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Abstract

Background:

Recently, the role of aldosterone in metabolic syndrome (MS) has aroused interest and several reports have suggested that aldosterone blockade could be beneficial in reducing blood pressure (BP).

Methods:

To examine the add-on effects of eplerenone (EP) on BP in patients with MS, 54 hypertensive patients with MS and 44 without MS were recruited. Systolic and diastolic BPs in mmHg before the initiation of EP was 144/84 ± 13/12 (MS group) and 147/85 ± 12/14 (non-MS group). Before the start of EP, all patients in both groups were treated with at least one antihypertensive drug. BPs were checked on every visit (at least every 2 months) and serum chemistries were measured every 4 months. The levels of microalbuminuria and aminoterminal pro-brain natriuretic peptide (NT pro-BNP) were determined before the start of and at the end of the study. Patients were followed for 1 year. If adverse effects were reported by patients or found in laboratory studies, EP was withdrawn.

Results:

One month after the start of EP, BPs were decreased to 140/80 ± 12/12 mmHg (MS group) versus 142/82 ± 11/12 mmHg (non-MS group) and there was no difference between the two groups. Towards the end of the study, BPs of both groups gradually decreased. At the end of the study, BPs of both groups were 129/76 ± 15/13 mmHg (MS group) versus 133/78 ± 13/11 mmHg (non-MS group). There was a significant difference in reduction of systolic BP between the two groups (p < 0.05). Add-on EP significantly decreased the levels of urinary excretion of albumin in MS patients but not in non-MS patients (p < 0.05). There was a significant correlation between reduction of systolic BP and NT pro-BNP but not microalbuminuria in the MS group (p < 0.05). There were no serious adverse effects in both groups.

Conclusion:

EP may have some beneficial effects in lowering BP in patients with reduction of microalbuminuria.

Keywords

aldosterone blocker angiotensin receptor antagonist calcium channel blocker metabolic syndrome renin–angiotensin–aldosterone system

Introduction

Eplerenone (EP), a selective aldosterone blocker, has a low binding affinity for androgen and progesterone receptors, and has demonstrated antihypertensive efficacy in several studies [Burgess et al. 2003]. Originally, EP was used for patients with congestive heart failure and the Eplerenone Post-AMI Heart Failure Efficacy and Survival Study (EPHESUS) demonstrated that mortality, risk of hospitalization and the onset of cardiovascular events decreased significantly after adding EP in patients suffering from acute myocardial infarction complicated with left ventricular dysfunction [Pitt et al. 2003]. Recently a number of studies revealed that aldosterone independently promoted potassium and magnesium loss, sodium retention, ventricular fibrosis and that these effects were mediated by the action of aldosterone on mineralocorticoid receptors in the kidney, brain, heart and vasculature [Miller and Srivastrava, 2001; McMahon, 2001].

In addition, recent studies of both clinical and basic research proposed a close relation between aldosterone and MS [Briet and Schiffrin, 2011]. Metabolic syndrome (MS), a cluster of cardiovascular risk factors including impaired glucose homeostasis, atherogenic dyslipidemia, obesity and hypertension, is closely related to insulin resistance. Activation of the renin–angiotensin–aldosterone (RAA) system is linked to insulin resistance [Manrique et al. 2009]. The close relationship between insulin resistance and an inappropriately overactive RAA system in the pathogenesis of essential hypertension has been recognized for a long time [Modan and Halkin, 1991; Sowers et al. 2009]. Kidambi and colleagues demonstrated that in Black patients with essential hypertension, plasma aldosterone concentrations were significantly higher in the group with MS in spite of no difference in plasma renin activity between the groups with or without MS [Kidambi et al. 2007]. A number of studies have shown the effectiveness of spironolactone or EP in combination with other antihypertensive agents, when administered as add-on therapy in patients with hypertension that had failed to respond to monotherapy with other drugs [Krum et al. 2002; Sharabi et al. 2006; Sato and Fukuda, 2010; Vaclavik et al. 2011]. Moreover, Croom and Perry introduced data from a couple of studies in their review article that showed add-on spironolactone was effective for obese patients with uncontrolled hypertension [Croom and Perry, 2005]. Previously, Sato and Fukuda proposed that EP may be effective in hypertensive patients with MS based on their findings [Sato and Fukuda, 2010]. From these previous studies, it is likely that add-on EP might be effective in obese patients whose blood pressures (BPs) were not lowered to satisfactory levels with angiotensin receptor blockers (ARBs) or calcium channel blockers (CCBs) or both in combination. To examine this possibility, this study was designed to examine the safety and antihypertensive efficacy of EP.

