Finerenone

Finerenone is a selective mineralocorticoid receptor (MR) antagonist being studied for its potential in reducing cardiovascular and renal adverse outcomes in people with diabetes and kidney disease (1). Other available mineralocorticoids such as eplerenone and spironolactone have been shown to reduce albuminuria in people with diabetes and elevated urinary albumin; however, concern exists regarding a risk for hyperkalemia and acute reversible reduction in estimated glomerular filtration rate (eGFR) (2). Use of MR antagonists in diabetic nephropathy is not a standard of care because long-term clinical effects on cardiorenal outcomes have not been demonstrated (2). Finerenone is more potent and selective for the mineralocorticoid receptor, potentially reducing adverse effects and leading to greater cardiovascular or renal benefits (1).

Indication

No U.S. Food and Drug Administration (FDA)-approved indication exists for finerenone at the time of writing. Finerenone is an investigational agent developed by Bayer that is being studied for possible use in people with diabetes and kidney disease (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease (3,4)], ARTS-HF [Mineralocorticoid Receptor Antagonist Tolerability Study-Heart Failure (5)], ARTS-DN [Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy (6)], and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease; NCT02545049]). Additional trials are studying its use in heart failure (ARTS [BAY94–8862 Dose Finding Trial in Subjects With Chronic Heart Failure and Mild (Part A) or Moderate (Part B) Chronic Kidney Disease; NCT01345656] and FINEARTS-HF [Finerenone in Heart Failure Patients; NCT04435626]). Only results from the ARTS-HF, ARTS-DN, and FIDELIO-DKD trials have been published at this time, but results should be available soon for the FIGARO-DKD trial.

Mechanism of Action

Finerenone inhibits the effects of mineralocorticoids like aldosterone and cortisol when the MR is overactivated, possibly reducing inflammation and fibrosis in the heart and kidney. Aldosterone is produced when the renin-angiotensin-aldosterone system pathway is activated, and this pathway has a role in regulating blood pressure and sodium and fluid retention (2).

Potential Advantages

Use of an ACE inhibitor or angiotensin II receptor blocker (ARB) is recommended for people with diabetes, hypertension, and albuminuria and also may be considered for individuals with diabetes and albuminuria but normal blood pressure (2). If approved by the FDA, finerenone will be the first and only selective MR antagonist for treatment of diabetic kidney disease that could lead to further reductions in urinary albumin and adverse renal outcomes (3–5).

Finerenone has potential advantages over other MR antagonists because of its high degree of selectivity and more favorable adverse effect profile. The risk of hyperkalemia is lower with finerenone than spironolactone (7), possibly similar to eplerenone (5). Finerenone causes relatively low rates of severe hyperkalemia, leading to low discontinuation rates ranging from 1.7 to 3.2% (3,4). It also has a modest effect on hemodynamics (3,4). Additionally, there are smaller decreases in eGFR with finerenone than with spironolactone (7). Because of its selective nature, finerenone does not have risks of gynecomastia or feminization, as does spironolactone (1).

Potential Disadvantages

Finerenone is being evaluated in people with diabetes with an eGFR of 25–75 mL/min/1.73 m² (8); thus, if approved, it may prove to be beneficial in only a subset of people with diabetes and kidney disease. Potential drug interactions may exist with finerenone, which is metabolized primarily by the cytochrome P450 3A4 enzyme and is highly protein bound (1).

Cost

No pricing information was available at the time of writing for this investigational drug.

Commentary

MR antagonists have been on the market for many years, but research has not yielded conclusive evidence of clinical benefit for people with diabetic nephropathy. Currently, the use of an ACE inhibitor or ARB is recommended for people with diabetes, hypertension, and albuminuria and also may be considered in people with diabetes and albuminuria but normal blood pressure (2). Recent evidence suggests that finerenone might be a promising therapy for these patients.

A dose-dependent decrease in urinary albumin-to-creatinine ratio was observed in a phase 2 trial of finerenone (5). FIDELIO-DKD (3), a phase 3 randomized, placebo-controlled, double-blind trial of finerenone, included ∼5,700 patients with type 2 diabetes and chronic kidney disease who were followed for a median of 2.6 years. Finerenone, when compared with placebo, led to a reduction in the time-to-event composite outcome of kidney failure, sustained decrease of at least 40% in eGFR from baseline, or death from renal causes (17.8 vs. 21.1%, hazard ratio [HR] 0.82, 95% CI 0.73–0.93, P = 0.001) (3). Additionally, finerenone led to a modest reduction in a compositive cardiovascular outcome that included time to first onset of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure (13.0 vs. 14.8%, HR 0.86, 95% CI 0.75–0.99, P = 0.034) (4). The FIDELIO-DKD and FIGARO-DKD trials required patients be on optimized treatment with an ACE inhibitor or ARB for at least 4 weeks before screening (8), so benefits of finerenone seen in these trials would be in addition to those afforded by a maximally tolerated dose of an ACE inhibitor or ARB.

Bottom Line

The addition of finerenone might prove to be beneficial to people with diabetes and kidney disease who are already on optimized therapy with an ACE inhibitor or ARB to reduce the risk of adverse renal outcomes. Although available data look promising, more data are needed, since finerenone is still an investigational agent. Its FDA review is expected to be completed in mid-July 2021.