Differentiation between emerging non-steroidal and established steroidal mineralocorticoid receptor antagonists: head-to-head comparisons of pharmacological and clinical characteristics

Figures & data

Table 1. Pharmacological characteristics of mineralocorticoid receptor antagonists: receptor affinity and tissue distribution

	Spironolactone [20-23]	Eplerenone [19-23]	Apararenone [28]	AZD9977 [19,29]	Esaxerenone (CS-3150) [21,25,26]	Finerenone (BAY 94–8862) [22,24,27,30]	KBP-5074 [23]
Generation	First	Second	Third
Class	Steroidal		Nonsteroidal
Receptor binding
Binding mode	Partial agonist	Partial agonist	Unknown	Partial agonist	Full antagonist with large side-chain rearrangements	Bulky antagonist and inverse agonist	Unknown
Affinity for MR Affinity for GR/AR/PR	++ +	+ ↓↓	+ ↓↓	+ ↓↓	++ ↓↓	++ ↓↓	++ ↓↓
MR IC50 (nM)	10^a- 36 ^c 66^b 24^d 14.3^e	-370^b 713 ^c 970^b 990^d 268^e	280^a	-370^b----	--9.4 ^c 3.7^b--	----18^d-	-----2.7^e
GR IC50 (nM)	-764 ^C 2600^b 2410^d 1950^e	-3060 ^C 36,000^b 21,980^d >10,000^e	-	-----	->10,000 ^c >5000^b--	--->10,000^d-	----2410^e
AR IC50 (nM)	-133 ^C 640^b 77^d 30.7^e	->100,000 ^c 42,000^b 21,240^d 2090^e	-	-----	->10,000 ^c >5000^b--	--->10,000^d-	----No activity^e
PR EC50 (nM)	-1200 ^C 180^b 740^d 906^e	->100,000 ^c 7400^b 31,210^d >10,000^e	-	-----	->10,000 ^c >5000^b--	--->10,000^d-	----122^e
GR, AR, PR IC50 (nM)^f	0.05–6050^a	-	>100,000^a	-	-	-	-
Tissue distribution (kidney/heart)^g	>6-fold higher in kidney > heart	3-fold higher in kidney > heart		-	Equal distribution	Equal distribution	-

Data are from direct comparative studies unless indicated otherwise. It should be noted that each study compared a single newer MRA versus spironolactone and/or eplerenone; no studies compared newer MRAs with each other. IC₅₀ values from different studies cannot be compared due to differences in assay methodology and agonist concentrations.

a Method not reported.

b Transcriptional activity reporter gene assay.

c Radioligand binding assay.

d The same functional cell-based steroid hormone receptor transactivation assay was used to evaluate finerenone [Bärfacker et al 2012, Pitt et al. 2012] and spironolactone and eplerenone [Fagart et al. 2010] in separate studies.

e Beta-lactamase reporter technology.

f Reported as a pooled range for all three receptors.

g Evaluated in rats.

EC₅₀ = half-maximal effective concentration; IC₅₀ = half-maximal inhibitory concentration; AR = androgen receptor; GR = glucocorticoid receptor; MR = mineralocorticoid receptor; PR = progesterone receptor.