Methods

This study was a prospective, multicenter and parallel-group trial. All patients that had been treated with either ARBs or CCBs or both in combination without achieving the target BP levels less than 140/90 mmHg were enrolled in this study. The target BP was under 140/90 mmHg. Patients with confirmed hyperaldosteronism or clinically suspected of having other causes of secondary hypertension were not included. After an initial workup, patients received EP 25 mg once every morning and if BP was not reduced below 140/90 mmHg at week 8, a dose of EP was increased to 50 mg once daily. Follow-up outpatient visits were scheduled at 2 weeks while BP was reduced below 140/90 mmHg. Visits continued at every 4 weeks for 48 weeks of treatment. If BP remained uncontrolled at week 12, the patients were withdrawn from the study. The clinic BP was measured in duplicate in the seated position at all visits. The two studies were conducted separately:

Study 1. Nonobese subjects were recruited.

Study 2. Subjects with MS were recruited.

MS was diagnosed according to the criteria established by the examination Committee of Criteria for Metabolic Syndrome in Japan. MS is defined for subjects with a waist circumference of >85 cm in men and >90 cm in women (essential criteria), and with at least two of the following three factors: serum triglycerides >150 mg/dl and/or high-density lipoprotein cholesterol <40 mg/dl; systolic BP >130 mmHg and/or diastolic BP >85 mmHg; fasting plasma glucose >110 mg/dl.

Study assessments

Hematology and biochemistry evaluations and urinalysis were conducted at 0, 4, 8, 12, 24 and 48 weeks after the start of administration of EP. At the start of and at the end of the study, the levels of microalbuminuria and aminoterminal pro-brain natriuretic peptide (NT pro-BNP) were measured. For determinations of mircoalbuminuria, a first morning voided spot urine sample for microalbumin (measured as the urinary albumin–creatinine ratio [UACR]) was collected and those of NT pro-BNP were measured by the Elecsys pro-BNP assay on an Elecsys 2010 instrument (Roche Diagnostics).

Statistics

All analyses were performed using SAS version 6.12.

Descriptive statistics were used for demographic and baseline characteristics, and for efficacy and safety measurements. Continuous variables were described using mean and standard deviation. The statistical significance of differences between study groups was analyzed using the Mann–Whitney U-test for continuous variables. Differences among MS and non-MS groups were evaluated by analysis of variance and with the chi-squared test. Association between changes in systolic and diastolic BP and delta microalbuminuria and NT pro-BNP were analyzed using linear regression analysis. p-values <0.05 were regarded as statistically significant.

Results

Patient disposition and baseline characteristics

The basic characteristics of the subjects are shown in Table 1. There were no differences in age, and systolic and diastolic BPs between the two groups. However, the differences in body mass index and waist circumference were significant. In Table 2, basal laboratory data are shown. There were no differences in serum creatinine, uric acid, serum potassium and hemoglobin A1c. However, differences in triglyceride and high-density lipoprotein were significant.

Table 1.

Characteristics of patient.

	Metabolic (n=54)	Nonmetabolic (n=44)	p-value
Age (years)	60.3±9.0	61.9±10.2	ns
BMI (kg/cm²)	26.9±2.2	21.8±1.8	0.03
Gender (F/M)	20/34	20/24	ns
Waist Circumference (cm)	F:91.5±0.2 M:88.4±2.1	F:81.6±1.4 M:83.2±1.2	F:.001 M:0.03
SBP (mmHg)	146±14	145/14	ns
DBP(mmHg)	83±14	85±13	ns

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 2.

Basal laboratory data of patients.

