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The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy

The second part of our series on influential trials from the book edited by Dr James Harrison


Lewis E, Hunsicker L,

Bain R et al. The effect of angiotensin-converting enzyme inhibition on diabetic nephropathy. NEJM 1993;329:1456-62

Study design: RCT

Evidence level: 1b

Key message

ACE inhibitors provide additional benefit beyond blood pressure control in slowing diabetic nephropathy.


ACE inhibitors are the first choice antihypertensive in patients with diabetes mellitus, especially those with proteinuria.


The progression of diabetic nephropathy is due to haemodynamic rather than metabolic factors. Prior to this trial, it was known that strict blood pressure control could slow the progression, but it remained unclear whether ACE inhibitors could have additional benefits, independent of their antihypertensive effect. This study aimed to resolve the issue.



409 patients at 30 nephrology centres in the US

Inclusion criteria

• Diabetic nephropathy

• Age18-49

• Type 1 diabetes for seven years or more with onset before age 30

• Diabetic retinopathy

• Urinary protein excretion more than 0.5g a day

• Serum creatinine more than 221µmol/l


Two groups, both had target blood pressure below 140/90mmHg:

• captopril (n=207)

• placebo (n=202)

Primary endpoint Time to doubling of baseline serum creatinine

Secondary endpoints

• Time to death, dialysis or transplantation

• Hyperkalaemia


• At two weeks, one month and then every three months until the patient died,

started dialysis or had renal transplant

• Median follow-up of three years


This study confirmed the central role of ACE inhibitors in the treatment of diabetic nephropathy. It was the first study to clearly demonstrate that they had additional benefits beyond simple lowering of blood pressure.


In current practice, the blood pressure control would no longer be considered optimal, so the additional benefits of ACE inhibitors if blood pressure was already below 130/80mmHg might not be as apparent.

The rate of progression of renal disease in the control group was higher than expected from the contemporary literature. However, as this was an RCT, effects causing this accelerated decline should have had an equal impact on both groups.

The patients were quite highly selected, but are still probably representative of the general type 1 diabetes population.

This is an extract from the Oxford Handbook of Key Clinical Evidence, which provides doctors with a quick route to the salient details of the trials that have most influenced clinical practice, selected by specialty experts who summarise the key message and clinical impact for each trial.

The book is published by Oxford University Press and edited by Harrison, Kulkarni, Baguneid and Prendergast (ISBN 9780199234073) price £27.95. Pulse readers can purchase the book at a 20% discount from OUP using the promotion code webkce10 (offer expires 30 June 2010)