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 subjects.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: dextroamphetamine 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 have not been associated with cardiac valvulopathy or PPH. Similarly, data from clinical trials have shown no evidence of either Figure 3 Mean body weight changes during weight loss and weight PPH, cardiac valve dysfunction13 or an increased incidence maintenance phases over 2 y in relation to the expected weight gain of dyspnoea. Interestingly, echocardiographic studies indi- without any intervention. Source: James et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study cate that subclinical valve incompetence is relatively Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet common in obese subjects irrespective of whether or not 2000; 356: 2119 – 2125. they have had drug therapy. induced weight loss may help to improve long-term control of diabetes and papers within this supplement (see Van Gaal Sibutramine — effects on cardiovascular risk factors and Peiffer, and Sharma, in this issue) consider in more detail The physiological effects of sibutramine include stimulation the role of sibutramine in the management of obesity of the sympathetic nervous system so pulse rates and blood in these obese=overweight patients with type 2 diabetes pressure increases are to be expected. Weight loss serves to and also in obese=overweight patients with hypertension, minimise or even reverse these effects — especially the effect respectively. on blood pressure — and sibutramine-treated patients have a fall in blood pressure proportional to their weight loss, albeit not as low as that seen in the smaller number of patients who Weight loss and weight maintenance manage to achieve the same weight loss by diet alone. The As shown in Figure 2, successful weight management is sibutramine-assisted weight loss itself then reduces the risk considered to include not only initial weight loss over a of other obesity-related comorbidities, such as abnormal matter of months, but also maintenance of weight at a lower lipids and type 2 diabetes, to the same degree as expected level over a period of years. from the amount of weight loss. The pharmacological actions of sibutramine result in A number of studies have shown that sibutramine treat- augmented weight loss, which is usually complete within 6 ment has beneficial effects on secondary efficacy variables months. Daily treatment with sibutramine then leads to a such as lipid profile and glycaemic control. Sibutramine- better maintenance of weight over at least a 24-month period than would be obtained when using diet and lifestyle changes alone, or by use of drugs such as fluoxetine which act on a single monoamine system.14 The results of the STORM study which looked at mean body weight changes during the weight-loss period and over a weight maintenance phase totalling 2 y, showed that, compared with patients managed by diet and exercise alone, some 43% of obese patients given daily sibutramine, in addition to the same diet and exercise, maintained 80% or more of their weight loss (see Figure 3). Only 16% of control patients (previously treated with sibutramine) managed to achieve this level of sustained weight loss. Thus sibutramine treatment had a significant (P < 0.001) effect on weight maintenance as compared with diet and exercise alone. The amount of weight loss maintained on sibutramine is about 12 kg below the expected weight with no inter- Figure 2 Successful weight management includes both initial weight 15 loss and long-term maintenance. Continued weight loss beyond about 6 vention, similar to that predicted from its effect on food months could be dangerous. consumption.3

International Journal of Obesity How does sibutramine work? MEJ Lean S11 Summary 7 Gundlah C, Martin KF, Heal DJ, Schjott J, Auerbach SB. In vivo criteria to differentiate monoamine reuptake inhibitors from Sibutramine offers three types of benefit in weight manage- releasing agents: sibutramine is a reuptake inhibitor. J Pharmac ment: by enhancing weight loss, improving weight main- Exp Ther 1997; 283:581– 591. tenance; and by reducing the comorbidities of obesity. The 8 Rowley HL, Butler SA, Prow MR, Dykes SG, Aspley S, Kilpatrick IC, clinical effects of sibutramine are explained through its Heal DJ. A comparison of the effects of sibutramine and other weight-modifying drugs on extracellular dopamine in the known mode of action. Sibutramine induces initial weight nucleus accumbens of freely-moving rats. Synapse 2000; 38: loss and continues to be effective long-term, once the 167 – 176. expected plateau in weight loss has occurred. The long- 9 Kilpatrick IC, Traut M, Heal DJ. Monoamine oxidase inhibition is term impact of sibutramine should be compared with the unlikely to be relevant to the risks associated with phentermine and fenfluramine: a comparison with their abilities to evoke expected weight gain of 1 – 2 kg per year in the obesity-prone monoamine release. Int J Obes Relat Metab Disord 2001: 25: 15 population. 1454 – 1458. 10 Cole JO, Levin A, Beake B, Kaiser PE, Scheinbaum ML. Sibutra- mine: a new weight loss agent without evidence of the abuse References potential associated with amphetamines. J Clin Psychopharm 1 Hansen DL, Toubro S, Stock MJ, MacDonald IA, Astrup A. The 1998; 18: 231 – 236. effect of sibutramine on energy expenditure and appetite during 11 Schuh LM, Schuster CR, Hopper JA, Mendel CM. Abuse liability chronic treatment without dietary restriction. Int J Obes Relat assessment of sibutramine, a novel weight control agent. Psycho- Metab Disord 1999; 23: 1016 – 1024. pharmacy 2000; 147: 339 – 348. 2 Sibutramine Clinical Summary November 2000, Abbot=Knoll 12 Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A data on file. population-based study of appetite-suppressant drugs and the 3 Chapelot D, Marmonier C, Thomas T, Hanotin C. Modalities of risk of cardiac-valve regurgitation. New Engl J Med 1998; 339: the food intake-reducing effect of sibutramine in humans. Physiol 719 – 724. Behav 2000; 68: 299 – 308. 13 Bach DS, Rissanen AM, Mendel CM Shepherd G, Weinstein SP, 4 Toubro S, Sorensen TI, Ronn B, Christensen NJ, Astrup A. Twenty- Kelly F, Seaton TB, Patel B, Pekkarinen TA, Armstrong WF. four-hour energy expenditure: the role of body composition, Absence of cardiac valve dysfunction in obese patients treated thyroid status, sympathetic activity, and family membership. with sibutramine. Obes Res 1999; 7: 363 – 369. J Clin Endocrinol Metab 1996; 81: 2670 – 2674. 14 James WPT, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, 5 Walsh KM, Leen E, Lean MEJ. The effect of sibutramine on resting Saris WH, Van Gaal LF. Effect of sibutramine on weight main- energy expenditure and adrenaline-induced thermogenesis in tenance after weight loss: a randomised trial. STORM Study obese females. Int J Obes Relat Metab Disord 1999; 23: 1009 – 1015. Group. Sibutramine Trial of Obesity Reduction and Maintenance. 6 Butler SA, Slater NA, Prow MR, Aspley S, Martin KF, Heal DJ. Lancet 2000; 356: 2119 – 2125. D-Fenfluramine-induced depletion of rat brain 5-HT is prevented 15 Heitmann BL, Garby L. Patterns of long-term weight changes in by fluoxetine or sibutramine pretreatment. Br J Pharmac 1997; overweight developing Danish men and women aged between 30 120(Suppl): 350. and 60 years. Int J Obes Relat Metab Disord 1999; 23: 1074 – 1078.

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