Can Glucagon-like peptide-1 (GLP-1) receptor agonists, such as liraglutide (generic name) or semaglutide (generic name), be used to treat macular degeneration?

GLP-1 Receptor Agonists and Macular Degeneration

GLP-1 receptor agonists are NOT used to treat macular degeneration and have no established role in its management. The provided evidence addresses diabetic retinopathy, not age-related macular degeneration (AMD), which are distinct disease entities with different pathophysiology.

Key Distinction: Diabetic Retinopathy vs. Macular Degeneration

The evidence exclusively discusses diabetic retinopathy (a microvascular complication of diabetes affecting the retina) rather than macular degeneration (typically age-related degeneration of the macula). These are fundamentally different conditions 1.

GLP-1 RAs and Diabetic Retinopathy: What the Evidence Shows

Cardiovascular Benefits in Diabetes

• Liraglutide, semaglutide, and dulaglutide are recommended in patients with type 2 diabetes and cardiovascular disease to reduce cardiovascular events 1.
• These agents reduce major adverse cardiovascular events (MACE) by approximately 12% in meta-analyses 1.

Retinopathy Risk Profile

The relationship between GLP-1 RAs and diabetic retinopathy is nuanced and requires careful consideration:

• GLP-1 RAs including liraglutide, semaglutide, and dulaglutide have been associated with a risk of mildly worsening diabetic retinopathy in randomized trials 1.
• Meta-analysis showed no association between GLP-1 RA treatment and retinopathy per se, except through rapid A1C reduction at 3-month and 1-year follow-up 1.
• Retinopathy status should be assessed when intensifying glucose-lowering therapies using GLP-1 RAs, since rapid reductions in A1C can be associated with initial worsening of retinopathy 1.

Conflicting Evidence on Retinopathy Risk

The evidence presents both sides:

Increased Risk Signal:

• Subcutaneous semaglutide showed increased relative risk for retinopathy (RR = 1.73; 95% CI: 1.10-2.71) in cardiovascular outcome trials 2.
• Risk appears predominantly with A1C decreases >1.0% and treatment duration >1 year 2.
• Case reports document new-onset diabetic retinopathy and diabetic macular edema following GLP-1 RA initiation 3.

No Increased Risk:

• A large retrospective cohort study (6,093 GLP-1 RA users vs. 14,122 controls) found no difference in progression to vision-threatening diabetic retinopathy (HR = 1.02,95% CI: 0.92-1.14) 4.
• The number needed to harm for worsening retinopathy was 1000 for the GLP-1 RA class overall, compared to number needed to treat of 77 for MACE prevention 2.

Preclinical Neuroprotective Effects

• Topical and systemic GLP-1 receptor agonists prevented retinal neurodegeneration in experimental diabetes models through reduction of extracellular glutamate and activation of prosurvival signaling pathways 5.
• GLP-1 receptors are abundantly expressed in human retina 5.
• These neuroprotective effects occurred independent of blood glucose reduction 5.

Clinical Implications for Diabetic Retinopathy

If a patient with diabetes requires GLP-1 RA therapy:

1. Perform dilated retinal examination before initiating therapy to establish baseline retinopathy status 1.

2. Monitor retinopathy status closely when intensifying therapy, particularly in patients with:

   • Established diabetic retinopathy at baseline 1
   • Anticipated rapid A1C reduction (>1.0%) 2
   • Treatment duration exceeding 1 year 2

3. The cardiovascular benefits typically outweigh retinopathy risks (NNT = 77 for MACE vs. NNH = 1000 for retinopathy worsening) 2.

4. Consider oral semaglutide over subcutaneous formulations if retinopathy concerns arise, as case reports suggest potentially lower risk 3.

Bottom Line

GLP-1 receptor agonists have no role in treating macular degeneration. For diabetic retinopathy, they are not therapeutic agents but glucose-lowering medications with cardiovascular benefits that require ophthalmologic monitoring due to potential early worsening of existing retinopathy through rapid glycemic improvement 1, 2.