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nr3c2

Properties1
aliasesMR, mineralocorticoid receptor, NR3C2, aldosterone receptor, MCR, MLR

18 min read

NR3C2 (Mineralocorticoid Receptor)

The mineralocorticoid receptor (MR; gene NR3C2) is a nuclear hormone receptor and ligand-activated transcription factor that is the highest-intervention-leverage cardiorenal aging target covered in this batch of protein pages. Mineralocorticoid receptor antagonists (MRAs) — spanning steroidal (spironolactone, eplerenone) and nonsteroidal (finerenone, esaxerenone) generations — have FDA-approved or guideline-endorsed uses across the full cardiorenal aging phenotype cluster: heart failure with reduced ejection fraction (HFrEF), heart failure with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF), resistant hypertension, and chronic kidney disease in type 2 diabetes. The 2024 Jhund et al. individual-patient meta-analysis (n=13,846; Lancet 2024) provides the highest-level synthesis that MRAs reduce cardiovascular death or HF hospitalization across HF subtypes, with the strongest benefit in HFrEF 1.

MR binds both aldosterone and cortisol with high affinity (Kd ~0.5–1 nM for cortisol, comparable to aldosterone), but epithelial selectivity for aldosterone in the kidney and colon is conferred by co-expression of 11β-HSD2 — which locally inactivates cortisol to cortisone before it can occupy MR 2. In non-epithelial tissues (heart, vasculature, brain, macrophages) where 11β-HSD2 is absent, cortisol is likely the dominant endogenous MR ligand, placing MR at the crossroads of the glucocorticoid and mineralocorticoid systems 3.

Identity

  • UniProt: P08235 (MCR_HUMAN)
  • NCBI Gene: 4306
  • HGNC: HGNC:7979
  • HGNC symbol: NR3C2
  • Ensembl: ENSG00000151623
  • Mouse ortholog: Nr3c2 (NCBI Gene ID 110784; one-to-one ortholog)
  • GenAge ID: null — NR3C2 does not have a confirmed GenAge/HAGR entry for aging-relevant genetic associations; aging relevance is pharmacological rather than GWAS-based. gap/needs-canonical-id (GenAge re-check recommended on next lint pass)
  • Chromosomal location: 4q31.23
  • Protein length: 984 amino acids (canonical isoform)
  • Family: Nuclear receptor superfamily, subfamily 3 (steroid receptors), group C (glucocorticoid/mineralocorticoid receptor sub-family). Sister paralogs: NR3C1 (GR), NR3C3 (PR), NR3C4 (AR).

Domain organization and key PTMs

DomainResidues (approx.)Function
N-terminal modulating domain (NTD)1–602Ligand-independent transactivation (AF-1 region); post-translational modification hub; contributes to context-specific gene regulation
DNA-binding domain (DBD)603–668Two C4-type zinc fingers; recognizes hormone response elements (HREs); dimerization interface
Hinge region669–725Nuclear localization signal; links DBD to LBD
Ligand-binding domain (LBD)726–984Binds aldosterone and cortisol with high affinity; AF-2 helix-12 repositions on ligand binding to recruit coactivators

Key phosphorylation sites (UniProt P08235): Ser250, Ser259, Ser283, Ser287, Ser299 — in the NTD, collectively modulating transcriptional activity and protein stability. Sumoylation and acetylation have also been reported in the literature, though specific sites are less well characterized than for GR/NR3C1.

Ligand binding and selectivity: the 11β-HSD2 gating mechanism

A critical point for understanding MR’s role in aging pathology: MR does not preferentially bind aldosterone over cortisol in biochemical terms. Cortisol and aldosterone bind with similar high affinity in vitro. The physiological selectivity for aldosterone in epithelial tissues (kidney cortical collecting duct, colon, sweat glands) is conferred by co-expressed 11β-HSD2 (encoded by HSD11B2; UniProt P80365; see hsd11b1-hsd11b2) 2:

  • 11β-HSD2 rapidly oxidizes cortisol → inactive cortisone (using NAD+ as cofactor), preventing cortisol from occupying MR in the renal tubule.
  • The net result: in mineralocorticoid-sensitive epithelial cells, only aldosterone (which is not a 11β-HSD2 substrate) activates MR.
  • In tissues lacking 11β-HSD2 — heart, vascular smooth muscle, endothelium, brain, immune cells — cortisol is the dominant MR ligand at physiological concentrations, given its ~1000-fold higher circulating concentration relative to aldosterone 3.

