Adding a mineralocorticoid receptor modulator in heart failure with CKD

Combining the SGLT2 inhibitor dapagliflozin with the mineralocorticoid receptor (MR) modulator balcinrenone was not associated with significantly improved proteinuria than dapagliflozin alone in patients with heart failure (HF) and chronic kidney disease (CKD). The role of mineralocorticoid receptor modulators in heart failure requires further study.

Patients with HF and concomitant CKD have a worse prognosis than those without concomitant CKD, complicating treatment. MR modulators are underused in patients with CKD and are not recommended in patients with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m². “Balcinrenone, previously known as AZD9977, is a selective MR modulator that can separate organ-protective effects from urinary electrolyte excretion,” said Prof. Carolyn Lam (Duke-National University, Singapore) [1]. She presented the results of the phase 2b MIRACLE trial (NCT04595370), which evaluated whether balcinrenone may improve outcomes when added to dapagliflozin in patients with HF and CKD.

Participants with established HF and eGFR 30–60 mL/min/1.73m² were randomised 1:1:1:1 to dapagliflozin plus placebo or dapagliflozin plus balcinrenone (15 mg, 50 mg, or 150 mg). The primary endpoint was the relative change in urine albumin-creatinine ratio (UACR) from baseline to week 12. Enrolment was terminated early because of slow recruitment, and as a result, the planned sample size was not achieved. The efficacy and safety analyses included 133 and 131 participants, respectively.

The investigators observed reductions in UACR from baseline to week 12 in all balcinrenone arms compared with the placebo arm. Mean percentage change from baseline was −33.61% in the 15 mg group (P=0.1588); −11.83% in the 50 mg group (P=0.6846); and −36.12% in the 150 mg group (P=0.1398). “The reductions in UACR from baseline to week 12 were not significantly different from dapagliflozin alone; there was also no clear dose-response relationship,” Prof. Lam observed.

Safety analyses showed a trend towards a dose-dependent increase in serum potassium. Although hyperkalaemia was rare in this population, 1 participant in the balcinrenone 150 mg group met the hyperkalaemia discontinuation criterion of >6.0 mmol/L serum potassium. There was also a trend towards reduction in eGFR, which was most pronounced in the belcinrenone 150 mg group.

Prof. Lam concluded that further larger studies are needed to decide whether balcinrenone plus dapagliflozin may offer a novel route to beneficial effects of MR modulation in patients with HF and CKD.

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   1. Lam CSP, et al. A phase 2b, randomised, double-blind, active controlled, multi centre study to evaluate the efficacy, safety and tolerability of oral AZD9977 and dapagliflozin treatment in patients with heart failure. Late-breaking clinical science: medical therapy, Heart Failure 2024, 11–14 May, Lisbon, Portugal.

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Posted on 16 July 202416 July 2024