- Email: [email protected]
The clinical effectiveness of weight loss drugs
Obesity Research & Clinical Practice (2007) 1, 1—5
REVIEW
The clinical effectiveness of weight loss drugs Gary Wittert a,∗, Ian Caterson b, Nick Finer c a
Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia Human Nutrition Unit, University of Sydney, Sydney, NSW, Australia c Wellcome Trust Clinical Research Facility, Addenbrooke’s Hospital, Cambridge, UK b
Received 18 December 2006; accepted 18 December 2006
KEYWORDS Obesity; Medications; Diabetes mellitus; Hypertension; Pharmacotherapy
Summary At a time when obesity is reaching epidemic proportions across the western world and increasing rapidly in developing countries, clinicians clearly are becoming more aware of the need to offer weight management advice and effective treatment to patients, especially those with a high risk of developing type 2 diabetes. For those patients with a BMI ≥ 30.0 kg/m2 or for those with a BMI of 27.0 kg/m2 with an obesity-related disease such as dyslipidaemia or type 2 diabetes mellitus, modest weight loss in the order of 5% achieved by modification of dietary intake and activity behaviour can significantly improve risk factors for obesity-related diseases and delay progression to type 2 diabetes. Unfortunately, rates of adherence with dietary-based weight management programmes are generally low and for most patients weight regain with time is common. The use of weight loss medications is recognised as a positive strategy for helping patients adhere to lifestyle advice, and has been shown to result in clinically significant and meaningful improvement of symptoms, risk factors and quality of life. Appropriate selection and use of weight management drugs requires an understanding of the benefits and risks associated with each of the available drugs. Clinical trials are ongoing to determine whether weight management interventions (including anti-obesity pharmacotherapy) will impact upon clinical outcome and life expectancy. © 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Contents Introduction................................................................................................... Weight loss drugs ......................................................................................... Weight loss and weight loss maintenance ...............................................................
∗ Corresponding author. Tel.: +61 8 8222 5502; fax: +61 8 8223 3870. E-mail address: [email protected] (G. Wittert).
1871-403X/$ — see front matter © 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2006.12.001
2 2 3
2
G. Wittert et al. Impact on metabolic and cardiovascular risk factors ...................................................... Adverse effects ........................................................................................... Conclusions ................................................................................................... Conflict of interest ............................................................................................ References ..................................................................................................
3 4 4 5 5
Introduction
Drugs for the treatment of obesity can be divided broadly into four main categories:
At a time when obesity is reaching epidemic proportions across the western world and increasing rapidly in developing countries, clinicians clearly are becoming more aware of the need to offer weight management advice and effective treatment to patients, especially those with a high risk of developing type 2 diabetes. For those patients with a BMI ≥ 30.0 kg/m2 or for those with a BMI of 27.0 kg/m2 with an obesityrelated disease such as dyslipidaemia or type 2 diabetes mellitus, modest weight loss in the order of 5% achieved by modification of dietary intake and activity behaviour can significantly improve risk factors for obesity-related diseases [7] and delay progression to type 2 diabetes [6]. Unfortunately, rates of adherence with dietary-based weight management programmes are generally low [2] and for most patients weight regain with time is common [15]. The use of weight loss medications is recognised as a positive strategy for helping patients adhere to lifestyle advice, and has been shown to result in clinically significant and meaningful improvement of symptoms, risk factors and quality of life. Appropriate selection and use of weight management drugs requires an understanding of the benefits and risks associated with each of the available drugs. Clinical trials are ongoing to determine whether weight management interventions (including anti-obesity pharmacotherapy) will impact upon clinical outcome and life expectancy [4,11].