Table 2. Pharmacokinetic properties of mineralocorticoid receptor antagonists

Parameter/Disease state	Spironolactone [6,32,33]	Eplerenone [6,34]	Apararenone [28]	AZD9977 [35,36]	Esaxerenone [37–40]	Finerenone [41–43]
Tmax	1–2 h^a	1–2 h^b	4.0 h^b	0.5–0.8 h^b	1.5–4.0 h^b	0.5–0.75 h^b
Elimination half-life	1.3–1.4 h for parent drug >12 h for active metabolites	3–6 h	275–285 h for parent drug >1100 h for active metabolite	2–10 h Increases with dose	20–30 h	2–3h^d
Metabolites	Multiple active metabolites	No active metabolites	Metabolite with low activity (MR binding affinity one-fiftieth of that of apararenone)	n/a	n/a	No active metabolites
Excretion	<1% unchanged drug recovered in urine; 10–15% of dose excreted in urine in form of metabolites	66% of dose excreted via urine; <3% unchanged drug recovered from urine	<14% of dose excreted in urine^c	24–37% of dose excreted in urine; 20% of dose excreted unchanged in urine	38.5% of dose excreted in urine; <2% unchanged drug excreted in urine	80% of dose excreted via urine; <1% unchanged drug excreted in urine
Mild/moderate/severe renal impairment (CLCR 50–80/30 to <50/<30 mL/min)	-	Non-significant increase in AUC as renal function decreased	-	-	-	Exposure (AUC) increased with moderate/severe (but not mild) renal impairment; no consistent effect on Cmax
Hypertension + moderate renal impairment (eGFR ≥30 to <60 mL/min/1.73 m^2)	-	-	-	-	Trough plasma levels increased dose-dependently, regardless of baseline eGFR	-
T2DM + microalbuminuria (UACR ≥45 to <300 mg/g creatinine); eGFR ≥30 mL/min/1.73 m^2	-	-	-	-	Trough plasma levels increased dose-dependently	-

Data are from separate studies performed for each compound. Values are for healthy volunteers unless indicated otherwise. No pharmacokinetic data for KBP-5074 in humans were found.

a Fed state.

b Fasting state.

c Not specified further.

d Value for clinically relevant doses of 10 or 20 mg.

AUC = area under the plasma concentration curve; C_max = maximum plasma concentration; eGFR = estimated glomerular filtration rate; h = hours; MD = multiple dose; MR = mineralocorticoid receptor; n/a = not available; SD = single-dose; T2DM = type 2 diabetes mellitus; T_max = time to maximum concentration; UACR = urinary albumin-creatinine ratio.

Table 3. Pharmacodynamic properties of non-steroidal mineralocorticoid receptor antagonists (compared with steroidal mineralocorticoid receptor antagonists)

