Elsevier

The Lancet

Volume 349, Issue 9068, 21 June 1997, Pages 1787-1792
The Lancet

Articles
Randomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria

https://doi.org/10.1016/S0140-6736(96)10244-0Get rights and content

Summary

Background

Renal disease in people with insulin-dependent diabetes (IDDM) continues to pose a major health threat. Inhibitors of angiotensin-converting enzyme (ACE) slow the decline of renal function in advanced renal disease, but their effects at earlier stages are unclear, and the degree of albuminuria at which treatment should start is not known.

Methods

We carried out a randomised, double-blind, placebo-controlled trial of the ACE inhibitor lisinopril in 530 men and women with IDDM aged 20–59 years with normoalbuminuria or microalbuminuria. Patients were recruited from 18 European centres, and were not on medication for hypertension. Resting blood pressure at entry was at least 75 and no more than 90 mm hg diastolic, and no more than 155 mm hg systolic. Urinary albumin excretion rate (AER) was centrally assessed by means of two overnight urine collections at baseline, 6, 12, 18, and 24 months.

Findings

There were no differences in baseline characteristics by treatment group; mean AER was 8.0 μg/min in both groups; and prevalence of microalbuminuria was 13% and 17% in the placebo and lisinopril groups, respectively. On intention-to-treat analysis at 2 years, AER was 2.2 μg/min lower in the lisinopril than in the placebo group, a percentage difference of 18.8% (95% CI 2·0–32·7, p=0·03), adjusted for baseline AER and centre, absolute difference 2.2 μg/min. In people with normoalbuminuria, the treatment difference was 1·0 μg/min (12·7% [−2·9 to 26·0], p=0·1). In those with microalbuminuria, however, the treatment difference was 34.2 μg/min (49·7% [−14·5 to 77·9], p=0·1; for interaction, p=0·04). For patients who completed 24 months on the trial, the final treatment difference in AER was 38·5 μg/min in those with microalbuminuria at baseline (p=0·001), and 0·23 μg/min in those with normoalbuminuria at baseline (p=0·6). There was no treatment difference in hypoglycaemic events or in metabolic control as assessed by glycated haemoglobin.

Interpretation

Lisinopril slows the progression of renal disease in normotensive IDDM patients with little or no albuminuria, though greatest effect was in those with microalbuminuria (AER ≥20 μg/min). Our results show that lisinopril does not increase the risk of hypoglycaemic events in IDDM.

Introduction

Rates of morbidity and mortality continue to be higher among people with insulin-dependent diabetes mellitus (IDDM) than in the general population.1, 2 Much of this increased risk results from renal and cardiovascular complications of IDDM; a strong predictor of these complications is the appearance of even small amounts of protein (mainly albumin) in the urine.3, 4 Blood pressure is an important modifiable risk factor for the progression of renal disease.5 Of all antihypertensive agents, inhibitors of angiotensin-converting enzyme (ACE) are regarded as particularly effective in limiting renal-disease progression, because of possible beneficial influences on kidney function, which are separate from the effects on systemic blood pressure.6 ACE inhibitors significantly limit the progression of renal disease in patients with macroalbuminuria,7 and, at the time our trial was designed, there were indications that this beneficial effect also occurred in patients with microalbuminuria.8, 9 If ACE inhibitors can slow the relentless decline of renal function in patients with microalbuminuria, it is reasonable to investigate whether use of ACE inhibitors in patients with normoalbuminuria may also be beneficial. However, previous trials of ACE inhibitors in normoalbuminuric patients are few,10, 11, 12 and have either lacked power,12 or have not been designed as randomised and controlled.10, 11 Consequently, the degree of albuminuria at which treatment with ACE inhibitors should start is unclear.

We carried out, therefore, a 2-year randomised, placebo-controlled trial of the ACE inhibitor lisinopril in patients with both normoalbuminuria and microalbuminuria. Our aim was to assess whether early-stage intervention in patients without hypertension would limit progression of renal disease, and whether this effect differed according to degree of albuminuria.

Section snippets

Methods

The EURODIAB controlled trial of lisinopril in insulin dependent diabetes (EUCLID) was a double-blind, randomised, parallel-design clinical trial of lisinopril and placebo in 18 European centres. The trial was done according to the Declaration of Helsinki. All centres obtained approval from local ethics authorities, and obtained written consent from participants.

Men and women aged between 20 and 59 years who had IDDM—which we defined as a diagnosis before age 36 and the need for continuous

Results

530 patients were randomly assigned active treatment (265) or placebo (figure 1). Factors associated with severity of diabetes and likelihood of complications, such as glycaemic control and duration of diabetes, showed a broad distribution within the study sample (table 1). HbA1c ranged from 2.5% to 14.4%, and diabetes duration from 1 to 51 years. However, there were no between-group differences in baseline measures (table 1).

At 1 month, mean diastolic blood pressure was 74 mm hg on active

Discussion

We show that the ACE inhibitor lisinopril slows the progression of AER in a mixed population of normoalbuminuric and microalbuminuric normotensive IDDM patients. After 2 years, AER was 18·8% lower on active treatment than on placebo—an absolute difference of 2·2 μg/min. Our findings apply to IDDM patients with a broad range of glycaemic control and duration of diabetes, and the treatment effect did not appear to differ according to the key confounders, except sex and baseline albuminuric

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