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(Circulation. 2002;106:2459.)
© 2002 American Heart Association, Inc.

Clinical Investigation and Reports

Paradoxical Effect of Sibutramine on Autonomic Cardiovascular Regulation

Andreas L. Birkenfeld, MD; Christoph Schroeder, MD; Michael Boschmann, MD; Jens Tank, MD, PhD; Gabi Franke; Friedrich C. Luft, MD; Italo Biaggioni, MD; Arya M. Sharma, MD; Jens Jordan, MD

From the Franz-Volhard Clinical Research Center (A.L.B., C.S., J.T., G.F., F.C.L., A.M.S., J.J.), Medical Faculty of the Charité, Humboldt-University, Berlin, Germany; German Institute of Human Nutrition (M.B.), Potsdam, Germany; and Autonomic Dysfunction Service (I.B.), Vanderbilt University, Nashville, Tenn.

Correspondence to Jens Jordan, MD, Clinical Research Center, Haus 129, Franz-Volhard-Clinic, Humboldt University, Wiltbergstraße 50, 13125 Berlin, Germany. E-mail jordan{at}fvk-berlin.de

	Abstract

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Background— Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive obesity treatment. Norepinephrine reuptake inhibition with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease.

Methods and Results— In 11 healthy subjects (7 men, age 27±2 years, body mass index 23.1±0.7 kg/m²), we compared the effect of sibutramine or matching placebo (ingested 26, 14, and 2 hours before testing) on cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test. In addition, we tested sibutramine in combination with metoprolol. Testing was conducted in a double-blind and crossover fashion. Supine systolic blood pressure was 113±3 mm Hg with placebo, 121±3 mm Hg with sibutramine (P<0.001 versus placebo), and 111±2 mm Hg with the combination of sibutramine and metoprolol. Similarly, sibutramine increased upright blood pressure. Sibutramine substantially increased upright heart rate. This effect was abolished with metoprolol. The blood pressure response to cold pressor and handgrip testing was attenuated with sibutramine compared with placebo. Furthermore, sibutramine decreased low-frequency oscillations of blood pressure and plasma norepinephrine concentrations in the supine position.

Conclusions— The cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous system effects. The inhibitory clonidine-like action of sibutramine on the central nervous system attenuates the peripheral stimulatory effect. Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reconsidered.

Key Words: obesity • norepinephrine • nervous system, sympathetic • catecholamines

	Introduction

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About one third of the adult population in the United States is obese.^1,2 Achieving weight control in this population would have a major effect on cardiovascular health. The first-line therapy of obesity is reduction in caloric intake and physical exercise. Unfortunately, many patients do not achieve sufficient weight loss with diet and exercise alone.³ One possible therapeutic approach is a combination of diet and exercise with medications. The serotonin and norepinephrine uptake inhibitor sibutramine is a frequently used antiobesity drug.^4–6 The beneficial effect of sibutramine on body weight is mainly mediated through an increase in satiety, although a mild increase in energy expenditure may also be contributory.⁷ Inhibition of norepinephrine uptake with sibutramine conceivably could exacerbate arterial hypertension and promote cardiovascular disease. Yet, data on the cardiovascular effects of sibutramine are surprisingly limited. When applied locally to peripheral tissues, norepinephrine transporter blockade increases norepinephrine overflow.⁸ This effect would tend to increase blood pressure. However, when applied to the central nervous system, norepinephrine transporter blockade paradoxically attenuates sympathetic activity.⁹ Thus, systemic changes in norepinephrine transporter function due to mutations in the norepinephrine transporter gene or pharmacological manipulation are associated with complex and opposing cardiovascular effects.^10–12 We conducted a randomized, double-blind, crossover study in young, healthy, normotensive volunteers to characterize the cardiovascular effects of sibutramine both at rest and during sympathetic stimulation. We also tested the hypothesis that systemic ß-adrenergic receptor blockade reverses the effects of norepinephrine transporter blockade. Finally, we conducted measurements of free-energy conversion by indirect calorimetry to assess the thermogenic profile of sibutramine in the presence or absence of systemic ß-adrenoceptor blockade.

