Re-examining the putative association between GLP-1 receptor agonists and nonarteritic anterior ischemic optic neuropathy

Introduction

Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common acute optic neuropathy in patients over the age of 50 years (1). It is characterized by acute, painless vision loss in one eye which is often noticed upon awakening. Commonly, there is an altitudinal visual field defect, though this can be variable (1). On examination, at onset, there is optic disc edema in the affected eye, which can be sectoral, that typically resolves over six weeks resulting in optic disc pallor (1). There is a 20% risk of fellow eye involvement over time. The estimated incidence of NAION is 2.3 to 10.2 per 100,000 (2,3). The pathophysiology of NAION is not fully understood and a crowded optic disc, vascular risk factors, obstructive sleep apnea, and systemic hypoperfusion are thought to play a role in contributing to microvascular injury and optic nerve infarction (1-5). However, the strongest risk factor is the small cup-to-disc ratio (“disc-at-risk”). Despite efforts to find a treatment, including topical, intravitreal, and oral medications, as well as surgical attempts to decompress the optic nerve, there is no known effective treatment (1). Because there is no known proven treatment, optimization of vascular risk factors is recommended, and attempts should be made to diminish any potential modifiable risk factors, including associated medications (1). The mechanism of medication-induced optic neuropathies is controversial, and it is unclear whether this represents causation versus association. Most recently, there has been a study suggesting a potential association between glucagon-like peptide-1 receptor agonists (GLP-1RAs) and NAION (6). This editorial commentary examines the advances in GLP-1RAs and discusses the evidence for and against the possible association with NAION.

The advent of GLP-1RAs

GLP-1RAs have been a topic of avid interest since the discovery of GLP-1 in 1983 (7). The first GLP-1RA was approved for type 2 diabetes mellitus (T2DM) in 2017, with a rapid increase in prescribing patterns over time (8). There are currently multiple GLP-1RA formulations available, which are administered orally or subcutaneously. Some examples include semaglutide, liraglutide, and dulaglutide (7,8). After binding to the GLP-1 receptor, a downstream cascade is triggered with activation of the cAMP-PKA pathway, and eventual release of insulin into the blood stream (7). Not only has this new drug class been an important addition in the therapeutic armamentarium for T2DM and obesity, which are current approved indications, but there is also potential benefit in a multiplicity of other conditions currently being investigated (7,8). The wide distribution of the GLP-1 receptor in many tissues, including the human eye, introduces the possibility of direct multi-system effects, indirect effects via altered metabolism, as well as pleiotropic effects (7-9). In the context of optimizing cardiovascular health, in addition to lowering glucose, GLP-1RAs may have positive effects in atherosclerosis and hypertension, though mechanisms of action have not been fully elucidated (7,8). Outside of the cardiovascular system, the possible neuroprotective effects of GLP-1RAs are also being investigated in the setting of stroke, idiopathic intracranial hypertension, and degenerative processes such as Alzheimer’s and Parkinson’s disease (7,8,10). However, amidst the many benefits of GLP-1RAs, recent attention has been drawn to the possible association between their use and increased risk of NAION (6).

Commentary

A recent retrospective matched cohort study by Hathaway et al. investigated the possible association of the GLP-1RA, semaglutide, and NAION in a neuro-ophthalmology practice at a single tertiary care center (6). Patients diagnosed with NAION by neuro-ophthalmologists over a 6-year period were included in the study. Patients who were prescribed semaglutide for T2DM and obesity were analyzed separately and compared to matched cohorts not on a GLP-1RA. The authors found that semaglutide prescription was associated with increased risk of NAION in both the T2DM cohort [hazard ratio (HR), 4.28; 95% confidence interval (CI): 1.62–11.29; P<0.001] and the obesity cohort (HR, 7.64; 95% CI: 2.21–26.36; P<0.001). The reported cumulative incidence of NAION was 8.9% in the group on semaglutide and 1.8% in the group not on a GLP-1RA (6).

While this study raises the concern for an association between NAION and GLP-1RAs, there are some limitations that need to be addressed. This study included patients based on referrals to a single sub-specialized neuro-ophthalmic practice. Therefore, this patient population differs significantly from other practices, which limits generalizability of the results (11). Additionally, as highlighted by the authors, the retrospective study design and relatively small sample size with a low number of outcome events need to be considered when interpreting the data (6).

In this study by Hathaway et al., the highest risk for NAION was found to be within the first year of starting semaglutide (6). This should be interpreted cautiously and should not be mistaken for temporal association equaling causation as this coincides with the period when glycemic control (and possibly other vascular risk factors affected by GLP-1RAs) are least controlled (12). Furthermore, important variables were matched between comparison groups, including demographics, comorbidities (hypertension, T2DM, obstructive sleep apnea, hyperlipidemia, and coronary artery disease), contraindications to semaglutide, and use of drugs previously associated with NAION (including amiodarone and phosphodiesterase-5 inhibitors) (6). However, additional potentially confounding factors which were not controlled for include hemoglobin A1c, insulin use, diabetes duration, and body mass index (13). Given GLP-1RAs are prescribed in more severe diabetes and obesity, markers of severity would be important to consider as this could be a confounding factor. Additionally, while patients in the study were stratified based on indication for GLP-1RA use (T2DM versus obesity), it is important to consider contamination between groups, with some patients having both T2DM and obesity being mixed into either cohort (13). Lastly, it would also be important to control for morphological cup-to-disc differences between the groups, as a crowded nerve is the most important known risk factor for NAION (11). If patients in the semaglutide group did not have a small cup-to-disc ratio, this could provide further indirect evidence that semaglutide played a causative role in increasing the risk of NAION.