	AZD9977	Esaxerenone	Finerenone	KBP-5074
Blood pressure	-	DOCA/high-salt rat model (high-aldosterone HT) (2 wks): ESA 3 mg/kg had a greater antihypertensive effect than SPI 30 mg/kg or EPL 30 mg/kg (SBP increased by 14 mmHg with ESA versus 60 mmHg with SPI, 72 mmHg with EPL and 68 mmHg in untreated rats) [21]. DSS high-salt rat model (low-aldosterone HT) (13 wks): ESA had dose-dependent antihypertensive (SBP) effect; effect on BP of ESA 0.5 mg/kg similar to that of SPI 100 mg/kg and EPL 100 mg/kg [26]. No hyperkalemia >5.5mEq/L seen, but mean serum potassium was higher with ESA 0.5–2 mg/kg (5.2–5.4 mEq/L) and EPL 100 mg/kg (5.2 mEq/L) vs untreated animals (4.7 mEq/L). HS-treated T2D mouse model (DKD with HT) (8 wks): ESA 1 mg/kg reduced BP to a similar extent to SPI 20 mg/kg [48]	DOCA/high-salt rat model (10 wks): FIN reduced SBP only at the highest investigated dose of 10 mg/kg (and not at 0.1 or 1 mg/kg), whereas EPL 30 and 100 mg/kg both had a significant hypotensive effect. [27].	DSS high-salt rat model (41 days): KBP (0.3–10 mg/kg) prevented increases in SBP (attenuated by 9–22%); the effect was greater than seen with EPL 120 mg/kg (~8%) [23]. SHRSP high-salt rat model (33 days): KBP (5–50 mg/kg) prevented elevation of SBP (attenuated by 12–20%) whereas EPL had no effect [23].
Renal effects
Electrolytes	Low-salt rat model (acute elevation of endogenous aldosterone) (single dose): AZD did not affect urinary Na^+/K^+ ratio, whereas EPL increased the ratio (by increasing Na^+ excretion) [19]. Uni-nephrectomized db/db mouse model (4 wks): Chronic administration of AZD or EPL both increased the urine Na^+/K^+ ratio (EPL increased Na^+ excretion; no increase in K^+ in either group) [19]. Healthy rats (single dose): When administered with aldosterone and salt, both AZD (2–120 mg/kg) and EPL (1–100 mg/kg) increased the urine Na^+/K^+ ratio dose-dependently. When administered with the synthetic mineralocorticoid fludrocortisone, EPL (1–30 mg/kg), but not AZD (3–100 mg/kg), caused a dose-dependent increase in urine Na^+/K^+ ratio [49].	Adrenalectomized rat model (20 hours): After 5 hours, ESA 0.3–3 mg/kg provided similar inhibition of aldosterone-induced decrease in urinary Na^+/K^+ ratio to that seen with SPI or EPL at 3–30 mg/kg. ESA had a longer duration of effect: at 3 hours, ESA, SPI and EPL inhibited the reduction in Na^+/K^+ ratio by 38% vs 57% vs 46%; at 20 hours, ESA had an inhibition value of 56%, whereas SPI and EPL had no effect [21].	-	Uni-nephrectomized aldosterone/high-salt rat model (4 wks): KBP and EPL blunted aldosterone-induced reduction in serum K^+; significant increases in K^+ seen with KBP 5 mg/kg (but not 0.5 or 1.5 mg/kg) and EPL 450 mg/kg (but not 15 or 50 mg/kg). Urinary Na^+/K^+ ratio increased with KBP 1.5 and 5 mg/kg and with EPL 450 mg/kg [50].
Inflammation/Fibrosis/ Remodeling/Albuminuria	Uni-nephrectomized aldosterone/high-salt rat model (4 wks): AZD dose-dependently reduced albuminuria and improved renal histopathology to a similar extent to EPL. Reduction in mean renal pathology score seen with AZD 30 and 100 mg/kg/day and with EPL 10 and 30 mg/kg/day [19]. Uni-nephrectomized db/db (obese diabetic) mouse model (4 wks): AZD reduced urinary albumin excretion and prevented further progression of nephropathy to a similar extent to EPL [19].	DSS high-salt rat model (7 wks): ESA inhibited proteinuria and renal hypertrophy, and ameliorated renal histopathological changes (e.g. fibrosis), to a greater extent than SPI or EPL. Inhibition of increased urinary protein was seen with ESA 0.5–2 mg/kg (but not 0.25 mg/kg); EPL 10 and 100 mg/kg (but not 30 mg/kg) also had an inhibitory effect, but SPI (10–100 mg/kg) did not [26]. HS-treated T2D mouse model (DKD with HT) (8 wks): ESA 1 mg/kg attenuated albuminuria, renal fibrosis, inflammation, and markers of oxidative stress to a greater extent than seen with SPI 20 mg/kg (while reducing BP to a similar extent as SPI) [48].	