This 11β-HSD2 gating mechanism explains why excess cortisol (as in Cushing syndrome) or deficiency of 11β-HSD2 (as in apparent mineralocorticoid excess, AME) produces severe sodium retention and hypertension — the MR sees unimpeded cortisol in the kidney. It also means that in aging, as basal cortisol levels modestly rise and/or 11β-HSD2 activity declines, non-aldosterone MR activation in non-epithelial tissues may contribute to vascular and cardiac pathology even without primary aldosteronism 3.

Signaling: epithelial vs non-epithelial MR

Epithelial MR — sodium/potassium handling

In the cortical collecting duct (CCD) principal cells:

  1. Aldosterone or cortisol (unimpeded when 11β-HSD2 is absent or overwhelmed) → binds MR in cytoplasm → receptor-chaperone complex dissociates → MR translocates to nucleus → binds hormone response element → transcriptional activation of:
    • SGK1 (serum/glucocorticoid-regulated kinase 1; see sgk1) — the primary rapid effector; SGK1 phosphorylates and inhibits NEDD4-2, preventing ENaC ubiquitination and degradation → ENaC accumulates at apical membrane → increased Na+ reabsorption → secondary K+ and H+ secretion.
    • ENaC subunits (SCNN1A/B/G) — direct transcriptional upregulation.
    • Na+/K+-ATPase — increased basolateral pump activity sustains the electrochemical gradient.
  2. Net effect: Na+ retention, K+ excretion, and blood pressure elevation.

Non-epithelial MR — cardiac, vascular, immune

In cardiomyocytes and cardiac fibroblasts, MR activation by cortisol (dominant ligand in the heart) or aldosterone drives:

  • Upregulation of collagen synthesis genes → interstitial cardiac fibrosis (see cardiac-fibrosis) 4
  • Activation of reactive oxygen species (ROS) generation → myocardial oxidative stress
  • Modulation of ion channels (KCND3 and others) affecting cardiac electrophysiology

In macrophages, MR is expressed and promotes a pro-inflammatory phenotype. Fraccarollo et al. 2024 demonstrated in murine cardiac macrophages that MR activation accelerates a transcriptional “inflammaging” signature, linking MR to the macrophage contribution to cardiac aging 5.

In vascular endothelium and smooth muscle, MR activation:

  • Impairs endothelial NO production → reduced vasodilation
  • Promotes oxidative stress and NADPH oxidase activation → endothelial dysfunction
  • Enhances angiotensin II receptor expression (AT1R) → amplified vasoconstriction

Aging relevance

Aldosterone excess, cortisol, and cardiorenal aging

In aging and in cardiorenal disease, the renin-angiotensin-aldosterone system (RAAS) frequently exhibits aldosterone excess relative to suppressed renin (“aldosterone escape” or primary aldosteronism in its subclinical forms). The clinical triad — hypertension, cardiac fibrosis, renal sodium retention — represents convergent MR overactivation in multiple tissue compartments.

Simultaneously, modest age-related increases in cortisol (and/or declines in 11β-HSD2 activity) amplify non-epithelial MR overactivation in the heart and vasculature independently of aldosterone.

The cardiac fibrosis pathway is mechanistically central:

  • Aldosterone directly activates MR in cardiac fibroblasts → myofibroblast differentiation → excess collagen I/III deposition → interstitial fibrosis → diastolic dysfunction → HFpEF (see cardiac-fibrosis and heart-failure) 4
  • This pathway is the mechanistic basis for MRA anti-fibrotic efficacy

Hypertension and vascular aging: MR-mediated sodium retention and vascular dysfunction contribute to isolated systolic hypertension — the dominant hypertension phenotype in aging (see hypertension). MR antagonism reduces resistant hypertension significantly even in RAAS-treated patients 3.

Renal aging/CKD: Aldosterone-driven SGK1 overactivation in aged kidneys promotes ENaC-mediated Na+ retention and glomerulosclerosis. Elevated aldosterone is a risk factor for CKD progression and albuminuria independent of blood pressure 6.

