Along with type 2 diabetes, arterial hypertension (AH) is one of the leading causes of morbidity and mortality and one of the main cause of cardiorenovascular (CVR) disease in the world. (1) It is estimated that approximately 1.56 billion people will be suffering from AH by 2025, and despite efforts to control arterial pressure and HbA1c levels in patients with diabetes, the progression of chronic kidney disease (CKD) has not slowed down but has instead reached pandemic levels. (2) Mineralocorticoid receptor antagonists (MRA) play a significant role in therapy for hypertension and heart failure. (3) No clinical trial data has shown that MRA are first-line drugs for the treatment of AH. Instead, MRA are considered “go-to drugs” for the treatment of primary hyperaldosteronism (when surgery is not indicated) and in secondary hyperaldosteronism due to edema and ascites, although the ESH guidelines from 2018 consider them an additional option for with treatment-resistant hypertension and heart failure. (3) Over the last few years, this group of drugs has received increased attention due to their beneficial effect on reducing albuminuria and slowing progression of CKD, especially for nonsteroidal MRA in patients with diabetic kidney disease (DKD). Herein we shall present both past and most recent insights related to the MRA drug group, which are divided into two groups: steroidal and nonsteroidal, with important differences in molecular and pharmacological properties between the two types. (4)
Steroidal mineralocorticoid receptor antagonists
Aldosterone synthesis
Aldosterone is an adrenal hormone which is synthesized from cholesterol in the cells of the zona glomerulosa. It is secreted based on stimulus from angiotensin II (AG II), adrenocortical hormones (ACTH), and potassium. (5) Aldosterone synthesis takes place in two phases, the acute phase and the chronic phase. The acute phase is regulated by the steroidogenic acute regulatory protein (StAR), which is responsible for delivering cholesterol to the inner mitochondrial membrane. Potassium, ACTH, and AG II regulate phosphorylation and StAR protein expression through secondary messengers. The chronic phase of aldosterone synthesis is regulated through enzymes on the mitochondrial membrane, and aldosterone synthase – CYP11B2 – is the limiting factor in this phase.
Genomic and nongenomic effects of aldosterone
By binding to mineralocorticoid receptors (MR), aldosterone affects transcription and translation, which is called a genomic effect. (5) The other effect of aldosterone is nongenomic and is achieved through membrane receptors. MR are intracellular cytoplasmatic receptors belonging to the family of ligand-dependent transcription factors. MR themselves have 3 domains, an N-terminal domain that activates transcription, the central domain binding to a specific part of targeted DNA (SRE – steroid response element), and the C-terminal domain binding aldosterone (LBD – ligand-binding domain). (5) In the inactive state, heat-shock proteins (HSP) are bound to the receptor, disallowing it to bind to SRE. After aldosterone binds to the receptor, HSP are released and a conformation change in the receptor takes place, translocating it to the nucleus and binding to a specific DNA sequence. This initiates transcription, and the resultant mRNA transfers to ribosomes, where aldosterone-induced proteins (AIP) are synthesized. This induces expression of the Na+ channel, K+ channel, Na+/K+-ATPase, the luminal Na+/H+ antiporter, but only in the proximal tubule, and the luminal Na+/Cl- cotransporter sensitive to thiazides in distal nephron tubules. Since these proteins must be synthetized, this phase takes place with a >2.5 hour delay and is therefore called the late phase.
The early nongenomic phase starts with a 20-60 minute delay upon the activation of existing channels and pump, thus increasing transport capacity in the cell. This phase takes place through second cell messengers: intermediary tyrosine kinase (IPYK), phospholipase C (PLC), inositol trisphosphate (IP3), diacylglycerol (DAG), protein kinase C (PKC), and increase in free intracellular calcium. Signal cascades initiated by second messengers act on the phosphorylation of membrane sodium channels or influence their expression through phosphorylation of transcription factors. (5) This nongenomic effect of aldosterone is not sensitive to mineralocorticoid antagonists. Finally, by binding to MR, aldosterone induces transcription and expression of epithelial sodium channels (ENaC) that resorb sodium (they are located on the apical membrane and actively transported via Na+/K+-ATPase on the basolateral membrane). In order to maintain osmotic balance, Na+ also binds water and thus increases circulating blood volume, contributing to AH. (5,6) Other than binding to MR in nephron and colon cells, aldosterone also binds to MR in cardiomyocytes, cardiac fibroblasts, and vascular smooth muscle cells, causing myocardial fibrosis, and, in addition to a profibrotic response, also causing oxidative stress in the vascular endothelium by blocking the glucose-6-phosphate dehydrogenase enzyme, which results in inflammation and hypertrophy of blood vessels, kidneys, and the heart and consequently progression of CVR disease. (7)
The role of mineralocorticoid receptor antagonists
Medications from the MRA group that are applied today are spironolactone (usually in doses of 12.5-50 mg) and eplerenone (in doses of 25-50 mg). Both drugs are equally effective in reducing blood pressure, but eplerenone is more selective for MR, which is why it has less unwanted adverse events (side-effects) compared with spironolactone, such as gynecomastia and/or breast and nipple sensitivity as well as sexual or menstrual dysfunction. Renal function must be assessed before introducing MRA into an existing treatment regime, and if glomerular filtration (eGFR) is <50 ml/L/1.73 m2, a daily dose above 25 mg per day is not recommended due to hyperkalemia, which is the limiting factor for this group of medications. (8) Factors for increased risk of hyperkalemia are advanced age, diabetes and/or CKD, adding MRA to therapy with angiotensin-converting enzyme inhibitors (ACEI) or sartans, and/or taking nonsteroidal anti-inflammatory drugs (NSAID). (8) Studies with spironolactone have demonstrated a renoprotective effect with a reduction in albuminuria and arterial pressure in patients with CKD. (5) Based on individual studies examining the effectiveness of spironolactone in patients with CKD, treatment with spironolactone in patients with stage 3-4 CKD was associated with a reduction in relative risk for end-stage renal disease (ESRD) of 34%, but with a three times higher risk of hospitalization for hyperkalemia, which is the most common cause for treatment discontinuation. (9)
