Adequate blood pressure (BP) control is no doubt crucial to prevent cerebrovascular/cardiovascular morbidity and mortality. In spite of the advancement and availability of various antihypertensive agents, however, there still have been a significant number of patients (~13–16% of all hypertensives) exhibiting treatment-resistant hypertension [1]. Among various mechanisms for such resistance to treatment, the activation of the mineralocorticoid receptor (MR) with related organ damage is an important clinical issue to be addressed [2,3,4], the condition often encountered in so-called MR-associated hypertension [5]. Disease states such as obesity, type 2 diabetes, chronic kidney disease (CKD), excessive salt intake, and aldosterone breakthrough typically form the condition [5].

Recently, MR activation and its role in target organ damage often become a topic of basic research as well as clinical studies, typically those in CKD [6,7,8]. As for basic research, MR activation has been shown in multiple cell types other than tubular epithelial cells, such as podocytes, endothelial cells, fibroblasts and immune cells, thereby potentially mediating podocyte injury, fibrosis, and chronic inflammation upon activation [6]. Furthermore, multiple clinical studies have defined the efficacy of MR antagonism in lowering BP as well as attenuating kidney disease progression and target organ damage [6, 7]. Finerenone, a novel non-steroidal MR antagonist that has been developed and approved for the treatment of diabetic kidney disease, demonstrated a significantly lower risk of CKD progression and cardiovascular events than placebo in FIDELIO-DKD study [8].

Esaxerenone, a non-steroidal MR antagonist with a high potency and specificity to MR, was approved in Japan to treat arterial hypertension in 2019. BP lowering effects of esaxerenone have been demonstrated in several clinical studies [7], and is occasionally used in hypertension treatment as a third- or fourth-line choice. Especially in patients with uncontrolled or treatment-resistant hypertension, esaxerenone may often be used in combination with a calcium-channel blocker (CCB), an angiotensin II receptor blocker (ARB)/angiotensin-converting enzyme (ACE) inhibitor, and/or a thiazide diuretic. Of note, esaxerenone has shown a sustained antihypertensive effect when added as a second-line agent in a phase 3 trial [9], and has shown favorable effects as a second- or third-line antihypertensive agent in patients with various conditions in post-marketing clinical studies [10,11,12,13]. More recently, esaxerenone has revealed its non-inferiority to trichlormethiazide in lowering home BP as a second-line treatment for patients with uncontrolled essential hypertension in the EXCITE-HT study [14].

In the current issue of Hypertension Research, Kario et al. reported the results of prespecified subanalysis of the EXCITE-HT study [15]. The study aimed to examine the non-inferiority of esaxerenone to trichlormethiazide as a second-line agent according to the basal antihypertensive agent used, i.e., ARB or CCB. The non-inferiority of esaxerenone in lowering morning home BP was demonstrated regardless of whether the basal antihypertensive agent was an ARB or a CCB. Esaxerenone with a CCB showed superiority to trichlormethiazide in lowering systolic BP, without any new safety concerns [15]. Serum potassium levels tended to be higher when esaxerenone was combined with an ARB than with a CCB, but this could be well tolerated if administered according to the package insert [15].

From these studies, there will be a promise that esaxerenone could be a second-line antihypertensive agent to choose in various conditions, especially in patients with suspected MR-associated and uncontrolled hypertension (Fig. 1). Further investigations should be warranted to validate this notion and to demonstrate its usefulness as well as its safety in the near future.

Fig. 1
figure 1

Use of antihypertensive drugs to achieve the target level of BP control in the absence of compelling indications. a A scheme proposed in JSH2019 [1], (b) a possible proposal from the current study. A: ARB, ACE inhibitor, C: CCB, D: Thiazide diuretic, M: MR antagonist (esaxerenone)

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