Finerenone, a Novel and Safer Approach toward Management of Diabetic Kidney Disease with Heart Failure

INTRODUCTION

Diabetes has tremendously spread worldwide continuously affecting millions of people. The prevalence of diabetes among people aged 20–79 around the world was predicted to be 10.5% (536.6 million) in 2021 and 12.2% (783.2 million) in 2045. The cost of treating diabetes-related illnesses worldwide was estimated to be 966 billion USD in 2021 and is expected to rise to 1054 billion USD by 2045.^[1] The comorbidities associated with diabetes also need to be addressed as complications may affect both small and large blood vessels, leading to organ damage like kidney disease which is a major microvascular complication.^[2] Chronic kidney disease (CKD) often leads to many serious complications as end-stage renal disease and cardiovascular complication.^[3] Heart failure (HF) is prevalent in diabetes as evident from various epidemiological and clinical studies from the past 20 years. The health-care outcomes in diabetic patients are poor as compared to non-diabetic patients with cardiovascular disorders,^[4] indicating that diabetic patients are more prone to develop cardiovascular diseases.^[5] In a multinational study involving more than 750 thousand cardiovascular and renal disease-free patients with type 2 diabetes mellitus (T2DM), association of cardiovascular and renal diseases with high mortality risks was observed. In light of all the associated risks and complications, new and improved strategies are required to be developed for the prevention of such complications.^[6]

In recent years, novel therapeutic categories have been developed involving several drug classes such as sodium glucose cotransporter 2 (SGLT2) inhibitors,^[7] glucagon-like peptide-1 (GLP-1) agonists,^[8] dipeptidyl-peptidase-4 (DPP4) inhibitors,^[9] and mineralocorticoid receptor antagonists (MRAs)^[10,11] to improve cardiorenal outcomes in diabetic patients. SGLT2 inhibitors are found to be associated with decreased risks of cardiovascular events.^[7] Similarly, GLP-1 agonists have also been proven to reduce cardiovascular events and renal disease progression.^[12] DPP4 inhibitors have found to have beneficial effects in reducing the risk of albuminuria progression^[9] but more evidence is needed regarding patients with the left ventricular systolic function and HF.^[13] MRAs are also the point of focus among these novel therapies to be used as an adjunct to reduce the risk of diabetic kidney disease (DKD) and cardiovascular disease in T2DM.^[14]

After the discovery of aldosterone in 1953, various synthetic steroids were produced to block the sodium uptake and excretion of potassium, leading to spironolactone discovery.^[15] Spironolactone was discovered as first MRA. Being non-selective, it was shown to exert harmful effects on glucose homeostasis and hyperkalemia.^[16,17] Spironolactone is also found to produce reproductive side effects,^[18] due to its anti-androgenic effects.^[19] Eplerenone, discovered in 2002, was the first selective mineralocorticoid receptor (MR) blocker due to its lesser side effects than spironolactone.^[20] This development did not resolve the risk of developing hyperkalemia.^[21,22] Clinical use of steroidal MRA due to the associated risks is limited and the need of development of non-steroidal MRA began to rise.^[23]

Finerenone is a recent, a novel selective non-steroidal MRA,^[24] approved in 2021 by FDA.^[25] It has shown efficacy for the management of cardiorenal diseases having stronger binding potential for MR compared to eplerenone and spironolactone.^[24] It is well-tolerated and shown to have more potent cardiorenal effects compared to eplerenone.^[26] Incidence of hyperkalemia and other adverse events is much lower in finerenone compared to steroidal MRA.^[27] This article is aimed to provide a brief review of all the published literature on PubMed and Google Scholar related to finerenone with review of its clinical efficacy to provide the medical community with a glance of all the recent advancements related to finerenone.

