Fast track — ArticlesEffect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials
Introduction
Loss of vision due to retinopathy remains one of the most feared complications in people with diabetes.1 Intense glycaemic control is the only proven intervention to reduce both incidence and progression of retinopathy in diabetes.2 However, optimised glycaemic control is not easy to achieve3, 4 and, even when it is achieved, cannot completely abolish risks of retinopathy.2, 5
The findings of the EUrodiab Controlled trial of Lisinopril in Insulin-dependent Diabetes (EUCLID)6 suggested that blockade of the renin-angiotensin system, with the angiotensin-converting enzyme inhibitor lisinopril, could reduce both incidence and progression of retinopathy in type 1 diabetes. However, since EUCLID6 was not primarily designed to study retinopathy, we sought to confirm and extend these findings definitively in a new series of clinical trials in the DIabetic REtinopathy Candesartan Trials (DIRECT) Programme.
In this programme, consisting of three separate randomised, double-blind, placebo-controlled clinical trials, we assessed whether the angiotensin-receptor antagonist candesartan could reduce incidence of retinopathy in type 1 diabetes (DIRECT-Prevent 1); progression of retinopathy in type 1 diabetes (DIRECT-Protect 1); and progression of retinopathy in type 2 diabetes (DIRECT-Protect 2).
In this paper, we report the findings of the first two trials (DIRECT-Prevent 1 and DIRECT-Protect 1).
Section snippets
Participants
Detailed methods and baseline data have already been published.7, 8 We enrolled men and women with type 1 diabetes (age at diagnosis <36 years, with continuous insulin use within 1 year of diagnosis) who were both normoalbuminuric (at least one of two overnight urinary albumin excretion rates <20 μg/min) and normotensive (systolic/diastolic blood pressures ≤130/85 mm Hg) in the studies in 309 centres worldwide. We assigned patients without retinopathy—ie, Early Treatment Diabetic Retinopathy
Results
Figure 1 shows the trial profile. We started randomisation in August, 2001, and the last patient was assessed in March, 2008. Median follow-up was 4·7 years in the candesartan (IQR 4·2–5·1) and placebo (4·3–5·2) groups in DIRECT-Prevent 1, and 4·8 years (4·4–5·3) in the candesartan and placebo groups in DIRECT-Protect 1. Table 2 shows the baseline characteristics of the participants. In DIRECT-Protect 1, very few participants had more than mild non-proliferative diabetic retinopathy (level >35).
Discussion
Candesartan reduced incidence of retinopathy in patients with type 1 diabetes. The effect did not reach conventional levels of statistical significance. With the more stringent definition of a three-step change, the numbers of patients developing retinopathy in the candesartan group were significantly reduced. However, we could not demonstrate a treatment advantage for progression of retinopathy.
Our findings are in agreement with the 30% reduction in incidence of retinopathy reported in the
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