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Comparison of Rilmenidine and Lisinopril on Ambulatory Blood Pressure and Plasma Lipid and Glucose Levels in Hypertensive Women With Metabolic Syndrome

Posted on: Thursday, 17 March 2005, 03:00 CST

Key words: Ambulatory blood pressure monitoring - Glucose metabolism disorders - Lipoproteins - Lisinopril - Metabolic syndrome X - Rilmenidine

ABSTRACT

Objective: In previous studies, the I^sub 1^ imidazoline specific agonist rilmenidine effectively lowered office blood pressure (BP) in patients with metabolic syndrome, improved glucose metabolism and did not demonstrate unfavourable effects on plasma lipids. The aim of the present study was to investigate the effects of 12 weeks' therapy with rilmenidine compared with the ACE inhibitor lisinopril on ambulatory BP, plasma lipid and fasting glucose levels in women with metabolic syndrome.

Research design: Prospective randomised open-label, blinded end- points study.

Methods: Female patients (n = 51) with hypertension and other components of metabolic syndrome were treated with 1 mg rilmenidine (n = 24) or 10mg lisinopril (n = 27), once- or twice-daily. Anthropometric measurements, office BP and heart rate (HR) measurements, ambulatory BP monitoring, lipid and fasting glucose assessment were performed before and after 12 weeks of treatment.

Main outcome measures: Changes in ambulatory BP and HR, including 24-h, daytime and night-time values, and in lipids and glucose levels. All changes were adjusted for baseline values using the analysis of covariance method.

Results: Ambulatory 24-h systolic BP and diastolic BP were decreased significantly in the rilmenidine group (-11.9 1.9 and - 7.7 0.8 mm Hg, p < 0.001) respectively and the lisinopril group (- 11.0 1.8 and -6.7 0.7 mm Hg respectively, p < 0.001). There were no significant differences between the two groups. Rilmenidine reduced 24-h ambulatory HR (-3.6 0.8bpm versus 0.3 0.8 bpm with lisinopril; p = 0.002). The reductions of day-time and night-time BP were also significant for both treatment groups, but the rilmenidine group demonstrated a greater decrease in night-time diastolic BP (p = 0.046). Rilmenidine significantly increased HDL cholesterol and decreased fasting glucose levels (p = 0.009 and p = 0.012, respectively). HDL cholesterol tended to increase and fasting glucose tended to decrease in the lisinopril group. However, differences between groups were not significant.

Conclusion: Rilmenidine has similar effects on ambulatory BP patterns in hypertensive women with metabolic syndrome as lisinopril. Rilmenidine compared with lisinopril significantly reduces ambulatory HR. In this study, rilmenidine and lisinopril demonstrate similar effects on plasma lipid and fasting glucose levels.

Introduction

Arterial hypertension is an established cardiovascular risk factor in women1,2. Hypertension, abdominal obesity, increased triglycerides, decreased high-density lipoprotein (HDL) cholesterol and glucose intolerance are features of the metabolic syndrome, which are closely related to insulin resistance3. Analysis of data from the NHANES III (Third National Health and Nutrition Examination Survey] shows, that the prevalence of the metabolic syndrome among US adults was similar for women (22.6%) and men (22.8%)4. Clustering of more than 3 metabolic risk factors is associated with a coronary heart disease relative risk of 5.90 (95% confidence interval 2.54- 13.73) for women and 2.39 (1.56-3.66) for men5.

As hypertensive patients with the metabolic syndrome are at high risk of cardiovascular disease, antihypertensive therapy is required in most cases6. Current guidelines recommend all effective and well- tolerated antihypertensive agents in patients with diabetes and metabolic syndrome7,8. Centrally acting drugs binding specifically to I^sub 1^ imidazoline receptors in the rostral ventrolateral medulla offer an innovative therapeutic approach to the treatment of hypertension with metabolic disturbances9. Rilmenidine is a representative of this new class of agent rilmenidine that reduces central sympathetic drive and attenuates peripherical vascular resistance10,11. Previous studies have shown that rilmenidine effectively lowered office BP in hyperlipidemic hypertensives12 and in patients with the metabolic syndrome13. Treatment with rilmenidine improves glucose metabolism13 and does not demonstrate any unfavourable effects on lipid metabolism12. A recent retrospective analysis supports the use of rilmenidine in a population of hypertensive diabetic patients14. However, studies using ambulatory blood pressure monitoring (ABPM) with rilmenidine were conducted in a non-comparative design.