	Methods

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Subjects
We approached 12 healthy subjects to participate in the study. Eleven subjects were included (7 men, 4 women, age 26.5±2 years, body mass index 23.1±0.7 kg/m²). One subject declined to participate. Written informed consent was obtained before study entry. All studies were approved by the institutional review board.

Protocol
Seven days before each study experiment, food and liquid uptake were recorded by a daily protocol. Forty-eight hours before the experiment, volunteers were asked to abstain from substances that interfere with catecholamine measurements. The subjects underwent 3 experiments on separate days. Subjects ingested either 10 mg of sibutramine (Reductil, Knoll) 26 hours before testing, 10 mg of sibutramine 14 hours before testing, and 20 mg of sibutramine 2 hours before testing or matching placebo at the same time points. On a third study day, subjects ingested 200 mg of metoprolol (Metoprolol Stada, STADApharm) 2 hours before study in addition to sibutramine. Studies with placebo, sibutramine, and sibutramine plus metoprolol were conducted on separate days, with at least 7 days between each intervention, in a double-blind, crossover fashion.

Instrumentation
After an overnight fast, a catheter was placed in a large antecubital vein for the determination of plasma catecholamines.¹³ Respiration, transthoracic bioimpedance, and ECG were measured continuously (Cardioscreen, Medis GmbH). Cardiac stroke volume was calculated according to Sramek’s formula.¹⁴ Beat-by-beat blood pressure (Finapres, Ohmeda) and brachial arterial blood pressure (Dinamap, Critikon) were determined. Oxygen consumption and carbon dioxide production were measured by indirect calorimetry (DeltatracII, Datex Ohmeda) during a resting phase and tilt testing to assess energy expenditure and substrate oxidation rate.¹⁵

Autonomic Reflex Testing and Head-Up Tilt Testing
The sinus arrhythmia ratio was calculated as the ratio of the longest to the shortest RR interval during 1 of 10 controlled breathing loops (5-second inhalation and 5-second exhalation). Patients performed a Valsalva maneuver (40 mm Hg pressure for 15 seconds). We determined responses to isometric handgrip (30% maximum contraction for 3 minutes) and cold pressor testing (1 minute immersion of the hand in ice water). After completion of autonomic reflex testing, subjects recovered for at least 30 minutes in the supine position. Then, subjects were gradually tilted upright by 15° every 3 minutes until 75° head-up tilt (HUT) was reached. The subjects remained at 75° HUT for an additional 30 minutes or until presyncopal symptoms occurred.

Spectral Analysis and Baroreflex Sensitivity
Heart rate and blood pressure variability were determined by standard techniques.^16,17 Spontaneous baroreflex sensitivity was assessed by the sequence technique and cross-spectral analysis.^18–20

Statistics
All data are expressed as mean±SEM. Repeated-measures ANOVA testing was used for multiple comparisons. Intraindividual differences were compared by 1-way ANOVA testing for repeated measures. Tukey’s post hoc test was performed when P<0.05. A value of P<0.05 was considered significant. All supine values are mean values obtained during 30 minutes of the resting phase.

	Results

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Resting Phase and HUT Testing
In the supine position, heart rate was 58±2 bpm with placebo, 62±2 bpm with sibutramine (P<0.001 versus placebo), and 54±2 bpm with sibutramine and metoprolol (Figure 1, top). After 3 minutes of 75° HUT, heart rate was 85±2 bpm with placebo, 97±3 bpm with sibutramine (P<0.01 versus placebo), and 68±2 bpm with sibutramine plus metoprolol, respectively. Immediately before the subjects were tilted back into the supine position, heart rate was 91±4 bpm with placebo, 106±4 bpm with sibutramine (P<0.001 versus placebo), and 66±3 bpm with sibutramine plus metoprolol. Supine blood pressure was 113±3/62±1 mm Hg with placebo, 121±3/65±1 mm Hg with sibutramine (P<0.001 for systolic blood pressure versus placebo), and 111±2/64±2 mm Hg with sibutramine plus metoprolol (P<0.001 for systolic blood pressure versus sibutramine; Figure 1, middle and bottom). After 3 minutes of 75° HUT, blood pressure was 108±3/68±2, 120±4/74±2 (P<0.01 for systolic and P<0.05 for diastolic blood pressure versus placebo), and 103±2/68±3 mm Hg (P<0.001 for systolic and P<0.01 for diastolic blood pressure versus sibutramine) with placebo, sibutramine, and sibutramine with metoprolol, respectively.

