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Obesity more to inactivity than to food intake. 4 the 1980s showed a strong correlation Worldwide, the adoption of industri- between the (thin, median alised western society lifestyles (urbani- weight, or obese) and the Nicholas Finer MBBS BSc FRCP , Clinical sation, western foods, increased BMI of the biological parents (for Director, Wellcome Trust Clinical Research sedentariness and car ownership ) is mothers p<0.0001, for fathers p<0.02), Facility and Honorary Consultant in associated with increasing obesity. but no correlation with the BMI of Medicine, Addenbrooke’s Hospital, In countries adopting these lifestyles their adoptive parents. 5 In a study in Cambridge; Visiting Professor, Institute for there appears to be a particularly rapid South-West American Indians, energy Health Services Research, Luton University increase in ; for expenditure correlated with the rate of example, in Chile, Peru and Mexico 25% change in body weight over a two-year Clin Med 2003;3:23–7 of children are overweight and obese. follow-up period. Also, in 94 siblings from 36 families, 24-hour energy expenditure aggregated in families. 6 Genetics Genetic factors are estimated to Prevalence At the same time, there is increasing explain 30– 50% of the heritability of obesity. The human obesity gene map 7 is In its recent world health report, 1 the evidence for a genetic predisposition to now complex. Currently identified are: World Health Organization stated that: obesity. Studies in adopted children in

We are facing a worldwide epidemic of obesity, a key risk factor in type2 , cardiovascular diseases, high blood pressure 25 Men >30 >40 and stroke, as well as various types of cancer. 21 More than one billion adults worldwide are 20 18.7 17.3 overweight, and at least 300 million of these 16.4 17 15.3 are clinically obese. 15 13.8 I 13.2 M

Obesity prevalence is 14– 20% in B industrialised countries, but the fastest 10 increases, particularly in childhood obesity, are seen in developing countries 5 such as Chile and China. 2 Worldwide, 22 million children under the age of five 0.2 0.4 0.3 0.4 0.8 0.6 0.8 0.6 0 are overweight; 10% of US preschool 1993 1994 1995 1996 1997 1998 1999 2000 children are obese, half of whom are likely to have impaired glucose toler- ance.3 In Europe, England and Wales have seen one of the most rapid increases 25 Women >30 >40 in prevalence of overweight and obesity. 21.2 21.1 21.4 19.7 There has been an increase from 6% and 20 18.4 17.3 17.5 8%, respectively, for men and women in 16.4

1980 to 8% and 12% in 1990, and to over 15 I

21% for both in 2000 (Fig1). More than M 50% of adults are overweight (body mass B index (BMI) 25). 10

5 Aetiology 2.3 2.3 1.4 1.6 1.4 1.4 1.9 1.9

Lifestyle 0 1993 1994 1995 1996 1997 1998 1999 2000 There are complex causes for this increasing prevalence, involving secular Year changes in lifestyles affecting both energy and energy expenditur e (T able 1). Fig1. Prevalence of different degrees of obesity in England and Wales (data from Analysis of food intake data and proxy Health Survey of England and Wales, 1993–2000) (BMI = ). These graphs allow the prescription of an individually tailored weight-reducing providing a measures of exercise and activity suggest 600 kcal (2.5 MJ)/day deficit to men and women of varying degrees of body weight, that the recent rise in overweight and according to sex (assuming mild to moderate activity level) with a minimum energy obesity in England can be attributed prescription of 122 kcal (5 MJ)/day.

