Addition of atrasentan to renin-angiotensin system blockade reduces albuminuria in diabetic nephropathy

Abstract

Although endothelin-receptor antagonists reduce albuminuria in diabetic nephropathy, fluid retention limits their use. Here, we examined the effect of atrasentan, a selective endothelin A receptor (ET(A)R) antagonist, on albuminuria in a randomized, double-blind, placebo-controlled trial of subjects with diabetic nephropathy already receiving stable doses of renin-angiotensin system (RAS) inhibitors. We randomly assigned 89 subjects with eGFR >20 ml/min per 1.73 m(2) and a urinary albumin-to-creatinine ratio (UACR) of 100 to 3000 mg/g to placebo or atrasentan (0.25, 0.75, or 1.75 mg daily) for 8 weeks. Compared with placebo, atrasentan significantly reduced UACR only in the 0.75- and 1.75-mg groups (P=0.001 and P=0.011, respectively). Compared with the 11% reduction in the geometric mean of the UACR from baseline to final observation in the placebo group during the study, the geometric mean of UACR decreased by 21, 42, and 35% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups (P=0.291, P=0.023, and P=0.073, respectively). In the placebo group, 17% of subjects achieved ≥40% reduction in UACR from baseline compared with 30, 50, and 38% in the 0.25-, 0.75-, and 1.75-mg atrasentan groups, respectively (P=0.029 for 0.75 mg versus placebo). Peripheral edema occurred in 9% of subjects receiving placebo and in 14, 18, and 46% of those receiving 0.25, 0.5, and 1.75 mg atrasentan, respectively (P=0.007 for 1.75 mg versus placebo). In summary, atrasentan, at the doses tested, is generally safe and effective in reducing residual albuminuria and may ultimately improve renal outcomes in patients with type 2 diabetic nephropathy.

Figure 1.

Disposition of subjects during the study. Subjects may have had more than one reason for discontinuation.

Figure 2.

Atrasentan treatment significantly reduces albuminuria. Effect of atrasentan on change in UACR from baseline. Significant reductions in UACR were seen with the 0.75-mg dose (P = 0.001 versus placebo by repeated measures analysis) and 1.75-mg dose (P = 0.011 versus placebo by repeated-measures analysis). UACR returned toward baseline values after 30 days from drug discontinuation.

Figure 3.

Atrasentan treatment significantly increases the percentage of subjects achieving ≥ 40% reduction in UACR compared to placebo.

Figure 4.

Atrasentan affects longitudinal measures of BP by repeated-measures analysis. Systolic BP was reduced in the 0.75-mg dose (P = 0.038 versus placebo by repeated-measures analysis). Diastolic BP was reduced in the 0.75-mg dose (P = 0.017 versus placebo by repeated-measures analysis). BP values returned toward baseline after 30 days from drug discontinuation.

Figure 5.

The effect of atrasentan on change in UACR from baseline to final visit is independent of edema occurrence during treatment.