A medication-wide association study to identify medications associated with incident clinically significant diabetic retinopathy

BACKGROUND: Diabetic retinopathy, a common microvascular complication of diabetes mellitus, is one of the leading causes of vision loss worldwide. Although some oral drugs have been suggested to affect the risk of diabetic retinopathy, systematic evaluation about the associations between medications and diabetic retinopathy is still absent. OBJECTIVE: To comprehensively investigate associations of systemic medications with incident clinically significant diabetic retinopathy (CSDR). DESIGN: Population-based cohort study. METHODS: From 2006 to 2009, more than 26 000 participants residing in New South Wales were enrolled in the 45 and Up study. Diabetic participants with self-reported physician diagnosis or records of anti-diabetic medication prescriptions were finally included in the current analysis. CSDR was defined as diabetic retinopathy cases requiring retinal photocoagulation recorded in the Medicare Benefits Schedule database from 2006 to 2016. Prescriptions of systemic medication from 5 years to 30 days prior to CSDR were retrieved from the Pharmaceutical Benefits Scheme. The study participants were equally split into training and testing datasets. Logistic regression analyses were performed for the association between each of systemic medication and CSDR in the training dataset. After controlling the false discovery rate (FDR), significant associations were further validated in the testing dataset. RESULTS: The 10-year incidence of CSDR was 3.9% (n = 404). A total of 26 systemic medications were found to be positively associated with CSDR, among which 15 were validated by the testing dataset. Additional adjustments for pertinent comorbidities suggested that isosorbide mononitrate (ISMN) (OR: 1.87, 95%CI: 1.00–3.48), calcitriol (OR: 4.08, 95% CI: 2.02–8.24), three insulins and analogues (e.g., intermediate-acting human insulin, OR: 4.28, 95% CI: 1.69–10.8), five anti-hypertensive medications (e.g., furosemide, OR: 2.53, 95% CI: 1.77–3.61), fenofibrate (OR: 1.96, 95% CI: 1.36–2.82) and clopidogrel (OR: 1.72, 95% CI: 1.15–2.58) were independently associated with CSDR. CONCLUSION: This study investigated the association of a full spectrum of systemic medications with incident CSDR. ISMN, calcitriol, clopidogrel, a few subtypes of insulin, anti-hypertensive and cholesterol-lowering medications were found to be associated with incident CSDR.