In studies conducted so far, eplerenone was demonstrated to be effective in patients with mild to moderate AH, with the same incidence of the most common unwanted adverse events such as dysmenorrhea, impotence, and gynecomastia as in the placebo group. Compared with spironolactone, eplerenone resulted in a lower increase of plasma levels of aldosterone, renin, and hyperkalemia in comparison with the spironolactone group. (10) Eplerenone is contraindicated in severe damage to liver and kidney function in stage 4 and 5 CKD (eGFR<30 mL/min/1.73 m2).
Studies have demonstrated the effectiveness of eplerenone in patients with previous myocardial infarction with reduced left ventricular ejection fraction (LVEF ≤40%) and symptoms of heart failure. (11) The results of the EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study, N = 6642) study have shown that taking eplerenone was associated with a reduction in risk of death by 15% in comparison with placebo and a reduction in relative risk and hospitalization of 13% in comparison with placebo. (10) Although the data obtained in the EPHESUS study are limited regarding patients with type 2 diabetes and A2 albuminuria, increased incidence of hyperkalemia was observed in patients with type 2 diabetes, which increased as renal function decreased. (10) EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure, N = 2737), an additional study conducted in 2011, demonstrated that eplerenone provided an additional CV protective effect in comparison with placebo, with a reduction in the risk of death and all-cause hospitalizations in patients with low ejection fraction (LVEF ≤30%) in patients who had previously (within six months) been hospitalized for CV symptoms and/or mild heart failure symptoms (NYHA II). (12)
In the EMPHASIS-HF study, hyperkalemia (serum potassium >5.5 mmol/L) was observed in 11.8% of patients in the group treated with eplerenone and in 7.2% of patients in the placebo group (p <0.001). On the other hand, hypokalemia is a problem that has often been neglected, especially in patients with heart failure, with hypokalemia defined as serum potassium levels <4.0 mmol/L, which was statistically significantly lower with eplerenone in comparison with placebo (38.9% with eplerenone in comparison with 48.4% in the placebo group, p <0.0001).
Eplerenone was shown to be safe and well-tolerated in patients with acute coronary syndrome and no heart failure in the REMINDER study (Impact of Eplerenone on Cardiovascular Outcomes in Patients Post Myocardial Infarction, N= 1012). Early application of MRA in this study was not associated with a clear benefit when added to the standard of care (SOC) for myocardial infarction. (13) Despite the demonstrated effectiveness and safety of treatment with eplerenone, its application in patients with CKD is still limited, primarily due to the associated risk of elevated potassium levels (hyperkalemia). (14,15)
The new, nonsteroidal generation of mineralocorticoid receptor antagonists
The results of previous studies on MRAs and the significant incidence of associated hyperkalemia in clinical practice resulted in the identification of potent and selective nonsteroidal MRAs by cloning human MR-complementary DNA. Recent studies have shown that medications from this group of new MRAs have an additional effect on the reduction of residual risk of kidney and heart disease progression. Finerenone is a new, nonsteroidal, and more selective MRA compared with spironolactone and a somewhat higher MR affinity in comparison with eplerenone, and it is distributed approximately equally between the heart and kidneys (spironolactone and eplerenone have a higher concentration in kidney tissue compared with heart tissue). Finerenone’s nonsteroidal structure allows it to bind to MR with a high affinity and inhibit co-activators involved in the expression of pro-fibrotic genes. (4) Consequently, it results in significantly fewer unwanted adverse events such as gynecomastia and has a lower incidence of hyperkalemia. In studies such as ARTS-DN, finerenone led to a significant reduction in urine albumin levels (albumin-to-creatinine ratio, UACR) even with initial doses of 7.5 mg in conjunction with basic treatment (ACE inhibitors or ARBs) after only 90 days of treatment. (16,17) The positive experiences of the initial studies, ARTS-HF (HFrEF) and ARTS-DN (KBB and A2/A3), were supported by a phase 3 finerenone trial on cardiovascular outcomes in patients with type 2 diabetes and CKD (FIDELIO-DKD, Finerenone in reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease). Inclusion criteria were being above 18 years of age, DKD, receiving medication from the ACE inhibitor or ARB group for longer than 4 weeks, potassium levels <4.8 mmol/L, diabetic retinopathy, and albuminuria A2 and higher. Exclusion criteria were unregulated diabetes with HbA1c >12%, lack of DKD, unregulated AH, NYHA II-IV, and heart failure with reduced ejection fraction. The primary outcome was the impact on albuminuria and kidney outcomes with loss of kidney function and the need for replacement therapy (kidney death). The secondary outcome was CV events, death, or hospitalization. Unwanted adverse events were significantly more common in the finerenone group, 18.3% in total in comparison with 9.0% in the placebo group, including 4.6% acute kidney damage in the finerenone group and 4.8% in the placebo group. In the finerenone group, 1.4% of patients were hospitalized for hyperkalemia, compared with 0.3% in the placebo group. Hyperkalemia was reported as the reason for leaving the study in 2.3% patients on finerenone and 0.9% in the placebo group, but it did not result in any deaths.
