Asia Pac J Clin Nutr 2006;15 (Suppl): 55-62 55
Review Article
Emerging pharmacotherapy for treating obesity and associated cardiometabolic risk
Ian D Caterson AM MBBS PhD FRACP1 and Nick Finer FRCP 2
1 Human Nutrition Unit, The University of Sydney, Sydney, Australia
2 Wellcome Trust Clinical Research Facility, and Cambridge University School of Clinical Medicine,
Cambridge, UK
The global obesity epidemic is causing much concern among health professionals due to the major health risks associated with obesity. Excess weight, particularly abdominal obesity, elevates multiple cardiovascular and metabolic risk factors, including Type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease. Thus obesity management goals should encompass health improvement and cardiometabolic risk reduction as well as weight loss. While lifestyle and diet modification form the basis of all effective strategies for weight reduction, some individuals may need additional intervention. About one in four people with BMI >27 kg/m2 (those who have weight-related morbidity and who have been unsuccessful losing weight in standard ways) may require adjunctive therapy such as pharmacotherapy, very low energy diets/meal replacements, or bariatric surgery. This review focuses on appropriate use of pharmacotherapy for obesity and cardiometabolic risk. Sibutramine and orlistat are currently available for use in Australia. Rimonabant has been approved for use in the European Union, and is being considered for regulatory approval in the USA and Australia. The efficacy and safety of these three agents are examined. In addition, several novel pharmacotherapy agents in development are discussed.
Key Words: obesity, pharmacotherapy, sibutramine, orlistat, rimonabant
Asia Pacific J Clin Nutr 2003;12 (1): 92-95 1
Introduction
The global obesity epidemic is a well-established reality. Worldwide more than one billion adults are overweight, with at least 300 million of these being defined as obese.1 The USA leads the way, with about two-thirds of the population being obese or overweight,2 but other countries are not far behind. In Australia, the prevalence of obesity has more than doubled in the past 20 years and at least 60% of Australian adults are now overweight or obese.3 The obesity epidemic is not limited to the affluent, industria-lised societies; rates of obesity are rapidly increasing in developing countries where the sheer size of the population means that numbers of obese individuals exceed even those of the West. In China, where the overall overweight and obesity prevalence is about 22.8% and 7.1% respectively, and 55.7% of the residents of Beijing are now overweight or obese; it is estimated overall that 200 million are over-weight and 60 million Chinese are obese.4
This obesity epidemic is causing concern among health-care professionals because obesity poses a major health risk. Excess weight, particularly abdominal adiposity, ele-vates multiple cardiovascular and metabolic risk factors: it is associated with increased risk of Type 2 diabetes melli-tus (T2DM), hypertension, dyslipidaemia and cardio-vascular disease.5 Obesity is expected to have a cata-strophic impact on health care and will increase healthcare costs in the coming decades. It has even been suggested that the obesity epidemic could reduce life expectancy in the USA during the 21st century.2,6
The chronic and debilitating nature of the diseases asso-ciated with obesity (which apart from metabolic and car-diovascular disease include cancers and mechanical com-plications such as osteoarthritis and sleep apnoea) underlies the imperative of its prevention and treatment. Treatment may be of overweight and obesity alone, or of obesity as part of a core set of risk factors. Numerous clinical guide-lines highlight the importance of addressing obesity, espe-cially abdominal obesity, for example the clinical practice guidelines produced by the National Health and Medical Research Council of Australia6 and the World Health Orga-nisation technical report.7 It is now accepted that a loss of 5–10% of body weight is extremely effective in reducing progression to Type 2 diabetes and improving risk factors.6 However, no outcome study has yet shown that this degree of weight loss, when sustained, prevents premature/excess mortality. Currently, a number of long-term studies are attempting to address this issue.
Correspondence address: Prof Ian Caterson, Human Nutrition Unit, The University of Sydney, NSW 2006, Australia.
