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GLP-1 Agonists: Balancing Cardiovascular Benefits with Potential Risks to Diabetic Retinopathy in Type 2 Diabetes Management

  • Overview of GLP-1 Receptor Agonists:

    • Glucagon-like peptide-1 (GLP-1) receptor agonists (e.g., semaglutide, dulaglutide, liraglutide) are incretin-based drugs used for type 2 diabetes mellitus (T2DM) and obesity management.

    • Act on pancreatic β-cells to enhance glucose-dependent insulin secretion, reduce gastric emptying, and promote satiety, leading to improved glycemic control and weight loss.

    • Semaglutide (third-generation): Weekly subcutaneous or oral dosing; most widely used in the US.

  • Mechanism and Effects:

    • GLP-1 overcomes β-cell dysfunction in T2DM, normalizing glucose responsiveness.

    • Reduces energy intake and appetite via central modulation of brain reward centers.

    • Delays gastric emptying, contributing to hypoglycemic and anorectic effects.

  • Clinical Efficacy:

    • SUSTAIN Trials (Semaglutide):

      • HbA1c reduction: 1.5–1.8% (1.0 mg weekly) vs. 0.1–0.4% (placebo) over 30–56 weeks.

      • Weight loss: 4.5–6.5 kg vs. 1.0–1.4 kg (placebo).

      • SUSTAIN 6: Reduced cardiovascular death/stroke risk (hazard ratio 0.74, P<0.001) over 104 weeks.

    • STEP Trials (Weight Loss):

      • Semaglutide 2.4 mg: ≥15% body weight loss in 50% of patients; placebo-subtracted loss 9.4–12.6% over 68–104 weeks.

      • Weight regain occurs post-discontinuation.

    • Tirzepatide (Dual GLP-1/GIP Agonist):

      • SURPASS Trials: HbA1c ≤7.0% in 80% of patients; superior to semaglutide in hyperglycemia reduction.

      • SURMOUNT-1: Weight loss of 15–20.9% (5–15 mg weekly) vs. placebo over 72 weeks.

    • Usage: GLP-1 agonist prescriptions quadrupled (2016–2022); 5.1 million US T2DM patients (1 in 5) in 2022.

  • Impact on Diabetic Retinopathy (DR):

    • Unclear relationship; mixed evidence on DR progression with GLP-1 agonists.

    • Meta-Analysis (93 Trials):

      • Increased risk of early-stage DR (e.g., nonproliferative DR, NPDR) vs. placebo (significant for albiglutide: RR 2.18, P=0.05; semaglutide: RR 1.26, P=0.02).

      • Decreased risk of late-stage DR (e.g., proliferative DR, PDR) vs. insulin (albiglutide: RR 0.25, P=0.008; dulaglutide: RR 0.62, P=0.02).

    • SUSTAIN 6: More patients on semaglutide required DR intervention (e.g., laser, anti-VEGF) vs. placebo, attributed to rapid HbA1c reduction.

    • Retrospective Studies:

      • No increased DR progression with semaglutide vs. non-insulin hypoglycemics.

      • Lower DR incidence in patients without baseline DR (adjusted hazard ratio 0.42).

    • Subgroup Risks:

      • Increased DR risk with semaglutide in patients >60 years (RR 1.27) or with T2DM ≥10 years (RR 1.28).

    • Study Limitations:

      • Non-ophthalmology focus; inconsistent DR measurement (serious vs. non-serious adverse events).

      • Broad “retinal adverse events” (e.g., macular edema, retinal detachment, melanoma) confound DR-specific outcomes.

      • Variable baseline DR exclusion and concurrent medications introduce bias.

    • FOCUS Trial (ongoing, ends 2027):

      • First prospective RCT on semaglutide’s long-term DR effects.

      • Primary outcome: ≥3-step ETDRS DR progression.

      • Secondary outcomes: Visual acuity decline, anti-VEGF use, panretinal photocoagulation, HbA1c changes.

  • Perioperative Considerations:

    • Delayed gastric emptying increases pulmonary aspiration risk during sedation.

    • ASA Recommendations:

      • Daily GLP-1 agonists: Hold on procedure day.

      • Weekly GLP-1 agonists: Hold 1 week prior.

      • Applies to both DM and weight loss indications; consult endocrinologist to manage hyperglycemia.

      • Delay elective surgery if severe GI symptoms (nausea, vomiting, dyspepsia, abdominal distention) are present.

  • Ophthalmology Recommendations:

    • No AAO consensus guidelines on GLP-1 agonists and DR.

    • Prioritize macrovascular benefits (cardiovascular/stroke risk reduction) over potential DR progression.

  • Management:

    • Treat severe NPDR/PDR before starting GLP-1 agonists.

    • Baseline ophthalmology exam and regular follow-up required.

    • Shorten follow-up intervals (e.g., moderate NPDR: 3 months vs. 6 months) due to potential accelerated DR progression.

    • Inform patients: DR worsening may occur initially but often stabilizes in 12–18 months.

  • Emphasize collaboration between ophthalmologists and primary care physicians.

Citation

Samanta A, Bordbar DD, Weng CY, Chancellor JR. Glucagon-like Peptide-1 Receptor Agonists in the Management of Diabetic Retinopathy. Int Ophthalmol Clin. 2025;65(1):23-26. doi:10.1097/IIO.0000000000000541