Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials
Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials
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DOI：
10.1016/s0140-6736(08)61412-9
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发表时间：
2008-10-18
期刊：
影响因子：
168.9
通讯作者：
Sjolie, Anne Katrin
中科院分区：
文献类型：
--
作者：
Chaturvedi, Nish;Porta, Massimo;Sjolie, Anne Katrin
背景：以往的研究结果表明，肾素-血管紧张素系统阻滞剂可能会减少糖尿病视网膜病变的负担。因此，我们设计了糖尿病视网膜病变坎地沙坦试验（直接）计划，以评估坎地沙坦是否可以减少1型diabetes.Methods视网膜病变的发病率和进展，两个随机，双盲，平行设计，安慰剂对照试验在全球309个中心。DIRECT-Prevent I试验招募了血压正常、白蛋白尿正常、无视网膜病变的1型糖尿病患者，DIRECT-Protect 1试验招募了现有视网膜病变患者，并分配坎地沙坦16 mg每日一次或匹配的安慰剂。1个月后，剂量加倍至32 mg。研究者和参与者不知道治疗分配状态。主要终点是视网膜病变的发生率和进展，分别定义为早期治疗糖尿病视网膜病变研究（ETDRS）量表上至少两步和至少三步增加。这些试验在www.example.com上注册ClinicalTrials.gov，DIRECT-Prevent 1的注册号为NCT 00252733，DIRECT-Protect 1的注册号为NCT 00252720。在DIRECT-Prevent 1研究中，随机分配坎地沙坦组（n=711）或安慰剂组（n=710），DIRECT-Protect 1中1905例（年龄18-55岁）接受坎地沙坦（n=951）或安慰剂（n=954）。坎地沙坦组178例（25%）受试者发生视网膜病变，安慰剂组217例（31%）。坎地沙坦组127例（13%）参与者发生视网膜病变进展，安慰剂组124例（13%）。视网膜病变发生率的风险比（坎地沙坦vs安慰剂的HR）为0.82（95% CI 0.67-1.00，p=0.0508），视网膜病变进展的风险比为1.02（0.80-1.31，p=0.85）。发生率至少增加三步的事后结局产生的HR为0.65（0.48-0.87，p=0.0034），其减弱，但在校正基线特征后仍具有显著性（0.71，0.53-0.95，p=0.046）。在DIRECT-Prevent 1（比值1.16，95% CI 1.05-1.30，p=0.0048）和DIRECT-Protect 1（1.12，95% CI 1.01-1.25，p=0.0264）中，坎地沙坦治疗后最终ETDRS水平更有可能改善。不良事件在治疗组之间没有差异。解释虽然坎地沙坦降低视网膜病变的发生率，但我们没有看到对视网膜病变进展的有益作用。
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 I 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 I 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 0.82 (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.Interpretation Although candesartan reduces the incidence of retinopathy, we did not see a beneficial effect on retinopathy progression.