Controversial Effects of Sibutramine on Autonomic Cardiovascular Regulation

Abstract

Background: Sibutramine, a serotonin and norepinephrine transporter blocker, is widely used as an adjunctive treatment of obesity. Genetic variability in the norepinephrine transporter gene and selective pharmacological blockade elicit profound changes in cardiovascular regulation, particularly with standing. Whether or not sibutramine elicits a similar response is unknown. Methods: In 11 healthy subjects (7 men, age 27±2 years, BMI 23.1±0.7 kg/m), we compared the effect of 20mg Sibutramine or matching placebo ingested 26h, 14h and 2h before testing. In addition, we tested sibutramine in combination with the beta-1 adrenoreceptor blocker metoprolol. The study was conducted in a randomized, double-blind, crossover fashion. We determined cardiovascular responses to autonomic reflex tests and to a graded head-up tilt test (HUT). Results: While supine, heart rate was 62±2 bpm with sibutramine, 58±2 bpm with placebo and 54±2 bpm with sibutramine and metoprolol. At 75° HUT, heart rate was 97±3 bpm with sibutramine, 85±2 bpm with placebo, and 66±3bpm with sibutramine and metoprolol (p<0.01 sibutramine vs placebo), respectively. Supine systolic arterial pressure was 121±3 mmHg with sibutramine, 113±3 mmHg with placebo and 111±2 mmHg with sibutramine and metoprolol and 120±4 mmHg, 108±3mmHg and 104±3mmHg with sibutramine, placebo and sibutramine with metoprolol at 75° HUT (p<0.01 sibutramine vs placebo). The rate pressure products, a rough estimate of myocarial oxygen consumption, was markedly increased with sibutramine and decreased with sibutramine and metoprolol. Sibutramine attenuated the blood pressure response to hand grip and cold pressor testing. Conclusion: In normotensive subjects, sibutramine increases resting blood pressure while attenuating the response to sympathetic stimuli. Sibutramine causes a marked increase in upright heart rate, which can be prevented with beta adrenoreceptor blockade.