Arne Astrup
MD DrMedSci
Director and Professor
Research Department of Human Nutrition
Royal Veterinary and Agricultural University
Frederiksberg
Copenhagen Denmark
Obesity is rising in prevalence, with significant proportions of the population now classified as obese or overweight. In the UK, the proportion of obese men rose from 14% to 17% and obese women from 17% to 21% between 1994 and 1998. Nearly two-thirds of men and just over half of women in the UK are either overweight or obese.(1) Similar rises are occurring across Europe, with a particularly worrying rise in the number of children classified as overweight or obese.
Long considered to be a lifestyle problem, it is only in recent years that obesity has attracted medical or scientific interest. Obesity is recognised as a major risk to health, associated with a range of adverse health complications such as hyperlipidaemia, hypertension, gallbladder disease, some cancers, sleep apnoea and degenerative joint diseases.(2) In particular, obesity is responsible for the serious increase in diabetes prevalence.(3) In addition, it exerts an adverse effect on health-related quality of life because of decreased psychological wellbeing, stigmatisation and less social integration.(4)
Doctors have long accepted the need to treat the consequences of obesity, but acceptance of the need to treat obesity itself is a more recent development,(5) and is recognised in various official reports and management guidelines.(6,7) This is partly because clinicians have traditionally had limited training in nutrition, and most dietary strategies result in only limited success. Furthermore, previously available drug treatments have been only partially effective or, in the case of the fenfluramines, have been associated with rare but potentially severe side-effects such as pulmonary hypertension and valvular defects.(8) The recent knowledge that weight loss of 4–5% in obese individuals with abnormal glucose tolerance is sufficient to reduce progression to type 2 diabetes by 50% has further increased interest in treating obesity.(3)
Weight loss with sibutramine
Recent years have seen the licensing of new antiobesity agents such as sibutramine. Sibutramine is a novel monoamine reuptake inhibitor that blocks the reuptake of both serotonin and noradrenaline. This differentiates it from drugs such as dexfenfluramine, which stimulates the release of monoamines and may cause depletion of serotonin within the brain. Sibutramine has two complementary physiological effects. First, it promotes satiety (the desire to stop eating) after eating, which leads to a reduced food intake. It is important to note that sibutramine does not induce, as a primary effect, a state of anorexia. Instead it enhances and may extend satiety after eating. Second, it stimulates energy expenditure and so limits the decline in metabolic rate that normally accompanies weight loss.(9,10)
Sibutramine is associated with significant and clinically relevant weight loss beyond that achieved by a reduced calorie diet or placebo,(11) and over one year’s treatment can amplify the effects of a very low calorie diet.(12)
More significantly, however, patients enrolled in the Sibutramine Trial of Obesity Reduction and Maintenance (STORM) were able to maintain their weight loss for up to two years.(13) All subjects received sibutramine 10mg once daily together with an individualised diet and exercise regimen for the first six months of the trial. Those patients who achieved weight loss of more than 5% during this six-month period were randomly assigned to sibutramine 15–20mg/day (plus diet and exercise) or placebo (plus the same diet and exercise) for a further 18 months. A total of 43% of sibutramine patients who completed the trial had maintained 80% or more of their original weight loss, compared with 16% of the control subjects (odds ratio 4.64, p<0.001). Furthermore, patients also achieved beneficial improvements in a range of cardiovascular and metabolic parameters, such as HDL-cholesterol, VLDL-cholesterol, triglycerides, insulin and uric acid.
Understandably, clinicians will wish to replicate the impressive results achieved in STORM in their obese and overweight patients. In order to do so, clinicians should adopt the integrated approach that helped to achieve long-term success in STORM. This requires selecting appropriate patients and using the drug in combination with an individualised diet and physical activity programme. The approach encompasses five phases:
1. Recruiting appropriate patients.
2. Patient assessment.
3. Initiation of weight management.
4. Follow-up visit.
5. Planning for weight plateau.
1. Recruiting appropriate patients
Few patients wish to be overweight, and there is likely to be great demand for weight management services given the availability of sibutramine. For healthcare professionals, managing this demand may pose a major challenge.