DimensionStatus
Pathway conserved in humans?Yes — MR/aldosterone/cortisol axis is fully conserved; drug trials are directly in humans
Phenotype conserved in humans?Yes — HFrEF, HFpEF, hypertension, CKD all confirmed in major RCTs as MRA-responsive
Replicated in humans?Yes — multiple Phase 3 RCTs across HF subtypes, CKD, and hypertension

Mendelian randomization evidence

mr-causal-evidence: partial

Direct Mendelian randomization studies using NR3C2 genetic instruments to establish causal effects of MR on aging phenotypes are sparse in the published literature (no major MR-polymorphism → cardiorenal outcome MR study confirmed via PubMed search). However, MR’s causal role in human cardiorenal disease is effectively established by treatment trials as experiments: multiple large Phase 3 RCTs with pre-specified primary endpoints provide the strongest available causal evidence that MR blockade protects cardiorenal outcomes in humans 78961011. The partial designation reflects absence of formal GWAS/MR studies; causal direction of MR → cardiorenal disease is not in serious scientific doubt given the RCT evidence base.

gap/needs-replication (formal Mendelian randomization using NR3C2 polymorphisms as instruments for cardiorenal outcomes — would complement the RCT evidence base with an observational causal design)

Pharmacology: MR antagonists across three generations

First generation: spironolactone (steroidal; non-selective)

Spironolactone is a competitive MR antagonist with substantial off-target activity at the androgen receptor (AR) and progesterone receptor (PR), producing dose-limiting anti-androgenic effects (gynecomastia in men, menstrual irregularity in women) that limit use in younger patients.

RALES (Pitt et al. 1999) — the landmark trial: n=1,663 patients with severe HFrEF (EF <35%, NYHA class III–IV); spironolactone 25 mg/day vs placebo; median follow-up 24 months. Spironolactone reduced all-cause mortality RR=0.70 (95% CI 0.60–0.82; P<0.001) — a 30% mortality reduction 7. The trial was stopped early for overwhelming benefit. This established MRA as a pillar of HFrEF GDMT.

Current use: Standard-of-care in HFrEF (typically 25–50 mg/day); widely used for resistant hypertension (often 25–100 mg/day off-label); primary hyperaldosteronism (higher doses). Off-target effects limit use in some patients.

Second generation: eplerenone (steroidal; selective)

Eplerenone is a selective MR antagonist with minimal AR/PR activity, improving the sex-hormone side-effect profile. It is less potent than spironolactone at MR (higher doses required).

EPHESUS (Pitt et al. 2003) — eplerenone in post-MI LV dysfunction: n=6,632 (3,319 eplerenone; 3,313 placebo); eplerenone 25–50 mg/day vs placebo; mean follow-up 16 months. The trial had two pre-specified primary endpoints: (1) all-cause mortality RR=0.85 (95% CI 0.75–0.96; P=0.008) and (2) cardiovascular death or hospitalization for CV events RR=0.87 (95% CI 0.79–0.95; P=0.002). Cardiovascular mortality RR=0.83 (95% CI 0.72–0.94; P=0.005) 8. Established MRA in acute MI with LV dysfunction.

EMPHASIS-HF (Zannad et al. 2011) — eplerenone in mild HFrEF (NYHA class II): n=2,737; eplerenone 25–50 mg/day; median follow-up 21 months. Primary composite (cardiovascular death or HF hospitalization): HR=0.63 (95% CI 0.54–0.74; P<0.001) — a 37% relative risk reduction 9. Confirmed MRA benefit even in mild HF, extending RALES findings.

Current use: Preferred over spironolactone in post-MI HFrEF (EPHESUS indication); used when spironolactone side-effects are dose-limiting.

Third generation: finerenone (nonsteroidal; highly selective)

Finerenone is a next-generation nonsteroidal selective MR antagonist with ~500-fold selectivity for MR over other steroid receptors, no active metabolites accumulating in cardiac tissue (unlike steroidal MRAs which accumulate in heart, potentially causing off-target effects), and a shorter half-life favoring renal-sparing. Its chemical scaffold produces a distinctly different receptor-binding mode (no agonist activity) and tissue-distribution profile vs steroidal MRAs.

