Introduction

Obesity is correlated with an increased risk of mortality and morbidity.¹ Obesity and related complications lead to an approximate total number of 300 000 deaths per year in the US.^2,3 Today, obesity is accepted as a multifactorial and chronic disease reaching to epidemiologic rates in industrialized countries and there is a general agreement for the necessity of appropriate treatment in such patients.⁴ Pharmacological agents used in the treatment of obesity increase the compliance of the patients to the treatment program in the short term and prevent regaining of the lost weight in long-term therapy.^5,6

Sibutramine is a central appetite suppresser agent that inhibits the reuptake of seratonine, noradrenaline, and dopamine at presynaptic neuronal terminals.⁷ A significant increase in the heart rate and blood pressure are well-defined side effects of sibutramine therapy in normotensive obese patients.^{6,7,8,9,10,11} Owing to these side effects, sibutramine therapy is not suitable for patients with coronary artery disease, congestive heart failure, arrhythmia, and stroke; moreover, all patients on therapy need to be closely monitored for heart rate and blood pressure changes.⁷ The most common causes of drug discontinuation are related to cardiovascular side effects.^12,13

Although the adrenergic side effects of sibutramine are well documented, there are no data regarding the combination of an adrenergic blocker to sibutramine therapy. In this study, we aimed to assess the effect of low-dose cardio-selective beta blocker combination with sibutramine treatment.

Materials and methods

Patient selection

Obese patients who had admitted to our endocrinology outpatient clinics for a weight reduction program were carefully evaluated for secondary causes of obesity and enrolled into a 3 months medical nutrition treatment period. At the end of this period, patients who could not manage a 10% weight loss were re-evaluated and those with a body mass index (BMI) over 30 kg/m² accompanied by a complication of obesity or those over 35 kg/m² were found eligible for drug therapy. Patients with diabetes mellitus, uncontrolled hypertension, stroke, malignancy, chronic respiratory diseases, renal or hepatic dysfunction, coronary artery disease, and heart valve disorders were excluded. The study protocol was approved by the local ethics committee. All patients were informed about the study protocol and gave informed consent. Finally, 57 patients had agreed to participate in the study.

Treatment groups and patient follow-up

All of the patients enrolled into the study were given sibutramine 10 mg/day in addition to previous medical nutrition therapy. Patients were separated into two groups in order to receive metoprolol 25 mg/day (group M) or placebo (group P) in combination with sibutramine. Patients were evaluated before the randomization and at 15th day, first, second, and third months of therapy. Patients were interrogated at each visit for probable side effects, and if there was any they were requested to grade it between 0 and 5 via a visual analog scale. This evaluation of the side effects was performed by the same researcher (KU), who was completely unaware of the patients' randomization group. A patient with an intolerable side effect at any time during the study period was recorded and treatment was discontinued immediately.

Anthropometric measurements

Body weight and height were measured in the morning with light clothing and without shoes. Body weight and fat percent were measured by Tanita^® impedance meter on bioelectric impedance basis.^14,15 BMI was calculated as body weight in kilograms divided by height in meters squared. Waist circumference was measured with a flexible plastic tape midway between the lower rib margin and iliac crest, and hip girth was measured at the widest part of the hip. Both circumferences were measured in the standing position after normal expiration. Skin fold thickness was measured at four different sites, which are triceps, biceps, subscapular, and abdominal suprailiac regions with a skin caliper in the standing position.

Cardiovascular evaluation

In the beginning and at the end of the third month, 24 h blood pressure and heart rate measurements were performed with an ambulatory blood pressure monitor (Spacelab, Washington, USA). Blood pressure and heart rate measurements were taken at every 15 min during daytime and every 30 min during sleeping period. The mean daily values for diastolic, systolic, and mean arterial blood pressures, and also heart rate were obtained for statistical analysis with a specific computer program. Pulse rates were counted manually and blood pressure measurements were performed with a sphygmomanometer cuff size tailored to the subject's arm (Ri-mega sphygmomanometer, Reistar Diagnostic Company, Jungingen, Germany) at sitting position after a 15 min rest at follow-up visits (at 15th day, first, and second months of therapy).

