The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy.
Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further reduces albuminuria when administered concomitantly with maximum tolerated labeled doses of RAS inhibitors. We enrolled 211 patients with type 2 diabetes, urine albumin/creatinine ratios of 300-3500 mg/g, and eGFRs of 30-75 ml/min per 1.73 m(2) in two identically designed, parallel, multinational, double-blind studies. Participants were randomized to placebo (n=50) or to 0.75 mg/d (n=78) or 1.25 mg/d (n=83) atrasentan for 12 weeks. Compared with placebo, 0.75 mg and 1.25 mg atrasentan reduced urine albumin/creatinine ratios by an average of 35% and 38% (95% confidence intervals of 24 to 45 and 28 to 47, respectively) and reduced albuminuria≥30% in 51% and 55% of participants, respectively. eGFR and office BP measurements did not change, whereas 24-hour systolic and diastolic BP, LDL cholesterol, and triglyceride levels decreased significantly in both treatment groups. Use of atrasentan was associated with a significant increase in weight and a reduction in hemoglobin, but rates of peripheral edema, heart failure, or other side effects did not differ between groups. However, more patients treated with 1.25 mg/d atrasentan discontinued due to adverse events. After stopping atrasentan for 30 days, measured parameters returned to pretreatment levels. In conclusion, atrasentan reduced albuminuria and improved BP and lipid spectrum with manageable fluid overload-related adverse events in patients with type 2 diabetic nephropathy receiving RAS inhibitors.
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; d.de.zeeuw@umcg.nl.
Dick
D
de Zeeuw
Renal Clinical Development and.
Blai
B
Coll
Renal Clinical Development and.
Dennis
D
Andress
Renal Clinical Development and.
John J
JJ
Brennan
Data and Statistical Sciences, AbbVie, North Chicago, Illinois;
Hui
H
Tang
Renal Clinical Development and.
Mark
M
Houser
Salvador Zubiran National Medical Science and Nutrition Institute, Mexico City, Mexico;
Ricardo
R
Correa-Rotter
Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah;
Donald
D
Kohan
Department of Clinical Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands;
Hiddo J
HJ
Lambers Heerspink
Okayama University Graduate School of Medicine, Okayama, Japan;
Hirofumi
H
Makino
George Institute for Global Health, University of Sydney, Sydney, Australia;
Vlado
V
Perkovic
Astellas Global Pharma Development, Inc., Northbrook, Illinois;
Yili
Y
Pritchett
Azienda Ospedaliera Papa Giovanni XXIII and IRCCS-Instituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy;
Giuseppe
G
Remuzzi
Sunnybrook Health Sciences Center, Toronto, Ontario, Canada;
Sheldon W
SW
Tobe
University of Texas Southwestern Medical Center, Dallas, Texas;
Robert
R
Toto
Kings' College London School of Medicine, London, United Kingdom; and.
Giancarlo
G
Viberti
Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
Hans-Henrik
HH
Parving
D000368:Aged; D000419:Albuminuria / Q000188:drug therapy* / Q000209:etiology; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D019332:Endothelin-1 / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D008055:Lipids / Q000097:blood; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use*
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D008055:Lipids; D011759:Pyrrolidines; D000077868:Atrasentan