ArticlesRandomised placebo-controlled trial of lisinopril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbuminuria
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
References (27)
- et al.
Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus
Lancet
(1982) - et al.
Prognostic significance of microalbuminuria in insulin-dependent diabetes mellitus: a twenty-three year follow-up study
Kidney Int
(1992) - et al.
Estimating rates of change in randomized clinical trials
Control Clin Trials
(1990) - et al.
The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria
Am J Med
(1995) - et al.
Hypoglycaemia associated with use of inhibitors of angiotensin converting enzyme
Lancet
(1995) - et al.
Do ACE inhibitors improve insulin sensitivity?
Lancet
(1995) - et al.
Cause-specific mortality in a population-based study of diabetes
Am J Public Health
(1991) Excess mortality and its relation to hypertension and proteinuria in diabetic patients: the WHO Multinational Study of Vascular Disease in Diabetes
Diabetes Care
(1996)Progression of nephropathy in long-term diabetics with proteinuria and effect of initial anti-hypertensive treatment
Scand J Clin Lab Invest
(1976)- et al.
Effect of antihypertensive therapy on the kidney in patients with diabetes: a meta-regression analysis
Ann Intern Med
(1993)
The effect of angiotensin converting enzyme inhibition on diabetic nephropathy
N Engl J Med
Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria
BMJ
Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria
BMJ
Cited by (529)
Kidney disease in diabetes: From mechanisms to clinical presentation and treatment strategies
2021, Metabolism: Clinical and ExperimentalPrevention of Microvascular Complications of Diabetes
2021, Endocrinology and Metabolism Clinics of North AmericaCalpastatin prevents Angiotensin II–mediated podocyte injury through maintenance of autophagy
2021, Kidney InternationalRecent trends in drug-delivery systems for the treatment of diabetic retinopathy and associated fibrosis
2021, Advanced Drug Delivery ReviewsKDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease
2021, Kidney InternationalKDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease
2020, Kidney International
Writing committee, study organisation, and participants listed at end of article