The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial

Abstract

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared with placebo, with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11 000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Keywords: CKD; aldosterone; cardiovascular; clinical trial; heart failure.

Graphical Abstract

Figure 1:

The renin-angiotensin-aldosterone system (RAAS) pathway and mechanisms of inhibition. Angiotensin-II causes sodium and water retention and increased blood pressure through several mechanisms including arteriolar vasoconstriction, increased sympathetic drive, hypothalamic thirst centre stimulation, posterior pituitary anti-diuretic hormone release, increased renal tubular sodium reabsorption, in addition to stimulating adrenal aldosterone synthesis. The activity of the renin-angiotensin system (RAS) is blocked by both ACE inhibitors and angiotensin-II receptor blockers. Classical genomic effects of aldosterone are mediated by aldosterone binding to cytoplasmic mineralocorticoid receptor (MR). Other modulators of the MR include sodium, caveolin-1, and Rac-1. Rapid non-genomic effects of aldosterone are modulated by intracellular second messenger molecules such as protein kinase C, epidermal growth factor receptor, and members of the mitogen-activated protein kinase family. The mechanism of interactions between genomic and non-genomic effects of aldosterone are unclear. Addition of MR antagonism has been shown to inhibit the effects of aldosterone, reducing albuminuria, risk of kidney disease progression, and heart failure hospitalization, but increases blood aldosterone levels. Aldosterone synthase inhibitors are an alternative method to target the effects of aldosterone excess.

Figure 2:

Aldosterone and cortisol synthesis pathway and the qualitative effects of inhibiting aldosterone synthase with vicadrostat (BI 690517) in patients with CKD. ASi = aldosterone synthase inhibitor. Arrows represent observed effects of vicadrostat on aldosterone and cortisol in the phase II CKD trial (1378-0005), and predicted directions of effect of vicadrostat on their circulating precursors. The comparator for the 250-fold selectivity is cortisol synthase. Hypothetically, adrenal effects of aldosterone synthase inhibition could result in no effect on serum cortisol, or could result in decreased or increased serum cortisol concentrations. Decreases may result from possible inhibition of cortisol synthase, which would inhibit conversion or 11-deoxycortisol to cortisol. Inhibition of aldosterone synthase also results in increased levels of 11-deoxycorticosterone (i.e. the shared precursor of both aldosterone and cortisol), which could lead to increased substrate for cortisol synthesis.

Figure 3:

Effect of vicadrostat (BI 690517) 10 mg once daily versus placebo on urine albumin-to-creatinine ratio (UACR) when given in combination with empagliflozin overall (Fig. 3A) and by diabetes status (Fig. 3B) from the phase II CKD trial (1378-0005 post-hoc analyses). Linear mixed models for repeated measures analyses were used to estimate the difference in log transformed uACR from baseline to 14 weeks. Dotted lines are for active vicadrostat, solid lines are for placebo.

Figure 4:

Effect of vicadrostat (BI 690517) 10 mg when combined with empagliflozin, compared with placebo on mean and median potassium concentration by baseline potassium from the phase II CKD trial (1378-0005 post-hoc analyses). P-value for trend across mean differences = 0.15.

Figure 5:

EASi-KIDNEY's double-blind placebo control design outline. Each stratum has the same design and will recruit in parallel. The sample sizes were selected in order that each stratum should separately accrue 1070 outcomes over a median follow-up of 3.0 years.