PAPER Sibutramine: Its Mode of Action and Efﬁcacy

N Finer1*

1Addenbrooke’s Hospital, Cambridge, UK

Sibutramine has a dual mode of action. It reduces food intake and attenuates the fall in metabolic rate associated with weight loss. The drug’s neurochemical actions can also be distinguished from those of previous centrally acting anti-obesity agents. Clinical trials show that two out of three patients taking sibutramine lose 5% weight and that the drug can enhance the maintenance of weight loss. Early weight loss predicts long-term success and can be used to guide clinical practice. To maximize the beneﬁts of sibutramine, it is important that patients receive adjunctive diet and lifestyle therapy. International Journal of Obesity (2002) 26, Suppl 4, S29 – S33. doi:10.1038/sj.ijo.802216

Keywords: sibutramine; mechanism of action; weight loss; predictors of success

Effect of sibutramine on energy balance reduced (P ¼ 0.003). These findings suggest that sibutramine Sibutramine has a dual physiological action, influencing is not acting as a classical anorectic drug because it does not both sides of the energy balance equation. It reduces food stop individuals from starting to eat but it enhances and (energy) intake by enhancing satiety (fullness) and it reduces prolongs the feeling of fullness that develops normally after the decline in metabolic rate that occurs with weight loss. eating. In other studies, this has been shown to result in earlier The acute effects of sibutramine on energy intake have been termination of a meal and the avoidance of inter-meal snacks. demonstrated in a laboratory setting.1 In a crossover study The effect on body weight of this reduced energy intake in normal-weight adult males, sibutramine significantly can be quantified. For example, for a subject weighing 83 kg, decreased the amount of food and the energy content of total daily energy expenditure can be predicted to be food that the subjects chose to consume, resulting in a reduc- about 3000 kcal. If sibutramine reduces energy intake by tion of 312 kcal during the day (P 0.001). In another study,2 300 – 400 kcal a day, over a 6 month period this would lead the effect of sibutramine on energy intake was measured to a predicted weight loss of around 10 kg. However, sibu- after 14 days’ treatment. Energy intake was recorded by detailed tramine has a second mechanism of action; its thermogenic diet diaries and dietary interviews. At each meal, individuals effects4 limit the fall in metabolic rate, and the consequent who had taken sibutramine consumed significantly less fall in energy expenditure, that occurs with weight loss. This food than those who had taken a placebo (P < 0.05) with a action produces additional weight loss. These dual actions reduction in total energy intake of 356 kcal per day. predict that sibutramine would lead to both weight loss and The psychological constructs, such as hunger or fullness, weight loss maintenance, findings confirmed in clinical that lead to eating behaviour can be measured by asking trials. subjects to record them at regular intervals using a visual analogue scale (VAS). These results can be plotted against time and the area under the curve taken as an index of the Neurochemical actions of sibutramine construct under investigation. In one study,3 subjects were Sibutramine influences both noradrenergic and serotonergic asked to complete a series of hourly VAS scores from 08:00 to (5HT) pathways within the hypothalamus concerned in 23:00 h. Compared with placebo, sibutramine was associated energy balance, inhibiting reuptake of both serotonin and with enhanced fullness (not significant) and satiety noradrenaline released from hypothalamic neurons. Both (P ¼ 0.003), while hunger and expectation (how much the these effects are integral to its anti-obesity actions. As subject thought they could eat) were both significantly shown in Table 1, these neurochemical actions serve to distinguish sibutramine from previous centrally acting anti- obesity agents. The early amphetamine-like drugs — dexamphetamine *Correspondence: N Finer, Wellcome Trust Clinical Research Facility, 5th Floor ACCI, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2QQ, UK. and phentermine — were potent agents that stimulated the E-mail: [email protected] release of dopamine and noradrenaline centrally. The next Mode of action and efficacy N Finer S30 Table 1 Pharmacology of centrally acting agents known to induce weight loss

Releasing agent Reuptake inhibitor

Agent Serotonin Noradrenaline Dopamine Serotonin Noradrenaline Dopamine pp Dexamphetamine pp Phentermine p Fenﬂuramine p Dexfenﬂuramine p Fluoxetine pp Sibutramine