• Drugs that work on neurotransmitter systems modulating food intake or affecting energy expenditure by central and/or peripheral mechanisms. These include those that affect serotonergic and noradrenergic (norepinephrine) neurones, and the more recently described endocannabinoid system. • Drugs that affect digestion and therefore subsequent absorption of macronutrients. • Drugs that affect gastrointestinal neuroendocrine function to alter appetite, satiety and metabolism. Some such agents are available for the management of type 2 diabetes and have been shown to produce weight loss. • Drugs that modify peripheral metabolism by affecting lipolysis, lipogenesis or muscle energy utilisation. Currently there are only three major agents licensed and recommended by Regulatory Agencies for the longer term management of weight loss:
Weight loss drugs
1. Sibutramine, which increases satiety by inhibiting the reuptake of serotonin and noradrenaline (norepinephrine), with a secondary effect on energy metabolism whereby it attenuates some of the fall in metabolic rate that follows weight loss. 2. Orlistat, which is a peripherally acting gastric and intestinal lipase inhibitor that reduces fat digestion and absorption. 3. Rimonabant, which reduces hunger and food intake by selectively inhibiting the CB1 receptor of the endocannabinoid system, but may also have peripheral metabolic actions.
Obesity is the result of a chronic excess energy intake relative to energy expenditure. Energy intake and body weight are tightly controlled by a complex web of signalling mechanisms from the gastrointestinal tract and adipose tissues that link with central pathways within the brain. Additional influences relate to higher level cognitive and behavioural influences that can modulate but not, it seems, successfully override the more physiological controls.
In addition there are two agents that have a direct appetite suppressing effect though neither is generally recommended for weight loss: the selective serotonin reuptake inhibitor fluoxetine has only a mild and poorly sustained impact on weight but is sometimes used in high doses in patients with bulimia or binge eating disorder, and the noradrenaline (norepinephrine) releasing agent phentermine which is not available in Europe but is used in the US and other parts of the world. Phen-
Weight loss drugs
3
termine is effective in producing weight loss in the short term although there are no long-term data available.
peripheral mechanism of action are significantly more effective than those where the mechanism of action is purely peripheral. Around two-third or more of patients achieve weight loss of 5% or more in 1 year with these drugs.
Weight loss and weight loss maintenance Choosing between currently available weight loss agents is extremely difficult as there have been few direct comparisons between drugs. Making comparisons across clinical trials is problematic because of fundamental differences in study design (for instance, whether the randomised pre-treatment period was preceded by a placebo run-in period) and differences in the patient demographics, in terms of the degree of obesity, gender, and the nature and degree of comorbidities such as impaired glucose tolerance, hypertension and so on. A further significant variable is the nature, implementation and monitoring of the lifestyle interventions, where present. Nevertheless, in relationship to weight loss, several meta-analyses of published studies using sibutramine, orlistat or rimonabant have been conducted.
Impact on metabolic and cardiovascular risk factors It is well known that obesity is associated with an increase in hypertension, type 2 diabetes and dyslipdaemia, which contribute to an increased risk of developing coronary heart disease and cerebrovascular disease. Obese patients tend to place most importance on the degree of weight loss that they can, or plan to, achieve, however, for the treating clinician it is the impact of weight loss on the patient’s metabolic and cardiovascular risk profile that is of more importance. Sibutramine, orlistat and rimonabant are all more effective than placebo at reducing waist circumference, indicating that a significant proportion of the weight loss is from visceral fat. A further Cochrane meta-analysis of trials
Medication
Source of data
Characteristics of study patients
Duration (weeks)
Placebo-subtracted weight change (kg) (mean; 95% CI)
Sibutramine Orlistat Rimonabant
Meta-analysis [9] Meta-analysis [9] Meta-analysis [1]
