FormalPara Key Summary Points

Why carry out this study?

Recently, several clinical trials have reported reduction in incidence of mineralocorticoid receptor blocker (MRB)-induced hyperkalemia when combined with sodium-glucose cotransporter 2 (SGLT2) inhibitors

Esaxerenone, a nonsteroidal MRB, has favorable antihypertensive and renoprotective effects in hypertensive patients with diabetes mellitus (DM) but with an increased clinical risk of hyperkalemia, and should be administered with care in this population

Evidence on the use of esaxerenone in combination with SGLT2 inhibitors has been reported from clinical trials but not from clinical practice. Thus, we investigated the efficacy and safety of esaxerenone combined with SGLT2 inhibitors in hypertensive patients with DM, possibly leading to a new treatment option for these patients

What was learned from the study?

Esaxerenone elicited significant antihypertensive and urinary albumin-to-creatinine ratio-lowering effects regardless of baseline creatinine-based estimated glomerular filtration rate, and its combination with SGLT2 inhibitors improved endpoints regarding serum potassium elevation against historical comparisons

Combining esaxerenone and SGLT2 inhibitors did not interfere with either drug’s efficacy and may reduce the frequency of serum potassium elevations, suggesting they are a compatible combination

Introduction

Hypertension is a cardiovascular risk factor in patients with type 2 diabetes mellitus (T2DM) [1]. The diseases often coexist, and the number of cases of hypertension and T2DM is expected to increase with the aging population [2,3,4].

The use of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with T2DM has shown favorable cardioprotective and renoprotective effects [5, 6]. Furthermore, SGLT2 inhibitors have been reported to reduce systolic blood pressure (SBP) and diastolic blood pressure (DBP) in addition to improving glycemic control [7, 8]. Therefore, for T2DM management, European clinical guidelines recommend that SGLT2 inhibitors be considered in patients with both diabetes and hypertension [9, 10]. The American Diabetes Association 2022 guidelines recommend SGLT2 inhibitors for T2DM complicated with cardiorenal organ damage [11]. Thus, the position of SGLT2 inhibitors in the treatment of diabetes is rising.

However, not much has changed in the management of hypertension. The 2019 Japanese Society of Hypertension (JSH) guidelines recommend angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, calcium channel blockers (CCBs), and a small dose of thiazide diuretics as antihypertensive treatment for hypertensive patients with T2DM, and mineralocorticoid receptor blockers (MRBs) as fourth-line treatment for hypertension [12].

MRBs have both cardio- and renoprotective effects [13,14,15,16,17,18] along with an antihypertensive effect. However, the MRB spironolactone is associated with adverse effects related to sex-hormone receptors, such as gynecomastia [19], and eplerenone is contraindicated in hypertensive patients with moderate or severe renal impairment, and T2DM with trace albuminuria or proteinuria [20] because of the risk of hyperkalemia. Therefore, while these MRBs are approved for hypertension, their use in hypertensive patients with diabetes and chronic kidney disease (CKD) is limited. Furthermore, while finerenone, another MRB, has shown renal event suppression in patients with CKD associated with T2DM, its antihypertensive effect is modest [21], and it is not approved for hypertension treatment.

Esaxerenone, a nonsteroidal MRB, has demonstrated favorable antihypertensive effects in hypertensive patients with various characteristics [22,23,24,25,26,27,28,29], and has good renoprotective effects in hypertensive patients with T2DM and albuminuria [26]. In patients with diabetic nephropathy, esaxerenone has exhibited favorable albuminuria reduction, albuminuria remission, and antihypertensive effects [28, 29].

Of note, MRB-induced hyperkalemia is of clinical concern, especially in patients with renal impairment and diabetes [30]. Recently, several clinical trials have reported reduced incidence of MRB-induced hyperkalemia when combined with SGLT2 inhibitors [31,32,33], although the detailed mechanism for this is unknown. A subanalysis of two phase 3 studies of esaxerenone also showed that its combination with an SGLT2 inhibitor reduced incidence of serum potassium elevation without affecting the antihypertensive and albuminuria-lowering effects of esaxerenone [34]. Thus, the efficacy and safety of esaxerenone in combination with SGLT2 inhibitors has been evaluated in these clinical trials; however, there is insufficient evidence from actual clinical practice. The combination of esaxerenone and SGLT2 inhibitors, which has a different mechanism of action to MRBs, in hypertensive patients with diabetes may result in a favorable efficacy and safety profile, possibly leading to a new treatment option for these patients.

The EAGLE-DH study aimed to assess the efficacy, in terms of antihypertensive and renoprotective effects, and safety of esaxerenone in hypertensive patients with T2DM receiving SGLT2 inhibitors.

