Journal of Human Hypertension (2004) 18, 669–675 & 2004 Nature Publishing Group All rights reserved 0950-9240/04 $30.00 www.nature.com/jhh ORIGINAL ARTICLE Moxonidine in the treatment of overweight and obese patients with the metabolic syndrome: a postmarketing surveillance study

AM Sharma1, T Wagner2 and P Marsalek2 1McMaster University, Hamilton, ON, Canada; 2Lilly Deutschland GmbH, Bad Homburg, Germany

Moxonidine is a centrally active imidazoline receptor drome. The recommended targets for antihypertensive agonist that effectively lowers blood pressure and has treatment of the German Diabetes Society/German been shown to have beneficial effects on lipid and Hypertension Society were reached by 30.5% of non- carbohydrate metabolism. We assessed the efficacy of diabetics (goal: o140/90 mmHg) and by 3.6% of dia- moxonidine in a postmarketing surveillance study betics (goal: o130/80 mmHg) observed. After 8 weeks of (CAMUS) conducted in 772 practices in Germany, treatment, patients achieved a mean weight loss of documenting 4005 patients with hypertension, who were 1.4 kg, which was particularly pronounced in obese overweight and/or suffered from metabolic syndrome. patients. The rate of patients receiving antihypertensive Patients were treated with moxonidine (Cynts) for the combination therapy was 81.1% for those with metabolic first time following the baseline visit for 8 weeks. Mean syndrome, and 63.3% for all other patients. Patients with blood pressure decreased from 168/97 to 141/83 mmHg metabolic syndrome were preferentially treated with for all patients and from 168/96 to 141/83 mmHg for ACE inhibitors and diuretics. We conclude that mox- patients with metabolic syndrome. Blood pressure onidine effectively reduces blood pressure in patients reduction was particularly pronounced in patients with with metabolic syndrome while simultaneously reducing severe hypertension at baseline. The response rate body weight in obese patients. (DBPp90 mmHg or reduction X10 mmHg) of antihyper- Journal of Human Hypertension (2004) 18, 669–675. tensive treatment with moxonidine was 94.0% for all doi:10.1038/sj.jhh.1001676 patients and 93.8% for patients with metabolic syn- Published online 22 July 2004

Keywords: hypertension; moxonidine; obesity; metabolic syndrome

Introduction metabolic syndrome, as defined by the WHO, is associated with a 2.6 to 3-fold relative risk for Since its recognition as early as 1966 by Camus, the cardiovascular mortality.8 The presence of the metabolic syndrome (also known as the insulin metabolic syndrome is also highly predictive for resistance syndrome or syndrome X) has been 9 1–4 the development of type II diabetes. repeatedly described by several authors. Although Recent studies have highlighted the importance of there are a number of different definitions of this adequate blood-pressure control in patients with syndrome, the most common definition used in type II diabetes.10–12 Based on these observations, Europe is that of the WHO, which includes the the target blood pressure for patients with diabetes presence of type II diabetes mellitus or impaired has recently been lowered to o130/80 in recent glucose tolerance and two of the following abnorm- guidelines from the WHO,13 the German Diabetes alities: abdominal obesity, essential hypertension, Society,14 and the German Hypertension Society, dyslipidemia with low high-density lipoprotein particularly in patients with microalbumiuria or (HDL) cholesterol, hypertriglyceridemia, and/or mi- 5 overt diabetic nephropathy. croalbuminuria. While the various components As documented in recent studies, most patients have long been identified as cardiovascular risk 6,7 with the metabolic syndrome will require combina- factors, recent studies have shown that the tion therapy, often including drugs other than those recommended for first-line therapy.15 The centrally Correspondence: AM Sharma, Canada Research Chair for Cardi- active imidazoline receptor agonist moxonidine is a ovascular Obesity Research & Management, McMaster University, sympatholytic drug that effectively lowers blood Hamilton General Hospital, 237 Barton Street East, Hamilton, pressure,16–20 is well tolerated, and has been shown Ont, Canada L8L 2X2. Received 20 June 2003; revised 20 November 2003; accepted 27 to have beneficial effects on lipid and carbohydrate 21–23 November 2003; published online 22 July 2004 metabolism and insulin sensitivity. Moxonidine in patients with metabolic syndrome AM Sharma et al 670 What is known:

• Moxonidine is a sympatholytic drug that effectively lowers blood pressure.

• Most hypertensive patients need combination therapy.

What is new:

• Moxonidine is as effective in lowering blood pressure in hypertensive patients

with the metabolic syndrome, as in patients without this syndrome.

