This study was designed to assess the effects of moxonidine on blood pressure and aspects of the metabolic syndrome in racially diverse population of patients encountered in routine medical practice. Physicians collected data on a minimum of three consecutive patients with uncontrolled essential hypertension and criteria for metabolic syndrome, eligible to receive moxonidine (0.2–0.4 mg once daily) for 6 months, either as monotherapy or as adjunct therapy to current antihypertensive treatment. Systolic and diastolic blood pressure (BP) declined by an average of
Hypertension is a major contributor to cardiovascular disease (CVD) risk, but a patient’s global CVD risk is determined by the interplay of multiple risk factors. In particular, the grouping of risk factors—elevated blood pressure, abdominal obesity, dyslipidaemia, and abnormalities of glucose and insulin metabolism, commonly referred to as metabolic syndrome has been associated with a substantial worsening of cardiovascular prognosis and all-cause mortality [
Abdominal obesity is not only a cardinal feature of the metabolic syndrome but also an important contributor to the development and progression of cardiovascular and metabolic disturbances linked to the syndrome. Overactivity of the sympathetic nervous system (SNS) is of particular importance in this context. The interplay between obesity, elevated SNS activity, and hypertensive target organ damage is already demonstrable in very young overweight or obese adults [
Targeting the SNS directly, therefore, provides a logical and attractive therapeutic target [
Moxonidine is a widely approved antihypertensive drug that lowers BP primarily by reducing central SNS activity via activation of imidazoline type-1 receptors in the rostral ventrolateral medulla [
To this end, we conducted a large, multinational study to appraise the effects of moxonidine on blood pressure, anthropometric, lipid, and metabolic parameters of the metabolic syndrome in patients encountered in routine (real world) medical practice.
MERSY was a multinational, open-label, observational study with a planned duration of 6 months. Participating physicians were asked to collect data on a minimum of three consecutive patients with uncontrolled essential hypertension and metabolic syndrome, for whom moxonidine might be prescribed.
The primary objective was to evaluate the long-term safety and efficacy of moxonidine in hypertensive patients with metabolic syndrome. The secondary objective was to assess the effect of long-term treatment of moxonidine on laboratory parameters associated with the metabolic syndrome.
Moxonidine was prescribed at a dose of 0.2–0.4 mg once daily, either as monotherapy or as adjunctive therapy when the current antihypertensive treatment (which was to the discretion of the treating physician) was insufficient to achieve individual blood pressure targets or if it was not tolerated. The preferred maintenance dose of moxonidine was 0.4 mg/day, but physicians were permitted to initiate therapy at 0.2 mg and titrate to 0.4 mg/day after 2 weeks. After the baseline visit, a first follow-up visit was scheduled for between 1 and 3 months, according to the treating physician’s usual practice for such consultations. A final visit was planned 6 months after starting moxonidine therapy. The study had no formal mechanisms to monitor compliance.
Adult patients (age ≥ 18 years) of either sex were eligible for enrolment if they had essential hypertension of any grade, as defined by the 2003 guidelines of the European Society of Hypertension. Patients were either newly diagnosed as hypertensive or had BP levels that were above target despite the use of other antihypertensive drugs measured according to the 2003 guidelines of the European Society of Hypertension or had failed to tolerate current antihypertensive treatment. For Australia only, supplementary inclusion criteria specified age not greater than 75 years and the persistence of hypertension despite concurrent antihypertensive therapy.
Criteria for a diagnosis of metabolic syndrome were based on the 2005 definition proposed by the International Diabetes Federation and comprised central obesity (defined as waist circumference ≥94 cm for Europid men and ≥80 cm for Europid women, with ethnicity-specific values for other groups) plus any two of the following: triglyceride (TG) levels ≥150 mg/dL (≥1.7 mmol/L) or specific treatment for this lipid abnormality; high-density lipoprotein (HDL) cholesterol <40 mg/dL (<1.03 mmol/L) in men or <50 mg/dL (<1.29 mmol/L) in women, or specific treatment for this lipid abnormality; systolic BP (SBP) ≥ 130 mmHg or diastolic BP (DBP) ≥ 85 mmHg, or treatment of previously diagnosed hypertension;fasting plasma glucose (FPG) ≥ 100 mg/dL (≥5.6 mmol/L) or previously diagnosed type 2 diabetes. If FPG was >5.6 mmol/L (>100 mg/dL), an oral glucose tolerance test was recommended, but this was not compulsory. Specific advice on lifestyle modification was not mandated by the protocol.