FIDELIO-DKD (Bakris et al. 2020, NEJM) — finerenone in CKD + type 2 diabetes (primary kidney endpoint): n=5,734; CKD stages 2–4 with severe albuminuria; finerenone 10–20 mg/day vs placebo; median follow-up 2.6 years. Primary composite (sustained ≥40% eGFR decline, kidney failure, or renal death): HR=0.82 (95% CI 0.73–0.93; P=0.001) 6. Finerenone became the first MRA with a specific indication for CKD in type 2 diabetes (FDA approved 2021).

FIGARO-DKD (Pitt et al. 2021, NEJM) — finerenone in CKD + type 2 diabetes (primary cardiovascular endpoint): n=7,437 randomized (3,686 finerenone; 3,666 placebo in the analysis); broader eGFR range including CKD stages 1–4 with varying albuminuria thresholds; finerenone 10–20 mg/day vs placebo; median follow-up 3.4 years. Primary composite (cardiovascular death, nonfatal MI, nonfatal stroke, or HF hospitalization): HR=0.87 (95% CI 0.76–0.98; P=0.03), driven largely by reduced HF hospitalization (HR=0.71; 95% CI 0.56–0.90) 10.

FINEARTS-HF (Solomon et al. 2024, NEJM) — finerenone in HFmrEF/HFpEF (LVEF ≥40%): n=6,001 (3,003 finerenone, 2,998 placebo); finerenone 20–40 mg/day; median follow-up 32 months. Primary composite (total worsening HF events or cardiovascular death): rate ratio=0.84 (95% CI 0.74–0.95; P=0.007) 11. This was the first large RCT to demonstrate meaningful benefit of an MRA in HFpEF/HFmrEF — a landmark result given the prior failure of spironolactone in TOPCAT (partially explained by geographic heterogeneity in adjudication).

Esaxerenone (nonsteroidal; approved in Japan by PMDA for hypertension) is a separate nonsteroidal MRA with a similar selectivity profile to finerenone; no major cardiorenal outcome data yet. See gap/long-term-unknown.

Summary: Jhund 2024 Lancet IPD meta-analysis

Jhund et al. 2024 pooled individual patient data from four major MRA trials (RALES, EMPHASIS-HF, TOPCAT, FINEARTS-HF; n=13,846 total) 1:

  • All MRA types: cardiovascular death or HF hospitalization HR=0.77 (95% CI 0.72–0.83)
  • HFrEF (LVEF ≤35%; RALES + EMPHASIS-HF): HR=0.66 (95% CI 0.59–0.73) — substantial reduction
  • HFmrEF/HFpEF (EF ≥40%; TOPCAT + FINEARTS-HF): HR=0.87 (95% CI 0.79–0.95) — meaningful HF hospitalization reduction; CV mortality not significantly reduced in this subgroup
  • Hyperkalemia doubled with MRAs vs placebo (OR 2.27), though serious hyperkalemia (K+ >6.0 mEq/L) occurred in 2.9% vs 1.4% — the primary safety consideration

Druggability-tier 1 justification: Multiple FDA-approved MRA drugs exist with clear aging-context approvals: spironolactone and eplerenone are guideline-recommended in HFrEF (aging-relevant mortality-reducing indications); finerenone is FDA-approved for CKD in type 2 diabetes (2021, first indication of this type for an MRA); FINEARTS-HF supports emerging use in HFpEF (the dominant HF phenotype in elderly). This is a clear tier-1 case — drugs exist, are approved, and are deployed for aging-relevant cardiorenal disease endpoints.

Druggability tier and aging-context note

Tier: 1 (clinical drugs exist for aging-relevant cardiorenal indications)

This is one of the most robustly tier-1 proteins in the aging-wiki. The tier-1 designation is conservative per the schema convention (aging-context, not maximum druggability across all indications):

  • Spironolactone and eplerenone are standard-of-care for HFrEF — a predominantly age-associated disease driving major mortality in adults 65+.
  • Finerenone is FDA-approved (2021) for CKD in type 2 diabetes — an aging-predominant indication.
  • FINEARTS-HF provides Phase 3 evidence supporting HFpEF/HFmrEF — the dominant HF phenotype of the elderly.
  • Resistant hypertension, a major aging phenotype, is guideline-endorsed for spironolactone add-on therapy.

No other nuclear receptor in the aging context has this density of large positive RCTs in multiple aging phenotype domains.