It remains unclear whether there is truly an association between GLP-1RAs and NAION. Nonetheless, this study has provoked more questions and has been a catalyst for further research. In a recent study which performed seven retrospective real-world matched cohort analyses of patients on GLP-1RAs using a dataset of 66 million patients, there was no significant increase of NAION (14). In another real-world study using the TriNetX Network looking at the association of semaglutide and NAION in a large global population, no increased risk was found (13). Conversely, a recent preprint Danish-Norwegian cohort study found an increased risk of NAION in patients using semaglutide for diabetes compared to sodium-glucose co-transporter 2 (SGLT-2) inhibitors (15). The authors reported a pooled hazard ratio of 2.81 (95% CI: 1.67–4.75) and absolute risk increase of +1.41 (95% CI: 0.53–2.29), recognizing the absolute risk is low. This study is limited by a small event rate (32 total NAION cases binationally) and lack of diagnostic code specificity with inability to filter out cases of arteritic anterior ischemic optic neuropathy in the Norway cohort (15). Further, there have been multiple randomized clinical trials looking at GLP-1RAs for T2DM or obesity, the large majority of which did not report cases of NAION (16-21). In one meta-analysis looking at serious adverse effects of GLP-1RAs in 69 randomized clinical trials, 64 did not report any cases of NAION. A total of eight NAION cases were described in the remaining five trials, versus four cases in the comparator arm. Overall, the meta-analysis did not detect a significant risk of NAION with GLP-1RA use (21). Additionally, using the Observational Health Data Sciences and Informatics (OHDSI) network, a recent retrospective study across 14 databases was performed, which included 37.1 million patients with T2DM, which found a small, but statistically significant increase in NAION in the semaglutide group, with an incidence rate ratio of 1.32 (95% CI: 1.14–1.54, P<0.001) and 1.50 (95% CI: 1.26–1.79, P<0.001) depending on the definition of NAION used (22). Overall, based on the results of this larger study with greater heterogeneity and improved generalizability, there may be a small magnitude increased risk of NAION in semaglutide users, though, if present, may be much smaller than described by Hathaway et al. (22).

Possible pathophysiology

If there is an association between GLP-1RA use and increased risk of NAION, the mechanism is unclear. Given the cardioprotective and suspected neuroprotective benefits of GLP-1RAs, it seems paradoxical (7,8). Systemic (and specifically nocturnal) hypotension may play a role especially as other blood pressure lowering medications, such as phosphodiesterase-5 inhibitors, may be associated with NAION (3,5). Anorexia, which is a side effect of GLP-1RAs, and subsequent dehydration could exacerbate systemic hypoperfusion and contribute to the possible risk of NAION after starting a GLP-1RA, though this is often a transient side effect, and not universally experienced by patients (8,23).

Another possible contributing factor may involve poorly understood early microvascular sequela of aggressive glycemic control. In SUSTAIN-6, a randomized controlled trial looking at cardiovascular safety in patients treated with semaglutide versus placebo, there was worse diabetic retinopathy seen in semaglutide users (16). It remains unclear whether this is by virtue of rapid tightening of glycemic control, which has been reported to worsen diabetic retinopathy in patients with type 1 diabetes, or possibly a direct effect of semaglutide, with further research in progress (24). In the Diabetes Control and Complications Trial, a multi-center trial looking at 1,441 patients with type 1 diabetes, there was upfront worsening of retinopathy within the first year in patients treated aggressively with insulin compared to the conventional therapy group. However, the intensive therapy group had better outcomes at 8–9 years in comparison to their conventional treatment group counterparts, echoing the known benefit of long-term glycemic control (24). The implications of rapid improvement in glycemic control have also been seen in treatment-induced neuropathy, whereby diabetic neuropathy can initially worsen with aggressive glycemic control, suggesting possible microvascular and inflammatory changes in the short term (25).

Conclusions

There remain many unanswered questions about the role of GLP-1RAs in NAION. What is known is that better control of vascular risk factors long term is protective for multiple organ systems. GLP-1RAs, such as semaglutide, can be helpful in diabetes management and have additional cardioprotective properties (7). Whether there is a small risk of semaglutide contributing to development of NAION requires further research. If there is a true association, it is a small risk and it is unclear whether this is semaglutide-specific or a class effect and whether a dose response exists. NAION is a multi-factorial process, with anatomy playing a role, along with other incompletely understood risk factors. As with all medications affecting blood pressure and glycemic index, an individualized risk-benefit analysis will need to be considered and patients should be counseled on the possible small risk of NAION to help make informed decisions when initiating medications such as GLP-1RAs. Future studies are required to confirm a potential causal relationship between GLP-1RAs and NAION. However, at this time, we believe the benefits of GLP-1RAs likely outweigh the small possible increased risk of NAION in most patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Eye Science. The article has undergone external peer review.