Mean age 38—53 years; 58—88% women Average age 49 years; 71% women Average age 45—55 years; 51—81% women
52 52 52
−4.3 (−3.6 to −4.9) −2.7 (−2.3 to −3.1) −4.6 (−5.0 to −4.3)
The Cochrane meta-analysis of orlistat and sibutramine found that compared to placebo, orlistat induced 2.7 kg (95% CI 2.3—3.1 kg) weight loss while sibutramine induced a 4.3 kg (95% CI 3.6—4.9 kg) weight loss [9]. In a recent Cochrane meta-analysis, average placebo-subtracted weight change in the rimonabant studies seems to result in comparable weight loss to sibutramine [1]. In terms of maintenance of weight loss, the Xenical in the prevention of Diabetes in Obese Subjects (XENDOS) study showed that over a 4-year period, orlistat produced a 3 kg greater weight loss than the placebo-treated group, indicating better maintenance of weight loss than an intensively administered lifestyle programme alone [14]. With sibutramine, responders in the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) achieved maintenance of around 5 kg weight loss over and above that achieved with lifestyle alone [5]. Similarly, in the 2-year RIO-North America study, ongoing treatment with rimonabant was essential for maintenance of weight loss [10]. In terms of categorical weight loss of at least 5% in 1 year, those drugs with a combined central and
conducted in patients with type 2 diabetes showed that for both sibutramine and orlistat there were reductions in glycated haemoglobin over and above that seen with placebo [8]. For both drugs, pooled data indicated a reduction in HbA1c of 0.5% in 1 year. The RIO-Diabetes study found similar clinically meaningful reductions in bodyweight and improvements in HbA1c for patients inadequately controlled by metformin or sulphonylureas who were treated with rimonabant 20 mg/day for 1 year [12]. Interestingly, the observed placebosubtracted 0.7% reduction in HbA1c with 20 mg/day rimonabant was about twice that attributable to concurrent weight loss alone. In relation to lipids, the drugs have different effects on the fasting lipid profile. The Cochrane meta-analysis shows that sibutramine reduces triglycerides of the order of −0.18 to −0.23 mmol/L and raises HDL-cholesterol by +0.08 to +0.09 mmol/L but with no effect on LDLcholesterol. Treatment with orlistat results in reductions in triglycerides (−0.05 mmol/L) and LDL (−0.27 mmol/L) but with a neutral or small effect
4 on HDL [9]. Rimonabant seems to produce a similar change in lipid parameters as sibutramine with changes in triglycerides of the order of −0.21 mmol/L and increases in HDL of around +0.09 mmol/L with no effect on LDL [1]. Across the orlistat trials, there appears to be a specific effect on LDL-cholesterol beyond that seen with weight loss alone. By contrast, the changes in HDLcholesterol levels in sibutramine and rimonabant trials seem to be more than would be expected from the amount of weight lost, while there were also decreases in triglyceride levels [5,10]. Again, the effects of the different weight loss agents on these various metabolic factors depends on individual patient’s baseline levels of risk and the magnitude of weight lost, together with any possible drug effects that may be independent of weight loss, all of which make comparisons between studies complex. Effects on blood pressure are important considerations in relation to the use of pharmacotherapy. The Cochrane meta-analysis shows a mean increase with sibutramine of 1.9 mmHg in systolic blood pressure relative to placebo and of 1—4 mmHg diastolic blood pressure relative to placebo over 52 weeks, while for orlistat, both systolic and diastolic blood pressure decrease over 52 weeks [9]. Rimonabant 20 mg/day was associated with average reductions in systolic blood pressure and diastolic blood pressure of 2 and 1 mmHg though with significant unexplained heterogeneity between studies [1]. However, there is a different pattern of effects when the data are stratified by weight loss category as opposed to the mean data irrespective of weight change. For example, in a meta-analysis of studies conducted in 4636 sibutramine-treated patients and 2255 placebo-treated patients, stratifying the change in blood pressure by weight loss indicates that while there is a small increase in blood pressure among those patients who did not lose weight or who lost less than 5% of their initial body weight, among patients who achieved weight loss of ≥5% there is a decline in blood pressure that correlates with the decline in weight, although this is slightly attenuated compared with those subjects who achieved such a weight loss by diet alone [13].
