What are the recommendations for managing a patient with a history of Non-Arteritic Anterior Ischemic Optic Neuropathy (NAION) who is taking Glucagon-Like Peptide-1 (GLP-1) receptor agonists, such as liraglutide (Victoza), semaglutide (Ozempic), or dulaglutide (Trulicity), for diabetes management?

NAION and GLP-1 Receptor Agonists: Clinical Management Recommendations

Primary Recommendation

For patients with a history of NAION, GLP-1 receptor agonists (semaglutide, liraglutide, tirzepatide) should be avoided or used with extreme caution only when cardiovascular or metabolic benefits clearly outweigh the potential risk of vision loss, with mandatory baseline and ongoing ophthalmologic monitoring. 1, 2, 3

Evidence Summary and Risk Assessment

Emerging Association Between GLP-1 RAs and NAION

The relationship between GLP-1 receptor agonists and NAION remains controversial but concerning:

• Case reports document temporal associations between semaglutide initiation and NAION development, with symptom onset occurring within 4-14 months of treatment initiation in patients with diabetes and obesity 1, 2, 3

• Retrospective cohort data from neuro-ophthalmology clinics show NAION rates 4.28 times higher in patients with type 2 diabetes and 7.64 times higher in patients with obesity treated with semaglutide compared to other agents 3

• Large healthcare registry studies show conflicting results: two of four studies covering >100,000 patients found relative rates of NAION 2-3 times higher with semaglutide, while others showed non-significant trends 3

• A 2025 retrospective cohort study found GLP-1 RAs associated with modestly increased incident diabetic retinopathy (HR 1.07,95% CI 1.03-1.11) but no statistically significant increase in NAION (HR 1.26,95% CI 0.94-1.70) 4

Proposed Mechanisms

The pathophysiology may involve:

• Rapid glycemic reduction causing early worsening of retinopathy and optic nerve ischemia, proportional to the antihyperglycemic potency of the agent 3

• Perfusion changes leading to venous dilation and congestion during relative hypoglycemia, particularly in patients with small, crowded optic discs 3

• Delayed gastric emptying and vascular effects that may compromise optic nerve blood flow 1

Clinical Decision Algorithm for Patients with Prior NAION

Absolute Contraindications to GLP-1 RA Use

• Personal history of NAION in either eye - the risk of fellow eye involvement is unacceptably high given emerging evidence 1, 2, 3

• Crowded optic discs ("disc-at-risk" characteristics) identified on optical coherence tomography, which predispose to NAION 3

• Concurrent optic disc edema or peripapillary exudation on baseline examination 3

Relative Contraindications Requiring Specialist Consultation

• Small optic disc cup-to-disc ratio (<0.2), which increases anatomical risk for NAION 3

• Multiple vascular risk factors including hypertension, hyperlipidemia, and sleep apnea in combination with diabetes 1, 2

• Recent rapid glycemic changes or HbA1c >9% requiring aggressive glucose lowering 3

When GLP-1 RAs Might Be Considered Despite NAION History

Only proceed if ALL of the following criteria are met:

1. Established cardiovascular disease where semaglutide provides proven 20% reduction in cardiovascular death, nonfatal MI, or stroke (HR 0.80) 5

2. No anatomical disc-at-risk features confirmed by ophthalmology with OCT imaging 3

3. Patient fully informed of the potential vision-threatening risk and provides documented consent 2, 6

4. Alternative therapies inadequate - SGLT2 inhibitors, metformin, and other agents cannot achieve necessary glycemic or cardiovascular goals 7

Mandatory Monitoring Protocol If GLP-1 RA Initiated

Pre-Treatment Ophthalmologic Evaluation

• Comprehensive dilated fundus examination with optic disc assessment for crowding, cup-to-disc ratio, and disc edema 3

• Optical coherence tomography (OCT) of the optic nerve head to document baseline disc characteristics and rule out subclinical edema 1, 2, 3

• Humphrey visual field testing to establish baseline and detect early scotomas 1, 2

• Fluorescein angiography if any concern for baseline vascular compromise 1

Ongoing Monitoring Schedule

• Ophthalmologic examination every 3 months for the first year after GLP-1 RA initiation, then every 6 months thereafter 2, 3

• Immediate ophthalmology referral for any visual symptoms including blurred vision, visual field defects, or decreased color vision 1, 2

• OCT imaging every 6 months to monitor for optic disc changes 1, 2

Warning Signs Requiring Immediate GLP-1 RA Discontinuation

• Any new visual symptoms including blurred vision, scotomas, or decreased visual acuity 1, 2

• Optic disc edema on examination or OCT 1, 2

• Visual field defects on Humphrey testing, particularly inferior altitudinal defects characteristic of NAION 1, 2

• Rapid glycemic changes with HbA1c dropping >2% within 3 months 3

Alternative Treatment Strategies

Preferred Alternatives for Patients with NAION History

For Type 2 Diabetes with Cardiovascular Disease:

• SGLT2 inhibitors provide cardiovascular and renal benefits without the ocular risks associated with GLP-1 RAs, with proven reduction in heart failure hospitalization 7

• Metformin remains first-line with established safety profile 7

• Pioglitazone offers cardiovascular benefits and robust HbA1c reduction without gastrointestinal or ocular side effects, though carries risks of weight gain and edema 7

For Obesity Management:

• Metabolic surgery should be strongly considered for patients with BMI ≥35 kg/m² or ≥30 kg/m² with comorbidities, as it provides superior weight loss without medication-related ocular risks 5

• Intensive lifestyle modification with structured programs, 500-kcal deficit diet, and minimum 150 minutes/week physical activity 5

• Naltrexone-bupropion achieves 3.01% weight reduction with different side effect profile, though less effective than GLP-1 RAs 5

If GLP-1 RA Previously Tolerated But NAION Develops

• Immediately discontinue the GLP-1 RA upon any visual symptoms or confirmed NAION diagnosis 2

• Initiate corticosteroid therapy in consultation with ophthalmology, though efficacy for NAION is limited 1, 2

• Optimize glycemic control with alternative agents to prevent further vascular complications 1

• Do not switch to another GLP-1 RA - the class effect likely applies to all agents including liraglutide, semaglutide, and tirzepatide 2, 3

Critical Clinical Pitfalls to Avoid

• Do not assume clinical trial safety data are definitive - meta-analyses of GLP-1 RA trials found no significant NAION signal, but trials were not powered to detect rare ocular events and follow-up may have been insufficient 3

• Do not continue GLP-1 RA therapy after visual symptoms develop - case reports show progressive visual deterioration with continued use 2

• Do not rely solely on patient-reported symptoms - proactive ophthalmologic screening is essential as early NAION may be asymptomatic 3

• Do not prescribe GLP-1 RAs for weight loss alone in patients with NAION history when safer alternatives exist - the risk-benefit ratio is unfavorable 2, 6

• Do not overlook the importance of baseline optic disc assessment - crowded discs can be identified with OCT and represent a modifiable risk factor 3

Shared Decision-Making Framework

When considering GLP-1 RAs in patients with NAION history, document discussion of:

• The emerging but not definitively proven association between GLP-1 RAs and NAION, with rates potentially 2-7 times higher than background 3

• The irreversible nature of vision loss from NAION, with limited treatment options once it occurs 1, 2

• Alternative therapeutic options that provide metabolic benefits without the same ocular risk profile 7

• The mandatory monitoring requirements and patient commitment to regular ophthalmologic follow-up 3

• The need for immediate medication discontinuation if any visual symptoms develop 2