2025 Volume 72 Issue 8 Pages 947-957
Esaxerenone, a nonsteroidal mineralocorticoid receptor blocker, may be an effective treatment for diabetes-associated mineralocorticoid receptor-related hypertension, but there have been few studies of its use in clinical practice. We aimed to determine the effects of esaxerenone on blood pressure (BP) and metabolic parameters of hypertensive subjects with diabetes in a clinical practice setting. We performed a retrospective multicenter observational study of hypertensive subjects with type 2 diabetes/prediabetes. We first compared the values of parameters at baseline and after 6 months of esaxerenone administration, then compared the changes in the parameters in propensity score-matched subjects who initiated esaxerenone or amlodipine administration. Correlation analysis was performed to identify factors associated with these changes. The single-arm analysis showed that esaxerenone caused significant reductions in systolic and diastolic BP from 155.2 ± 17.7 and 83.3 ± 12.3 mmHg at baseline to 132.9 ± 15.5 and 72.3 ± 12.9 mmHg, respectively, after 6 months of treatment (p < 0.01). In addition, body mass index (BMI), glycated hemoglobin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein-cholesterol, estimated glomerular filtration rate, and urine albumin/creatinine ratio (UACR) significantly decreased (p < 0.05). The esaxerenone group showed significantly larger reductions in systolic BP, AST, ALT, and UACR than the amlodipine group (p < 0.05). Furthermore, there was a negative correlation between the change in ALT and baseline BMI (p < 0.05). Esaxerenone has an antihypertensive effect, reduces the albuminuria, and reduces the activities of liver enzymes in hypertensive subjects with type 2 diabetes/prediabetes. The present findings suggest that esaxerenone has pleiotropic effects in such subjects.
Type 2 diabetes (T2D) is often complicated by hypertension [1], which is highly prevalent in subjects with impaired glucose tolerance or T2D (25.4% and 39.7%, respectively), compared to those without diabetes (18.4%). Subjects with hypertension also have a higher prevalence of diabetes (10.7%) than those without (3.9%) [2]. In addition, hypertensive subjects with diabetes tend to be resistant to anti-hypertensive treatment [3].
Hypertension in combination with diabetes is associated with a higher risk of macrovascular disease [4, 5], and a 10-mmHg increase in systolic BP (SBP) is associated with an 18% higher risk of mortality owing to macrovascular disease [6]. Therefore, BP control is important in subjects with diabetes. A European study showed that only 54% of subjects with T2D achieve a BP <140/90 mmHg [7], which implies that BP is poorly controlled in such subjects. Insulin resistance has been suggested to be an underlying mechanism of diabetes-associated hypertension [8]. Insulin resistance is caused by obesity and physical inactivity, but is thought to be involved in the development of hypertension through the induction of compensatory hyperinsulinemia, an increase in circulating plasma volume that occurs because of an increase in renal sodium reabsorption [9], and an increase in catecholamine production associated with activation of the sympathetic nervous system [10, 11]. Mineralocorticoid receptors (MRs) have been reported to be involved in insulin resistance [12], and the inadequate control of diabetes-associated hypertension may be, at least in part, MR-mediated.
MR is activated by aldosterone, and this causes fluid retention and an increase in BP [13]. In addition, salt overload, diabetes, obesity, and chronic kidney disease (CKD) are known to cause pathologic activation of MR and hypertension, independent of the circulating aldosterone concentration, a phenomenon referred to as MR-related hypertension [14]. MR activation causes not only hypertension, but also chronic inflammation in organs, and affects systemic metabolism, which has effects such as the exacerbation of hepatosteatotic disease [14].
Eplerenone, spironolactone, esaxerenone (Esax), and finerenone are the principal MR antagonists used in clinical practice. However, eplerenone is contraindicated in subjects with proteinuria that is more substantial than microalbuminuria and moderate or severe renal impairment [15], which limits its use in subjects with diabetes. Spironolactone can be administered to such subjects, but has the side effect of gynecomastia, because of its low MR selectivity [16]. Esax and finerenone are novel non-steroidal selective MR blockers (MRBs) that are more potent MR antagonists and show higher MR selectivity than conventional MRBs. Finerenone has been shown to reduce cardiovascular and renal damage in subjects with CKD and T2D, but its antihypertensive effect is modest [17].
