Obesity: The new pill - Any practicable improvements?
A R P Walker
Human Biochemistry Research Unit Department of Tropical Diseases School of Pathology University of the Witwatersrand and South African Institute for Medical Research Johannesburg

S A J Clin Nutr 2000 February Vol 13 No 1

Obesity, increasingly common, is now recognised as a major public health problem worldwide. In the UK about 13% of men and 16% of women are now obese, with a body mass index of ³ 30, proportions having doubled in the last decade.1 In the USA20% of men and 25% of women are affected.2 In South Africa, proportions in the white population are 15% and 18% and in the black population 8% and 44%.3 As a comparison, proportions in African Americans have been given as 19% and 49%.4 The cardiovascular and other adverse sequelae of obesity are well known. Mortality rates from any cause are higher in the obese than in the non-obese.5 Treatments directed toward the long range reduction of body weight, in relation to the control of energy intake and additional exercise, have been described as ‘largely ineffective’, since 90 - 95% of persons who lose weight subsequently regain it.6 To help in the control of obesity in the USA, a recent authoritative report included the following recommendations: there must be a clear motivation for weight loss; it should be limited to 10% of current weight; the aim should be 0.45 - 0.90 kg per week over 6 months; daily energy intake should be reduced by 500 - 1 000 kCal; and physical activity should be pursued for 30 minutes daily. Drug treatment should be limited to a year; all smokers should quit smoking; and weight reduction in older persons should be undertaken with caution. The history of drug treatment has been described as ‘strewn with catastrophes’.7 The latest has been the association between valvular heart disease and the use of the drugs dexfenfluramine and phenfluramine, both of which have now been withdrawn.8 The newest drug available, which has attracted a great deal of attention, is orlistat, a gastro-intestinal lipase inhibitor which prevents absorption of about 30% of dietary fat from the gut.

In the first major study on the drug’s efficacy, which was conducted in European countries, a 2-year double-blind multicentre trial was carried out on 743 obese patients (average weight 100 kg).9 They were prescribed a diet in which 30% of the energy was from fat, and which provided 600 kCal/day less than calculated expenditure.

The 688 patients (93%) who were compliant during the 4-week run-in period on this diet, and who were on placebo capsules, lost about 2 kg. They were then randomised to either 120 mg orlistat 3 times daily, or to placebo, for 12 months. The orlistat group lost 10.3 kg compared with 6.1 kg in the placebo group. As is usual, almost all of this loss occurred in the first 6 months. Patients were then randomly re-assigned to orlistat or to placebo and went onto a weight maintenance diet. At the end of the second year, those continuing on orlistat had regained about 2 kg whereas those who had switched to placebo had regained 4.6 kg. The drop-out rate was low. Concentrations of cholesterol, glucose and insulin decreased more in the orlistat group than in the placebo group. Many patients taking the drug experienced fatty stools, increased defaecation and oily spotting (so that the test was not completely double-blind), and after 2 years on orlistat, up to 5.8% of them had abnormally low blood concentrations of b-carotene, vitamin D and vitamin E. Some of the weight loss in patients taking orlistat could have resulted from a reduction in fat intake to avoid the adverse effects of steatorrhoea.1 In the USA, a major multicentre randomised placebo-controlled trial on this pill has just been completed.11 It commenced with 1 187 obese American adults who had no other significant chronic health conditions, and continued for 2 years. At the end of the study period 403 participants remained, representing 45% of those randomised and 34% of those who began the run-in period. During the first year, the drug increased weight loss by about 3.15 kg, and in the second year by about 2.25 kg. In an editorial comment on the study, four key questions were listed.12 First, will the weight loss from orlistat result in meaningful changes in physiological risk factors in the absence of lifestyle intervention? Next, will what modest changes occur in physiological risk factors translate into meaningful improvements in health events — e.g. a reduction in heart attack, stroke, etc? Further, given the selection criteria and the high drop-out rates, will the benefits be generalisable to any but a small minority of obese patients? The fourth question raised was whether inordinate emphasis is not being placed on the treatment of obesity rather than on its prevention. At present, the situation is that ‘neither clinicians nor public health workers have any tools with proven effectiveness in preventing obesity — there must therefore be fundamental changes in cultural conceptions and expectations regarding physical activity and dietary intake’.12 A further question concerns the cost of the drug, particularly in poor populations.