The only criterion prohibiting patients from taking part in this study was the presence of contraindications to moxonidine, as identified in the relevant National Summary of Product Characteristics (SPC).
From observations and experience in a previous postmarketing surveillance study [
Nominal qualitative variables were compared using the
BP, laboratory and weight parameters were compared between visits using covariance analysis, with the baseline value as the adjusted variable.
The absolute changes in heart rate (HR) between the baseline and postbaseline visits were summarized and analyzed through a one-sample
In addition to pooled results, subgroup analyses were undertaken according to menopause status (as determined by questioning), type of antihypertensive regimen (monotherapy or combination therapy), and age (<65 years and ≥65 years).
Data management and statistical analysis were conducted by the FOVEA Group, Rueil-Malmaison, France. Data entry was performed using Access version 9.0. Double data entry was used. Entered data were verified against case record form data when a discrepancy was found during double data entry. Quality control was performed using SAS version 8.2.
The primary efficacy variable was the percentage of patients responding to antihypertensive therapy during the study. A response was defined as attainment of systemic arterial BP < 140/90 mmHg from baseline to each follow-up visit. BP limits of <130/80 mmHg were set for patients with a diagnosis of diabetes at baseline.
Secondary efficacy variables comprised the absolute change in BP from baseline to each follow-up visit, the absolute change in laboratory parameters for metabolic syndrome (FPG, TG, total cholesterol, HDL-cholesterol, low-density lipoprotein (LDL)-cholesterol, and creatinine, urinary albumin) from baseline to final visit at 6 months, and the absolute change in weight parameters (body mass index (BMI), waist-hip circumferences) from baseline to each follow-up visit.
Suspect adverse drug reactions (SADRs)—defined as a response to a drug that was noxious and unintended and that occurred at doses normally used in humans for prophylaxis or treatment of a disease or to modify physical function—were screened for via active enquiry during follow-up and final visits. Each SADR was evaluated for duration, severity (mild, moderate, or severe), and seriousness. Physicians’ assessment of the causal relationship to the investigational drug was documented, as was the action taken to address all SADRs and the outcome of each event. Special provisions were made for the reporting of all SADRs regarded as serious. Any pregnancies identified during the study were recorded and monitored as discrete events.
The study was conducted in accordance with the ICH GCP (1997) and the Therapeutic Goods Administration (TGA) “Note for Guidance on Good Clinical Practice” (CPMP/ICH/135/95) annotated with TGA comments (July 2000). Patients were free to withdraw from the study at any time, for any reason, specified or unspecified, without prejudice to their medical care. Physicians were free to exclude any patient at any time if this was judged to be in the interests of the patient.
The MERSY study was conducted in 13 countries between December 2006 and March 2008. Figure
CONSORT summary of population recruitment.
Principal demographic details of the ITT population are depicted in Tables
Summary demographic details of the intent-to-treat (ITT) population.
Total patients |
|
---|---|
Sex ( |
|
Male | 2793 (50.2%) |
Female | 2772 (49.8%) |
Age (yrs) ( |
|
|
397 (7.1%) |
40–49 | 1045 (18.8%) |
50–59 | 1854 (33.4%) |
60–69 | 1458 (26.2%) |
>69 | 804 (14.5%) |
<65 | 4102 (73.9%) |
≥65 | 1452 (26.1%) |
Menopause status ( |
|
Postmenopausal | 1856 (71.0%) |
Non postmenopausal | 759 (29.0%) |
Height (mean ± SD, cm) ( |
168.1 ± 8.9 |
Weight (mean ± SD, kg) ( |
91.9 ± 15.6 |
BMI (mean ± SD, kg/m2) ( |
32.5 ± 5.0 |
Waist circumference (mean ± SD, cm) ( |
104.6 ± 13.3 |
Hip circumference (mean ± SD, cm) ( |
107.7 ± 13.7 |
Race/ethnicity ( |
|
White | 2312 (48.0%) |
American Indian or Alaska native | 1496 (31.1%) |
Asian | 835 (17.3%) |
Black of African heritage or African American | 149 (3.1%) |
Native Hawaiian or other Pacific Islander | 17 (0.4%) |
Aboriginal/Torres Strait Islander | 6 (0.1%) |
Smoker status ( |
|
Yes | 1292 (23.7%) |
No | 4161 (76.3%) |
Baseline metabolic indices in the intent-to-treat (ITT) population. The sample sizes for variables are less than the full ITT population (
Means ± SD | |
---|---|
Fasting plasma glucose ( |
6.8 ± 2.1 |
Triglycerides ( |
2.4 ± 1.1 |
Cholesterol ( |
5.8 ± 1.1 |
HDL-cholesterol ( |
1.2 ± 0.5 |
LDL-cholesterol ( |
3.5 ± 1.1 |
Creatinine ( |
0.09 ± 0.06 |
Urinary albumin ( |
92.7 ± 191.6 |
There was statistical evidence of variations in various metabolic syndrome-related metabolic parameters according to age, therapeutic regimen, and menopause status, but with the exception of FPG according to menopause status (
In the month preceding the baseline visit, most patients (
A baseline diagnosis of diabetes was present for 47.1% (2623) of the ITT population for whom data were available (
Documented reasons for initiating moxonidine therapy comprised lack of efficacy of current antihypertensive medication (
Moxonidine 0.2 mg/day was prescribed to 1731 patients at the baseline visit. Doses up to 0.4 mg/day were prescribed to a further 3635 patients. Among the 4118 patients of the ITT cohort for whom medication data were available from the last study visit, 20.0% (
The proportion of patients classified as responding to hypertension therapy increased progressively during the study, from 24.2% (
SBP and DBP declined by an average of
SBP and DBP responses during moxonidine therapy. Mean ± SD.
