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Ara R, Blake L, Gray L, et al. What is the Clinical Effectiveness and Cost-Effectiveness of Using Drugs in Treating Obese Patients in Primary Care? A Systematic Review. Southampton (UK): NIHR Journals Library; 2012 Feb. (Health Technology Assessment, No. 16.5.)

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What is the Clinical Effectiveness and Cost-Effectiveness of Using Drugs in Treating Obese Patients in Primary Care? A Systematic Review.

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1Background

Description of health problem

Prevalence

The increasing prevalence of obesity in the UK represents a considerable public health problem. The prevalence of obesity [defined as a body mass index (BMI) ≥ 30 kg/m2] in England is reported to have increased between 1993 and 2004 from 13.6% to 24.0% among men and from 16.9% to 24.4% among women.1 When waist circumference was measured in a UK adult primary care sample in 2005, 38.8% of men and 51.2% of women were classed as abdominally obese (waist circumference > 102 cm and > 88 cm, respectively).2 It has been estimated that, among young people aged 20 years and under in England, 10% of females and 8% of males are obese.3 Should increases in the prevalence of obesity continue at the same rate, Zaninotto et al.1 predicted that the prevalence of obesity in 2012 would be 32% in men and 31% in women, with a likely higher prevalence among adults in manual social classes (43%) than in non-manual social classes (35%). Projections by the UK government's Foresight programme have postulated that by 2025 40% of Britons may be classed as obese.3,4

The World Health Organization (WHO) estimated in 2005 that, internationally, there were over 1.6 billion overweight adults, of whom at least 400 million were obese. They also projected that, by 2015, approximately 2.3 billion adults would be overweight and over 700 million would be obese.5

The estimated prevalence of overweight and obesity among male and female adults in 2010 demonstrated considerable differences by geographical region, with several hotspots of prevalence exceeding 80%, including the USA, Barbados, Dominica, Kuwait and the South Pacific islands.5

Groups at risk of obesity

A number of population groups are considered at increased risk of obesity. Variation in obesity by ethnic group has been described in a report published by the NHS Information Centre.6 Data relating to obesity and overweight among ethnic minority groups were drawn from the Health Survey for England (HSE) 2004. The survey applied the definition of overweight and obesity as used in the general population. It was reported that the prevalence of obesity was higher among black Caribbean men and women, black African women, Pakistani women and Irish men than among the general population. Obesity was lower among Chinese, Indian and Bangladeshi men and women than among the general population. Groups at risk of becoming obese also include children with overweight or obese parents79 and individuals giving up smoking.10 A high prevalence of obesity has been observed in adults and children with intellectual disabilities.1113 An association also exists between low socioeconomic status in early life and adult obesity.9 Data from the HSE 2007 indicated that, among women, the age-standardised prevalence of obesity and raised waist circumference increased as the quintile of equivalised household income decreased, but these measures were not related to income in men.6

Aetiology

Previous work by the Foresight group indicated that the energy imbalance that precedes obesity (whereby energy intake exceeds energy expenditure) is governed by what was described as a ‘complex multifaceted system of determinants’.1416 These factors include biological propensity (such as genetic risk and the influence of early life experiences), the generation of an obesogenic external environment (based on, for example, changes in food production and lifestyle, such as increased wealth, increased sedentary lifestyle and increased availability of energy-dense foods), a life course component (whereby the risks of becoming obese may be present at an early stage of life) and a generational dimension (in which parental obesity is known to act as a significant predictor of childhood obesity).17

Comorbidities associated with obesity

Overweight and obesity are associated with a significant range of comorbidities, including type 2 diabetes (T2DM), hypertension, dyslipidaemia, coronary artery disease, stroke, osteoarthritis, reproductive problems, respiratory and liver conditions and cancers.1820 Obstructive sleep apnoea is also associated with obesity, with a potential predisposition among Asian individuals.21,22 The National Audit Office23 estimated the increased relative risk of the development of comorbidities among obese individuals, which is shown in Table 1.

TABLE 1. Relative risk of development of obesity-related comorbidities.

TABLE 1

Relative risk of development of obesity-related comorbidities.

