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)
Year published
2008
Metadata
Show full item recordAbstract
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 ...
View more >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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View more >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
Subject
Medical and Health Sciences