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The widening landscape of synthetic incretin treatment: possible association of ischaemic optic neuropathy risk and the need for a cautious approach

Eye volume 39, pages 1648–1649 (2025)Cite this article

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Gregory and Mollan have provided a comprehensive overview on the up-to-date deliberations in the literature [1]. The authors have drawn attention to the risk of non-arteritic anterior ischaemic optic neuropathy (NAION) with Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RA) and the renewed interest in this regard lately. They have rightly pointed out the significant metabolic and cardiovascular benefits for patients with type 2 diabetes mellitus (T2DM) as well as for those with obesity, given the overall low risk profile.

Whilst there is controversy between the possible association versus definite causation between GLP-1RA and NAION, the topic remains debatable for now. Nonetheless, a very recent disproportionality analysis was conducted utilising the United States Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). They assessed data from 01 January 2004 to 30 September 2024 and demonstrated a stronger association of NAION with semaglutide over the other GLP-1RA class of medications [2]. The Reporting Odds Ratios (ROR) and Proportional Reporting Ratios (PRR) were calculated to evaluate the association between GLP-1RA and NAION. Semaglutide demonstrated a significant ROR and PRR for NAION, implying a stronger association compared to other GLP-1RA. Indeed, the results of both these ROR and PRR analyses met the established thresholds for identifying a potential adverse drug reaction, signifying a feasible causal relationship between semaglutide and NAION, as informed in some of the other studies cited by Gregory and Mollan [1, 2]. They have suggested that semaglutide may influence vascular tone and endothelial function, potentially leading to NAION through vasoconstriction and reduced optic nerve perfusion [2]. Nevertheless, the authors have cautioned about interpreting the results of disproportionality analysis in isolation, as they cannot prove causation or measure incidence, as it relies on reported cases and it is not always plausible to determine whether an event was caused by the drug per se as opposed to other variables such as the underlying disease, other concomitant medications or by other drugs previously administered to these patients.

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References

  1. Gregory V, Mollan SP Are synthetic incretins associated with ischaemic optic neuropathy? Eye. 2025. https://doi.org/10.1038/s41433-025-03718-0.

  2. Azab M, Pasina L. Semaglutide: Nonarteritic Anterior Ischemic Optic Neuropathy in the FDA adverse event reporting system - A disproportionality analysis. Obes Res Clin Pract. 2025:S1871-403X(25)00017-1. https://doi.org/10.1016/j.orcp.2025.01.011.

  3. Azzam AY, Essibayi MA, Farkas N, Azab MA, Morsy MM, Elamin O, et al. Efficacy of Tirzepatide Dual GIP/GLP-1 Receptor Agonist in Patients With Idiopathic Intracranial Hypertension. A Real-World Propensity Score-Matched Study. Endocrinol Diabetes Metab. 2025;8:e70019. https://doi.org/10.1002/edm2.70019.

  4. Ray A, Paik JM, Wexler DJ, Sreedhara SK, Bykov K, Feldman WB et al. Glucose-lowering medications and risk of chronic obstructive pulmonary disease exacerbations in patients with type 2 diabetes. JAMA Intern Med. 2025:e247811. https://doi.org/10.1001/jamainternmed.2024.7811.

  5. Ilias I, Zabuliene L, Rizzo M. GLP-1 receptor agonists in diabetes and weight loss: the double-edged sword of innovation and risks. Front Clin Diabetes Health. 2025;5:1530811. https://doi.org/10.3389/fcdhc.2024.1530811.

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Authors and Affiliations

  1. University of Sheffield, School of Medicine and Population Health, Sheffield, South Yorkshire, UK

    Maria S. Varughese

  2. Department of Diabetes & Endocrinology, University Hospitals of North Midlands NHS Trust, Sheffield, UK

    Sushuma Kalidindi

  3. School of Medicine, Faculty of Health, Keele University, North Staffordshire, Sheffield, UK

    Sushuma Kalidindi

Authors
  1. Maria S. Varughese
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  2. Sushuma Kalidindi
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Contributions

MSV wrote the correspondence and reviewed the literature. SK conceptualised the theme, examined the evidence base, and revised the manuscript. MSV and SK contributed equally to this correspondence article.

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Correspondence to Sushuma Kalidindi.

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None – the authors declare that they have no conflict of interest. MSV is a medical student aspiring to pursue an intercalated MSc in Ophthalmology. SK is a Consultant Physician involved in treating patients with type 1 & type 2 diabetes mellitus and weight management in the outpatient bariatric endocrine clinic.

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Varughese, M.S., Kalidindi, S. The widening landscape of synthetic incretin treatment: possible association of ischaemic optic neuropathy risk and the need for a cautious approach. Eye 39, 1648–1649 (2025). https://doi.org/10.1038/s41433-025-03776-4

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