Elsevier

The Lancet

Volume 372, Issue 9647, 18–24 October 2008, Pages 1394-1402
The Lancet

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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

https://doi.org/10.1016/S0140-6736(08)61412-9Get rights and content

Summary

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 0·82 (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.

Funding

AstraZeneca and Takeda.

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

References (34)

  • Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS report number 12

    Ophthalmology

    (1991)
  • R Klein et al.

    How many steps of progression of diabetic retinopathy are meaningful? The Wisconsin epidemiologic study of diabetic retinopathy

    Arch Ophthalmol

    (2001)
  • J Sun et al.

    Generalised log-rank tests for interval-censored failure time data

    Scand J Stat

    (2005)
  • JA Wellner et al.

    A hybrid algorithm for computation of the NPMLE from censored data

    JASA

    (1997)
  • A Alioum et al.

    A proportional hazards model for arbitrarily censored and truncated data

    Biometrics

    (1996)
  • SJ Aldington et al.

    Methodology for retinal photography and assessment of diabetic retinopathy: the EURODIAB IDDM complications study

    Diabetologia

    (1995)
  • P Hovind et al.

    Decreasing incidence of severe diabetic microangiopathy in type 1 diabetes

    Diabetes Care

    (2003)
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