Increased levels of overweight and obesity are linked with increases in mortality, with subjects who have never smoked and with no history of disease but a BMI > 40 kg/m2 having a relative risk of death 2.7 times higher for men and 1.9 times higher for women than that among subjects with a lower BMI (between 23.5 and 24.9 kg/m2).24 Obesity is also associated with psychological stigma.25 The proportion of chronic disease attributable to obesity has been predicted to undergo a considerable increase by 2050, particularly for T2DM, stroke and coronary heart disease (CHD).3 It has been suggested that adults in the upper half of the healthy weight category (22.0 kg/m2 < BMI < 24.9 kg/m2) are more likely to develop health problems than their leaner counterparts and that adults should attempt to maintain a BMI of between 18.5 kg/m2 and 21.9 kg/m2 to minimise their risk of disease.20

Measurements of obesity

Obesity is frequently reported in terms of BMI. BMI is a measurement of body weight relative to height. Based on the WHO criteria, overweight is classed as a BMI of 25–29.9 kg/m2, while obesity is defined as a BMI > 30 kg/m2.5 The current National Institute for Health and Clinical Excellence (NICE) clinical guideline for obesity26 states that waist circumference may also be used in addition to BMI in adults with a BMI < 35 kg/m2 and may be used to provide additional information on the risk of the development of comorbidities in children. Among adults, waist circumference can be used as an indicator of health risk, with increased risk being identified based on a waist circumference of ≥ 94 cm in men and ≥ 80 cm in women and greatly increased risk with a waist circumference of ≥ 102 cm in men and ≥ 88 cm in women.27 Other measurements of obesity include body weight, percentage over ideal body weight, waist–hip ratio and skinfold thickness. It is worth noting that a lower cut-off point has been suggested for certain ethnic groups including South Asians.28

A report suggested that debate surrounded the use of standard BMI cut-offs among some ethnic groups on the basis that variation exists in the association between BMI and body fat according to ethnicity.6 Dhaliwal and Welborn29 and Kumar et al.30 proposed that waist–hip ratio be used as a measure of central obesity because of its high precision and no bias across ethnic groups.29,30

Impact of health problem and significance for the NHS

Most obesity management is undertaken in primary care settings. Hospital admissions for people with obesity-related conditions place a significant burden on the health service, particularly in relation to circulatory diseases, musculoskeletal disorders and endocrine disorders including diabetes.31

Allender and Rayner32 produced a new estimate of the burden of overweight- and obesity-related disease in the UK. The authors estimated that, when the rates for the burden of overweight-attributable disease were applied to mortality figures for 2003–4, over 203,000 deaths occurred in the UK as a result of diseases associated with overweight and obesity. The authors stated that it was further estimated that approximately 66,737 deaths were directly attributable to overweight and obesity, over half (54%) of these being due to CHD and 31% to stroke.

Current service provision

Management of obesity

The primary aim of the management of obesity is to achieve weight reduction in the interests of health. The Royal College of Physicians33 described the clinical benefits of weight loss (based on a scenario of an individual weighing 100 kg losing 10% of their body weight), estimates of which included decreased blood pressure, a 10% decrease in cholesterol, a > 50% reduction in the risk of developing diabetes, reductions of 30–40% and 40–50% in diabetes-related deaths and obesity-related cancer deaths, respectively, and a 20–25% reduction in total mortality. Non-pharmacological methods for the management of obesity include dietary modification, exercise, structured education and weight management programmes. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, a number of pharmacological interventions exist to aid weight reduction, including sibutramine (Reductil®, Abbott), orlistat (Xenical®, Roche; Alli®, GlaxoSmithKline) and rimonabant (Acomplia®, Sanofi-Aventis). Drug therapy has been shown to be most effective when combined with dietary modification, physical exercise and behaviour change34 and is recommended for use in the management of obesity in combination with non-pharmacological interventions. Surgical procedures, such as gastric bypass and banding, also play a role in the management of obesity.

Current service cost

The treatment of obesity and its complications is associated with significant health and social care costs, in addition to wider societal financial costs. The House of Commons Select Committee estimated that the direct health-care costs arising from the treatment of obesity and its complications ranged from £991M to £1124M in 2002. This level of expenditure represented approximately 2.3–2.6% of the total NHS spending for the period 2001–2.35 Allender and Rayner32 estimated the direct cost of overweight and obesity to the NHS to be £3.2B, of which the greatest proportion was attributable to stroke (£983M), followed by CHD (£773M), hypertensive disease (£576M) and diabetes (£533M). The costs arising from overweight and obesity are likely to escalate (from the estimate for 2007 of £4.2B) in the forthcoming years if current increasing trends in the prevalence of obesity continue, with a predicted overall annual total cost to the NHS of overweight and obesity of £9.7B (based on today's prices) by 2050, representing an increase in the projected percentage of NHS costs (at £70B) from 6.0% in 2007 to 13.9% in 2050.3

