Institute of Pharmaceutical Education, Boradi, Maharashtra, India 425428
Diuretics are mainly used in the management of hypertension, chronic kidney disease (CKD), heart failure, and numerous hypervolemic disorders. Different diuretics work on different ion channels together with the nephron, increasing sodium excretion through urination. Promoting the renin-angiotensin-aldosterone system (RAAS) pathway causes the construction of the steroid hormone aldosterone by the adrenal cortex, which acts on receptors in the distal and collecting tubules of the nephron, promoting the secretion of potassium and reabsorption of sodium. Finerenone is a newly approved non-steroidal mineralocorticoid receptor antagonist (MRA) indicated for chronic kidney disease (CKD) in patients with type 2 diabetes (T2D). This review summarizes its pharmacological action, clinical efficacy from major trials, and safety profile. Compared to older MRAs, finerenone offers improved receptor selectivity and reduced risk of hyperkalemia.
It is projected that 537 million people globally between the ages of 20 and 79 will have diabetes mellitus in 2021. Additionally, diabetes only led to 6.7 million fatalities and was linked to costly medical expenses, mainly as a result of the difficulties the condition causes. However, it is predicted that these numbers will increase to 783 million people by 2045 as a result of both population aging and lifestyle choices (sedentary lifestyle and overweight/obesity). Additionally, chronic kidney disease (CKD) affects 850 million individuals [1].
A group of medications known as mineralocorticoid receptor antagonists (MRA) reduces the impact of the steroid hormone aldosterone on the mineralocorticoid receptor (MR) [2]. Finerenone is also known as the (BAY 94-8862) For the treatment of chronic kidney disease in individuals with type 2 diabetes (T2D), this was authorized by the United States Food and Drug Administration (FDA) in July 2021 and then approved by the European Medicine Agency (EMA) in February 2022, and the Drug Controller General of India (DCGI) in April 2022. Three novel selective non-steroidal mineralocorticoid receptor antagonists (NMRA) are Finerenone, esaxerenone, and apararenon. They are newly developed drugs, but Finerenone has only been approved in different countries.
Finerenone can be involved in several clinical trials, such as FINEARTS-HF (Finerenone in heart failure patients with Reduced Ejection Fraction). This trial is used to study Finerenone in heart failure patients. FINE-CKD (Finerenone in Decreasing Cardiovascular Mortality and Morbidity in Chronic Kidney Disease): This is another phase III study aimed to determine whether Finerenone could reduce cardiovascular death and chronic renal disease morbidity. FIONA (Finerenone ON Albuminuria): This is part of a phase III study to determine whether Finerenone could minimize albuminuria (this is the condition when albumin is present in urine in patients with chronic kidney disease). FINE-ONE (Finerenone in patients with chronic kidney disease): This is the part of phase III aimed to study whether Finerenone can improve kidney function and minimize the occurrence of kidney-related complications in patients. Along with this important clinical study, there are two main clinical studies including FIDELIO-DKD (Finerenone in reducing kidney failure and disease progression in Diabetic Kidney Disease) and FIGARO-DKD (Finerenone in reducing cardiovascular mortality and morbidity in Diabetic Kidney Disease) FIDELIO-DKD a clinical trial is designed to study the efficacy and safety of Finerenone in a patient with type 2 diabetes and chronic kidney disease (CKD). FIGARO-DKD This clinical trial also focused on patients with CKD and type 2 diabetes and investigated Finerenone's effectiveness and safety in lowering cardiovascular mortality and morbidity [3-4]. Clinical trial outcomes are summarized in Table 1.
TABLE 1: Summary of Trials on Finerenone in Diabetic Kidney Disease [7-8]
|
Trial |
FIDELIO-DKD[5] |
FIGARO-DKD[6] |
|
Drug |
Finerenone |
Finerenone |
|
Outcome |
Kidney Failure, eGFR decrease >=40%, or Renal Death |
Cardiovascular Morbidity and Mortality |
|
Result |
Reduced risk by 18% |
Reduced risk by 13% |
|
Details |
The trial involved patients with CKD and type 2 diabetes. |
The trial involved patients with CKD and type 2 diabetes. |
|
Follow-up Duration |
2.6 years |
3.4 years |
|
Number of Patients |
5734 |
7437 |
|
Mean Age |
66 years |
64.1 years |
|
% Female |
30% |
31% |
|
% with CV Disease |
N/A |
45% |
|
Mean eGFR |
44 ml/min/1.73 m2 |
67.8 ml/min/1.73 m2 |
ABBREVIATIONS: eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; CV, cardiovascular
Finerenone is a mineralocorticoid receptor antagonist (MRA). MRAs are a class of drugs that includes older, widely used medications such as spironolactone and eplerenone. Finerenone is a newer addition to this class. First-generation MRA spironolactone proves potent yet nonselective. and is also known as a diuretic it was discovered in 1957 and was introduced in 1959. A second-generation MRA, eplerenone is more selective but less effective. It also functions as a diuretic by preventing the body's natural production of aldosterone, which raises blood pressure[9]. TABLE 2 The comparison of Finerenone with spironolactone and eplerenone with their general chemical and pharmacological activity. Finerenone is a novel nonsteroidal MRA that has high superior receptor affinity over eplerenone and is superior to spironolactone[10].
