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Obesity 

Chapter:
Obesity
Author(s):

I. Sadaf Farooqi

DOI:
10.1093/med/9780199204854.003.1105

May 29, 2014: This chapter has been re-evaluated and remains up-to-date. No changes have been necessary.

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Essentials

Obesity is defined as an excess of body fat that is sufficient to affect health adversely. It is associated with an increased risk of type 2 diabetes, cardiovascular disease, and some forms of cancer and is a serious medical disorder. In routine practice, body mass index (BMI) is most often used to define obesity in population studies and in the clinic: overweight, BMI 25 to 29.9 kg/m2; obese, BMI 30.0 to 39.9 kg/m2; morbid obesity, BMI >40 kg/m2. By this definition about 20% of men and 25% of women in the United States of America and Europe are obese.

Causes of obesity

The rising global prevalence of obesity is driven by environmental factors including the increased availability of palatable energy-dense foods and the reduced requirement for physical exertion during working and domestic life.

The heritability of body weight and fat mass is very high and genetic variation determines the inter-individual differences in susceptibility or resistance to the ‘obesogenic’ dietary environment. Studies of genetic obesity syndromes have revealed mutations that all arise in molecules involved in the leptin–melanocortin pathway, which plays a key role in the regulation of body weight. Genome wide association studies, which have proved to be an extremely valuable tool for unravelling the aetiology of complex diseases, have shown that variants in the FTO gene are strongly associated with increased BMI.

Management of obesity

Management of patients with severe obesity is a challenge, but success is enhanced by a sympathetic approach from the physician, with realistic weight loss goals and monitoring of the effects of treatment. Interventions include (1) low-calorie diets, energy-deficit diets and diets that are low in fat, which should initially provide a 600 kcal/day (2.5 MJ/day) energy deficit, based on estimated energy requirements; (2) behavioural approaches to help subjects to implement and sustain changes to their eating and activity behaviour; (3) drug treatment—which should always be regarded as a therapeutic trial and stopped if weight loss is not apparent after one to two months—with agents used including pancreatic lipase inhibitors (orlistat); (4) surgery—an option for carefully selected patients with morbid obesity, with procedures including laparoscopic gastric banding, gastric bypass, and duodenal switch.

Introduction

Obesity is frequently considered to be a ‘modern’ disease—a reflection of the excesses of urbanized society. However, artefacts dating from the Palaeolithic age clearly represent subjects with an excess of body fat, and descriptions of obese individuals in medical texts from many of the ancient civilizations, suggest that, throughout history, certain individuals have harboured the tendency to store excess energy as fat. Hippocrates recognized that obesity posed a threat to health when he wrote that, ‘sudden death is more common in those who are naturally fat than in the lean’. Galen elaborated upon earlier descriptions of the obese state, distinguishing between different degrees of obesity, ‘moderate’ or common obesity and ‘immoderate’ or morbid obesity. Many Greek and Roman physicians documented some of the clinical complications associated with obesity, including reduced frequency of menses and infertility. The first known description of obesity and sleep apnoea dates from Roman times; Dionysius, the tyrant of Heracleia of Pontius who reigned from about 360 bc, was described as ‘an enormously fat man who frequently fell asleep’. The obesity-related changes in respiratory function, which are most prominent during sleep, are now recognized as the obesity–hypoventilation or Pickwickian syndrome.

Definition of obesity as a medical disorder

The recognition that obesity represents a serious medical disorder at a population level came with pooled life insurance data from the United States of America, showing that increasing degrees of overweight and obesity were important predictors of decreased longevity, much of which was attributed to cardiovascular disease. Subsequently, a number of epidemiological studies, including the Framingham Study and the Build and Blood Pressure Study have shown that the adverse effects of excess weight tend to be delayed, sometimes for 10 years or longer. These observations led to the recognition that obesity should be defined as a disorder in which excess body fat has accumulated such that health may be adversely affected. We now recognize that obesity is associated with substantially increased mortality from cardiovascular and cerebrovascular disease, type 2 diabetes, and certain cancers. Obesity is also associated with increased morbidity from musculoskeletal, gastrointestinal, psychiatric, and reproductive diseases (Table 11.5.1) and is associated with lowered quality of life, self-esteem, and socioeconomic performance.