Methods

Study Design and Treatment

This was a multicenter (24 sites), open-label, prospective, interventional study conducted in Japan from January 2021 to February 2022. The participating institutions and research physicians are listed in Table S1 in the supplementary material.

After a 4-week run-in period, esaxerenone was initiated at a dose of 2.5 mg/day or at a dose of 1.25 mg/day (in patients with creatinine-based estimated glomerular filtration rate [eGFR] 30 to < 60 mL/min/1.73 m2 or urinary albumin-to-creatinine ratio [UACR] ≥ 30 mg/gCr). The dose could be gradually increased on the basis of blood pressure (BP) and serum potassium level monitoring as shown in Fig. S1.

Oral hypoglycemic or antihypertensive medications prior to obtaining consent were continued at a constant dose throughout the study, and the dose and type of antihypertensive and hypoglycemic drugs could not be changed. Prohibited concomitant drugs from 4 weeks before treatment start to the end of treatment (EOT) or the time of discontinuation included antihypertensive and antianginal drugs (e.g., α-blockers, β-blockers, or αβ-blockers, other sympatholytic agents, vasodilators, renin inhibitors), diuretics (e.g., thiazide, thiazide-like, loop, or potassium-sparing diuretics), aldosterone antagonists, angiotensin receptor neprilysin inhibitors, potassium preparations, serum potassium suppressants, and hyperkalemia ameliorants.

This study was conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act in Japan. The study protocol was approved by the Shinshu University Certified Review Board of Clinical Research (CRB3200010). The study was prospectively registered with the Japan Registry of Clinical Trials under the identifier number jRCTs031200273. All patients provided written informed consent before enrollment.

Patients

The inclusion criteria were patients ≥ 20 years, with a diagnosis of T2DM, for whom home morning/bedtime BP measurements could be obtained by using a brachial sphygmomanometer, who had received oral hypoglycemic medications (an SGLT2 inhibitor, an SGLT2 inhibitor plus one or two other oral hypoglycemic medications) at the same dose for 4 weeks prior to registration, who had received prior basal antihypertensive agents (a renin–angiotensin system [RAS] inhibitor, CCB, or RAS inhibitor plus CCB) at the same dose for 4 weeks prior to registration, with a mean sitting home morning SBP of 125 to < 160 mmHg and/or DBP of 75 to < 100 mmHg in the last 5 days prior to the registration date, and with an eGFR ≥ 30 mL/min/1.73 m2.

The main exclusion criteria were patients diagnosed with secondary hypertension (e.g., endocrine hypertension, pregnancy-induced hypertension, hypertension due to a single kidney) or malignant hypertension; prescribed insulin and glucagon-like peptide 1 receptor agonists; those with nephrotic syndrome, hyperkalemia, or serum potassium level > 5.0 mEq/L; those who had been hospitalized for myocardial infarction, angina pectoris, heart failure, percutaneous coronary angioplasty, coronary artery bypass surgery, chronic atrial fibrillation, stroke, cerebral hemorrhage, subarachnoid hemorrhage, or transient ischemic attack within 12 weeks prior to obtaining consent; patients with heart failure grade IV according to the New York Heart Association classification; those who used concomitant medications prohibited in this study within 4 weeks prior to enrollment; with serious hepatic dysfunction; and other patients deemed inappropriate by the study investigator.

BP Measurements

Home BP was self-measured two times (at morning and bedtime) using the same upper arm cuff sphygmomanometer throughout the study period within the last 5 days before the patient’s visit, and the average of the two measurements at each timepoint was recorded. Each study patient was given the same sphygmomanometer model (HCR-7502T, OMRON, Kyoto, Japan). Morning home BP was measured after urination within 1 h after waking up and before breakfast, medication, and caffeine intake. Bedtime home BP was measured more than 1 h after bathing, drinking, or caffeine intake before bedtime. Office BP and pulse rate were measured two times at each visit (at baseline; 4, 12, and 24 weeks; and at discontinuation), and the average of the two measurements was used. Office BP was measured after at least 5 min of rest in a sitting position. BP measurements at week 8 were used to determine if the esaxerenone dose should be increased further in patients not receiving the maximum dose of 5 mg.

Measurement of Other Outcomes

The albumin and creatinine concentrations in the collected spot urine samples were measured in a central measurement laboratory (LSI Medience Corp., Tokyo, Japan) at each visit (at baseline, 12 and 24 weeks, and at discontinuation). The UACR was calculated as follows: UACR (mg/gCr) = urinary albumin (µg/mL)/urinary creatinine (mg/dL) × 100. The eGFR was calculated as follows: 194 × serum creatinine−1.094 × age−0.287, multiplied by 0.739 for female patients.

