Is semaglutide (glucagon-like peptide-1 receptor agonist) associated with an increased risk of blindness?

Semaglutide and Risk of Blindness: Current Evidence and Recommendations

Semaglutide does not directly cause blindness, but it has been associated with worsening of diabetic retinopathy in certain patients, particularly those with pre-existing retinopathy and when rapid glycemic control occurs. 1

Retinopathy Risk with Semaglutide

Evidence from Clinical Guidelines

• The American Diabetes Association (ADA) acknowledges that GLP-1 receptor agonists including semaglutide have been associated with worsening diabetic retinopathy in randomized trials 1
• In the SUSTAIN-6 trial, semaglutide was associated with an increase in diabetic retinopathy complications compared to placebo 1
• This effect is hypothesized to be related to rapid reduction in blood glucose and A1C levels rather than a direct toxic effect on the eye 1

Recent Research Findings

• A 2022 meta-analysis of 23 randomized trials involving 22,096 patients found that overall, semaglutide was not associated with increased diabetic retinopathy risk when all trials were combined (RR 1.14,95% CI 0.98-1.33) 2
• However, subgroup analysis showed increased risk compared with placebo (RR 1.24,95% CI 1.03-1.50) 2
• Higher risk was observed in:
  • Patients aged ≥60 years (RR 1.27,95% CI 1.02-1.59)
  • Patients with diabetes duration ≥10 years (RR 1.28,95% CI 1.04-1.58) 2

Emerging Concerns: NAION

Recent case reports and studies have raised concerns about a possible association between semaglutide and non-arteritic anterior ischemic optic neuropathy (NAION):

• A 2025 review found that in some studies, semaglutide was associated with 2-3 times higher relative rates of NAION compared to controls 3
• A case series reported 7 patients with NAION, 1 with bilateral papillitis, and 1 with paracentral acute middle maculopathy associated with semaglutide or tirzepatide use 4
• A case report described a 55-year-old female who developed NAION after four months of semaglutide therapy 5

Mechanism of Action

• GLP-1 receptor expression is low in normal human eyes and was not detected in eyes with advanced stages of proliferative diabetic retinopathy 6
• The retinopathy effect is likely related to rapid glycemic improvement rather than direct toxicity 1, 4
• Potential mechanisms for NAION may involve changes in perfusion leading to venous dilation and congestion during relative hypoglycemia 3

Recommendations for Clinical Practice

1. Assess retinopathy status before initiating semaglutide 1

   • Patients should undergo appropriate eye examinations before starting therapy if not completed within the last 12 months

2. Monitor for retinopathy during treatment

   • If any level of diabetic retinopathy is present, dilated retinal examinations should be performed at least annually 1
   • If retinopathy is progressing or sight-threatening, more frequent examinations are required 1

3. Consider patient risk factors

   • Exercise caution in patients with:
     • Pre-existing diabetic retinopathy
     • Age ≥60 years
     • Diabetes duration ≥10 years 2
     • Crowded optic discs (can be identified by optical coherence tomography) 3

4. Gradual glycemic control

   • Consider slower dose titration in patients with established retinopathy to avoid rapid A1C reduction 1

5. Patient education

   • Inform patients about potential vision changes and the importance of reporting any visual symptoms promptly

Conclusion

While semaglutide provides significant cardiovascular and glycemic benefits for patients with type 2 diabetes, clinicians should be aware of the potential risk of worsening retinopathy, particularly in high-risk patients. Proper screening, monitoring, and patient education are essential to minimize this risk. Recent concerns about NAION require further investigation, but suggest caution in patients with additional risk factors for optic nerve ischemia.