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The paradox of bardoxolone methyl: a call for every witness on the stand?
Author(s) -
Van Laecke S.,
Van Biesen W.,
Vanholder R.
Publication year - 2015
Publication title -
diabetes, obesity and metabolism
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.445
H-Index - 128
eISSN - 1463-1326
pISSN - 1462-8902
DOI - 10.1111/dom.12356
Subject(s) - heart failure , medicine , placebo , disease , clinical trial , intensive care medicine , population , diabetes mellitus , kidney disease , hindsight bias , endocrinology , alternative medicine , psychology , pathology , environmental health , cognitive psychology
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.