Serum potassium and serum creatinine were measured at baseline; at 2, 4, 6, 8, 10, 12, and 24 weeks; and at discontinuation at each study site. Serum potassium measurements at 4 and 8 weeks were used to determine if the esaxerenone dose should be increased, while measurements at 6 and 10 weeks were used to confirm the safety of patients receiving dose escalations at 4 and 8 weeks, respectively.

Plasma aldosterone concentration and plasma renin activity were measured at baseline, at 12 and 24 weeks, and at discontinuation in the central measurement laboratory, at intervals of at least 2 h after meals and after resting in the supine position for at least 30 min. Serum N-terminal pro-brain natriuretic peptide, glycated hemoglobin, urinary concentrations of sodium, potassium, and biomarkers including liver-type fatty acid binding protein, N-acetyl-β-d-glucosaminidase, β2-microglobulin, and 8-hydroxydeoxyguanosine were also measured at baseline, at 12 and 24 weeks, and at discontinuation in the central measurement laboratory.

Efficacy Endpoints

The primary efficacy endpoint was the change in morning home SBP and DBP from baseline to weeks 12 and 24. The secondary efficacy endpoints were the following: change in bedtime home and office SBP and DBP from baseline to weeks 12 and 24, time course change of home (morning, bedtime) and office SBP and DBP during the study, achievement rate of target BP levels (SBP/DBP, home < 125/75 mmHg and office < 130/80 mmHg) at weeks 12 and 24 [12], change and percentage change in UACR from baseline to weeks 12 and 24, and changes in serum and urinary biomarkers from baseline to weeks 12 and 24.

At first, the percentage change in UACR was evaluated by classifying the data into three UACR subgroups (A1, < 30; A2, 30 to < 300; and A3, ≥ 300 mg/gCr). However, as there were only six patients in the A3 UACR subgroup, the A2 and A3 UACR subgroups were merged, and the UACR data were classified into two UACR subgroups and analyzed post hoc: A1 (UACR < 30 mg/gCr) and A2/A3 merged (UACR ≥ 30 mg/gCr). Improvement rate of UACR (defined as transition from A2 to A1, A3 to A2, or A3 to A1), rate of ≥ 30% reduction from baseline to EOT in UACR, and remission rate of UACR (remission was defined as patients with transition from A2 to A1 or A3 to A1 and ≥ 30% reduction) were also analyzed post hoc. Here, were report the data at EOT.

Safety Endpoints

The following safety endpoints were evaluated: treatment-emergent adverse events (TEAEs), the incidence of serum potassium level ≥ 5.5 and ≥ 6.0 mEq/L, time course changes and change from baseline in serum potassium, and time course change and change from baseline in eGFR and pulse rate.

Statistical Analysis

This was an exploratory study, and the number of cases was determined on the basis of practicality; the analysis was not adjusted for the multiplicity of testing caused by multiple evaluation groups and multiple timepoints. When setting the target sample size, it was assumed that the change in sitting morning home blood pressure ± standard deviation with esaxerenone would be − 10.0 ± 19.0 mmHg for SBP and − 5.0 ± 11.0 mmHg for DBP based on previous studies [23, 35]. With this assumption, the statistical power was calculated as ≥ 90% for SBP and ≥ 80% for DBP with a sample size of 40 patients, and the significance level was set at a two-sided significance level of < 0.05. Thus, considering five patients excluded from the analyses, we set the target sample size at 45 patients in each subcohort (eGFR ≥ 60 mL/min/1.73 m2 [G1–G2 subcohort] and 30 to < 60 mL/min/1.73 m2 [G3 subcohort]) [36].

Analyses were conducted in total and by baseline eGFR (G1–G2 and G3 subcohorts). No statistical comparisons were made between subcohorts. Efficacy endpoints were analyzed in the full analysis set (FAS), defined as all patients who provided informed consent, met the eligibility criteria, took at least one dose of esaxerenone, and had at least one efficacy measurement recorded. Summary statistics and 95% confidence intervals (CIs) for the change in BP from baseline to each measurement point were calculated and compared using the paired t test. For the BP and post hoc UACR analyses, missing values at the EOT were imputed using the last observation carried forward method. The 95% CIs for achievement rate of target BP levels were calculated using the Clopper–Pearson method. The 95% CIs for change and percentage change from baseline in UACR, serum biomarkers, and urinary biomarkers were calculated and compared using the paired t test. The per-protocol set (PPS) was defined as FAS patients who adhered to the package insert of esaxerenone.

Safety endpoints were evaluated in the safety analysis set, defined as all enrolled patients who took at least one dose of esaxerenone, and were summarized using descriptive statistics. TEAEs were coded by System Organ Class and Preferred Term according to the Medical Dictionary for Regulatory Activities, version J.24.1.