	Metabolic (n=54)	Nonmetabolic (n=44)	p-value
Serum creatinine (mg/dl)	0.69±0.16	0.66±0.22	ns
Triglyceride (mg/dl)	196±18	127±16	0.05
Uric acid (mg/dl)	7.1±0.8	6.9±1.0	ns
High-density lipoprotein (mg/dl)	37±1	42±6	0.05
Fasting glucose (mg/dl)	116±8	101±6	0.05
Serum potassium (mEq/l)	4.0±0.4	4.1±0.4	ns
HbA1C (%)	5.4±0.8	5.6±0.9	0.06

In patients with MS, 26 were receiving an ARB, 14 were taking CCBs and 14 were taking both ARB and a CCB in combination. In patients without MS, 14 were receiving an ARB, 8 were taking CCBs and 22 were taking both ARB and a CCB in combination. In patients with MS, ARBs including those used in combination with CCBs were losartan (16), valsartan (6), candesartan (6) and telemisartan (12). In patients without MS, ARBs used were losartan (6), valsartan (12), candesartan (14) and telemisartan (4). Amlodipine (4) and benidipine (24) in MS patients and amlodipine (6) and benidipine (24) in non-MS patients were the most commonly used CCBs.

A total of 25 patients did not complete the study, including 10 in the MS group and 15 in the non-MS group because of failure to achieve target blood pressure of less than 140/90 mmHg.

Changes in BP

At week 12, BPs of 46/54 (85%) MS patients and 29/44 (66%) of non-MS patients were reduced to less than 140/90 mmHg.

In MS patients who received ARBs, add-on EP effects on BP were remarkable, but in non-MS patients who received ARBs, BP reduction was not remarkable.

In Figure 1A and B, serial changes are shown of systolic and diastolic BPs. In both groups, systolic BPs were reduced significantly from the 0 time starting level at 2 months and continued to decrease to the end of the study (p < 0.01). At the end of the study, the differences in systolic BP between the two groups became significant (p < 0.05).

Figure 1.

(A) Systolic blood pressure of both groups significantly decreased from 2 months, and maintained this difference to the end of the study and finally there was a significant difference between the two groups at 1 year. (B) Diastolic blood pressure of both groups significantly decreased toward the end of the study at 9 months, and finally there was a significant difference between the two groups to the end at 1 year.

Figure 2.

Before the start of the study, the levels of urinary albumin excretion were significantly greater in patients with metabolic syndrome (MS) than in those with non-MS. At 1 year, the excretion level was still greater in the MS group than in the non-MS group. In addition, the levels in the MS group but not in the non-MS group were significantly lower than before the start of the study.

Figure 3.

Before the start of the study, the levels of NT pro-BNP were significantly greater in patients with metabolic syndrome than in those with nonmetabolic syndrome. At 1 year, this level was still greater in the metabolic syndrome (MS) group than in the non-MS group. In addition, the levels in MS group were significantly lower than before the start of the study.

Figure 4.

Illustration of significant correlations between systolic blood pressure and NT pro BNP in patients with MS.

The levels of diastolic BP tended to decrease and achieved a significant reduction at 6 months after the start of EP (p < 0.05), and maintained this significance until the end of the study. There were significant differences (p < 0.05) in diastolic BP between the two groups at the end of the study.

Changes in microalbuminuria

At the start of the study, the levels of urinary excretion of albumin in MS patients were significantly higher than in non-MS patients (p < 0.05). Add-on EP significantly decreased the levels of urinary excretion of albumin in MS patients but not in non-MS patients (p < 0.05). There were no significant association between reduction of systolic and diastolic BP and delta microalbuminuria both in MS and non-MS patients.

Changes in NT pro-BNP

At the start of the study, the levels of NT pro-BNP in MS patients were significantly higher than in non-MS patients (p < 0.05). Add-on EP significantly decreased the levels of NT pro-BNP in MS patients but not in non-MS patients (p < 0.05). There was a significant association between reduction of systolic and diastolic BP and delta NT pro-BNP in MS but not in non-MS patients (p < 0.05).

Adverse events

The most common adverse events that emerged during treatment were headache and nausea, which however disappeared in spite of continued administration of EP.

Gynecomastia, breast tenderness and menstrual irregularities were not reported. No clinical consequences of elevations in serum potassium levels were reported during EP treatment in the present study.

Discussion

This study demonstrated that add-on antihypertensive therapy with EP was effective in both groups of patients with or without MS. Although there were no differences in responder rate between the two groups, at the end of the study, the addition of EP resulted in greater reduction of both systolic and diastolic BPs in patients with MS than in those patients without MS. Moreover, EP reduced significantly both NT pro-BNP and microalbuminuria in MS patients.

