Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials.

Background Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden ofdiabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme toassess whether candesartan could reduce the incidence and progression of retinopathy in type 1 diabetes.Methods Two randomised, double-blind, parallel-design, placebo-controlled trials were done in 309 centres worldwide.Participants with normotensive, normoalbuminuric type 1 diabetes without retinopathy were recruited to theDIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned tocandesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators andparticipants were unaware of the treatment allocation status. The primary endpoints were incidence and progressionof retinopathy and were defi ned as at least a two-step and at least a three-step increase on the Early Treatment DiabeticRetinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbersNCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1.Findings 1421 participants (aged 18–50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) inDIRECT-Prevent 1, and 1905 (aged 18–55 years) to candesartan (n=951) or to placebo (n=954) in DIRECT-Protect 1.Incidence of retinopathy was seen in 178 (25%) participants in the candesartan group versus 217 (31%) in the placebogroup. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in theplacebo group. Hazard ratio (HR for candesartan vs placebo) was 0·82 (95% CI 0·67–1·00, p=0·0508) for incidence ofretinopathy and 1·02 (0·80–1·31, p=0·85) for progression of retinopathy. The post-hoc outcome of at least a three-stepincrease for incidence yielded an HR of 0·65 (0·48–0·87, p=0·0034), which was attenuated but still signifi cant afteradjustment for baseline characteristics (0·71, 0·53–0·95, p=0·046). Final ETDRS level was more likely to haveimproved with candesartan treatment in both DIRECT-Prevent 1 (odds 1·16, 95% CI 1·05–1·30, p=0·0048) andDIRECT-Protect 1 (1·12, 95% CI 1·01–1·25, p=0·0264). Adverse events did not diff er between the treatment groups.