title: The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.
abstract: We assessed the effect of atrasentan therapy on a pre-specified panel of 13 urinary metabolites known to reflect mitochondrial function in patients with diabetic kidney disease. This post-hoc analysis was performed using urine samples collected during the RADAR study which was a randomized, double-blind, placebo-controlled trial that tested the effects of atrasentan on albuminuria reduction in patients with type 2 diabetes and nephropathy. At baseline, 4 of the 13 metabolites, quantified by gas-chromatography mass spectrometry, were below detectable levels, and 6 were reduced in patients with eGFR < 60 mL/min/1.73 m2. After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m2, a single-value index of the metabolites changed by -0.31 (95%CI -0.60 to -0.02; P  = .035), -0.08 (-12 to 0.29; P  = .43) and 0.01 (-0.21 to 0.19; P  = .913) in placebo, atrasentan 0.75 and 1.25 mg/d, respectively. The metabolite index difference compared to placebo was 0.13 (-0.17 to 0.43; P  = .40) and 0.35 (0.05-0.65; P  = .02) for atrasentan 0.75 and 1.25 mg/d, respectively. These data corroborate previous findings of mitochondrial dysfunction in patients with type 2 diabetes, nephropathy and eGFR < 60 mL/min/1.73 m2, suggesting that atrasentan may prevent the progression of mitochondrial dysfunction common to this specific patient population. Future studies of longer treatment duration with atrasentan are indicated.
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Michelle J
authors.identifier: 0000-0003-3340-2893
authors.initials: MJ
authors.lastname: Pena
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Renal Clinical Development, AbbVie, North Chicago, Illinois.
authors.forename: Dennis
authors.initials: D
authors.lastname: Andress
authors.affiliation: Renal Clinical Development, AbbVie, North Chicago, Illinois.
authors.forename: John J
authors.initials: JJ
authors.lastname: Brennan
authors.affiliation: Department of Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Correa-Rotter
authors.affiliation: Clinical Research Cardiovascular, Amgen Inc., Thousand Oaks, California.
authors.forename: Blai
authors.initials: B
authors.lastname: Coll
authors.affiliation: Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah.
authors.forename: Donald E
authors.initials: DE
authors.lastname: Kohan
authors.affiliation: Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Okayama, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Makino
authors.affiliation: George Institute for Global Health, University of Sydney, Sydney, Australia.
authors.forename: Vlado
authors.initials: V
authors.lastname: Perkovic
authors.affiliation: Unit of Nephrology and Dialysis, Azienda Ospedaliera Papa Giovanni XXIII, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy.|Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.affiliation: Department of Hypertension and Nephrology, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.
authors.forename: Sheldon W
authors.initials: SW
authors.lastname: Tobe
authors.affiliation: Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Robert
authors.initials: R
authors.lastname: Toto
authors.affiliation: Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.affiliation: Clinical Metabolomics, La Jolla, California.
authors.forename: Shoba
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Clinical Metabolomics, La Jolla, California.
authors.forename: Tom
authors.initials: T
authors.lastname: Corringham
authors.affiliation: Institute of Metabolomic Medicine, Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Division of Medical Genetics, Department of Medicine, University of California San Diego, San Diego, California.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
authors.forename: Hiddo J L
authors.initials: HJL
authors.lastname: Heerspink
mesh_terms: D000419:Albuminuria / Q000209:etiology / Q000517:prevention & control; D000077868:Atrasentan; D015415:Biomarkers / Q000652:urine; D002170:Canada; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology / Q000652:urine; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D065128:Endothelin Receptor Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005500:Follow-Up Studies; D008401:Gas Chromatography-Mass Spectrometry; D005919:Glomerular Filtration Rate; D006801:Humans; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011759:Pyrrolidines / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D051437:Renal Insufficiency / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D015203:Reproducibility of Results; D013624:Taiwan; D014481:United States
chemical_list: D015415:Biomarkers; D065128:Endothelin Receptor Antagonists; D011759:Pyrrolidines; D000077868:Atrasentan
keywords: 
  eGFR decline; diabetic kidney disease; metabolomics