The significance level was set as 5% (two-sided). All statistical analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA).

Results

Patients

A total of 115 patients provided informed consent, among whom 93 met eligibility criteria and were enrolled in the study (n = 49 in the G1–G2 subcohort and n = 44 in the G3 subcohort). All patients were included in the FAS and the safety analysis set. The PPS included 80 patients (n = 36 in the G1–G2 subcohort and n = 44 in the G3 subcohort). A total of 81 patients (45 and 36 in each eGFR subcohort, respectively) completed the study.

Baseline demographic and clinical characteristics of the study population are summarized in Table 1. In the total population, mean age was 66.3 years; morning home, bedtime home, and office SBP/DBP values were 136.4/82.3 mmHg, 131.9/78.0 mmHg, and 136.5/80.0 mmHg, respectively; mean UACR was 145.3 mg/gCr; mean eGFR was 66.8 mL/min/1.73 m2; mean serum potassium level was 4.2 mEq/L; and mean HbA1c was 6.8%. Regarding basal antihypertensive agents, 33.3% and 19.4% of patients were receiving RAS inhibitor and CCB monotherapy, respectively; 47.3% were receiving a RAS inhibitor + CCB combination. Regarding hypoglycemic medications, 33.3% of patients were receiving SGLT2 inhibitor monotherapy; the rest were receiving one or two hypoglycemic medications other than SGLT2 inhibitors. Compared with the G1–G2 subcohort, the G3 subcohort tended to be older, have a higher baseline UACR (mean, 263.6 vs. 39.0 mg/gCr), have a longer history of hypertension and T2DM, and have used combination basal antihypertensive agents, which is considered a more severe disease condition. SBP was similar in both subcohorts, but DBP tended to be 4.0 to 8.0 mmHg lower in the G3 subcohort.

Table 1 Baseline patient characteristics (full analysis set)
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The last dose of esaxerenone was 1.25, 2.5, and 5 mg/day in 23.7%, 48.4%, and 28.0% of patients in the total population, respectively. In the G1–G2 subcohort, 63.3% of patients received 2.5 mg/day and 34.7% received 5 mg/day, while in the G3 subcohort, 47.7% of patients remained at 1.25 mg/day, and 31.8% and 20.5% increased to 2.5 and 5 mg/day, respectively.

BP-Lowering Effects of Esaxerenone

In the FAS, there were significant reductions in morning home SBP/DBP from baseline to week 12 (− 11.8 ± 10.8/− 5.1 ± 6.3 mmHg, both P < 0.001) and week 24 (− 12.9 ± 10.5/− 5.7 ± 6.3 mmHg, both P < 0.001) (Fig. 1A, Table S2). A significant reduction in SBP/DBP was also observed in the two eGFR subcohorts (at week 24, G1–G2 subcohort, − 16.5 ± 9.7/− 7.7 ± 6.0 mmHg; G3 subcohort, − 8.0 ± 9.8/− 3.0 ± 5.9 mmHg, all P < 0.05) (Fig. 1B, Table S2). Similar to the morning home BP, significant reductions were shown in bedtime home SBP/DBP (all P < 0.01, except for bedtime home DBP in the G3 subcohort, P = 0.326) and office SBP/DBP (all P < 0.001) (Fig. 1C, D, Table S2). Morning home SBP/DBP decreased incrementally until week 12 and this reduction in BP was maintained until week 24 and EOT in the total population and eGFR subcohorts (Fig. 2). Similar decreasing trends were also observed in bedtime home and office BP (Figs. S2 and S3, Table S2). Similar results were obtained in the PPS (Table S3). The achievement rate of target morning home SBP/DBP level at week 24 in the FAS was 23.7% in the total population, 28.6% in the G1–G2 subcohort, and 18.2% in the G3 subcohort (Table S4). Similar trends were observed in the PPS (Table S5).

Fig. 1
figure 1

Change from baseline in morning home BP levels at weeks 12 and 24 in the total population (A) and in eGFR subcohorts at week 24 (B) and change from baseline in bedtime home BP level (C) and office BP level (D) at week 24 (full analysis set). Data are mean (95% confidence interval). *P < 0.05, **P < 0.01, ***P < 0.001 vs. baseline, paired t test. BP blood pressure, DBP diastolic blood pressure, eGFR creatinine-based estimated glomerular filtration rate, SBP systolic blood pressure

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Fig. 2
figure 2

Time course changes (A) and change from baseline (B) in morning home SBP and DBP throughout the study period (full analysis set). Data are mean ± standard deviation. *P < 0.05, **P < 0.01, ***P < 0.001 vs. baseline, paired t test. BP blood pressure, DBP diastolic blood pressure, EOT end of treatment, SBP systolic blood pressure

