Does pharmacologically induced weight loss improve cardiovascular outcome? Impact of anti-obesity agents on cardiovascular risk factors
Clinical Director, Wellcome Trust CRF, Addenbrooke's Hospital, Cambridge, UK
* Corresponding author. E-mail address: nf237{at}medschl.cam.ac.uk
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Abstract |
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 Top Abstract Mode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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Currently available anti-obesity drugs sibutramine and orlistat, and the soon to be available rimonabant, all produce similar degrees of clinically meaningful weight loss and weight loss maintenance, even though they differ considerably in their mode of action. Pharmacologically induced weight loss has a beneficial impact on a number of metabolic and cardiovascular risk factors, such as glucose homeostasis, blood pressure, central adiposity, and dyslipidaemia. In some cases, these effects appear to be over and above that explained by weight loss. These effects are important if obese patients are to be treated not just for their weight but also to reduce co-existing metabolic and cardiovascular risk factors.
Key Words: Anti-obesity drugs • Cardiovascular risk • HDL-cholesterol • Metabolic risk • Obesity • Orlistat • Rimonabant • Risk factors • Sibutramine • Weight loss
The understanding of body weight control has developed considerably in recent decades. Twenty years ago, it was commonly stated that people became obese merely because they ate too much and exercised too little. Although positive energy balance does result from an intake in excess of expenditure, this is merely the mechanism not the cause. Research has increasingly shown that the brain plays a fundamental role in regulating energy intake and controlling body weight. With increasing sophistication, it is now possible to look into more detailed areas of the brain and to recognize that there are distinct areas involved in food regulation. The use of molecular biology techniques and knock-out animal models over the past 10–12 years has opened up this field enormously, and the main hypothalamic and other brain pathways that regulate energy balance and body weight are well characterized (Figure 1). The more recent advent of neuro-imaging techniques, such as functional MRI and PET scanning is now opening up the areas of higher (cognitive and other) brain centres that may modulate the downstream hypothalamic controls. This knowledge is exposing plentiful new drug targets; indeed, the future for anti-obesity pharmacotherapy is rapidly evolving with many compounds in pre-clinical and clinical development by the pharmaceutical industry and academic community.
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-MSH, The recognition of the central role of adipose tissue as an endocrine organ, responsible for the production of a large number of hormones and cytokines, is also transforming our approach to obesity. The major step forward came with the recognition that leptin is produced by adipocytes and acts as an afferent signal through pathways in the brain involved with either stimulating feeding behaviour (orexigenic pathways) or inhibiting food intake (anorectic pathways). We now understand that the adipocyte is an active endocrine organ producing other hormones, cytokines, and inflammatory mediators which may also be involved in energy regulation as mediating the adverse effect of obesity.
Important, probably in the main short-term, meal-related signalling systems from the gastrointestinal tract exist. These appear to be involved in the initiation of eating behaviour and the termination of eating behaviour following a meal, acting through afferent signalling to the hypothalamus directly or indirectly through the hind brain and via the vagus.
The combined impact of these long-term and short-term signalling pathways is to drive both functional outputs, such as reproduction, growth and energy partitioning as well as behavioural outputs that promote appetite, energy expenditure, food seeking behaviour, and other aspects of nutrition. It is this latter area about which least is known. The complexity of these systems suggests that they have evolved to make weight regulation and weight maintenance a core body function, and may serve to explain why, in our present society of low activity and high food availability, people have difficulty in maintaining compliance with dietary and exercise advice, even when their motivation is high. It also logically dictates a role for pharmacotherapy, particularly in breaking the cycle of short-term weight loss followed by regain. The complexity of the systems reveals many potential targets for pharmacotherapy, but also suggests that multiple drugs may be needed to achieve the greatest effects.
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Mode of action of currently available drugs |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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At present, two drugs are licensed and approved (in Europe) for obesity treatment. These are the centrally acting sibutramine, and the peripherally acting orlistat. In addition, a new class of drugs that antagonize central and peripheral cannabinoid receptors is in clinical development and the first agent, rimonabant, may soon be licensed.