Variation in services and/or uncertainty about best practice

The management of obesity in primary care has been described as being uncoordinated and inconsistent.36 The Counterweight Project Team (2004) undertook a series of structured interviews with general practitioners (GPs) and practice nurses and analysed patient records from primary care settings across England and Scotland in order to investigate the range of approaches to obesity management utilised by primary care professionals. Although the majority of GPs (83%) and practice nurses (97%) reported that they would raise weight as an issue with obese patients, only 15% of GPs would spend up to 10 minutes in a weight-related consultation compared with 76% of nurses (p < 0.001). BMI was recorded for 64.2% of patients. GPs and practice nurses reported making patient referrals to a dietician (58% vs 59%), exercise referral schemes (50% vs 56%) and commercial weight loss agencies (41% vs 68%). Audit of obese patients' records showed the use of practice-based diet counselling (20%), dietetic (4%) and obesity centre (1%) referrals and any anti-obesity medication (2%) recorded over 18 months. Patients prescribed anti-obesity medication were more likely to be female (p < 0.01) and more obese (p < 0.01) than, but with a similar prevalence of comorbidities to, patients who were not prescribed medication.

Relevant national guidelines

Healthy Weight, Healthy Lives is a cross-government strategy for England involving a range of programmes across a number of sectors, including schools and food, physical activity, transport and the health service.17 The strategy is focused on five areas: the healthy growth and development of children; promoting healthier food choices; promoting physical activity; creating incentives for better health; and personalised advice and support. The development of strategies for the management of obesity is also linked to requirements under the national service frameworks for CHD and diabetes.

NICE issued clinical guideline 4326 to provide guidance on the prevention, identification, assessment and management of overweight and obese adults and children. The guidance superseded previous pieces of guidance on orlistat,38 sibutramine39 and surgery for morbid obesity.40 The clinical guideline recommended that dietary changes and physical exercise should be the first options in the management of obesity before the use of pharmacological interventions is considered. Bariatric surgery was recommended if all of the following criteria were fulfilled: a BMI of ≥ 40 kg/m2 (or between 35 kg/m2 and 40 kg/m2 in the presence of other significant disease that could be improved in the event of weight loss); all appropriate non-surgical measures have been attempted and been unsuccessful; person has or will receive intensive management in a specialist obesity service; patient is generally fit for anaesthesia and surgery; and the patient commits to requirement for long-term follow-up. In addition, bariatric surgery can be considered as a first-line option when appropriate in adults who have a BMI of ≥ 50 kg/m2. Surgical intervention was not generally recommended for children or young people. In 2008, NICE guidance was issued relating to the use of rimonabant.41 However, the marketing authorisation for this drug has since been suspended.42

The NHS Health Checks Programme was launched in April 2009. Designed to address health inequalities, the vascular risk assessment programme consists of systematic screening of individuals aged 40–74 years of age for cardiovascular and T2DM risk with lifestyle interventions offered to those considered to be at risk.43

Description of technology under assessment

Summary of interventions

Orlistat functions by inhibiting the uptake of dietary fats by the gastrointestinal tract, whereas both sibutramine and rimonabant are centrally acting appetite suppressants. The following sections summarise the product characteristics of each of these interventions using the Summary of Product Characteristics (SPC) for each drug (obtained from the Electronic Medicine Compendium at www.medicines.org.uk; SPC not available for rimonabant) and information from the British National Formulary (BNF).

Sibutramine

Description of intervention

Sibutramine is a centrally acting appetite suppressant that acts as an inhibitor of the reuptake of noradrenaline and serotonin.

Licensed indications

The marketing authorisation for sibutramine was suspended following a review by the European Medicines Agency in 2010.44 The agency concluded that the benefits of treatment with sibutramine did not outweigh the associated cardiovascular risks and that prescriptions should not be issued and that the treatment of patients receiving sibutramine should be reviewed.

Dosage and administration

Reductil was available as blue/yellow capsules containing 10 mg of sibutramine hydrochloride or as blue/white capsules containing 15 mg of sibutramine hydrochloride.

