What are the considerations for using spironolactone (aldosterone antagonist) versus eplerenone (selective mineralocorticoid receptor antagonist) in a male patient?

Spironolactone vs Eplerenone in Male Patients

In male patients requiring mineralocorticoid receptor antagonist therapy, start with spironolactone 25 mg daily as first-line therapy due to superior efficacy and lower cost, but switch to eplerenone 50 mg daily if gynecomastia, breast tenderness, or sexual dysfunction develops. 1

Efficacy Considerations

Spironolactone demonstrates superior antihypertensive efficacy compared to eplerenone. In a direct head-to-head randomized controlled trial in patients with primary aldosteronism, spironolactone reduced diastolic blood pressure by 12.5 mmHg compared to only 5.6 mmHg with eplerenone (difference of 6.9 mmHg, p<0.001). 2 This represents a clinically meaningful difference in blood pressure control that directly impacts cardiovascular outcomes.

For heart failure with reduced ejection fraction:

• Spironolactone reduced all-cause mortality by 30% and heart failure hospitalizations by 35% in the RALES trial, with a number needed to treat of only 9 patients for 2 years to prevent one death. 1
• Eplerenone reduced all-cause mortality by 15% in post-MI patients with heart failure in the EPHESUS trial. 1

The dosing equivalence ratio is approximately 1:2 (spironolactone:eplerenone), meaning 25 mg of spironolactone equals approximately 50 mg of eplerenone in terms of mineralocorticoid receptor blockade. 3

Sex-Specific Side Effects in Males

The critical differentiating factor in male patients is the anti-androgenic side effect profile:

• Spironolactone causes gynecomastia in 10-21% of men compared to 4.5% with eplerenone. 1, 3, 2
• Breast tenderness (mastodynia) occurs significantly more frequently with spironolactone (21.2% vs 4.5% with eplerenone, p=0.033). 2
• Sexual dysfunction and impotence are more common with spironolactone due to its non-selective binding to androgen and progesterone receptors. 1, 4

The ESC guidelines explicitly state that the main indication for eplerenone outside of post-MI heart failure is in men with breast discomfort and/or enlargement caused by spironolactone. 1

Clinical Algorithm for Male Patients

Initial Selection:

1. Start with spironolactone 25 mg daily in most male patients requiring MRA therapy for heart failure (LVEF ≤35%, NYHA class III-IV) or resistant hypertension. 1
2. Check baseline potassium (<5.0 mEq/L required) and creatinine clearance (>30 mL/min required). 1, 5

When to Choose Eplerenone Initially:

• Patient expresses strong concern about gynecomastia risk (e.g., younger men, those with body image concerns)
• History of breast tissue sensitivity or prior gynecomastia
• Willingness to accept potentially lower efficacy and higher cost for better tolerability

Switching from Spironolactone to Eplerenone:

Switch immediately if the patient develops:

• Gynecomastia or breast tenderness 1, 6
• Sexual dysfunction attributed to spironolactone 1

Conversion dosing: Replace spironolactone 25 mg with eplerenone 50 mg daily (2:1 ratio). 3, 7

After switching, monitor potassium and creatinine within 3 days, then at 1 week, and continue at 1,2,3,6,9, and 12 months. 6

Shared Monitoring Requirements

Both agents require identical monitoring for hyperkalemia and renal dysfunction:

• Check potassium and renal function at baseline, 1 week, and 4 weeks after initiation or dose changes. 1, 3
• Continue monitoring at 1,2,3, and 6 months, then every 6 months thereafter. 1

Management of hyperkalemia:

• Potassium 5.5-5.9 mEq/L: Reduce dose by 50% (e.g., spironolactone 25 mg every other day). 1
• Potassium ≥6.0 mEq/L: Stop medication immediately and treat hyperkalemia. 1

Renal function thresholds:

• Creatinine >2.5 mg/dL in men: Reduce dose by 50%. 1
• Creatinine >3.5 mg/dL: Stop medication immediately. 1

Common Pitfalls to Avoid

Do not use spironolactone and eplerenone together - this is explicitly contraindicated by the FDA. 4

Do not combine MRAs with both ACE inhibitors AND ARBs - this triple combination significantly increases hyperkalemia risk without additional benefit. 1, 3

Do not prescribe eplerenone with strong CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir) as this is contraindicated due to dramatically increased hyperkalemia risk. 5

In patients with diabetes, proteinuria, or moderate renal impairment (CrCl 30-50 mL/min), hyperkalemia risk is substantially higher with both agents (26% vs 16% in diabetics with proteinuria). 5 Consider starting at lower doses (spironolactone 12.5 mg or eplerenone 25 mg every other day) and monitor more frequently. 3

Cost considerations matter in real-world practice: Spironolactone is significantly less expensive than eplerenone, which may affect long-term adherence. 8 This economic factor, combined with superior efficacy data, supports spironolactone as first-line unless side effects develop.