What are nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)?

Nonsteroidal Mineralocorticoid Receptor Antagonists (MRAs)

Nonsteroidal MRAs are a newer class of selective mineralocorticoid receptor antagonists that provide cardiorenal protection with a lower risk of hyperkalemia compared to traditional steroidal MRAs like spironolactone and eplerenone. 1, 2

Definition and Mechanism

• Nonsteroidal MRAs competitively bind to mineralocorticoid receptors, blocking the effects of aldosterone while having a different chemical structure than traditional steroidal MRAs 2
• They exert anti-inflammatory and antifibrotic effects beyond the classical functions of maintaining fluid and electrolyte homeostasis 2
• Their unique molecular structure allows for more selective inhibition of mineralocorticoid receptors with fewer off-target effects compared to steroidal MRAs 3

Key Differences from Steroidal MRAs

• Selectivity: Nonsteroidal MRAs have higher selectivity for mineralocorticoid receptors with minimal binding to other steroid receptors (androgen, progesterone) 3
• Safety profile: Lower incidence of hyperkalemia compared to steroidal MRAs, making them more suitable for patients with reduced kidney function 1, 2
• Tissue distribution: Different tissue distribution patterns with potentially enhanced cardiac and renal tissue penetration 4

Available Nonsteroidal MRAs

• Finerenone: The first FDA-approved nonsteroidal MRA with proven clinical kidney and cardiovascular benefits 5

  • Indicated for patients with type 2 diabetes and chronic kidney disease with persistent albuminuria (ACR ≥30 mg/g) despite maximum tolerated doses of RAS inhibitors 6, 5
  • Can be used in patients with eGFR ≥25 ml/min/1.73m² 6
  • Reduces the risk of kidney failure progression (HR: 0.82,95% CI: 0.73-0.93) and cardiovascular events 5

• Esaxerenone: Approved in some countries for hypertension and diabetic kidney disease 2

  • Demonstrated to be noninferior to eplerenone in lowering blood pressure in patients with primary hypertension 6
  • Effective in reducing albuminuria in diabetic patients with CKD 2

Clinical Applications

• Primary indication: Patients with type 2 diabetes and CKD with persistent albuminuria despite maximum tolerated doses of RAS inhibitors 6
• Positioning in therapy: Current guidelines position nonsteroidal MRAs as "additional risk-based therapy" after optimization of first-line treatments 6
• Dosing considerations:
  • For finerenone: 10 mg daily for patients with eGFR 25-60 ml/min/1.73m² and 20 mg daily for those with eGFR >60 ml/min/1.73m² 5
  • Serum potassium should be <4.8 mmol/L before initiation and monitored regularly 5

Benefits in Clinical Trials

• Reduction in albuminuria in patients with type 2 diabetes and CKD 5, 2
• Modest blood pressure lowering effects (2-3 mmHg systolic) 5
• Significant reduction in kidney disease progression 5, 7
• Reduction in cardiovascular events including death from cardiovascular causes, nonfatal MI, nonfatal stroke, and hospitalization for heart failure 5, 7

Safety Considerations

• While hyperkalemia can occur (14% with finerenone vs. 6.9% with placebo), the risk of severe hyperkalemia requiring drug discontinuation is relatively low (1.7% vs. 0.6%) 5
• Regular monitoring of serum potassium is essential, especially when initiating therapy 6
• No deaths due to hyperkalemia were reported in clinical trials over 3 years of follow-up 5

Future Directions

• Combination therapy with SGLT2 inhibitors may provide complementary cardiorenal protection 6, 2
• Use of potassium binders may allow safer use in patients at higher risk for hyperkalemia 2
• Ongoing research into applications for non-diabetic kidney disease and heart failure 7

Clinical Practice Algorithm

1. Identify eligible patients: Type 2 diabetes with CKD and persistent albuminuria (ACR ≥30 mg/g) despite maximum tolerated RAS inhibitor 6
2. Check baseline potassium (<4.8 mmol/L) and kidney function (eGFR ≥25 ml/min/1.73m²) 6, 5
3. Initiate appropriate dose based on kidney function 5
4. Monitor serum potassium at 4 weeks and periodically thereafter 6
5. Consider dose adjustment based on potassium levels and clinical response 5