(a) Evolution of SBP by type of antihypertensive treatment (ITT), (b) evolution of DBP by age cohort between V1 and V3 (ITT population,
On-treatment changes were recorded for mean values of every nominated laboratory parameter except creatinine (Table
In-study trends in laboratory parameters associated with the metabolic syndrome (secondary efficacy endpoints). All results expressed as mmol/L unless indicated otherwise. Data are expressed as mean ± SD.
Total patients |
|
---|---|
Fasting plasma glucose | |
At study start | 6.8 ± 2.1 |
At study end | 6.2 ± 1.6 |
In-study change | −0.8 ± 1.6 |
Triglycerides | |
At study start | 2.4 ± 1.1 |
At study end | 2.0 ± 0.9 |
In-study change | −0.6 ± 1.0 |
Cholesterol | |
At study start | 5.8 ± 1.1 |
At study end | 5.2 ± 0.9 |
In-study change | −0.7 ± 1.0 |
HDL-cholesterol | |
At study start | 1.2 ± 0.5 |
At study end | 1.3 ± 0.5 |
In-study change | 0.1 ± 0.5 |
LDL-cholesterol | |
At study start | 3.5 ± 1.1 |
At study end | 3.0 ± 0.9 |
In-study change | −0.5 ± 0.9 |
Creatinine | |
At study start | 0.09 ± 0.06 |
At study end | 0.10 ± 0.07 |
In-study change | 0.01 ± 0.04 |
Urinary albumin | |
At study start | 92.7 ± 191.6 |
At study end | 83.3 ± 205.5 |
In-study change | −7.6 ± 153.1 |
Body weight (kg) | |
At study start | 92.0 ± 15.6 |
At study end | 90.0 ± 15.3 |
In-study change | −2.1 ± 5.4 |
By contrast, the reduction in TG and the increase in HDL-C levels was more marked in younger (versus older) patients, and the reduction in TGs was significantly larger in nonpostmenopausal women (versus postmenopausal) (
Average weight declined by –
Patients’ assessments of treatment were “excellent,” “good,” “tolerable,” or “bad" in 44.4%, 48.3%, 6.4%, and 0.9% (
During the course of the study, 195 SADRs were recorded in 132 patients (2.2% of the study population) (Table
Summary of suspected adverse drug reactions (SADRs) recorded during the study.
No. of events | No. of patients (%) | |
---|---|---|
All SADRs | 195 | 132 (2.2%) |
SADRs considered related |
151 | 97 (1.6%) |
SADRs leading to study termination | 93 | 62 (1.1%) |
Severe SADRs | 15 | 10 (0.2%) |
Serious SADRs | 12 | 6 (0.1%) |
Of the 12 serious SADRs, 2 each were classified as nervous system disorders; vascular disorders; infections and infestations; or respiratory, thoracic, and mediastinal disorders. The remaining four serious SADRs comprised one case each in the categories of psychiatric disorder; pregnancy, puerperium, and perinatal conditions; renal and urinary disorders; and cardiac disorders.
No deaths were reported during the study.
