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

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. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported in part by an unrestricted research award by Novartis Pharmaceuticals. No member or affiliate of Novartis had any input into data analysis interpretation of the data or writing the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Declaration of Helsinki and the United Kingdom Data Protection Act. The lead clinician and Caldicott Guardian responsible for protecting the confidentiality of patient information, at each centre, gave written approval for extraction of anonymised data. The study protocol was approved by the head of research governance at Moorfields Eye Hospital NHS Foundation Trust, the lead clinical centre. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Owing to the comprehensive multicentre electronic medical record data collection, the tables required to reproduce the aforementioned findings cannot be shared at this time due to ethical considerations.