Table 11.5.1 Medical complications associated with obesity

Type 2 diabetes

90% of type 2 diabetics have a BMI of >23 kg/m2

Hypertension

60–80% of hypertension is linked to excess weight

Coronary artery disease (CAD) and stroke

3.6-fold risk of CAD for each unit change in BMI

Respiratory effects

Neck circumference of >43 cm in men and >40.5 cm in women is associated with obstructive sleep apnoea, daytime somnolence, and development of pulmonary hypertension

Cancers

10% of all cancer deaths among nonsmokers are related to obesity (30% of endometrial cancers)

Reproductive function

6% of primary infertility in women is attributable to obesity

Impotency and infertility are frequently associated with obesity in men

Osteoarthritis (OA)

Frequent association in older people with increasing body weight

Liver disease

Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis (NASH); 40% of NASH patients are obese

Gallbladder disease

Threefold risk of gallbladder disease in women

The precise measurement of body fat is quite challenging, and accurate methods are not applicable to large populations; therefore, surrogate markers such as the body mass index (BMI—weight in kilograms divided by the square of the height in metres) are most often used to define obesity in population studies and in the clinic. The underlying assumption is that most variation in weight for persons of the same height is due to fat mass and there is a close correlation between BMI and the incidence of type 2 diabetes, hypertension, and coronary heart disease. A World Health Organization Expert Committee has proposed a classification of overweight and obesity (Table 11.5.2) using BMI.

Table 11.5.2 Cut-off points proposed by a World Health Organization Expert Committee for the classification of overweight and obesity

BMI

WHO classification

<18.5

Underweight

18.5–24.9

Normal weight

25–29.9

Overweight

30.0–39.9

Obesity

40.0 or greater

Morbid obesity

Worldwide prevalence of obesity

Obesity, defined as a BMI of more than 30 kg/m2, is a common condition in Europe and the United States of America. The most comprehensive information in Europe comes from the data collected between 1983 and 1986 for the MONICA study. On average, 15% of men and 22% of women were found to be obese and more than 50% of the adult population in Europe were either overweight or obese. The striking increase in prevalence between 1980 and 1994 confirms that population-wide increases in overweight and obesity have taken place over a short time interval. The most recent data from the United States of America shows about 20% of American men and about 25% of American women to be obese. In South-East Asia and the Middle East, a dramatic rise is being seen in all populations.

In children the relationship between BMI and body fat varies markedly with age and with pubertal maturation; however, when adjusted for age and gender, BMI is a reasonable proxy for fat mass. BMI percentile charts using national BMI reference data have now been published in several countries and facilitate the graphical plotting of serial BMI measurements in individual patients. The International Obesity Task Force (IOTF) has recommended the use of BMI data derived from six countries, which extrapolate risk from the adult experience to children. These age- and gender-specific BMI cut-offs (overweight as approximately 91st percentile or greater and obesity as approximately 99th percentile or greater) allow the comparison of obesity prevalence in different populations. Using these criteria, it is clear that the prevalence of overweight and obesity in childhood is a global concern (Table 11.5.3). Although there is no accepted definition for severe or morbid obesity in childhood, a BMI of more than 2.5 standard deviations from the mean (weight off the chart) is often used in specialist centres, and the crossing of major weight percentile lines upwards is an early indication of risk of severe obesity.

Table 11.5.3 Childhood prevalence (% of population) of overweight (including obesity) in selected countries, by WHO region using IOTF definitions

WHO Region

Year of survey

Age (years)

