Non-steroidal MRA in The Treatment Of Cardiorenal Diseases: From Mechanism To Clinical Evaluation
Feb 08, 2023
With existing treatments, patients with heart failure and chronic kidney disease (CKD) remain at high risk of adverse outcomes and progression. Steroidal mineralocorticoid receptor antagonists (MRA), such as spironolactone and eplerenone, can reduce the mortality of patients, but there is a high risk of side effects, so the clinical application is limited, non-steroidal MRA The research and development of the drug have brought new options for the treatment of heart and kidney diseases.
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Non-steroidal MRAs have high affinity and selectivity for mineralocorticoid receptors (MRs) and are different from steroidal MRAs in terms of physicochemical properties, pharmacodynamics, and pharmacokinetics. Non-steroidal MRAs have beneficial anti-inflammatory, dysfunctional, anti-remodeling, and anti-fibrotic effects in the kidney, heart, and vasculature.
In Japan, eplerenone is approved for the treatment of essential hypertension and has been studied in diabetic nephropathy. Finerenone has been approved for the treatment of chronic kidney disease associated with type 2 diabetes. Compared with steroidal MRA, finerenone is more effective in inhibiting MR receptors and fibrosis and has a more uniform distribution in the heart and kidney. The phase 3 FIGARO-DKD and FIDELIO-DKD trials demonstrated that finerenone reduced major renal and cardiovascular events in patients with type 2 diabetes-associated chronic kidney disease. Nonsteroidal MRAs are currently being evaluated in patients with heart failure, and in combination with SGLT2 inhibitors.
Mineralocorticoid receptor is an important therapeutic target in cardiorenal disease
The mineralocorticoid receptor is a ligand-activated nuclear transcription factor expressed in the gastrointestinal tract, heart, brain, kidney, immune cells, and vasculature. MR has a similar affinity for many endogenous steroids, including progesterone, cortisol, and aldosterone.
In renal epithelial cells, MR activation leads to sodium and fluid retention through increased epithelial sodium channel (ENaC) activity and K+ excretion. In the central nervous system, MR may play a role in blood pressure regulation; in adipose tissue, MR overactivation may be associated with insulin resistance and metabolic syndrome. In the heart, kidney, and vasculature, MR overactivation is associated with tissue remodeling, dysfunction, inflammation, and fibrosis.
There is a complex interplay between heart failure and chronic kidney disease. Chronic volume and pressure overload, anemia, neurohormonal dysregulation (including RAAS and sympathetic nervous system activation), oxidative stress, inflammation and fibrosis, and the direct effects of uremic toxins can cause remodeling and ultimately cardiac and renal failure. These metabolic, hemodynamic, and inflammatory/fibrotic processes are all important targets for therapy. Among them, MR-induced inflammation, fibrosis, and remodeling are important therapeutic targets for cardiorenal diseases. Cell type-specific MR antagonism in cardiomyocytes and myeloid cells may be associated with reduced inflammation and fibrosis, organ dysfunction, and pathological remodeling while reducing the risk of hyperkalemia associated with epithelial MR inhibition.
Non-steroidal MRA for cardiorenal disease: advantages and clinical evaluation
In June 2022, finerenone was approved in China for the treatment of chronic kidney disease associated with type 2 diabetes. Compared with eplerenone and spironolactone, finerenone is more selective for MR, has less effect on other steroid receptors and ion channels, and accumulates more in the kidney. Finerenone is less lipophilic, more polar, and does not cross the blood-brain barrier. Finerenone has no active metabolites, a short half-life, hyperkalemia can be corrected more quickly, and has less effect on blood pressure.
Preclinical and clinical data suggest that finerenone is an important drug for the treatment of cardiorenal disease. Animal experiments showed that, compared with eplerenone, finerenone improved myocardial and renal hypertrophy, BNP and proteinuria, and the expression of pro-inflammatory/pro-fibrotic genes in cardiac and renal tissue. The phase 3 FIDELIO-DKD and FIGARO-DKD trials demonstrated that finerenone was both renoprotective and improved cardiovascular outcomes in patients with type 2 diabetes-associated chronic kidney disease. The FIDELITY trial (n = 13,026) further confirmed the clinical benefit of finerenone, with a composite cardiovascular risk reduction of 14% (HR 0.86, 95% CI: 0.78, 0.95) and a composite renal outcome risk reduction of 23% (HR 0.77, 95% CI: 0.67, 0.88). Finerenone was well tolerated.
Prespecified subgroup analyses of FIDELIO-DKD demonstrated consistent benefits for the composite cardiac and renal endpoint in patients treated with finerenone, regardless of whether patients had heart failure at baseline. FIGARO-DKD subgroup analysis showed that the risk of new-onset heart failure was significantly reduced in the finerenone group (HR 0.68, 95% CI: 0.50, 0.93). Results of an exploratory analysis suggest that the reduction may be greater in patients who received an SGLT2 inhibitor at baseline. FIDELIO-DKD preset analysis results showed that finerenone also reduced the incidence of new-onset atrial fibrillation/flutter (HR 0.71, 95% CI: 0.53, 0.94).
The FIND-CKD trial will investigate the effectiveness of finerenone in preventing the progression of kidney disease in nondiabetic CKD patients. The FINEARTS-HF trial was designed to assess the effect of finerenone on the composite endpoint of heart failure hospitalization and cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). The CONFIDENCE trial will evaluate finerenone plus empagliflozin in diabetic patients with CKD.
With the continuous accumulation of clinical evidence, non-steroidal MRA is expected to become an important treatment method across the spectrum of cardiorenal diseases.
