Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl

J Card Fail. 2014 Dec;20(12):953-8. doi: 10.1016/j.cardfail.2014.10.001. Epub 2014 Oct 13.


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.

Methods and 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.

Keywords: B-type natriuretic peptide; Bardoxolone methyl; chronic kidney disease; randomized controlled trial.

Publication types

  • Clinical Trial, Phase III
  • Comparative Study
  • Randomized Controlled Trial

MeSH terms

  • Aged
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / diagnosis*
  • Diabetes Mellitus, Type 2 / drug therapy
  • Diabetes Mellitus, Type 2 / mortality
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Early Termination of Clinical Trials*
  • Female
  • Follow-Up Studies
  • Glomerular Filtration Rate
  • Heart Failure / chemically induced*
  • Heart Failure / mortality
  • Heart Failure / physiopathology
  • Humans
  • Male
  • Middle Aged
  • Natriuretic Peptide, Brain / blood
  • Oleanolic Acid / administration & dosage
  • Oleanolic Acid / adverse effects
  • Oleanolic Acid / analogs & derivatives*
  • Patient Safety
  • Predictive Value of Tests
  • Reference Values
  • Renal Insufficiency, Chronic / complications
  • Renal Insufficiency, Chronic / drug therapy*
  • Renal Insufficiency, Chronic / mortality
  • Risk Factors
  • Severity of Illness Index
  • Survival Rate
  • Treatment Outcome


  • Natriuretic Peptide, Brain
  • Oleanolic Acid
  • bardoxolone methyl