Can Glucagon-like peptide-1 (GLP-1) receptor agonists worsen macular degeneration?

GLP-1 Receptor Agonists and Macular Degeneration

GLP-1 receptor agonists do not worsen macular degeneration and may actually provide protective benefits against age-related macular degeneration (AMD) in patients with type 2 diabetes. The most recent high-quality evidence demonstrates risk reduction rather than disease progression.

Evidence for Protective Effects

The strongest and most recent evidence comes from a 2025 retrospective cohort study examining 600,816 matched patients with type 2 diabetes 1. This study found:

• 15% relative risk reduction in incident nonexudative AMD (RR 0.851; 95% CI, 0.801-0.905; p<0.0001) 1
• 20% relative risk reduction in incident exudative AMD (RR 0.80; 95% CI, 0.808-0.989; p<0.0001) 1

For patients with existing early or intermediate AMD, GLP-1 receptor agonists demonstrated even more pronounced benefits 1:

• 29% relative risk reduction in progression to advanced nonexudative AMD (RR 0.715; 95% CI, 0.529-0.967; p=0.028) 1
• 27% relative risk reduction in progression to exudative AMD (RR 0.729; 95% CI, 0.601-0.883; p=0.001) 1

Mechanisms of Retinal Protection

The neuroprotective effects are mediated through multiple pathways 2:

• Reduction of extracellular glutamate (preventing excitotoxicity) 2
• Activation of prosurvival signaling pathways 2
• Anti-inflammatory properties that protect against neurodegeneration 3, 1
• Promotion of neuronal survival in retinal tissue 1

Notably, these protective effects occur independently of blood glucose reduction, as demonstrated in experimental models where topical GLP-1 receptor agonists prevented retinal neurodegeneration without lowering systemic glucose levels 2.

Clinical Implications for Diabetic Retinopathy

While there is a modest association with incident diabetic retinopathy (7% increased risk; HR 1.07; 95% CI, 1.03-1.11), this must be contextualized 4:

• No increased risk of progression to proliferative diabetic retinopathy in patients with preexisting disease (HR 1.06; 95% CI, 0.97-1.15) 4
• Reduced sight-threatening complications including:
  • 26% reduction in vitreous hemorrhages (HR 0.74; 95% CI, 0.68-0.80) 4
  • 22% reduction in neovascular glaucoma (HR 0.78; 95% CI, 0.68-0.88) 4
  • 23% reduction in blindness (HR 0.77; 95% CI, 0.73-0.82) 4

The increased incident diabetic retinopathy risk is likely related to rapid hemoglobin A1c correction rather than direct drug toxicity 3, a phenomenon well-documented with any intensive glycemic control.

Practical Management Algorithm

For patients without macular degeneration:

• GLP-1 receptor agonists can be prescribed without concern for AMD development 1
• Standard age-appropriate ophthalmologic screening should continue 4

For patients with existing early or intermediate AMD:

• GLP-1 receptor agonists are preferred given the 27-29% risk reduction in progression to advanced disease 1
• Continue routine retinal monitoring as clinically indicated 4

For patients with diabetic retinopathy:

• GLP-1 receptor agonists should not be withheld due to retinopathy concerns 4
• Ensure regular ophthalmologic follow-up to monitor for any progression 3, 4
• The overall benefit-risk profile favors use given reduced sight-threatening complications 4

Important Caveats

The modest increase in incident diabetic retinopathy appears confined to the initial treatment period and is mechanistically linked to rapid glycemic improvement rather than direct retinal toxicity 3. This is similar to the early worsening phenomenon seen with intensive insulin therapy and should not preclude GLP-1 receptor agonist use in appropriate patients 4.

GLP-1 receptor agonists demonstrate protective effects against multiple retinal conditions including glaucoma and dry eye disease through anti-inflammatory mechanisms 3, 5, further supporting their favorable ocular safety profile.