Adverse events

Possible side effects included dry mouth, taste disturbances, abdominal pain, diarrhoea, constipation, nausea, vomiting, gastrointestinal haemorrhage, haemorrhoid aggravation, tachycardia, palpitations, hypertension, insomnia, hot flushes, lightheadedness, paraesthesia, anxiety and panic attacks, depression, seizures, transient memory disturbance, blurred vision, sexual dysfunction, menstrual disturbances and cramps, urinary retention, thrombocytopenia, sweating, alopecia, cutaneous bleeding disorders, hypersensitivity reactions including Henoch–Schönlein purpura, rash, urticaria, angioedema and anaphylaxis, interstitial nephritis and glomerulonephritis. The following were reported rarely: headache and increased appetite on withdrawal, angle-closure glaucoma and cardiovascular events. The adverse events potentially relating to the withdrawal of the intervention are highlighted in bold.

Orlistat

Description of intervention

Orlistat is a lipase inhibitor that reduces the absorption of dietary fat in the gastrointestinal tract. Orlistat is available in the UK without prescription.

Licensed indications

Orlistat is indicated in combination with a mildly hypocaloric diet in the management of obesity in patients with a BMI ≥ 30 kg/m2 or in overweight patients with a BMI ≥ 28 kg/m2 with associated risk factors.

Dosage and administration

Xenical is available as turquoise hard capsules containing 120 mg of orlistat. Alli is available as 60-mg turquoise/dark blue hard capsules.

The recommended dose of Xenical in adults aged > 18 years is one 120-mg capsule to be taken with water immediately before, during or up to 1 hour after each main meal (up to a maximum dose of 360 mg daily).

The recommended dose of Alli is one 60-mg capsule taken three times daily with water immediately before, during or up to 1 hour after each main meal.

If a meal is missed or does not contain fat, the dose of orlistat should not be taken. Treatment should be continued beyond 12 weeks only if weight loss since the start of treatment exceeds 5% of the initial body weight (the target for initial weight loss may be lower in people with T2DM). Treatment should not exceed 6 months (Alli). Use in children aged > 12 years should be initiated by a specialist only (unlicensed use). If a multivitamin supplement is required, this should be taken at least 2 hours after the orlistat dose or at bedtime.

Contraindications

Orlistat is contraindicated in patients who:

  • have chronic malabsorption syndrome
  • have cholestasis
  • are breastfeeding
  • are undergoing concurrent treatment with ciclosporin (Alli)
  • are undergoing concurrent treatment with warfarin or other anticoagulants (Alli).
Cautions

The effects of orlistat in children, the elderly and patients with hepatic or renal impairment have not been studied. Orlistat may impair the absorption of fat-soluble vitamins. Other cautions include epilepsy and pregnancy. Interactions may occur with ciclosporin, acarbose, oral anticoagulants and amiodarone.

Adverse events

Adverse events associated with the use of orlistat include the following gastrointestinal effects: oily leakage from the rectum, flatulence, liquid or oily stools, faecal urgency and incontinence, and abdominal pain/discomfort. Such gastrointestinal effects may be minimised by reducing fat intake in the diet. Other side effects include headache, tooth and gingival disorders, respiratory infections, fatigue, anxiety, menstrual disturbances, urinary tract infection and hypoglycaemia. The following have also been reported rarely: rectal bleeding, hypothyroidism, diverticulitis, cholelithiasis, hepatitis, bullous eruptions and oxalate nephropathy.

Rimonabant

Description of intervention

Rimonabant is a centrally acting appetite suppressant that acts as a cannabinoid receptor antagonist.

Licensed indications

The European Medicines Agency reported that the marketing authorisation for rimonabant was suspended across the European Union following a review by the Committee for Medicinal Products for Human Use in 2008, which concluded that the benefits of rimonabant treatment did not outweigh the risks of psychiatric adverse reactions.42 Therefore, it was stipulated that prescriptions should not be issued and the treatment of patients who are taking rimonabant should be reviewed.

Dosage and administration

Rimonabant was available as tablets containing 20 mg of rimonabant.

Adverse events

Reported side effects included nausea, vomiting, diarrhoea, dry mouth, anorexia, depression, anxiety, irritability, nervousness, sleep disorders, impaired memory, dizziness, paraesthesia, hypoaesthesia, sciatica, hot flush, asthenia, impaired attention, tendonitis, muscle cramp, pruritus and hyperhidrosis. The following were reported less commonly: hiccups, anger, aggression, suicidal ideation and hallucinations. The adverse events potentially relating to the withdrawal of the intervention are highlighted in bold.