Esax is approved for administration to subjects with moderate renal dysfunction, albuminuria, and T2D in Japan, and is effective if their hypertension is MR-related to some extent. In addition, clinical trials have demonstrated antihypertensive effects of Esax [18] in subjects with essential hypertension when it is administered in combination with a renin–angiotensin system (RAS) inhibitor or a calcium channel blocker (CCB) [19], as well as to reduce albuminuria in subjects with T2D [20]. However, few real-world clinical studies have been conducted and no comparisons have been made with the effects of other antihypertensive drugs. Therefore, in the present study, we aimed to characterize the effects of Esax on the BP and metabolic parameters of hypertensive subjects with T2D or prediabetes, and to compare these with the effects of amlodipine (Amlo), a CCB, in a clinical practice setting.
We performed a retrospective multicenter observational study of hypertensive subjects with T2D or prediabetes who were undergoing outpatient treatment at one of seven medical institutions (a university hospital, four hospitals, and two clinics) between May 2019 and May 2022. Subjects were enrolled who fulfilled the following criteria: hypertension with T2D or prediabetes, age ≥20 years, and the initiation of Esax and administration for 6 months during the study period. Hypertension was defined as an SBP ≥140 mmHg and/or a diastolic BP (DBP) ≥90 mmHg, or the use of antihypertensive drugs. Diabetes and prediabetes were diagnosed using the American Diabetes Association diagnostic criteria [21]. We excluded subjects with a history of hypersensitivity to the drugs, hyperkalemia ([K] ≥5.0 mEq/L), severe renal dysfunction (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2), or primary aldosteronism, and those administering potassium preparations and/or another MRB. In addition, subjects who were pregnant, had severe infection, heart disease, or liver disease, and changed their antihypertensive, antidiabetic, or antihyperlipidemic drugs during the 6 months following the initiation of Esax administration were excluded. An opt-out informed consent procedure was used. The study was approved by the Institutional Review Board of Hokkaido University Hospital and Medical Innovation Center (approved on November 18, 2020; Clinical Research No. 020-0246).
MethodsEsax administration was commenced at 1.25 or 2.5 mg/day, according to the manufacturer’s guidelines, in which 1.25 mg is recommended for subjects with albuminuria and moderate or severe renal dysfunction, and the dose was increased at the physicians’ discretion. We collected data regarding clinical parameters, including SBP, DBP, and liver enzyme activities, and the type of antihypertensive drugs used, and then compared the values of these parameters at baseline with those after 6 months of Esax administration. The tolerance for data collection was ±1 month. SBP and DBP were measured in the clinic with the participant in a sitting position. Blood collection was performed at arbitrary times. Next, we identified subjects who initiated administration of the CCB Amlo at 2.5 or 5 mg/day during the study period for use as a control group, and the same inclusion and exclusion criteria as for the Esax group were applied. Propensity score matching was used to adjust for differences between the groups, and we compared the changes (Δ) in the parameters that occurred in each group. In addition, the parameters associated with the change in BP or the metabolic parameters in the Esax single-arm group were identified using correlation analysis.
Statistical analysisWe used JMP Pro software (version 16; SAS Institute Inc., Cary, NC, USA) for the statistical analysis. Normally distributed continuous data are expressed as mean ± standard deviation and non-normally distributed data as median [interquartile range]. The Shapiro–Wilk test was performed to assess the normality of the distribution of each dataset. We used the paired t-test or Wilcoxon signed-rank test to compare the baseline and post-treatment data for each group. We calculated propensity scores for the Esax and control groups using the baseline covariates age, sex, BMI, SBP, glycated hemoglobin (HbA1c), serum K concentration, ALT activity, total cholesterol (T-Chol) concentration, eGFR, and the concomitant use of an angiotensin II receptor blocker (ARB) in a multivariate logistic regression model. The participants were matched 1:1 within 0.20-caliper widths of the pooled standard deviation of the logit of the propensity scores. We then used the unpaired t-test, Wilcoxon rank-sum test, or Fisher’s exact test, as appropriate, to compare the changes in the parameters between the groups. Finally, we performed Spearman’s rank correlation analysis or partial correlation analysis of the relationships between key parameters. P < 0.05 was considered to represent statistical significance.