So what conclusion may be drawn regarding this new drug treatment? Certainly, it is a new class of drugs acting on the gastro-intestinal tract only, and its use may be considered an advance on previous treatments. But the results by no means lessen the general reservations expressed on the use of drugs. In the recently published Report of the Royal College of Physicians, which concerns the clinical management of overweight in obese patients in which guidance is given on both current and future drugs for obesity, the conclusion was reached that the first strategy should be a combination of supervised diet, exercise, and changes in behaviour patterns. 13 But if this is unsuccessful in achieving a 10% weight reduction after 3 months, then drug treatment ‘may be justified’. However, if after 3 months of taking drug treatment the patient has not achieved a 5% weight reduction, the drug should be stopped.

A further well-researched drug is sibutramine or reductil. It produces dose-related weight loss through reduction of food intake and stimulation of energy expenditure.14 It has also been shown to be effective in long-term maintenance of weight loss after a very-low-calorie diet.15 Notwithstanding the recent measures of success resulting from drug treatments, in an outspoken essay in the Lancet it was maintained that ‘The first fact to be grasped is that the treatment of fatness does not work. Indeed, if all doctors practiced evidence-based medicine, half of the dietitians in any one country would be out of a job . . . Diets don’t work, commercial clinics rarely publish unselected results . . .’.16 Clearly, the usual advice given ‘eat more of this’, ‘eat less of that’, no matter how encouragingly expressed and attractively illustrated, does not engender the motivation essential for sustained weight loss.

Could there be a change in approach? It is now widely recognised that there must be a radical alteration in this regard. In a recent article concerning ‘putting prevention into practice’,17 it was emphasised that ‘Physicians should be ready to provide understandable information about healthy behaviors . . . and help patients glean useful information from the daily deluge of data and hype provided by the mass media and the Internet. The ability of physicians to figure out good sources of information for their patients is a very important challenge in prevention . . .’. In brief, as many others have concluded,18,19 providing dietary intake advice alone is insufficient. Those seeking to reduce weight must be given more education and greater understanding of obesity — in relation to its past history, how common it is, the various risk factors involved, and the circumstances where there have been successful long-term outcomes. It is noteworthy that in the UK the prevalence of obesity in the middle class, with their higher level of education, and healthier diet, is a half of that among the poor.20 Not least of the anxieties surrounding overweight and its control concerns the insufficiently appreciated increasing desire of children to remain thin. ‘The worship of the willowy supermodel has become a cult, and the parent of even the scrawniest 6-year-old girl will know that she is quite likely to come home from school announcing that she is starting a diet.’ 16 In Wales, in a study on schoolchildren aged 6 - 10 years, over 50% thought it healthy to be thin, 30% expressed the desire to be thinner, and 20% reported that they had at some time decreased their food intake to lose weight.21 In older children and young adults, as is well known, prevalences of anorexia nervosa and bulimia are rising. In Spain, the disorders now affect 0.5% and 2% of 14 - 24-year-olds.22 Interestingly, in that country the main opposition socialist party wants the government to introduce new regulations obliging dress designers and manufacturers to make women’s clothes in larger sizes than those currently available in the shops, and is urging a dialogue with advertisers and marketing companies to persuade them to use models who are ‘in harmony with social reality’, rather than the exceptionally thin. So what can be done about the control of the world-wide epidemic of obesity? Clearly medication alone is not the answer, and drugs should be reserved for patients whose obesity places them at medical risk.23 It has been stressed that ‘policies must focus on prevention, healthy lifestyles and especially exercise. The principal cause of obesity is not diet, although that is obviously a major component, but inactivity relative to diet.’ Because of the now well-recognised difficulties of adopting the necessary lasting lifestyle changes, the cry ‘I don’t want to change my diet, and I don’t want to exercise: I just want to be skinny. Give me the pill that will make me skinny’ is often heard. Alas, the envisaged ‘magic bullet’ is far over the horizon.24 As already indicated, all authoritative advisory bodies strongly emphasise that the primary health message to the public is to seek to avoid excessive weight gain. Hence the question, why haven’t campaigns been launched against obesity with the same rigour as those successfully launched against smoking practice?24 Has anyone seen a billboard warning of the perils of the overweight? Or one urging greater physical activity, since lack of physical activity is now considered to be the preponderant risk factor in obesity?24,25 As stressed in the Lancet’s ‘Hard sell for health’,26 only by aggressive approaches between health authorities and the public is any success in altering lifestyles likely to be forthcoming.