TABLE 2. Comparison of Finerenone with spironolactone and eplerenone.[7-11-12]
|
Spironolactone |
Eplerenone |
Finerenone |
|
|
Name |
SC 9420 |
BAY 94-8862 |
|
|
Dose |
10mg to 20mg |
25mg to 20mg |
10mg to 20mg |
|
Steroidal/ Nonsteroidal |
Steroidal |
Steroidal |
Nonsteroidal |
|
Manufacturer |
Pfizer |
Pfizer |
Bayer |
|
Generation of MRA |
First |
Second |
Third |
|
Structure |
|
|
|
|
Molecular Formula |
C24H32O4S |
C24H30O6 |
C21H22N4O3 |
|
Half-life |
12 to 24 h |
3 to 6 h |
2 to 3h |
|
Mode of MR antagonism |
Potent and non-selective |
Less potent and more selective than Spironolactone |
Potent and selective |
|
Heart-kidney distribution ratio |
1:6 |
1:3 |
1:1; cannot cross the Blood-Brain Barrier |
|
Safety |
High risk of hyperkalemia |
High risk of hyperkalemia |
low risk of hyperkalemia |
|
Ratio of Protein Binding |
90% |
35-60% |
92% |
The NR3C2 gene on the human chromosome encodes the protein known as the mineralocorticoid receptor (MR) and MR plays a major role in fluid balance, renal sodium handling, renal blood flow, and osmolarity. aldosterone,11-deoxycorticosterone, and cortisol are endogenous agonists of the MR. Mineralocorticoid receptor antagonist (MRAs) is a group of drugs that inhibit or reduce the result of aldosterone on the MR[10]. They work by blocking the action of aldosterone at MR. there are two types of MRAs: steroidal and non-steroidal. Steroidal drug is often used in the treatment of heart failure and resistant hypertension. Spironolactone and eplerenone are examples of steroidal MRA drugs[2]. other sites non-steroidal MRAs, Finerenone is a selected MRA that shows high effectiveness in treating heart failure and diabetic nephropathy.
MODE OF ACTION OF FINERENONE:
Finerenone is a non-steroidal, third-generation MR antagonist that shows action by attach to the mineralocorticoid receptor and showing resistance to the action of mineralocorticoids like aldosterone and cortisol when the mineralocorticoid is overactivated [14]. These hormones are mainly involved in regulating water and salt in the body, affecting blood volume and pressure. After binding with Finerenone to MR, which is expressed in many tissues and cells, including in the heart, kidneys, and blood vessels. Unlike spironolactone and eplerenone Finerenone binds to MR as a bulky antagonist and its result inhibits the transcription cofactor requirement implicated in the expression of hypertrophic, profibrotic, and proinflammatory [15]. It also shows the protective role of anti-inflammatory, anti-remodelling, and anti-fibrotic in kidney and cardiac tissues[16]. The mechanism of Finerenone is illustrated in Figure 1.
Figure 1. Mechanism of action of Finerenone
Aldosterone is translocated into the cell nucleus after binding to the mineralocorticoid receptor and causing a conformational change. Following its binding to a particular hormone response element (HRE), the mineralocorticoid receptor enlists a transcriptional cofactor and initiates the transcription of target genes. The same processes are changed by using the Finerenone after binding with the mineralocorticoid receptor. Finerenone blocks the cofactor binding with the mineralocorticoid receptor, and for that reason, cofactor complexes are not attached to the HRE and causing DNA transcription is stop. The result shows the decreased inflammation and fibrosis.
ADVERSE EFFECT OF FINERENONE:
Hyperkalaemia, characterized by elevated levels of potassium in the blood, is a common adverse reaction associated with Finerenone. In clinical trials, approximately 18.3% of patients treated with Finerenone experienced hyperkalaemia. Most hyperkalaemia events were mild to moderate, but serious cases occurred more often with Finerenone than with a placebo of patients treated with Finerenone, 21.7% had serum potassium levels above 5.5 mmol/L, and 4.5% had levels above 6 mmol/L [17].
CONCLUSIONS
Finerenone represents a significant advancement in the field of nephrocardiology and endocrinology by offering a novel, non-steroidal approach to mineralocorticoid receptor antagonism. Unlike traditional agents such as spironolactone and eplerenone, Finerenone provides enhanced receptor selectivity and a favourable safety profile, particularly regarding hyperkalaemia and hormonal side effects. Clinical trials like FIDELIO-DKD and FIGARO-DKD have established their efficacy in reducing the progression of chronic kidney disease and cardiovascular events in patients with type 2 diabetes mellitus. As an emerging therapeutic agent, Finerenone holds promise for redefining the standard of care in cardiorenal protection. Continued post-marketing surveillance and long-term studies will be crucial to fully understand its therapeutic potential and optimize its use in diverse patient populations.
AUTHOR CONTRIBUTION
The first author was responsible for the main conceptualization, analysis, and manuscript preparation. The second author provided supporting assistance in the literature review and editing.
CONFLICT OF INTEREST: None to declare.
ETHICS APPROVAL: None to declare.
REFERENCES
Sandip Bhoi, Nitin Ahire, Finerenone: A Novel Non-Steroidal MRA for Diabetic Kidney Disease and Cardiovascular Risk Reduction, Int. J. of Pharm. Sci., 2025, Vol 3, Issue 8, 849-854. https://doi.org/10.5281/zenodo.16778496
10.5281/zenodo.16778496