Adverse effects Each of these drugs, however, is associated with a characteristic side-effect profile. In the case of orlistat, as might be expected from the mechanism of action, most side-effects relate to the gastrointestinal system and include oily spotting, flatus with discharge, faecal urgency, fatty/oily stool, oily
G. Wittert et al. evacuation, increased defecation and occasionally faecal incontinence. These effects are proportional to fat content and so may encourage patients to reduce the amount of fat they consume. However, they may also have an adverse effect on compliance, with patients avoiding medication if they are planning to consume a high-fat meal. With sibutramine, minor side-effects include insomnia, nausea, dry mouth and constipation although the major effects are cardiovascular — hypertension, tachycardia and palpitation — and so require regular monitoring of blood pressure and pulse rate. In the case of rimonabant, the side-effects are predominantly central and include an increase in depressive disorders, mood alterations, anxiety as well as gastrointestinal-related side effects.
Conclusions In conclusion, orlistat, sibutramine and rimonabant all produce clinically meaningful weight loss in significant numbers of patients, beyond that achieved with lifestyle modification alone. They variably improve a range of co-morbid risk factors, but these effects are different in different groups of patients, and difficult to compare directly without matched patient populations. Each drug has a different side-effect profile and therefore, without direct comparisons, the choice of an anti-obesity drug should reflect the underlying metabolic and cardiovascular risk profile of the patient and the specific contraindications to the use of each agent by a given patient. In addition, it is important to consider the individual needs or preferences of that patient. Recent work on the ‘‘psychological profiling’’ of the drugs suggests that it may be possible to target specific drugs to the patient’s personality. There is a suggestion that those patients with personality traits that imply order and conscientiousness may do better with orlistat, while those patients with little control over their eating habits may respond better to the satiety-enhancing properties of sibutramine [3]. It is important to stress that weight loss drugs are not ‘‘magic bullets’’ to induce involuntary weight loss: rather, they should only be used as part of a comprehensive weight management programme. Evidence shows that when combined in this way, the more comprehensive the weight management programme the greater the results achieved [15]. In one study, a comprehensive behavioural programme combined with sibutramine treatment resulted in 52% of patients losing and maintaining >10% of their weight and 73% losing >5% in 1 year.
Weight loss drugs For many patients, such modest weight loss may appear disappointing, leading to frustration and limiting compliance with the overall weight management programme. In order to avoid this, it is essential at the outset that clinicians spend time counselling patients and managing their expectations. The aim should be to improve well being and reduce cardiometabolic risk. It has been shown that modest weight loss induced by Xenical can reduced the incidence of diabetes mellitus over and above that which can be achieved by lifestyle alone. Whether there will be beneficial effects to prevent cardiovascular events and a reduction in overall mortality will be known once the outcomes of the large multicentre outcomes trials using sibutramine (SCOUT) and rimonabant (CRESECENDO) are known.
Conflict of interest The authors have professional relationships with Roche, Sanofi Aventis, and Abbott. A medical writer was funded by Abbott to work on this manuscript.
References [1] Curioni C, Andr´ e C. Rimonabant for overweight or obesity. Cochrane Library 2006;(4) [review]. [2] Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA 2005;293:43—53. [3] Elfhag K, R¨ ossner S, Barkeling B, Rooth P. Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood. Pharmacol Res 2005;51:159—63.
5 [4] James WPT. The SCOUT study: risk—benefit profile of sibutramine in overweight high risk cardiovascular patients. Eur Heart J 2005;7(Suppl. L):L44—8. [5] James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomized trial. Lancet 2000;356:2119—25. [6] Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002;346:393—403. [7] National Institutes of Health. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults: the evidence report. Obes Res 1998;6(Suppl. 2):51S—209S. [8] Norris SL, Zhang X, Avenell A, et al. Pharmacotherapy for weight loss in adults with type 2 diabetes mellitus. Cochrane Database Syst Rev 2005;1:CD004096. [9] Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev 2004;3:CD004094. [10] The RIO-North America Study Group. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients: RIO-North America: a randomized controlled trial. JAMA 2006;295:761—75. [11] Ryan DH, Espeland MA, Foster GD, et al. Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials 2003;24(5):610—28. [12] The RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet 2006 [published online October 27, 2006]. [13] Sharma AM. Sibutramine in overweight/obese hypertensive patients. Int J Obes Relat Metab Disord 2001;25(Suppl. 4):S20—3. [14] Torgerson JS, Hauptman J, Boldrin MN, Sjostrom L. XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diab Care 2004;27:155—61. [15] Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005;353:2111—20.
