Can a patient with diabetic retinopathy continue taking a Glucagon-like peptide-1 (GLP-1) receptor agonist?

Can Patients with Diabetic Retinopathy Continue GLP-1 Receptor Agonists?

Yes, patients with diabetic retinopathy can generally continue GLP-1 receptor agonists, but this requires careful ophthalmologic assessment before intensification, close monitoring during treatment, and slower dose titration to minimize the risk of rapid A1C reduction that can transiently worsen retinopathy. 1, 2, 3

Understanding the Risk Profile

The concern about GLP-1 RAs and diabetic retinopathy stems from the mechanism of rapid glycemic improvement rather than a direct toxic effect of the medication itself. 1, 3 The worsening of retinopathy is associated with rapid A1C reduction, particularly at 3-month and 1-year follow-up, not the drug per se. 1

Key evidence points:

• Meta-analyses show no association between GLP-1 RA treatment and retinopathy except through the association with average A1C reduction. 1
• The cardiovascular and renal benefits of GLP-1 RAs are substantial and should be weighed against the modest and primarily transient retinopathy risk. 4
• Real-world data from 2025 actually shows GLP-1 RA use was associated with decreased risk of DR (HR: 0.31), DME (HR: 0.40), and treatment-requiring DR/DME (HR: 0.18) compared to never users. 5

Pre-Treatment Requirements

Before initiating or continuing a GLP-1 RA in a patient with known diabetic retinopathy, you must:

• Obtain a comprehensive dilated eye examination if not performed within the last 12 months. 3
• Document the severity of retinopathy, specifically noting whether proliferative diabetic retinopathy is present. 3
• Assess for diabetic macular edema. 3

Critical pitfall: Do not initiate GLP-1 RA therapy in an uncontrolled diabetic whose last eye exam was over 1 year ago until current retinopathy status is documented. 3

Risk Stratification by Retinopathy Severity

No Retinopathy or Mild NPDR

• GLP-1 RAs can be initiated with standard titration. 2, 4
• Screen every 1-2 years if glycemia is well controlled. 2, 4

Moderate to Severe NPDR

• GLP-1 RAs can be used but require more cautious approach. 2, 3
• Consider more gradual improvement in glycemic control to minimize worsening risk. 2, 4
• Increase monitoring frequency to every 6 months rather than annually. 3
• Dilated retinal examinations should be repeated at least annually. 2, 4

Proliferative Diabetic Retinopathy

• Exercise significant caution—this is the highest risk group. 2, 3
• The American College of Cardiology specifically lists "history of proliferative retinopathy" as requiring caution with dulaglutide and semaglutide. 2, 3
• Consider alternative GLP-1 RAs or other drug classes first, such as SGLT2 inhibitors for cardiovascular risk reduction. 3
• If GLP-1 RA is chosen due to compelling cardiovascular/renal benefits, use the slowest possible titration and closest ophthalmologic monitoring. 3

Dose Titration Strategies to Minimize Risk

The key to preventing retinopathy worsening is avoiding aggressive A1C reduction. 3, 6

Specific titration protocols:

• Start at the lowest dose and up-titrate slowly, particularly in patients with established retinopathy. 3
• For patients on insulin: Reduce total daily insulin dose by 20% when starting GLP-1 RA to slow the rate of glycemic improvement. 3
• For patients on sulfonylureas with well-controlled baseline HbA1c: Reduce sulfonylurea dose by 50%. 3
• Patients with poor baseline glycemic control (HbA1c >9%) and concurrent insulin therapy are at higher risk and need the most gradual approach. 3

Evidence basis: Meta-regression analysis showed that decreases in A1c >1.0% were associated with increased retinopathy worsening (RR: 1.59), particularly with subcutaneous semaglutide given for >1 year. 6

Monitoring Protocol During Treatment

Establish this surveillance schedule:

• Baseline examination before starting therapy (as noted above). 2, 3
• If any level of diabetic retinopathy is present: dilated retinal examinations at least annually. 2, 4
• If retinopathy is progressing or sight-threatening: more frequent examinations by an ophthalmologist are required. 2
• High-risk patients (proliferative DR, rapid A1C reduction): consider every 6 months. 3

Risk-Benefit Analysis

The numbers strongly favor continuing GLP-1 RAs even in patients with retinopathy:

• For the GLP-1 RA class overall: Number needed to harm (NNH) for worsening retinopathy = 1000, while number needed to treat (NNT) for preventing MACE = 77. 6
• For semaglutide specifically: NNH = 77 versus NNT = 43 for cardiovascular benefit. 6
• Semaglutide reduces cardiovascular events and new/worsening nephropathy by 36%. 3
• A 2024 study found no association between GLP-1 RA use and DR worsening compared to SGLT2 inhibitors (OR: 0.33). 7

Specific GLP-1 RA Considerations

Agents with documented retinopathy concerns in trials:

• Semaglutide (subcutaneous): Associated with diabetic retinopathy complications, predominantly in patients with prior proliferative retinopathy. 3
• Dulaglutide: May cause worsening of diabetic retinopathy, particularly in patients with pre-existing proliferative retinopathy. 2
• Liraglutide: Associated with increased risk of rapidly worsening diabetic retinopathy in randomized trials. 1

Potential alternative: One case report suggested oral semaglutide may have a lower risk profile than subcutaneous formulations, with improvement in DR and resolution of DME after switching. 8 However, this is limited evidence and requires further study.

Documentation Requirements

Document the following in the medical record:

• Pre-treatment ophthalmologic assessment results. 3
• Informed consent discussion about retinopathy risks, particularly in patients with proliferative disease. 3
• Rationale for choosing GLP-1 RA despite retinopathy (typically cardiovascular/renal benefits). 3
• Titration plan to minimize rapid A1C reduction. 3

Common Pitfalls to Avoid

• Failing to obtain current eye exam: Never start or intensify GLP-1 RA without knowing current retinopathy status. 3
• Aggressive titration in high-risk patients: The mechanism of harm is rapid A1C reduction, not the drug itself. 1, 3
• Abandoning beneficial therapy unnecessarily: The cardiovascular and renal benefits substantially outweigh the modest retinopathy risk in most patients. 4, 6
• Inadequate monitoring: Patients with any retinopathy need at least annual dilated exams, more frequently if proliferative disease. 2, 4

Additional Risk Reduction Strategies

Beyond GLP-1 RA management, optimize other modifiable risk factors:

• Implement strategies to reach blood pressure goals to reduce risk or slow progression of diabetic retinopathy. 1
• Optimize serum lipid control to reduce risk or slow progression of diabetic retinopathy. 1, 2