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

BackgroundTo 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. MethodsMulticentre 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). ResultsWe 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. ConclusionThe 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. PrecisThis study describes the impact on PDR risk of anti-VEGF injections for DMO in routine care and data-driven reassessment recommendations of the peripheral retina for people in long term injection clinics. Key messages What is already known on this topic- Clinical trials have shown that intravitreal anti-vascular endothelial growth factor (VEGF) injections reduce the incidence rate of proliferative diabetic retinopathy (PDR). - Repeated intravitreal anti-VEGF injections are the mainstay of treatment for diabetic macular oedema (DMO), however, there is little evidence on how these exposures impact on the risk of PDR in clinical practice. What this study adds- The impact of anti-VEGF on PDR risk varies based on the timing of exposure and the effect is not permanent. - Despite repeated treatments with anti-VEGF injections, patients with DMO may still progress to PDR. How this study might affect research, practice, or policy- Our work underscores the significance of taking into account repeated treatments at varying time intervals in ophthalmology, highlighting the utility of the weighted cumulative exposure method. - Implementing adequate modelling strategies to address the complexities of exposures in clinical settings can improve predictions and patient outcomes. - We provide PDR screening recommendations for DMO patients undergoing anti-VEGF treatments in injection clinics. Implementation would improve the safety and efficiency of treatment pathways.