We enrolled 46 subjects (26 men and 20 women) who initiated Esax administration (Fig. 1). Their baseline characteristics are shown in Table 1.
| Esax group (n = 46) | |
|---|---|
| Age (years) | 66 ± 11 |
| Female (n) | 20 (43%) |
| Duration of diabetes (years) | 12 [6–17] |
| BW (kg) | 71.1 ± 15.6 |
| BMI (kg/m2) | 25.6 [22.8–28.8] |
| SBP (mmHg) | 155.2 ± 17.7 |
| DBP (mmHg) | 83.3 ± 12.3 |
| HbA1c (%) | 6.8 [6.3–7.3] |
| Na (mEq/L) | 140 [139–142] |
| K (mEq/L) | 4.4 [4.1–4.6] |
| AST (U/L) | 22 [17–30] |
| ALT (U/L) | 20 [14–35] |
| Cr (mg/dL) | 0.80 [0.69–0.85] |
| eGFR (mL/min/1.73 m2) | 68.8 ± 15.8 |
| T-Chol (mg/dL) | 191 ± 32 |
| TG (mg/dL) | 155 [102–196] |
| HDL-C (mg/dL) | 57 [51–66] |
| LDL-C (mg/dL) | 99 ± 28 |
| UACR (mg/gCr)† | 32.0 [15.7–85.9] |
| log10UACR† | 1.6 ± 0.6 |
| Antihypertensive drugs | |
| CCB (n) | 38 (83%) |
| ARB (n) | 38 (83%) |
| α-blocker (n) | 8 (17%) |
| β-blocker (n) | 4 (9%) |
| Antihyperlipidemic drugs | |
| Statins (n) | 18 (39%) |
| Fibrates (n) | 7 (15%) |
| Antidiabetic agents | |
| Insulin (n) | 11 (24%) |
| GLP-1 receptor agonist (n) | 6 (13%) |
| SGLT2 inhibitors (n) | 10 (22%) |
| DPP-4 inhibitors (n) | 33 (72%) |
| Biguanides (n) | 28 (61%) |
| Sulfonylurea (n) | 7 (15%) |
Data are shown as mean ± standard deviation, median [interquartile range], or numbers of participants. †n = 37. BW, body weight; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine; eGFR, estimated glomerular filtration rate; T-Chol, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; UACR, urine albumin/creatinine ratio; CCB, calcium channel blocker; ARB, angiotensin II receptor blocker; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2; DPP-4, dipeptidyl peptidase-4.
A total of 58 subjects were enrolled in the control group and started Amlo administration during the study period (Fig. 1). After 1:1 propensity score matching, 30 subjects in the Esax group were matched with those in the control group. The baseline characteristics of these groups are shown in Table 2. There were no differences between the two groups at baseline.
| Esax group (n = 30) | control group (n = 30) | p value | |
|---|---|---|---|
| Age (years) | 63 ± 11 | 64 ± 13 | 0.76 |
| Female (n) | 11 (37%) | 13 (43%) | 0.79 |
| Duration of diabetes (years) | 10 [4–16] | 7 [3–14] | 0.12 |
| BW (kg) | 71.1 ± 15.6 | 72.9 ± 15.2 | 0.91 |
| BMI (kg/m2) | 26.0 [23.1–30.0] | 25.7 [23.2–28.8] | 0.82 |
| SBP (mmHg) | 158.0 ± 14.6 | 154.8 ± 18.4 | 0.46 |
| DBP (mmHg) | 84.6 ± 11.0 | 87.7 ± 13.2 | 0.73 |
| HbA1c (%) | 6.9 [6.5–7.6] | 7.1 [6.7–7.4] | 0.78 |