Sibutramine and its mode of action
Sibutramine inhibits the neuronal re-uptake of noradrenaline and serotonin (5-HT) within the hypothalamus. The effect is to increase neuronal transmission in pathways that rely on these two neurotransmitters. This translates into two methods of action, the predominant one being an enhancement of satiety; a feeling of fullness that is characterized by early termination of eating behaviour during a meal and prolonged satiation. This mechanism can be clearly distinguished from ‘classical’ stimulant anorectic drugs.1,2
The second mode of action is an effect on metabolic rate, specifically a prevention of the decline in energy expenditure that accompanies weight loss. At doses higher than those used in clinical practice, sibutramine has been shown to have a direct effect on increasing energy expenditure. In the doses commonly used in weight management, the effects are somewhat more subtle, but nonetheless important.3
It is known that when patients lose weight, their metabolic rate falls. It is this fall in metabolic rate that results in a new steady state or equilibrium being reached, producing the classical plateau seen in weight loss studies. This typically occurs around 6 months after initiation of a weight loss strategy, whether induced by a calorie deficit diet or by pharmacotherapy. It is important to realize that this is not a sign of tolerance to a drug, but rather a sign that the effect of the drug has been matched by adaptation of the body to the lower body weight, easily confirmed by the demonstration of weight regain when the drug is withdrawn.4
Three components contribute to the observed decrease in metabolic energy expenditure during weight reduction when energy intake is reduced.5 These are:
- A loss of metabolically-active tissue (lean body mass) of about 42 kJ/d per kilogram body weight lost.
- A fall in dietary-induced thermogenesis—this normally approximates to 10% of the total energy expenditure, but may be reduced by a third or 50% during weight loss.
- An adaptation to negative energy balance that may be due to a fall in leptin, thyroid hormones and an associated decrease in sympathetic nervous system activity.
Administration of sibutramine with a reduced calorie diet results in a reduction in energy intake. This translates into a fall in body weight. The fact that there is a small protection from sibutramine against the fall in energy expenditure means that there is a slightly greater weight loss than can be explained simply by its effect on reducing energy intake. It is this combination that is important for the overall efficacy of sibutramine on weight loss and weight loss maintenance.
For an average person weighing 83 kg, the total daily energy expenditure is about 3000 kcal. As Figure 2 demonstrates, treatment with sibutramine has the effect of reducing energy intake by about 300/400 kcal a day. Over a 6-month period, this would lead to a 10 kg weight loss. Normally, this would be accompanied by a compensatory reduction in energy expenditure, but sibutramine attenuates this fall leading to a further reduction in weight.
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Orlistat and its mode of action
Orlistat has a very different mode of action from sibutramine. It irreversibly blocks secreted lipases in the jejunum and small intestine, the result being to block the breakdown and subsequent absorption of triglycerides. Consequently, there is an obligatory loss of
30% of dietary fat. This mechanism leads to the loss of overall energy intake, and, therefore, in addition to the prescribed diet, contributes to weight loss.6 Some have suggested that compliance with a low fat diet is enhanced by the unwanted effects of malabsorption (urgency of defaecation, diarrhoea, abdominal discomfort) in patients who exceed 50–60 g dietary fat/day. However, it is important to recognize that side effects are not necessary for orlistat to be effective, and if severe will contribute to patient non-compliance with treatment. They should be avoided by appropriate dietary advice and explanation.
Rimonabant and its mode of action
A new class of drugs that antagonize central and peripheral cannabinoid receptors is in clinical development and the first agent, rimonabant, may soon be licensed. The endocannabinoid system has only recently been described. In normal individuals, this system appears to be quiescent. However, it becomes overactive or hyperstimulated in a number of conditions, such as cigarette smoking, overweight and obesity, and possibly stress.
Two types of cannabinoid receptors, the CB1 and CB2 receptors, have been identified and cloned. CB1 receptors are located in several brain areas and in a variety of peripheral tissues, including adipose tissue, the gastrointestinal tract, the pituitary and adrenal glands, sympathetic ganglia, heart, lung, liver, and urinary bladder; CB2 receptors are found in the immune system.7
Rimonabant is a specific CB1 receptor antagonist. The effect of this drug is to block the overactive endocannabinoid system in the adipocyte and brain. This increases levels of adiponectin, thereby increasing fat oxidation and improving insulin sensitivity. There is a central inhibitory effect on food seeking and other ‘addictive’ behaviours, and also a direct effect through leptin pathways that leads to diminished food intake and possibly an increase in energy expenditure. The net effect is to produce weight loss, with a probable added direct effect on the adipocyte.