• Overweight patients with the metabolic syndrome are more likely to be on

combination therapy.

• Overweight patients with the metabolic syndrome were more likely to be on ACE

inhibitors and diuretics than patients without the metabolic syndrome.

• Despite good blood pressure response to moxonidine and more frequent use of

combination therapy, less than 5% of diabetic patients achieve blood pressure

target (<130/80 mmHg).

While the efficacy and safety of moxonidine has tions regarding antihypertensive therapy for enrol- been previously documented in a postmarketing ment. Physicians were referred to the product surveillance study,24 its effect has not been pre- information for moxonidine for information on viously examined in patients who were overweight contraindications. and/or had the metabolic syndrome. We therefore examined the efficacy and safety of moxonidine in these patients within the framework of a postmar- keting surveillance study in Germany. Monitoring Materials and methods Patient data were recorded at baseline, at 4 and at 8 Patients weeks following commencement of moxonidine. All patients were started on moxonidine after the base- CAMUS was conducted as an observational post- line visit. Baseline data included demographic and marketing surveillance study in a convenience disease variables. The diagnosis of a metabolic sample of general practitioners, internists, and syndrome was assessed based on the WHO definition diabetologists in Germany. Male and female patients (Table 1). Each of these parameters was documented with essential hypertension, who were assessed separately by the physicians (present, absent, not by the physician as being overweight or obese assessed), except for BMI, which was calculated and/or having the metabolic syndrome, were pro- based on height and body weight. Classification into spectively followed. Patients previously treated patients with and without metabolic syndrome was with moxonidine were excluded. In patients not done in the statistical analysis. The initial dose of on antihypertensive medication, blood pressure moxonidine as well as all concomitant antihyperten- levels were required to be 4140 mmHg (systolic) sive medication was recorded and changes were and/or 490 mmHg (diastolic). The metabolic documented at each visit. Blood pressure, heart rate, syndrome was diagnosed based on the WHO body weight, WHR, and adverse events were likewise definition (Table 1). There were no further restric- documented at each visit.

Journal of Human Hypertension Moxonidine in patients with metabolic syndrome AM Sharma et al 671 Table 1 WHO definition of the metabolic syndrome

Patient meets one of the following criteria Definition of criteria

Diabetes mellitus Fasting blood glucose X126 mg/dl (X7 mmol/l) and/or venous plasma glucose 2 h after OGTT X200 mg/dl (X11.1 mmol/l) Reduced glucose tolerance Venous plasma glucose 2 h after OGTT X140 mg/dl (X7.8 mmol/l) Elevated fasting blood glucose Fasting blood glucose X110 mg/dl (X6.1 mmol/l)

AND two out of four of the following criteria: Obesity or unfavourable waist-to-hip ratio (WHR) Obesity: BMI 430 kg/m2, WHR: 40.90 for men or 40.85 for women Hypertension SBP 4160 mmHg or DBP 489 mmHg or antihypertensive therapy Dyslipidemia Triglycerides 4150 mg/dl and/or HDL cholesterol o35 mg/dl for men or o39 mg/ dl for women Microalbuminuria 420 mg/min overnight

