Impact of Anti-VEGF Treatment for Diabetic Macular Oedema on Progression to Proliferative Diabetic Retinopathy: Data-driven Insights from a Multicentre Study

Abstract

Background: To report insights on proliferative-diabetic-retinopathy (PDR) risk modification with repeated anti-vascular endothelial-growth-factor (VEGF) injections for the treatment of diabetic-macular-oedema (DMO) in routine care, and present data-driven PDR screening recommendations for injection clinics. Methods: Multicentre study (27 UK-NHS centres) of patients with non-PDR with and without DMO. Primary outcome was PDR development. Repeated anti-VEGF injections were modelled as time-dependent covariates using Cox regression and weighted cumulative exposure (WCE) adjusting for baseline diabetic retinopathy (DR) grade, age, sex, ethnicity, type of diabetes, and deprivation. A propensity score matched cohort was used to estimate the treatment effect on PDR incidence rates (IR). Results: We included 5716 NPDR eyes (5716 patients, 2858 DMO eyes). The WCE method showed a better model fit. Anti-VEGF injections showed a protective effect on risk of PDR during the most recent 4-weeks from exposure which rapidly decreased. There was a 20% reduction in risk of PDR (p0.006) in treated eyes. Severe-NPDR had a 4.6-fold increase in PDR hazards when compared with mild-NPDR (p<0.001). The annual IR of untreated mild-NPDR cases was 2.3 [95%CI 1.57-3.23] per 100 person-years). In NPDR DMO cases treated with anti-VEGF, similar IR would occur with annual review for mild, 6-monthly for moderate, and 3-monthly for severe-NPDR. Conclusion: The WCE method is a better modelling strategy than traditional Cox models for repeated exposures in ophthalmology. Injections are protective against PDR predominantly within the most recent 4 weeks. Based on observed data, we suggest follow-up recommendations for PDR detection according to retinopathy grade at first injection.