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Efficacy in weight loss and maintenance |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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Weight loss maintenance is the most important aim of obesity management, particularly in terms of long-term weight and cardiovascular risk reduction. In a study by Apfelbaum et al.,8 weight loss was induced with a period on a very low calorie diet after which patients were randomized to continue on a more moderate diet together with either a placebo or sibutramine. This study found that there was an increased period of weight loss on sibutramine and that weight loss was maintained over a 1-year period. The total weight loss and weight loss maintenance in this study was around 13 kg for those randomized to sibutramine (
13% of initial body weight), compared with 7 kg in the placebo group. A further demonstration of the efficacy of sibutramine in weight loss and weight loss maintenance was provided by the Sibutramine Trial in Obesity Reduction and Maintenance (STORM). In this trial, patients were treated with sibutramine together with an individualized and fixed energy deficit diet and exercise programme over a 6-month period.4 Those who achieved a 5% weight loss without >2 kg weight regain from months 4–6 were then entered into the weight loss maintenance phase of the trial. They continued on the diet and exercise programme and were randomized to sibutramine or placebo for a further 18 months. Figure 3 shows that the intensive dietary and lifestyle programme with sibutramine produced a weight loss of around 13 kg over the first 6 months which was maintained over the next 12 months, with a small upward trend over the last 6 months of the 2-year trial. In contrast, the placebo group began to regain weight at randomization, and continued to regain weight faster as the trial continued, despite receiving the same ancillary therapy as the sibutramine group. Patients such as those included in STORM, in an untreated situation, might well be gaining 1–2 kg per year. Therefore, the ‘baseline’ is the rising trajectory shown in the figure, not a flat line. This is analogous to Type 2 diabetes, a disease in which diabetic control progressively worsens, despite treatment; no matter how effective an anti-obesity treatment is, there is always likely to be a small rise in body weight with increasing age of the patient.
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The weight loss efficacy of orlistat has been studied in many trials. The XENical in the prevention of Diabetes in Obese Subjects (XENDOS) study was designed to look not only at weight loss, but also at the effect of orlistat on the development of Type 2 diabetes.9 A subgroup of patients with impaired glucose tolerance were, therefore, included to assess this possible effect. Orlistat produced greater weight loss and greater retention of weight loss than placebo. The placebo-subtracted difference in this 4-year study although modest was statistically significant (–6.9 kg vs. –4.1 kg; P<0.001) and translated into a marked risk reduction for the development of Type 2 diabetes.
Among the trials conducted with rimonabant, only the Rimonabant in Obesity—Europe (RIO-Europe) study has so far been published. This was a 2-year trial with a classical design that comprised a short placebo run-in and an individualized mild hypocaloric diet (–600 kcal/day deficit). Patients were randomized to rimonabant 5 mg, rimonabant 20 mg, or placebo. The 1-year data show slightly more protracted weight loss with rimonabant than that seen with sibutramine and orlistat, continuing out to about 36 weeks, after which it reaches a plateau.10 Subsequent analyses will show whether this weight loss is maintained over the second year.
Taken together, these studies show that the three drugs are very successful not only at inducing weight loss, but also in maintaining it. Overall, in placebo controlled studies, the percentage of patients achieving 5% weight loss at 1 year is broadly similar with sibutramine, orlistat, and rimonabant (Figure 4); the small differences may be due to differences in patient inclusion and the nature of the interventions delivered in the different trials.10–12
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Impact on metabolic and cardiovascular risk factors |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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Weight loss induced with the help of pharmacotherapy results in positive effects on a range of cardiovascular and metabolic risk factors,including glucose homeostasis, blood pressure, central adiposity, and dyslipidaemia.
Glucose homeostasis
Data from a 12-month randomized trial conducted in obese Type 2 diabetic patients treated with metformin demonstrate that sibutramine not only induced significant weight loss, but also improved glycaemic control.13 Those patients who lost 5–10% or lost >10% of their initial body weight had improved levels of HbA1c, with highly significant falls of about 0.7 (P<0.02) and 1.2% (P<0.0001), respectively (Figure 5). As is known from the United Kingdom Prospective Diabetes Study, reductions in HbA1c of this magnitude should translate into very real morbidity reductions.14
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In the XENDOS study, orlistat plus lifestyle modification was associated with a 37% reduction in the progression to Type 2 diabetes compared with placebo and lifestyle modification (P=0.0032) at the end of 4 years.9
To date, data on the use of rimonabant in patients with Type 2 diabetes have not been published.
Blood pressure
Weight loss among patients taking sibutramine appears to be accompanied by a proportional fall in blood pressure. Data from a meta-analysis of studies conducted in 4636 sibutramine-treated patients and 2255 placebo-treated patients show that among those patients who did not lose weight or who lost <5% of their initial body weight, there is a slight increase in blood pressure.15 But patients achieving 5% or more weight loss have a decline in blood pressure that correlates with the decline in weight (Figure 6). The decrease in blood pressure in patients treated with sibutramine is slightly attenuated compared with those subjects who achieved such a weight loss by diet alone. However, only 22% of patients taking placebo achieved weight loss of more than 5% in comparison to >50% of those who were taking sibutramine. This difference is even greater in the group of patients who lost >10% of their weight.