Data quality and statistics Table 2 Severity of hypertension, metabolic syndrome, and overweight at initial observation In order to ensure data quality, a predefined data validation plan was implemented. This included Patients (N ¼ 4005) rechecking of predefined variables, exploratory statistics for consistency, and a comparison of the n% data to the Lilly Pharmacovigilance Database. Severity of hypertension All data were analysed by descriptive statistics. Mild (SBP 140 to o160 mmHg, DBP 90 to 718 17.9 All outcome variables were analysed with regard to o100 mmHg) changes at 8 weeks from baseline (95% confidence Moderate (SBP 160 to o180 mmHg, DBP 100 2142 53.5 intervals). Responders were defined as patients with to o110 mmHg) Severe (SBP X180 mmHg, DBP X110 mmHg) 1130 28.2 diastolic blood pressure o90 mmHg or decrease Not assessable 15 0.4 410 mmHg, and as the proportion of patients who reached the target blood pressure defined by the Metabolic syndrome according to WHO German Diabetes Society/German Hypertension So- criteria ciety. Patients with metabolic syndrome 2128 53.1 Patients without metabolic syndrome 1854 46.3 The following subgroup analyses were also per- Not assessable 23 0.6 formed: presence of metabolic syndrome (yes/no), severity of hypertension at baseline; degree of Overweight Normal weight (BMI o25 kg/m2) 322 8.0 overweight/obesity, degree of congestive heart fail- 2 ure (NYHA), previous antihypertensive medication Overweight (BMI 25 to o30 kg/m ) 1744 43.5 Obesity Grade 1 (BMI 30 to o35 kg/m2) 1331 33.2 (yes/no), and antihypertensive comedication (med- Obesity Grade 2 (BMI 35 to o40 kg/m2) 448 11.2 ication class). Obesity Grade 3 (BMI X40 kg/m2) 156 3.9 Adverse effects, vital signs, and body weight were Not assessable 4 0.1 analysed by descriptive analyses. All adverse effects were coded according to MedDRA. indicating that the vast majority of patients were overweight or obese. Moxonidine was started as Results first-time antihypertensive treatment in 777 (19%) Patients newly diagnosed patients with essential hyperten- sion. The majority of patients had moderate hyper- A total of 772 physicians (general practitioners, tension, whereas metabolic syndrome was present internists, diabetologists) participated in CAMUS in just over half of the patients (Table 2). While and documented 4005 patients with essential physicians diagnosed overweight/obesity in 80% of hypertension, overweight/obesity, and/or metabolic patients, the actual prevalence based on BMI was syndrome. Complete data sets were available for 92% (BMI425 kg/m2 ¼ 92%, BMI430 kg/m2 ¼ 48%). 3939 patients (98%). Median observation time was Concomitant cardiovascular diseases were left- 64 days. Only 87 patients (2%) were discontinued ventricular hypertrophy in 35% of the patients, before the end of the 8-week period, 0.5% because of followed by coronary artery heart disease (25%). adverse events. Congestive heart failure, most often of NYHA class II, was present in 19% of the patients. Triglycerides Demographics and diagnoses were elevated in 2732 patients (68%), and 1986 patients (50%) had low HDL cholesterol. Of the 4005 patients, aged 20–93 years (median 61 Some risk factors for metabolic syndrome (apart years), 49% were female. Average height was 170 cm from obesity) were more common in obese patients. and body weight was 86 kg (BMI ¼ 30.5 kg/m2), This was most striking for elevated triglycerides,

Journal of Human Hypertension Moxonidine in patients with metabolic syndrome AM Sharma et al 672 which were found in 43% of patients with normal (13.279.5 mmHg; 95% CI: 12.9–13.5) blood pressure weight but in 77% of Grade 3 obese patients. (Figure 1, Table 3). Patients with the highest Similarly, the rate of patients with severe hyperten- blood pressure experienced the greatest reduction sion was 27 and 43%, the rate of diabetes 41 and in blood pressure (Figure 2, Table 3). The blood 63%, and the rate of elevated fasting blood glucose pressure reduction was similar in patients with 45 and 69% for normal weight and Grade 3 obese and without the metabolic syndrome. Blood pres- patients, respectively. No major differences in the sure reduction was successful for patients in all presence of risk factors by BMI category were found weight classes (BMI, see Table 3). Likewise, blood for low HDL cholesterol or presence of microalbu- pressure reduction was similar in patients with minuria. congestive heart failure, with or without previous antihypertensive therapy, or antihypertensive come- Antihypertensive medication dication. Response to moxonidine (diastolic pressure Moxonidine was most commonly used as 0.3 mg/ o90 mmHg and/or reduction in diastolic pressure day (65%), followed by 0.4 mg/day (26%). During 410 mmHg) was seen in 3764 (94%) patients. the observation period, the proportion of patients Similar response rates were seen in patients with with 0.4 mg/day increased to 38%, while the metabolic syndrome (1997 (94%) of 2128), obese proportion of patients with the 0.6 mg/day dose patients (1802 (93%) of 1935), with diabetes (1792 increased from 3.5 to 10%. (94%) of 1909), or treated with monotherapy (1032 Previous antihypertensive treatment was docu- (95%) of 1086). Target blood pressure (o140/ mented in 78% of all patients (ACE inhibitors 52%, 90 mmHg and o130/80 in diabetes) was reached in diuretics 36%, b-blockers 34%, calcium channel only 706 (17.7%) of the 4005 patients. More patients blockers 29%). The majority of patients received without diabetes achieved target blood pressure (640 moxonidine as supplemental therapy to their exist- (30.5%) of 2095) than patients with diabetes (68 ing antihypertensive medication (73%). Concomi- (3.6%) of 1909). tant antihypertensive medications given at initial There was a modest reduction in heart rate from observation were ACE inhibitors (50%), diuretics 79.2 þ 9.8 bpm at baseline to 74.0 þ 7.5 bpm at 8 (36%), b-blockers (30%), Ca-antagonists (26%), weeks. The mean change in heart rate was alpha-1-receptor blockers (6%), and other sub- À5.2 þ 8.2 (95% CI: À5.0 to À5.5). The decrease in stances (9%). There was little change in the heart rate in patients with severe hypertension was comedication over the 8-week observation period. greater than in patients with mild hypertension (À6.0 þ 9.6 bpm; 95% CI: À5.4 to À6.5 vs Blood pressure and heart rate À4.3 þ 7.4 bpm; 95% CI: À3.7 to À4.8). The reduc- tion in heart rate in patients with meta- There was a marked reduction in systolic bolic syndrome was similar to that in the whole (26.9715.1 mmHg; 95% CI: 26.4–27.3) and diastolic population.

