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

    Author(s)
    Chaturvedi, Nish
    Porta, Massimo
    Klein, Ronald
    Orchard, Trevor
    Fuller, John
    Parving, Hans-Henrik
    Bilous, Rudy
    Sjolie, Anne Katrin
    Fox, Ywonne
    George, Michael
    Svensson, Anders
    Hainer, James
    Warnold, Ingrid
    Agardh, Carl-David
    Bonnici, Francois
    Charbonnel, Bernard
    Cooper, Mark
    Dedov, Ivan
    Gardiner, Robert
    Gomis, Ramon
    Ilkova, Hasan
    Katsilambros, Nicholas
    Kerenyi, Zsuzsa
    Martin, Stephan
    Massin, Pascale
    Pirags, Valdis
    Raz, Itamar
    Rusavy, Zdenek
    Schernthaner, Guntram
    Shestakova, Marina
    Strojek, Krzysztof
    Olofsson, Bertil
    Malm, Anders
    Wissmar, Jenny
    Brayshaw, Nigel
    Wedel, Hans
    Wilhelmsen, Lars
    Bird, Alan
    Price, Graham
    Adler-Ekholm, Elisabeth
    Aldington, Stephen
    Dahl, Magnus
    Deveney, Aaron
    Karlsten, Eva
    Levins, Philippa
    Lipinski, Helen
    Prenter, Carol
    Walkey, Helen
    Walters, Nicola
    Chen, Roger
    Colman, Peter
    Davoren, Peter
    Donelly, Thomas
    et al.
    Griffith University Author(s)
    Davoren, Peter M.
    Year published
    2008
    Metadata
    Show full item record
    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 ...
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    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. Findings: 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縲 (95% CI 0綷-1簰, p=0簵08) for incidence of retinopathy and 1簲 (0縰-1糱, p=0縵) for progression of retinopathy. The post-hoc outcome of at least a three-step increase for incidence yielded an HR of 0綵 (0紸-0縷, p=0簰34), which was attenuated but still significant after adjustment for baseline characteristics (0緱, 0絳-0繵, p=0簴6). Final ETDRS level was more likely to have improved with candesartan treatment in both DIRECT-Prevent 1 (odds 1籶, 95% CI 1簵-1糰, p=0簰48) and DIRECT-Protect 1 (1籲, 95% CI 1簱-1粵, p=0簲64). Adverse events did not differ between the treatment groups. Interpretation: Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression. Funding: AstraZeneca and Takeda.
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    Journal Title
    Lancet
    Volume
    372
    Publisher URI
    http://www.thelancet.com/
    DOI
    https://doi.org/10.1016/S0140-6736(08)61412-9
    Subject
    Medical and Health Sciences
    Publication URI
    http://hdl.handle.net/10072/26241
    Collection
    • Journal articles

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