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Effects of Esaxerenone on the UACR

The changes in the UACR from baseline to weeks 12 and 24 in the FAS are shown in Table S6, and these results were similar in the PPS (Table S7). The UACR decreased from baseline to weeks 12 and 24 in the total population (geometric percentage change from baseline to weeks 12 and 24, − 42.7% and − 49.1%, both P < 0.001) (Fig. 3A). The UACR also decreased in both eGFR subcohorts; the geometric percentage change from baseline to week 24 was − 50.8% and − 46.8% in the G1–G2 and G3 subcohorts, respectively (both P < 0.001) (Fig. 3A). Analysis by baseline UACR (UACR < 30 or ≥ 30 mg/gCr) also showed significant reduction of UACR irrespective of baseline UACR at week 24 in the total population (geometric percentage change from baseline: UACR < 30 mg/gCr, − 44.9%; UACR ≥ 30 mg/gCr, − 55.2%) and both eGFR subcohorts (G1–G2 and G3 subcohorts, respectively: UACR < 30 mg/gCr, − 44.7 and − 45.4%; UACR ≥ 30 mg/gCr, − 63.1% and − 48.2%) (all P < 0.001) (Fig. 3B). In the overall population, the UACR improvement rate was 42.4% (Fig. 3C), the rate of ≥ 30% reduction from baseline in UACR was 74.1% (Fig. 3D), and the remission rate of UACR was 36.4% (Fig. 3E) at EOT (all post hoc analysis). According to eGFR subcohort, the respective improvement rate, rate of ≥ 30% reduction from baseline in UACR, and remission rate were 50.0%, 76.1%, and 50.0% in the G1–G2 subcohort; and 36.8%, 71.8%, and 26.3% in the G3 subcohort (post hoc analysis).

Fig. 3
figure 3

Geometric percentage change in UACR from baseline at week 12 and 24 in the total population and eGFR subcohorts (A), geometric percentage change in UACR from baseline at week 24 in the total population and eGFR subcohorts based on UACR subcohorts (B), improvement rate in UACR (C), UACR ≥ 30% reduction (D), and UACR remission rate (E) at EOT in the total population and eGFR subcohorts (full analysis set). Error bars indicate 95% confidence intervals. ***P < 0.001 vs. baseline, paired t test. B–E were post hoc analyses. A significance test was not performed in C–E. Improvement rate of UACR was defined as transition from A2 to A1, A3 to A2, or A3 to A1 (C). Remission rate of UACR was defined as patients with transition from A2 to A1 or A3 to A1 and ≥ 30% reduction (E). eGFR creatinine-based estimated glomerular filtration rate, EOT end of treatment, UACR urinary albumin-to-creatinine ratio

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Effects of Esaxerenone on Biomarkers

Biomarker data are shown in Table S8. Plasma aldosterone concentration (PAC) and plasma renin activity (PRA) significantly increased with esaxerenone administration from baseline to week 24 in the total population (mean ± SD change: PAC, 33.3 ± 53.8 pg/mL, P < 0.001; PRA, 7.4 ± 16.9 ng/mL/h, P < 0.001). Similar significant increases were observed in all eGFR subcohorts (all P < 0.01), and results in the PPS were similar to those in the FAS (Table S9).

Safety

The proportion of patients with at least one TEAE was 45.2% (Table 2). Drug-related TEAEs were reported in 12 (12.9%) patients, of whom six (6.5%) discontinued the study treatment. Most TEAEs were mild or moderate. Serious TEAEs were reported in two (2.2%) patients, and these events (one colon polyp and one cellulitis) were not related to esaxerenone treatment. The most frequent TEAE was dizziness (7.5%). TEAEs related to serum potassium elevation were blood potassium increased in two (2.2%) patients and hyperkalemia in one (1.1%) patient. The case of hyperkalemia resulted in study discontinuation. No cardiovascular-related adverse events or deaths were reported during the treatment period.

Table 2 Summary of treatment-emergent adverse events (TEAEs) (safety analysis set)
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The eGFR initially decreased at weeks 0 to 2 and remained constant from week 2 to week 24 (Fig. 4A). The mean change from baseline to week 24 in eGFR was − 5.2 ± 7.9 mL/min/1.73 m2 (Fig. S4A). A similar trend of reduction in the eGFR was observed in the G1–G2 and G3 subcohorts (mean change from baseline to week 24 was − 6.9 ± 9.1 and − 3.0 ± 5.3 mL/min/1.73 m2, respectively).