Tel: +61 2 9351 5010; Fax: +61 2 9351 6022
Email:
Accepted 30 June 2006
Emerging pharmacotherapy in obesity 61
Obesity therapy
There is a range of treatment options available for over-weight and obesity, including diet and lifestyle modi-fication, behavioural therapy, pharmacotherapy, very low calorie diets and meal replacements and bariatric surgery. No single approach will suit all overweight or obese indi-viduals, but education and support to allow the patient to modify lifestyle and diet forms the basis of all effective strategies.6 This review will concentrate on the appro-priate use of pharmacotherapy, particularly as there are new agents in the later stages of development and the approval process. Other strategies have been discussed in previous reviews.8,9
In the past, use of obesity pharmacotherapy has been controversial and somewhat difficult. Available therapies were not ideal,6 and to this was added the belief or per-ception that losing weight or maintaining weight loss was all down to willpower and individual choice.10 This atti-tude still persists despite the advances in knowledge on the physiology of energy balance that show that body weight (and weight maintenance) are as powerfully de-fended as respiration and blood pressure.11 For example a recent study showed that the lower leptin levels after weight loss may produce hunger, or drive to eat, and this may explain the propensity to regain lost weight.10 De-spite this, food intake is clearly a behaviour that is in part modifiable by volition12 and this accounts for the sy-nergism of interventions that include behavioural therapy and pharmacotherapy in terms of amplified weight loss.13,14 It needs to be reemphasised that targeting obesity as a therapeutic goal is important as weight loss effectively reduces many cardiometabolic risk factors.
Although overweight people (body mass index, BMI, 25–30 kg/m2) are at increased risk of dyslipidaemia, hypertension and T2DM, lifestyle and diet interventions are generally considered sufficient to help reduce weight and control risk in these individuals.6 Such lifestyle inter-vention can be effective but require considerable re-sources to deliver.15–17 About 25–30% of obese people and those with a BMI >27 kg/m2 may require some form of adjunctive therapy to supplement diet and lifestyle changes.8 Such an intervention is generally reserved for those whose health is impaired and who have been un-successful at losing weight in standard ways.6
Assessment of obesity
For years, weight alone or BMI (weight in kg/height in m2) have been used to assess obesity and overweight, but it is now recognised that body-fat distribution should be taken into account. Those with upper body or abdominal obesity are at greater risk. Such distribution may be assessed by waist-to-hip (w/h) ratios but waist circum-ference (WC) has been identified as the most clinically relevant measure of abdominal obesity6 and its response to treatment.18 Specific cut-points for the definition of obesity by BMI, and of those at increased risk by WC, have been developed, and there is continuing debate as to whether these need to be made ethnic specific.19,20
Treatment goals should emphasise health improve-ments, not just reduced body weight and WC (BMI change is not a good measure of individual success in a programme). Success should be measured by the ability to achieve and maintain significant weight loss (5-10% of body weight) and by the beneficial effects of weight loss on the co-morbidities of obesity, such as T2DM, hyper-tension and dyslipidaemia.6,21
Most individuals measure the effectiveness of a weight loss programme simply in terms of weight loss in kilo-grams. However, waist circumference is one of the most useful clinical measures of disease risk. It is easy to de-termine in practice, it is obvious to the patient (change in belt size) and a reduction in WC produces a reduction in risk. Realistic goals are shown in Table 1.6
Adjunctive therapy
If patients do not achieve sufficient weight loss to meet their goals, or to control their obesity-associated co-morbidities, with a lifestyle intervention alone, then adjunctive therapy should be considered. Adjunctive the-rapy includes specific pharmacotherapy, very low energy diets or meal replacements, and bariatric (obesity) sur-gery. All are useful and effective, but in this review only pharmacotherapy will be considered.
Pharmacotherapy: When and how?
Pharmacotherapy should be considered for people who have:6
- a BMI of ≥30 kg/m2, or ≥27 kg/m2 together with other
risk factors
- failed to lose weight through diet, exercise and
behavioural therapy.