Biochemical analysis

Blood samples were obtained in the morning after 10–12 h fast from an antecubital vein. Serum glucose, total cholesterol, triglyceride, HDL, and LDL cholesterol levels were measured with a Hitachi 917 auto analyzer by original Roche Diagnostics kits (Roche Diagnostics, Mannheim, Germany). Serum apoprotein A1 and B100 levels were measured with a Dade Behring auto analyzer by original kits (Dade Behring, Marburg, Germany). Serum insulin levels were measured with an Immulite One auto analyzer by DPC original kit (DPC, Los Angeles, USA). Peripheral insulin resistance was calculated with Homeostasis Model Assessment (HOMA) method.¹⁶

Statistical analysis

Statistical calculations were performed with an SPSS 10.0 program. The basal and final values were compared with a paired t-test or Wilcoxon rank test within groups and Student's t-test or Mann–Whitney U test between groups where appropriate. A P-value of less than 0.05 was accepted as significant. Data are presented as means.d.

Results

A total of 57 patients with a mean age of 36.710.5 y were enrolled into the study (54 female and three male patients); 29 patients were randomized to group P and 28 to group M. There was no significant difference between the two groups in the beginning of the study regarding the biochemical, anthropometric, and cardiovascular measurements (Table 1). At the end of the third month, patients who had completed the treatment period were re-evaluated and final data were compared with the basal values of these patients.

Table 1 - Anthropometric, metabolic parameters, and ABPM results of the patients in the beginning of the study.

Full table

There was a significant weight loss in both groups (100.911.5 to 91.812.8 kg for group P, P<0.0001 and 97.913.2 to 88.913.8 kg for group M, P<0.0001). Weight loss was similar between the two groups (9.14.9 kg for group P and 9.03.9 kg for group M, NS), so was the case for BMI (38.95.1 to 35.55.1 kg/m² for group P, P<0.0001 and 39.46.4 to 35.77.3 kg/m² for group M, P<0.0001). There were also significant reductions in body fat percent, waist circumference, hip circumference, and skin fold thickness values in both groups compared with basal measurements, but these reductions were again similar between the two groups (Table 2). There was no significant difference between the two groups regarding the metabolic parameters at the end of the study (Table 3).

Table 2 - Anthropometric parameters of the patients in the beginning and at the third month of the study.

Full table

Table 3 - Metabolic parameters and ABPM results of the patients in the beginning and at the third month of the study.

Full table

There was a significant increase in diastolic blood pressure (73.09.3 to 78.611.6 mmHg, P=0.003), mean arterial pressure (90.18.2 to 93.811.9 mmHg, P=0.029), and heart rate (78.17.3 to 84.36.1 beats/min, P<0.0001) in group P compared with basal values. These increases were not evident in group M. Furthermore, more prominent differences were observed when the third month values of group P and group M were compared (diastolic blood pressure 78.611.6 and 70.64.8 mmHg, respectively, P=0.013; mean arterial pressure 93.811.9 and 85.85.0 mmHg, respectively, P=0.015; heart rate 84.36.1 and 75.88.4 beats/min, respectively, P=0.003) (Table 3). These differences between the two groups became evident at the end of the first month for diastolic blood pressure (81.66.2 and 74.25.1 mmHg, respectively, P<0.0001) (Figure 1) and at the end of the second month for pulse rate (92.44.2 and 72.75.1 beats/min, respectively, P<0.0001) (Figure 2).

Figure 1.

Diastolic blood pressure measurements throughout the study.

Full figure and legend (22K)

Figure 2.

Pulse rate measurements throughout the study.

Full figure and legend (20K)

There were significant differences between the two groups regarding patient adherence to drug therapy and side effects. During the study period, the drop-out rate was significantly higher in group P compared with group M (55 and 21%, respectively, P=0.014); 22 patients over 28 were adherent to treatment in group M, while this was only 13 over 29 in group P. Treatment was discontinued in two patients in group P and one in group M because of pregnancy. Eight patients in group P and two in group M discontinued the treatment on their own will, while six patients in Group P and three in group M discontinued the treatment because of intolerable side effects, which were palpitations, headache, constipation, and dry mouth in group P, and constipation, dry mouth, and emotional instability in group M (Table 4). All of the side effects reported during the study period are summarized in Table 5. Palpitation (37 and 7%, respectively, P=0.006) and headache (34 and 14%, respectively, P=0.05) complaints were significantly more common in group P compared with group M.