generation of drugs — the fenfluramines — acted predomi- recruited 605 patients with a mean age of 40 y. Around 500 nantly by stimulating release of serotonin, both centrally patients completed the weight-loss phase and 467 were and almost certainly peripherally. Continued stimulation led randomized (352 sibutramine and 115 placebo) into the to depletion of presynaptic neurotransmitters and possible 18-month, double-blind, weight-maintenance phase. Over- neurotoxicity. It is that direct releasing effect, particularly in all, 204 subjects completed the sibutramine arm of the study the periphery, that is likely to have led to the unwanted and 57 the placebo arm. effects associated with the fenfluramines. With sibutramine, Despite the continued lifestyle programme, patients physiological, rather than directly stimulated, release of assigned to placebo began to regain weight 2 months after neurotransmitter occurs but, because reuptake is blocked, randomization. Their weight trajectories subsequently clearly the effect of the neurotransmitter on post-synaptic receptors separated from the sibutramine group (Figure 1). The placebo is enhanced. There is no depletion of neurotransmitter in group continued to regain weight steadily and by month 24 the presynaptic vesicles and this difference is fundamental to had regained nearly 80% of the weight loss achieved during an understanding of sibutramine and its different, and the initial weight-loss phase. In contrast, in the sibutramine improved, safety profile. group, weight loss was maintained to 18 months (12 months Fluoxetine, an anti-depressant, is also a serotonin but not after the weight loss phase) before there was evidence of a noradrenaline reuptake inhibitor and has been evaluated as weight regain. This regain was slight and reflected the a weight loss agent. While it produced modest short-term normal weight increase that might be expected with time. At weight loss, weight was regained, despite continued adminis- month 24, the sibutramine group had maintained over 85% tration, and the drug therefore has no proven value for of the weight loss achieved at the end of the weight loss phase. weight management. This 2 y study therefore demonstrates that sibutramine not only induces weight loss but is also able to maintain that weight loss in the long term. Figure 2 compares the results of Weight loss with sibutramine sibutramine treatment in the STORM study against a weight Clinicians are interested not just in weight loss, but also in trajectory predicted for untreated obese patients over a 2 y maintenance of weight loss. The ultimate goal of treatment period (2 kg=y). The divergence between the two lines shows for obese patients is to lose weight and then to maintain the the drug’sefficacy in long-term weight maintenance. new weight, ie to reach a perfect plateau. However some Adjunctive diet and lifestyle therapy is important to weight regain with time is probably inevitable. The natural maximize the effects of any drug treatment of obesity. This history of body weight is to increase with age, usually at the rate of 1 – 2kg=y. To achieve a complete plateau would require a drug not only to continue exerting its effect, but to exert an ever-increasing effect to counteract the natural course of weight gain. It seems likely that a small degree of weight regain is biologically almost inevitable with any drug, and not a sign of declining efficacy. The STORM (Sibutramine Trial on Obesity Reduction and Maintenance) trial5 was designed to evaluate the effects of sibutramine on weight maintenance after an initial period of weight loss. It was a double-blind, randomized, placebo- controlled study conducted over 18 months in patients who had successfully lost weight (> 5%) in a 6 month open-label weight loss phase in which all subjects were given sibutramine (10 mg=day), diet, exercise and behavioural support. Figure 1 Weight loss and weight maintenance in the STORM study. The study was conducted in eight European centres and Source: James et al.5

International Journal of Obesity Mode of action and efﬁcacy N Finer S31 Table 2 Clinical beneﬁts from different degrees of weight loss at 1 y

Degree of Nature of weight loss improvement Reference

< 5% Loss Improved CV risk proﬁle Wilson9 5% Diabetes prevention Tuomilehto,11 Knowler10 Improved quality of life Kolotkin12 Symptomatic improvements, Felson13 eg osteoarthritis of the knee

10% Loss Improvements in sleep apnoea Largerstrand14 Improved lung function in Stenius-Aarniala15 asthma Decreased mortality Singh,16 Williamson17 Figure 2 Weight maintenance in the STORM study compared with expected weight gain over a two-year period. Source: adapted from James et al.5 both diet and exercise. It showed that extremely good weight can be illustrated by a comparison of four sibutramine loss can be achieved if the drug is given continuously, together clinical trials.5 – 8 with diet and lifestyle advice and support. A 12 month placebo controlled trial conducted in general Considering these four trials together (Figure 3) shows practice6 used one of two doses of sibutramine (10 and clearly that the two trials that provided sibutramine with 15 mg) in combination with simple, written, dietetic only minimal diet and lifestyle advice produced modest advice. Sibutramine was effective but the difference weight loss, but were not nearly as successful as those between the 10 mg dose and the placebo group was small providing a more intensive support programme. Thus, to (about 4 – 5%). Weight loss was maintained throughout the achieve the best results from sibutramine, patients should be year but the absolute weight loss was relatively limited. treated comprehensively, and the drug must not be used in The second trial was a 6 month dose-ranging study con- place of diet and lifestyle advice. ducted in a hospital setting but again with limited dietary As shown in Table 2, while there is benefit from any degree of intervention.7 Overall, weight loss with sibutramine was weight loss, there are greater benefits from modest weight approximately 10 lb (4.5%). loss of 5%, while a weight loss of 10%, if this can be A third trial8 used 4 weeks of a very-low energy diet achieved, has been reported to be associated with improve- 9 – 17 (220 – 800 kcal=day) for weight loss induction. This resulted ments in sleep apnoea and asthma and decreased mortality. in a weight loss of approximately 7 kg. Patients were then Data collated from six 1 y placebo-controlled studies of 18 randomized to a more modest diet, which was tightly super- sibutramine show that 76% of subjects who received vised, and individually prescribed, together with sibutra- placebo failed to achieve even a 5% weight loss, despite the mine or placebo for 12 months. In placebo-treated drug being used in a clinical trial setting. In contrast, two- patients, maintenance of the weight lost in the initial 4 thirds of those who received sibutramine achieved 5% weeks was quite good. However, patients in the sibutramine weight loss and a third achieved 10% weight loss (Figure 4). group continued to lose weight and then maintain this It is important to remember that analysis of clinical trials further weight loss over the 12-month study period. Total requires that all patients entered are retained even if they are weight loss was significantly greater in the sibutramine early non-responders. In clinical practice, a patient who had group (P < 0.001 compared with placebo). failed to respond in the first weeks or months of treatment The hospital-based STORM study5 provided comprehensive, individual and supervised lifestyle management incorporating

