title: Bardoxolone methyl in type 2 diabetes and stage 4 chronic kidney disease.
abstract: Although inhibitors of the renin-angiotensin-aldosterone system can slow the progression of diabetic kidney disease, the residual risk is high. Whether nuclear 1 factor (erythroid-derived 2)-related factor 2 activators further reduce this risk is unknown.
  
  
  
  We randomly assigned 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease (estimated glomerular filtration rate [GFR], 15 to <30 ml per minute per 1.73 m(2) of body-surface area) to bardoxolone methyl, at a daily dose of 20 mg, or placebo. The primary composite outcome was end-stage renal disease (ESRD) or death from cardiovascular causes.
  
  
  
  The sponsor and the steering committee terminated the trial on the recommendation of the independent data and safety monitoring committee; the median follow-up was 9 months. A total of 69 of 1088 patients (6%) randomly assigned to bardoxolone methyl and 69 of 1097 (6%) randomly assigned to placebo had a primary composite outcome (hazard ratio in the bardoxolone methyl group vs. the placebo group, 0.98; 95% confidence interval [CI], 0.70 to 1.37; P=0.92). In the bardoxolone methyl group, ESRD developed in 43 patients, and 27 patients died from cardiovascular causes; in the placebo group, ESRD developed in 51 patients, and 19 patients died from cardiovascular causes. A total of 96 patients in the bardoxolone methyl group were hospitalized for heart failure or died from heart failure, as compared with 55 in the placebo group (hazard ratio, 1.83; 95% CI, 1.32 to 2.55; P<0.001). Estimated GFR, blood pressure, and the urinary albumin-to-creatinine ratio increased significantly and body weight decreased significantly in the bardoxolone methyl group, as compared with the placebo group.
  
  
  
  Among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease, bardoxolone methyl did not reduce the risk of ESRD or death from cardiovascular causes. A higher rate of cardiovascular events with bardoxolone methyl than with placebo prompted termination of the trial. (Funded by Reata Pharmaceuticals; BEACON ClinicalTrials.gov number, NCT01351675.).
authors.affiliation: From the University of Groningen, Groningen, the Netherlands (D.Z., H.J.L.H.); Showa University School of Medicine, Tokyo (T.A.); Reata Pharmaceuticals, Irving, TX (P.A., M.C., A.G., M.K., C.J.M.); University of Chicago (G.L.B.) and AbbVie Pharmaceuticals (M.H.) - both in Chicago; Statistics Collaborative, Washington, DC (H.C.-S., J.W., D.W.); University of Glasgow, Glasgow, United Kingdom (J.J.M.); Rigshospitalet, University of Copenhagen, Copenhagen (H.-H.P.); Istituto di Ricovero e Cura a Carattere Scientifico-Istituto di Ricerche Farmacologiche Mario Negri, Bergamo, Italy (G.R.); University of Texas Southwestern Medical Center, Dallas (R.D.T.); University of California, Irvine (N.D.V.); University of Würzburg, Würzburg, Germany (C.W.); and Stanford University, Palo Alto, CA (G.M.C.).
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.forename: Tadao
authors.initials: T
authors.lastname: Akizawa
authors.forename: Paul
authors.initials: P
authors.lastname: Audhya
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.forename: Melanie
authors.initials: M
authors.lastname: Chin
authors.forename: Heidi
authors.initials: H
authors.lastname: Christ-Schmidt
authors.forename: Angie
authors.initials: A
authors.lastname: Goldsberry
authors.forename: Mark
authors.initials: M
authors.lastname: Houser
authors.forename: Melissa
authors.initials: M
authors.lastname: Krauth
authors.forename: Hiddo J
authors.initials: HJ
authors.lastname: Lambers Heerspink
authors.forename: John J
authors.initials: JJ
authors.lastname: McMurray
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
authors.forename: Hans-Henrik
authors.initials: HH
authors.lastname: Parving
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
authors.forename: Robert D
authors.initials: RD
authors.lastname: Toto
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Christoph
authors.initials: C
authors.lastname: Wanner
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.forename: Danielle
authors.initials: D
authors.lastname: Wrolstad
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Chertow
mesh_terms: D000368:Aged; D002318:Cardiovascular Diseases / Q000209:etiology / Q000401:mortality*; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D003928:Diabetic Nephropathies / Q000188:drug therapy*; D004311:Double-Blind Method; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D057194:Intention to Treat Analysis; D053208:Kaplan-Meier Estimate; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000517:prevention & control*; D008297:Male; D008875:Middle Aged; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy* / Q000503:physiopathology; D017211:Treatment Failure; D015431:Weight Loss / Q000187:drug effects
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009828:Oleanolic Acid; C445068:bardoxolone methyl