Boys

Girls

Africa

Algeria

2003

7–17

6.0

5.6

Mali

1993

5–17

0.2

0.5

South Africa

2001–2004

6–13

14

17.9

Americas

Brazil

2002

7–10

23.0

21.1

Chile

2000

6

26.0

27.1

USA

2003/2004

6–11

31.7

37.5

Eastern Mediterranean

Bahrain

2000

12–17

29.9

42.4

Iran

1995

6

24.7

26.8

Saudi Arabia

2002

5–17

16.7

19.4

Europe

Czech Republic

2001

5–17

14.7

13.4

Portugal

2002/3

7–9

29.5

34.3

Spain

1998–2000

5–16

31.0

19.5

England

2001

5–17

21.8

27.1

South-East Asia

India

2002

5–17

12.9

8.2

Sri Lanka

2002

10–15

1.7

2.7

Thailand

1997

5–15

21.1

12.6

Western Pacific

Australia

1995

7–17

21.1

21.3

China

1999–2000

11, 15

14.9

8.0

Japan

1996–2000

6–14

16.2

14.3

New Zealand

2000

11, 12

30.0

30.0

Aetiology of obesity

Body weight is determined by an interaction between genetic, environmental, and psychosocial factors acting through the physiological mediators of energy intake and expenditure. By definition, obesity results from an imbalance between energy intake and energy expenditure and, in any individual, excessive caloric intake or low energy expenditure, or both, may explain the development of obesity. A third factor, nutrient partitioning, a term reflecting the propensity to store excess energy as fat rather than lean tissue, may contribute.

A physiological system for the homeostatic regulation of body weight was first proposed by Kennedy, who envisaged a mechanism that monitored changes in energy stores and initiated compensatory changes in food intake and energy expenditure to maintain fat mass at a physiological set point. This adipostatic model of body weight regulation is consistent with the observation that adipose tissue mass remains relatively stable over long periods of time and a decrease in adiposity from fasting causes hyperphagia and a decrease in energy expenditure, thereby restoring body weight. Thus, marked increases in the prevalence of human obesity over a 10-year period may be the consequence of relatively minor changes in food intake and physical activity and current trends could readily be explained by an increase in the mean weight of an individual of 10 kg over 30 years.

Environmental factors

There are some obvious candidates for increase in obesity prevalence, including the increased availability of palatable energy-dense foods and the reduced requirement for physical exertion during working and domestic life. Globally, as the proportion of a population with a low BMI decreases, there is an almost reciprocal increase in the proportion of the population who are overweight or obese. Further evidence for the critical role of environmental factors in the development of obesity comes from migrant studies, where a marked change in BMI is frequently witnessed where populations with a common genetic heritage live under new and different environmental circumstances. Pima Indians living in the United States are on average 25 kg heavier than Pima Indians living in Mexico. The two priority areas for public health strategies aimed at preventing obesity are increasing physical activity and improving the quality of the available diet within a community. However, such strategies must address the need to improve the population’s understanding of the nature of obesity and its management and reduce exposure to an environment that promotes obesity. Achievement of these aims requires the involvement of individuals, their families, health professionals, health services, and a commitment from all sectors of the community.

Genetic factors

Obesity represents a heterogeneous group of conditions with multiple causes. Twin studies, adoption studies, and studies of familial aggregation confirm a major contribution of genes to the development of obesity. Indeed, the heritability of fat mass and of body weight is equivalent to that of height and exceeds that of many disorders for which a genetic basis is generally accepted. As with other common, complex traits, the genetic determinants of interindividual variation in body fat mass are likely to be multiple and interacting, with each single variant producing only a moderate effect. Recently, genome-wide association studies have proved to be an extremely valuable tool for unravelling the aetiology of complex diseases. Variants in the FTO gene are strongly associated with increased BMI, a finding that has been replicated in multiple studies. It is likely that genome-wide approaches in larger cohorts and/or those with early-onset disease will result in the identification of other common variants that contribute to obesity risk in populations. To date, the common variants that have been identified explain less than 5% of the heritability of increased BMI. It is likely that rare variants that are more highly penetrant will explain more of the missing heritability of obesity.

Genetic obesity syndromes

Classically, patients affected by genetic obesity syndromes have been identified as a result of their association with developmental delay, dysmorphic features, or other developmental abnormalities. More recently, several single gene disorders resulting from disruption of the hypothalamic leptin–melanocortin signalling pathway have been identified. In these disorders, obesity itself is the predominant presenting feature, although frequently accompanied by characteristic patterns of neuroendocrine dysfunction that will only become apparent on investigation. For the purposes of clinical assessment, it remains useful to categorize the genetic obesity syndromes as those with dysmorphism and/or developmental delay, and those without these features. There are about 30 Mendelian disorders with obesity as a clinical feature but often associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities (Table 11.5.4).