Fig. 4
figure 4

Time course changes in eGFR (A) and serum potassium levels (B) during the study period in the total population and eGFR subcohorts (safety analysis set). Data are mean ± standard deviation. eGFR creatinine-based estimated glomerular filtration rate

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Serum potassium levels increased over the first 2 weeks after starting esaxerenone treatment, gradually decreased by week 12, and then remained constant up to week 24 in the total population and eGFR subcohorts (Fig. 4B). The maximum change in serum potassium was at week 2 (0.21 ± 0.33 mEq/L), and at week 24, it was 0.07 ± 0.36 mEq/L. In the G1–G2 and G3 subcohorts, the change in serum potassium levels also reached the maximum at week 2 (0.24 ± 0.32 and 0.16 ± 0.33 mEq/L, respectively), and at week 24, it was 0.01 ± 0.37 and 0.15 ± 0.34 mEq/L, respectively (Fig. S4B).

The incidence of serum potassium level ≥ 5.5 and ≥ 6.0 mEq/L are shown in Table S10. One (1.1%) patient in the G1–G2 subcohort had serum potassium levels ≥ 5.5 mEq/L during the study period. No patients had serum potassium ≥ 6.0 mEq/L.

Discussion

The objective of the EAGLE-DH study was to assess the efficacy and safety of esaxerenone in hypertensive patients with T2DM receiving an SGLT2 inhibitor. SGLT2 inhibitors have been reported to reduce the risk of cardiovascular and renal events in hypertensive patients with T2DM via suppressing eGFR decline, and reducing BP and UACR [5]. Similarly, in previous phase 3 trials, esaxerenone has been reported to decrease BP and UACR in hypertensive patients with T2DM [26, 28, 29]. In this study, even in the presence of an SGLT2 inhibitor, esaxerenone significantly reduced the primary endpoint of morning home SBP/DBP, as well as bedtime home and office SBP/DBP, and UACR from baseline to week 24 in the total population and in both eGFR subcohorts. Changes in eGFR and serum potassium in the total population were also comparable in both eGFR subcohorts, with eGFR decreasing at week 2 but remaining constant through week 24, and serum potassium transiently increasing at week 2, but decreasing by week 12, and remaining constant through week 24. Together with the lack of new safety concerns, these results demonstrate that esaxerenone can be safely administered to hypertensive patients with T2DM who are receiving an SGLT2 inhibitor to consistently reduce BP and UACR, regardless of their baseline eGFR.

SGLT2 inhibitors were prescribed at least 4 weeks prior to the start of esaxerenone dosing, and the effects of the first dose of SGLT2 inhibitor in decreasing BP and UACR (which became steady at week 4 [37]) and the initial fall in eGFR (which became steady at weeks 3–4 [37, 38]) were considered to have reached steady state at the start of esaxerenone administration. Therefore, the efficacy confirmed in this study was considered to be attributable to esaxerenone administration. Independent efficacy of esaxerenone in combination with SGLT2 inhibitor was also reported in a subanalysis of two phase 3 studies of esaxerenone [34]. Similarly, in the FIDELIO-DKD study, combination therapy with finerenone and an SGLT2 inhibitor was also confirmed to have a reducing effect on BP and UACR [33]. The details of the mechanism by which the efficacy of each drug is not counteracted are unclear, but it may be that SGLT2 inhibitors and MRBs act in the proximal and distal renal tubules, respectively [39,40,41,42,43], so that their efficacy would be complementary.