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The XENDOS study also included data on the effects of orlistat treatment on blood pressure.9 At 1 year, there were marked falls in systolic and diastolic blood pressure in all patients, although the fall was greater in those treated with orlistat compared with placebo for the same degree of weight loss. Interestingly, by 4 years, part of this effect had been attenuated; a similar effect has been seen in a long-term observational study of surgically induced weight reduction, where blood pressure falls do not appear to be well maintained.16
Central adiposity
Two-year studies with both sibutramine and orlistat4,17 and the 1-year study with rimonabant10 show patients achieve marked decreases in waist circumference, an index of visceral adiposity (Figure 7). Confirmation of the fat redistribution that occurs with anti-obesity treatment is provided by a subset of the STORM study, in which computed tomography measurements were taken in the first 6 months. This shows that following treatment with sibutramine, there is a marked and preferential decrease in visceral fat of around 24% (P<0.001 compared with baseline) and a reduction of 17% in subcutaneous fat (P<0.001 compared with baseline).18
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Dyslipidaemia
Robust and repeated observations have suggested that weight loss with sibutramine is associated with a specific increase in HDL-cholesterol, with a neutral effect on LDL-cholesterol, and a fall in triglycerides. In the STORM study, for example, those subjects who lost the most weight showed the greatest metabolic improvements in terms of triglyceride and VLDL cholesterol (Figure 8). However, the rise in HDL cholesterol appeared to be partially independent of weight loss. There were similar rises of
20% in all patients, as well as those who lost >5 and >10%. This effect on HDL cholesterol has been compared with the 6% increase in HDL cholesterol achieved with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) study.19 It is of note that among the 16% of STORM patients who would have met the entry criteria for the VA-HIT study, sibutramine resulted in a 30.6% increase in HDL-cholesterol.
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The effects of orlistat are most marked with regard to LDL-cholesterol. Analysis of data from four placebo-controlled studies confirms that treatment with orlistat results in large falls in LDL-cholesterol, as would be predicted by its mechanism of action in blocking dietary fat absorption.9,17,20,21
The impact of rimonabant on lipid profile is similar to that seen with sibutramine; data from the RIO-Europe study show that patients taking 20 mg rimonabant show a progressive rise in HDL-cholesterol of 22% at 1 year and a 7% reduction in triglycerides.10 As with sibutramine, these improvements could not be fully explained by the observed weight loss.
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Effects independent of weight loss |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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Importantly, some of these positive effects of anti-obesity agents appear to be independent of weight loss. Effects independent of weight are clearly important if obese patients are to be treated not just for their weight but also to reduce co-existing metabolic and cardiovascular risk factors. However, it is important to note that studies are rarely performed specifically to address this question as they are difficult to do; looking for an independent effect would require that patients be given a weight loss drug without producing weight loss. Therefore, most of the data available come from post-hoc analyses of trial data.
A meta-analysis was conducted of the effects on HDL-cholesterol at 1 year from a large number of studies in which patients received long-term sibutramine treatment. Analysis by categories of weight loss shows that for most degrees of weight loss there is a marked increased effect on raising HDL-cholesterol regardless of the degree of weight loss, suggesting that there may be an independent effect.22
A similar relationship has been suggested for orlistat and LDL-cholesterol when pooled data are analysed by category of weight loss. For each weight loss category, patients taking orlistat had greater reductions in LDL-cholesterol than placebo patients. Similarly, a prospective 6-month study conducted in Type 2 diabetes patients in whom all diabetic medication was withdrawn 1 month preceding randomization to either behavioural intervention and orlistat or behavioural intervention and placebo has shown that at equivalent weight loss, use of orlistat resulted in greater improvement in free fatty acids levels and insulin sensitivity.23
Similarly, summary statistical analyses of the results from the RIO-Europe study suggest that about half of the rise in HDL-cholesterol and about half of the fall in triglycerides cannot be accounted for by weight loss alone, suggesting possible independent effects.10
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Summary |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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Currently available anti-obesity drugs do produce weight loss in more patients and sustain their effects over longer periods than lifestyle interventions alone. There are very positive effects from these pharmacotherapy-induced weight loss interventions on a range of metabolic and cardiovascular risk factors, making it possible to tackle more than one risk factor at a time. Some of the positive effects of these anti-obesity agents appear to be independent of weight loss.
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Key points |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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- Energy intake and body weight are tightly regulated through complex central mechanisms that integrate information on the body energy stores with short-term, meal-related signals.