REVIEW
The clinical effectiveness of weight loss drugs Gary Wittert a,∗, Ian Caterson b, Nick Finer c a
Discipline of Medicine, University of Adelaide, Adelaide, SA 5005, Australia Human Nutrition Unit, University of Sydney, Sydney, NSW, Australia c Wellcome Trust Clinical Research Facility, Addenbrooke’s Hospital, Cambridge, UK b
Received 18 December 2006; accepted 18 December 2006
KEYWORDS Obesity; Medications; Diabetes mellitus; Hypertension; Pharmacotherapy
Summary At a time when obesity is reaching epidemic proportions across the western world and increasing rapidly in developing countries, clinicians clearly are becoming more aware of the need to offer weight management advice and effective treatment to patients, especially those with a high risk of developing type 2 diabetes. For those patients with a BMI ≥ 30.0 kg/m2 or for those with a BMI of 27.0 kg/m2 with an obesity-related disease such as dyslipidaemia or type 2 diabetes mellitus, modest weight loss in the order of 5% achieved by modification of dietary intake and activity behaviour can significantly improve risk factors for obesity-related diseases and delay progression to type 2 diabetes. Unfortunately, rates of adherence with dietary-based weight management programmes are generally low and for most patients weight regain with time is common. The use of weight loss medications is recognised as a positive strategy for helping patients adhere to lifestyle advice, and has been shown to result in clinically significant and meaningful improvement of symptoms, risk factors and quality of life. Appropriate selection and use of weight management drugs requires an understanding of the benefits and risks associated with each of the available drugs. Clinical trials are ongoing to determine whether weight management interventions (including anti-obesity pharmacotherapy) will impact upon clinical outcome and life expectancy. © 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
Contents Introduction................................................................................................... Weight loss drugs ......................................................................................... Weight loss and weight loss maintenance ...............................................................
∗ Corresponding author. Tel.: +61 8 8222 5502; fax: +61 8 8223 3870. E-mail address: [email protected] (G. Wittert).
1871-403X/$ — see front matter © 2006 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.orcp.2006.12.001
2 2 3
2
G. Wittert et al. Impact on metabolic and cardiovascular risk factors ...................................................... Adverse effects ........................................................................................... Conclusions ................................................................................................... Conflict of interest ............................................................................................ References ..................................................................................................
3 4 4 5 5
Introduction
Drugs for the treatment of obesity can be divided broadly into four main categories:
At a time when obesity is reaching epidemic proportions across the western world and increasing rapidly in developing countries, clinicians clearly are becoming more aware of the need to offer weight management advice and effective treatment to patients, especially those with a high risk of developing type 2 diabetes. For those patients with a BMI ≥ 30.0 kg/m2 or for those with a BMI of 27.0 kg/m2 with an obesityrelated disease such as dyslipidaemia or type 2 diabetes mellitus, modest weight loss in the order of 5% achieved by modification of dietary intake and activity behaviour can significantly improve risk factors for obesity-related diseases [7] and delay progression to type 2 diabetes [6]. Unfortunately, rates of adherence with dietary-based weight management programmes are generally low [2] and for most patients weight regain with time is common [15]. The use of weight loss medications is recognised as a positive strategy for helping patients adhere to lifestyle advice, and has been shown to result in clinically significant and meaningful improvement of symptoms, risk factors and quality of life. Appropriate selection and use of weight management drugs requires an understanding of the benefits and risks associated with each of the available drugs. Clinical trials are ongoing to determine whether weight management interventions (including anti-obesity pharmacotherapy) will impact upon clinical outcome and life expectancy [4,11].
