PAPER How Does Sibutramine Work?
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International Journal of Obesity (2001) 25, Suppl 4, S8–S11 ß 2001 Nature Publishing Group All rights reserved 0307–0565/01 $15.00 www.nature.com/ijo PAPER How does sibutramine work? MEJ Lean1* 1Department of Human Nutrition, University of Glasgow, Glasgow Royal Infirmary, Glasgow, UK Sibutramine offers three types of benefit in weight management: by enhancing weight loss, by improving weight maintenance and by reducing the comorbidities of obesity. The clinical effects of sibutramine are explained through its known mode of action as a serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI). This dual mechanism of action results in two synergistic physiological effects — a reduction in energy intake and an increase in energy expenditure, which combine to promote and maintain weight loss. International Journal of Obesity (2001) 25, Suppl 4, S8 – S11. Keywords: sibutramine; serotonin and noradrenaline reuptake inhibitor (SNRI); energy intake; energy expenditure; weight loss Introduction a 1 y, family practitioner study reported that daily sibutra- Sibutramine is a novel compound which establishes a new mine treatment was associated with significant enhance- class of drug for weight management. When administered ment of satiety (P < 0.01), a reduction in hunger scores daily as part of a weight management programme that (P < 0.001), and reduced cravings for sweet foodstuffs includes diet and exercise, sibutramine allows patients to (P < 0.05) and for carbohydrates (P < 0.01).2 lose weight and to maintain energy balance at a lower body A study by Chapelot et al designed to assess energy intake weight. over a 24 h period found that sibutramine treatment could The weight loss induced by sibutramine is achieved by significantly (P < 0.001) reduce total daily energy intake two complementary physiological effects. by about 1.3 MJ (310 kcal=day).3 From such evaluations of reduced energy intake, it is possible to predict the potential effect of sibutramine on weight over time. Assuming a Enhanced satiety continued total energy deficit per day of 1.3 MJ or 310 First, sibutramine promotes satiety after eating. This leads to calories, it can be calculated that, over a 3-month period, a a reduced food intake and decreased tendency towards deficit of some 27 900 kcal will occur, approximating to snacking. It is important to note that sibutramine does not around 4 kg of weight loss. More importantly, if this deficit induce, as a primary effect, a state of anorexia which can be is maintained and assuming no compensatory reduction in unpleasant. Instead, it enhances and may extend satiety by energy expenditure, the calculation can be extrapolated inducing a feeling of fullness after eating. Studies in which further to predict that reduced energy intake would achieve patients have been asked to rate their feelings of satiety on a energy balance with the mainenance of 13 kg weight loss. visual analogue scale (VAS) have shown that sibutramine- treated subjects achieve higher scores than untreated sub- jects.1 Eighteen clinical studies conducted with sibutramine Energy expenditure stimulated assessed satiety using VAS and, despite these studies not Energy intake to maintain a given body weight comprises being powered to detect secondary end-points, data from three major drivers — the basal metabolic rate, thermogen- nine of the 18 studies show a significant effect of sibutramine esis in response to food and the thermogenic consequences on satiety, food cravings, hunger and snacking. For example, of supporting physical activity. The cost of movement and activity is increased in obese subjects, thermogenesis may be reduced, and basal rate is known to increase with a rise in body fat and the associated rise in lean body mass. It is also known that during and following weight gain, *Correspondence: MEJ Lean, Department of Human Nutrition, University of Glasgow, Queen Elizabeth Building, Glasgow, G31 2ER, UK. there is an increase in total daily energy requirement, and E-mail: [email protected] that conversely, with weight loss, there is normally a decline How does sibutramine work? MEJ Lean S9 in metabolic rate. The second effect of sibutramine is to Enhanced actions on noradrenaline and=or 5-HT systems stimulate energy expenditure, so limiting the decline in such as those displayed by sibutramine leads to an earlier metabolic rate that normally accompanies weight loss. This onset of satiety after meals. Finally, sibutramine does not action, mediated in experimental animals by brown adipose inhibit monoamine oxidase,9 thus avoiding the side effects tissue thermogenesis, is well described. The relative effect is associated with this mode of action. smaller in humans but can be estimated as a relative