Impact of diabetic foot ulcers and nephropathy on risk of treatment-warranted diabetic eye disease: A retrospective cohort study

• DFU and DN increases risk of treatment-warranted diabetic eye disease (TW-DED) • DFU alone poses higher TW-DED risk than DN alone in NPDR patients • Coexisting DFU+DN nearly doubles risk of PDR, VH, and vitrectomy • NPDR with DFU or DN warrants more frequent ophthalmic assessment Microvascular complications of type 2 diabetes (T2DM), such as diabetic retinopathy, nephropathy (DN), and foot ulcers (DFU), are interrelated outcomes of hyperglycemia-induced vascular injury. Whether comorbid DFU or DN merely indicate diabetic microvascular disease burden or specifically contribute to progression to treatment-warranted diabetic eye disease (TW-DED) remains insufficiently explored. We hypothesized that DFU and DN are independently associated with increased risk of TW-DED. This retrospective cohort study used electronic health records from a nationwide federated database and followed patients for up to 10 years after index non-proliferative diabetic retinopathy (NPDR) diagnosis. Data were aggregated from a multicenter network of 70 U.S.-based healthcare organizations, including both academic and non-academic institutions. Patients aged ≥40 years with T2DM and NPDR were included, while those with prior TW-DED were excluded. Baseline DN and/or DFU, with propensity-matched clinical covariates, including demographics, comorbidities, medications, laboratory values, and healthcare utilization. The primary outcome was progression to TW-DED, defined as proliferative DR, macular edema, vitreous hemorrhage, or need for DR-related treatments (intravitreal injection, panretinal photocoagulation, pars plana vitrectomy). Risk of blindness or low vision, defined by ICD-10 code H54, was also assessed. Cox proportional hazard models estimated hazard ratios (HRs) and 95% confidence intervals (CIs). Among 135,172 patients with NPDR, 21.5% had DN only, 8.5% had DFU only, and 7.0% had both. Compared to those without DN or DFU, patients with DFU (HR 1.27, 95% CI 1.19-1.36), DN (HR 1.17, 95% CI 1.05-1.21), or both DFU and DN (HR 1.49, 95% CI 1.33-1.68) were associated with increased risk of TW-DED. DFU alone was associated with greater risk of TW-DED than DN alone (HR 1.15, 95% CI 1.05-1.28). Patients with DFU or DN had a 2-fold increased risk of PDR and VH, 50% increased risk of blindness, and 2-fold increased risk of undergoing vitrectomy. Comorbid DFU and DN are associated with increased risk of diabetic eye disease progression, with DFU showing greater individual risk. Proactively identifying these complications may support risk stratification and guide more intensive ophthalmic monitoring for patients with NPDR.