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Table 1. Examples of changes in energy intake (diet) and energy expenditure (clinically assessed by the waist circum- (physical activity and exercise) over the past 50 years. ference). This relationship has been particularly well defined for type2 Energy intake Energy expenditure diabetes mellitus (Fig 3) 8 and highlights Cheaper food Increased ownership of cars the need to assess both BMI and waist cir- cumference in the clinical evaluation of Greater availability of food: Change in work practices: • Supermarkets • Construction machines the obese patient (T able2). Different • Freezers • Production lines criteria are proposed for non-European • Fast food outlets • Computers ethnic groups (egadult Asians: over- 9 Change in diet composition: Labour-saving devices: weight BMI >23, obesity >25). In • Increased fat • Washing machines addition, obesity impairs quality of life, • Increased refined sugars • Dishwashers increases morbidity and leads to prema- • Less complex carbohydrates • Remote controls ture mortality. • More alcohol • Cordless phones Change in eating patterns: Sedentary relaxation: More snacks Television Treatment • Fewer ‘family’ meals • Computer games • Increased portion sizes • Lifts Lifestyle interventions • • Escalators • Treatment aims to produce clinically Children: Children: valuable (5–10%) Targeted by food industry Push chairs (Table 3)10,11 that is maintaine d • Greater autonomy • Fewer walk to school • Greater spending power • Decreased sport at school long-term. Lifestyle modificati on • • remains a cornerstone of obesity treatment, combining dietary modifica- • six single gene mutations which the prevalence of obesity has tion, increased activity and exercise, • 25 Mendelian disorders with map increased, thus pointing to the impor- behavioural and cognitive therapy. location tance of gene–environment interactions. Therapy is often delivered to groups of 48 candidate genes patients who need to be ‘ ready to • change’, and able and willing to spend 33 human quantitative trait loci, Health risks • time working on learning and practising and The health risks of overweight are well new skills. • 48 other human linkages. defined (Fig2). They increase with Current dietary management com- Clearly, the human gene pool has not greater degrees of obesity as well as with monly advises on healthy eating princi- changed over the past 50 years during central or visceral fat accumulation ples and a fixed of 600 kcal

Fig 2. Schematic representation of some of the major Hirsutism ~2 Stroke ~1.6 Sweating Low mood complications of Low self-esteem overweight and obesity and their approximate relative risks for body Hypoventilation ~2.9 mass index greater than Sleep apnoea CHD ~2.5 27–30 (CHD = coronary Breathlessness ~3.5 Thromboembolism~1.5 heart disease). Heart failure ~1.5

Infertility Breast cancer ~1.3 Pregnancy problems~2 Cancer of uterus ~4.6 Menorrhagia ~1.8 Gallstones ~2.7 Cancer of colon~1.5 ~2 Cancer of pancreas ~1.6 Gout ~3 Kidney disease Varicose veins

Diabetes mellitus 10 Dyslipaemia 1.5 Hyperinsulinaemia

24 Clinical Medicine Vol 3No 1January/February 2003 CME Endocrinology

(2.5MJ) from the calculated energy monoamine uptake inhibitor that Table 3. Benefits of a 10kg weight loss expenditure (Fig 4). If complied with, enhances satiety and possibly (based on data from Scottish Intercollegiate Guidelines Network). 10 such diets reliably predict a loss of attenuates the fall in metabolic rate 0.5 kg/week. The short-term use of that occurs with weight loss. Mortality liquid, very low calorie diets (ca800 kcal Both drugs have been approved by the Reduction: (3.4MJ)) can be an effective strategy to National Institute for Clinical Excellence >20% total mortality produce initial weight loss, but requires (NICE).12,13 They have slightly differing >30% diabetes-related deaths adjunctive treatment for longer-term prescribing guidance, precautions and >40% obesity-related cancer deaths weight maintenance. adverse events (T able4). Both drugs Blood pressure achieve an approximate 10% weight loss Reduction: Pharmacological interventions that reaches a maximum after sixmonths 10 mmHg systolic which is almost totally maintained for 20 mmHg diastolic Two drugs are currently licensed for use twoyears. Patients losing weight success- in the UK: fully with either drug will show improve- Diabetes orlistat, a pancreatic and gastric ment in metabolic factors such as fasting Reduction: • 50% fasting glucose lipase inhibitor that produces about glucose, lipids and urate. There is no 30% fat malabsorption evidence that combining the drugs is Lipids • sibutramine, a centrally acting worthwhile. Reduction: 10% total cholesterol 15% LDL Fig 3. Age-adjusted incidence rates of type2 diabetes cross-classified according to 30% triglycerides quintile of body mass index (BMI) and waist circumference. Increase: 8% HDL

