Effect of bardoxolone methyl on the urine albumin-to-creatinine ratio in patients with type 2 diabetes and stage 4 chronic kidney disease.

Abstract

Bardoxolone methyl attenuates inflammation by inducing nuclear factor erythroid-derived 2-related factor 2 and suppressing nuclear factor κB. The Bardoxolone Methyl Evaluation in Patients With Chronic Kidney Disease and Type 2 Diabetes (BEACON) trial was a phase 3 placebo-controlled, randomized, double-blind, parallel-group, international, multicenter trial in 2185 patients with type 2 diabetes mellitus and stage 4 chronic kidney disease. BEACON was terminated because of safety concerns, largely related to a significant increase in early heart failure events in patients randomized to bardoxolone methyl. Bardoxolone methyl resulted in increased estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio. Herein, we present post hoc analyses characterizing the relation between the urine albumin-to-creatinine ratio and eGFR. The urine albumin-to-creatinine ratio and eGFR were assessed every four weeks through Week 12, followed by assessments every eight weeks thereafter, and 4 weeks after the last dose of bardoxolone methyl was administered. The initial increases in urine albumin-to-creatinine ratio observed in patients randomized to bardoxolone methyl were attenuated after six months. Multivariable regression analysis identified baseline eGFR and eGFR over time as the dominant factors associated with change in the urine albumin-to-creatinine ratio. Relative to placebo, bardoxolone methyl resulted in a significant decrease in albuminuria when indexed to eGFR (least-squared means: -0.035 [95% confidence interval -0.031 to -0.039]). Thus, among patients with type 2 diabetes mellitus and stage 4 chronic kidney disease treated with bardoxolone methyl, changes in albuminuria are directly related to changes in eGFR, challenging the conventional construct that increases in albuminuria universally reflect kidney injury and denote harm.

• Authors: Peter Rossing, Geoffrey A Block, Melanie P Chin, Angie Goldsberry, Hiddo J L Heerspink, Peter A McCullough, Colin J Meyer, David Packham, Pablo E Pergola, Bruce Spinowitz, Stuart M Sprague, David G Warnock, Glenn M Chertow
• Journal: Kidney international (Kidney Int) Vol. 96 Issue 4 Pg. 1030-1036 (10 2019) ISSN: 1523-1755 [Electronic] United States
• PMID: 31377056 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Oleanolic Acid
• Creatinine
• bardoxolone methyl

Topics

• Adult
• Albuminuria (diagnosis, drug therapy, etiology)
• Creatinine (urine)
• Diabetes Mellitus, Type 2 (complications, urine)
• Diabetic Nephropathies (drug therapy, etiology, urine)
• Double-Blind Method
• Early Termination of Clinical Trials
• Female
• Glomerular Filtration Rate (drug effects)
• Heart Failure (chemically induced, epidemiology)
• Humans
• Kidney Failure, Chronic (drug therapy, etiology, urine)
• Male
• Middle Aged
• Oleanolic Acid (administration & dosage, adverse effects, analogs & derivatives)
• Treatment Outcome