The primary objective of the present study was to compare effects of the I^sub 1^ imidazoline specific agent rilmenidine and the angiotensin converting enzyme (ACE) inhibitor lisinopril on ABPM in hypertensive women with the metabolic syndrome. The secondary objective was to assess the influence of both drugs on the plasma lipid profile and fasting glucose levels in these patients.

Methods

Study population

The present study was conducted in a single centre. Patients included in the study were recruited from our outpatient clinic between January 2002 and June 2002. Inclusion criteria at screening were age from 35 years to 65 years, female gender, association of hypertension (systolic BP [SBP] ≥ 130mm Hg and/or diastolic BP [DBP] ≥ 85mm Hg) and at least two other features of the metabolic syndrome according to new Adult Treatment Panel III (ATP III) definition16, including waist circumference > 88cm; triglycerides ≥ 1.69 mmol/ L (≥ 150mg/dL); HDL cholesterol < 1.29mmol/L (< 50mg/dL) and fasting glucose ≥ 5.6mmol/L (≥ 100mg/dL). Additional inclusion criterion was 24- h ambulatory BP level after the washout period: SBP > 130mm Hg and DBP > 80mm Hg17.

Exclusion criteria were: known or expected secondary hypertension, cardiovascular events in history, arrhythmias, uncontrolled or insulin-dependent diabetes mellitus, congestive heart failure, hepatic disease, renal disease (or serum creatinine level > 0.11 mmol/L) and lack of a reliable method of contraception for fertile women.

At screening all patients were subjected to a careful clinical history and physical examination. Sixty-two patients who fulfilled the inclusion criteria were identified. Five patients did not provide informed consent. Two patients did not finish the washout period as a result of apparent BP elevation. Four patients had 24-h ambulatory systolic BP < 130mm Hg and diastolic BP < 80mm Hg before randomisation and were excluded. Thus, in total 51 patients were included in the study.

Study design

The prospective randomised open-label, blinded end-point design18 was chosen because the primary objective of our study was to assess treatment effects on automatically analysed ambulatory BP. This design for ABPM based studies has been validated (in comparison with the double-blind method) in meta-analysis of Smith et al.19.

After the screening examination, previous antihypertensive drugs were withdrawn for 2 weeks. After the washout period, patients were randomised by computer to open-label therapy with rilmenidine (Albarel, Egis, Budapest, Hungary under licence from Servier, Neuillysur-Seine, France) 1 mg once a day in the morning hours or lisinopril (Diroton, Richter, Budapest, Hungary) 10 mg once a day. If office DBP was ≥ 90 mm Hg after 4 weeks, the study drug dose was doubled. In this case, rilmenidine (1 mg) or lisinopril (10mg) were administrated twice a day (morning and evening). At the 4-week and 12-week visits office BP was measured approximately 2h- 3h after taking the study drugs.

Anthropometric measurements, office BP and HR measurements, ABPM, plasma lipid and fasting glucose measurements were performed before and after 12 weeks of treatment.

The study protocol was approved by the Ethics Committees of the Russian State Medical University. Informed consent was obtained and signed by all patients.

Measurements and calculations

Anthropometric measurements

Body mass index (BMI) was calculated using the formula BMI = body weight (kg)/height^sup 2^ (m^sup 2^). Waist circumference was measured mid-way between the lower rib margin and the iliac crest.

Office BP and HR measurements

Sitting BP was measured by standard sphygmomanometer to the nearest 5 mm Hg. Three consecutive systolic and diastolic BP measurements were taken 2min apart. The BP measurements recorded were the mean of the three measurements. Resting HR was obtained by palpation of the left wrist of subjects during a 1-min interval.

