Steroidal and Non-steroidal Mineralocorticoid Receptor Antagonists in Cardiorenal Medicine

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


Eur Heart J. 2021;42(2):152-161. 

In This Article

Clinical Development Programme of Nonsteroidal Mineralocorticoid Receptor Antagonists

Two nonsteroidal MRAs have progressed into Phase III development: finerenone and esaxerenone. The first large Phase III trial on finerenone's kidney outcomes (FIDELIO-DKD; N = 5734) in patients with CKD and T2D was recently completed, meeting its primary endpoint.[1,82] Two Phase III studies are ongoing for finerenone to investigate its effect on CV outcomes in patients with CKD and T2D (FIGARO-DKD),[2] and to evaluate morbidity and mortality outcomes in patients with symptomatic HF (NYHA Class II–IV and LVEF ≥40%; FINEARTS-HF).[83] Esaxerenone is approved for the treatment of essential hypertension in Japan.[84] Albuminuria reduction was demonstrated in a Phase III trial of patients with T2D and high albuminuria [urine albumin-to-creatinine ratio (UACR) ≥45 to ≤300 mg/g and eGFR ≥30 mL/min/1.73 m2);[3] treatment discontinuation rate due to hyperkalaemia was 3%, 3%, and 10% in patients treated with 1.25, 2.5, and 5 mg esaxerenone, respectively, vs. placebo.[3] Differences in clinical effects between nonsteroidal MRAs, such as BP and hyperkalaemia, appear to exist based on indirect comparisons, but definitive conclusions cannot be made without head-to-head studies.[16]

The Phase II ARTS programme investigating finerenone comprised five Phase II studies in over 2000 patients (Figure 4).[73,85,86] ARTS was designed to test the safety and tolerability of finerenone in patients with HFrEF and mild-to-moderate CKD.[73] Mean increases in serum potassium concentration were significantly smaller with all doses of finerenone vs. spironolactone 50 mg daily, and decline in eGFR was reduced with finerenone, leading to fewer patients with hyperkalaemia, kidney failure, or kidney impairment (Figure 4).[73] The primary endpoint in ARTS-HF was proportion of patients with >30% decline in NT-proBNP from baseline to day 90.[86] Achievement of this endpoint was comparable with eplerenone at all finerenone doses tested (2.5–20.0 mg), but the composite secondary endpoint of all-cause mortality, CV hospitalization, and emergency presentation for HF was nominally improved with finerenone 10–20 mg vs. eplerenone. However, these results must be interpreted with caution as the study was not powered to investigate treatment effects on hard outcomes (Figure 4).[86] The primary outcome in ARTS-DN of UACR reduction from baseline to day 90 was found to be dose dependent for finerenone (Figure 4).[85] This was statistically significant for the four highest doses of finerenone, with a placebo-corrected UACR reduction of 38% at 20 mg/day.[85] Post hoc analysis showed that UACR changes were independent of changes in BP or eGFR, suggesting non-haemodynamic effects.[85] There were no differences in the overall incidence of adverse events, including an eGFR reduction of ≥30%, between finerenone and placebo.[85] The rate of treatment discontinuation due to hyperkalaemia was low and not dose dependent.[85]

Figure 4.

Key results of the ARTS, ARTS-HF, and ARTS-DN Phase II studies. *Significant (P ≤ 0.001); #Nominal statistical significance in the finerenone 10–20 mg group (hazard ratio = 0.56, 95% confidence interval 0.35; 0.90, P = 0.02). CV, cardiovascular; CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; HFrEF, heart failure with reduced ejection fraction; NT-proBNP, N-terminal pro-B-type natriuretic peptide; T2D, Type 2 diabetes; UACR, urine albumin-to-creatinine ratio.

A meta-regression analysis of drug trials correlated interventions leading to UACR reductions of 30% with a 23.7% reduced risk of kidney failure (95% CI 11.4–34.2%).[87] Based on promising Phase II results from ARTS-DN, with 30–40% UACR reduction at doses with minimal effects on potassium and BP,[73,85,86] finerenone is being investigated in the largest event-driven Phase III clinical programme of CKD in T2D to date; it is powered to detect a 20% relative risk reduction in the primary endpoint. FIDELIO-DKD (NCT02540993) is a randomized, double-blind, placebo-controlled, event-driven study investigating the safety and efficacy of finerenone plus SOC on kidney disease progression in patients with CKD and T2D.[1] The primary endpoint was time to first occurrence of onset of kidney failure, a sustained decrease of eGFR ≥40%, or renal death.[1] Finerenone significantly reduced the combined primary endpoint and the combined secondary endpoint (time to first occurrence of CV death, non-fatal MI or stroke, or HHF) compared with placebo.[82]