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.