Clinical efficacy of the selective endothelin A receptor antagonist, atrasentan, in patients with diabetes and chronic kidney disease (CKD).
OBJECTIVE
Progression of chronic kidney disease (CKD) in patients with diabetes is a growing problem. Diabetes is associated with elevated endothelin-1 (ET-1) and enhanced renal expression of the endothelin A receptor (ETAR). Atrasentan, a highly selective ETAR antagonist, reduces albuminuria in patients with DN. KEY METHODS: This was a randomized, double-blind trial of subjects with type 2 diabetes on renin-angiotensin system (RAS) inhibitors having eGFR >20 ml/min, and urine albumin-to-creatinine ratio (UACR) of 100-3000 mg/g, who were allocated to placebo, 0.25, 0.75 or 1.75 mg atrasentan.


RESULTS
UACR was reduced in the 0.75 mg and 1.75 mg groups (42% and 35% vs placebo, P<0.011) over the 8 week treatment period. Edema was reported in 21 subjects: 62% of edema events emerged during the first 4 weeks. There were no significant changes in serum hsCRP, IL-6, NT-pro-BNP, ET-1, urine TGFb or MCP-1. Urine NGAL was reduced 24% in the 1.75 mg group (P=0.044). Hispanic subjects (58% of total) tended to have greater UACR reductions than non-Hispanics (0.75 mg dose: Hispanic: 41-60%; non-Hispanic: 18-37%; P=0.012 and 0.048 vs placebo, respectively) without different rates of edema. Mean UACR reduction in subjects receiving maximum doses of RAS inhibitors (38%) was 32% and 35% in the 0.75 and 1.75 mg groups, respectively, and similar to overall UACR changes.


CONCLUSIONS
Edema formation was dose-dependent and occurred early. The decrease in urine NGAL warrants further study in renal tubular disease attenuation. UACR responses based on ethnicity need further characterization. Results suggest atrasentan may have additive effects to RAS inhibition in treatment of DN.
Abbott Laboratories, Abbott Park, IL 60064, United States. dennis.andress@abbott.com
Dennis L
DL
Andress
Blai
B
Coll
Yili
Y
Pritchett
John
J
Brennan
Mark
M
Molitch
Donald E
DE
Kohan
D000368:Aged; D000419:Albuminuria / Q000188:drug therapy / Q000209:etiology; D000077868:Atrasentan; D003404:Creatinine / Q000652:urine; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy* / Q000503:physiopathology; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000503:physiopathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced; D065130:Endothelin A Receptor Antagonists; D005260:Female; D005919:Glomerular Filtration Rate; D006630:Hispanic or Latino; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D012084:Renin-Angiotensin System / Q000187:drug effects
D065130:Endothelin A Receptor Antagonists; D011759:Pyrrolidines; D003404:Creatinine; D000077868:Atrasentan