title: Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials.
abstract: BACKGROUND
  Results of previous studies suggest that renin-angiotensin system blockers might reduce the burden of diabetic retinopathy. We therefore designed the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme to assess 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 the DIRECT-Prevent 1 trial and those with existing retinopathy were recruited to DIRECT-Protect 1, and were assigned to candesartan 16 mg once a day or matching placebo. After 1 month, the dose was doubled to 32 mg. Investigators and participants were unaware of the treatment allocation status. The primary endpoints were incidence and progression of retinopathy and were defined as at least a two-step and at least a three-step increase on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale, respectively. These trials are registered with ClinicalTrials.gov, numbers NCT00252733 for DIRECT-Prevent 1 and NCT00252720 for DIRECT-Protect 1.
  
  
  RESULTS
  1421 participants (aged 18-50 years) were randomly assigned to candesartan (n=711) or to placebo (n=710) in DIRECT-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 placebo group. Progression of retinopathy occurred in 127 (13%) participants in the candesartan group versus 124 (13%) in the placebo group. Hazard ratio (HR for candesartan vs placebo) was 0.82 (95% CI 0.67-1.00, p=0.0508) for incidence of retinopathy and 1.02 (0.80-1.31, p=0.85) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0.65 (0.48-0.87, p=0.0034), which was attenuated but still significant after adjustment for baseline characteristics (0.71, 0.53-0.95, p=0.046). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1.16, 95% CI 1.05-1.30, p=0.0048) and DIRECT-Protect 1 (1.12, 95% CI 1.01-1.25, p=0.0264). Adverse events did not differ between the treatment groups.
  
  
  CONCLUSIONS
  Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.
authors.affiliation: International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College Healthcare NHS Trust, London, UK.
authors.forename: Nish
authors.initials: N
authors.lastname: Chaturvedi
authors.forename: Massimo
authors.initials: M
authors.lastname: Porta
authors.forename: Ronald
authors.initials: R
authors.lastname: Klein
authors.forename: Trevor
authors.initials: T
authors.lastname: Orchard
authors.forename: John
authors.initials: J
authors.lastname: Fuller
authors.forename: Hans Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Rudy
authors.initials: R
authors.lastname: Bilous
authors.forename: Anne Katrin
authors.initials: AK
authors.lastname: Sjølie
mesh_terms: D000293:Adolescent; D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000009:adverse effects / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D003922:Diabetes Mellitus, Type 1 / Q000150:complications* / Q000188:drug therapy; D003930:Diabetic Retinopathy / Q000145:classification / Q000188:drug therapy* / Q000209:etiology; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007328:Insulin / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D012720:Severity of Illness Index; D013777:Tetrazoles / Q000009:adverse effects / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D007328:Insulin; D013777:Tetrazoles; C081643:candesartan