Those patients at greatest health risk are most likely to benefit from treatment with sibutramine and are therefore important targets for recruitment to weight management programmes. They include patients with a body mass index (BMI) of more than 30kg/m(2) or a BMI of 27kg/m(2) with associated risk factors or complications. Often these patients will present with the consequences of obesity such as hypertension, joint problems, dyslipidaemia, hyperuricaemia and the metabolic syndrome. Those with the highest initial BMI are also more likely to achieve a greater percentage of weight loss on sibutramine.(14) These people will often have made previous attempts at weight loss. Although previous weight loss attempts are thought to reduce the impact of any novel approach, many patients included in the STORM study had made repeated weight loss attempts yet went on to achieve and maintain impressive degrees of weight loss with sibutramine.
2. Patient assessment
Once identified, patients need careful assessment before being assigned to a treatment programme. This should involve a comprehensive medical history and physical examination, which usually highlights problems such as high blood pressure, diabetes and insulin resistance (or hyperinsulinaemia in its early stages). Despite early concerns, hypertension is not a contraindication for treatment with sibutramine, providing that blood pressure is controlled and monitored accurately every two weeks for three months, with patients having rested for five minutes and the use of a larger cuff size. The cuff size should fit the larger overarm of the obese patient. For this purpose, use special large cuff sizes developed for obese subjects.
At present, sibutramine is contraindicated in those groups of patients for whom there are no data available to support its use. This includes those aged under 18 years or over 65 years, pregnant or lactating women, patients with renal or hepatic impairment, psychiatric illnesses, a history of substance misuse or concomitant use of monoamine oxidase inhibitors and other centrally acting drugs, and patients with inadequately controlled hypertension (>145/90mmHg), or those with a history of ischaemic cardiovascular disease and arrhythmias.
The assessment should also identify the patient’s exercise and dietary routines and consider any relevant factors in the patient’s social environment that may influence eating patterns and dietary habits and affect the patient’s compliance with the treatment programme.
3. Initiation of weight management
Established guidelines identify diet, exercise and behavioural changes as the approaches that underpin successful weight management; all are needed before medical therapy is initiated.(15)
A team approach is essential. The patient must understand that in addition to the doctor, he or she may be seen by the nurse and dietician who will help to produce a dietary plan and provide practical advice on day-to-day coping strategies (shopping, eating out, snacking and so on). In some cases, professional psychological help may be required to ensure behavioural change.
It is essential to set small, achievable weight loss goals. Patients always want 30–40% weight loss, but for a patient who weighs, say 125kg, this is clearly unrealistic. A 5–10% weight loss is more realistic and is associated with major health benefits, provided it is maintained.(16) A suitable goal might be weight loss of about 2kg in one month, and 5–10% by six months, and this can be presented to the patient as the initial target. Patients unable or unwilling to accept this management approach are unlikely to benefit from treatment with sibutramine, and alternative management strategies should be sought. But for those who do accept and comply, sibutramine 10mg can be initiated.
It is important to help the patient by making the recommendations for successful weight loss as simple as possible, such as the “10, 20, 30” regimen: published data show that 10mg of sibutramine will help the patient to consume approximately 20% less food; when this is added to an extra 30 minutes of exercise per day, successful weight loss may be anticipated, as the STORM study has shown.
Exercise can be taken either in one session each day or in several sessions, and can be as simple as taking three walks per day – for instance, in the morning, at lunchtime and in the evening. It is important that the recommendation is tailored to what the patient is able and willing to commit to.
Patients should also be educated about the side-effects they may experience with sibutramine. These are generally mild, reversible and diminish over time. Dry mouth and insomnia are the most common side-effects. However, small increases in heart rate can be expected with a small increase in blood pressure if weight loss does not occur. Any clinically significant increases tend to occur early in treatment. In the first three months of treatment, these parameters should be checked every two weeks; between month four and six these parameters should be checked once every month and regularly thereafter, at maximum intervals of three months. The drug should be discontinued if the resting heart rate rises by >10bpm or if the blood pressure increases by more than 10mmHg at two consecutive visits.
4. Follow-up visit
Patients should be assessed at one month, which provides an opportunity to discontinue drug therapy in non- responders. Analyses suggest that, at one month, those patients who have achieved a weight loss of >-2kg are likely to go on to achieve good weight reduction in the long term. A greater initial weight loss is generally associated with a better long-term outcome.(17) The clinician may need to reassess the programme through discussion with the patient if weight loss is less than 1–2kg. Although a slower rate of weight loss is common in some patients, such as those with type 2 diabetes, a poor response may be due to the patient eating too much or taking too little exercise, or they may require a higher dose of sibutramine. At this stage, the 10mg dose may be increased to 15mg for a further four weeks. Those patients who then lose >-2kg in this further four weeks are likely to go on and achieve long-term success.
