Addition of Atrasentan to Renin-Angiotensin System Blockade ... : Journal of the American Society of Nephrology (original) (raw)

Clinical Research

Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy

Kohan, Donald E.*; Pritchett, Yili†; Molitch, Mark‡; Wen, Shihua†; Garimella, Tushar†; Audhya, Paul†; Andress, Dennis L.†

*Division of Nephrology, Department of Medicine, University of Utah Health Sciences Center, Salt Lake City, UT;

†Abbott Laboratories, Abbott Park, IL; and

‡Division of Endocrinology, Metabolism and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL

Correspondence: Dr. Donald Kohan, Division of Nephrology, University of Utah Health Sciences Center, 1900 East 30 North, Salt Lake City, UT 84132. Phone: 801-581-2726; Fax: 801-581-4343; E-mail: [email protected]

Received August 23, 2010

Accepted November 22, 2010

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 (ETAR) 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 m2 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.