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-38/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-38/coif). The authors have no conflicts of interest to declare.

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References

1. Berry S, Lin WV, Sadaka A, et al. Nonarteritic anterior ischemic optic neuropathy: cause, effect, and management. Eye Brain 2017;9:23-8. [Crossref] [PubMed]
2. Kupersmith MJ, Fraser CL, Morgenstern R, et al. Ophthalmic and Systemic Factors of Acute Nonarteritic Anterior Ischemic Optic Neuropathy in the Quark207 Treatment Trial. Ophthalmology 2024;131:790-802. [Crossref] [PubMed]
3. Foster RC, Bhatti MT, Crum OM, et al. Reexamining the Incidence of Nonarteritic Anterior Ischemic Optic Neuropathy: A Rochester Epidemiology Project Study. J Neuroophthalmol 2024;44:337-41. [Crossref] [PubMed]
4. Arnold AC. Pathogenesis of nonarteritic anterior ischemic optic neuropathy. J Neuroophthalmol 2003;23:157-63. [Crossref] [PubMed]
5. Hayreh SS, Zimmerman MB, Podhajsky P, et al. Nonarteritic anterior ischemic optic neuropathy: role of nocturnal arterial hypotension. Arch Ophthalmol 1997;115:942-5. [Crossref] [PubMed]
6. Hathaway JT, Shah MP, Hathaway DB, et al. Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. JAMA Ophthalmol 2024;142:732-9. [Crossref] [PubMed]
7. Zhao X, Wang M, Wen Z, et al. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol (Lausanne) 2021;12:721135. [Crossref] [PubMed]
8. Wojtara M, Mazumder A, Syeda Y, et al. Glucagon-Like Peptide-1 Receptor Agonists for Chronic Weight Management. Adv Med 2023;2023:9946924. [Crossref] [PubMed]
9. Hebsgaard JB, Pyke C, Yildirim E, et al. Glucagon-like peptide-1 receptor expression in the human eye. Diabetes Obes Metab 2018;20:2304-8. [Crossref] [PubMed]
10. Mitchell JL, Lyons HS, Walker JK, et al. The effect of GLP-1RA exenatide on idiopathic intracranial hypertension: a randomized clinical trial. Brain 2023;146:1821-30. [Crossref] [PubMed]
11. Singh AK, Kesavadev J, Tiwaskar M. Nonarteritic Anterior Ischemic Optic Neuropathy and Semaglutide: What is This All About? J Assoc Physicians India 2024;72:11-2. [PubMed]
12. Xie JS, Trobe J, Margolin E. Considerations Regarding Association of Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy. JAMA Ophthalmol 2024;142:1174. [Crossref] [PubMed]
13. Chou CC, Pan SY, Sheen YJ, et al. Association between Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy: A Multinational Population-Based Study. Ophthalmology 2025;132:381-8. [Crossref] [PubMed]
14. Klonoff DC, Hui G, Gombar S. Real-World Evidence Assessment of the Risk of Nonarteritic Anterior Ischemic Optic Neuropathy in Patients Prescribed Semaglutide. J Diabetes Sci Technol 2024;18:1517-8. [Crossref] [PubMed]
15. Simonsen E, Lund LC, Ernst MT, et al. Use of semaglutide and risk of non-arteritic anterior ischemic optic neuropathy: A Danish-Norwegian cohort study. Diabetes Obes Metab 2025; Epub ahead of print. [Crossref] [PubMed]
16. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016;375:1834-44. [Crossref] [PubMed]
17. Aroda VR, Rosenstock J, Terauchi Y, et al. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care 2019;42:1724-32. [Crossref] [PubMed]
18. Wilding JPH, Batterham RL, Calanna S, et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med 2021;384:989-1002. [Crossref] [PubMed]
19. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023;389:2221-32. [Crossref] [PubMed]
20. Knop FK, Aroda VR, do Vale RD, et al. Oral semaglutide 50 mg taken once per day in adults with overweight or obesity (OASIS 1): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023;402:705-19. [Crossref] [PubMed]
21. Silverii GA, Pala L, Cresci B, et al. Glucagon-like peptide 1 (GLP1) receptor agonists and risk for ischemic optic neuropathy: A meta-analysis of randomised controlled trials. Diabetes Obes Metab 2025;27:1005-9. [PubMed]
22. Cai CX, Hribar M, Baxter S, et al. Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy. JAMA Ophthalmol 2025;e246555. [Crossref] [PubMed]
23. Feldman-Billard S. Considerations Regarding Association of Semaglutide and Nonarteritic Anterior Ischemic Optic Neuropathy. JAMA Ophthalmol 2024;142:1174-5. [Crossref] [PubMed]
24. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. Arch Ophthalmol 1995;113:36-51. [Crossref] [PubMed]
25. Diaz LA, Gupta V. Diabetic Amyotrophy. [Updated 2023 Aug 14]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. Available online: https://www.ncbi.nlm.nih.gov/books/NBK560491/