• Drugs that work on neurotransmitter systems modulating food intake or affecting energy expenditure by central and/or peripheral mechanisms. These include those that affect serotonergic and noradrenergic (norepinephrine) neurones, and the more recently described endocannabinoid system. • Drugs that affect digestion and therefore subsequent absorption of macronutrients. • Drugs that affect gastrointestinal neuroendocrine function to alter appetite, satiety and metabolism. Some such agents are available for the management of type 2 diabetes and have been shown to produce weight loss. • Drugs that modify peripheral metabolism by affecting lipolysis, lipogenesis or muscle energy utilisation. Currently there are only three major agents licensed and recommended by Regulatory Agencies for the longer term management of weight loss:
Weight loss drugs
1. Sibutramine, which increases satiety by inhibiting the reuptake of serotonin and noradrenaline (norepinephrine), with a secondary effect on energy metabolism whereby it attenuates some of the fall in metabolic rate that follows weight loss. 2. Orlistat, which is a peripherally acting gastric and intestinal lipase inhibitor that reduces fat digestion and absorption. 3. Rimonabant, which reduces hunger and food intake by selectively inhibiting the CB1 receptor of the endocannabinoid system, but may also have peripheral metabolic actions.
Obesity is the result of a chronic excess energy intake relative to energy expenditure. Energy intake and body weight are tightly controlled by a complex web of signalling mechanisms from the gastrointestinal tract and adipose tissues that link with central pathways within the brain. Additional influences relate to higher level cognitive and behavioural influences that can modulate but not, it seems, successfully override the more physiological controls.
In addition there are two agents that have a direct appetite suppressing effect though neither is generally recommended for weight loss: the selective serotonin reuptake inhibitor fluoxetine has only a mild and poorly sustained impact on weight but is sometimes used in high doses in patients with bulimia or binge eating disorder, and the noradrenaline (norepinephrine) releasing agent phentermine which is not available in Europe but is used in the US and other parts of the world. Phen-
Weight loss drugs
3
termine is effective in producing weight loss in the short term although there are no long-term data available.
peripheral mechanism of action are significantly more effective than those where the mechanism of action is purely peripheral. Around two-third or more of patients achieve weight loss of 5% or more in 1 year with these drugs.
Weight loss and weight loss maintenance Choosing between currently available weight loss agents is extremely difficult as there have been few direct comparisons between drugs. Making comparisons across clinical trials is problematic because of fundamental differences in study design (for instance, whether the randomised pre-treatment period was preceded by a placebo run-in period) and differences in the patient demographics, in terms of the degree of obesity, gender, and the nature and degree of comorbidities such as impaired glucose tolerance, hypertension and so on. A further significant variable is the nature, implementation and monitoring of the lifestyle interventions, where present. Nevertheless, in relationship to weight loss, several meta-analyses of published studies using sibutramine, orlistat or rimonabant have been conducted.
