Key result
Aldosterone synthase inhibitors lower blood pressure and albuminuria but lack hard renal or CV outcome data.
Why the study?
Aldosterone excess causes maladaptive cardiorenal effects that persist despite RAS blockade, and current MRAs have limitations including aldosterone escape and side effects, motivating evaluation of highly selective aldosterone synthase inhibitors in CKD and cardiovascular risk.
Do highly selective aldosterone synthase inhibitors improve surrogate renal and cardiovascular endpoints in patients with chronic kidney disease?
Do highly selective aldosterone synthase inhibitors improve surrogate renal and cardiovascular endpoints in patients with chronic kidney disease?
Highly selective aldosterone synthase inhibitors effectively reduce surrogate markers like blood pressure and albuminuria, with manageable safety profiles, though hard clinical outcome data is still pending.
Aldosterone synthase inhibitors should not yet alter cardiorenal management; extends surrogate reductions but leaves hard renal and CV outcomes unproven.
Aldosterone excess contributes to a range of maladaptive cardiorenal consequences—including glomerulosclerosis, tubulointerstitial fibrosis, proteinuria, podocyte injury, cardiac fibrosis, and endothelial dysfunction—that may persist despite optimal renin–angiotensin system (RAS) blockade. Although efficacious, steroidal mineralocorticoid receptor antagonists (MRAs) are limited by aldosterone escape, hyperkalaemia, and, in the case of spironolactone, anti-androgenic side effects; the nonsteroidal MRA finerenone mitigates the sex-steroid liabilities but does not eliminate reactive aldosterone elevation. Highly selective aldosterone synthase inhibitors (ASIs) act upstream by inhibiting CYP11B2. Among second-generation agents, baxdrostat (CIN-107; CinCor Pharma/AstraZeneca) has been studied across the broadest range of indications, whereas vicadrostat (BI 690517; Boehringer Ingelheim) is the agent furthest advanced specifically for renal endpoints. In a phase 2 randomised controlled trial, vicadrostat 10 mg reduced the urine albumin-to-creatinine ratio (UACR) by approximately 39–40% versus placebo, with similar reductions whether given alone or on an empagliflozin background. In phase 3 hypertension trials, baxdrostat and lorundrostat (MLS-101; Mineralys Therapeutics) produced placebo-corrected office systolic blood pressure reductions of 9.8 mmHg and 9.1 mmHg, respectively. Importantly, no completed trial has yet demonstrated that any ASI reduces hard renal or cardiovascular outcomes; all current efficacy data rest on surrogate endpoints (albuminuria and blood pressure), and the phase 3 EASi-KIDNEY and BaxDuo-Pacific outcome trials remain ongoing. The reported safety profile of second-generation ASIs includes dose-dependent but generally manageable hyperkalaemia (approximately 15% at the vicadrostat 10 mg dose), a low incidence of adrenal insufficiency (≤3%), and preservation of cortisol synthesis without sex-steroid side effects. This review appraises the mechanism, current clinical evidence, safety considerations, and future directions of highly selective ASIs in chronic kidney disease (CKD).
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Nandicoor et al. (2026) conducted a review in Chronic kidney disease. Highly selective aldosterone synthase inhibitors was evaluated. Highly selective aldosterone synthase inhibitors reduce surrogate endpoints like albuminuria and blood pressure, but no trial has yet demonstrated reductions in hard renal or cardiovascular outcomes.
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