Figure 4 Weight loss in sibutramine-treated patients (data taken from Figure 3 Effect of adjunctive therapy on weight loss with sibutramine. six 12 month placebo controlled studies). Source: Astrup et al.18

International Journal of Obesity Mode of action and efﬁcacy N Finer S32 In clinical practice, these ﬁgures can be used to target treatment to appropriate patients in order to achieve medi- cally valuable weight loss.

Summary Sibutramine has two modes of action, affecting both energy intake and energy expenditure. Clinical trials show that two-thirds of patients will achieve a weight loss of 5% and one-third a weight loss of 10%. Weight loss is enhanced if intensive lifestyle therapy is also provided. In clinical practice, a patient’sresponsetothefirst month of treatment is an important predictor of long-term weight loss and maintenance. Figure 5 Weight loss at one month predicts success of sibutramine treatment at 1 y. Source: Abbott Laboratories, data on file. References 1 Chapelot D, Marmonier C, Thomas F, Hanotin C. Modalities of the food intake-reducing effect of sibutramine in humans. Physiol Behav 2000; 68: 299 – 308. 2 Rolls BJ, Shide DJ, Thorwart ML, Ulbrecht JS. Sibutramine reduces food intake in non-dieting women with obesity. Obes Res 1998; 6:1– 11. 3 Hansen DL, Toubro S, Stock MJ, Macdonald IA, Astrup A. The effect of sibutramine on energy expenditure and appetite during chronic treatment without dietary restriction. Int J Obes Relat Metab Disord 1999; 23: 1016 – 1024. 4 Hansen DL, Toubro S, Stock MJ, Macdonald IA, Astrup AV. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998; 68: 1180 – 1186. 5 James WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Figure 6 Weight loss at three months predicts success of sibutramine Lancet 2000; 356: 2119 – 2125. treatment at 1 y. Source: Abbott Laboratories, data on file. 6 Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001; 50:505– 512. 7 Bray GA, Blackburn GL, Ferguson JM, Greenway FL, Jain AK, would not continue to be treated for a year or more. Mendel CM, Mendels J, Ryan DH, Schwartz SL, Scheinbaum ML, Mean weight loss and weight maintenance data from trials Seaton TB. Sibutramine produces dose-related weight loss. Obes Res 1999; 7: 189 – 198. therefore will tend to underestimate the likely clinical weight 8 Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, loss that might be expected on average in clinical practice. Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med 1999; 106: 179 – 184. Predictors of success 9 Wilson PW, Kannel WB, Silbershatz H, D’Agostino RB. Clustering Data from the STORM study have been evaluated to see if pre- of metabolic factors and coronary heart disease. Arch Intern Med treatment factors can be identified that predict treatment 1999; 159: 1104 – 1109. response.19 Although some factors did predict successful weight 10 Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, Nathan DM. Reduction in the incidence loss (eg pre-treatment body weight, resting metabolic rate), these of type 2 diabetes with lifestyle intervention or metformin. New were poor predictors and accounted for less than 10% of the Engl J Med 2002; 346: 393 – 403. variability between individuals in their response to sibutramine. 11 Tuomilehto J, Lindstrom J, Eriksson JG, Valle TT, Initial weight loss in response to sibutramine treatment, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaaniemi S, Laakso M, Louheranta A, Rastas M, Salminen V, Uusitupa M. however, is known to be an important predictor of long-term Prevention of type 2 diabetes mellitus by changes in lifestyle success.20 Patients who lose between 1 kg and 2 kg at 1 month among subjects with impaired glucose tolerance. New Engl J Med are predicted to achieve a 3.5 kg weight loss at 1 y while those 2001; 344: 1343 – 1350. who lose more than 3 kg at 1 month might be expected to 12 Kolotkin RL, Head S, Hamilton M, Tse CK. Assessing impact of weight on quality of life. Obes Res 1995; 3:49– 56. achieve a 10.5 kg weight loss. Patients who do not achieve 13 Felson DT, Zhang Y, Anthony JM, Naimark A, Anderson JJ. 3 kg weight loss by 3 months are unlikely to achieve any Weight loss reduces the risk for symptomatic knee osteoarthritis significantly important weight loss at 1 y (Figures 5 and 6). in women. The Framingham Study. Ann Intern Med 1992; 116: 535 – 539. Further analysis of sibutramine trial data suggests that 72% of 14 Largerstrand L, Rossner S. Effects of weight loss on pulmonary patients who lost 2 kg at week 4 went on to become 5% function in obese men with obstructive sleep apnoea syndrome. responders (Abbott Laboratories, data on file). J Intern Med 1993; 234: 245 – 247.

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