The effects of atrasentan on urinary metabolites in patients with type 2 diabetes and nephropathy.

Michelle J Pena, Dick de Zeeuw, Dennis Andress, John J Brennan, Ricardo Correa-Rotter, Blai Coll, Donald E Kohan, Hirofumi Makino, Vlado Perkovic, Giuseppe Remuzzi, Sheldon W Tobe, Robert Toto, Hans-Henrik Parving, Shoba Sharma, Tom Corringham, Kumar Sharma, Hiddo J L Heerspink

Journal: Diabetes, obesity & metabolism 2017;19(5):749-753

PMID: 28019071

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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 m . After 12 weeks of atrasentan treatment in patients with eGFR < 60 mL/min/1.73 m , 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 m , 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.

Address: Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.; Renal Clinical Development, AbbVie, North Chicago, Illinois.; Department of Nephrology and Mineral Metabolism, National Medical Science and Nutrition Institute Salvador Zubirán, Mexico City, Mexico.; Clinical Research Cardiovascular, Amgen Inc., Thousand Oaks, California.; Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City, Utah.; Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Okayama, Japan.; George Institute for Global Health, University of Sydney, Sydney, Australia.; 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.; Department of Hypertension and Nephrology, Sunnybrook Health Sciences Center, Toronto, Ontario, Canada.; Department of Clinical Science, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Medical Endocrinology, Rigshospitalet University Hospital of Copenhagen, Copenhagen, Denmark.; Clinical Metabolomics, La Jolla, California.; 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.

DOI: 10.1111/dom.12864