PMID- 24903467
OWN - NLM
STAT- MEDLINE
DCOM- 20150330
LR  - 20210716
IS  - 1421-9670 (Electronic)
IS  - 0250-8095 (Linking)
VI  - 39
IP  - 6
DP  - 2014
TI  - Mechanisms contributing to adverse cardiovascular events in patients with type 2 
      diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone 
      methyl.
PG  - 499-508
LID - 10.1159/000362906 [doi]
AB  - BACKGROUND: Bardoxolone methyl, an Nrf2-activating and nuclear 
      factor-kappaB-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.
FAU - Chin, Melanie P
AU  - Chin MP
AD  - Reata Pharmaceuticals, Irving, Tex., USA.
FAU - Reisman, Scott A
AU  - Reisman SA
FAU - Bakris, George L
AU  - Bakris GL
FAU - O'Grady, Megan
AU  - O'Grady M
FAU - Linde, Peter G
AU  - Linde PG
FAU - McCullough, Peter A
AU  - McCullough PA
FAU - Packham, David
AU  - Packham D
FAU - Vaziri, Nosratola D
AU  - Vaziri ND
FAU - Ward, Keith W
AU  - Ward KW
FAU - Warnock, David G
AU  - Warnock DG
FAU - Meyer, Colin J
AU  - Meyer CJ
LA  - eng
PT  - Clinical Trial, Phase III
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20140603
PL  - Switzerland
TA  - Am J Nephrol
JT  - American journal of nephrology
JID - 8109361
RN  - 6SMK8R7TGJ (Oleanolic Acid)
RN  - 9NEZ333N27 (Sodium)
RN  - CEG1Q6OGU1 (bardoxolone methyl)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/*complications
MH  - Double-Blind Method
MH  - *Early Termination of Clinical Trials
MH  - Heart Failure/*chemically induced
MH  - Humans
MH  - Macaca fascicularis
MH  - Male
MH  - Oleanolic Acid/adverse effects/*analogs & derivatives
MH  - Rats
MH  - Renal Insufficiency, Chronic/complications/*drug therapy
MH  - Sodium/urine
MH  - Urine
MH  - Water-Electrolyte Imbalance/*chemically induced
EDAT- 2014/06/07 06:00
MHDA- 2015/03/31 06:00
CRDT- 2014/06/07 06:00
PHST- 2013/03/30 00:00 [received]
PHST- 2014/04/14 00:00 [accepted]
PHST- 2014/06/07 06:00 [entrez]
PHST- 2014/06/07 06:00 [pubmed]
PHST- 2015/03/31 06:00 [medline]
AID - 000362906 [pii]
AID - 10.1159/000362906 [doi]
PST - ppublish
SO  - Am J Nephrol. 2014;39(6):499-508. doi: 10.1159/000362906. Epub 2014 Jun 3.