What is the difference between Spironolactone and Finerenone in the context of heart failure and resistant hypertension management?

Spironolactone vs. Finerenone: Mechanisms and Clinical Context

What is Spironolactone?

Spironolactone is a first-generation steroidal mineralocorticoid receptor antagonist (MRA) that blocks aldosterone's effects on sodium retention and cardiac/vascular remodeling, originally marketed as a potassium-sparing diuretic but now recognized as a critical therapeutic agent in heart failure and resistant hypertension. 1

• Spironolactone is non-selective, meaning it also blocks androgen and progesterone receptors, leading to hormonal side effects including gynecomastia, breast tenderness (particularly in men), and sexual dysfunction 1
• It has been used for over 50 years with an established safety profile when appropriately monitored 2, 3
• The drug works by antagonizing the mineralocorticoid receptor in the distal collecting duct of the kidney, promoting sodium excretion and potassium retention 1

What is Finerenone?

Finerenone is a third-generation nonsteroidal MRA with higher selectivity for the mineralocorticoid receptor compared to spironolactone and stronger binding affinity than eplerenone, designed specifically to reduce cardiovascular and renal complications in patients with chronic kidney disease and type 2 diabetes. 1, 4

• Finerenone blocks sodium reabsorption through the mineralocorticoid receptor and reduces overactivation of this receptor in the kidney, heart, and blood vessels 1
• Its nonsteroidal structure eliminates the hormonal side effects (gynecomastia, sexual dysfunction) seen with spironolactone 5, 4
• Clinical trials demonstrated that finerenone reduced CKD progression, end-stage kidney disease, heart failure hospitalization, and other cardiovascular outcomes in persons with CKD and type 2 diabetes 1

Clinical Context for Use

Resistant Hypertension

For resistant hypertension, spironolactone (25-50 mg daily) is the preferred fourth-line agent after optimizing a three-drug regimen of RAS blocker, long-acting calcium channel blocker, and thiazide-like diuretic, with evidence showing blood pressure reductions of approximately 21.7/8.5 mmHg. 1, 6, 7

• Spironolactone lowered systolic and diastolic blood pressure by 24 and 10 mm Hg respectively when added to regimens of patients uncontrolled on at least 2 medications including an ACE inhibitor or ARB and diuretic 1
• The 2024 ESC Guidelines provide spironolactone a Class IIa recommendation for resistant hypertension, acknowledging its effectiveness but noting the lack of dedicated cardiovascular outcome trials in primary hypertension populations 1
• Finerenone is mentioned as a potential future option for hypertension trials but currently lacks evidence in this specific indication 1

Heart Failure with Reduced Ejection Fraction (HFrEF)

Spironolactone is a cornerstone therapy in HFrEF as part of guideline-directed medical therapy, proven to reduce both morbidity and mortality when added to standard treatment with ACE inhibitors/ARBs and beta-blockers. 1, 2, 3

• MRAs including spironolactone are recommended as part of combination therapy, not monotherapy, for heart failure with reduced ejection fraction 7
• The standard regimen includes an ACE inhibitor/ARB, beta-blocker, and MRA, with loop diuretics added as needed for volume management 7
• Finerenone is currently being studied in dedicated heart failure trials but does not yet have established indications for HFrEF 5, 4

Chronic Kidney Disease with Type 2 Diabetes

Finerenone is specifically indicated for patients with type 2 diabetes, eGFR ≥25 mL/min/1.73 m², normal serum potassium, and albuminuria (ACR ≥30 mg/g) despite maximum tolerated RAS inhibitor therapy, representing a major advancement over spironolactone in this population. 1

• Finerenone should be started at 20 mg daily for eGFR >60 mL/min/1.73 m² and 10 mg for eGFR 25-60 mL/min/1.73 m², with uptitration to 20 mg if tolerated 1
• Initiation requires serum potassium ≤4.8 mmol/L (per trial criteria) or ≤5.0 mmol/L (per FDA label), with potassium monitoring at 4 weeks after dose changes 1
• The drug can be continued with eGFR <25 mL/min/1.73 m² as long as potassium remains acceptable and the drug is tolerated 1