DOCA/high-salt rat model (10 wks): Dose-dependent protection from functional and structural renal damage, reduction in proteinuria, and reduction in renal expression of proinflammatory and profibrotic biomarker genes with FIN 0.1–10 mg/kg. Protection at dosages that did not reduce SBP. At equinatriuretic doses, FIN 10 mg/kg provided greater protection than EPL 100 mg/kg. Proteinuria significantly lower with FIN 10 mg/kg vs EPL 100 mg/kg [27]. FIN dose-dependently reduced the induction of important pro-inflammatory/remodeling marker genes, including PAI-1, MCP-1, OPN and MMP-2, with FIN 1 mg/kg having similar inhibitory efficacy to EPL 100 mg/kg [27].	DSS high-salt rat model (41 days): KBP 1–10 mg/kg reduced urinary albumin excretion by 35–57% (no change with 0.3 mg/kg); albumin excretion increased with EPL 120 mg/kg. KBP dose-dependently reduced kidney-body weight ratio (reflecting fibrosis/inflammation) and showed a trend toward reduced kidney injury (not seen with EPL) [23] SHRSP high-salt rat model (29 days): KBP 5–50 mg/kg reduced urinary albumin excretion by 51–63%; a reduction was seen with EPL (39%) only on day 29 and not at earlier timepoints. KBP and EPL reduced kidney-body weight ratio to a similar extent. KBP reduced renal small artery cross-sectional area more than seen with EPL [23]. Uni-nephrectomized aldosterone/high-salt rat model (4 wks): KBP 0.5, 1.5 and 5 mg/kg and EPL 50 and 450 mg/kg (but not 15 mg/kg) prevented increase in UACR. Therapeutic index (ratio of EC50 for increasing serum K+ to EC50 for decreasing UACR) was 39-fold better for KBP vs EPL (24.5 vs 0.62) [50].
Cardiac effects
Inflammation/Fibrosis/ Remodeling	-	DSS high-salt rat model (7 wks): ESA inhibited LV hypertrophy/reduced LV weight (as did SPI and EPL). However, EPL and SPI showed only partial efficacy at doses up to 100 mg/kg whereas ESA (0.25, 0.5, 1, 2 mg/kg) dose-dependently reduced LV weight with a clearly higher maximal efficacy. ESA 1 and 2 mg/kg (but not SPI 10–100 mg/kg or EPL 1–100 mg/kg) inhibited plasma BNP elevation; mean BNP level with ESA 1 and 2 mg/kg was 153.9 and 140.9 ng/mL vs 246.5 ng/mL in untreated animals, while BNP levels were >200 ng/mL with SPI and EPL [26].	DOCA/high-salt rat model (10 wks): Dose-dependent reduction in pro-BNP and protection from structural heart damage with FIN 1 and 10 mg/kg. Protection at dosages that did not reduce SBP. Heart: body weight ratio reduced with FIN 1 and 10 mg/kg vs PL but relative heart weight did not differ vs PL with EPL 30 or 100 mg/kg [27]. At equinatriuretic doses, FIN provided greater protection than EPL. FIN 1 mg/kg reduced proBNP to similar extent as EPL 100 mg/kg [27]. Post-MI chronic HF rat model (8 wks): FIN 1 mg/kg, but not EPL 100 mg/kg, improved LV function and reduced plasma pro-BNP level [27]. Transverse aortic constriction (TAC) mouse model: FIN 10 mg/kg attenuated pressure-overload induced cardiac hypertrophy to a greater extent than EPL 200 mg/kg. Mean increase in LV mass with FIN 28.4 mg vs 38.4 mg with EPL vs 39.3 mg in vehicle-treated mice). TAC-induced increase in myocyte size inhibited by both FIN and EPL vs vehicle-treated mice (mean cross-sectional area 296.1 and 332.1 vs 369.1 square micrometers). FIN induced a distinct cardiac gene expression profile (e.g. Tnnt2 expression reduced with FIN but not EPL; FIN reduced BNP expression less than seen with EPL) [51]. Isoproterenol-induced cardiac fibrosis mouse model (2 wks): At equinatriuretic doses, FIN 10 mg/kg had superior cardiac antifibrotic and anti-inflammatory effects, and provided greater improvement in global longitudinal peak strain, than EPL 200 mg/kg. Cardiac fibrosis and macrophage infiltration were blocked only by FIN and not EPL. FIN but not EPL inhibited profibrotic cardiac TNX gene expression [52].	DSS high-salt rat model: KBP 1, 3 and 10 mg/kg (but not EPL 100 mg/kg) reduced heart: body weight ratio. Both KBP and EPL reduced LV wall thickness [23]. SHRSP high-salt rat model: KBP and EPL both reduced heart: body weight ratio; neither KBP nor EPL reduced heart small artery cross-sectional area [23].
Obesity	-	-	Mouse model of very high-fat diet-induced obesity: FIN but not SPI improved insulin resistance, as shown by a significant reduction in the homeostasis model assessment of insulin resistance (HOMA) index. FIN but not SPI increased recruitment of interscapular brown adipose tissue [53].	-