View larger version (18K): [in this window] [in a new window]   Figure 1. Heart rate (HR, top), systolic blood pressure (SBP, middle), and diastolic blood pressure (DBP, bottom) in supine position and with incremental HUT angle. Testing was conducted after treatment with placebo, sibutramine, or combination of sibutramine and metoprolol. ***P<0.001.

In the supine position, stroke volume was attenuated with sibutramine compared with placebo (P<0.05). The effect was reversed by metoprolol. With HUT, stroke volume decreased to a similar degree with sibutramine and placebo. When subjects were treated with sibutramine plus metoprolol, stroke volume was better maintained. Cardiac output was similar with placebo and sibutramine while supine but decreased slightly with sibutramine plus metoprolol. With HUT, cardiac output was better maintained with sibutramine than with placebo (P<0.05). However, sibutramine attenuated the increase in peripheral resistance with HUT (P<0.05). This effect was not abolished with metoprolol.

With placebo, vasovagal reactions, with a typical decrease in heart rate and blood pressure, occurred in 1 subject. Tilting had to be stopped because of presyncopal symptoms in a second subject. With sibutramine, all subjects reached the end of tilt testing. With sibutramine plus metoprolol, 3 vasovagal reactions occurred, and tilting had to be stopped in 2 subjects because of presyncopal symptoms.

Autonomic Reflex Testing
Respiratory sinus arrhythmia ratio tended to be decreased with sibutramine (Table 1). The decrease in systolic and diastolic blood pressure during phase II of the Valsalva maneuver was more pronounced with sibutramine than with placebo (P<0.05). The blood pressure overshoot during phase IV was similar with placebo, sibutramine, and sibutramine plus metoprolol. The Valsalva ratio was increased with sibutramine and attenuated with sibutramine plus metoprolol. The pressor response to handgrip testing was blunted with sibutramine (Figure 2). Similarly, sibutramine attenuated the cold pressor response.

View this table: [in this window] [in a new window]   TABLE 1. Autonomic Reflex Testing

View larger version (14K): [in this window] [in a new window]   Figure 2. Individual changes in systolic blood pressure (SBP) after 3 minutes’ handgrip testing (top) and 1 minute of cold pressor testing on placebo and on sibutramine. Sibutramine blunted response to handgrip and to cold pressor testing. *P<0.05, **P<0.01.

Heart Rate and Blood Pressure Variability and Baroreflex Sensitivity
In the supine position and with HUT test, heart rate variability (square root of the mean squared differences of successive normal-to-normal intervals) was lower with sibutramine than with placebo (Table 2). The reduction in heart rate variability was mainly due to a decrease in the high-frequency component of the RR interval. Sibutramine attenuated the low-frequency component of blood pressure variability in the supine position (Figure 3). This effect was not reversed with metoprolol. Supine spontaneous baroreflex variability was similar with placebo, sibutramine, and sibutramine plus metoprolol. The reduction in baroreflex sensitivity with HUT was more pronounced with sibutramine. Metoprolol reversed the effect of sibutramine on upright baroreflex sensitivity.

View this table: [in this window] [in a new window]   TABLE 2. Heart Rate Variability and Baroreflex Sensitivit

View larger version (12K): [in this window] [in a new window]   Figure 3. Low-frequency oscillations of systolic blood pressure (LFSBP) in supine position after placebo, sibutramine, or combination of sibutramine and metoprolol. Low-frequency oscillations are related to sympathetic modulation of systolic blood pressure. Sibutramine attenuated low-frequency oscillations of systolic blood pressure. *P<0.05, **P<0.01.