Table 11.5.4 Obesity syndromes with developmental delay

Name of syndrome

Gene/genetic region involved

Clinical characteristics

Prader–Willi

Deletion or uniparental maternal disomy of chromosome 15q11.2–-q12

Hypotonia, short stature, hypogonadotropic hypogonadism, feeding difficulties <2 years of age, then hyperphagia with pica behaviour

Bardet–Biedl

Mutations in multiple genes affect the function of cilia

Polydactyly, retinitis pigmentosa, and hypogonadism are consistent features

Fragile X

Unstable expansion of trinucleotide repeats in the FMR1 gene

Moderate to severe developmental delay, macro-orchidism, prominent jaw, and high-pitched jocular speech

Cohen

COH1 mutations

Microcephaly, characteristic facial features, progressive retinochoroidal dystrophy, myopia, and a cheerful disposition

Albright hereditary osteodystrophy

GNAS1 mutations

Short stature, round facies, brachydactyly, and ectopic soft tissue ossification (osteoma cutis), variable hormone (TSH, PTH) resistance, short fourth metacarpal

BDNF/TrkB deficiency

Mutations/deletions in BDNF or its receptor TrKB

Delayed speech and language development, impaired short term memory and loss of nociception

BDNF, brain-derived neurotrophic factor; PTH, parathyroid hormone; TrkB, neurotrophic tyrosine kinase, receptor, type 2; TSH, thyroid-stimulating hormone.

Several genetic disorders result in severe obesity commencing in childhood without developmental delay (Table 11.5.5). These mutations all arise in molecules involved in the leptin–melanocortin pathway, which plays a key role in the regulation of body weight. Energy homeostasis is tightly regulated, with the hypothalamus playing a pivotal role in integrating signals from adipose tissue stores, such as leptin and short-term meal-related signals from the gut (peptide-YY, glucagon like peptide-1 (GLP-1), cholecystokinin, and ghrelin) (Fig. 11.5.1). Leptin stimulates the expression of pro-opiomelanocortin (POMC), which is cleaved by prohormone convertases to yield the melanocortin peptides, which act as suppressors of feeding through the melanocortin 4 receptor (MC4R) (Fig. 11.5.2). Mutations in several of these molecules cause severe obesity associated with specific neuroendocrine abnormalities (Table 11.5.5). One rare genetic disorder, leptin deficiency, is entirely treatable with daily subcutaneous injections of recombinant human leptin, and another, MC4R deficiency, is relatively common, with a population prevalence of 1 in 1000 unselected individuals and 1 in 100 obese people.

Table 11.5.5 Obesity syndromes in the absence of developmental delay

Name of syndrome

Clinical characteristics

Alstrom

Progressive nephropathy, photophobia, retinitis pigmentosa, deafness, diabetes mellitus due to marked insulin resistance

Leptin

Severe hyperphagia, frequent infections, hypogonadism

Prohormone convertase 1

Neonatal diarrhoea, postprandial hypoglycaemia, multiple endocrine abnormalities

Leptin receptor

Severe hyperphagia, frequent infections, hypogonadism

POMC

Isolated ACTH deficiency, hypopigmentation

MC4R

Increased linear growth, severe hyperinsulinaemia, ‘big-boned’ appearance

ACTH, adrencorticotrophic hormone; MC4R, melanocortin 4 receptor; POMC, pro-opiomelanocortin

Fig. 11.5.1 Peripheral homeostatic regulators of energy balance include adipocyte-derived hormones, particularly leptin, which is responsible for signalling long-term energy stores; and gut-derived hormones, which are concerned with short-term control of food intake. These peripheral signals are sensed by the brain, particularly the hypothalamus, and to a lesser extent the brainstem, where the long- and short-term nutritional signals are integrated resulting in the regulation of food intake and energy expenditure.

Fig. 11.5.1
Peripheral homeostatic regulators of energy balance include adipocyte-derived hormones, particularly leptin, which is responsible for signalling long-term energy stores; and gut-derived hormones, which are concerned with short-term control of food intake. These peripheral signals are sensed by the brain, particularly the hypothalamus, and to a lesser extent the brainstem, where the long- and short-term nutritional signals are integrated resulting in the regulation of food intake and energy expenditure.