ABPM

All subjects underwent 24-h ABPM with a non-invasive oscillometric device (ABPM-04, Meditech Ltd., Budapest, Hungary)20, using an adapted cuff size: normal or large. BP was measured every 15 min during the day and every 30 min during the night. The nighttime period was defined as the interval from 11:00 pm to 7:00 am and was corrected according to the patient's diary. ABPM data were stored and analysed with MEDIBase 1.42R software (Meditech Ltd., Budapest, Hungary).

Laboratory tests

Blood samples were taken between 8:30 am and 9:30 am after a 12- h fast. Plasma lipids were measured on the Express Plus 550 analyser (Ciba-Corning, Halsted, Essex, England). Enzymatic methods were used in the determination of total cholesterol and triglycerides (CHOL FS and TG FS kits, DiaSys, Holzheim, Germany). Plasma HDL cholesterol was determined after precip\itation of LDL and VLDL using HDL- cholesterin (precipitant) and CHOL FS kits. LDL cholesterol was calculated by the Friedewald Equation21. Fasting plasma glucose was determined by the glucose oxidase/peroxidase method (BioSystems S.A., Barcelona, Spain). All laboratory tests were carried out by one investigator (OVS) blinded for treatment regimen.

Statistical analysis

The size of the study population was calculated assuming a clinically important difference between groups in 24-h diastolic BP changes of 5mm Hg (standard deviation [SD] 8mm Hg) after 12 weeks of therapy. At a significance level of 0.05 and study power of 0.80, 24 patients per group were required.

Data are presented as mean values (SD) for baseline values or mean values standard error of the mean (SEM) with 95% confidence intervals in brackets for changes in parameters. Variables were assessed for normality by Shapiro-Wilk's test. To compare baseline characteristics of the two study groups, data were analysed by two- tailed unpaired Student's t-test. The chi-square (χ^sup 2^) test was used for categorical data. Treatment effects from baseline in each group were analysed using a paired Student's t-test or Wilcoxon matched pairs test as appropriate. In order to take into account baseline values of all parameters, the analysis of covariance (ANCOVA) for comparison between groups was performed. Additionally, the Mann-Whitney U test was used for comparison unadjusted changes in lipid and glucose levels between groups. All statistical tests were carried out to a significance level of 0.05. The data were analysed using STATISTICA 6.0 for Windows package (StatSoft, Inc., Tulsa, OK, USA).

Results

Demographic data and baseline characteristics for the study groups are given in Table 1. There were no significant differences between groups. Baseline ABPM and HR were also comparable (Table 2). Following randomisation, 1 patient in the lisinopril group discontinued due to adverse event (intense coughing). Thus, 50 patients completed the 12-week study. However, one patient from the rilmenidine group was excluded from the database due to unusual changes in ambulatory HR (-29bpm) and the total number of patients included in the analysis was 49.

Doses after 4 weeks of treatment were doubled in 18 of the 23 patients (78%) in rilmenidine group and in 15 of the 26 patients (58%) in the lisinopril group (χ^sup 2^ = 2.35, p = 0.126).

Ambulatory systolic BP and diastolic BP were significantly reduced in both treatment groups (-11.0 1.8 [-14.8, -7.3]/-6.7 0.7 [-8.2, -5.2] mmHg with lisinopril and -11.9 1.9 [-15.7, -8.0]/-7.7 0.8 [-9.3, -6.2] mm Hg with rilmenidine, Figure 1). There was no significant difference between the groups. Interestingly, 24-h ambulatory HR significantly decreased in the rilmenidine group (- 3.6 0.8 [-5.2, -1.9] bpm), but not in the lisinopril group (0.3 0.8 [-1.3, 1.8]bpm). The difference between groups was significant (Figure 1).

The reductions of daytime and nighttime BP and HR were also significant for both treatment groups (Figure 2). The nighttime DBP decrease in the rilmenidine group was slightly greater than that noted for lisinopril, but this difference was of borderline significance (p = 0.046). The differences between the groups in HR changes were significant for daytime values (p = 0.007) and approached significance for nighttime values (p = 0.087).

