The EXCITE-HT study is the first randomized controlled trial to compare the antihypertensive effect of esaxerenone as a second-line antihypertensive agent with another agent class in patients with uncontrolled essential hypertension. The non-inferiority of esaxerenone to trichlormethiazide in antihypertensive effects was demonstrated based on morning home BP. Target BP level achievement rates of esaxerenone were comparable to or higher than those of trichlormethiazide. The range of serum K elevation observed during esaxerenone treatment was similar to that of previous esaxerenone clinical studies [14, 19,20,21,22,23]. The validation of the non-inferior antihypertensive efficacy of esaxerenone compared with thiazide diuretics, one of the first-line agents according to guidelines [3,4,5,6], is important evidence for considering the early use of esaxerenone in hypertension treatment.

The change from baseline in morning home SBP/DBP was −12.2/−6.5 mmHg and −10.0/−5.9 mmHg in the esaxerenone and trichlormethiazide, with intergroup differences of −2.2 (95% CI, −3.6, −0.8)/−0.6 (−1.4, 0.2) mmHg. This reduction in morning home BP with esaxerenone was similar to that observed in the ENaK study [22]. It has been reported that a −2.5 mmHg reduction in morning home SBP contributes to a 3.5–9.5% reduction in cardiovascular disease risk [27]. Although no superiority was demonstrated for DBP, esaxerenone significantly lowered SBP by −2.2 mmHg versus trichlormethiazide, indicating a clinically meaningful reduction. In the NOCTURNE study, the addition of 1 mg trichlormethiazide to an ARB led to a change in morning home SBP/DBP of −9.4/−4.8 mmHg [28]. In the present study, trichlormethiazide was prescribed at a low dose according to the guidelines, but the antihypertensive effect on SBP was comparable to that in the NOCTURNE study [28], whereas a stronger antihypertensive effect on DBP by 1 mmHg was confirmed. The degree of BP reduction with antihypertensive agents is more pronounced in patients with untreated and/or severe hypertension. In the present study, baseline morning home SBP/DBP values were 140.1/86.8 mmHg for esaxerenone and 139.4/86.6 mmHg for trichlormethiazide, indicating that the majority of patients had mild hypertension. This patient background characteristic should be noted in comparisons with other clinical studies.

The achievement rate of target morning home BP levels (SBP/DBP < 135/85 mmHg) with esaxerenone was high (60.8%) and was higher than that with trichlormethiazide. However, the achievement rates for target BP level in morning home BP were found to be lower than those for bedtime home and office BP in both treatment groups. In both the J-HOP and HONEST studies, the risk of stroke was higher in patients with morning home SBP ≥ 135 mmHg versus <135 mmHg [1, 2].

In addition to its potent antihypertensive effect, esaxerenone has been shown to exert UACR-lowering effects in hypertensive patients with diabetic kidney disease, similar to finerenone [19, 29,30,31]. The reduction of UACR and NT-proBNP was significant compared with baseline values, but was comparable between the two groups, even though the morning home SBP reduction in the esaxerenone group was superior to the trichlormethiazide group. The predominant reduction of these biomarkers may result from the relief of hemodynamic stress due to the reduction of circulating volume by these drugs in the hypertensive patients with these biomarkers almost within the normal range. Future long-term studies on hypertensive patients with higher levels of these biomarkers are needed to conclude the difference in benefit of organ protection between the two groups.

Serum K levels ≥5.5 and ≥6.0 mEq/L were observed in 2% and 0% of patients in the esaxerenone group, respectively, which is comparable to a previous report [14]. Serum K levels increased over the first 2 weeks after starting esaxerenone treatment, then gradually decreased to a comparable level to baseline by Week 12 without specific treatment to lower serum K. A possible explanation for this observed trend may be that patients in this study were those with inadequate antihypertensive response to an ARB or CCB. Because the mineralocorticoid receptor is constantly activated in such patients, it is assumed that renal (urinary) reabsorption of sodium (Na) is enhanced and, conversely, K excretion is induced. When esaxerenone, an MRB, is administered in such patients, Na excretion is increased and K excretion is suppressed, thereby improving Na homeostasis. This effect reaches a steady state 2–4 weeks after esaxerenone administration. In terms of homeostasis, once Na homeostasis reaches normalization (steady state), K homeostasis will also normalize (i.e., serum K levels will return to normal).