Regarding serum potassium elevation, a well-known characteristic adverse effect of MRBs, historical comparisons with other studies indicate that combination therapy with SGLT2 inhibitors can suppress the serum potassium elevation associated with esaxerenone treatment. The maximum increase in serum potassium in this study was observed at 2 weeks (0.21 ± 0.33 mEq/L), decreased up to 12 weeks, and remained constant until 24 weeks (week 12, 0.07 ± 0.37 mEq/L; week 24, 0.07 ± 0.36 mEq/L) in the total population. The G1–G2 (eGFR ≥ 60 mL/min/1.73 m2) and G3 (30 to < 60 mL/min/1.73 m2) subcohorts also showed similar trends as those in the total population. These transitions differ from the previously reported phase 3 studies J306 [26], ESAX-DN (J308) [28], J309 [29], and the EX-DKD study [44] in patients with T2DM complications, which increased by 2 weeks and then remained constant. The maximum increase of 0.21 mEq/L in the present study was lower than that of 0.45 mEq/L (week 10), 0.29 mEq/L (week 8), 0.41 mEq/L (week 6), and 0.29 mEq/L (weeks 2 and 12) reported in the J306, ESAX-DN, J309, and the EX-DKD study, respectively. Moreover, the incidence of serum potassium level ≥ 5.5 mEq/L reinforces the hypothesis that the combination with SGLT2 inhibitor may reduce the risk of serum potassium elevation. In this study, one patient (1.1%) presented with serum potassium level ≥ 5.5 mEq/L, and no patient presented with serum potassium level ≥ 6.0 mEq/L. In contrast, in the previous studies, the incidence of serum potassium level ≥ 5.5 mEq/L was 3.9% in the J306 study [26], 22.1% in the ESAX-DN study [28], 19.6% in the J309 study [29], and 2.7% in the EX-DKD study [44]. Considering that the rate of concomitant use of SGLT2 inhibitors in those studies ranged from 11.8% to 19.6%, which was considerably lower than that in the present study, it suggests that the difference in effect on serum potassium elevation between this study and previous studies may be due to the frequency of SGLT2 inhibitor use. Indeed, in the ESAX-DN/J309 study subanalysis, SGLT2 inhibitor use was shown to reduce the elevated serum potassium levels with esaxerenone administration [34]. More recently, it has been increasingly reported that SGLT2 inhibitors suppress serum potassium elevation, and that combination with SGLT2 inhibitors ameliorates MRB-induced serum potassium elevation [45, 46]. However, these results were mostly derived from subanalyses of clinical trials, and there is insufficient evidence from clinical practice because no studies have aimed to examine changes in serum potassium level with the combination of SGLT2 inhibitors and MRBs. For esaxerenone as well, the evidence is still lacking; therefore, we conducted this study to evaluate the changes in serum potassium level with the combination of SGLT2 inhibitors in a clinical setting, rather than in a controlled situation as in a clinical trial. It is noted that future randomized studies comparing patients treated with esaxerenone with and without SGLT2 inhibitors are still needed.

The 2019 JSH guideline mentions that home BP is a better predictor of cerebrovascular risk than office BP [12, 47, 48]. In this study, esaxerenone significantly reduced morning home BP in hypertensive patients with T2DM inadequately controlled with a RAS inhibitor, CCB, or RAS inhibitor plus CCB. Currently, only two studies have examined the effect of esaxerenone on home BP: the EX-DKD [44] and the present EAGLE-DH study, both in hypertensive patients with T2DM. In the EX-DKD study, a 12-week study in patients with eGFR 30–60 mL/min/1.73 m2 inadequately controlled with a RAS inhibitor or RAS inhibitor plus CCB, esaxerenone reduced morning home BP by − 11.6/− 5.2 mmHg. This value was equivalent to the 12-week change in morning home BP of − 11.8/− 5.1 mmHg in this study, suggesting that esaxerenone would have a consistent antihypertensive effect in hypertensive patients with T2DM. Furthermore, the change in the morning home BP at 24 weeks in this study was − 12.9/− 5.7 mmHg, indicating that the morning home BP-lowering effect of esaxerenone persisted through 24 weeks. This sustained antihypertensive effect of esaxerenone was confirmed not only for morning home BP but also for bedtime home and office BP. Compared to the EX-DKD study, in which bedtime home and office BP were reduced by − 10.0/− 4.4 mmHg and − 11.5/− 5.2 mmHg, respectively, the EAGLE-DH study showed reductions in bedtime home BP of − 10.6/− 4.8 mmHg (12 weeks) and − 11.8/− 5.5 mmHg (24 weeks), and reductions in office BP of − 11.3/− 6.8 mmHg (12 weeks) and − 11.8/− 7.1 mmHg (24 weeks).

The office BP allows historical comparison of antihypertensive effect of esaxerenone with previous phase 3 studies. The significant antihypertensive effect observed in the present study was comparable to that in previous clinical trials in hypertensive patients with T2DM [26, 28, 29] and without T2DM [23]. In the phase 3 placebo-controlled trial (ESAX-DN) [28] in hypertensive patients with T2DM associated with microalbuminuria under treatment with RAS inhibitor, the changes in office BP at 12 and 24 weeks were − 8.9/− 3.7 mmHg and − 13.1/− 6.0 mmHg, respectively; these results were consistent with the antihypertensive effect observed in the EAGLE-DH study. Although this study lacked a placebo control, together with the fact that PAC and PRA, indicators of mineralocorticoid receptor activity inhibition [49], increased with BP reduction, a placebo antihypertensive effect was not considered to be the main contributor for BP reduction in this study.