Table 3 Blood pressure at initial observation and after 8 weeks (final documentation)

Start of observation Final documentation

Mean BP (mmHg) Mean BP (mmHg) Mean BP reduction (mmHg)

n SBP DBP n SBP DBP SBP 7s.d. DBP 7s.d.

Total 4004 167.5 96.6 3941 140.5 83.4 À26.9 15.1 À13.2 9.5

Metabolic syndrome (MS) MS yes 2128 167.9 96.2 2090 140.9 83.3 À26.8 15.3 À13.0 9.5 MS no 1853 166.9 96.9 1828 140.1 83.6 À26.9 14.8 À13.4 9.4

Severity of hypertension at baseline Mild 718 150.8 90.0 709 134.9 81.1 À15.9 9.1 À8.9 7.1 Moderate 2142 163.6 95.4 2118 139.2 83.2 À24.5 10.4 À12.2 7.9 Severe 1130 185.8 103.1 1102 146.7 85.2 À38.9 17.4 À17.9 11.3

Weight class Normal weight 322 166.6 94.4 315 140.5 14.0 À26.1 15.3 À12.3 9.6 Overweight 1744 166.5 96.0 1717 140.2 11.5 À26.2 14.6 À13.2 9.5 Obesity Grade 1 1331 167.8 97.1 1309 140.4 10.9 À27.2 15.1 À13.2 9.0 Obesity Grade 2 448 169.1 97.8 431 140.7 11.5 À28.4 16.3 À13.7 9.9 Obesity Grade 3 155 171.9 98.9 153 143.6 14.3 À28.1 15.1 À12.8 11.1

Journal of Human Hypertension Moxonidine in patients with metabolic syndrome AM Sharma et al 673 Body weight, BMI, and waist-to-hip Ratio (WHR) overweight patients (À1.172.1 kg); weight reduc- tion by baseline BMI category is presented in more At the end of the 8-week observation period, detail in Figure 3. There was no change of WHR and patients lost an average of 1.4 þ 2.9 kg (0.5 þ 1.0 kg/ girth over the observation period. m2 BMI change). This change was independent of sex or the presence of the metabolic syndrome. The reduction in body weight was greater in obese (À1.873.5 kg) vs normal-weight (À0.071.9 kg) and Management decisions While similar doses of moxonidine were used in patients with and without metabolic syndrome, the 200 latter were more likely to be on antihypertensive 180 comedication (Figure 4). Combination therapy was 160 more common in patients with severe (80%) than with moderate (70%) or mild (68%) hypertension. 140 The proportion of patients with the 0.4 mg/day dose 120 increased from 24% in patients with mild to 38% in

100 patients with severe hypertension. With increasing severity of blood pressure, all antihypertensive 80 classes were used more often, especially diuretics Blood Presure: SBP and DBP [mmHg] 60 (mild: 30%, severe: 42%), calcium channel blockers Initial Observation 4 Weeks 8 Weeks (mild 22%, severe 33%), and alpha-1-receptor Figure 1 Mean blood pressure (SBP and DBP, 7s.d.) at initial blockers (mild 4.2%, severe 7.6%). In contrast, the observation and after 4 and 8 weeks of therapy with moxonidine. ACE inhibitors were used similarly in mild (51%),

5 10 0 5 -5 -10 0 -15 -20 -5 -25 -10 -30 -35 -15 -40 -20 -45 -50 -25 SBP reduction [mmHg] reduction SBP -55 DBP reduction [mmHg] -60 -30 -65 -35 -70 -75 -40 overall Yes No mild moderate severe overall Yes No mild moderate severe Metabolic Syndrome Hypertension at Baseline Metabolic Syndrome Hypertension at Baseline

5 10 0 5 -5 -10 0 -15 -20 -5 -25 -10 -30 -35 -15 -40 -20 -45 -50 -25 SBP reduction [mmHg] SBP reduction -55 DBP reduction [mmHg] -60 -30 -65 -35 -70 -75 -40 Normal weight Overweight Grade 1 Grade 2 Grade 3 Normal weight Overweight Grade 1 Grade 2 Grade 3 Obesity Obesity Figure 2 Blood pressure reduction after 8 weeks of therapy with moxonidine (final observation; box plots with medians). (a) Systolic blood-pressure reduction: overall, by presence of metabolic syndrome, and by baseline severity of hypertension. (b) Diastolic blood pressure reduction: overall, by presence of metabolic syndrome, and by baseline severity of hypertension. (c) Systolic blood pressure reduction: by baseline weight categories. (d) Diastolic blood pressure reduction: by baseline weight categories.