DISCOVERY OF FINERENONE

Dihydropyridines (DHPs) were known to have L-type calcium channel antagonizing effects. By ultra-high-throughput screening, 1,4-DHPs were found to have significant MR antagonistic activity in vitro. The major candidate was found to be DHP-1 which showed selectivity (>20-fold) over glucocorticoid receptor, androgen, and progesterone receptors. Further studies were performed due to of extremely low metabolic stability in human liver and significant L-type calcium channel interaction. A significant step forward in the development of finerenone (BAY 94-8862) was made by substituting a 4-cyano2-methoxyphenyl moiety in the naphthyridine series (conformationally frozen bioisosteres of 1,4-DHPs) for the chromanone head group which resulted in dihydronaphthyridine series [Figure 1]. More active enantiomer was found by chiral HPLC then further exploration including introduction of methyl group at C8 and the replacement of cyano group by primary amide at C3 as a final step led to the development of dihydronaphthyridine (BAY 94-8862), a potent MRA (IC₅₀ 18 nm) with excellent selectivity versus GR, AR, PR (>500-fold), and virtually no L-type Ca2+ channel activity (IC₅₀ >10 mm). It showed a good pharmacokinetic profile (low blood clearance, long half-life of 0.014 L h1 kg1, and 8.5 h, respectively, by IV administration) as well as high oral bioavailability of 94% in rats. More natriuretic effects were observed in finerenone compared to eplerenone due to its 10-fold higher potency and more efficacy.^[28]

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Figure 1:

Structure of finerenone.

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PATHOPHYSIOLOGY OF DKD AND HF BY MR ACTIVATION

MR is expressed in multiple cells including cardiac myocytes, vascular endothelial cells, and vascular smooth muscle cells of kidney. Aldosterone is a steroid hormone produced in the adrenal cortex, maintains sodium and potassium balance, as well as provides blood pressure control through its MR activity. It exerts its physiological mechanism of maintaining electrolyte balance through MR binding in the connecting tubules and collecting duct in kidneys.^[29] Increased oxidative stress, endothelial dysfunction, and activation of sympathetic nervous system are some of the damaging effects associated with aldosterone. It promotes myocardial fibrosis and tubular necrosis when overly expressed in heart and kidneys.^[30] The activation of local MR in heart and kidney leads to cardiovascular and renal injury through aldosterone dependent and independent mechanisms [Table 1].^[31]

FINERENONE AND OTHER MRAS

CLINICAL PHARMACOLOGY

FINERENONE IN NEPHROPATHY AND HF

Finerenone (Kerendia^®), a selective non-steroidal MRA, is developed by Bayer Healthcare Pharmaceuticals. It is approved in the USA to decrease the risk of cardiac and renal events associated with type 2 diabetes including end-stage renal disease, cardiovascular death, sustained estimated GER decline, and hospitalization for HF in CKD patients.^[61,62] Finerenone has shown to decrease myofibroblast accumulation and collagen deposition in a study conducted on mice, in which kidney fibrosis was induced through ureteral obstruction. The antifibrotic activity of finerenone was accompanied by decreased kidney plasminogen activator inhibitor-1 and naked cuticle 2 expression. The antifibrotic activity was dose dependent with no effect on systemic blood pressure.^[63]

HF

The MRA tolerability study (ARTS), a Phase 2A clinical trial, was designed to evaluate the tolerability and safety of finerenone in patients of HF with reduced ejection fraction (HFrEF) and mild-to-moderate CKD. The study concluded that finerenone 5–10 mg/day in patients with HFrEF and mild or moderate CKD was at least as effective as spironolactone 25 or 50 mg/day in decreasing biomarkers of hemodynamic stress and was associated with lower incidence of worsening of the kidney function and hyperkalemia.^[64] A randomized, double-blind Phase 2b clinical trial called ARTS-HF was conducted to evaluate oral doses of finerenone given for 90 days in patients with worsening HF and REF and CKD and/or DM. One thousand and sixty-six patients (with type 2 DM and/or CKD presented with worsening HF and REF) were randomized in this study. For 90 days, once daily dosing of finerenone and eplerenone was administered to the patients. The results showed that finerenone was well tolerated and reduced N-terminal pro-brain natriuretic peptide levels by 30% or more in a similar proportion of patients as eplerenone. Compared to eplerenone, the composite endpoint of mortality from any cause, cardiovascular hospitalization, or emergency presentation for worsening HF occurred less frequently.^[26]

