Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Captopril postponed nephropathy in insulin-dependent diabetes with microalbuminuria and normal blood pressure

ACP J Club. 1991 Nov-Dec;115:74. doi:10.7326/ACPJC-1991-115-3-074


Source Citation

Mathiesen ER, Hommel E, Giese J, Parving HH. Efficacy of captopril in postponing nephropathy in normotensive insulin dependent diabetic patients with microalbuminuria. BMJ. 1991 Jul 13;303:81-7.


Abstract

Objective

To assess the effect of an angiotensin-converting enzyme (ACE) inhibitor (captopril) in preventing the development of diabetic nephropathy in normotensive insulin-dependent diabetic patients with microalbuminuria.

Design

Open, randomized, controlled trial of 4 years' duration. Patients were randomized in pairs matched for urinary albumin excretion (UAE), blood pressure (BP), hemoglobin A1c and glomerular filtration rate (GFR).

Setting

Outpatient diabetic clinic in Denmark.

Patients

Patients had to be insulin dependent, between 18 and 50 years of age, with onset of diabetes before age 41 years, with duration of diabetes 5 to 30 years, with diastolic BP < 95 mm Hg, with microalbuminuria and no other disease (n = 130). 52 patients had persistent microalbuminuria (2 of 3 consecutive urine samples in the range of 30 to 300 mg/d). 45 patients with BP < 160/95 mm Hg and GFR > 90 mL/min·1.73 m2 participated. 44 patients were included in the analysis.

Intervention

The goal was to prevent a rise in arterial BP and to decrease diastolic BP by 5 mm Hg. 21 patients were treated with captopril, 25 mg/d; if the BP goal was not achieved, the dose of captopril was doubled after 6 months and 12 months to a maximum of 100 mg/d. During the last 18 months, bendrofluazide was added, with potassium chloride supplementation. 23 patients were untreated. All patients continued with their diabetic diet and 2 or more daily insulin injections.

Main outcome measures

Diabetic nephropathy defined as persistent albuminuria (mean UAE > 300 mg/d, based on ≥ 6 consecutive measurements during a 6-month period) GFR and arterial BP.

Main results

During the trial, 2 patients in each group required furosemide for edema or hypertension. 3 patients became pregnant. At the end of 4 years, UAE decreased in the captopril group from a geometric mean of 82 mg/d (95% CI 66 to 106 mg/d) to 57 mg/d (CI 39 to 85 mg/d) compared with increased UAE in the untreated group from 105 mg/d (CI 77 to 153 mg/d) to 166 mg/d (CI 83 to 323 mg/d), (P < 0.05 for difference between groups). 7 of the 23 untreated patients but none of the captopril group (n = 21) progressed to diabetic nephropathy ({30% vs 0%}*, P < 0.05). There was little change in BP or GFR in either group.

Conclusion

Over a period of 4 years, captopril was effective in postponing nephropathy in normotensive insulin-dependent diabetic patients with microalbuminuria.

Sources of funding: The Danish Medical Research Foundation and the Danish Diabetes Association.

Address for article reprint: Dr. E.R. Mathiesen, Hvidore Hospital, 2930 Klampenborg, Denmark.

*Numbers calculated from data in article.


Commentary

This study extends the observation of Marre and colleagues that long-term administration of an ACE inhibitor reduces urinary albumin excretion in normotensive insulin-dependent diabetic patients with persistent microalbuminuria and is well tolerated (1). It also appears to postpone the development of overt diabetic nephropathy.

These important findings should be interpreted with caution because the authors' definition of overt diabetic nephropathy did not include a measure of structural renal injury. The study, therefore, left unanswered the question of whether the antiproteinuric effect of ACE inhibition is only a consequence of its hemodynamic actions or whether it reflects a favorable effect on the rate of development of glomerular lesion. Repeated morphologic assessment of renal tissue would help to answer this question.

The relative importance of the decrease in systemic blood pressure and the intrarenal actions of ACE inhibition in reducing proteinuria were not specifically addressed in this study. The lack of an effect of captopril on blood pressure would point to a specific advantage of this class of drugs, but this finding needs confirmation.

Evidence from this study suggests that patients with insulin-dependent diabetes and persistent microalbuminuria would benefit by the addition of captopril to their treatment regimen. The clinical implications, however, are enormous because as many as 40% of all patients with insulin-dependent diabetes will develop persistent microalbuminuria and thus would become eligible for this therapy. Before recommending such large-scale intervention, it seems prudent to confirm the results of this important study in a larger, blinded trial, using a more specific measure of structural renal injury than urinary albumin excretion as the primary end point.

Alexander G. Logan, MD
Mount Sinai HospitalToronto, Ontario, Canada


Reference

1. Marre M, Leblanc H, Suarez L, et al. Converting enzyme inhibition and kidney function in normotensive diabetic patients with persistent microalbuminuria. BMJ. 1987;294:1448-52.