The frequencies of serum K level <3.5 mEq/L were higher in the trichlormethiazide group than esaxerenone group (11.5% versus 3.1%). Serum K levels decreased over the first 2 weeks in the trichlormethiazide group, then continued to slightly decrease up to Week 12. Adverse events of hypokalemia were more frequent in this study (the trichlormethiazide group) compared with the DIME study (1.3% versus 0.4%) [32], which may be due to differences in study designs: the DIME study evaluated hypokalemia that persists after addition of K-retaining agents or K supplementation [32], whereas concomitant use of these agents was prohibited in the present study. Trichloromethiazide had a higher incidence of hyperuricemia than esaxerenone (3.7% and 1.3%, respectively) in the present study, which is consistent with the DIME study in which diuretics significantly increased UA [32]. No notable effects on other metabolic biomarkers, such as blood glucose and lipids, were observed, and these were similar in both groups. However, this study had a short 12-week study period, and a longer study period is needed to assess metabolic safety. The complication rate of hyperuricemia at baseline was approximately 15% in both groups; no patient developed gout during the study period, although UA levels were increased in the trichlormethiazide group. Given the safety results from the EXCITE-HT study, esaxerenone had no new safety concerns, and can be used safely if dose adjustments are made according to the package insert and serum K levels are regularly monitored.

MRBs, including esaxerenone, are considered effective for treatment-resistant hypertension according to the 2019 JSH guidelines [5], but are positioned as fourth-line in the list of treatments. Although previous clinical studies have demonstrated a reliable antihypertensive effect when esaxerenone is administered as second-line treatment [17,18,19,20,21,22,23], these studies did not compare esaxerenone with any of the five major first-line antihypertensive agents [5]. The antihypertensive effect, UACR improvement, and safety profile of esaxerenone were non-inferior to those of trichlormethiazide, which is one of the first-line agents. We hope that the EXCITE-HT study will provide new antihypertensive strategies that include treatment with esaxerenone for patients with uncontrolled hypertension.

This study has some strengths, including the large sample size and multicenter study design. Another strength of this study is that it may be generalizable to a wide range of hypertensive patients. In real-world clinical settings, ARBs or CCBs are typically administered as first-line antihypertensive agents. However, controlling BP with one ARB or CCB is often difficult.

This study has some limitations, including the open-label design and relatively short-term duration. In a longer-term study, the intergroup difference in the incidence of hypokalemia and hyperuricemia between groups may increase. Second, this study was designed to compare the usefulness of esaxerenone versus a diuretic as a second concomitant antihypertensive agent, with concomitant use of a third antihypertensive agent during the study period being prohibited. Therefore, the achievement of target morning home SBP/DBP level <125/75 mmHg was lower (esaxerenone group, 18.1%; thiazide group, 12.2%) than that of target morning home SBP/DBP level <135/85 mmHg. Long-term (10-year) prognosis is better when a target home SBP of <125 mmHg is achieved compared with ≥135 mmHg [33]. In real-world clinical practice, combination with a third agent is considered in cases of inadequate BP control, and the intergroup difference may increase in a longer-term study. Additionally, nocturnal BP was not evaluated. When morning home SBP/DBP was controlled to <135/85 mmHg, 72% of patients had better control of nocturnal SBP/DBP (<120/70 mmHg) [34]. Previous studies have also shown that esaxerenone significantly controls not only morning home BP but also nocturnal BP [18, 20, 35].