Compared with the G1–G2 subcohort (eGFR ≥ 60 mL/min/1.73 m2), the G3 subcohort (30 to < 60 mL/min/1.73 m2) appeared to have lower antihypertensive effects both in home and office BP, although no significance tests were performed. This may be due to the advanced arterial stiffness in the G3 subcohort of patients. In fact, the arterial stiffness in the G3 subcohort could be predicted by the baseline SBP being similar to the G1–G2 subcohort but with lower DBP, and by the older age and longer duration of hypertension and T2DM. This hypothesis is also reinforced by the different final doses of esaxerenone in both subcohorts. Because of concerns about excessive DBP reduction in this patient population, the final doses of esaxerenone were 1.25 mg and 2.5 mg in 2.0% and 63.3% of patients in the G1–G2 subcohort compared with 47.7% and 31.8% of patients in the G3 subcohort, respectively.

In the present study, even under combination therapy with RAS inhibitor, which decreases the UACR, the additional use of esaxerenone further reduced UACR, and the percentage change from baseline in the total population was comparable to that shown in previous clinical trials (J306, 32.4% at 12 weeks [26]; ESAX-DN, 42% at 52 weeks [28]; and J309, 54.6% at 28 weeks [29]). The UACR percentage changes from baseline in the G1–G2 and G3 subcohorts were also comparable to those shown in previous clinical trials (ESAX-DN, G1–G2 subcohort 43% and G3 subcohort 38% at 52 weeks [unpublished data]; J309, G1–G2 subcohort 55.9% and G3 subcohort 53.5% at 28 weeks [29]) and a clinical study (EX-DKD, G3 subcohort 50.9% at 12 weeks [44]). In addition, although not strictly comparable, the UACR-lowering effect of esaxerenone appears to be superior to the results of previous finerenone studies (FIDELIO-DKD trial, 31% reduction in UACR from baseline to month 4 [21]; FIGARO-DKD trial, the reduction in UACR from baseline to month 4 was 32% greater with finerenone vs. placebo [18]). As for the antihypertensive effect, the mean changes in SBP from baseline to month 1 and 12 for finerenone in the FIDELIO-DKD trial were − 3.0 and − 2.1 mmHg, respectively [21], and compared to a change in SBP of > 10 mmHg for esaxerenone, the antihypertensive effect of esaxerenone also appears to be stronger. The cardiorenal protective effect of finerenone is attributed to its ability to lower BP and UACR and to prevent a decrease in eGFR [50], and together with the fact that the eGFR reductions of esaxerenone at weeks 12 and 24 in this study were similar to that of finerenone at week 12 [51, 52], esaxerenone may have the potential to reduce cardiovascular/renal events to the same or greater extent as finerenone.

In combination with SGLT2 inhibitors, esaxerenone not only showed reliable and sustained antihypertensive and UACR-reducing effects but also ameliorated serum potassium elevation, and the 24-week eGFR reduction was well tolerated. Recently, combination treatment with the “fantastic four” (MRBs, SGLT inhibitors, β-blockers, and angiotensin receptor/neprilysin inhibitors) has gained importance as an effective regimen for cardiac event prevention [53]. The results of this study reinforce the importance of the combination of MRBs and SGLT2 inhibitors for hypertensive patients with diabetes who have inadequately controlled BP, a risk stratum for cardiorenal events, and suggest a promising new treatment option.

This study has some limitations, including those inherent to the exploratory, open-label, single-arm study design, with a lack of an active comparator and no comparison between cohorts. At the time when this study was initiated, esaxerenone had just been launched and evidence was lacking regarding its efficacy in a clinical practice setting, so we wanted to first confirm its home BP-reducing effect in hypertensive patients with T2DM as well as its effect on serum potassium level when administered in combination with SGLT2 inhibitors. Therefore, we first adopted a single-arm study design based on historical comparisons for both endpoints. In the future, on the basis of the results of this study, we would like to further reinforce the evidence on esaxerenone by conducting comparative studies (e.g., comparing changes in serum potassium level with esaxerenone administered in combination with dipeptidyl peptidase 4 and SGLT2 inhibitors). Multiplicity was also not adjusted for as this was an exploratory study. Ambulatory BP was not measured in this study; however, phase 3 studies confirmed a favorable antihypertensive effect of esaxerenone over a 24-h period by ambulatory BP monitoring [22, 23, 54, 55]. A 24-week study period may not be sufficient to assess the safety of the combination therapy of esaxerenone and SGLT2 inhibitors, including effects on serum potassium and eGFR. Finally, this study was conducted in Japan and therefore the findings cannot be generalized to other ethnic populations.

Conclusion

In Japanese hypertensive patients with T2DM receiving SGLT2 inhibitor treatment, esaxerenone showed BP-lowering and renoprotective effects. The beneficial effects were consistent regardless of the baseline eGFR without clinically relevant eGFR reduction. Esaxerenone and SGLT2 inhibitors did not interfere with either drug’s efficacy and may reduce the frequency of serum potassium elevations, suggesting that they are a compatible combination.