What are nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)?

Nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)

Nonsteroidal MRAs are a novel class of medications that selectively block the mineralocorticoid receptor with improved tissue distribution and fewer adverse effects compared to traditional steroidal MRAs, with finerenone being the only currently approved agent with proven cardiorenal benefits in patients with type 2 diabetes and chronic kidney disease.

Definition and Mechanism of Action

Nonsteroidal MRAs differ fundamentally from traditional steroidal MRAs (spironolactone, eplerenone) in several important ways:

• Structure: Unlike steroidal MRAs which are derived from progesterone, nonsteroidal MRAs have a completely different molecular structure 1
• Tissue Distribution: Nonsteroidal MRAs like finerenone have a more balanced distribution between heart and kidney compared to spironolactone, which concentrates primarily in the kidneys 2
• Receptor Binding: They exhibit more selective binding to the mineralocorticoid receptor with different conformational changes upon binding 2
• Gene Expression: This results in different downstream gene expression patterns compared to steroidal MRAs 2

Clinical Applications

Nonsteroidal MRAs are primarily indicated for:

1. Type 2 diabetes with CKD: For patients with T2D, eGFR ≥25 ml/min/1.73 m², normal serum potassium, and albuminuria (≥30 mg/g) despite maximum tolerated dose of RAS inhibitor 3

2. Risk Reduction: They reduce:

   • Kidney disease progression by 23% (HR 0.77,95% CI: 0.67-0.88)
   • Cardiovascular events by 14% (HR 0.86,95% CI: 0.78-0.95)
   • Hospitalization for heart failure by 29% (HR 0.71,95% CI: 0.56-0.90) 4

Available Nonsteroidal MRAs

Currently, there are two nonsteroidal MRAs in clinical use:

1. Finerenone:

   • The only nonsteroidal MRA with proven clinical kidney and cardiovascular benefits 3
   • Approved in the US for treating CKD associated with type 2 diabetes 5
   • Demonstrated significant reduction in kidney disease progression and cardiovascular events in the FIDELIO-DKD and FIGARO-DKD trials 3, 4

2. Esaxerenone:

   • Currently licensed only in Japan for treating hypertension 5
   • Shown to effectively reduce blood pressure and albuminuria in diabetic CKD patients 1
   • Long-term kidney and cardiovascular benefits not yet established 3

Dosing and Administration of Finerenone

• Initial dosing:

  • 10 mg once daily for eGFR 25-60 ml/min/1.73 m²
  • 20 mg once daily for eGFR >60 ml/min/1.73 m² 4

• Dose titration:

  • Can be uptitrated to 20 mg daily after 1 month if serum potassium ≤4.8 mmol/L and eGFR remains stable 3, 4
  • Withhold if potassium >5.5 mmol/L; can restart at 10 mg daily when potassium ≤5.0 mmol/L 3

Monitoring Requirements

• Baseline: Serum potassium and renal function
• Follow-up: 4 weeks after initiation or dose change, then every 4 months 4
• Discontinuation criteria: Serum potassium >5.5 mmol/L despite medical management or severe hyperkalemia requiring emergency intervention 4

Safety Profile

• Hyperkalemia risk: Lower than steroidal MRAs but still present

  • FIGARO-DKD: 10.8% with finerenone vs. 5.3% with placebo
  • FIDELIO-DKD: 2.3% discontinuation due to hyperkalemia with finerenone vs. 0.9% with placebo 4

• Contraindications:

  • eGFR <25 ml/min/1.73 m²
  • Serum potassium >4.8 mmol/L
  • Adrenal insufficiency 4

Combination Therapy

Nonsteroidal MRAs can be effectively combined with:

• SGLT2 inhibitors
• GLP-1 receptor agonists
• Metformin (if eGFR >30 ml/min/1.73 m²) 3, 4

This combination approach provides additive cardiorenal protection in patients with type 2 diabetes and CKD.

Differences from Steroidal MRAs

Feature	Nonsteroidal MRAs	Steroidal MRAs
Tissue distribution	Balanced between heart and kidney	Primarily concentrated in kidneys
Anti-inflammatory/anti-fibrotic effects	More potent	Less potent
Risk of hyperkalemia	Lower	Higher
Hormonal side effects	Minimal	More common
Primary indication	CKD with T2D	Heart failure, hyperaldosteronism, resistant hypertension

Future Directions

Current research is expanding the potential applications of nonsteroidal MRAs:

• Non-diabetic CKD: The FIND-CKD trial is investigating finerenone in adults with non-diabetic CKD 4
• Pediatric populations: The FIONA program is studying finerenone in children with glomerular and non-glomerular CKD 4
• Combination therapy: Studies are examining synergistic effects with SGLT2 inhibitors 6

Nonsteroidal MRAs represent a significant advancement in cardiorenal medicine, offering improved tissue selectivity and potentially better safety profiles compared to traditional steroidal MRAs, with finerenone currently being the only agent with proven clinical outcomes benefits.