Connections to other aging hallmarks

Chronic inflammation

In cardiac macrophages, MR promotes age-associated inflammatory gene expression (“inflammaging”). Fraccarollo et al. 2024 (Basic Res Cardiol) demonstrated that myeloid-specific MR activation drives macrophage polarization toward a pro-inflammatory, NLRP3-inflammasome-activating phenotype in aged mouse hearts — mechanistically linking MR to the chronic-inflammation hallmark 5.

Altered intercellular communication

Aldosterone is a long-range endocrine signal whose dysregulated secretion in aging (aldosterone escape, primary aldosteronism spectrum) drives pathological paracrine and endocrine communication across tissue compartments — impaired vasodilation (endothelium → VSMC), fibroblast activation (cardiomyocyte SASP × aldosterone → cardiac fibroblasts), and renal tubular Na+ dyshomeostasis. This places MR at the intersection of altered-intercellular-communication.

Sodium restriction and lifestyle context

Dietary sodium restriction reduces the magnitude of aldosterone-driven MR activation in the kidney by lowering the Na+ gradient against which ENaC must work; however, in the context of disease (HF, CKD), sodium restriction acts synergistically with MRA therapy rather than substituting for it. See sodium-restriction for quantitative sodium reduction data. Sodium restriction alone does not substantially address the cardiac fibrotic or macrophage-inflammatory actions of MR in non-epithelial tissues.

Pathway membership

  • hpa-axis — MR is a critical node in the corticosteroid signaling network; receives cortisol (dominant non-epithelial ligand) from the adrenal axis
  • nr3c1 — GR (glucocorticoid receptor), the primary cortisol receptor at stress concentrations; MR and GR can form heterodimers and act on overlapping response elements (concurrent-seed sibling)
  • hsd11b1-hsd11b2 — 11β-HSD2 is the critical pre-receptor gating enzyme that confers aldosterone specificity in epithelial MR targets (concurrent-seed sibling)
  • sgk1 — the primary rapidly-induced downstream effector of MR in the kidney; mediates ENaC/NEDD4-2 phosphorylation and Na+ retention
  • hypertension — major downstream phenotype; MRA reduces resistant hypertension
  • cardiac-fibrosis — aldosterone/cortisol → fibroblast MR → collagen synthesis; MRA reduces cardiac fibrosis
  • heart-failure — MRA mortality benefit proven across HFrEF (RALES, EMPHASIS-HF, EPHESUS) and HFpEF/HFmrEF (FINEARTS-HF)
  • chronic-kidney-disease — finerenone approved for CKD in T2D; MR drives tubular Na+ retention and glomerulosclerosis amplification

Limitations and gaps

  • #gap/needs-replication — Formal Mendelian randomization studies using NR3C2 polymorphisms as genetic instruments for cardiorenal outcomes are absent from the published literature; the causal direction is established by RCTs but not by population genetics.
  • #gap/needs-human-replication — The cardiac macrophage inflammaging mechanism (Fraccarollo 2024) is a murine study; human macrophage MR-driven inflammaging phenotypes have not been independently characterized in aged human cardiac biopsies.
  • #gap/long-term-unknown — Esaxerenone’s cardiorenal outcome evidence base is limited to hypertension trials; no Phase 3 outcome trial in HF or CKD completed as of 2026.
  • #gap/no-mechanism — The precise mechanism by which finerenone’s nonsteroidal scaffold reduces cardiac fibrosis vs steroidal MRAs in non-epithelial tissues is not fully characterized; proposed to relate to different tissue accumulation, no active cardiac metabolite, and binding kinetics, but not proven by head-to-head mechanistic studies.
  • #gap/contradictory-evidence — TOPCAT trial (spironolactone in HFpEF): primary endpoint negative overall (HR=0.89; P=0.14), but post-hoc analyses suggested a real effect in patients enrolled in the Americas with confirmed elevated natriuretic peptides and documented hospitalization events; geographic heterogeneity complicates interpretation. FINEARTS-HF addressed this in a better-designed trial with positive results, but the discordance between TOPCAT and FINEARTS-HF is not fully mechanistically resolved.
  • #gap/needs-canonical-id — GenAge ID for NR3C2 not confirmed; no entry identified in the HAGR GenAge database (aging relevance is pharmacological rather than GWAS/longevity-gene based).
  • #gap/dose-response-unclear — Optimal finerenone dosing in HFpEF (20 vs 40 mg) and in CKD strata beyond FIDELIO/FIGARO enrollment criteria is not fully established.