| Na (mEq/L) | 140 [139–142] | 140 [138–142] | 0.33 |
| K (mEq/L) | 4.4 [4.2–4.6] | 4.3 [4.1–4.5] | 0.63 |
| AST (U/L) | 24 [18–31] | 21 [19–24] | 0.37 |
| ALT (U/L) | 24 [15–38] | 22 [14–33] | 0.42 |
| Cr (mg/dL) | 0.76 [0.66–0.83] | 0.75 [0.57–0.97] | 0.96 |
| eGFR (mL/min/1.73 m2) | 74.7 ± 14.9 | 71.3 ± 19.5 | 0.45 |
| T-Chol (mg/dL) | 192 ± 35 | 196 ± 31 | 0.65 |
| TG (mg/dL) | 170 [108–202] | 129 [89–175] | 0.13 |
| HDL-C (mg/dL) | 56 [46–65] | 60 [52–66] | 0.27 |
| LDL-C (mg/dL) | 100 ± 31 | 109 ± 27 | 0.20 |
| UACR† | 34.0 [17.0–93.9] | 22.4 [10.6–61.5] | 0.32 |
| log10UACR† | 1.5 [1.2–1.9] | 1.3 [1.0–1.8] | 0.32 |
| Antihypertensive drugs | |||
| CCB (n) | 24 (80%) | — | |
| ARB (n) | 21 (70%) | 17 (57%) | 0.42 |
| α-blocker (n) | 3 (10%) | 0 | 0.24 |
| β-blocker (n) | 3 (10%) | 0 | 0.24 |
| Antihyperlipidemic drugs | |||
| Statins (n) | 7 (23%) | 4 (13%) | 0.51 |
| Fibrates (n) | 3 (10%) | 5 (17%) | 0.71 |
| Antidiabetic agents | |||
| Insulin (n) | 9 (30%) | 4 (13%) | 0.21 |
| GLP-1 receptor agonist (n) | 5 (17%) | 1 (3%) | 0.19 |
| SGLT2 inhibitors (n) | 8 (27%) | 9 (30%) | 1.00 |
| DPP-4 inhibitors (n) | 21 (70%) | 21 (70%) | 0.78 |
| Biguanides (n) | 19 (63%) | 21 (70%) | 1.00 |
| Sulfonylurea (n) | 4 (13%) | 2 (7%) | 0.67 |
Data are shown as mean ± standard deviation, median [interquartile range], or numbers of participants. †n = 25 in the Esax group, n = 24 in the control group. BW, body weight; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine; eGFR, estimated glomerular filtration rate; T-Chol, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; UACR, urine albumin/creatinine ratio; CCB, calcium channel blocker; ARB, angiotensin II receptor blocker; GLP-1, glucagon-like peptide-1; SGLT2, sodium-glucose cotransporter 2; DPP-4, dipeptidyl peptidase-4. The unpaired t-test, Wilcoxon rank-sum test or Fisher’s exact test was used to compare the parameters between the groups.
Table 3 shows the baseline and 6-month data for the 46 subjects. Their SBP significantly decreased from 155.2 ± 17.7 mmHg at baseline to 132.9 ± 15.5 mmHg after 6 months of Esax administration (p < 0.01), and their DBP also decreased from 83.3 ± 12.3 mmHg to 72.3 ± 12.9 mmHg (p < 0.01). In addition, their BMI, HbA1c, AST, ALT, eGFR, T-Chol, low-density lipoprotein-cholesterol (LDL-C), UACR, and log10UACR significantly decreased (all p < 0.05). However, their serum K and creatinine (Cr) concentrations significantly increased (both p < 0.05). Their mean dose of Esax was increased from 2.3 ± 0.5 mg to 3.2 ± 1.4 mg during the study. Severe adverse events were not reported by any of the subjects.
