How Finerenone Compares to Other Mineralocorticoid Receptor Antagonists

Mineralocorticoid receptor antagonists (MRAs) also referred as aldosterone antagonists or anti-mineralocorticoids are class of drugs that block the effects of aldosterone.¹

Aldosterone synthesis, which occurs primarily in the adrenal gland, is modulated by multiple factors and may lead to oxidative stress, inflammation and organ fibrosis. Aldosterone binds to mineralocorticoid receptors in both epithelial (e.g., kidney) and nonepithelial (e.g., heart, blood vessels) tissues and increases blood pressure through induction of sodium reabsorption and potassium excretion. Mineralocorticoid receptor overactivation is a major driver of cardiovascular and kidney damage.¹

Aldosterone antagonists are important pharmacologic therapy in the neurohormonal blockade necessary in the treatment of hypertension and heart failure. Recent studies demonstrated that renal failure, proteinuria, and histologic renal lesions can be prevented by mineralocorticoid receptor antagonists.

Currently spironolactone, eplerenone, and finerenone are MRAs available for US patients. All drugs in class have similar mechanism of action as the potassium sparing diuretics the are competitively inhibiting mineralocorticoid receptors in the distal convoluted tubule to promote sodium and water excretion and potassium retention.²

Table 1: Mineralocorticoid receptor antagonists comparison, structure, chemistry, distribution, and receptors affinity.^3,4

^{*Lower values mean stronger inhibition.}

Spironolactone and eplerenone are steroidal MRAs but finerenone is a non-steroidal MRA. Spironolactone is non-selective MRA, however, eplerenone and finerenone are selective MRAs.^3,4

Spironolactone is a drug used as an add-on therapy in hypertension and New York Heart Association Class III-IV heart failure. It is used for a management of edema in cirrhotic adults not responsive to fluid and sodium restrictions. Additional indications include hyperaldosteronism and in nephrotic syndrome when treatment of the disease as well as fluid and sodium restriction with other diuretics is inadequate.^5,6

Spironolactone has antiandrogenic activity that leads to many of its off label uses, such as treatment of hirsutism, female pattern hair loss, and adult acne vulgaris.⁷ Spironolactone is a drug used for its antiandrogenic effects in transgender female patients for reducing male-pattern hair growth.⁸

Spironolactone structure

The main contraindications to use the drug include hyperkalemia and Adison disease. The adverse effects (AEs) include gynecomastia, hyperkalemia,impotence, and menstrual irregularities.^5,6

Eplerenone is a compound similar to spironolactone; however, it is selectively binding to mineralocorticoid receptors relative to its binding to glucocorticoid, progesterone, and androgen receptors.⁹ Gynecomastia and hyperkalemia are less likely with eplerenone than spironolactone.^10,11

Eplerenone structure

Finerenone is a dihydropyridine-based nonsteroidal mineralocorticoid receptor antagonist approved by the FDA in July 2021 to reduce the risk of kidney function decline, kidney failure, cardiovascular death, nonfatal heart attack, and hospitalization for heart failure in adults with chronic kidney disease (CKD) associated with type 2 diabetes mellitus (T2DM).¹² By binding to the MR receptor, it reduces inflammation, fibrosis, and albuminuria in patients with diabetes and lowered the risk of first onset of kidney failure.¹³

Finerenone blocks the mineralocorticoid receptor to reduce mortality and morbidity in patients with chronic severe congestive heart failure with an ejection fraction.¹⁴ It is distributed relatively equally between the heart and the kidney.

Finerenone structure

In comparison, spironolactone and eplerenone have higher concentrations in renal tissue than in cardiac tissue.⁴ Finerenone has no significant affinity or activity at androgen, progesterone, estrogen, and glucocorticoid receptors.

The drug binds selectively to the mineralocorticoid receptor and it is at least as potent as spironolactone with lower incidence of hyperkalemia and other AEs compared with both spironolactone and eplerenone.⁴ Finerenone was previously studied in the ARTS-DN randomized clinical trial to determine its efficacy on albuminuria in patients with diabetic nephropathy.¹⁵

In another clinical trial, finerenone was associated with a reduction of a composite end point of all-cause mortality and heart failure outcomes in comparison to eplerenone.¹⁶

The drug is currently investigated in study FINEARTS-HF to find its effect in heart failure with reduced ejection fraction and heart failure with preserved ejection fraction and in FIGARO-DKD to investigate the effect of medication on reducing cardiovascular mortality and morbidity with less advanced stages of CKD and T2DM.^17,18

Recent studies demonstrated that renal failure, proteinuria, and histologic renal lesions can be prevented by mineralocorticoid receptor antagonists.19Despite guideline-directed therapies, there remains a high unmet medical need in patients with CKD and T2DM, and there is increasing prevalence of patients with T2DM who are at risk for CKD.²⁰

The FIDELIO-DKD trial indicated that finerenone reduced the risk of cardiovascular and kidney failure outcomes in patients with and without a history of atherosclerotic cardiovascular disease. The results suggest that finerenone may represent an important treatment advance to reduce cardiovascular morbidity and mortality in patients with CKD and T2DM.¹⁸

It may be recommended for reduction of the risk of sustained decline in glomerular filtration rate, end-stage kidney disease, cardiovascular death, heart attacks, and hospitalization due to heart failure in adults with CKD with T2DM.