Fig. 11.5.2 Several single-gene defects that disrupt the molecules in the leptin–melanocortin pathway cause severe obesity (indicated by *). Leptin is released from adipose tissue to act on receptors expressed on the surface of distinct populations of neurones in the arcuate nucleus of the hypothalamus. Leptin stimulates a neuropeptide called pro-opiomelanocortin (POMC), which is then cleaved by the enzyme prohormone convertase 1 (PC1) to yield the melanocortin peptides. Leptin inhibits the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP). Both sets of neurons project to synapse, with second-order neurons expressing the melanocortin 4 receptor (MC4R), ultimately leading to an inhibition of food intake.

Fig. 11.5.2
Several single-gene defects that disrupt the molecules in the leptin–melanocortin pathway cause severe obesity (indicated by *). Leptin is released from adipose tissue to act on receptors expressed on the surface of distinct populations of neurones in the arcuate nucleus of the hypothalamus. Leptin stimulates a neuropeptide called pro-opiomelanocortin (POMC), which is then cleaved by the enzyme prohormone convertase 1 (PC1) to yield the melanocortin peptides. Leptin inhibits the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP). Both sets of neurons project to synapse, with second-order neurons expressing the melanocortin 4 receptor (MC4R), ultimately leading to an inhibition of food intake.

Programming and epigenetics

Recent evidence suggests that undernutrition of the fetus during intrauterine development can influence the later onset of obesity, hypertension, and type 2 diabetes, independent of genetic factors. Such a phenomenon suggests the possibility of long-term programming of genetic expression as a consequence of altered intrauterine growth. The influence of maternal diet and other factors on the regulation of genes in their offspring, referred to as epigenetics, is the focus of much current research.

Clinical history, examination, and investigation

For the assessment of severely obese patients, the consultation room should be properly equipped with larger than average chairs, access for wheelchairs for patients with mobility problems, and medical equipment of appropriate size (examination couch, blood pressure cuff, weighing scales, stadiometer, and tape measure). In addition to a general medical history, a specific weight history should be taken carefully establishing the age of onset (clinical photographs are helpful here), as it is useful to distinguish obesity that began in childhood (stronger genetic component) from that occurring later in life either in relation to specific physiological ‘critical periods’ such as pregnancy, illness, or concomitant medications. A history of previous treatment for obesity, diet, and levels of physical activity should be noted. The assessment of severely obese children and adults should include screening for potentially treatable endocrine and neurological conditions and identifying genetic conditions so that appropriate genetic counselling and, in some cases, treatment can be instituted. In most patients, these specific causes can be excluded by a careful clinical history (Box 11.5.1), examination, and investigations (Table 11.5.6), which should also address the potential hidden complications of severe obesity such as sleep apnoea, coronary heart disease, type 2 diabetes, gynaecological abnormalities, osteoarthritis, gallstones, and stress incontinence. Height should be measured accurately using a stadiometer and weight measured by accurate scales calibrated against known weights. Fat distribution is assessed by measurement of the waist circumference and is used to refine an assessment of risk for patients with a BMI of 25 to 34.9. Waist circumference is taken as the mid point between the lower rib margin and the iliac crest. An examination of the skin is important: thin, atrophic skin is a feature of excess corticosteroids; acanthosis nigricans (pigmented ‘velvety’ skin creases, especially in the axillae) suggests insulin resistance; severe hirsutism in women may indicate polycystic ovary syndrome. A neck circumference of more than 43 cm indicates a likelihood of obstructive sleep apnoea.