Table 1. Baseline characteristics of the patients

Table 2. Baseline ambulatory blood pressure and heart rate values

Figure 1. Adjusted changes from baseline in 24-h blood pressure and heart rate by 12-week treatment with lisinopril and rilmenidine (mean values SEM). Significance levels of changes from baseline are p < 0.001 (by paired t-test), differences between the two study drugs are shown (by ANCOVA). SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate

Figure 2. Adjusted changes from baseline in daytime and nighttime blood pressure and heart rate by 12-week treatment with lisinopril and rilmenidine (mean values SEM). Significance levels of changes from baseline are p < 0.001 (by paired t-test), differences between the two study drugs are shown (by ANCOVA). SBP = systolic blood pressure; DBP = diastolic blood pressure; HR = heart rate

Office SBP and DBP were significantly decreased from baseline for both rilmenidine (-19 3/-10 2mm Hg) and lisinopril (-26 3/-10 2mm Hg). There was no significant difference between the two groups by the end of the observation period, despite a tendency in favour of lisinopril. HR was not affected in either of the treatment groups (adjusted changes 1.3 0.7 bpm in the rilmenidine group and -0.4 0.7 bpm in the lisinopril group) and there was no significant difference between groups (p = 0.103; by ANCOVA).

Baseline lipids and fasting glucose levels are shown in Table 3. Changes in lipid and glucose parameters are presented in Table 4. Lisinopril did not significantly change any parameter, although HDL cholesterol tended to increase and fasting glucose tended to decrease. Rilmenidine significantly increased HDL cholesterol and decreased fasting glucose levels (p = 0.009 and p = 0.012, respectively, by Wilcoxon matched pairs test). However, differences between groups were not significant for all parameters before and after adjusting for baseline values (Table 4).

Body weight and waist circumference remain unchanged in the both groups (lisinopril: weight from 90 (14) kg to 90 (13) kg, waist circumference from 106 (10) cm to 105 (11) cm; rilmenidine: weight from 88 (10) kg to 87 (11) kg, waist from 103 (10) cm to 102 (9) cm; data are presented as mean values (SD); all differences from baseline were tested by paired t-test).

Table 3. Baseline lipids and fasting glucose levels

Discussion

The present study has demonstrated that in hypertensive women with the metabolic syndrome, treatment with the I^sub 1^ imidazoline specific agonist, rilmenidine, for 12 weeks led to a similar decrease in 24-h ambulatory BP as was achieved with treatment with the ACE inhibitor, lisinopril. On searching the MEDLINE database, comparative studies of rilmenidine and ACE inhibitors with ABPM were not found. However, a similar reduction in 24-h ABPM has been observed with lisinopril by other authors using ABPM in hypertensive patients22,23.

Table 4. Changes from baseline in lipid and fasting glucose levels by a 12-week treatment with lisinopril and rilmenidine

Previous double-blind, randomised studies in hypertensives with metabolic abnormalities demonstrated that rilmenidine treatment leads to a similar office BP reduction as that achieved using the ACE inhibitor captopril12'24 or the calcium antagonist, amlodipine13. In the present study, changes in office BP values were more prominent in the lisinopril group, although the difference was of borderline significance. Patients' and physicians' prior knowledge of treatment allocation may explain these data25. Moreover, office BP changes may be influenced by the placebo effect, in contrast with ambulatory BP26. This may help explain the variation recorded for measurements of office BP. Importantly, that primary objective of the study was to assess ambulatory, not office BP changes.

Treatment with rilmenidine significantly decreased 24-h ambulatory HR suggesting a decrease in sympathetic activity. Recently, Esler et al.27 have studied the sympatholytic and BP- lowering effects of rilmenidine in hypertensive patients. The authors observed an intraarterial BP decrease of 15/7 mm Hg with rilmenidine and a reduction in norepinephrine spillover rate, indicative of whole body sympathetic activity, by 35% without affecting adrenaline release. Therefore, a parallel 24-h BP and HR reduction by rilmenidine may reflect a decrease in sympathetic activity.