Plasma Catecholamines
Venous plasma catecholamine data in the supine and upright positions are given in Table 3. In the supine position, sibutramine decreased plasma norepinephrine. This effect was attenuated with metoprolol. In contrast, plasma norepinephrine in the upright position was similar among the interventions. Plasma epinephrine concentrations were increased markedly with sibutramine plus metoprolol. Sibutramine markedly reduced plasma dihydroxyphenylglycol concentrations. Dihydroxyphenylglycol reflects intraneuronal metabolism of norepinephrine.²¹ Plasma dihydroxyphenylacetic acid, the main intraneuronal metabolite of dopamine,¹³ was similar between interventions. Plasma dihydroxyphenylalanine concentrations were not changed with sibutramine.

View this table: [in this window] [in a new window]   TABLE 3. Plasma Catechols

Indirect Calorimetry
In the supine position, energy expenditure was 1680±60 kJ/6 hours with placebo, 1710±75 kJ/6 hours with sibutramine, and 1620±70 kJ/6 hours with sibutramine plus metoprolol (P<0.05, sibutramine versus sibutramine plus metoprolol; Figure 4). Energy expenditure increased with HUT testing. The increase was similar with sibutramine compared with placebo but was attenuated with sibutramine plus metoprolol (P<0.05; Figure 4). As in previous studies, there was a sex effect on the sibutramine response. Sibutramine increased energy expenditure slightly in men but not in women. In the supine position and during tilt testing, the respiratory quotient, which is related to the relative amount of lipid and carbohydrate oxidation, did not differ between treatments. When analyzed separately, in men, sibutramine blunted the respiratory quotient increase with standing (P<0.01 versus placebo).

View larger version (21K): [in this window] [in a new window]   Figure 4. Individual responses of energy expenditure (EE) to sibutramine and combination of sibutramine with metoprolol compared with placebo. Responses were determined as difference between energy expenditure with active drug and response to placebo. Difference greater than 0 suggests that individual energy expenditure was greater during active treatment than during placebo treatment.

Side Effects
Nine of 11 subjects experienced side effects of sibutramine. Six volunteers noticed sleeplessness; in 3 cases, fatigue, dryness of the mouth, and sweating were experienced. Headache and palpitations were mentioned by 1 subject each. With placebo, 1 subject noted sleeplessness, sweating, and dizziness, whereas 1 reported dryness of the mouth.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
We tested the effect of the widely used antiobesity drug sibutramine on cardiovascular regulation at rest and during sympathetic stimulation in young healthy volunteers. We observed that sibutramine increased resting blood pressure slightly. In contrast, the pressor response to sympathetic stimuli was attenuated with sibutramine. In the supine position, sibutramine decreased blood pressure variability in the low-frequency range and plasma norepinephrine concentrations. These paradoxical clonidine-like effects of sibutramine have not been appreciated previously. Sibutramine increased heart rate moderately in the supine position and substantially with standing. In addition, sibutramine elicited subtle changes in heart rate variability. The increase in basal blood pressure and the tachycardic effect of sibutramine were abolished with ß-adrenoceptor blockade. However, ß-adrenoceptor blockade also diminished resting energy expenditure.

When applied to isolated organs or given intra-arterially in low doses, norepinephrine transport inhibitors increase norepinephrine washout.⁸ This effect increases the amount of norepinephrine to which adrenergic receptors are exposed. The effect of sibutramine on peripheral norepinephrine turnover may explain the increase in resting blood pressure, heart rate, and energy expenditure with sibutramine. The heart is particularly dependent on the uptake of norepinephrine for its inactivation.¹⁰ This feature may explain the disproportional increase in heart rate with standing on sibutramine. The heart rate increase with sibutramine was associated with a trend for the ratio between low-frequency and high-frequency oscillations of heart rate to increase.²²

If all the cardiovascular effects of sibutramine could be explained by a peripheral effect, the response to sympathetic stimuli should be increased markedly. Instead, sibutramine clearly attenuated the response to cold pressor and handgrip testing. Moreover, sibutramine attenuated the increase in systemic vascular resistance with standing. Similar but even larger effects can be observed with application of the more potent and selective norepinephrine transport inhibitor reboxetine.¹² Thus, sibutramine must have additional and previously unrecognized effects opposing the peripheral stimulatory effect. This hypothesis is supported by the observation that the increase in energy expenditure with sibutramine treatment is much smaller than one might expect.^7,23

