Incidence and Risk Factors for Early Worsening of Diabetic Retinopathy Following Rapid Improvement in Glycaemic Control

Background: Diabetic retinopathy (DR) is a microvascular complication of diabetes, characterized by progressive retinal changes leading to vision loss. Chronic hyperglycaemia triggers alterations in the retinal neurovascular unit, manifesting as retinal ischemia, increased vascular permeability, neovascularization, and macular oedema. Modifiable risk factors, including poor glycaemic control, hypertension, and dyslipidaemia, contribute to DR development and progression. Achieving near-normal blood glucose levels is crucial for managing diabetes and preventing microvascular complications. However, the initiation of intensive glycaemic control measures can sometimes result in the phenomenon known as early worsening of diabetic retinopathy. Understanding the incidence of this phenomenon and who is at risk is important and topical given recent developments in diabetes medications and associated technologies. I aimed to report the prevalence and incidence rates of early worsening of DR in individuals with a rapid, substantial reduction in HbA1c and to investigate risk factors for the progression of DR. Methods: I completed a systemic review of the epidemiology of early worsening of diabetic retinopathy. An analysis of the Individualised Screening for Diabetic Retinopathy (ISDR) cohort dataset was performed to examine the association between changes in glycaemic control, other systemic variables and demographic factors, and progression of retinopathy. I produced a refined dataset focused on screening episodes in the years 2014/15 and 2015/16 and corresponding HbA1c measurements derived from primary care data. Chronological differences between each pair of HbA1c measurements were assessed, flagging individuals who demonstrated a maximum reduction of ≥22, ≥33, and ≥44 mmol/mol. The association between worsening of retinopathy and demographic variables, cardiovascular risk factors, and glycaemic parameters were examined within the groups categorized by reduction in HbA1c. Results: The dataset, derived from the ISDR cohort study, encompassed 8,850 subjects, of which 5,964 had at least 2 HbA1c readings in the study window. Worsening of retinopathy and maculopathy was observed between the 2 screening episodes in 9.6% iii and 1.6% of subjects, respectively. The majority of subjects demonstrated well- regulated diabetes, characterized by a positively skewed distribution of HbA1c levels. Subjects who did not show a substantial reduction in HbA1c and those who demonstrated a maximum reduction of ≥22, ≥33 and ≥44mmol/mol exhibited mean initial HbA1c values of 54.3, 79.5, 86.4 and 101.9, respectively. Subjects who did not show a substantial reduction in HbA1c and those who demonstrated a maximum reduction in HbA1c of ≥22, ≥33 and ≥44mmol/mol, showed rates of retinopathy progression of 5.1% (P=0.04), 7.3% (P=, 13.7%) and 15.9% (P=0.14) respectively. Subjects with a higher baseline DR grading, longer duration of diabetes and higher initial HbA1c levels were found to have a higher risk of worsening of retinopathy. Conclusions: My analysis revealed a discernible trend towards an elevated risk of worsening of DR with greater reductions in HbA1c levels. Additionally, significant associations were observed between higher baseline DR gradings, longer diabetes duration, higher initial HbA1c measurements, and the progression of diabetic retinopathy. It is imperative to develop optimal glycaemic control strategies, particularly tailored for individuals with higher baseline HbA1c levels, pre-existing DR grading, and prolonged diabetes duration, to prevent the worsening of DR. This thesis offers valuable insights into the early worsening phenomenon of diabetic retinopathy, enhancing our understanding of its aetiology, clinical manifestations, and therapeutic implications. Our study findings highlight the need for personalized approaches to glycaemic control in diabetic patients to optimize both glycaemic outcomes and ocular health. Prospective studies including people with a wide range of retinopathy severities at baseline are now required.