All studies used male animals.

AZD = AZD9977; BP = blood pressure; DKD = diabetic kidney disease; DOCA/salt = deoxycorticosterone acetate-/salt-challenge model of cardiorenal damage; DSS = Dahl salt-sensitive; EPL = eplerenone; ESA = esaxerenone; FIN = finerenone; HS = high-salt; HT = hypertension; KBP = KBP-5074; LV = left ventricular; MI = myocardial infarction; PL = placebo; pro-BNP = prohormone of brain natriuretic hormone; SBP = systolic blood pressure; SHRSP = stroke-prone spontaneous hypertensive rat; SPI = spironolactone; T2D = type 2 diabetes; TNX = tenascin-X; Tnnt2 = troponin T type 2; UACR = urinary albumin-to-creatinine ratio; wks = weeks.

Table 4. Comparison of clinical effects between the steroidal mineralocorticoid receptor antagonists eplerenone and spironolactone

Clinical condition Study design/duration / N/Sex ratio [Reference]	Treatment groups	Blood pressure	Cardiac effects: B-type natriuretic peptide; composite clinical endpoint	Renal effects: Protein/albumin excretion	Adverse effects
Hypertension (mild to moderate) R, DB/8 wks/N = 417/M:F 58%:42% [60]	EPL 50, 100 or 400 mg od EPL 25, 50 or 200 mg bd SPI 50 mg bd PL	EPL 50–400 mg daily reduced mean SBP and DBP (PEP) vs PL (p < 0.05). SPI acted as a positive control (EPL 100 mg reduced BP by 75% vs SPI 100 mg).	–	–	Overall incidence of AEs similar for EPL vs PL and EPL vs SPI. Serum K level increased with EPL 400 mg od, and 25, 50 and 200 mg bd, and with SPI (all p < 0.05 vs PL). No gynecomastia with EPL. Incidence of impotence similar for EPL vs PL.
Hypertension with primary aldosteronism
R, OL-BE/24 wks/N = 34/M:F 8:9 (EPL) and 7:10 (SPI) [61]	EPL 25–100 mg bd SPI 25–200 mg bd Dose titrated up if BP <140/90 mmHg not achieved	PEP: Similar percentage of patients achieved BP <140/90 mmHg at week 16 with EPL (82.4%) and SPI (76.5%) (p = 1.00).	–	–	Similar risk of mild hyperkalemia with EPL vs SPI (3 cases with EPL 150 mg daily vs 2 cases with SPI 400 mg daily). No gynecomastia with EPL. Two cases of painful gynecomastia with SPI 400 mg; resolved after switching to EPL 150 mg, with continued BP control.
R, DB/16 wks/N = 141/M:F 96:45 [62]	EPL 100–300 mg od SPI 75–225 mg od Dose titrated up if DBP ≤90 mmHg not achieved	PEP: Smaller mean decrease in DBP with EPL vs SPI (–5.6 vs – 12.5 mmHg; difference – 6.9 mmHg, p < 0.001).	–	–	Overall incidence of AE similar with EPL vs SPI. Male gynecomastia (4.5% vs 21.2%, p = 0.033) and female mastodynia (4.5% vs 21.1%, p = 0.026) less common with EPL vs SPI. Hyperkalemia occurred in 1 EPL vs 7 SPI recipients.
R, OL/12 mon/N = 54/M:F 24/30 [63]	EPL 25–100 mg daily SPI 12.5–100 mg daily	No significant difference in effect on BP with EPL vs SPI (–28/–16 vs – 30/–19 mmHg).	–	No significant difference in effect on urinary albumin excretion with EPL vs SPI (–3.8 vs – 4.4 mg/g creatinine).	Gynecomastia seen in spironolactone group (n = 2) but not EPL group. No patients had serum K > 5.0 mEq/L in either group.
Heart failure (acute decompensated) OB/594 ± 317 days/N = 838/M:F 492:305 [64]	EPL 34 ± 15 mg SPI 27 ± 8 mg	No significant difference in effect on SBP with EPL vs SPI (+12 ± 24 vs +16 ± 26 mmHg).	No significant difference in effect on serum BNP with EPL vs SPI (–55 ± 58 vs – 163 ± 644 pg/mL, p = 0.372). PEP: No significant difference in risk of composite of cardiovascular death or hospitalization (hazard ratio 1.1016, 95% CI 0.567–1.764).	–	Gynecomastia/breast pain seen with SPI (4%) but not EPL (p = 0.018). Prevalence of severe hyperkalemia >6 mEq/L did not differ between EPL and SPI (6% vs 8%, p = 0.549).

bd = twice daily; BNP = brain natriuretic peptide; BP = blood pressure; DB = double-blind; DBP = diastolic blood pressure; EPL = eplerenone; F = female; OB = observational; od = once daily; OL = open-label; OL-BE = open-label, blinded-endpoint; M = male; mon = months; PEP = primary endpoint; PL = placebo; R = randomized; SBP = systolic blood pressure; SPI = spironolactone; wks = weeks.

