Systemic Interleukin-6 Inhibition and Risk of Diabetic Retinopathy Development and Progression.

Abstract

To evaluate whether systemic interleukin-6 (IL-6) inhibitor use is associated with reduced risk of incident diabetic retinopathy (DR), DR progression, vision-threatening complications, and retinal interventions in adults with diabetes. Retrospective propensity score-matched cohort study. Adults with type 1 or type 2 diabetes were identified using the US TriNetX electronic health record network from January 1, 2004, through May 30, 2026. After 1:1 propensity score matching, the primary analysis included 2,605 diabetic patients receiving IL-6 inhibitors and 2,605 matched diabetic controls. The secondary analysis included 1,057 matched patients per group with known nonproliferative diabetic retinopathy (NPDR). Cohorts were matched on baseline characteristics, medication exposure, inflammatory disease burden, and ophthalmic history. The primary analysis assessed incident DR among patients without baseline retinopathy. Secondary analyses evaluated progression from NPDR to proliferative diabetic retinopathy (PDR) and compared IL-6 inhibitors with alternative immunosuppressants. Sensitivity analyses compared IL-6 inhibitors with intravitreal steroid injections among patients with severe NPDR or PDR and evaluated outcomes by IL-6 inhibitor occurrence frequency. Risk ratios for incident NPDR, PDR, vitreous hemorrhage (VH), diabetic macular edema (DME), neovascular glaucoma (NVG), and receipt of anti-vascular endothelial growth factor (anti-VEGF) injections, panretinal photocoagulation (PRP), and pars plana vitrectomy (PPV) at 1, 3, and 5 years. In the primary analysis, IL-6 inhibitor use was associated with significantly lower 5-year risks of NPDR (RR: 0.50; 95% CI: 0.42-0.60), PDR (RR: 0.47; 95% CI: 0.35-0.61), DME (RR: 0.37; 95% CI: 0.27-0.51), and VH (RR: 0.41; 95% CI: 0.28-0.61), with no significant difference in NVG. Anti-VEGF therapy, PRP, and PPV use were also significantly lower at 5 years. Among patients with baseline NPDR, IL-6 inhibitor use was associated with lower 5-year risks of progression to PDR, DME, VH, NVG, and retinal interventions. Findings were consistent in active comparator analyses. Systemic IL-6 inhibitor use was associated with lower risk of incident DR, DR progression, vision-threatening complications, and retinal interventions over 5 years, with findings persisting in active comparator and sensitivity analyses. Prospective studies are needed to evaluate whether IL-6 pathway modulation may have a therapeutic role in diabetic eye disease.