Impact on metabolic and cardiovascular risk factors It is well known that obesity is associated with an increase in hypertension, type 2 diabetes and dyslipdaemia, which contribute to an increased risk of developing coronary heart disease and cerebrovascular disease. Obese patients tend to place most importance on the degree of weight loss that they can, or plan to, achieve, however, for the treating clinician it is the impact of weight loss on the patient’s metabolic and cardiovascular risk profile that is of more importance. Sibutramine, orlistat and rimonabant are all more effective than placebo at reducing waist circumference, indicating that a significant proportion of the weight loss is from visceral fat. A further Cochrane meta-analysis of trials
Medication
Source of data
Characteristics of study patients
Duration (weeks)
Placebo-subtracted weight change (kg) (mean; 95% CI)
Sibutramine Orlistat Rimonabant
Meta-analysis [9] Meta-analysis [9] Meta-analysis [1]
Mean age 38—53 years; 58—88% women Average age 49 years; 71% women Average age 45—55 years; 51—81% women
52 52 52
−4.3 (−3.6 to −4.9) −2.7 (−2.3 to −3.1) −4.6 (−5.0 to −4.3)
The Cochrane meta-analysis of orlistat and sibutramine found that compared to placebo, orlistat induced 2.7 kg (95% CI 2.3—3.1 kg) weight loss while sibutramine induced a 4.3 kg (95% CI 3.6—4.9 kg) weight loss [9]. In a recent Cochrane meta-analysis, average placebo-subtracted weight change in the rimonabant studies seems to result in comparable weight loss to sibutramine [1]. In terms of maintenance of weight loss, the Xenical in the prevention of Diabetes in Obese Subjects (XENDOS) study showed that over a 4-year period, orlistat produced a 3 kg greater weight loss than the placebo-treated group, indicating better maintenance of weight loss than an intensively administered lifestyle programme alone [14]. With sibutramine, responders in the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) achieved maintenance of around 5 kg weight loss over and above that achieved with lifestyle alone [5]. Similarly, in the 2-year RIO-North America study, ongoing treatment with rimonabant was essential for maintenance of weight loss [10]. In terms of categorical weight loss of at least 5% in 1 year, those drugs with a combined central and
conducted in patients with type 2 diabetes showed that for both sibutramine and orlistat there were reductions in glycated haemoglobin over and above that seen with placebo [8]. For both drugs, pooled data indicated a reduction in HbA1c of 0.5% in 1 year. The RIO-Diabetes study found similar clinically meaningful reductions in bodyweight and improvements in HbA1c for patients inadequately controlled by metformin or sulphonylureas who were treated with rimonabant 20 mg/day for 1 year [12]. Interestingly, the observed placebosubtracted 0.7% reduction in HbA1c with 20 mg/day rimonabant was about twice that attributable to concurrent weight loss alone. In relation to lipids, the drugs have different effects on the fasting lipid profile. The Cochrane meta-analysis shows that sibutramine reduces triglycerides of the order of −0.18 to −0.23 mmol/L and raises HDL-cholesterol by +0.08 to +0.09 mmol/L but with no effect on LDLcholesterol. Treatment with orlistat results in reductions in triglycerides (−0.05 mmol/L) and LDL (−0.27 mmol/L) but with a neutral or small effect
4 on HDL [9]. Rimonabant seems to produce a similar change in lipid parameters as sibutramine with changes in triglycerides of the order of −0.21 mmol/L and increases in HDL of around +0.09 mmol/L with no effect on LDL [1]. Across the orlistat trials, there appears to be a specific effect on LDL-cholesterol beyond that seen with weight loss alone. By contrast, the changes in HDLcholesterol levels in sibutramine and rimonabant trials seem to be more than would be expected from the amount of weight lost, while there were also decreases in triglyceride levels [5,10]. Again, the effects of the different weight loss agents on these various metabolic factors depends on individual patient’s baseline levels of risk and the magnitude of weight lost, together with any possible drug effects that may be independent of weight loss, all of which make comparisons between studies complex. Effects on blood pressure are important considerations in relation to the use of pharmacotherapy. The Cochrane meta-analysis shows a mean increase with sibutramine of 1.9 mmHg in systolic blood pressure relative to placebo and of 1—4 mmHg diastolic blood pressure relative to placebo over 52 weeks, while for orlistat, both systolic and diastolic blood pressure decrease over 52 weeks [9]. Rimonabant 20 mg/day was associated with average reductions in systolic blood pressure and diastolic blood pressure of 2 and 1 mmHg though with significant unexplained heterogeneity between studies [1]. However, there is a different pattern of effects when the data are stratified by weight loss category as opposed to the mean data irrespective of weight change. For example, in a meta-analysis of studies conducted in 4636 sibutramine-treated patients and 2255 placebo-treated patients, stratifying the change in blood pressure by weight loss indicates that while there is a small increase in blood pressure among those patients who did not lose weight or who lost less than 5% of their initial body weight, among patients who achieved weight loss of ≥5% there is a decline in blood pressure that correlates with the decline in weight, although this is slightly attenuated compared with those subjects who achieved such a weight loss by diet alone [13].
