The paradox of bardoxolone methyl: a call for every witness on the stand?

Abstract

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.

Insulin Inhibits Nrf2 Gene Expression via Heterogeneous Nuclear Ribonucleoprotein F/K in Diabetic Mice

“…It has been noted (53), however, that bardoxolone methyl heightened SBP and worsened albuminuria, whereas selective ET-A antagonists lessened them in the Efficacy and Safety of Pirfenidone in Patients With Idiopathic Pulmonary Fibrosis trial (54). Our study demonstrates that insulin treatment prevents oltipraz and Nrf2 stimulation of Agt gene expression, suggesting that chronic Nrf2 activation by hyperglycemia and/or Nrf2 activator(s) may exaggerate renal dysfunction via activation of the intrarenal RAS, thereby enhancing renal fluid and salt reabsorption.…”

The protective effect of CDDO-Me on lipopolysaccharide-induced acute lung injury in mice

“…Unfortunately, it suffered a termination in the phase 3 trial of Chronic Kidney Disease and Type 2 diabetes for the reason of excessive cardiovascular disease and especially heart failure in patients [13]. Presently it is being further tested for the intervention of patients with cancer, chronic kidney disease and pulmonary arterial hypertension.…”

Diabetic nephropathy: Time to withhold development and progression - A review

“…Reduced cardioprotective, nephroprotective, and antihypertensive effects of RAS blockers because of their increased excretion in the bardoxolone methyl group may be responsible for the increased cardiovascular events [87]. Endothelial dysfunction, a possible sequence of hypomagnesemia, might be another explanation for increased proteinuria, heart failure, increased mortality and muscle spasm [88].…”