Table 11.5.6 Key points in the examination and investigation of an obese patient

Examination

Height, weight—calculate BMI

Blood pressure

Waist circumference

Neck circumference

Acanthosis nigricans

Body fat distribution

Secondary sexual characteristics

Any evidence of cardiac disease

Signs of hyperlipidaemia

Signs of thyroid disease

Ophthalmic evidence of diabetes or sustained hypertension

Investigations

Fasting and postprandial blood glucose

Fasting lipid profile

Strip test for urine glucose and protein

Free thyroxine and thyroid-stimulating hormone

Clinicians should use laboratory testing to evaluate overweight and obese patients who may be at high risk for cardiovascular disease, diabetes, and thyroid disease. Some useful tests to consider are fasting plasma glucose or 2-h postprandial glucose levels and serum lipid levels. Thyroid-stimulating hormone (TSH) may be helpful in excluding hypothyroidism. Urinary free cortisol can be obtained if hypercortisolism is suspected. Other tests to consider depend on clinical assessment and include ultrasonography for hepatic steatosis, gallstones, and the polycystic ovary syndrome; electrocardiography in patients at high risk for cardiovascular disease; polysomnography for patients with possible sleep apnoea; and head CT or MRI when pituitary or hypothalamic disorders are suspected. Genetic testing is needed to confirm the diagnosis in patients with rare genetic disorders. The measurement of serum leptin is not recommended as a routine examination, but should be undertaken in cases of severe early onset obesity, since, although it is rare, congenital leptin deficiency is a potentially treatable disorder.

Approach to the treatment of obesity

The recommendation to treat obesity is based on evidence that relates obesity to increased mortality and the results from randomized controlled trials, which demonstrate that weight loss reduces the risk of disease. Professional, governmental, and other bodies have drawn up guidelines for obesity management and its advisable to seek out the latest national and international guidelines as newer evidence is incorporated. These strategies provide useful evidence-based guidance for clinical management, but it is important to remember that an individually tailored approach is often required and that any treatment programme for obese patients should address weight reduction and the maintenance of the lowered weight and take account of individual circumstances.

Goals of weight loss

Achievement of normal or ideal body weight is not a necessary goal in the management of obesity, and is rarely reached in practice. There is evidence from epidemiological studies of intentional weight loss that modest weight loss, of the order of 5 to 10% from presentation weight, is associated with clinically worthwhile reductions in comorbidities, such as hypertension, dyslipidaemia, and diabetes risk (Table 11.5.7). In some patients, particularly in those with severe comorbidity, prevention of weight gain may be a reasonable aim of treatment. Weight loss should be approached incrementally, with new goals for weight loss negotiated with the patient once the original target has been achieved.

Table 11.5.7 Potential health benefits that may accrue from the loss of 10 kg from the initial body weight

Mortality

20–25% fall in total mortality

30–40% fall in diabetes-related deaths

40–50% fall in obesity-related cancer deaths

Blood pressure

c.10 mmHg fall in both systolic and diastolic values

Diabetes

>50% reducution in risk of developing diabetes

30–50% fall in fasting glucose

15% fall in haemoglobin A1c

Lipids

10% fall in total cholesterol

15% fall in LDL cholesterol

30% fall in triglycerides

8% increase in HDL cholesterol

HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Dietary treatment of obesity

A number of dietary approaches have been advocated for the treatment of obesity. Recent evidence-based reviews support the use of low-calorie diets, energy-deficit diets, and diets that are low in fat as being most likely to be effective for modest weight loss. A review of 48 randomized control trials shows that an average weight loss of 8% of the initial body weight can be obtained over 3 to 12 months with a low-calorie diet, and that this weight loss can lead to a decrease in abdominal fat. Such a treatment may require a period of supervision for at least 6 months. The weight-reducing dietary regimen tailored to an individual’s need should initially provide a 600 kcal/day (2.5 MJ/day) energy deficit, based on estimated energy requirements. After 6 months, the rate of weight loss usually declines and a further adjustment of calorie intake may be indicated at this stage. The use of very low-calorie diets can be considered, but their use should follow all of the recommendations from the Committee on Medical Aspects of Food Policy, in particular that such preparations must provide a minimum of 400 kcal (1.7 MJ) per day for women and 50 kcal (2.1 MJ) per day for men. Evidence from randomized trials confirms that over the longer term (more than a year), weight loss following very low-calorie diets is no different from that obtained with low-calorie diets.

Behavioural therapy and exercise

Behavioural approaches aim to help subjects to implement and sustain changes to their eating and activity behaviour and require trained health professionals with good interpersonal skills to use the approach appropriately and in a supportive manner. There is evidence that combining a behavioural approach with more traditional dietary and activity advice leads to improved short-term weight loss. However, these studies are of relatively short duration, so the evidence base is limited to 1 year at present. In general, weight loss with these approaches is modest (about 4 kg or 4% of body weight on average).