Finerenone is both a cardiovascular and kidney protective medication for individuals with T2DM and may be an option where SGLT2 inhibitors are not preferred.²⁰

References

1. Chrousos GP. Adrenocorticosteroids & Adrenocortical Antagonists. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw Hill; 2021. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2988&sectionid=250600694 Accessed March 09, 2022.
2. Sam R, Pearce D. Diuretic Agents. In: Katzung BG, Vanderah TW. eds. Basic & Clinical Pharmacology, 15e. McGraw Hill; 2021. https://accesspharmacy.mhmedical.com/content.aspx?bookid=2988&sectionid=250596112 Accessed March 9, 2022.
3. Schubert-Zsilavecz M, Wurglics M. Neue Arzneimittel Herbst. 2015.
4. Bärfacker L, Kuhl A, Hillisch A, et al. Discovery of bay 94‐8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of Cardiorenal diseases. Chemistry Europe. https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/cmdc.201200081. Published July 12, 2012. Accessed March 9, 2022.
5. Aldactone (spironolactone) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada Inc; July 2015.
6. Aldactone (spironolactone) [prescribing information]. New York, NY: Pfizer Inc; April 2018.
7. Millington K, Liu E, Chan YM: The Utility of Potassium Monitoring in Gender-Diverse Adolescents Taking Spironolactone. J Endocr Soc. 2019 Apr 4;3(5):1031-1038. doi: 10.1210/js.2019-00030.
8. Kim GK, Del Rosso JQ: Oral Spironolactone in Post-teenage Female Patients with Acne Vulgaris: Practical Considerations for the Clinician Based on Current Data and Clinical Experience. J Clin Aesthet Dermatol. 2012 Mar;5(3):37-50.
9. Rogerson FM, Yao Y, Smith BJ, Fuller PJ: Differences in the determinants of eplerenone, spironolactone and aldosterone binding to the mineralocorticoid receptor. Clin Exp Pharmacol Physiol. 2004 Oct;31(10):704-9.
10. Inspra (eplerenone) [prescribing information]. New York, NY: Pfizer Inc; May 2018.
11. Inspra (eplerenone) [product monograph]. Kirkland, Quebec, Canada: Pfizer Canada Inc; October 2016.
12. KERENDIA (finerenone) [prescribing information]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; July 2021.
13. Grune J, Beyhoff N, Smeir E, et al. Selective mineralocorticoid receptor cofactor modulation as molecular basis for finerenone’s antifibrotic activity. Hypertension. 2018; 71:599-608.
14. Pitt B, Kober L, Ponikowski P, et al. Safety and tolerability of the novel nonsteroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013; 34:2453-63.
15. Bakris GL, Agarwal R, Chan JC, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA 2015; 314:884-94.
16. Filippatos G. et al. Finerenone and Cardiovascular Outcomes in Patients With Chronic Kidney Disease and Type 2 Diabetes. Circulation. 2021;143:540–552. DOI: 10.1161/CIRCULATIONAHA.120.051898.
17. U.S. National Library of Medicine. Study to Evaluate the Efficacy (Effect on Disease) and Safety of Finerenone on Morbidity (Events Indicating Disease Worsening) & Mortality (Death Rate) in Participants With Heart Failure and Left Ventricular Ejection Fraction (Proportion of Blood Expelled Per Heart Stroke) Greater or Equal to 40% (FINEARTS-HF). https://clinicaltrials.gov/ct2/show/NCT04435626 Accessed March 9, 2022.
18. U.S National Library of Medicine Clinical Trials. Efficacy and Safety of Finerenone in Subjects With Type 2 Diabetes Mellitus and Diabetic Kidney Disease (FIDELIO-DKD) https://www.clinicaltrials.gov/ct2/show/NCT02540993 Accessed March 9, 2022.
19. Haller H, et al. Finerenone: a New Mineralocorticoid Receptor Antagonist Without Hyperkalemia: an Opportunity in Patients with CKD? Curr Hypertens Rep. 2016;18: 41 DOI 10.1007/s11906-016-0649-2.
20. Bakris GL., et al. Design and Baseline Characteristics of the Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease Trial. Am J Nephrol. 2019;50:333–344 DOI: 10.1159/000503713.