title: Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.
abstract: BACKGROUND
  A phase 3 randomized clinical trial was designed to test whether bardoxolone methyl, a nuclear factor erythroid-2-related factor 2 (Nrf2) activator, slows progression to end-stage renal disease in patients with stage 4 chronic kidney disease and type 2 diabetes mellitus. The trial was terminated because of an increase in heart failure in the bardoxolone methyl group; many of the events were clinically associated with fluid retention.
  
  
  RESULTS
  We randomized 2,185 patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD) (estimated glomerular filtration rate 15 to <30 mL min(-1) 1.73 m(-2)) to once-daily bardoxolone methyl (20 mg) or placebo. We used classification and regression tree analysis to identify baseline factors predictive of heart failure or fluid overload events. Elevated baseline B-type natriuretic peptide and previous hospitalization for heart failure were identified as predictors of heart failure events; bardoxolone methyl increased the risk of heart failure by 60% in patients with these risk factors. For patients without these baseline characteristics, the risk for heart failure events among bardoxolone methyl- and placebo-treated patients was similar (2%). The same risk factors were also identified as predictors of fluid overload and appeared to be related to other serious adverse events.
  
  
  CONCLUSIONS
  Bardoxolone methyl contributed to events related to heart failure and/or fluid overload in a subpopulation of susceptible patients with an increased risk for heart failure at baseline. Careful selection of participants and vigilant monitoring of the study drug will be required in any future trials of bardoxolone methyl to mitigate the risk of heart failure and other serious adverse events.
authors.affiliation: Reata Pharmaceuticals, Irving, Texas.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Chin
authors.affiliation: Statistics Collaborative, Washington, DC.
authors.forename: Danielle
authors.initials: D
authors.lastname: Wrolstad
authors.affiliation: University of Chicago Medicine, Chicago, Illinois.
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.affiliation: Department of Medicine, Stanford University School of Medicine, Palo Alto, California.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Chertow
authors.affiliation: Department of Clinical Pharmacology, University of Groningen University Medical Center, Groningen, the Netherlands.
authors.forename: Dick
authors.initials: D
authors.lastname: de Zeeuw
authors.affiliation: Reata Pharmaceuticals, Irving, Texas.
authors.forename: Angie
authors.initials: A
authors.lastname: Goldsberry
authors.affiliation: Abbvie Pharmaceuticals, Chicago, Illinois.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Linde
authors.affiliation: Baylor University Medical Center, Dallas, Texas; Baylor Heart and Vascular Institute, Baylor Jack and Jane Hamilton Heart and Vascular Hospital, Heart Hospital, Plano, Texas.
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.affiliation: BHF Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom.
authors.forename: John J
authors.initials: JJ
authors.lastname: McMurray
authors.affiliation: Statistics Collaborative, Washington, DC.
authors.forename: Janet
authors.initials: J
authors.lastname: Wittes
authors.affiliation: Reata Pharmaceuticals, Irving, Texas. Electronic address: colin.meyer@reatapharma.com.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
mesh_terms: D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D005500:Follow-Up Studies; D005919:Glomerular Filtration Rate; D006333:Heart Failure / Q000139:chemically induced* / Q000401:mortality / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D009828:Oleanolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D061214:Patient Safety; D011237:Predictive Value of Tests; D012016:Reference Values; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D012307:Risk Factors; D012720:Severity of Illness Index; D015996:Survival Rate; D016896:Treatment Outcome
chemical_list: D020097:Natriuretic Peptide, Brain; D009828:Oleanolic Acid; C445068:bardoxolone methyl
keywords: B-type natriuretic peptide; Bardoxolone methyl; chronic kidney disease; randomized controlled trial