CLINICAL RESEARCH www.jasn.org Addition of Atrasentan to Renin-Angiotensin System Blockade Reduces Albuminuria in Diabetic Nephropathy Donald E. Kohan,* Yili Pritchett,† Mark Molitch,‡ Shihua Wen,† Tushar Garimella,† Paul Audhya,† and Dennis L. Andress† *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 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 Ͼ20 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 ϭ 0.001 and P ϭ 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 ϭ 0.291, P ϭ 0.023, and P ϭ 0.073, respectively). In the placebo group, 17% of subjects achieved Ն40% 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 ϭ 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 ϭ 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. J Am Soc Nephrol 22: 763–772, 2011. doi: 10.1681/ASN.2010080869 Diabetic nephropathy (DN) continues to be the The endothelin (ET) system is chronically ac- most common cause of ESRD, despite attempts at tivated in patients with diabetes and in preclini- rigorous control of hyperglycemia and hyperten- cal models as evidenced by elevated circulating sion.1,2 The addition of renin-angiotensin system levels of endothelin-1 (ET-1),6 enhanced kidney (RAS) inhibitors to reduce the deleterious effects ET-1 concentrations,7 and increased renal and CLINICAL RESEARCH of excessive renal angiotensin receptor activation systemic endothelin A receptor (ETAR) activa- has been the only kidney-specific therapy devel- oped for DN during the past 10 years. Although Received August 23, 2010. Accepted November 22, 2010. treatment with RAS inhibitors shows reductions in albuminuria in association with delays in Published online ahead of print. Publication date available at www.jasn.org. chronic kidney disease (CKD) progression,3,4 Correspondence: Dr. Donald Kohan, Division of Nephrology, there remains a significant unmet need to de- University of Utah Health Sciences Center, 1900 East 30 North, velop therapies that completely prevent progres- Salt Lake City, UT 84132. Phone: 801-581-2726; Fax: 801-581- sion to ESRD or even induce regression of glo- 4343; E-mail: [email protected] merular pathology.5 Copyright © 2011 by the American Society of Nephrology J Am Soc Nephrol 22: 763–772, 2011 ISSN : 1046-6673/2204-763 763 CLINICAL RESEARCH www.jasn.org 8 tion. Glomerular ETAR, but not ETBR, activation promotes Patient Characteristics podocyte and mesangial cell dysfunction, leading to pro- Baseline demographic, clinical and biochemical characteris- teinuria and glomerulosclerosis.9 A recent clinical trial with tics, and concomitant therapies were balanced between the avosentan, an endothelin receptor antagonist that likely four groups (Table 1). At baseline, 27% of subjects had 30 to Ͼ blocked both ETAR and ETBR, reduced albuminuria in pa- 200 mg/g creatinine, 72% of subjects had 200 mg/g creati- tients with macroalbuminuria and type 2 diabetes, although nine, and 26% of subjects had an estimated GFR Ͼ60 ml/min significant safety concerns related to fluid retention resulted per 1.73 m2. The majority of subjects (87%) were white, and in early trial termination.10 the mean age of the study population was 64 years. Atrasentan is a highly selective ETAR antagonist with an 11 approximate 1800:1 selectivity for ETARtoETBR. Such Primary and Secondary Outcomes ETAR, as opposed to ETBR, selectivity may be ideal for tar- The primary efficacy analysis, comparing treatment group dif- geting the ET pathogenicity in DN. The purpose of this ferences between each atrasentan group and placebo for randomized, double-blind, placebo-controlled clinical trial change from baseline to each postbaseline assessment (after a was to prospectively evaluate the efficacy and safety of atra- log transformation) using a