Journal of Human Hypertension Moxonidine in patients with metabolic syndrome AM Sharma et al 674 4 this agent has not been previously evaluated in overweight/obese patients. This postmarketing sur- 2 veillance study in over 4000 patients demonstrates 0 that moxonidine effectively lowers blood pressure

-2 and is well tolerated by patients who are over- weight/obese and/or have the metabolic syndrome. -4 Systolic blood pressure was lowered by 26 mmHg, -6 whereas diastolic pressure was lowered by

-8 13 mmHg. Over 94% of patients responded to

Weight change [kg] moxonidine, with diastolic blood pressure -10 o90 mmHg or a reduction by 410 mmHg. These -12 observations were similar to those of previous open 24–26 -14 and randomised-controlled studies. As noted previously, the blood pressure lowering effect of Normal weight Overweight Grade 1 Grade 2 Grade 3 moxonidine was greatest in those with the highest Obesity blood pressure24 and response was similar in Figure 3 Weight reduction (box plots with medians) in patients patients with and without the metabolic syndrome. after 8 weeks of treatment with moxonidine. The low side-effect profile of moxonidine is docu- mented by the low rate of adverse events (1.3%) and Patients with Medication [%] the low rate of discontinuation (2.2%) during the 0 102030405060708090 course of the study. This corroborates results from a

81.1 comparative study regarding tolerability of moxoni- Combination 63.3 dine versus nitrendipine in hypertensive patients 27 61.3 with renal failure. In this study, the decrease in ACE-Inhibitors 37.2 creatinine clearance and the increase in serum

43.5 creatinine during 24 weeks of add-on treatment Diuretics 27.2 were significantly lower for moxonidine than for

31.5 nitrendipine. Beta-blockers 27.2 Although three out of four patients were on

31.0 combination therapy, only 31% of patients without Ca-Antagonists 20.0 diabetes reached the target blood pressure of o140/

With MS (N=2128) Without MS (N=1854) 90 mmHg. In patients with diabetes, the lower target of o130/80 was reached by only 3.6%. These figures Figure 4 Antihypertensive concomitant medication in patients with and without metabolic syndrome (MS). are similar to recent reports in other European countries of rather poor blood pressure control in general practice.28 Poor control may be attributable moderate (48%), and severe (54%) hypertension. At in part both to poor compliance29 and inadequate the final visit, physicians reported that they in- familiarity with current guidelines.30 On the other tended to continue moxonidine in 96% of all hand, it must be noted that due to the rather short patients. duration of the study, the blood pressure plateau may not have been reached in all patients. The high rate of combination therapy (73%) is Adverse events similar to that noted in previous studies.11 As expected, high-risk patients with more severe Adverse events were reported in 54 (1.3%) of 4005 hypertension and those with the metabolic syn- patients. The most common side effects were dry drome8 were more likely to be on combination mouth (0.5%) and headaches (0.2%). Drowsiness, therapy, whereby ACE inhibitors and diuretics were vertigo, and nausea were reported in 1% of patients; used most often. all other side effects were reported at less than 0.1%. Interestingly, body weight decreased by 1.4 kg No adverse effects unknown for moxonidine were over the observation period. This observation is in noted. Five severe adverse events (0.1%) were line with previous observations with moxoni- reported (congestive heart failure, cholelithiasis, dine.31,32 Whether or not this is favourable, albeit a haemorrhagic stroke, hyperventilation, lower limb modest effect on body weight is related to the fracture). None of these were seen as being related to positive metabolic effects observed with moxoni- moxonidine by the treating physician. No lethality dine in previous studies (improvement in insulin was reported. sensitivity, reduction in plasma leptin levels and serum triglycerides),33 remains to be determined. Discussion In summary, moxonidine effectively lowers blood pressure in overweight and obese patients with and While the use of moxonidine in patients with without the metabolic syndrome and is well toler- hypertension is well documented, the efficacy of ated. Moxonidine also appears to have a favourable

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