Long-term Effect of Losartan on Kidney Disease in American Indians With Type 2 Diabetes: A Follow-up Analysis of a Randomized Clinical Trial

Abstract

Objective: To determine whether early administration of losartan slows progression of diabetic kidney disease over an extended period.

Research design and methods: We conducted a 6-year clinical trial in 169 American Indians with type 2 diabetes and urine albumin/creatinine ratio <300 mg/g; 84 participants were randomly assigned to receive losartan and 85 to placebo. Primary outcome was a decline in glomerular filtration rate (GFR; iothalamate) to ≤60 mL/min or to half the baseline value in persons who entered with GFR <120 mL/min. At enrollment, GFR averaged 165 mL/min (interquartile range 49-313 mL/min). During the trial, nine persons reached the primary outcome with a hazard ratio (HR; losartan vs. placebo) of 0.50 (95% CI 0.12-1.99). Participants were then followed posttrial for up to 12 years, with treatment managed outside the study. The effect of losartan on the primary GFR outcome was then reanalyzed for the entire study period, including the clinical trial and posttrial follow-up.

Results: After completion of the clinical trial, treatment with renin-angiotensin system inhibitors was equivalent in both groups. During a median of 13.5 years following randomization, 29 participants originally assigned to losartan and 35 to placebo reached the primary GFR outcome with an HR of 0.72 (95% CI 0.44-1.18).

Conclusions: Long-term risk of GFR decline was not significantly different between persons randomized to early treatment with losartan and those randomized to placebo. Accordingly, we found no evidence of an extended benefit of early losartan treatment on slowing GFR decline in persons with type 2 diabetes.

Trial registration: ClinicalTrials.gov NCT00340678.

Figure 1

Cumulative incidence of the first occurrence of the primary GFR outcome by treatment group (top panel). Dashed line, placebo; solid line, losartan. Log-rank test for the GFR outcome yielded P = 0.28. Cumulative HRs and 95% CIs for the primary GFR outcome at trial closeout and each year of the posttrial follow-up (bottom panel). Cumulative HRs were not shown prior to the end of the trial because of the few number of events and the absence of events prior to year 4 in the losartan group.

Figure 2

Annual mean ± SE of MAP and HbA_1c by treatment group (dashed line, placebo; solid line, losartan). There was a significant difference in MAP by treatment group throughout the study period (P = 0.04), but not for HbA_1c.