This open-label phase IV trial was designed to assess the effect of moxonidine on BP and laboratory parameters associated with the metabolic syndrome after 6 months of treatment in a general practice setting. We sought to enlarge on previous experience in a single country [
The results of the MERSY study are consistent with the previous experience with moxonidine in the management of hypertension [
While blood pressure reduction is the primary goal of antihypertensive therapy, potential effects on metabolic parameters also need to be taken into account. Such considerations have led to widespread recommendations in national and international guidelines to avoid beta-blockers and diuretics in patients with metabolic disturbances or diabetes mellitus if not indicated for additional comorbidities. The reasoning for these recommendations relates to the well-described weight gain with beta-blockers and the adverse metabolic effects (such as insulin resistance and hyperuricemia) encountered with both beta-blockers and diuretics. In contrast, antihypertensive agents that exert no or even beneficial metabolic effects, such as calcium channel blockers (considered neutral in this regard) and inhibitors of the renin-angiotensin-system (ACE inhibitors, angiotensin receptor blockers, and direct renin inhibitors), which have been shown to reduce new onset of diabetes [
Moxonidine clearly falls into the second category, with proven efficacy in regard to blood pressure lowering and beneficial effects in regard to diverse metabolic parameters. While the effects of moxonidine on individual metabolic indices in our study could be considered as modest, the trends of all the changes seen were towards a profile of lower overall CVD risk, which was particularly evident in the subgroup analyses.
In this context, the average reduction in body weight of 2.1 kg in our patients is noteworthy and replicates earlier studies of moxonidine in populations with metabolic syndrome [
Several lines of evidence suggest that sympathetic activation is of particular relevance in the earlier stages of hypertension [
Our observation of reductions in TG and body weight in conjunction with improvement in blood pressure control are compatible with the suggestion [
Additional, albeit indirect evidence for this concept comes from the ALMAZ study [
Moxonidine was well tolerated when used in combinations with the range of first-line antihypertensives in MERSY, as was the case in other studies. More generally, the safety profile of moxonidine in the MERSY study was fully in accordance with the known effects of the drug. The overall incidence of SADRs was very low (<2.5%) and the nature of the SADRs observed was consistent with previous experience. No previously unreported terms of SADR were encountered during our study. The incidence of SADRs with moxonidine is usually highest during the first weeks of treatment and thereafter declines to very low levels. The independent decision of many investigators to start therapy at doses <0.4 mg/day may have contributed to the excellent tolerability profile of moxonidine in the MERSY study and may be regarded as an example of skill in clinical practice.
In summary, in this large sample of patients with hypertension and concomitant metabolic syndrome, moxonidine enhanced blood pressure control when used alone or in combination and was associated with improvement in several aspects of metabolic syndrome. Moxonidine was well-tolerated during 6 months of continuous use. Given current estimations suggesting that approximately 70% of all incident hypertension is associated with overweight or obesity, it appears justified to recommend antihypertensive treatment with an agent that targets the underlying pathophysiology including sympathetic activation, particularly so if additional benefits can be achieved in regard to control of body weight and other metabolic markers characterizing the metabolic syndrome.
What Is Known about the Topic. Hypertension is often associated with relevant comorbidities, particularly metabolic disturbances. Antihypertensive drug therapy should be safe, well tolerated, effective in lowering blood pressure and ideally have a beneficial effect on comorbidities. Sympathetic activation plays a role in blood pressure elevation and metabolic disturbances and can be targeted therapeutically.
What This Study Adds. Use of the centrally acting imidazoline receptor agonist moxonidine (0.2–0.4 mg once daily) for 6 months, either as monotherapy or as adjunct therapy to current antihypertensive treatment in patients with uncontrolled essential hypertension and criteria for metabolic syndrome, was associated with (i) improvement in control of blood pressure, (ii) neutral or beneficial trends in a range of metabolic indices including lipid fractions and fasting plasma glucose, and (iii) an average reduction in body weight of ~2 kg. Antihypertensive treatment with a centrally acting sympatholytic agent that targets common underlying pathophysiologic pathways is a safe and effective treatment strategy in a general practice setting with potential additional benefits in regard to metabolic disturbances frequently encountered in hypertensive populations.
The MERSY study was supported administratively and financially by Abbott Products Operations AG, Allschwil, Switzerland. I. Chazova also reports receiving travel support/speaker fees from Abbott, Astra Zeneca, Boehringer Ingelheim, Novartis, Pfizer, Servier, and Solvay. M. Schlaich has received research grant support from Deutsche Forschungsgemeinschaft, National Health and Medical Research Council of Australia, Kidney Health Australia, National Heart Foundation of Australia, Diabetes Australia, Heart Kids Australia, Abbott, Ardian Inc./Medtronic, and Servier and has received travel support/speaker fees/consulting fees from Abbott, Ardian, Astra Zeneca, Boehringer Ingelheim, MMI, Novartis, Omron, Pfizer, Servier, and Solvay.