1. Garrow J. Flushing away the fat. BMJ 1998; 317: 830-831.
2. Bray GA. Obesity: a time bomb to be defused. Lancet 1998; 352: 160-161.
3. Steyn K, Jooste PL, Bourne L, et al. Risk factors for coronary heart disease in the black population of the Cape Peninsula. S Afr Med J 1991; 79: 480-485.
4. Van Itallie TB, Simopoulos AP. Summary of the National Obesity and Weight Control Symposium. Nutr Today Jul-Aug: 33-35.
5. Stevens J, Cat J, Pamuk ER, et al. The effect of age on the association between body mass index and mortality. N Engl J Med 1998; 338: 1-7.
6. Rosenbaum M, Leibel RL, Hirsch J. Obesity. N Engl J Med 1997; 337: 396-407.
7. Bray G. Drug treatment of obesity: don’t throw the baby out with the bath water. Am J Clin Nutr 1998; 67: 1-2.
8. Proietto J. New drugs and old drugs. Med J Austr 1998; 168: 409-412.
9. Sjostrom L, Rissanen A, Andersen T et al. Randomized placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. Lancet 1998; 352: 167-173.
10. McCarthy WJ. Orlistat and weight loss. Lancet 1998; 352: 1473.
11. Davidson MH, Hauptman J, Di Girolamo M, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized control trial. JAMA 1999; 281: 235-242.
12. Williamson DF. Pharmacotherapy for obesity. JAMA 1999; 281: 278-280.
13. Clinical Management of Overweight and Obese Patients — with Particular Reference to the Use of Drugs. London: Royal College of Physicians of London, 1998.
14. Bray GA, Blackburn GL, Ferguson JM, et al. Sibutramine produces dose-related weight loss. Obes Rev 1999; 7: 189-198.
15. 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.
16. Jeffcoate W. Obesity is a disease: food for thought. Lancet 1998; 351: 903-904.
17. Reynolds T. Putting prevention into practice. Ann Intern Med 1999; 130: 707-708.
18. Kirk SFL. Joint Symposium with British Dietetic Association on Implementing dietary changes: theory and practice’. Session 2: Obesity. Treatment of obesity theory into practice. Proc Nutr Soc 1999; 58: 53-58.
19. Rogers PJ. Joint Symposium with British Dietetic Association on ‘Implementing dietary changes: theory and practice’. Session 3: Changing eating habits ... Eating habits and appetite control: a psychological perspective. Proc Nutr Soc 1999; 58: 59-67.
20. Prentice AM, Jebb SA. Obesity in Britain: gluttony or sloth? BMJ 1995; 311: 437-439.
21. Blissett J, Lysons A, Norman P. Dieting behaviour and views of young children in Wales. Health Educ J 1996; 55: 101-107.
22. Bosch X. Spain tackles eating disorders. BMJ 1999; 318: 960.
23. Foreyt JP. An aetiologic approach to obesity. Hosp Pract 1997; 32: 123-148.
24. Hirsch J. Magic bullet for obesity. BMJ 1998; 317: 1136-1137.
25. Weinsier RL, Hunter GR, Heini AF, Goran MI, Sell SM. The etiology of obesity: relative contribution of metabolic factors, diet, and physical activity. Am J Med 1998; 105: 145-150.
26. Hard sell for health. Lancet 1998; 351: 687.

Last updated: 17-Feb-2004