Due to the progress of aging in recent years, the number of elderly hypertensive patients with multiple organ dysfunction is increasing compared to hypertensive patients without complications. In addition, non-communicable diseases (NCDs) such as hypertension, diabetes, dyslipidemia, and visceral obesity increase the risk of developing cardiovascular diseases such as myocardial infarction and heart failure. Recent large-scale real-world data analyzes in Japan have shown that diabetes and its comorbidity exacerbates the risk of death [1, 2]. In addition, in a large-scale cohort study of chronic kidney disease (CKD) patients in Japan, it has been reported that heart failure is more frequent than myocardial infarction and cerebrovascular disease (CVD) as complications of CKD patients [3, 4]. CKD complications with risk of acute kidney injury and cardiovascular-kidney comorbidity (i.e., cardiorenal syndrome with heart failure and CKD) are recent pathological features [3, 4].

Regarding the involvement of mineralocorticoid receptor (MR) activation in the pathophysiology, hypertension, CVD and CKD develop and progress due to MR activation due to increased circulating aldosterone levels, such as primary aldosteronism caused by adrenal adenoma, has been known [5, 6]. In addition, in such as type 2 diabetes and obesity, hyperactivation of MR can occur so as to provoke CVD and CKD, through the activated MR-mediated metabolic, hemodynamic, inflammatory and fibrotic effects [7,8,9].

Spironolactone and eplerenone are traditionally used as indications for heart failure and hypertension [10,11,12], and recently esaxerenone, a selective nonsteroidal MR antagonist, is used for hypertension [13, 14]. Aldosterone exerts serious deleterious effects on the cardiovascular and kidney tissues via MR activation, and several large-scale clinical trials have shown that MR antagonists have organ-protective effects and improve prognosis in heart failure and post-myocardial infarction as described in clinical guidelines of heart failure [11]. Therefore, MR antagonists are recommended as therapeutic agents for heart failure, especially heart failure with decreased left ventricular systolic function (LVEF < 40%) (HFrEF), as an important therapeutic regimen of the “fantastic four” of the standard treatment for heart failure [11, 15].

In the treatment of hypertension, calcium (Ca) channel blockers, renin-angiotensin (RA) system inhibitors [angiotensin II receptor blockers (ARBs), angiotensin-converting enzyme (ACE) inhibitors], diuretics (Thiazide-type and thiazide-like diuretics) and β-blockers (including αβ-blockers) are the major antihypertensive agents [10]. If the target blood pressure cannot be achieved with only one antihypertensive drug, combination therapy with antihypertensive drugs with different mechanisms of action (including combination drugs) is recommended [10]. Alternatively, it is recommended to select an appropriate antihypertensive drug according to the comorbidity and/or specific organ dysfunction requiring careful pathological consideration [10]. In addition, JSH2019 guideline stipulates that the main antihypertensive drug (first-line drug) that should be administered first for hypertension in the absence of active indications should be selected from Ca channel blockers, ARBs, ACE inhibitors, and diuretics [10].

In the blood pressure management of high-risk hypertension complicated by diabetes and/or CKD, it is important to select an antihypertensive drug according to the pathology and to select an antihypertensive drug that can achieve the blood pressure target, but the current situation is not satisfactory [10]. According to various surveys, the target achievement rate is about 50% for those taking antihypertensive drugs, and about 40% for antihypertensive drug monotherapy [10]. Furthermore, achievement of target blood pressure in hypertension complicated by diabetes and/or CKD is reportedly less than 50% [16, 17].

On the other hand, among antihypertensive drugs, MR antagonists, which have been known to antagonize the action of aldosterone, which is involved in the maintenance of body fluid volume homeostasis, act on MR classically in the distal tubules and junction collecting ducts of the kidney [10, 12]. As a result, sodium excretion is promoted without loss of potassium, resulting in an antihypertensive effect [10, 12]. Spironolactone and eplerenone have been used clinically as MR antagonists. Although spironolactone has a strong MR inhibitory effect, it has low MR selectivity, and thus side effects mediated by sex hormones (eg, gynecomastia, menstrual disorders, etc.) have been reported [10, 12]. Although eplerenone has reduced sex hormone receptor-related side effects, it is contraindicated in patients with moderate or severe kidney dysfunction, microalbuminuria, or diabetes with proteinuria. Therefore, eplerenone is difficult to use clinically in hypertension with diabetes mellitus and/or CKD, in which the RA system is deeply involved in the pathology [10, 12].

In January 2019, esaxerenone, an MR antagonist with a non-steroidal structure, was approved for insurance coverage for hypertension [18]. The efficacy and safety of esaxerenone in patients with essential hypertension, diabetes mellitus, and hypertension with CKD have been confirmed in Japan [13, 19,20,21]. In this issue of Hypertension Research, Kario et al. extended their previous study [21] and sought to examine the effects of esaxerenone on nighttime and daytime blood pressure in patients with uncontrolled nocturnal hypertension being treated with an ARB or Ca channel blocker, with the inclusion criteria of nighttime systolic blood pressure ≥120 mmHg was set according to the definition of nocturnal hypertension in the JSH 2019 guideline (systolic blood pressure of ≥120 mmHg and/or diastolic blood pressure of ≥70 mmHg) [10, 22]. Kario K et al showed that esaxerenone reduced nighttime as well as daytime blood pressure with a reduced cardiac and renal biomarkers or arterial stiffness estimated by cardio-ankle vascular index [22]. The present study also evaluated the efficacy of new brachial and wrist home blood pressure monitoring devices in measuring bedtime blood pressure, and the results suggested that the wrist-type device can be used to monitor changes in nighttime blood pressure as well as the brachial-type device recommended in hypertension guidelines [10, 22]. This study provides new evidence supporting the efficacy of esaxerenone for nocturnal hypertension and subsequent organ protection. Therefore, “Is esaxerenone the ultimate mineralocorticoid receptor antagonist?” is a very interesting and exciting question [23, 24].

As the population ages, the number of patients suffering from combined and complex conditions such as “hypertension-cardiovascular-kidney comorbidity “ is increasing, rather than having hypertension, CVD and CKD alone. Therefore, the comprehensive therapeutic management has become essential as the therapeutic strategy of complex pathophysiology such as “hypertension-cardiovascular-kidney comorbidity”, in which hypertension is typically complicated by heart failure and CKD and often exhibits nocturnal hypertension [10]. Based on the recent progress in research and development of therapeutic drugs for cardiovascular-kidney disease, it is expected that new therapeutic drugs will be used to efficiently and safely control “hypertension-cardiovascular-kidney comorbidity” (Fig. 1), and further evidence is needed in the future [25]

Fig. 1
figure 1

Conventional treatment for blood pressure management and proposed new comprehensive therapeutic management for hypertension-cardiovascular-kidney comorbidity. CKD, chronic kidney disease; CVD, cardiovascular disease; ARBs, angiotensin II receptor blockers; ACE inhibitors, angiotensin-converting enzyme inhibitors; Ca channel blockers, calcium channel blockers; SGLT2 inhibitors, sodium-glucose cotransporter 2 inhibitors; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus; ARNI, angiotensin receptor-neprilysin inhibitor; MRAs, mineralocorticoid receptor antagonists

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