Respiratory Reduced sleep apnoea Decreased breathlessness 600 Gynaecological Improved ovarian function Log age- adjusted and fertility in POS incidence/ >27.4 100,000 HDL = high-density lipoprotein; <27.4 LDL = low-density lipoprotein; person- POS = polycystic ovary syndrome. years <24.4 <22.7 BMI <21.1 0 >86.4 <86.4 <78.7 <73.7 <70 Key Points Waist (cm)

Obesity is reaching pandemic proportions due to environmental changes affecting both sides of the Table 2. World Health Organization definitions of obesity, amended to take account energy balance of fat distribution assessed by waist circumference. Modest weight reduction of 10% Disease risk* achieves medically important outcomes Classification of BMIObesityMen <102cm Men 102 cm obesity class Women <88cm Women 88cm Pharmacotherapy can be a useful adjunct to lifestyle modification to <18.5 achieve medically worthwhile Normal 18.5–24.9 Average Average weight loss Overweight 25.0–29.9 Increased High should be considered Obesity 30.0–34.9 I High Very high in those with a body mass index Obesity 35.0–39.9 II Very high Very high above 35 and comorbidities Extreme obesity >40 III Extremely high Extremely high KEY WORDS: diet, energy balance, * relative to normal weight and waist circumference. exercise, leptin, lifestyle modification, BMI = body mass index. orlistat, sibutramine, waist circumference

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circulating leptin levels (as a conse- >60 years 31± 60 years 18± 30 years quence of increased fat mass), augmenta- tion of which has proved disappointing 2,800 in clinical trials so far. 2,600 Women 2,600 Men ) l a

c 2,400 2,400 k (

Surgery

n 2,200 2,200 o i t Operations to produce gastric restriction,

p 2,000 2,000 i r

c with or without a degree of malabsorp-

s 1,800 1,800 e

r tion, are highly effective at producing

p 1,600 1,600

y weight loss and weight loss maintenance g r 1,400 1,400 16 e (30–40%) and are approved by NICE. n 1,200 1,200 E Current operations include: 1,000 1,000 purely restrictive procedures 40 50 60 70 80 90 100110120 40 50 60 70 80 90 100110120 • (egvertical-banded gastroplasty Present weight (kg) (laparoscopic or open surgery), gastric banding (laparoscopic)), Fig 4. An individually tailored weight reducing diet providing a 600kcal or (2.5MJ)/ day deficit, with a minimum energy content of 1,200kcal (5MJ)/ day. 10 • restrictive and malabsorptive procedures (eggastric bypass). The recent XENDOS trial of orlistat neuropeptide Y/ melanocortin pathways There are no controlled comparative (presented at the International Congress or vagally-mediated afferent pathways trials, but weight loss may be greater after on Obesity, September 2002) showed a from the gastrointestinal tract (cholecys- gastric bypass (30–40%) than following 6.9 kg loss after four years compared tokinin, glucagon-like peptide). Leptin restrictive procedures (25– 35%). Con- with 4.1 kg on placebo and was associ- replacement therapy is highly effective in siderable investment in facilities , ated with a 37% relative risk reduction of the handful of children with mutations surgical, anaesthetic and medical skills is progression to diabetes. 14 leading to leptin deficiency (Fig5), required to support bariatric surgical Newer pharmacological targets focus acting as a proof of principle that disor- programmes which are aimed at patients on the complex central/ hypothalamic ders of body weight regulation exist. with a BMI above 40, or above 35 when control of obesity through either leptin/ However, most obese subjects have high there are comorbid complications.

Table 4. Comparison of prescribing/National Institute for Clinical Excellence guidance for sibutramine and orlistat.