Recently, several small, uncontrolled trials showed the positive effect of spironolactone or EP in lowering BP in patients with resistant arterial hypertension [Ouzan et al. 2002; Nishizaka et al. 2003; Lane et al. 2007]. In the present study, add-on EP produced BP reduction in patients receiving any of the antihypertensive treatments with ARBs, CCBs or both in combination. Krum and colleagues reported that in patients whose BP was not controlled with an angiotensin converting enzyme (ACE) inhibitor or ARB, the addition of EP over an 8-week period significantly lowered systolic BP as well as diastolic BP [Krum et al. 2002]. Also, as preliminary data, the addition of EP reduced BP in patients whose hypertension was uncontrolled on CCBs or β-adrenoceptor antagonists [Croom and Perry, 2005]. In the present study, benidipine was predominantly used as a CCB for no specific reason. Recent experimental data have shown that benidipine directly inhibits aldosterone-induced mineralocorticoid receptor activation, and the antagonistic activity might contribute to the pleiotropic pharmacological features of the drug [Kosaka et al. 2010]. From the experimental and clinical study [Matsuzaki et al. 2011], unknown effects of benidipine might be contributing to add-on EP reduction of BP by benidipine.

Studies in healthy volunteers [de Gasparo et al. 1989] showed that aldosterone mediated changes in sodium/potassium ratio were blocked by a mineralocorticoid receptor antagonist leading to natriuresis with increased sodium excretion and reduced potassium excretion. In addition to the diuretic effect of spironolactone or EP [Pitt, 2004; Reyes et al. 2005], the reduction of vascular stiffness probably plays a major role in patients with resistant hypertension, and contributes to reducing systolic BP because aldosterone promotes renal sodium retention, potentiates the actions of Ang II, impaired endothelial function and reduces vascular compliance [Schrier et al. 2010; Briet and Schiffrin, 2011].

Recently, Bao and colleagues demonstrated that low NT pro-BNP levels were associated with almost all components of the MS except elevated systolic BP, which was associated with higher plasma NT pro-BNP levels [Bao et al. 2011], although several previous studies reported that NT pro-BNP are significantly decreased in patients with MS [Wang et al. 2007; Li et al. 2011]. In the present study, the basal values of NT pro-BNP were significantly higher and EP reduced them significantly. In addition, there was a significant association between reduction of systolic BP and delta changes in NT pro-BNP in MS patients. Combined the previous findings with our present data, the levels of NT pro-BNP are higher and its reduction will associate with decreases in systolic BP in MS patients with hypertension.

In the present study, we evaluated the effects of EP on microalbuminuria. Previously several studies have shown that EP at dosages of 50–200 mg once daily reduced proteinuria in patients with hypertension [White et al. 2003; Flack et al. 2003]. Two studies found that administration of EP for 24 weeks to patients with mild-to-moderate hypertension who had elevated microalbuminuria at baseline resulted in reduced urinary excretion of microalbumin, which was significantly greater than with enalapril [Flack et al. 2003; Williams et al. 2004]. Moreover, a combination of EP plus enalapril reduced microalbuminuria to a greater extent than either EP or enalapril alone [Williams et al. 2004]. In the present study, the baseline levels of urinary excretion of albumin were greater in patients with MS than in those without MS. After add-on EP, the levels of urinary excretion of albumin in MS patients were reduced significantly. Also, it is known that patients with MS have significantly higher prevalence of microalbuminuria than those without MS [Chen et al. 2004]. From these findings, add-on EP might be effective in reducing microalbuminuria in hypertensive patients with MS whose BPs were uncontrolled in spite of administering ARBs or CCBs, or both in combination. Moreover, it is suggested that the combination of ARB and EP is effective for MS patients in reducing BP and for organ protection.

Study limitations

Some limitations of this study need to be highlighted. First, the population sample was too small to draw clinically significant conclusions. Second, this study was carried out as a prospective and open-label trial, but randomization was not included. From these caveats, the recommendations that add-on EP for patients with MS whose BPs were not controlled with ARBs, or ARBs and CCBs in combination will await until confirming these findings by a relatively large prospective controlled study.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflicts of interest in preparing this article.

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Eplerenone,an aldosterone blocker,is more effective in reducing blood pressure in patients with,than without,metabolic syndrome

Abstract

Background:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Study assessments

Statistics

Results

Patient disposition and baseline characteristics

Changes in BP

Changes in microalbuminuria

Changes in NT pro-BNP

Adverse events

Discussion

Study limitations

Footnotes

Funding

Conflict of interest statement

References