We also observed the divergence between HR and 24-h ambulatory HR changes which may be explained by better reproducibility with the ABPM recorder28. On the other hand, reduction of 24-h HR may be linked with a decrease in the 24-h load on the arterial wall29. It has been shown that 24-h ambulatory HR, but not office HR, closely correlates with the carotid-femoral pulse wave velocity in hypertensive women older than 50years30. Consequently, a reduction in ambulatory HR by rilmenidine in our female patients (mean age 5 3 years) may also be a result of the arterial wall load decrease and this may be a clinically relevant benefit.

Lisinopril did not influence the 24-h HR in our study. These data may be explained in context with results of the study by Grassi et al.3]. These authors have demonstrated that plasma norepinephrine and muscle sympathetic nerve activity were not affected by lisinopril treatment.

Both study drugs significantly reduced day-time and night-time ABPM. Rilmenidine, compared with lisinopril, more markedly influenced night-time DBP and HR. However, these differences were at borderline significance level and may be due to a dose effect (in 78% of patients in the rilmenidine group, the dose was doubled at week 4 versus 58% in the lisinopril group).

Previous studies did not demonstrate an unfavourable effect of rilmenidine on lipid metabolism12,13. In our study, HDL cholesterol significantly increased in the rilmenidine group and tended to increase in the lisinopril group, but the differences in lipid changes between groups were non-significant. The effect of rilmenidine and lisinopril on HDL cholesterol level may be caused by sympathetic activity decrease and/or insulin sensitivity increase32,33.

Fasting plasma glucose decreased in the rilmenidine group (significantly) and in the lisinopril group (tended to significant change). The reduction in fasting glucose levels by rilmenidine and by lisinopril have also been observed by others23'13. The mechanism of these changes may be due to enhanced sensitivity to insulin. It has been shown that rilmenidine increased insulin sensitivity in an anim\al model of insulin resistance34. Haenni et al.35 demonstrated a decrease in insulin resistance by another I^sub 1^ imidazoline receptor agonist moxonidine in human hypertension. It has been also shown that lisinopril decreased insulin levels36 and significantly increased glucose infusion rate, as an indicator of insulin sensitivity, in hypertensives37. However, other authors have not confirmed these data38,39.

Although prospective randomised open-label, blinded end-point design yields the same results as double-blind, placebo-controlled studies with respect to ABPM measurements19, our data on plasma lipid and glucose values should be confirmed in double-blind, placebo-controlled studies with a larger sample size.

Conclusions

In conclusion, the I^sub 1^ imidazoline receptor agonist rilmenidine has the same effects on ABPM in hypertensive women with metabolic syndrome as the ACE inhibitor, lisinopril. Rilmenidine compared with lisinopril, significantly reduces ambulatory HR. In this study, rilmenidine and lisinopril demonstrate similar effects on plasma lipid and fasting glucose levels. On the basis of these clinical results, rilmenidine seems to be an appropriate antihypertensive treatment for middle-aged hypertensive women having metabolic syndrome. However, further studies should be carried out to confirm these findings.

Acknowledgements

The authors express gratitude to Moscow Representatives of Egis and Richter for the drugs used in this trial, and to Les Laboratoires Servier, Paris for their support in the preparation of this manuscript. The authors also thank Mrs Stella Bystrova for technical assistance in English manuscript preparation.

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CrossRef links are available in the online published version of this paper: http://www.cmrojournal.com

Paper CMRO-2830_2, Accepted for publication: 10 December 2004

Published Online: 24 December 2004

doi: 10.1185/030079904X20277

Dmitrii A. Anichkov(a), Nadezhda A. Shostak(a) and Olga V. Schastnaya(b)

a Department of Faculty Therapy, Russian State Medical University, Moscow, Russia

b Biochemistry Laboratory, Pirogov Clinical Hospital No. 1, Moscow, Russia

Address for correspondence: Dr Dmitrii A. Anichkov, Department of Faculty Therapy, Russian State Medical University, 8/10 Leninsky Ave, 119049 Moscow, Russia. Tel.: +7 095 236 9920; Fax: + 7 095 237 6948; email: dmitrii.anichkov@mtu-net.ru

Copyright Librapharm Jan 2005

Source: Current Medical Research and Opinion

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