CKD

The MR ARTS-Diabetic Nephropathy, a randomized, double-blind, and placebo-controlled Phase 2b study, was conducted to investigate the safety and efficacy of different doses of finerenone given for 90 days to diabetic patients with high or remarkably high albuminuria. Eight hundred and twenty-three patients were randomized to receive an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Out of which 36.7% of patients treated had extremely high albuminuria (UACR ≥300 mg/g) and 40.0% had an estimated glomerular filtration rate (eGFR) of ≤60 mL/min/1.73 m² at baseline. Dose-dependent reduction of urine albumin-creatinine ratio was shown by finerenone at different doses once daily against placebo for 90 days. The study showed improvement in the urinary albumin-creatinine ratio by the addition of finerenone compared with placebo among the patients with diabetic nephropathy.^[65]

An upgraded Phase 3 study, FIDELIO-DKD (finerenone in reducing kidney failure and disease progression in DKD) included 5734 patients with CKD and type 2 diabetes to receive finerenone or placebo. The study showed that finerenone, in patients with CKD and type 2 diabetes, resulted in lower risks of CKD progression (kidney failure, a sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes) and cardiovascular events (death from cardiovascular causes, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for HF) than placebo. Both the finerenone and placebo groups experienced a same number of adverse events during the course of therapy; patients in the finerenone group experienced major adverse events at a rate of 31.9% and 34.3%, respectively. Serious adverse events and adverse events associated with acute renal damage were distributed equally. In general, adverse events associated with hyperkalemia were twice as common with finerenone than with placebo, and hyperkalemia-related regimen termination was more common with finerenone.^[66]

Finerenone in reducing cardiovascular mortality and morbidity in DKD, a large scale, randomized, double-blind, placebo-controlled Phase 3 clinical trial conducted by Filippato et al. who investigated finerenone effectiveness in preventing cardiovascular events in patients with type 2 diabetes and albuminuria from chronic renal disease. Seven thousand three hundred and fifty-two patients were included having T2DM and CKD without symptomatic HF with REF, which were randomized to finerenone or placebo. Finerenone was found to have a considerably lower risk of all HF events than placebo, including an 18% decreased risk of cardiovascular mortality. In all, 31.4% of patients receiving finerenone experienced a major adverse event, compared to 33.2% of patients receiving a placebo. The frequency of acute renal damage was comparable in all groups. Finerenone had a greater rate of hyperkalemia than the placebo (10.8% vs. 5.3%); however, none of these side effects were fatal. Hypokalemia incidence was lower with finerenone than with placebo. The results demonstrated that finerenone reduces the risk of HF outcomes and reduces the new-onset HF in T2DM and CKD patients regardless of HF history.^[67,68]

CONCLUSION

Steroidal MRAs have long been used to treat refractory hypertension, and a variety of nephropathies, including diabetic nephropathy. They block receptor activation by inhibiting the action of aldosterone at the MR which reduces inflammation, inhibits remodeling, and improves proteinuria. Because these drugs are steroidal in nature, they interact with other receptors and cause undesired effects such as sexual side effects and hyperkalemia which a major reason their use is restricted. Finerenone is a new advancement in pharmacotherapy for diabetic patients with CKD and HF as it has lesser side effects and a good safety profile compared to steroidal MRAs. Additional to the typical MR inhibitory effect on fluid and electrolyte balance, Finerenone has a potent anti-inflammatory and anti-fibrotic effect. In individuals with cardiorenal disorders, these effects have been shown to be beneficial. Finerenone has shown lesser incidence of developing hyperkalemia compared to steroidal MRAs which is undoubtedly a great progress in diabetes management. Moreover, it is shown to be equipotent and have more targeted activity compared to other MRAs due to its comparatively safer therapeutics.