The most extensive analysis to date was published by Cai, et al., who used data from 37 million adults across 14 countries in the Observational Health Data Sciences and Informatics network [11]. They found a small but statistically significant increase in NAION risk with semaglutide, though the magnitude of risk was lower than earlier studies. The authors highlighted persistent limitations, including reliance on diagnostic coding, lack of ophthalmic diagnostic confirmation, and residual confounding by diabetes severity and duration.
Clinical implications and takeaways for ophthalmologists
Should clinicians be concerned? The short answer is not yet but stay alert. While some large-scale studies suggest a delayed yet modest increase in risk of NAION among semaglutide users, these findings remain observational and must be carefully weighed against semaglutide’s clear benefits in reducing cardiovascular and renal morbidity and mortality.
Closer monitoring may be warranted in patients with known risk factors – such as prior NAION, crowded discs and optic disc drusen, or poorly controlled vascular disease. Patient counselling should be nuanced: reassure the majority but discuss symptoms to watch for and consider baseline optic disc examination where appropriate.
Looking ahead
Further prospective studies to explore causality are urgently needed. Ideally, these would incorporate detailed disease phenotyping, longer follow-up, and imaging-based confirmation of NAION diagnoses. In the meantime, a balanced, pragmatic approach is warranted. Though prescribing semaglutide remains the domain of our medical colleagues, ophthalmologists have a key role to play in: staying vigilant for early signs of NAION, educating at-risk patients, and contributing to surveillance as new evidence emerges.
References
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2. Pratley RE, Aroda VR, Lingvay I, et al. Semaglutide versus dulaglutide once weekly in patients with type 2 diabetes (SUSTAIN 7): a randomised, open-label, phase 3b trial. Lancet Diabetes Endocrinol 2018;6(4):275–86.
3. Hjerpsted JB, Flint A, Brooks A, et al. Semaglutide improves postprandial glucose and lipid metabolism, and delays first‐hour gastric emptying in subjects with obesity. Diabetes Obes Metab 2018;20(3):610–9.
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5. Hayreh SS. Ischaemic optic neuropathy. Prog Retin Eye Res 2009;28(1):34–62.
6. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of nonarteritic anterior ischaemic optic neuropathy in patients prescribed semaglutide. JAMA Ophthalmol 2024;142(8):732–9.
7. Hsu AY, Kuo H, Wang Y, et al. Semaglutide and NAION risk among patients with diabetes. JAMA Ophthalmol 2025;143(5):400–7.
8. Grauslund J, Taha AA, Molander LD, et al. Once-weekly semaglutide doubles five-year NAION risk in a Danish cohort. Int J Retin Vitr 2024;10:97.
9. Abbass NJ, Nahlawi R, Shaia JK, et al. Effect of semaglutide and GLP-1 RAs on NAION risk. Am J Ophthalmol 2025;274:24–31.
10. Klonoff DC, Hui G, Gombar S. Real-world evidence on NAION risk in semaglutide users. J Diabetes Sci Technol 2024;18(6):1517–8.
11. Cai CX, Hribar M, Baxter S, et al. Semaglutide and NAION. JAMA Ophthalmol 2025;143(4):304–14.
Declaration of competing interests: None declared.