The need to review progress with the patient, however small, is vital: patient motivation is key, and reinforcement of goals and the continuation with the programme of diet and exercise must be highlighted at every opportunity. This visit provides an opportunity for the team to intensify its efforts and to remotivate the patient.
At this stage, the patient should be prepared for a slowing down in the rate of weight loss and the possible weight loss plateau, which usually occurs after 4–6 months of continued therapy. By preparing for it, the patient will know exactly what can be done should problems arise.
5. Planning for weight plateau
Having lost some weight, patients are often highly optimistic and believe they will continue to lose more weight simply by continuing to take the drug; most, however, will undergo a weight plateau phase at some stage. It is important that the patient understands that this can be dealt with by increasing metabolic rate, which by this time will have dropped. Many patients have previous experience of dieting and anticipate a yo-yo effect. Further weight loss can be encouraged by reinforcing the dietary and exercise components of the programme and by stressing the behavioural initiatives and providing continued patient support. Patients may need regular contact and support, which can be provided through groups, perhaps by the internet or by telephone.
Conclusion
Obesity is a chronic disease that requires long-term management strategies. The launch of sibutramine in Europe offers the medical community a new opportunity to engage in the active management of obese and overweight patients. However, in order to make the most of this opportunity, clinicians need to use the drug in appropriately selected patients who are willing and able to adopt a programme of lifestyle modification. Since early weight loss predicts longer-term success in weight management, the effect of the drug should be monitored intensively through the early stages of management and continued or discontinued as necessary.
References
- Department of Health. Health Survey for England: Cardiovascular Disease 1998. London: HMSO; 1999.
- Pi-Sunyer FX. Medical hazards of obesity. Ann Intern Med 1993;119:655-60.
- Astrup A, Finer N. Redefining type 2 diabetes: diabesity or obesity dependent diabetes mellitus? Obes Rev 2000;1:57-9.
- Mathias SD, Williamson CL, Colwell HH, et al. Assessing health-related quality of life and health state preferences in persons with obesity: a validation study. Qual Life Res 1997;6:311-22.
- National Audit Office. Tackling obesity in England: report by the Comptroller and Auditor General. London: HMSO; 2001.
- Royal College of Physicians. Clinical management of overweight and obese patients with particular reference to the use of drugs. London: RCP; 1998.
- Scottish Intercollegiate Guidelines Network. Obesity in Scotland: integrating prevention with weight management. SIGN; 1996.
- Abenhaim L, Moride Y, Brenot F, et al. Appetite- suppressant drugs and the risk of primary pulmonary hypertension. International Primary Pulmonary Hypertension Study Group. N Engl J Med 1996;335:609-16.
- Astrup A. Thermogenic drugs as a strategy for treatment of obesity. Endocrine 2000;13:207-12.
- Hansen DL, Toubro S, Stock MJ, Macdonald IA, Astrup A. Thermogenic effects of sibutramine in humans. Am J Clin Nutr 1998;68:1180-6.
- Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Res 1999;7:189-98.
- Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, 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;106:179-84.
- James WPT, Astrup A, Finer N, et al, for the STORM Study group. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet 2000;356:2119-25.
- Hansen DL, Astrup A, Toubro S, et al, for the STORM study group. Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in obesity. Results from the European multi-center STORM trial. Int J Obes 2001;25:496-501.
- Astrup A. Dietary approaches to reducing body weight. In: Bray GA, editor. Obesity – from science to treatment. Baillière’s Best Practice & Research: Clinical Endocrinology and Metabolism. London: Ballière Tindall; 1999.
- Goldstein DJ. Beneficial health effects of modest weight loss. Int J Obes Relat Metab Disord 1992;16:397-415.
- Astrup A, Rössner S. Lessons from obesity management programmes: greater initial weight as an integrated part of an obesity management program improves long-term maintenance. Obes Rev 2000;1:17-19.
Resources
European Childhood Obesity Group
W:www.childhoodobesity.net
European Society of Cardiology
W:www.escardio.org
European Association for the Study of Diabetes
W:www.easd.org
Forthcoming events
23–25 May 2002
European Childhood Obesity Group Meeting
Prague
Czech Republic
E:[email protected]
24–29 Aug 2002
9th International Congress on Obesity
Sao Paulo, Brazil
E:[email protected]
W:www.abeso.org.br
