Initial Changes in eGFR During Treatment with Balcinrenone and Dapagliflozin: An Exploratory Analysis of the MIRO-CKD Trial.

Abstract

Key points: Treatment with balcinrenone/dapagliflozin resulted in an acute reduction in eGFR, which was reversible after treatment discontinuation. Larger acute eGFR reductions were associated with greater reductions in urinary albumin-to-creatinine ratio and systolic BP during balcinrenone/dapagliflozin treatment. An acute reduction in eGFR during treatment with balcinrenone/dapagliflozin did not lead to increased rates of adverse events.

Introduction: The novel nonsteroidal mineralocorticoid receptor antagonist balcinrenone in combination with dapagliflozin reduced urinary albumin-to-creatinine ratio (UACR) over 12 weeks in the MIRO-CKD phase 2 trial in CKD and induced a modest acute eGFR reduction upon treatment initiation. This prespecified analysis explored the acute eGFR changes in response to balcinrenone/dapagliflozin and the association of these acute eGFR changes on safety and efficacy parameters.

Methods: Adults with CKD ( N =324, eGFR ≥25-<60 ml/min per 1.73 m 2 ; UACR ≥100-<5000 mg/g) were randomized to balcinrenone/dapagliflozin 15/10 mg, balcinrenone/dapagliflozin 40/10 mg, or dapagliflozin 10 mg/placebo as adjunct to renin-angiotensin system therapy. The primary outcome was the relative change in UACR from baseline over 12 weeks. Acute eGFR changes 4 weeks post randomization and 4 weeks post treatment were assessed using mixed model repeated measures. We categorized participants according to relative eGFR changes: ≥10% reduction (eGFR dip); >0-<10% reduction; or an eGFR increase. We examined safety and concomitant changes in systolic BP (SBP) and UACR across categories of eGFR changes.

Results: Relative to dapagliflozin/placebo, the acute eGFR dip at week 4 with balcinrenone/dapagliflozin 15/10 mg was -0.6 ml/min per 1.73 m 2 (95% confidence interval, -2.4 to 1.1) and with balcinrenone/dapagliflozin 40/10 mg -1.7 ml/min per 1.73 m 2 (95% confidence interval, -3.5 to -0.01). The acute reduction in eGFR with balcinrenone/dapagliflozin was reversible 4 weeks after treatment discontinuation. This finding was consistent across subgroups. In the overall cohort, larger acute eGFR reductions were associated with larger reductions in UACR and SBP across treatment arms. Rates of serious adverse events and adverse events of special interest were low, similar in the balcinrenone/dapagliflozin versus placebo/dapagliflozin group, and unrelated to the acute eGFR change.

Conclusion: In adults with CKD, balcinrenone/dapagliflozin induced a modest acute eGFR reduction that was reversible after treatment discontinuation, did not lead to increased rates of adverse events, and was associated with greater SBP and UACR lowering.

Clinical trial registry name and registration number: NCT06350123 .