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Obesity is epidemic; new medications and therapeutic options are urgently needed to reduce the associated health care burden. The initial clinical strategy for weight loss is lifestyle modification involving a combination of diet, exercise, and behavior change. However, it is difficult for many to achieve and maintain weight loss solely through this approach. Only two drugs, orlistat and sibutramine, have been approved by the US Food and Drug Administration (FDA) to treat obesity long term, and both medications have undesirable side effects, leaving an enormous unmet need for efficacious and safe therapy for obesity. Other medications with weight-loss effects have been approved by the FDA for short-term treatment of obesity or for disorders other than obesity, but these also have potential adverse effects. This article discusses the perceived benefits and risks of these approved medications along with emerging drugs that have shown weight-loss effects.
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.