Table 5. Comparison of clinical effects between emerging non-steroidal MRAs and older steroidal MRAs

Clinical condition Study design/duration / N/Sex ratio [Reference]	Treatment groups	Blood pressure	Cardiovascular effects: B-type (brain) natriuretic protein; composite clinical endpoint	Renal effects: protein/albumin excretion; electrolytes; eGFR	Adverse effects
Healthy volunteers
AZD9977 R, CO/Single dose / N = 23/Male [35]	FLU AZD 200 mg + FLU EPL 100 mg + FLU AZD 200 mg + EPL 100 mg + FLU	–	–	PEP: In the presence of FLU, AZD 200 mg had similar effect to EPL 100 mg on urinary Na^+/K^+ ratio (by increasing Na^+ excretion). Coadministration of AZD + EPL had an additive effect.	Frequency of AEs similar across groups.
Apararenone R, DB, PC, AC/ Single dose/N = 36/Male [28]	APA 160, 640 mg EPL 200 mg PL	-	-	PEP: After FLU challenge, APA 640 mg (but not 160 mg) and EPL 200 mg increased Na^+/K^+ ratio significantly vs PL. EPL effect peaked at 8 h; APA effect increased from 8–12 h onwards. EPL had greater effect than APA 160 mg for 0–24 h; APA 160 and 640 mg had greater effect than EPL for 24–48 h.	Incidence of AEs: APA 160 mg 33.3%, APA 640 mg 33.3%, EPL 11.1%, PL 16.7%.
Essential hypertension
Esaxerenone R, DB-PC, OL-AC/12 wks^a/N = 423/M:F 295:128 [39]	ESA 1.25, 2.5, 5 mg od EPL 50→100 mg od (escalated after 2–4 weeks) PL	PEP: Dose-response reduction in SBP/DBP of – 10.7/–5.0, – 14.3/–7.6 and – 20.6/–10.4 mmHg with ESA 1.25, 2.5, 5 mg (p < 0.05, p < 0.001, p < 0.001 vs PL). Reduction of – 17.4/–8.5 mmHg with EPL.	–	Mean change in creatinine-adjusted eGFR – 2.31 to – 6.36 mL/min/1.73 m^2 with ESA vs – 2.11 mL/min/1.73 m^2 with EPL.	Incidence of AEs similar between groups (ESA 30.1–40.5%, EPL 36.9%, PL 46.0%).
Esaxerenone (ESAX-HTN) R, DB/12 wks^a / N = 998/M:F 721:277 [65]	ESA 2.5, 5 mg od EPL 50 mg od	PEP: ESA 2.5 mg non-inferior to EPL 50 mg for reduction in SBP/DBP (between-group difference – 1.6/–0.7 mmHg). ESA 5 mg superior to EPL 50 mg (difference – 4.8/–2.3 mmHg, both p < 0.0001). Percentage achieving BP <140/90 mmHg: 31.5% and 41.2% with ESA 2.5 and 5 mg vs 27.5% with EPL 50 mg.	–	eGFR decreased slightly in both ESA groups vs remained stable in EPL group.	Incidence of AEs similar between groups: ESA 2.5 mg, 38.4%; ESA 5 mg, 44.1%, EPL 50 mg, 37.0%. Incidence of hyperkalemia (two consecutive levels ≥5.5 or one ≥6.0 mEq/L): ESA 2.5 kg, 0.9%; ESA 5 mg, 0.6%; EPL 50 mg, 0%.
Heart failure^b + chronic kidney disease^c
Finerenone (ARTS) R, DB-PC^d, OL-AC/4 wks/N = 392/M:F 312:80 [66]	FIN 2.5, 5, 10 mg od, 5 mg bd SPI 25→50 mg od (uptitrated day 15^e; mean dose 37 mg/day) Both added to evidence-based therapy for HF	Smaller reduction in mean SBP with all doses of FIN vs SPI (–1.9 to – 4.2 mmHg vs – 10.1 mmHg, p = 0.0023–0.0255). Changes with FIN similar to PL (–3.1 mmHg).	Similar reductions in median levels of BNP and NT-proBNP with FIN 10 mg od/5 mg bd vs SPI (–31.0/–35.0 vs – 47.0 pg/mL, and – 193.65/–106.40 vs – 170.30 pg/mL, respectively).	Similar reduction in mean UACR with all FIN doses and SPI (geometric mean ratio versus baseline 0.69–0.86 vs 0.61). Smaller decrease in mean eGFR with FIN vs SPI (–0.85 to – 2.69 vs – 6.7 mL/min/1.73 m^2, p = 0.0001–0.0133).	Lower overall incidence of AEs with all FIN doses vs SPI (47.0–53.7% vs 79.4%). PEP: Smaller increase in mean serum K with FIN vs SPI (0.04–0.30 vs 0.45 mmol/L, p < 0.0001–0.0107). Lower incidence of hyperkalemia with FIN vs SPI (5.3% vs 12.7%, p = 0.048). Lower incidence of worsening renal function with FIN vs SPI (1.5–10.4% vs 38.1%).
Worsening heart failure^f + chronic kidney disease and/or diabetes mellitus^g
Finerenone (ARTS-HF) R, DB/90 days / N = 1055/M:F 816:239 [67]	FIN 2.5→5, 5→10, 7.5→15, 10→20, 15→20 mg od (uptitrated day 30)^h EPL 25 mg qad→25 mg od→50 mg od (uptitrated on days 30 and 60)^h; mean dose 38.6 mg/day Both added to evidence-based therapy for HF	Mean SBP decreased by <3 mmHg in all groups.	PEP: No significant difference in proportions achieving a decrease in NT-proBNP of >30% from baseline with any FIN dose (30.9–38.8%) vs EPL (37.2%). Exploratory: Incidence of composite endpoint (death from any cause, cardiovascular hospitalization, emergency presentation for worsening HF) lower in all FIN groups (except 2.5→5 mg) vs EPL; nominal significance achieved for FIN 10→20 mg (HR 0.56, p = 0.02).	No significant difference for change in eGFR with FIN vs EPL. Mean eGFR increased with the two lowest FIN doses (+ 1.317 and +0.431 mL/min/1.73 m^2) and decreased with the three higher FIN doses (–0.146 to – 2.440 mL/min/1.73 m^2) and with EPL (–1.085 mL/min/1.73 m^2).	Similar overall incidence of AEs with all FIN doses (62.9–78.5%) and EPL (76.9%). Mean change in serum K smaller with all FIN doses (+0.119–0.202 mmol/L) vs EPL (+0.262 mmol/L). Similar incidence of hyperkalemia ≥5.6 mmol/L with FIN (3.6–6.3%) vs EPL (4.7%). Renal AEs leading to hospitalization occurred in 1 patient each with FIN 2.5→5, 7.5→15, and 15→20 mg vs 2 with EPL.

