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

Chin, M. P. et al. (2014) Risk factors for heart failure in patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl. Journal of Cardiac Failure, 20(12), pp. 953-958. (doi:10.1016/j.cardfail.2014.10.001) (PMID:25307295)

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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.

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:McMurray, Professor John
Authors: Chin, M. P., Wrolstad, D., Bakris, G. L., Chertow, G. M., de Zeeuw, D., Goldsberry, A., Linde, P. G., McCullough, P. A., McMurray, J., Wittes, J., and Meyer, C. J.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Journal of Cardiac Failure
Publisher:Elsevier B.V.
ISSN:1071-9164
ISSN (Online):1532-8414
Copyright Holders:Copyright © 2014 The Authors
First Published:First published in Journal of Cardiac Failure 20(12):953-958
Publisher Policy:Reproduced under a Creative Commons License

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