| baseline | 6 months | p value | |
|---|---|---|---|
| BW (kg) | 71.1 ± 15.6 | 70.1 ± 15.6 | <0.01 |
| BMI (kg/m2) | 25.6 [22.8–28.8] | 25.0 [22.8–28.9] | <0.01 |
| SBP (mmHg) | 155.2 ± 17.7 | 132.9 ± 15.5 | <0.01 |
| DBP (mmHg) | 83.3 ± 12.3 | 72.3 ± 12.9 | <0.01 |
| HbA1c (%) | 6.8 [6.3–7.3] | 6.6 [6.2–7.1] | 0.03 |
| Na (mEq/L) | 140 [139–142] | 140 [139–142] | 0.10 |
| K (mEq/L) | 4.4 [4.1–4.6] | 4.5 [4.2–4.7] | 0.04 |
| AST (U/L) | 22 [17–30] | 19 [15–25] | 0.02 |
| ALT (U/L) | 20 [14–35] | 18 [13–29] | <0.01 |
| Cr (mg/dL) | 0.80 [0.69–0.85] | 0.86 [0.76–0.99] | <0.01 |
| eGFR (mL/min/1.73 m2) | 68.8 ± 15.8 | 63.0 ± 16.3 | <0.01 |
| T-Chol (mg/dL) | 191 ± 32 | 183 ± 34 | <0.01 |
| TG (mg/dL) | 155 [102–196] | 153 [118–186] | 0.66 |
| HDL-C (mg/dL) | 57 [51–66] | 58 [47–66] | 0.05 |
| LDL-C (mg/dL) | 99 ± 28 | 92 ± 28 | 0.01 |
| UACR (mg/gCr)† | 32.0 [15.7–85.9] | 15.1 [7.1–28.6] | <0.01 |
| log10UACR† | 1.6 ± 0.6 | 1.2 ± 0.5 | <0.01 |
Data are shown as mean ± standard deviation, median [interquartile range], or numbers of participants. †n = 37. BW, body weight; BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine; eGFR, estimated glomerular filtration rate; T-Chol, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; UACR, urine albumin/creatinine ratio. The paired t-test or Wilcoxon signed-rank test was used to compare baseline and post-treatment data.
To further evaluate the effects of Esax on the liver, we conducted additional analyses of 13 subjects who had liver enzyme activities above the reference range (AST >30 U/L or ALT >42 U/L). The median AST and ALT activities decreased from 33.0 [31.0–42.5] U/L to 28.0 [24.0–40.0] U/L (p = 0.07) and 48.0 [30.5–74.5] U/L to 35.0 [26.0–59.5] U/L (p < 0.01), respectively. The changes in the AST and ALT activities are shown in Fig. 2.
Table 4 shows the baseline and 6-month data for the Esax and control groups after matching. The Esax group showed significant decreases in body weight (BW), SBP, DBP, HbA1c, ALT, eGFR, UACR, and log10UACR, and a significant increase in Cr. The control group showed significant decreases in SBP and DBP, and a significant increase in UACR, unlike in the Esax group. The mean dose of Esax was increased from 2.3 ± 0.5 mg to 3.1 ± 1.3 mg during the study, and that of Amlo was increased from 3.8 ± 1.3 mg to 5.0 ± 2.1 mg. Severe adverse events were not reported by any of the participants.
| Esax group | Control group | p value between groups |
|||
|---|---|---|---|---|---|
| baseline | 6 months | baseline | 6 months | ||
| BW (kg) | 73.3 ± 14.7 | 72.5 ± 14.5** | 72.9 ± 15.2 | 72.5 ± 15.4 | 0.50 |
| BMI (kg/m2) | 26.0 [23.1–30.0] | 25.7 [23.4–28.9] | 25.7 [23.2–28.8] | 25.0 [23.3–28.6] | 0.21 |
| SBP (mmHg) | 158.0 ± 14.6 | 136.3 ± 14.1** | 154.8 ± 18.4 | 144.0 ± 15.3** | 0.02 |
| DBP (mmHg) | 84.6 ± 11.0 | 75.1 ± 12.1** | 87.7 ± 13.2 | 78.3 ± 16.1** | 0.23 |
| HbA1c (%) | 6.9 [6.5–7.6] | 6.7 [6.2–7.3]** | 7.1 [6.7–7.4] | 7.0 [6.5–7.3] | 0.27 |
| Na (mEq/L) | 140 [139–142] | 140 [138–142] | 140 [138–142] | 139 [138–141] | 0.48 |
| K (mEq/L) | 4.4 [4.2–4.6] | 4.5 [4.2–4.7] | 4.3 [4.1–4.5] | 4.4 [4.1–4.6] | 0.92 |
| AST (U/L) | 24 [18–31] | 21 [18–27] | 21 [19–24] | 22 [18–32] | 0.03 |
