Nonsteroidal MRAs: Will finerenone take the throne?

Mineralocorticoid receptor antagonists disrupt the renin-angiotensin-aldosterone system and provide beneficial outcomes in several renin-angiotensin-aldosterone system-mediated disease states.

Consensus guidelines in hypertension, diabetes and chronic kidney disease (CKD) recommend mineralocorticoid receptor antagonists (MRAs) for resistant hypertension to reduce albuminuria and provide CV benefit. MRAs are also recommended to prevent mortality and adverse CV outcomes in HF with reduced ejection fraction and, more recently, HF with mildly reduced, improved or preserved EF.

Until recently, spironolactone and eplerenone were the only MRAs available in the United States. In 2021, the FDA approved finerenone (Kerendia, Bayer), a novel, selective, nonsteroidal MRA, for use in CKD caused by type 2 diabetes. Finerenone has a high selectivity for the mineralocorticoid receptor and a low affinity for off-target receptors such as androgen, estrogen, glucocorticoid and progesterone. Its chemical structure is similar to that of a dihydropyridine, such as nifedipine, but with no effect on the L-type calcium channel. Interestingly, finerenone has only mild BP-lowering effects compared with other MRAs. The mechanism of this difference is unknown, as esaxerenone, another nonsteroidal MRA approved in Japan, was found to have a significant 10 mm Hg systolic BP reduction compared with placebo. The discrepancy between BP effects among the nonsteroidal MRAs is unclear at this time.

Based on phase 3 trial results, the 2022 American Diabetes Association (ADA) guidelines recommended finerenone specifically for patients with diabetic kidney disease (DKD) at risk for CV events or CKD progression, or patients unable to use SGLT2 inhibitors.

Comparisons of MRAs available in the United States are summarized in the Table.

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Landmark trials

Two phase 3, multicenter, randomized, double-blind, controlled trials among patients with DKD already on maximally tolerated ACE inhibitor or angiotensin receptor blocker (ARB) therapy have been published.

In the FIDELIO-DKD trial, finerenone 20 mg daily reduced the composite renal outcome by 18% during a median of 2.6 years among patients with type 2 diabetes, CKD stage 3 or 4, and moderate to severe albuminuria compared with placebo (HR = 0.82; 95% CI, 0.73-0.93). The composite outcome included kidney failure, sustained at least 40% estimated glomerular filtration rate (eGFR) decrease during at least 4 weeks, or death from renal causes, but only rates of sustained eGFR decline differed between groups (HR = 0.81; 95% CI, 0.72-0.92).

The FIGARO-DKD trial compared CV outcomes of finerenone 20 mg daily compared with placebo among patients with DKD with less severe CKD than FIDELIO-DKD. During a median of 3.4 years, finerenone reduced the composite CV outcome of death from CV causes, nonfatal MI, nonfatal stroke and HF hospitalization by 13% compared with placebo (HR = 0.87; 95% CI, 0.76-0.98). These results were driven by a reduction in HF hospitalization (HR = 0.71; 95% CI, 0.59-0.9).

A prespecified pooled analysis of both trials, FIDELITY, confirmed the composite renal (HR = 0.77; 95% CI, 0.67-0.88) and CV (HR = 0.86; 95% CI, 0.78-0.95) benefits of the drug across most CKD stages and for many prespecified subgroups. Safety outcomes were similar between groups except for a higher rate of drug discontinuation due to hyperkalemia in patients treated with finerenone vs. placebo (1.7% vs. 0.6%). Of note, finerenone demonstrated a small reduction in mean systolic BP (–3.2 mm Hg) at 4 months; the effect dissipated by the trial end.

Notably, patients with symptomatic HFrEF were excluded from both trials. Additionally, although use of ACE inhibitor/ARB was high, use of SGLT2 inhibitors was low. Finally, an initial decline in eGFR within the first 2 to 4 weeks of finerenone initiation, which stabilized thereafter, was noted; this effect is similar to that of other renin-angiotensin-aldosterone system (RAAS) inhibitors with known renal and CV benefit.

Future directions

In addition to the class I recommendation for MRA use among patients with HFrEF, the 2022 American College of Cardiology/American Heart Association guidelines also recommend MRAs for use in patients with HF with mildly reduced EF, preserved EF and recovered EF. These statements refer specifically to spironolactone and eplerenone, which were studied among patients with HF in the EMPHASIS-HF, EPHESUS and TOPCAT trials.

Current data present a clinical conundrum for patients with both HF and DKD, as both finerenone and steroidal MRAs carry recommendations in these patients. To date, no studies have adequately investigated clinical outcomes of finerenone vs. older MRAs among patients with HF. The phase 2b ARTS-HF trial demonstrated similar reductions in natriuretic peptides among patients with HFrEF treated with finerenone and eplerenone. Although not powered adequately, exploratory CV outcomes were overall similar between groups. A trial investigating finerenone in HFpEF is currently recruiting. It is also notable that ADA recommends finerenone use in DKD, but benefits in nondiabetic kidney disease have not been established. Future studies will determine whether the renal and CV benefits of finerenone among patients with DKD extend to nondiabetic CKD.

Finally, rates of hyperkalemia requiring drug discontinuation are consistently higher among patients treated with MRAs compared with placebo. Both CKD and use of ACE inhibitor/ARBs commonly indicated among CKD and HF patients increase the risk and often limit treatment. The role of potassium binders in allowing uptitration of MRAs has been explored among patients with HF receiving spironolactone; combination use of finerenone and potassium binders remains to be explored.

Key takeaways

Overall, finerenone has demonstrated renal and CV benefit compared with placebo among patients with DKD without symptomatic HFrEF when added to ACE inhibitor/ARB therapy.

Regular potassium monitoring is important, although hyperkalemia risk may be lower with finerenone compared with steroidal MRAs.

Finerenone may lack the clinically meaningful BP-lowering effect of other MRAs. Benefits of finerenone among patients with nondiabetic CKD, patients with DKD on SGLT2 inhibitors and patients with symptomatic HFrEF are unknown; more studies are forthcoming.

Currently available data suggest a role for nonsteroidal MRAs in many CV patient populations; how finerenone will ultimately fit into an already crowded lineup of goal-directed medication therapy will become more clear with future studies.

• References:
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• For more information:
• Caitlin M. Gibson, PharmD, MEd, BCPS, BCCP, is associate professor in the department of pharmacotherapy and outcomes science at Virginia Commonwealth University School of Pharmacy.
• Rachel W. Flurie, PharmD, BCPS, is assistant professor in the department of pharmacotherapy and outcomes science at Virginia Commonwealth University School of Pharmacy.
• Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is the Cardiology Today Pharmacology Consult column editor. She is professor and chair of the department of pharmacy services in the School of Pharmacy and Pharmaceutical Sciences at Binghamton University. Spinler can be reached at sspinler@binghamton.edu.