Cross-references

  • hpa-axis — MR is embedded within the full corticosteroid signaling axis
  • nr3c1 — GR (NR3C1); paralog and heterodimerization partner; cortisol-receptor at stress concentrations
  • hsd11b1-hsd11b2 — 11β-HSD2 gates MR selectivity in epithelial tissues; 11β-HSD1 amplifies cortisol in adipose/liver
  • crh — upstream of cortisol production; indirect MR ligand supply
  • sgk1 — direct MR transcriptional target; ENaC-mediated Na+ retention effector
  • hypertension — major downstream phenotype; aldosterone-MR axis drives salt-sensitive hypertension
  • cardiac-fibrosis — aldosterone/MR → fibroblast activation → collagen; MRA anti-fibrotic mechanism
  • heart-failure — MRA mortality benefit across HF spectrum (RALES → FINEARTS-HF)
  • chronic-kidney-disease — finerenone CKD indication; aldosterone-SGK1-ENaC axis in tubular injury
  • sodium-restriction — synergistic with MRA; reduces aldosterone demand; does not substitute for cardiac/renal MRA action
  • chronic-inflammation — cardiac macrophage MR inflammaging link
  • altered-intercellular-communication — aldosterone as dysregulated endocrine signal in aging

Footnotes

Footnotes

  1. doi:10.1016/S0140-6736(24)01733-1 · Jhund PS, Talebi A, Henderson AD et al. · Lancet 2024;404(10458):1119–1131 · individual patient-level meta-analysis · n=13,846 across four trials (RALES, EMPHASIS-HF, TOPCAT, FINEARTS-HF); MRAs vs placebo; composite CV death or HF hospitalization HR=0.77 (95% CI 0.72–0.83); HFrEF HR=0.66; HFmrEF/HFpEF HR=0.87; hyperkalemia OR=2.27 (2.9% vs 1.4% serious); differential efficacy by EF subtype (p-interaction=0.0012); highest-level evidence synthesis for MRA class across HF spectrum ↩ ↩2

  2. doi:10.1152/ajprenal.2001.280.2.F181 · Farman N, Rafestin-Oblin ME · Am J Physiol Renal Physiol 2001;280(2):F181–192 · review · mechanism of mineralocorticoid selectivity in epithelial vs non-epithelial tissues; 11β-HSD2 as the pre-receptor cortisol inactivation enzyme in kidney and colon; MR binds cortisol and aldosterone with similar high affinity; in tissues lacking 11β-HSD2, cortisol is the dominant physiological MR ligand at its ~1000-fold higher circulating concentration · model: human and rodent data synthesis ↩ ↩2

  3. doi:10.1007/s11906-007-0020-8 · Funder JW · Curr Hypertens Rep 2007;9(3):222–226 · review · why MR is nonselective; cortisol and aldosterone bind with similar Kd; 11β-HSD2 gating in epithelial tissues; implications for non-epithelial MR activation by cortisol in aging and stress; cortisol-driven cardiac MR activity · model: human physiology review ↩ ↩2 ↩3 ↩4

  4. doi:10.1093/cvr/cvaa324 · Frangogiannis NG · Cardiovasc Res 2021;117(6):1450–1488 · review · mechanistic review of cardiac fibrosis; aldosterone acts directly on cardiac fibroblast MR to upregulate collagen synthesis; RAAS-MR axis as pro-fibrotic driver; MRA anti-fibrotic mechanism · model: human + animal data synthesis ↩ ↩2

  5. doi:10.1007/s00395-024-01032-6 · Fraccarollo D et al. · Basic Res Cardiol 2024 · PMID 38329499 · in-vivo (murine) · mineralocorticoid receptor promotes cardiac macrophage inflammaging; myeloid-specific MR activation drives NLRP3-inflammasome-activating pro-inflammatory phenotype in aged mouse hearts; links MR to the macrophage contribution to cardiac aging and the chronic-inflammation hallmark · model: mus-musculus (murine cardiac macrophages) ↩ ↩2