| ALT (U/L) | 24 [15–38] | 18 [14–29]** | 22 [14–33] | 22 [15–38] | <0.01 |
| Cr (mg/dL) | 0.76 [0.66–0.83] | 0.84 [0.73–0.91]** | 0.75 [0.57–0.97] | 0.82 [0.64–0.95] | 0.31 |
| eGFR (mL/min/1.73 m2) | 74.7 ± 14.9 | 68.5 ± 14.6** | 71.3 ± 19.5 | 69.6 ± 19.5 | 0.05 |
| T-Chol (mg/dL) | 192 ± 35 | 185 ± 35 | 196 ± 31 | 190 ± 43 | 0.60 |
| TG (mg/dL) | 170 [108–202] | 163 [122–191] | 129 [89–175] | 128 [107–201] | 0.35 |
| HDL-C (mg/dL) | 56 [46–65] | 56 [46–66] | 60 [52–66] | 55 [50–69] | 0.65 |
| LDL-C (mg/dL) | 100 ± 31 | 95 ± 30 | 109 ± 27 | 111 ± 28 | 0.22 |
| UACR (mg/gCr)† | 34.0 [17.0–93.9] | 15.1 [7.6–34.6]** | 22.4 [10.6–61.5] | 32.3 [11.3–66.8]* | <0.01 |
| log10UACR† | 1.5 [1.2–1.9] | 1.2 [0.9–1.5]** | 1.3 [1.0–1.8] | 1.5 [1.0–1.8]* | <0.01 |
Data are shown as mean ± standard deviation, median [interquartile range], or numbers of participants. *p < 0.05 and **p < 0.01 vs. baseline. †n = 25 in the Esax group, n = 24 in the control group. BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; AST, aspartate aminotransferase; ALT, alanine aminotransferase; Cr, creatinine; eGFR, estimated glomerular filtration rate; T-Chol, total cholesterol; TG, triglyceride; HDL-C, high-density lipoprotein-cholesterol; LDL-C, low-density lipoprotein-cholesterol; UACR, urine albumin/creatinine ratio. The paired t-test or Wilcoxon signed-rank test was used to compare baseline and post-treatment data for each group. The unpaired t-test or Wilcoxon rank-sum test was used to compare the changes between the groups.
We next compared the changes in the parameters of interest during the 6 months following the initiation of the drugs between the groups (Table 4, Fig. 3). The SBP of the subjects in the Esax group decreased more than in those in the control group (ΔSBP: –20 [–27 to –10] mmHg vs. –13 [–30 to 0] mmHg, respectively; p < 0.05), but the change in DBP did not significantly differ between the groups (ΔDBP: –12 [–19 to –6] mmHg vs. –8 [–15 to –3] mmHg, respectively). The Esax group showed larger decreases in AST, ALT, UACR, and log10UACR than the control group (ΔAST: –3 [–6 to +2] U/L vs. +1 [–2 to +3] U/L, ΔALT: –4 [–9 to –1] U/L vs. +1 [–3 to +6] U/L, ΔUACR: –17.7 [–52.7 to –6.8] vs. +5.6 [–2.1 to +17.5] mg/gCr, and Δlog10UACR: –0.3 [–0.5 to –0.2] vs. +0.2 [0 to 0.3], respectively; all p < 0.05).
Next, to help identify the group of subjects who would most benefit from Esax administration, we evaluated the relationships of the ΔSBP, ΔAST, and ΔALT with the baseline values of parameters of interest in the participants who administered Esax (Fig. 4). A negative correlation was found between ΔALT and BMI (ρ = –0.34, p = 0.02), but no correlation was found between ΔSBP and BMI (ρ = 0.07, p = 0.65) or ΔAST and BMI (ρ = 0.17, p = 0.27). Further data are shown in the Supplementary table.
In the present study, we characterized the changes in BP and various blood parameters that occur following Esax administration in hypertensive subjects with T2D or prediabetes. Esax administration was found to be associated with a significantly larger reduction in SBP than Amlo administration, as well as larger reductions in circulating liver enzyme activities and urinary albumin concentration.