Direct Comparison

Selectivity and Side Effect Profile

Finerenone's nonsteroidal structure and higher mineralocorticoid receptor selectivity eliminate the hormonal side effects that limit spironolactone use, particularly gynecomastia and sexual dysfunction in men. 5, 4

• Spironolactone's most common adverse effect is breast tenderness with or without breast enlargement, particularly in men, due to its non-selective receptor binding 1
• Finerenone has stronger MR-binding affinity than eplerenone (the second-generation MRA) and higher selectivity than spironolactone 4
• Both agents carry hyperkalemia risk, but finerenone's selectivity may theoretically reduce this risk, though close monitoring remains essential 1, 5, 4

Hyperkalemia Risk

Both agents increase hyperkalemia risk, particularly in older patients, those with diabetes, CKD, or concurrent use of ACE inhibitors/ARBs/NSAIDs, requiring identical vigilance in potassium monitoring regardless of which agent is chosen. 1

• For spironolactone, hyperkalemia is uncommon but can occur, necessitating close monitoring especially in high-risk populations 1
• For finerenone, if potassium increases to >5.5 mmol/l, the drug should be withheld and can be restarted at 10 mg daily when potassium is ≤5.0 mmol/l 1
• Risk factors are identical for both drugs: renal impairment, diabetes, concurrent ACE inhibitor/ARB use 1

Evidence Base and Indications

Spironolactone has decades of proven cardiovascular mortality benefit in heart failure and robust blood pressure reduction data in resistant hypertension, while finerenone has specific trial-proven benefits for preventing kidney disease progression and cardiovascular events in diabetic CKD patients. 1, 2, 3

• Spironolactone's evidence spans resistant hypertension, HFrEF, and cirrhotic ascites with established mortality benefits 1, 2, 3
• Finerenone's evidence is specifically in CKD with type 2 diabetes, where it reduced CKD progression, end-stage kidney disease, and heart failure hospitalization 1
• The 2024 ESC Guidelines note that future outcome trials of MRAs, perhaps including finerenone, are encouraged in patients with hypertension 1

Practical Algorithm for Selection

Choose spironolactone for resistant hypertension (after optimizing three-drug regimen) and HFrEF; choose finerenone for patients with type 2 diabetes and CKD with albuminuria despite RAS inhibitor therapy. 1, 6, 7

• For resistant hypertension: Start spironolactone 25 mg daily if potassium <4.5 mEq/L and eGFR >45 mL/min/1.73m², increase to 50 mg if needed 6
• For diabetic CKD: Add finerenone to standard care if ACR ≥30 mg/g, eGFR ≥25 mL/min/1.73 m², and potassium ≤5.0 mmol/L 1
• If spironolactone causes gynecomastia or sexual side effects: Switch to eplerenone (50-200 mg daily) or consider finerenone if patient has diabetic CKD 1, 6
• Both drugs require potassium and creatinine monitoring before initiation, at 1 week, then periodically 7

Common Pitfalls

The most critical error is failing to monitor potassium adequately with either agent, particularly in patients on concurrent RAS inhibitors, which dramatically increases hyperkalemia risk. 1

• Do not combine spironolactone or finerenone with both an ACE inhibitor AND an ARB, as this triple combination significantly increases hyperkalemia and AKI risk 1
• Do not use thiazide diuretics if eGFR <30 mL/min/1.73m²; switch to loop diuretics as thiazides become ineffective at lower GFR 6, 7
• Do not assume finerenone can replace spironolactone in resistant hypertension or HFrEF, as it lacks dedicated outcome trial evidence in these populations 1, 5
• Do not continue hydrochlorothiazide in resistant hypertension; switch to chlorthalidone or indapamide for superior efficacy before adding any MRA 6