Sibutramine Orlistat

Indications BMI >27 with significant comorbidity BMI >27 with significant comorbidity BMI >30 BMI >30 Inadequate response (<5% loss) to previous 2 kg weight loss in 4 weeks with diet before starting ‘serious’ attempts to lose weight orlistat Age 18–65 years Age 18–65 years Continued prescribing 2 kg loss at 4 weeks 5% loss at 12 weeks 5% loss at 12 weeks 10% loss at 24 weeks Monitoring BP and pulse 2-weekly, then monthly for 24 weeks Duration of treatment 1 year 1 or 2years Contraindications Include: antidepressants, antipsychotics, Chronic malabsorption syndromes, pregnancy, breast- inadequately controlled hypertension or significant feeding cardiovascular or peripheral vascular disease, prostatic hyperplasia, hyperthyroid Side effects Blood pressure and heart rate increase, dry mouth, Gastrointestinal constipation, insomnia, sweating Metabolic benefits 20–30% increase in HDLcholesterol, improved Decreased total cholesterol, BP HbA1c in diabetics 37% fewer patients progress from IGT to diabetes over 4 years

BMI = body mass index; BP = blood pressure; HbA1c = glycated haemoglobin; HDL = high-density lipoprotein; IGT = impaired glucose tolerance.

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Start of 5Stunkard AJ, Sorensen TI, Hanis C, leptin therapy Teasdale TW et al. An adoption study of human obesity. N Engl J Med 1986;314: (a) 193–8. 100 6Ravussin E, Lillioja S, Knowler WC, Christin L et al. Reduced rate of energy 90 expenditure as a risk factor for body-. N Engl J Med 1988;318:467–72. 80 7Rankinen T, Perusse L, Weisnagel SJ, Snyder EE et al. The human obesity gene map: the 70 2001 update. Review. Obes Res 2002;10: 196–243. ) 60 g 98th 8Carey VJ, Walters EE, Colditz GA, Solomon k ( percentile t CG et al. Body fat distribution and risk of

h 50

g non-insulin-dependent diabetes mellitus in i

e women. The Nurses’ Health Study. Am J

W 40 50th Epidemiol 1997;145:614–9. percentile 9Inoue S, Zimmett P. The Asia-Pacific per- 30 spective: redefining obesity and its treatment . Australia: Health Communications pty, 20 2nd 2000. percentile 10 Scottish Intercollegiate Guidelines 10 Network. Obesity in Scotland: integrating prevention with . A 0 national clinical guideline recommended for 0 1 2 3 4 5 6 7 8 9 10 use in Scotland . Edinburgh: Royal College of Age (years) Physicians, Scotland, 1996. (b) 2 11 Clinical Guidelines on the Identification,

) 0 Evaluation, and T reatment of Overweight g

k ± 2 (

n Lean m ass

and Obesity in Adults: The Evidence i

s e s ± 6 Report. National Institutes of Health. g a

n 6

m Review. Obes Res 1998; (Suppl 2): a ± 10 Total weight Fat mass h y 51S–290S. C d

o ± 14 12 National Institute for Clinical Excellence. b ± 18 Guidance on the use of orlistat for the treat- 0 2 4 6 8 10 12 ment of obesity in adults . Technology Months of treatment Appraisal Guidance No.22. London: NICE, 2001:1–12. Fig 5. Weight in a girl with congenital 13 National Institute for Clinical Excellence. leptin deficiency before and in response Guidance on the use of sibutramine for the to leptin treatment: (a) changes in treatment of obesity in adults . Technology weight from birth to the age of 10 years, Appraisal No.31. London: NICE, 2001. showing the 2nd, 50th and 98th 14 Sjöströ m L. Intervenire necesse est. Int J percentiles for weight among girls; Obesity 2002;26(Suppl 1):S3. (b) changes in body composition during 15 Farooqi IS, Jebb SA, Langmak G, Lawrence treatment (reproduced from Ref 15). E et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N Engl J Med 1999;341:879–84. 16 National Institute for Clinical Excellence. Guidance on the use of surgery to aid weight reduction for people with morbid obesity. References Technology Appraisal Guidance No. 46. London: NICE, 2002. 1The World Health Report 2002. Reducing risks, promoting healthy life . France, Sadag-7000: World Health Organization, 2002:1–177. 2World Health Organization. Obesity: pre- venting and managing the global epidemic . Report of a WHO consultation on obesity. WHO/NUT/NCD/981. Geneva:WHO, 1998:1–275. 3Rocchini AP. Childhood obesity and a dia- betes epidemic. N Engl J Med 2002;346: 854–5. 4Prentice AM, Jebb SA. Obesity in Britain: gluttony or sloth? BMJ 1995;311:437–9.

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