Adverse effects Each of these drugs, however, is associated with a characteristic side-effect profile. In the case of orlistat, as might be expected from the mechanism of action, most side-effects relate to the gastrointestinal system and include oily spotting, flatus with discharge, faecal urgency, fatty/oily stool, oily
G. Wittert et al. evacuation, increased defecation and occasionally faecal incontinence. These effects are proportional to fat content and so may encourage patients to reduce the amount of fat they consume. However, they may also have an adverse effect on compliance, with patients avoiding medication if they are planning to consume a high-fat meal. With sibutramine, minor side-effects include insomnia, nausea, dry mouth and constipation although the major effects are cardiovascular — hypertension, tachycardia and palpitation — and so require regular monitoring of blood pressure and pulse rate. In the case of rimonabant, the side-effects are predominantly central and include an increase in depressive disorders, mood alterations, anxiety as well as gastrointestinal-related side effects.
Conclusions In conclusion, orlistat, sibutramine and rimonabant all produce clinically meaningful weight loss in significant numbers of patients, beyond that achieved with lifestyle modification alone. They variably improve a range of co-morbid risk factors, but these effects are different in different groups of patients, and difficult to compare directly without matched patient populations. Each drug has a different side-effect profile and therefore, without direct comparisons, the choice of an anti-obesity drug should reflect the underlying metabolic and cardiovascular risk profile of the patient and the specific contraindications to the use of each agent by a given patient. In addition, it is important to consider the individual needs or preferences of that patient. Recent work on the ‘‘psychological profiling’’ of the drugs suggests that it may be possible to target specific drugs to the patient’s personality. There is a suggestion that those patients with personality traits that imply order and conscientiousness may do better with orlistat, while those patients with little control over their eating habits may respond better to the satiety-enhancing properties of sibutramine [3]. It is important to stress that weight loss drugs are not ‘‘magic bullets’’ to induce involuntary weight loss: rather, they should only be used as part of a comprehensive weight management programme. Evidence shows that when combined in this way, the more comprehensive the weight management programme the greater the results achieved [15]. In one study, a comprehensive behavioural programme combined with sibutramine treatment resulted in 52% of patients losing and maintaining >10% of their weight and 73% losing >5% in 1 year.
Weight loss drugs For many patients, such modest weight loss may appear disappointing, leading to frustration and limiting compliance with the overall weight management programme. In order to avoid this, it is essential at the outset that clinicians spend time counselling patients and managing their expectations. The aim should be to improve well being and reduce cardiometabolic risk. It has been shown that modest weight loss induced by Xenical can reduced the incidence of diabetes mellitus over and above that which can be achieved by lifestyle alone. Whether there will be beneficial effects to prevent cardiovascular events and a reduction in overall mortality will be known once the outcomes of the large multicentre outcomes trials using sibutramine (SCOUT) and rimonabant (CRESECENDO) are known.
Conflict of interest The authors have professional relationships with Roche, Sanofi Aventis, and Abbott. A medical writer was funded by Abbott to work on this manuscript.
References [1] Curioni C, Andr´ e C. Rimonabant for overweight or obesity. Cochrane Library 2006;(4) [review]. [2] Dansinger ML, Gleason JA, Griffith JL, et al. Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial. JAMA 2005;293:43—53. [3] Elfhag K, R¨ ossner S, Barkeling B, Rooth P. Sibutramine treatment in obesity: initial eating behaviour in relation to weight loss results and changes in mood. Pharmacol Res 2005;51:159—63.
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