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Long-Term Stabilizing Effect of Angiotensin-Converting Enzyme Inhibition on Plasma Creatinine and on Proteinuria in Normotensive Type II Diabetic Patients

Mordchai Ravid, MD; Hilel Savin, MD; Itzhak Jutrin, MD; Tamir Bental, MD; Bernard Katz, MSc; and Michael Lishner, MD
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From the Sackler Faculty of Medicine, Tel Aviv University, Israel; Meir Hospital, Kfar-Saba, Israel. Requests for Reprints: Mordchai Ravid, MD, Department of Medicine A, Meir Hospital, Kfar-Saba 44281, Israel. Grant Support: By the Nissenson-Tyomkin medical research grant.

Copyright 2004 by the American College of Physicians

Ann Intern Med. 1993;118(8):577-581. doi:10.7326/0003-4819-118-8-199304150-00001
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Objective: To evaluate the long-term effect of angiotensin-converting enzyme inhibition on proteinuria and on the rate of decline in kidney function in patients with type II diabetes mellitus and microalbuminuria.

Design: Randomized, double-blind, placebo-controlled trial. Each patient was followed for 5 years.

Setting: Six clinics for diabetes mellitus coordinated by a department of medicine in a university hospital in Israel.

Patients: Ninety-four normotensive, type II diabetic patients with microalbuminuria and normal renal function.

Intervention: The patients were randomly assigned to receive enalapril, 10 mg per day, or placebo. Any increase in blood pressure was treated with long-acting nifedipine.

Measurements: Albuminuria, blood pressure, serum creatinine, fasting blood glucose, and glycosylated hemoglobin levels, every 3 to 4 months.

Results: In the patients treated with enalapril, albuminuria decreased from 143 64 (mean SD) mg/24 h to 122 67 mg/24 h during the first year. Thereafter, we observed a slow increase to 140 134 mg/24 h after 5 years. In the placebo group, albuminuria increased from 123 58 mg/24 h to 310 167 mg/24 h after 5 years. (Difference in rate of change in proteinuria [P < 0.05]). Kidney function (expressed as mean reciprocal creatinine) declined by 13% in the placebo group and remained stable (1%) in the enalapril group (P < 0.05). Control of blood glucose levels remained stable, in both groups, throughout the study. The mean blood pressure was stable in the enalapril group (initial group mean, 99 2.1 mm Hg; fifth-year mean, 100 3.2 mm Hg) and increased in the placebo group from an initial mean value of 97 3.2 mm Hg to 102 3.4 mm Hg at the end of the study period (P = 0.082).

Conclusions: In normotensive patients with diabetes mellitus type II, the institution of angiotensin-converting enzyme inhibition during early stages of diabetic nephropathy results in long-term stabilization of plasma creatinine levels and of the degree of urinary loss of albumin. These effects are probably independent of the antihypertensive action of these agents.


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Figure 1.
Proteinuria during 5-year follow-up in diabetics treated with enalapril or placebo.PPP

Each point on the curve represents the annual group average of 3 to 4 determinations per patient. Data are mean SD. Less proteinuria occurred in the enalapril group compared with placebo after the second year ( < 0.05 for the second year, < 0.01 for the third year, and < 0.005 for the fourth and fifth years).

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Figure 2.
Reciprocal creatinine (100/cr) levels expressed as percentage of initial value, during 5 years of follow-up in placebo-and enalapril-treated type II diabetics.PP

Each value represents the annual average of the group composed of three to four determinations per year per patient. Values are mean SD. The mean rate of decline of reciprocal creatinine differed between the two groups ( < 0.05 for the second and third years, < 0.02 for the fourth and fifth years).

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Figure 3.
Mean blood pressure values during 5-year follow-up in diabetic patients treated with enalapril or placebo.P

Each group mean represents 3 to 4 double determinations (blood pressure taken twice at same office visit) of mean blood pressure per year per patient. Values are mean SD. The group annual means did not differ ( = 0.14).

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