The BNF stated that combination therapy involving more than one anti-obesity drug is contraindicated until additional information about efficacy and long-term safety is available.45

A previous systematic review of randomised controlled trial (RCT) evidence found considerable differences between orlistat, sibutramine and rimonabant in terms of discontinuation due to adverse events and underlying causes of such discontinuations.46 Higher risk ratios for discontinuation due to adverse events were observed for patients who were treated with rimonabant and orlistat but not sibutramine in this review. The most common adverse events associated with discontinuation were gastrointestinal for orlistat (40%) and psychiatric for rimonabant (47%) (information stated as not being available for sibutramine).

Current usage in the NHS

The NICE clinical guideline for obesity26 recommended that dietary changes and physical exercise should be the first options in the management of obesity. The use of pharmacological interventions for weight loss was not generally recommended for children younger than 12 years but the guideline stated that such measures may be used in exceptional circumstances (e.g. the presence of severe comorbidities). In children aged ≥ 12 years, treatment with orlistat or sibutramine was recommended only in the presence of severe physical or psychological comorbidities. In adults, it was recommended that orlistat be prescribed as part of an overall obesity management plan in patients with a BMI of ≥ 28.0 kg/m2 (with associated risk factors) or ≥ 30.0 kg/m2. It was recommended that orlistat therapy should be continued beyond 3 months only if the patient had lost at least 5% of his or her initial body weight since commencing therapy. Treatment with orlistat beyond 12 months should be made after discussing the potential benefits and limitations with the patient. The guideline also recommended that sibutramine be prescribed as part of a weight reduction plan in patients meeting one of the following criteria: a BMI of ≥ 27.0 kg/m2 (with associated risk factors) or a BMI of ≥ 30.0 kg/m2, with careful monitoring of weight loss and adverse events. Therapy with sibutramine was to be continued beyond 3 months only if the patient had lost at least 5% of initial body weight while taking the drug. Treatment with sibutramine was not recommended beyond the licensed duration of 12 months. Co-prescribing of pharmacological interventions for weight reduction was not recommended. As noted above, the marketing authorisations for rimonabant and sibutramine have been suspended following reviews by the European Medicines Agency.42,44

Anticipated costs associated with intervention

Using the latest data available,47 Figure 1 shows the number of items prescribed annually from 1999 to 2008 in the treatment of obesity in England. There was a substantial increase in prescribing rates for both orlistat and sibutramine following publication of guidance from NICE in March 200138 and October 2001,39 respectively. After a period of relatively steady use, prescription numbers started to increase again after the publication of revised guidance in 2004.48

FIGURE 1. Annual number of prescription items for the treatment of obesity.

FIGURE 1

Annual number of prescription items for the treatment of obesity.

Table 2 shows the number of items and associated net ingredient cost (NIC) of drugs for the treatment of obesity prescribed in primary care. Rimonabant became available on prescription in July 2006; thus, the figure for that year reflects just 6 months of data. In 2008, there were 1.28 million prescription items for the treatment of obesity. Overall, the total number of prescription items in 2008 was ten times the number in 1999, and the current trend is an increase of around 14% per year.

TABLE 2. Number of prescription items and net ingredient cost.

TABLE 2

Number of prescription items and net ingredient cost.

The total NIC for drugs for the treatment of obesity increased from £4.9M in 1999 to £51.6M in 2007, but fell in 2008 to £44.8M. Correspondingly, the NIC per item increased from £38 in 1999 to £42 in 2007 and then fell to £35 in 2008.

Following the withdrawal of rimonabant in 2008 and the suspension of sibutramine prescribing in 2010, it is reasonable to expect that the uptake of orlistat will increase as patients switch treatments and the alternatives available for new patients decrease. As orlistat was already the main treatment, accounting for two-thirds of all prescriptions, and the NICs per item for sibutramine (£30) and rimonabant (£50) are similar to that for orlistat (£35), it is not expected that this change in prescribing patterns will affect the observed trend in total costs. If total prescribing rates for orlistat increase at 14% (5–20%) per annum, the total annual net cost for prescriptions directly related to obesity treatment is estimated to be approximately £57.8M in 2010 and over £109M in 2015.

© 2012, Crown Copyright.

Included under terms of UK Non-commercial Government License.

Bookshelf ID: NBK97594

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