Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

Rajiv Agarwal; Peter Kolkhof; George Bakris; Johann Bauersachs; Hermann Haller; Takashi Wada; Faiez Zannad

Disclosures

Eur Heart J. 2021;42(2):152-161. 

In This Article

Nonsteroidal Mineralocorticoid Receptor Antagonism for Cardiorenal Disease

Results of RALES[17] and EPHESUS[21] trials, and a subsequent observation of high incidence of spironolactone-associated hyperkalaemia in clinical practice,[58] sparked considerable efforts to identify potent, yet selective, nonsteroidal MRAs for cardiorenal medicine with a favourable benefit–risk profile. Technological advances, such as cloning human MR complementary DNA[38] and high-throughput screening assays, led to the discovery of novel, nonsteroidal MRAs.[59] Several pharmaceutical companies are investigating this new class of compounds, some of which include: LY 2623091 (Eli Lilly; no longer in development), PF-03882845 (Pfizer; no longer in development), AZD9977 (AstraZeneca; Phase I), apararenone (Mitsubishi Tanabe; unknown status after Phase II), KBP-5074 (KBP Biosciences; Phase II), esaxerenone (Daiichi Sankyo; launched in Japan for hypertension), and finerenone (Bayer AG; Phase III).[16,60]

Several key differences exist between steroidal and nonsteroidal MRAs. Most of the available evidence exploring these differences is available for finerenone; therefore, in this section and in Table 1, we have focused our discussion on the characteristics of steroidal MRAs with those of finerenone. Finerenone is a novel, selective, nonsteroidal MRA, currently under investigation in patients with CKD and T2D to slow the progression of kidney disease and reduce risk of CV events.[1,2] We draw from other nonsteroidal MRAs where relevant comparisons are available.[69–71] Other nonsteroidal MRAs have different physicochemical and pharmacological properties, but corresponding comparisons within this class are pending due to missing data.

Comparison Between Nonsteroidal Mineralocorticoid Receptor Antagonist (Finerenone) and Steroidal Mineralocorticoid Receptor Antagonists

Mode of Mineralocorticoid Receptor Antagonism. Nuclear receptors such as the MR comprise discrete domains for specific functions including ligand binding, activation, and DNA recognition. There are at least 22 known cofactors that associate with MR[72] that determine the full transcriptional response mediated by the MR in a cell-specific manner.[68,72] Molecular modelling studies of the finerenone–MR complex suggest that finerenone blocks the MR as a bulky, passive antagonist. This mechanism is distinct from steroidal MRAs, which might impact its differential clinical response.[61] Finerenone's unique binding mode determines potency, selectivity, and nuclear cofactor recruitment, while its physicochemical properties, including lipophilicity and polarity, determine tissue penetration and distribution, which in combination offer a novel MRA pharmacology with pronounced anti-fibrotic efficacy in animal models. Compared with other MRAs, finerenone has differential downstream effects on MR blockade (Figure 2). Finerenone is more selective for the MR than eplerenone and spironolactone and is at least as potent as spironolactone.[16]

Figure 2.

Finerenone reduces cofactor recruitment to the mineralocorticoid receptor, thereby reducing downstream expression of pro-inflammatory and pro-fibrotic factors following mineralocorticoid receptor overactivation. MR, mineralocorticoid receptor.

Tissue Distribution. Experiments using [14C]-labelled eplerenone or [3H]-spironolactone demonstrated a higher accumulation of drug-equivalent concentrations in kidney vs. heart tissue in rodents, whereas [14C]-labelled finerenone demonstrated a balanced kidneys–heart distribution in rats.[62–64] This may contribute to the greater effect of spironolactone and eplerenone on sodium and potassium balance.[62] In addition, finerenone does not cross the blood–brain barrier; finerenone was not detected in brain tissue following oral application of the radio-labelled drug in preclinical studies.[73]

