What is the mechanism of action of finerenone?

Mechanism of Action of Finerenone

Finerenone is a nonsteroidal, selective mineralocorticoid receptor antagonist that blocks sodium reabsorption through the mineralocorticoid receptor and reduces overactivation of this receptor in the kidney, heart, and blood vessels. 1

Key Molecular Characteristics

• Receptor Selectivity: Unlike steroidal MRAs (spironolactone and eplerenone), finerenone selectively binds to mineralocorticoid receptors with higher affinity, minimizing off-target hormonal side effects 2
• Classification: Third-generation mineralocorticoid receptor antagonist with a nonsteroidal structure 2
• Binding Properties: Higher binding affinity to mineralocorticoid receptors compared to traditional MRAs 3

Physiological Effects

Renal Effects

• Blocks mineralocorticoid receptor-mediated sodium reabsorption in the kidney 1
• Reduces albuminuria in patients with CKD and type 2 diabetes 4
• Decreases risk of kidney disease progression by 23% (HR 0.77,95% CI: 0.67-0.88) 5
• Reduces risk of kidney failure requiring dialysis or transplantation (HR 0.80,95% CI: 0.64-0.99) 5

Cardiovascular Effects

• Reduces overactivation of mineralocorticoid receptors in the heart and blood vessels 1
• Lowers blood pressure with persistent 24-hour effects despite short half-life 6
  • Placebo-adjusted reductions in 24-hour systolic BP:
    • 10 mg dose: -8.3 mmHg
    • 15 mg dose: -11.2 mmHg
    • 20 mg dose: -9.9 mmHg
• Decreases risk of composite cardiovascular events by 13-14% (HR 0.86,95% CI: 0.78-0.95) 5
• Specifically reduces hospitalization for heart failure (HR 0.71,95% CI: 0.56-0.90) and new-onset heart failure by 32% (HR 0.68,95% CI: 0.50-0.93) 5

Anti-inflammatory and Anti-fibrotic Actions

• Targets inflammation and fibrosis pathways that are not addressed by traditional treatments like RAS inhibitors or SGLT2 inhibitors 7
• Provides cardiorenal protection through non-hemodynamic pathways in addition to its blood pressure-lowering effects 6

Pharmacokinetic Considerations

• Has a short half-life but produces persistent 24-hour blood pressure reduction with once-daily morning dosing 6
• Requires lower doses to achieve similar cardiorenal protective effects compared to spironolactone and eplerenone 3

Clinical Implications

• Finerenone represents a significant advancement in MRA therapy for patients with type 2 diabetes and CKD 2
• Unlike traditional MRAs, finerenone has a lower incidence of hyperkalemia, though monitoring is still required 5
• Can be effectively combined with SGLT2 inhibitors and other diabetes medications for comprehensive cardiorenal protection 5

Cautions and Monitoring

• Primary adverse effect is hyperkalemia (10.8% incidence vs. 5.3% with placebo) 5
• Contraindicated in patients with adrenal insufficiency 1
• Should not be initiated if eGFR is <25 mL/min/1.73 m² 1

Finerenone's unique mechanism as a nonsteroidal, selective mineralocorticoid receptor antagonist allows it to provide cardiorenal protection through both hemodynamic and non-hemodynamic pathways, making it an important therapeutic option for patients with type 2 diabetes and chronic kidney disease.