Table 4 - Drop-out rates and causes throughout the study.

Full table

Table 5 - Side effects observed throughout the study period.

Full table

Discussion

Obesity is closely correlated with hypertension, and weight reduction leads to lower blood pressure values.^17,18 Even a small decrease in blood pressure is quite effective for the reduction of cardiovascular risk.^19,20 Although sibutramine has been shown to be effective in promoting weight loss in obese subjects, it is associated with an increase in diastolic blood pressure. On the other hand, patients who had achieved a weight loss without pharmacological treatment experienced significant reductions in blood pressure levels.^6,8,9,10,11 Furthermore, sibutramine treatment is also associated with a significant increase in resting heart rate.⁶ As a central appetite suppressant, the interaction of sibutramine with the autonomic nervous system leads to sympathetic hyperactivity and this has undesired effects on blood pressure and heart rate.²¹ Theoretically, a beta adrenergic antagonist might overcome these side effects. In our study, we observed significant increases in diastolic blood pressure and heart rate soon after the initiation of sibutramine treatment. This undesired effect was not observed in sibutramine and low-dose metoprolol combination group, indicating the beneficial influence of beta adrenergic antagonist in the treatment. Although there is a significant elevation with sibutramine treatment, diastolic blood pressure and heart rate mostly remain in the normal range and are considered to be acceptable in the course of therapy.¹¹ Moreover, it has been shown that hypertensive subjects may have a different adrenergic response to sibutramine than normotensive subjects, such that the inhibitory clonide-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect and does not cause a further increase in blood pressure.²² However, in normotensive subjects or in patients with an overt cardiovascular risk, these deleterious effects of the drug are quite limiting and combination with low-dose beta adrenergic antagonists seems to be a solution.

It is well known that pharmacological treatment of obesity with sibutramine, in combination with basic lifestyle changes and medical nutrition therapy, is often very effective in promoting weight loss in obese subjects.^6,7,13 However, beta adrenergic antagonists have been shown to cause weight gain in hypertensive obese individuals.^23,24 It is shown that the hypophagic response to sibutramine in rats is partially blocked by metoprolol due to a beta-1 effect.²⁵ High-dose beta blocker treatment blocked the rise in oxygen consumption in sibutramine treatment, but a low dose of a beta-1-selective beta blocker did not.²⁶ The dose of metoprolol may be the key to successful blocking of the cardiovascular adverse effects while preserving the efficacy for weight loss. In our study, we observed a significant weight reduction of more than 10% in nearly all of our patients. Weight reduction was quite effective and similar in both groups, thus combination of low-dose metoprolol with sibutramine did not alter the therapeutic effect of the drug. A similar finding was reported by Sramek et al²⁷ previously, in that study sibutramine was found to be effective in obese hypertensive patients already on beta adrenergic blocker treatment.

Beta adrenergic antagonists have some deleterious effects on energy and lipid metabolism, leading to peripheral insulin resistance and dyslipidemia.^23,24 With respect to the metabolic parameters, we did not find any difference between the two groups at the end of the study period. Combination of low-dose beta adrenergic antagonist with sibutramine treatment does not cause significant deleterious effects on metabolic parameters.

The hyperadrenergic effects of sibutramine often became symptomatic and led to discontinuation of the treatment in up to 5% of the patients.^12,13,28 In our study population, we observed a significantly lower drop-out rate in the metoprolol group. Both groups experienced some side effects, which could be attributed to sibutramine treatment, but reported side effects were lower in the metoprolol group, especially being significant for palpitations and headache.

As a result, pharmacological treatment of obesity with sibutramine, in combination with basic lifestyle changes and medical nutrition therapy, is quite effective in promoting weight loss in obese subjects. However, treatment is associated with an increase in diastolic blood pressure, heart rate and sometimes intolerable side effects. The addition of low-dose metoprolol to sibutramine therapy increased patient compliance to the treatment and decreased the frequency and severity of side effects including hypertension and palpitations, without decreasing the drug efficacy or causing significant deleterious changes in metabolic parameters.

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Acknowledgements

Part of this study was presented at the Ninth International Congress on Obesity in Sao Paulo-Brasília and printed as an abstract in the International Journal of Obesity Related Metabolic Disorder 2002; 26: S151.