Pharmacotherapy is not, and should not be viewed as an ‘easy option’ that can replace diet and lifestyle change - all clinical studies demonstrating successful weight loss have combined pharmacotherapy with an energy-restricted diet and activity.6 Weight loss should be eva-luated in the first six weeks to three months of therapy, as patients who experience early weight loss are more likely to obtain long-term benefit. If there is inadequate weight loss (<1.5 kg) in the first 6 weeks of therapy or if less than 5% of body weight is lost during the first 6 months, then discontinuation of pharmacotherapy should be con-sidered.8
During a weight loss programme, most weight is lost over the first six months and often a plateau phase is then entered. Maintaining a steady weight is a valid goal and a major benefit in itself, since the natural history of volun-tary weight loss, especially for obese people is weight re-gain. Clearly if pharmacotherapy has contributed to the weight loss and weight loss maintenance it should be con-tinued. Patients do need the support of an ongoing life-style programme. If weight is regained, more intensive therapy needs to be started and consideration given to re-starting pharmacotherapy, if the patient has discontinued it.8
Current and emerging pharmacotherapies
Obesity is a chronic condition, and pharmacotherapy is only effective while it is being taken. Most clinical trials of obesity pharmacotherapy have been limited to 1 or 2 years of drug therapy (there is a single, published 4 year trial14 and other longer trials are in progress), so the effects of long term treatment are not really known. As for any other long term drug treatment, if therapy is to be continued it must be with minimal potential risks and side effects; trials in progress will help determine both effectiveness and any potential risks or problems.6 Still other trials will need to be performed to determine the lowest effective dose of specific obesity pharmacothera-peutic agents for long term treatment.
Current pharmacotherapy
Several drugs are approved for weight loss in Australia. Older drugs such as phentermine will not be considered here, since there is too small a ‘modern’ evidence base. Newer, approved drugs are sibutramine (Reductil®, Abbott Laboratories) and orlistat (Xenical®, Roche Pro-ducts).
Sibutramine
Mechanism of action
Sibutramine is a selective serotonin and noradrenaline re-uptake inhibitor with both central and peripheral effects. It increases satiety, thereby acting as an appetite suppress-ant. It also prevents the normal fall in resting metabolic rate that occurs during weight loss.8
Use
Sibutramine is effective at doses ranging from 5–15 mg/ day. The usual starting dose of 10 mg/day is increased to 15mg/day if a weight loss of >1.5kg is not achieved during the first 4–6 weeks of treatment.8 It should be used with caution in people with a history of hyper-tension, and is not recommended for those with coronary artery disease, arrhythmias, congestive heart failure or stroke.6 There is a current trial of cardiovascular outcome with weight loss induced by lifestyle programme and with sibutramine in such patients (SCOUT), and results should be available within a few years. In Australia sibutramine
is not recommended for use in conjunction with anti-depressants, both other selective serotonin re-uptake inhi-bitors and particularly monoamine oxidase inhibitors.8 Since there is a high prevalence of depression in patients presenting for treatment,22 this may limit the use of sibu-tramine in clinical practice.
Efficacy
Randomised controlled trials have compared sibutramine with placebo.6,23,24 In these trials, a greater proportion of patients in the sibutramine groups achieved weight losses of ≥5% and ≥10% of baseline body weight than in the placebo groups (Fig. 1). The weight loss with active treatment is about double that with lifestyle therapy alone, on average an extra 4.5 kg. Other trials have compared the combination of lifestyle therapy plus placebo with lifestyle therapy plus sibutramine in maintenance of weight loss, enrolling those patients who lost weight during either a run-in period with sibutramine or a four-week very-low energy diet.13,25 Sibutramine was effective both in producing weight loss and in maintaining weight loss for up to 2 years.13 The combination of intensive life-style therapy and sibutramine was more effective than either approach alone.25
Sibutramine therapy improves several cardiovascular risk factors. Beneficial changes in glycaemic control (in patients with Type 2 diabetes), serum lipids, insulin, C-peptide, uric acid and waist circumference have been ob-served in clinical trials, and there is an important increase of more than 20% in HDL-cholesterol occurring after weight was stabilised (placebo-subtracted increase was 9% at 2 years and 4.8% at 1 year).13 Most of these changes were in proportion to the degree of weight lost, although the effect on HDL appeared was greater than might be expected from weight loss.13
Safety
Sibutramine is well tolerated and effective, but is asso-ciated with an increase in blood pressure (of 1 to 3 mm Hg) and heart rate (4 to 5 beats per minute) in some people. The most commonly-reported adverse events in clinical trials include headache, dry mouth, constipation and insomnia.6