Effect of losartan on prevention and progression of early diabetic nephropathy in American Indians with type 2 diabetes

Abstract

Angiotensin receptor blockers are renoprotective in hypertensive azotemic patients with type 2 diabetes, but their efficacy in early diabetic kidney disease is uncertain. We performed a 6-year randomized clinical trial in 169 American Indians with type 2 diabetes and normoalbuminuria (albumin/creatinine ratio [ACR] <30 mg/g; n = 91) or microalbuminuria (ACR 30-299 mg/g; n = 78) at baseline. The primary outcome was decline in glomerular filtration rate (GFR) to ≤60 mL/min or to half the baseline value in subjects who entered with GFR <120 mL/min. Another outcome was differences in glomerular structure at end of treatment. Subjects received 100 mg losartan or placebo daily. GFR was measured annually; 111 subjects underwent kidney biopsies. Only nine subjects reached the GFR outcome, and the unadjusted hazard ratio (losartan vs. placebo) was 0.50 (95% CI, 0.12-1.99). Differences in mesangial fractional volume were not estimated in the combined albuminuria groups because of an interaction with treatment assignment. In separate analyses, mesangial fractional volume was lower in subjects treated with losartan in the microalbuminuria group (18.8 vs. 25.6%; P = 0.02), but not in the normoalbuminuria group (19.6 vs. 17.8%; P = 0.86). Treatment with losartan may preserve some features of kidney structure in American Indians with type 2 diabetes and microalbuminuria.

FIG. 1.

Enrollment, randomization, and follow-up of the study subjects. All subjects were included in intention-to-treat analyses, except one person in the normoalbuminuria group who was randomized to losartan but could not be found after the baseline examination.

FIG. 2.

Annual mean ± standard error MAP (upper panels), HbA_1c (middle panels), and GFR (lower panels) in subjects with normoalbuminuria (left panels) or microalbuminuria (right panels) at baseline by treatment group (dashed line = placebo; solid line = losartan). There were no significant differences in any of these measures by treatment group throughout the treatment period (for MAP, P = 0.21 in the normoalbuminuria group and P = 0.73 in the microalbuminuria group; for HbA_1c, P = 0.48 in the normoalbuminuria group and P = 0.43 in the microalbuminuria group; and for GFR, P = 0.11 in the normoalbuminuria group and P = 0.42 in the microalbuminuria group).

FIG. 3.

Cumulative percentage of the first occurrence of the GFR outcome by treatment group (dashed line = placebo; solid line = losartan). Log-rank tests for the GFR outcome yielded P = 0.31.

FIG. 4.

Effect of treatment with losartan or placebo on mesangial fractional volume (logarithmic scale) according to duration of diabetes in subjects with normoalbuminuria or microalbuminuria at baseline (open circles [○] = treatment with placebo; filled circles [●] = treatment with losartan). Regression lines are shown by treatment group (dashed line = placebo; solid line = losartan). After adjusting for duration of diabetes, mesangial fractional volume was 22.9% (95% CI, 4.6–37.7%) lower in subjects with microalbuminuria who received losartan than in those who received placebo. Mesangial fractional volume was not statistically significantly higher (10.1% [−8.9 to 33.0%]) in subjects with normoalbuminuria who received losartan than in those who received placebo.

FIG. 5.

Cumulative percentage of the first occurrence of the macroalbuminuria outcome in subjects with normoalbuminuria or microalbuminuria at baseline by treatment group (dashed line = placebo; solid line = losartan). Log-rank tests for the macroalbuminuria outcome yielded P = 0.02 in the normoalbuminuria group and P = 0.08 in the microalbuminuria group.