title: Mechanisms contributing to adverse cardiovascular events in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl.
abstract: BACKGROUND
  Bardoxolone methyl, an Nrf2-activating and nuclear factor-κB-inhibiting semisynthetic oleanane triterpenoid compound, was evaluated in a phase 3 trial (BEACON) in patients with type 2 diabetes mellitus (T2DM) and stage 4 chronic kidney disease (CKD). The trial was terminated because of an increase in heart failure events in the bardoxolone methyl group, many of which appeared related to fluid retention. Thus, additional analyses were conducted to explain these serious adverse events.
  
  
  METHODS
  Patients (n = 2,185) were randomized to receive once-daily bardoxolone methyl (20 mg) or placebo. Twenty-four-hour urine collections were analyzed in a subset of the BEACON population and from a separate, open-label pharmacology study in patients with stage 3b/4 CKD and T2DM administered 20 mg bardoxolone methyl once daily for 56 consecutive days.
  
  
  RESULTS
  Bardoxolone-methyl-treated patients in the BEACON substudy had a clinically meaningful reduction in urine volume and sodium excretion at week 4 relative to baseline (p < 0.05), and a separate study revealed that decreased sodium excretion and urine output occurred in some patients with stage 4 CKD but not those with stage 3b CKD. The clinical phenotype of fluid overload and heart failure in BEACON was similar to that observed with endothelin receptor antagonists in advanced CKD patients, and preclinical data demonstrate that bardoxolone methyl modifies endothelin signaling.
  
  
  CONCLUSIONS
  The totality of the evidence suggests that through modulation of the endothelin pathway, bardoxolone methyl may pharmacologically promote acute sodium and volume retention and increase blood pressure in patients with more advanced CKD.
authors.affiliation: Reata Pharmaceuticals, Irving, Tex., USA.
authors.forename: Melanie P
authors.initials: MP
authors.lastname: Chin
authors.forename: Scott A
authors.initials: SA
authors.lastname: Reisman
authors.forename: George L
authors.initials: GL
authors.lastname: Bakris
authors.forename: Megan
authors.initials: M
authors.lastname: O'Grady
authors.forename: Peter G
authors.initials: PG
authors.lastname: Linde
authors.forename: Peter A
authors.initials: PA
authors.lastname: McCullough
authors.forename: David
authors.initials: D
authors.lastname: Packham
authors.forename: Nosratola D
authors.initials: ND
authors.lastname: Vaziri
authors.forename: Keith W
authors.initials: KW
authors.lastname: Ward
authors.forename: David G
authors.initials: DG
authors.lastname: Warnock
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Meyer
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D004311:Double-Blind Method; D057239:Early Termination of Clinical Trials; D006333:Heart Failure / Q000139:chemically induced*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009828:Oleanolic Acid / Q000009:adverse effects / Q000031:analogs & derivatives*; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000150:complications / Q000188:drug therapy*; D012964:Sodium / Q000652:urine; D014556:Urine; D014883:Water-Electrolyte Imbalance / Q000139:chemically induced*
chemical_list: D009828:Oleanolic Acid; D012964:Sodium; C445068:bardoxolone methyl