The results of the FIDELIO-DKD were presented in November 2020 and showed a significant reduction in albuminuria by 31%, a reduction in the deterioration of kidney function (by more than 40%), and reduced CV outcomes in comparison with placebo in patients with CKD and type 2 diabetes, with and without previous CV disease. (18) The number needed to treat (NNT) to achieve this outcome was 29 for the primary outcome and 42 for the secondary outcome. (18)
Discussion
Despite growing evidence for the effectiveness of MRA use in patients with heart failure, very few MRA trials have been performed in patients with CKD. Mortality in patients with CKD is characteristically caused by CV complications, especially if they also have type 2 diabetes. Patients with CKD and type 2 diabetes a three times higher risk of CV death compared with patients with those who do not have CKD. (19) This is due to MR overactivation in these patients, which drives inflammation and fibrosis formation, which can lead to target organ damage (primarily the heart, kidneys and peripheral vasculature) that is associated with increased CVR risk. This is where MRA can play a role, especially new groups such as finerenone that inhibit the inflammatory response and reduce fibrosis, providing an additional protective effect for tissue and organs without causing hyperkalemia, which has previously been the main limiting factor for the application of this group of drugs. (8) Based on the AMBER study published in 2019 that evaluated spironolactone (and patiromer added to reduce potassium), as many as 23% of patients were excluded from the study due to hyperkalemia, and application was limited in more advanced stages of kidney damage, i.e. stage 4 and 5 CKD (eGFR <30mL/min/1.73m2). (20)
For more than 20 years, guidelines recommended that patients who had diabetes and CKD with albuminuria >300 mg/day should receive ACE inhibitors or ARBs. (3) Since mid-2019, SGLT2 inhibitors have been recommended for patients with diabetes with albuminuria >300 mg/g if the estimated glomerular filtration rate (eGFR) is >30 mL/min/1.73 m2. (21) It has also been demonstrated that the risk of kidney and heart failure in patients with DKD is reduced by drugs in the sodium-glucose co-transporter-2 (SGLT2) group in combination with a RAS blocker, but CKD progression was not delayed. (21,22) The terminal stage of CKD (ESRD) remain unacceptably high, with ×2 more rapid progression of kidney damage than in the population without type 2 diabetes. (21) Attempts to find drugs from other groups that can prevent CKD progression are therefore not surprising. The newest data from additional analysis of a study on diabetic nephropathy with atrasentan (SONAR) have shown that combination treatment led to a greater reduction in albuminuria compared with monotherapy with atrasentan. (23)
This new generation of MRA opens up new possibilities in the treatment of diabetic kidney disease, which still represents the most prevalent cause of end-stage renal disease, while having to replace kidney function with the numerous associated micro- and macrovascular complications that significantly affect the quality of life in patients with DKD. These new drugs from the MRA group can therefore provide a better and brighter future for patients with type 2 diabetes. (23-25)
Future research
The data obtained in the latest studies support the hypothesis of prolonged and long-term renal protection with combined treatment, with an emphasis on multidisciplinary collaboration in translational medicine. Further studies are expected regarding the effectiveness and safety of by combination therapy with SGLT2 and nonsteroidal MRA for DKD in the future.
Conclusion
Despite proven efficacy with reduced relative risk for ESKD treatment, the use of MRA (especially spironolactone, eplerenone less so) in patients with CKD is still limited due to the increased risk of hyperkalemia. Studies with new MRAs such as finerenone represent a new era in the effective treatment of patients with CKD, primarily diabetic kidney disease, with a proven lower incidence of hyperkalemia and with a slowing of the progression of target organ damage.