Phase III clinical trials have shown that Esax reduces both SBP and DBP in subjects with diabetes [18-20], and we obtained similar results in the present study. The ESAX-HTN study [18], which was designed to compare the administration of Esax and eplerenone in subjects with essential hypertension, showed that Esax 2.5 mg or 5 mg/day caused decreases of 13.1 mmHg or 16.5 mmHg in SBP, and 6.4 mmHg or 8.1 mmHg in DBP, respectively. In addition, the long-term administration of Esax alone or in combination with a CCB or RAS inhibitor (an angiotensin-converting enzyme inhibitor or ARB) to subjects with essential hypertension caused decreases of 23.7, 20.5, and 23.0 mmHg in SBP, and 12.3, 13.1, and 12.5 mmHg in DBP, respectively [19]. Furthermore, when Esax administration was added to that of an RAS inhibitor in hypertensive subjects with T2D and albuminuria, additional decreases of 13.7 mmHg in SBP and 6.2 mmHg in DBP were achieved [20]. Finally, a prospective intervention study of the effects of Esax in hypertensive subjects with diabetes who were administering a sodium–glucose cotransporter-2 (SGLT2) inhibitor (the EAGLE-DH study [22]) showed that they achieved reductions in SBP and DBP of 12.9 mmHg and 5.7 mmHg, respectively, implying that Esax is efficacious such subjects.
Both groups in the present study showed decreases in SBP and DBP, but the mean SBP of the subjects who administered Esax decreased more than that of the propensity score-matched participants in the control group. These results suggest that Esax is efficacious in hypertensive subjects with diabetes, probably because this combination involves MR to some extent.
We also found that Esax administration was associated with lower liver enzyme activities in both the single-group and propensity score matching analyses. The effects of MR antagonists on hepatic steatosis have previously been studied using mice with nonalcoholic steatohepatitis induced by feeding a high-fat, high-fructose diet. Spironolactone reduced the serum triglyceride, free fatty acid, and T-Chol concentrations of the mice, and oil red O staining showed that the accumulation of lipid droplets in the liver was also reduced by spironolactone administration [23]. In addition, treatment with eplerenone has been shown to ameliorate hepatic stenosis [24]. However, studies performed in humans have shown no beneficial effects of eplerenone on the hepatic steatosis of subjects with T2D [25]. Further analysis of the Esax group revealed a negative correlation between ΔALT and the basal BMI, suggesting that this drug may reduce the liver pathology of subjects with obesity. There was no correlation between ΔBMI and ΔALT. In the Esax single-arm group, 29 subjects with ΔBW <0 kg and 17 subjects with ΔBW ≥0 kg exhibited ΔALT –3 [–7 to –1.5] and ΔALT +1 [–6 to +2], respectively, with no significant difference between the groups. Furthermore, the 29 subjects with weight reduction were stratified into two subgroups: those with ΔBW <–2 kg (13 subjects) and those with –2 ≤ ΔBW < 0 kg (16 subjects). Subsequent analysis revealed ΔALT –4 [–8 to –1.5] and –3 [–5.5 to –1.25], respectively, with no significant difference between these subgroups. Correlation analysis was conducted to assess the potential influence of SGLT2 inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, weight reduction, and HbA1c levels on ALT. The results indicated that ALT levels were reduced with Esax administration, independent of these aforementioned factors (Table 5). Since obesity contributes to MR-related hypertension [14], it is possible that Esax has beneficial effects in the livers of subjects with T2D and obesity.
| ΔAST | ΔALT | |||
|---|---|---|---|---|
| γ | p value | γ | p value | |
| ΔAST | — | — | 0.39 | <0.01 |
| ΔALT | 0.39 | <0.01 | — | — |
| ΔBW | –0.37 | <0.01 | 0.22 | 0.11 |
| ΔHbA1c | 0.23 | 0.10 | –0.03 | 0.86 |
| SGLT2 inhibitor | 0.16 | 0.24 | –0.32 | 0.02 |
| GLP-1 receptor agonist | 0.26 | 0.05 | –0.24 | 0.08 |
| Esax | –0.19 | 0.17 | –0.28 | 0.04 |
AST, aspartate aminotransferase; ALT, alanine aminotransferase; BW, body weight; HbA1c, glycated hemoglobin; SGLT2, sodium–glucose cotransporter-2; GLP-1, glucagon-like peptide-1; Esax, esaxerenone.
