Management of hyperkalemia during treatment with mineralocorticoid receptor blockers: findings from esaxerenone

Abstract

The nonsteroidal mineralocorticoid receptor (MR) blocker esaxerenone has demonstrated good antihypertensive activity in a variety of patients, including those with uncomplicated grade I–III hypertension, hypertension with moderate renal dysfunction, hypertension with type 2 diabetes mellitus with albuminuria, and hypertension associated with primary aldosteronism. Hyperkalemia has long been recognized as a potential side effect occurring during treatment with MR blockers, but there is a lack of understanding and guidance about the appropriate management of hyperkalemia during antihypertensive therapy with MR blockers, especially in regard to the newer agent esaxerenone. In this article, we first highlight risk factors for hyperkalemia, including advanced chronic kidney disease, diabetes mellitus, cardiovascular disease, age, and use of renin-angiotensin-aldosterone system inhibitors. Next, we examine approaches to prevention and management, including potassium monitoring, diet, and the use of appropriate therapeutic techniques. Finally, we summarize the currently available data for esaxerenone and hyperkalemia. Proper management of serum potassium is required to ensure safe clinical use of MR blockers, including awareness of at-risk patient groups, choosing appropriate dosages for therapy initiation and dosage titration, and monitoring of serum potassium during therapy. It is critical that physicians take such factors into consideration to optimize MR blocker therapy in patients with hypertension.

Physiologically based pharmacokinetic modelling to predict the clinical effect of CYP3A inhibitors/inducers on esaxerenone pharmacokinetics in healthy subjects and subjects with hepatic impairment

“…Both doses of esaxerenone demonstrated efficacy in lowering blood pressure and were well tolerated. However, hyperkalaemia has long been recognized as a potential side effect that occurs during treatment with mineralocorticoid receptor blockers [ 5 ]. The approved dosing regimen of esaxerenone for hypertension is to initiate treatment at 2.5 mg once daily and titrate to a maximum of 5 mg once daily within 4 weeks when the effect is insufficient [ 2 ].…”

Safety and efficacy of esaxerenone in Japanese hypertensive patients with heart failure with reduced ejection fraction: A retrospective study

“…Moreover, we were unable to follow-up the patients long-term, which seems to be one reason why the number of AEs was small. In previous studies regarding MRBs, however, K + elevation and eGFR decrease were reported to be most conspicuous within the first month [ 18 , 23 ]. We intended to investigate mainly the safety of the drug; thus, our results have a certain significance regarding safety.…”

“…Hyperkalemia (K + >5.5 mEq/L) occurred in 11.8% [ 6 ]. Several phase III clinical trials of esaxerenone, which included patients with essential hypertension, hypertension with renal dysfunction, type 2 diabetes, or primary aldosteronism, but all without HF, showed that hyperkalemia occurred in 1.7% of esaxerenone-treated patients (including unpublished data) [ 12 , 16 – 18 ]. In the present study, no patient showed hyperkalemia, although K + was similarly elevated by 0.28±0.59 mEq/L in the first-MRB cohort in the short-term assessment.…”

Approaches towards tissue‐selective pharmacology of the mineralocorticoid receptor

“…Esaxerenone was approved in Japan in 2019 for the treatment of essential hypertension (Duggan, 2019). Available data from phase III clinical trials suggests a similar incidence of hyperkalemia in patients treated with esaxerenone compared to eplerenone (Rakugi et al, 2021). Finerenone has very recently been approved by the United States Food and Drug Administration (FDA) for patients with chronic kidney disease associated with type 2 diabetes (FDA, 2021).…”