  6. doi:10.1056/NEJMoa2025845 · Bakris GL, Agarwal R, Anker SD et al. (FIDELIO-DKD) · N Engl J Med 2020;383(23):2219–2229 · RCT · n=5,734 (2,833 finerenone; 2,841 placebo); CKD stages 2–4 eGFR 25 to <60 mL/min/1.73m² (or <75 with high albuminuria) + T2D; finerenone 10–20 mg/day; median follow-up 2.6 years; primary composite (sustained ≥40% eGFR decline, kidney failure, or renal death) HR=0.82 (95% CI 0.73–0.93; P=0.001); first MRA with dedicated CKD indication; FDA approved 2021 for CKD in T2D · model: human RCT (CKD+T2D) ↩ ↩2 ↩3

  7. doi:10.1056/NEJM199909023411001 · Pitt B et al. (Randomized Aldactone Evaluation Study Investigators) · N Engl J Med 1999;341(10):709–717 · RCT · n=1,663 (822 spironolactone; 841 placebo); severe HFrEF EF <35%, NYHA III–IV; spironolactone 25 mg/day; median follow-up 24 months; all-cause mortality RR=0.70 (95% CI 0.60–0.82; P<0.001); 30% mortality reduction; trial stopped early; 46% placebo deaths vs 35% spironolactone deaths · model: human HFrEF RCT ↩ ↩2

  8. doi:10.1056/NEJMoa030207 · Pitt B, Remme W, Zannad F et al. (EPHESUS) · N Engl J Med 2003;348(14):1309–1321 · RCT · n=6,632 (3,319 eplerenone; 3,313 placebo); post-acute MI LV dysfunction (EF ≤40%) and HF or diabetes; eplerenone 25–50 mg/day vs placebo; two pre-specified primary endpoints: (1) all-cause mortality RR=0.85 (95% CI 0.75–0.96; P=0.008) and (2) CV death or CV hospitalization RR=0.87 (95% CI 0.79–0.95; P=0.002); CV mortality RR=0.83 (95% CI 0.72–0.94; P=0.005); note: EPHESUS reported relative risks, not hazard ratios; selective MR antagonist with minimal anti-androgen effects; established MRA in post-MI LV dysfunction · model: human RCT (post-MI HFrEF) ↩ ↩2

  9. doi:10.1056/NEJMoa1009492 · Zannad F, McMurray JJV, Krum H et al. (EMPHASIS-HF) · N Engl J Med 2011;364(1):11–21 · RCT · n=2,737; mild HFrEF (NYHA II, EF ≤35%); eplerenone 25–50 mg/day vs placebo; median follow-up 21 months; primary composite CV death or HF hospitalization HR=0.63 (95% CI 0.54–0.74; P<0.001); 37% relative risk reduction; all-cause mortality HR=0.76; confirmed MRA benefit in mild symptomatic HFrEF; trial stopped early · model: human RCT (mild HFrEF) ↩ ↩2

  10. doi:10.1056/NEJMoa2110956 · Pitt B, Filippatos G, Agarwal R et al. (FIGARO-DKD) · N Engl J Med 2021;385(24):2252–2263 · RCT · n=7,437 randomized (3,686 finerenone; 3,666 placebo in analysis); CKD stages 1–4 + T2D; eGFR 25–90 ml/min/1.73m² with albuminuria 30–5000 mg/g; finerenone 10–20 mg/day vs placebo; median follow-up 3.4 years; primary composite (CV death, nonfatal MI, nonfatal stroke, HF hospitalization) HR=0.87 (95% CI 0.76–0.98; P=0.03); driven by HF hospitalization reduction HR=0.71 (95% CI 0.56–0.90); complementary cardiovascular endpoint to FIDELIO kidney endpoint · model: human RCT (CKD+T2D) ↩ ↩2

  11. doi:10.1056/NEJMoa2407107 · Solomon SD, McMurray JJV, Claggett B et al. (FINEARTS-HF) · N Engl J Med 2024;391(16):1475–1485 · RCT · n=6,001 (3,003 finerenone; 2,998 placebo); HFmrEF/HFpEF (LVEF ≥40%); finerenone 20–40 mg/day vs placebo; median follow-up 32 months; primary composite (total worsening HF events + CV death) rate ratio=0.84 (95% CI 0.74–0.95; P=0.007); first large positive MRA trial in HFpEF; nonsteroidal scaffold; complements the TOPCAT null result · model: human Phase 3 RCT (HFmrEF/HFpEF) ↩ ↩2

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