Treatment with Esax also reduced the UACR of the subjects with diabetes and albuminuria, which suggests that it may have a renoprotective effect, as shown in previous clinical studies [26, 27]. In the present study, the serum Cr of the participants increased and their eGFR decreased during the 6 months of the study, which is consistent with the results of a previous study [26]. The reduction in UACR suggests that the decrease in eGFR may be the result of a reduction in hyperfiltration, secondary to its antihypertensive effect [27]. In addition, none of the participants discontinued Esax administration because of renal dysfunction. SGLT2 inhibitors induce similar decreases in eGFR, and long-term effects, including a reduction in UACR and the prevention of end-stage renal disease, have also been reported [28-33]. We have shown that Esax causes an initial decrease in eGFR, but the long-term preservation of eGFR has also been reported [34], suggesting that it may have a renoprotective effect similar to that of SGLT2 inhibitors.
The present study had several limitations. First, its retrospective observational design may introduce potential biases. Although we attempted to limit the disadvantages by employing propensity score matching to create a control group with compatible baseline characteristics, certain confounding variables remained challenging to control. Specifically, lifestyle factors including diet, physical activity, and alcohol consumption could not be adequately adjusted in the analysis. Second, the sample size was relatively small. Third, the treatment period was relatively short; therefore, longer-term studies should be performed to confirm the present findings. Finally, because it was not a prospective controlled study, the antihypertensive drugs were administered at doses determined by the treating physician.
In conclusion, Esax has a larger antihypertensive effect and reduces UACR more effectively than Amlo in hypertensive subjects with T2D or prediabetes, implying that it is useful for subjects with diabetes. In addition, the pleiotropic effects of Esax include reductions in the high circulating liver enzyme activities of such subjects (Graphical Abstract).
Kuwabara S analyzed the data and wrote the manuscript. Kameda H contributed to the design of the study and the data analysis and wrote the manuscript. Yokozeki K, Miya A, Nomoto H, Cho KY, Nakamura A, and Atsumi T contributed to the interpretation of the results and manuscript revision. Koyanagawa N, Yamamoto K, Takeuchi J, Nagai S, Miyoshi A, Wada N, Taneda S, and Kurihara Y assisted with the data collection and manuscript revision.
We thank all the subjects and staff who participated in this study. We also thank Mark Cleasby, PhD from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. The authors declare the following financial interests/personal relationships that may be considered to be competing interests. Kameda H, Nomoto H, Nakamura A, Taneda S, Kurihara Y, and Atsumi T have received honoraria for lectures and/or research funding from the organizations listed below. The other authors declare no conflicts of interest. Kameda H received honoraria for lectures from Daiichi Sankyo Co., Ltd. Nomoto H received research grants from Kowa Pharmaceutical Co., Ltd., and honoraria for lectures from Novo Nordisk Pharma and Sumitomo Pharma Co., Ltd. Nakamura A received honoraria for lectures from Novo Nordisk Pharma and research support from Kowa Pharmaceutical Co., Ltd. Taneda S received honoraria for lectures from Eli Lilly Japan, Novo Nordisk Pharma, and Sumitomo Pharma Co., Ltd. Kurihara Y received honoraria for lectures from Taisho Pharmaceutical Holding, Eli Lily Japan, and Sumitomo Pharma Co., Ltd. Atsumi T received research grants from Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Pfizer Inc., Alexion Inc., Ono Pharmaceutical Co., Ltd., and Teijin Pharma Limited; speaking fees from Mitsubishi Tanabe Pharma Co., Chugai Pharmaceutical Co., Ltd., Astellas Pharma Inc., Takeda Pharmaceutical Co., Ltd., Pfizer Inc., AbbVie Inc., Eisai Co., Ltd., Daiichi Sankyo Co., Ltd., Bristol Myers Squibb Co., UCB Japan Co., Ltd., Eli Lilly Japan K.K., Novartis Pharma K.K., Kyowa Kirin Co., Ltd., and Taisho Pharmaceutical Co., Ltd.; and fees for consultancies from AstraZeneca plc., Medical & Biological Laboratories Co., Ltd., Pfizer Inc., AbbVie Inc., Ono Pharmaceutical Co., Ltd., Novartis Pharma K.K., and Nippon Boehringer Ingelheim Co., Ltd.
The data obtained during the study will be made available by the corresponding author upon reasonable request.