Pharmacokinetics. Differential effects have been observed with once-daily and twice-daily dosing of MRAs, suggesting that length of exposure might influence pharmacodynamic response.[16] For example, eplerenone twice daily (half-life of 4–6 h)[64] has a greater BP-lowering effect than once-daily administration;[27] however, single daily dosing is sufficient to observe mortality benefits in HF.[21] It is, therefore, hypothesized that effects including BP control and serum potassium changes may result from longer MRA exposure and that the anti-inflammatory and anti-fibrotic response might be exerted via a signalling cascade that can be sufficiently blocked by a shorter MRA exposure.[16] Compared with steroidal MRAs, finerenone has greater polarity and is 6- to 10-fold less lipophilic.[60] Kidney elimination of finerenone is minimal; it has a short half-life (2–3 h in patients with kidney failure) and no active metabolites.[66,67,74] Conversely, spironolactone is a prodrug with biologically active metabolites (e.g. canrenone and 7-α-thiomethylspironolactone), which have long half-lives and can accumulate over time.[65] This is evident in a clinical setting, where spironolactone metabolites were measured in patients with eGFR 25–45 mL/min/1.73 m2: 38% of patients had detectable urinary levels of metabolites up to 3 weeks after stopping treatment (Figure 3). In fact, over half of the systolic BP-lowering effect was retained 2 weeks after stopping treatment, suggesting that the metabolite-induced haemodynamic effects had persisted especially among patients with moderate-to-advanced CKD.[75] Likely, spontaneous recovery from hyperkalaemia may not be expected immediately after spironolactone discontinuation.

Figure 3.

Mean relative exposure of spironolactone and spironolactone metabolites in healthy volunteers (n = 12). AUC, area under the concentration–time curve.

Effect on Cofactor Recruitment to the Mineralocorticoid Receptor Complex in the Presence or Absence of Aldosterone. Finerenone can act in vitro as an inverse agonist to the MR, i.e. reducing cofactor recruitment even in the absence of aldosterone, whereas spironolactone and eplerenone exhibit partial agonism on cofactor recruitment, but to a lesser extent than aldosterone.[61,68] This suggests that, unlike other MRAs, finerenone blocks deleterious gene activation by the MR independently of aldosterone.[60,68] Finerenone also blocks the human mutant MR, S810L, which is activated by both progesterone and steroidal MRAs (spironolactone and eplerenone) and associated with hypertension during pregnancy.[61,76] The combination of a specific antagonistic binding mode for finerenone with its physicochemical properties yielded in a novel MRA pharmacology with a pronounced anti-hypertrophic/-fibrotic efficacy for a given natriuretic activity, as demonstrated in preclinical models.[16,60,68]

Electrolyte Effects vs. Anti-fibrotic Effects

Both eplerenone[77] and finerenone[78] have been associated with anti-fibrotic effects in preclinical studies. MR antagonism decreases macrophage expression of the pro-fibrotic genes tumour growth factor-β1 and plasminogen activator inhibitor-1 and increases the expression of anti-fibrotic genes.[79]

In models of kidney injury, finerenone reduced the expression of pro-inflammatory and pro-fibrotic markers and reduced proteinuria and tubulointerstitial fibrosis, including at doses that did not significantly affect BP.[62,80] Compared with eplerenone at equinatriuretic doses, finerenone was associated with less kidney hypertrophy, proteinuria, and renal pro-inflammatory/pro-fibrotic gene expression in response to kidney injury.[62] Compared with eplerenone in models of cardiac fibrosis, finerenone also demonstrated qualitatively different effects on pro-fibrotic gene expression and measures of inflammation and fibrosis.[62,68] However, the benefits of MRAs on kidney and cardiac outcomes need to be balanced against the risk of hyperkalaemia. A nonsteroidal MRA (PF-03882845) was compared with eplerenone in a rat model of CKD[81] and a therapeutic index was calculated as the ratio of drug concentration that increased serum potassium to the respective drug concentration that lowered urinary albumin. This was 1.5-fold for eplerenone but 84-fold for PF-03882845,[81] providing further evidence for a reduced risk of hyperkalaemia with the nonsteroidal MRA PF-03882845 vs. steroidal MRA in a relevant preclinical CKD model.

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