increase Sibutramine decreases food intake by enhancing central of around 100 kcal per day.4,5 Whether the thermogenic noradrenaline and 5-HT function — the synergistic effects of effect of sibutramine is mediated by brown adipose tissue these neurotransmitters are mediated through a1 and b1 in humans is unproven. In human adults, brown adipose adrenoceptors and 5-HT2A=2C receptors. The attenuation in tissue (all the internal, non-subcutaneous fat) is usually the decline in energy expenditure post-weight loss also inactive and greatly expanded by lipid accumulation. How- involves the combined interaction between enhanced nora- ever, its metabolic capacity for the thermogenesis remains, drenaline and increased 5-HT function in the central ner- and can be stimulated by catecholamines, eg with a phao- vous system (CNS). This results in the selective activation of chromocytoma. sympathetic drive to a variety of tissues. In rodents, this These dual actions of sibutramine to restrain food intake includes brown adipose tissue via indirect activation of b3 and to limit the decline in metabolic rate post-weight loss adrenoceptors. combine to ensure that the weight loss achieved by this treatment is greater than that which would be possible through reduced energy intake alone. Improved pharmacological profile The amphetamines, which also induce weight loss, are associated with addiction and alteration of mood — proper- Dual pharmacological action ties thought to be particularly associated with the trans- The pharmacological effect of sibutramine is also two-fold. mitter-releasing actions of these drugs on dopaminergic Sibutramine is a centrally acting, monoamine reuptake inhi- pathways. Sibutramine’s distinct mechanism of action to bitor, blocking the reuptake of both serotonin (5-HT) and reduce the reuptake of noradrenaline and 5-HT from noradrenaline. This unique mechanism of action distin- central neurones, but without significantly influencing the guishes sibutramine from other centrally acting agents that dopamine system, supports the wealth of extensive pre- are known to promote weight loss (see Table 1). clinical, clinical and post-marketing data to demonstrate Unlike drugs such as dexfenfluramine, which cause that sibutramine has a low potential for abuse.10,11 In the release of the neurotransmitter 5-HT and its subsequent study by Cole et al,10 which was designed to evaluate depletion,6 sibutramine is devoid of neurotransmitter- the potential abuse liability of sibutramine compared with releasing activity.7 It is this lack of transmitter-releasing dexamphetamine and placebo in recreational stimulant activity that is believed to distinguish sibutramine, which users, the response to the ‘street value’ questions also indi- effects its action through reuptake inhibition, from all pre- cated a lack of abuse potential for sibutramine (see Figure 1). vious or current weight-loss agents. This is particularly so for the amphetamines, including phentermine, which operate principally by stimulating noradrenaline and dopamine release,8 a feature which physiologically promotes anorexia. Sibutramine has the effect of a reuptake inhibitor in aug- menting the stimuli to satiety in the hypothalamus, rather than creating new signals by causing transmitter release. Table 1 Principals of pharmacological actions of centrally acting agents known to produce weight loss Releasing agents Reuptake inhibitors Agents 5-HT NA DA 5-HT NA DA MAOI Dexamphetamine [[ Phentermine [[ [ Fenfluramine [ Dexfenfluramine [ Sibutramine [[[ Fluoxetine [ Figure 1 Lack of abuse potential with sibutramine: street value. Source: Large ticks indicate where there is statistically and either preclinically and=or Cole et al. Sibutramine: a new weight loss agent without evidence of the clinically significant evidence for this mode of action. A small tick abuse potential associated with amphetamines. J Clin Psychopharm demonstrates where this evidence is not statistically and clinically significant. 1998; 18: 231 – 236. International Journal of Obesity How does sibutramine work? MEJ Lean S10 Mean dollar estimates of ‘street value’ for dexamphetamine were significantly greater than placebo (P < 0.05). Estimates for sibutramine 20 and 30 mg did not separate from placebo, but were significantly different (P < 0.05) from both dose levels of dextroamphetamine. The percentages of patients by treatment for the most enjoyed session were: dextroam- phetamine 30 mg: 45%; dextroamphetamine 20 mg: 28%; placebo: 14%; sibutramine 30 mg: 7%; sibutramine 20 mg: 0%. The use of fenfluramines is associated with the rare but important risk of primary pulmonary hypertension and uncontrolled case reports suggested possible heart valve incompetence.12 Post-marketing surveillance data based on over 3.7 million patient-exposures to sibutramine