Although modest physical activity has undoubted health benefits and can contribute to weight loss, it is not usually advocated as a sole treatment option. Many studies, however, do suggest that it can be helpful to improve weight loss maintenance, although activity levels equivalent to 45 to 60 min of brisk walking each day may be needed to achieve this. The results from randomized controlled trials suggest that a combination of diet and exercise generally produces more weight loss than diet alone.

Principles of drug therapy

Despite the availability of evaluated and approved obesity drugs, doctors have been reluctant to prescribe drugs. The reasons for this may include memories of the adverse events with amphetamine and amphetamine-like drugs and the serious complications from combining phentermine and fenfluramine. The use of obesity drugs should follow the same principles as for any condition and be prescribed after assessment of the potential benefits and risks with appropriately informed patients, and with medical monitoring of the results of treatment. Many people, including doctors, still believe that a short course of drug treatment might ‘cure’ obesity or that efficacy is measured only by ever-continuing weight loss. These ideas are inconsistent with the known biology, as people who become obese have a lifelong tendency both to defend their excess weight and to continue to gain extra body fat. Effective management must be lifelong and focused on weight loss maintenance in a similar fashion to the effective treatment for hypertension or diabetes. Starting drug treatment should always be regarded as a therapeutic trial and stopped if weight loss is not apparent after 1 or 2 months.

The initiation of drug treatment will depend on the physician’s judgement about the risks to an individual from continuing obesity. A drug should not be considered ineffective because weight loss has stopped, provided that the lowered weight is maintained. However, continuation of the drug should depend on the balance between the health benefits of maintained weight and the potential adverse effects of the drug.

Types of drug treatment for obesity

Drugs acting on the gastrointestinal system (pancreatic lipase inhibitors)

Orlistat inhibits pancreatic and gastric lipases decreasing the hydrolysis of ingested triglycerides. It produces a dose-dependent reduction in absorption of dietary fat that is near maximum at a dose of 120 mg, three times daily. It leads to 5 to 10% weight loss in 50 to 60% of patients, and in clinical trials, the loss (and related clinical benefit) is largely maintained up to at least 4 years. Adverse effects of orlistat are predominantly related to malabsorption of fat. These include loose or liquid stools, faecal urgency, and oily discharge; they can be associated with malabsorption of fat-soluble vitamins. As the consumption of a high-fat meal will inevitably lead to severe gastrointestinal symptoms, it is possible that some of the weight loss with orlistat treatment results from an ‘antabuse effect’, leading to behavioural change.

Centrally acting antiobesity drugs

Sibutramine

Sibutramine inhibits the reuptake of noradrenaline and serotonin, promoting and prolonging satiety. It may also have an enhancing effect on thermogenesis through the stimulation of peripheral noradrenergic receptors. Sibutramine is well absorbed following oral ingestion and undergoes first-pass metabolism in the liver to produce two active metabolites that have long elimination half-lives. This enables sibutramine to be given on a single daily basis at a starting dose of 10 mg. Adverse effects include nausea, dry mouth, rhinitis, and constipation. It produces 5 to 10% weight loss in 60 to 70% of patients, and in clinical trials, it is well maintained for at least 2 years. If weight loss is less than 2 kg at 4 weeks, the dose can be increased from 10 mg to 15 mg. The noradrenergic action increases heart rate by 1 to 2 beats/min and attenuates the fall in blood pressure expected with weight loss. Some patients, especially if they fail to lose weight, may record a rise in their blood pressure; it is therefore essential to monitor blood pressure during the first 12 weeks of treatment. Controlled hypertension is not a contraindication for prescribing sibutramine. Recent concerns about increased cardiovascular morbidity associated with Sibutramine have led to prescribing restrictions, particularly relevant to those patients with established cardiovascular disease. Current guidelines in Europe and the USA vary and physicians should consult local guidelines where available.