- The complexity of the systems suggests a long-term role for medication, particularly in breaking the cycle of short-term weight loss followed by regain.
- Currently available anti-obesity drugs sibutramine and orlistat, and the soon to be available rimonabant, all produce similar degrees of clinically meaningful weight loss and weight loss maintenance, even though they differ considerably in their mode of action.
- Pharmacologically induced weight loss has a beneficial impact on a number of metabolic and cardiovascular risk factors; some of these effects may be independent of weight loss.
Conflict of interest statement: The author has consulted for Abbott and lectured at Abbott-sponsored symposia.
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References |
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TopAbstractMode of action of...Efficacy in weight loss...Impact on metabolic and...Effects independent of weight...SummaryKey pointsReferences |
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- Hansen DL, Toubro S, Stock MJ et al. 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.[CrossRef][ISI][Medline]
- Hansen DL, Toubro S, Stock MJ et al. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998;68:1180–1186.[Abstract]
- Walsh KM, Leen E, Lean ME. The effect of sibutramine on resting energy expenditure and adrenaline-induced thermogenesis in obese females. Int J Obes Relat Metab Disord 1999;23:1009–1015.[CrossRef][ISI][Medline]
- James WP, Astrup A, Finer N et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 2000;356:2119–2125.[CrossRef][ISI][Medline]
- Webber J. Energy balance in obesity. Proc Nutr Soc 2003;62:539–543.[CrossRef][ISI][Medline]
- Guerciolini R. Mode of action of orlistat. Int J Obes Relat Metab Disord 1997;21(Suppl. 3):S12–S23.
- Horvath TL. Endocannabinoids and the regulation of body fat: the smoke is clearing. J Clin Invest 2003;112:323–326.[CrossRef][ISI][Medline]
- Apfelbaum M, Vague P, Ziegler O et al. 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.[CrossRef][ISI][Medline]
- Torgerson JS, Hauptman J, Boldrin MN et al. 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. Diabetes Care 2004;27:155–161.
[Abstract/Free Full Text] - Van Gaal LF, Rissanen AM, Scheen AJ et al.; for the RIO-Europe Study Group. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet 2005;365:1389–1397.[CrossRef][ISI][Medline]
- Chong E. Weight loss produced by sibutramine: a meta-analysis. Int J Obes Relat Metab Disord 2001;25(Suppl. 2):S104.
- O'Meara S, Riemsma R, Shirran L et al. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. Health Technol Assess 2001;5(18):1–81.[Medline]
- McNulty SJ, Ur E, Williams G; Multicenter Sibutramine Study Group. A randomized trial of sibutramine in the management of obese Type 2 diabetic patients treated with metformin. Diabetes Care 2003;26:125–131.
[Abstract/Free Full Text] - Turner R, Cull C, Holman R. United Kingdom Prospective Diabetes Study 17: a 9-year update of a randomized, controlled trial on the effect of improved metabolic control on complications in non-insulin-dependent diabetes mellitus. Ann Intern Med 1996;124:136–145.
[Abstract/Free Full Text] - Sharma AM. Sibutramine in overweight/obese hypertensive patients. Int J Obes Relat Metab Disord 2001;25(Suppl. 4):S20–S23.
- Sjöström L, Lindroos AK, Peltonen M et al. Swedish Obese Subjects Study Scientific Group. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683–2693.
[Abstract/Free Full Text] - Rossner S, Sjostrom L, Noack R et al. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res 2000;8:49–61.[ISI][Medline]
- Van Gaal LF, Wauters MA, Peiffer FW, De Leeuw IH. Sibutramine and fat distribution: is there a role for pharmacotherapy in abdominal/visceral fat reduction? Int J Obes Relat Metab Disord 1998;22(Suppl. 1):S38–S40.
- Rubins HB, Robins SJ, Collins D et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410–418.
[Abstract/Free Full Text] - Sjöström L, Rissanen A, Andersen T et al. Randomised placebo- controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet 1998;352:167–172.[CrossRef][ISI][Medline]
- Muls E, Kolanowski J, Scheen A et al.; ObelHyx Study Group. The effects of orlistat on weight and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind, placebo-controlled, multicentre study. Int J Obes Relat Metab Disord 2001;25:1713–1721.[CrossRef][ISI][Medline]
- Abbott Laboratories. Data on file.
- Kelley DE, Kuller LH, McKolanis TM et al. Effects of moderate weight loss and orlistat on insulin resistance, regional adiposity, and fatty acids in Type 2 diabetes. Diabetes Care 2004;27:33–40.
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