Several lines of evidence suggest that the mechanism opposing the peripheral effects of sibutramine is a reduction in sympathetic outflow from the central nervous system. The low-frequency component of blood pressure variability was markedly reduced with sibutramine. Low-frequency blood pressure oscillations, the so-called Mayer waves, are mediated by the sympathetic nervous system.^24,25 Similarly, selective norepinephrine transporter blockade with reboxetine attenuates low-frequency systolic blood pressure oscillations.¹² Moreover, we observed a marked reduction in venous plasma norepinephrine concentration with sibutramine. Norepinephrine transporter blockade with desipramine decreases sympathetic nerve traffic, whole-body norepinephrine spillover, and renal as well as forearm norepinephrine spillover.¹⁰ A similar reduction in systemic norepinephrine spillover was observed in rabbits when desipramine was applied locally to the brain.⁹ Thus, selective and nonselective norepinephrine transporter blockade leads to a substantial inhibition of sympathetic outflow from the central nervous system. The sympatholytic effect of norepinephrine transporter inhibition is mediated at least in part by central nervous system ₂-adrenoreceptors.^9,21 Baroreflex-mediated inhibition of sympathetic activity in response to the increase in blood pressure may also be contributory. Interestingly, a sympatholytic effect indicated by a marked reduction in 24-hour urinary norepinephrine excretion has also been described for ephedrine, which is sometimes used in the treatment of obesity.²⁶

The fact that sibutramine increases basal blood pressure even though plasma norepinephrine levels and low-frequency oscillations of systolic blood pressure decrease is difficult to explain. One possible explanation is that during inhibition of norepinephrine uptake with sibutramine, the cardiovascular system becomes more responsive to stimulation of adrenergic receptors by endogenous catecholamines. Indeed, in a previous study, selective norepinephrine transporter blockade substantially increased the response to - and ß-adrenergic stimulation.¹²

Because sibutramine may have a central inhibitory effect mediated by ₂-adrenergic receptors, the concomitant use of drugs that act on central ₂-adrenergic receptors should be avoided. This information should be conveyed to patients. ₂-Adrenergic receptor antagonists (yohimbine)²⁷ are readily available as dietary supplements in health-food stores. Our findings suggest that the most obvious cardiovascular effect of sibutramine is a marked increase in standing heart rate. We recommend that heart rate should be measured while patients are upright, particularly in patients who report orthostatic symptoms, palpitations, or angina pectoris. Systemic ß-adrenergic receptor blockade attenuates the effect of sibutramine on resting blood pressure and supine and upright heart rate. However, ß-adrenergic receptor blockade may also attenuate the effect of sibutramine on energy expenditure. ß-Adrenergic receptor blockers are associated with weight gain.²⁸ Nevertheless, preliminary studies suggest that the weight-reducing effect of sibutramine is not completely abolished by ß₁-adrenergic receptor blockade.²⁹

We conclude that the cardiovascular effect of the antiobesity drug sibutramine results from a complex interaction of peripheral and central nervous effects. In a resting young, healthy subject with low sympathetic activity, the peripheral effect of sibutramine may dominate: resting blood pressure increases. However, when sympathetic nervous system activity is acutely increased, the central clonidine-like inhibitory effect of sibutramine becomes apparent: the pressor response to sympathetic stimuli is attenuated. When sympathetic activity is increased even at rest, such as in a larger subgroup of obese hypertensive patients,³⁰ the inhibitory clonidine-like effects of sibutramine might prevail. Even though this hypothesis needs to be tested formally, it could explain the recent preliminary observation that sibutramine markedly decreases resting blood pressure in a significant proportion of hypertensive patients.³¹ Our findings strongly suggest that current concepts regarding the action of sibutramine on the sympathetic nervous system should be reevaluated.

	Acknowledgments

 
This work was supported by Deutsche Forschungsgemeinschaft grant No. 284/3-1. Dr Jordan is the recipient of a Helmholtz fellowship of the Max-Delbrueck-Center of Molecular Medicine.

	Footnotes

 
Dr Sharma is a consultant and speaker for and receives research support from Abbott Pharmaceuticals.

Received June 3, 2002; revision received August 16, 2002; accepted August 16, 2002.

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