The paradox of bardoxolone methyl: a call for every witness on the stand?
Article first published online: 4 AUG 2014
© 2014 John Wiley & Sons Ltd
Diabetes, Obesity and Metabolism
Volume 17, Issue 1, pages 9–14, January 2015
How to Cite
Van Laecke, S., Van Biesen, W. and Vanholder, R. (2015), The paradox of bardoxolone methyl: a call for every witness on the stand?. Diabetes, Obesity and Metabolism, 17: 9–14. doi: 10.1111/dom.12356
- Issue published online: 8 DEC 2014
- Article first published online: 4 AUG 2014
- Accepted manuscript online: 14 JUL 2014 07:11AM EST
- Manuscript Revised: 7 JUL 2014
- Manuscript Accepted: 7 JUL 2014
- Manuscript Received: 20 FEB 2014
- bardoxolone methyl;
People with type 2 diabetes and chronic kidney disease (CKD) remain an extremely vulnerable population with increased cardiovascular morbidity, mortality and mounting societal costs. As such, any effort to improve their dismal outcome is heavily supported. Yet, most drugs fail to replicate the promising signals of early experiments in humans in large and methodologically sound trials. As a recent example, an independent data and safety committee advised the termination of a phase 3 trial due to excessive cardiovascular disease and especially heart failure in patients allocated to the antioxidant synthetic triterpenoid bardoxolone methyl versus placebo. We evaluate the reasons why this outcome in hindsight was possibly not totally unexpected and develop a mechanistic model that shows that the consistent drop in serum magnesium concentration in patients exposed to bardoxolone methyl might have contributed to the development of heart failure. As such, this trial, despite its negative outcome, might provide additional pieces of the puzzle enabling us to get a better grip on diseases that share increased inflammation and oxidative stress, such as type 2 diabetes, metabolic syndrome, heart failure and CKD.