repeated-measures analysis sentan for the reduction of residual albuminuria in subjects showed that urinary albumin-to-creatinine ratio (UACR) was with type 2 DN who were receiving stable doses of angioten- significantly reduced during the course of the 8-week treat- sin converting enzyme inhibitors (ACEIs) or angiotensin ment period in the 0.75- and 1.75-mg groups (P ϭ 0.001 and receptor blockers (ARBs). P ϭ 0.011 versus placebo, respectively; Figure 2). For the 0.75-mg group, a significant treatment effect was seen as early as week 1 (P ϭ 0.005) and was sustained to the last treatment RESULTS visit (week 8) of the study (P ϭ 0.008). The modest UACR reduction in the 0.25-mg group was not significant (P ϭ The disposition of study subjects is shown in Figure 1. Of the 0.150). 239 subjects screened, 89 subjects comprised the intent-to- Multiplicity adjustments were not made among the three treat population and were randomly assigned to one of four pairwise comparisons for the primary efficacy analysis because treatment groups: placebo (n ϭ 23), atrasentan 0.25 mg daily this was an exploratory phase 2a study. However, if a Bonfer- (n ϭ 22), 0.75 mg daily (n ϭ 22), or 1.75 mg daily (n ϭ 22). roni adjustment is made post hoc to adjust for multiplicity of Figure 1. Disposition of subjects during the study. Subjects may have had more than one reason for discontinuation. 764 Journal of the American Society of Nephrology J Am Soc Nephrol 22: 763–772, 2011 www.jasn.org CLINICAL RESEARCH Table 1. Subject demographics and baseline characteristics Atrasentan Placebo Variable mg 0.75 mg 1.75 mg 0.25 (23 ؍ n) (22 ؍ n) (22 ؍ n) (22 ؍ n) Gender, n (%) female 4 (17%) 9 (41%) 8 (36%) 6 (27%) male 19 (83%) 13 (59%) 14 (64%) 16 (73%) Race, n (%) white 22 (96%) 19 (86%) 18 (82%) 18 (82%) black 0 3 (14%) 2 (9%) 2 (9%) other 1 (4%) 0 2 (9%) 2 (9%) Ethnicity, n (%) Hispanic or Latino 13 (57%) 14 (64%) 14 (64%) 11 (50%) no ethnicity 10 (44%) 8 (36%) 8 (36%) 11 (50%) Age, years, n (%) Ͻ65 12 (52%) 13 (59%) 7 (32%) 11 (50%) Ն65 11 (48%) 9 (41%) 15 (68%) 11 (50%) Age, years mean (SD) 61 (8) 63 (12) 67 (9) 64 (13) Weight, kg mean (SD) 99 (20) 84 (13) 96 (19) 97 (20) Body mass index, kg/m2 mean (SD) 34 (5) 31 (4) 34 (6) 33 (5) UACR, mg/g creatinine median (Q1 to Q3) 515 (170 to 1477) 350 (194 to 1226) 360 (209 to 726) 433 (157 to 998) Estimated GFR, ml/min/BSA mean (SD) 52 (25) 50 (24) 61 (25) 48 (20) Serum creatinine, mg/dl Mean (SD) 1.6 (0.6) 1.5 (0.6) 1.3 (0.5) 1.8 (0.8) SBP, mmHg mean (SD) 138 (14) 134 (14) 137 (15) 135 (11) DBP, mmHg mean (SD) 78 (8) 75 (8) 74 (8) 75 (9) Hemoglobin, g/dl mean (SD) 13 (1) 12 (1) 13 (2) 13 (1) Hemoglobin A1c, % mean (SD) 7.4 (0.9) 7.6 (1.0) 7.6 (1.2) 7.3 (1.1) comparisons among three pairs, the study can still claim suc- ment groups: 0.25 mg, 40% (P ϭ 0.999); 0.75 mg, 68% (P ϭ cess because the significance level of 0.017 (0.05/3) was 0.075); 1.75 mg, 62% (P ϭ 0.227). achieved by the prespecified primary efficacy analysis in the There was an early and sustained reduction in systolic BP 0.75 mg (P ϭ 0.001 versus placebo) and 1.75 mg groups (P ϭ (SBP) in the 0.75-mg group (P ϭ 0.038 by repeated-measures 0.011 versus placebo). analysis versus placebo) as shown in Figure 4A. The mean The geometric mean reduction from baseline to final UACR change from baseline to week 8 of treatment SBP was Ϫ0.3 was significantly greater in the 0.75-mg group (42% reduction) mmHg in the 0.25-mg group (P ϭ 0.834 versus 0.7 mmHg in compared with placebo (11% reduction, P ϭ 0.023). For the placebo), Ϫ8.8 mmHg (P ϭ 0.049 versus placebo) in the 1.75-mg group, the effect did not quite meet significance (35% 0.75-mg group, and Ϫ7.6 mmHg (P ϭ 0.086 versus placebo) in reduction, P ϭ 0.073), whereas the reduction by the 0.25-mg the 1.75-mg group.