Finerenone: Fiddling With Hyperkalemia?

Abstract

Finerenone was recently approved by the US Food and Drug Administration for treatment of diabetic kidney disease (DKD). However, the commentary from Sridhar et al1Sridhar V.S. Liu H. Cherney D.Z.I. Finerenone - a new frontier in renin-angiotensin-aldosterone system inhibition in diabetic kidney disease.Am J Kidney Dis. 2021; 78: 309-311Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar on the FIDELIO trial2Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (280) Google Scholar minimizes hyperkalemia and overstates the superiority of finerenone over other mineralocorticoid receptor antagonists (MRAs). The authors state that few patients discontinued finerenone owing to hyperkalemia (2.3% vs 0.9%). However, the enrollment criteria were crafted to minimize this, requiring a potassium level <4.8 mEq/L during screening and run-in, resulting in almost 60% exclusion.2Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (280) Google Scholar Other clinically significant hyperkalemia outcomes are also higher (Table 1). It is likely that hyperkalemia will be more common in a real-world population of patients with chronic kidney disease (CKD), given the experience with spironolactone in heart failure.3Juurlink D.N. Mamdani M.M. Lee D.S. et al.Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study.N Engl J Med. 2004; 351: 543-551Crossref PubMed Scopus (1371) Google ScholarTable 1Details About Hyperkalemia in the FIDELIO TrialCharacteristicaNumbers as reported based on the trial outcome definitions; see Bakris et al2 for details.FinerenonePlaceboPotassium binder use at baseline70 (2.5 %)66 (2.3 %)Potassium binder use through the trial307 (10.8%)184 (6.5%)Investigator-reported hyperkalemia516 (18.3 %)255 (9 %)Serious hyperkalemia44 (1.6 %)12 (0.4 %)Hospitalization owing to hyperkalemia40 (1.4 %)8 (0.3 %)Development of end-stage kidney diseasebPresented to contrast magnitude of small absolute benefit against the similar or higher absolute risk of hyperkalemia events.119 (4.2 %)139 (4.9 %)a Numbers as reported based on the trial outcome definitions; see Bakris et al2Bakris G.L. Agarwal R. Anker S.D. et al.Effect of finerenone on chronic kidney disease outcomes in type 2 diabetes.N Engl J Med. 2020; 383: 2219-2229Crossref PubMed Scopus (280) Google Scholar for details.b Presented to contrast magnitude of small absolute benefit against the similar or higher absolute risk of hyperkalemia events. Open table in a new tab Additionally, the claim that finerenone is superior to and safer than other MRAs reflects an absence of evidence rather than an evidence of absence of benefit. Steroidal MRAs reduce proteinuria and blood pressure in CKD,4Currie G. Taylor A.H.M. Fujita T. et al.Effect of mineralocorticoid receptor antagonists on proteinuria and progression of chronic kidney disease: a systematic review and meta-analysis.BMC Nephrol. 2016; 17: 127Crossref PubMed Scopus (73) Google Scholar and the larger and longer trials for kidney protection have just not been done. Only 1 trial directly compared finerenone and spironolactone in CKD patients,5Pitt B. Kober L. Ponikowski P. et al.Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial.Eur Heart J. 2013; 34: 2453-2463Crossref PubMed Scopus (272) Google Scholar enrolling ~65 participants per arm and reporting a very modest difference (<0.1 mEq/L) in mean potassium concentration over 1 month of follow-up. We need clear guidance to navigate through the embarrassment of riches suddenly at our disposal for treatment of DKD. In order to fully understand the role of finerenone in this armamentarium, larger and adequately powered trials will help establish finerenone’s superiority to other MRAs. The authors declare that they have no relevant financial interests. Received July 5, 2021. Direct editorial input from an Associate Editor and a Deputy Editor. Accepted in revised form July 25, 2021. Finerenone—A New Frontier in Renin-Angiotensin-Aldosterone System Inhibition in Diabetic Kidney DiseaseAmerican Journal of Kidney DiseasesVol. 78Issue 2PreviewGlycemic control, blood pressure control, and single-agent renin-angiotensin-aldosterone system (RAAS) blockade were, until recently, the pillars of managing diabetic kidney disease (DKD). Although the introduction of sodium/glucose cotransporter 2 (SGLT2) inhibitors has further reduced DKD progression, patients continue to have significant residual risk, underlying the importance of identifying new therapies. In FIDELIO-DKD, Bakris et al1 demonstrate that the nonsteroidal mineralocorticoid receptor antagonist (MRA) finerenone (once daily 10-20 mg), on top of standard of care, is beneficial in DKD management. Full-Text PDF In Reply to ‘Finerenone: Fiddling With Hyperkalemia?’American Journal of Kidney DiseasesVol. 78Issue 5PreviewWe thank Waitzman et al1 for their comments. We agree that MRAs raise hyperkalemia risk and should be used cautiously to avoid subsequent higher rates of hyperkalemia.2 While there is evidence that nonsteroidal MRAs including finerenone increase potassium to a lesser extent than spironolactone,3 clinicians will need to exercise caution when using these therapies in patients with CKD. Full-Text PDF