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JAK1/JAK2 inhibition by baricitinib in diabetic kidney disease: results from a Phase 2 randomized controlled clinical trial.

Authors
  • Tuttle, Katherine R1, 2, 3
  • Brosius, Frank C 3rd4, 5
  • Adler, Sharon G6
  • Kretzler, Matthias4
  • Mehta, Ravindra L7
  • Tumlin, James A8
  • Tanaka, Yoshiya9
  • Haneda, Masakazu10
  • Liu, Jiajun11
  • Silk, Maria E11
  • Cardillo, Tracy E11
  • Duffin, Kevin L11
  • Haas, Joseph V11
  • Macias, William L11
  • Nunes, Fabio P11
  • Janes, Jonathan M11
  • 1 Providence Health Care, Spokane, WA, USA.
  • 2 The Kidney Research Institute, Division of Nephrology, University of Washington School of Medicine, Seattle, WA, USA.
  • 3 The Institute of Translational Health Sciences, University of Washington School of Medicine, Seattle, WA, USA.
  • 4 Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
  • 5 Department of Internal Medicine, University of Arizona College of Medicine, Tucson, AZ, USA.
  • 6 Division of Nephrology and Hypertension, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA.
  • 7 Division of Nephrology, University of California, San Diego, CA, USA.
  • 8 University of Tennessee College of Medicine, Chattanooga, TN, USA.
  • 9 The First Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. , (Japan)
  • 10 Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan. , (Japan)
  • 11 Eli Lilly and Company, Indianapolis, IN, USA. , (India)
Type
Published Article
Journal
Nephrology Dialysis Transplantation
Publisher
Oxford University Press
Publication Date
Nov 01, 2018
Volume
33
Issue
11
Pages
1950–1959
Identifiers
DOI: 10.1093/ndt/gfx377
PMID: 29481660
Source
Medline
Language
English
License
Unknown

Abstract

Inflammation signaled by Janus kinases (JAKs) promotes progression of diabetic kidney disease (DKD). Baricitinib is an oral, reversible, selective inhibitor of JAK1 and JAK2. This study tested the efficacy of baricitinib versus placebo on albuminuria in adults with Type 2 diabetes at high risk for progressive DKD. In this Phase 2, double-blind, dose-ranging study, participants were randomized 1:1:1:1:1 to receive placebo or baricitinib (0.75 mg daily; 0.75 mg twice daily; 1.5 mg daily; or 4 mg daily), for 24 weeks followed by 4-8 weeks of washout. Participants (N = 129) were 63±9.1 (mean±standard deviation) years of age, 27.1% (35/129) women and 11.6% (15/129) African-American race. Baseline hemoglobin A1c (HbA1c) was 7.3±1% and estimated glomerular filtration rate was 45.0±12.1 mL/min/1.73 m2 with first morning urine albumin-creatinine ratio (UACR) of 820 (407-1632) (median; interquartile range) mg/g. Baricitinib, 4 mg daily, decreased morning UACR by 41% at Week 24 compared with placebo (ratio to baseline 0.59, 95% confidence interval 0.38-0.93, P = 0.022). UACR was decreased at Weeks 12 and 24 and after 4-8 weeks of washout. Baricitinib 4 mg decreased inflammatory biomarkers over 24 weeks (urine C-X-C motif chemokine 10 and urine C-C motif ligand 2, plasma soluble tumor necrosis factor receptors 1 and 2, intercellular adhesion molecule 1 and serum amyloid A). The only adverse event rate that differed between groups was anemia at 32.0% (8/25) for baricitinib 4 mg daily versus 3.7% (1/27) for placebo. Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

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