Intravitreal anti-VEGF therapy and risk of limb complications in individuals with diabetic eye disease

Aims: To evaluate the association between intravitreal anti-VEGF therapy and lower extremity complications in diabetic eye disease (DED), and compare risks among ranibizumab, aflibercept, and bevacizumab. Methods: This retrospective cohort study used a U.S. electronic health records network. Adults with DED receiving ≥3 intravitreal anti-VEGF injections (IVI) were compared to those receiving ≤2 (controls). Outcomes included diabetic foot ulcer (DFU) and lower extremity amputation (LEA). Propensity score matching (1:1) balanced baseline characteristics. Cox models estimated hazard ratios (HRs) with 95 % confidence intervals (CIs) for LEA, above-ankle LEA, and DFU in the overall cohort and subgroups with proliferative diabetic retinopathy (PDR), peripheral artery disease (PAD), end-stage renal disease (ESRD), or prior DFUs. Results: Of 448,100 individuals with DED, 35,269 received ≥3 injections; 34,070 remained in each group after matching. IVI was associated with higher risk of LEA (HR 1.54 [95 % CI 1.38–1.72]), above-ankle LEA (HR 1.31 [1.08–1.59]), and DFU (HR 1.36 [1.30–1.42]) versus controls. LEA risk was greater in IVI versus control subgroups with PDR, PAD, ESRD, or DFUs. Risks were similar across agents. Conclusions: Anti-VEGF therapy in DED was linked to increased DFU and LEA risk, especially in high-risk subgroups. Prospective studies are needed for confirmation.