a Preceded by a 4-week washout period to remove effects of previous antihypertensive treatments.

b Chronic heart failure with reduced ejection fraction.

c Moderate chronic kidney disease (eGFR 30–60 mL/min/1.73 m²).

d Results not reported here.

e SPI titrated up provided serum potassium remained ≤4.8 mmol/L.

f Worsening chronic heart failure with reduced ejection fraction, requiring hospitalization and intravenous diuretics.

g Patients with type 2 diabetes mellitus had an eGFR of >30 mL/min/1.73 m²; those without diabetes had an eGFR of 30–60 mL/min/1.73 m².

h Both study drugs were titrated up provided serum potassium remained ≤5.0 mmol/L.

AE = adverse effect; APA = apararenone; bd = twice daily; BNP = B-type (brain) natriuretic peptide; CO = cross-over; DB = double-blind; DB-PC = double-blind placebo-controlled; eGFR = estimated glomerular filtration rate; EPL = eplerenone; ESA = esaxerenone; FIN = finerenone; FLU = fludrocortisone (synthetic mineralocorticoid); HF = heart failure; HR = hazard ratio; K = potassium; M:F = male:female; MRA = mineralocorticoid receptor antagonist; NT-proBNP = amino-terminal proBNP; od = once daily; OL-AC = open-label active comparator; PEP = primary endpoint; PL = placebo; qad = every other day; R = randomized; SBP = systolic blood pressure; UACR = urinary albumin:creatinine ratio.

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