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

Nephrol Dial Transplant. 2018 Nov 1;33(11):1950-1959. doi: 10.1093/ndt/gfx377.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Baricitinib decreased albuminuria in participants with Type 2 diabetes and DKD. Further research is required to determine if baricitinib reduces DKD progression.

Publication types

  • Clinical Trial, Phase II
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / drug therapy*
  • Albuminuria / etiology
  • Albuminuria / pathology
  • Azetidines / therapeutic use*
  • Diabetes Mellitus, Type 2 / physiopathology*
  • Diabetic Nephropathies / complications*
  • Double-Blind Method
  • Female
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glomerular Filtration Rate
  • Humans
  • Janus Kinase 1 / antagonists & inhibitors*
  • Janus Kinase 2 / antagonists & inhibitors*
  • Male
  • Middle Aged
  • Prognosis
  • Protein Kinase Inhibitors / therapeutic use
  • Sulfonamides / therapeutic use*

Substances

  • Azetidines
  • Protein Kinase Inhibitors
  • Sulfonamides
  • JAK1 protein, human
  • JAK2 protein, human
  • Janus Kinase 1
  • Janus Kinase 2
  • baricitinib