INTRODUCTION AND AIMS: Bardoxolone methyl (BARD) promotes resolution of inflammation by inducing Nrf2 and suppressing NF-kB. Treatment with bardoxolone methyl in a phase 2 study (BEAM) and a subsequent phase 3 study (BEACON) in patients with type 2 diabetes and chronic kidney disease (CKD) resulted in increases in estimated glomerular filtration rate (eGFR) as well as urinary albumin-to-creatinine ratio (UACR). Additional post-hoc analyses were performed to further understand the relationship between urinary albumin excretion and eGFR with BARD in CKD patients.
METHODS: Patients in BEAM (n=227) were randomized 1:1:1:1 to oral placebo or bardoxolone methyl (25, 75, or 150 mg of crystalline formulation) for 52 weeks. Patients in BEACON (n=2185) were randomized 1:1 to placebo or bardoxolone methyl (20 mg of amorphous spray-dried dispersion formulation). A longitudinal model was used to compare log UACR/eGFR changes in BARD versus placebo groups in BEAM and BEACON.
RESULTS: Initial UACR increases in BEAM and BEACON were attenuated after 6 months in bardoxolone methyl-treated patients. The increases in UACR were significantly correlated with increases in eGFR in both studies. Furthermore, overall changes in log UACR/eGFR ratios with BARD were lower than placebo (least-squared means: -0.017 and -0.024 versus placebo in BEAM and BEACON, respectively), suggesting that when adjusted for eGFR changes, bardoxolone methyl may reduce albumin excretion relative to placebo.
CONCLUSIONS:Conclusions: The profile of proteinuria increases with bardoxolone methyl treatment is distinct from those associated with the progression of CKD. Instead, the transient increases in urinary albumin excretion are likely due to increases in filtration and decreased tubular albumin absorption.
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