Rimonabant

Rimonabant is the first cannabinoid-1 receptor antagonist to be licensed for obesity treatment. Blockade of cannabinoid-1 receptors in the brain produces weight loss, which is maintained for up to 2 years in clinical trials. However, adverse effects on mood and an increased risk of depression and suicide risk have recently led to this drug being withdrawn in many countries.

New drugs in development

Clinical trials are now well advanced for several drugs with different modes of action. Many of the hormones and hormone receptors that contribute to regulation of appetite or satiety are targets for drug treatment and under active development in preclinical and early clinical trials. Newer agents primarily designed to treat diabetes, such as the synthetic amylin pramlintide and GLP-1 analogue exenatide, are licensed in some countries and lead to clinically important weight loss. There is also interest in gut-derived peptides such as oxyntomodulin to improve satiety.

Most obese people have high concentrations of leptin, and early trials of leptin supplementation in common obesity were disappointing. However, leptin may prove to be useful in combination with other drugs and as an adjunct to weight maintenance strategies.

Surgical treatment of obesity

Randomized controlled trials confirm that surgery for obesity is an option for carefully selected patients with severe obesity 0(BMI >40 kg/m2 or BMI >35 kg/m2 with comorbid conditions). The nature of the surgical procedures necessitates long-term hospital follow-up for such patients. The initial findings from the Swedish Obese Subjects study of severely obese subjects (those with a BMI >40) indicate that weight loss of approximately 30 kg over 2 years is associated with a 60% reduction in plasma insulin, a 25% decrease in plasma glucose and triglycerides, and a 10% reduction in blood pressure with associated effects on the risk of cardiovascular disease. Poor health-related quality of life was dramatically improved after gastric restriction surgery, while only minor fluctuations in health-related quality of life were observed in subjects treated by conventional dietary methods. Most surgical treatment is now carried out laparoscopically. Three approaches are widely used.

Laparoscopic gastric banding

This operation involves gastric restriction with the creation of a small compartment (<20 ml) by either a combination of vertical stapling and a constrictive band opening or a gastric band pinching off a small proximal pouch. A modification of the latter procedure is an inflatable gastric band attached to a subcutaneous reservoir which allows access by a hypodermic syringe to inject or withdraw fluid thereby tightening or enlarging the band width. This method mainly works by restricting how much food patients can eat. The average weight loss is around 15 to 20% of body weight, although some weight regain occurs over time. Morbidity and mortality are relatively low (mortality <0.2%), but patients do need to return for band adjustments.

Gastric bypass

This involves creating a small-volume gastric pouch and producing a Roux-en-Y diversion so that food bypasses the duodenum and upper jejunum. This works by both restricting food intake and causing a modest degree of malabsorption. Weight loss is generally greater than with the band. Operative mortality is less than 0.2% for laparoscopic procedures and 0.5% for open procedures.

Duodenal switch

A variant of the older biliopancreatic diversion, this involves a partial (sleeve gastrectomy) and bypass of a long loop of jejunum. Weight loss is greatest with this procedure, but malabsorption is more likely and patients need careful follow-up and attention to their diet, vitamin, and mineral supplementation.

Concluding remarks

As the prevalence of obesity is rising, we are seeing a greater proportion of patients with severe obesity. It is important to have a practical approach to the investigation and management of these vulnerable patients who have considerably increased morbidity and mortality. The clinical evaluation of severely obese patients will become increasingly sophisticated, and novel biochemical and molecular genetic diagnostics will need to be combined with the more traditional nutritional and behavioural approaches to optimize treatment for individual patients.

Further reading

Barsh GS, Farooqi IS, O’Rahilly S (2000). Genetics of body weight regulation: applications and opportunities. Nature, 404, 644–51.Find this resource:

Goldstone, AP (2004). Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab, 15, 12–20.Find this resource:

Kopelman PG (2000). Obesity as a medical problem. Nature, 404, 635–43.Find this resource:

Padwal RS, Majumdar SR (2007). Drug treatments for obesity: orlistat, sibutramine and rimonabant. Lancet, 369, 71–7.Find this resource:

Schwartz MW et al. (2000). Central nervous system control of food intake. Nature, 404, 661–71.Find this resource:

Wilding J (2007). Treatment strategies for obesity. Obes Rev, 8 Suppl 1, 137–44.Find this resource: