Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy

Abstract

Aldosterone promotes glomerular and tubular sclerosis independent of angiotensin II in animal models of diabetic nephropathy. Most human studies testing the renoprotective benefit of adding an angiotensin receptor blocker or a mineralocorticoid receptor antagonist to a regimen based on inhibition of angiotensin-converting enzyme (ACE) used relatively low doses of ACE inhibitors. Furthermore, these studies did not determine whether antiproteinuric effects were independent of BP lowering. We conducted a double-blind, placebo-controlled trial in 81 patients with diabetes, hypertension, and albuminuria (urine albumin-to-creatinine ratio > or =300 mg/g) who all received lisinopril (80 mg once daily). We randomly assigned the patients to placebo, losartan (100 mg daily), or spironolactone (25 mg daily) for 48 wk. We obtained blood and urine albumin, urea, creatinine, electrolytes, A1c, and ambulatory BP at baseline, 24, and 48 wk. Compared with placebo, the urine albumin-to-creatinine ratio decreased by 34.0% (95% CI, -51.0%, -11.2%, P = 0.007) in the group assigned to spironolactone and by 16.8% (95% CI, -37.3%, +10.5%, P = 0.20) in the group assigned to losartan. Clinic and ambulatory BP, creatinine clearance, sodium and protein intake, and glycemic control did not differ between groups. Serum potassium level was significantly higher with the addition of either spironolactone or losartan. In conclusion, the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP. These results support the need to conduct a long-term, large-scale, renal failure outcomes trial.

Figure 1.

The UACR and BP treatment responses for each study group. Solid lines indicate active treatment weeks, and the dotted lines indicate the washout phase. (A) The UACR percentage change for spironolactone versus placebo (−34.0%, 95% CI, −51.0%, −11.2%, P = 0.007) and losartan versus placebo (95% CI, −37.3%, +10.5%, P = 0.2). Data are presented as the percentage change from the baseline geometric mean and 95% CI. The P values are from mixed-model repeated-measures analysis. See the text for within-group differences. (B) Twenty-four-hour systolic BP percentage change was not statistically different between groups. Data are presented as the mean and 95% CI. (C) Clinical BP responses were not statistically different between groups. Data are presented as the mean and 95% CI.

Figure 2.

Serum potassium treatment response by study group. Serum potassium for losartan versus placebo, P = 0.03; spironolactone versus placebo, P < 0.0001; losartan versus spironolactone, P = 0.05. Solid lines indicate active treatment weeks, and the dotted lines indicate the washout phase. Data are presented as the mean and standard error.

Figure 3.

Study Design. Asterisks denote inpatient CTRC admission.

Figure 4.

Number of study subjects who were screened, enrolled, randomized, and completed the study.