Evidence Based Review of Weight Loss Medicines

NZHTA REPORT

August 2004

Volume 7 Number 6

Evidence Based Review

of Weight Loss Medicines:

A report commissioned by the New Zealand

Accident Compensation Corporation (ACC)

Pamela Smartt

New Zealand

Health Technology Assessment

Department of Public Health and General Practice Christchurch School of Medicine

Christchurch, NZ.

Division of Health Sciences, University of Otago

NEW ZEALAND HEALTH TECHNOLOGY ASSESSMENT (NZHTA)

Department of Public Health and General Practice Christchurch School of Medicine, Christchurch, New Zealand

Evidence Based Review of Weight Loss Medicines: A report commissioned by the New Zealand Accident Compensation Corporation (ACC)

Pamela Smartt

NZHTA REPORT August 2004 Volume 7 Number 6

This report should be referenced as follows: Smartt, P. Evidence based review of weight loss medicines: a report commissioned by the New Zealand Accident Compensation Corporation (ACC). NZHTA Report 2004; 7(6). 2004 New Zealand Health Technology Assessment (NZHTA) ISBN 1-877235-70-9 ISSN 1174-5142

EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC

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Acknowledgements

This report was prepared by Dr Pamela Smartt (Principal Investigator) who conducted the critical appraisals and prepared the project report. Dr Ray Kirk (NZHTA Director until February 2005) also provided comment on various drafts and coordinated the overall project. Dr Robert Weir (NZHTA Acting Director from February 2005) coordinated the project from February 2005. Ms Margaret Paterson (NZHTA Information Specialist) developed and undertook the search strategy and coordinated retrieval of documents. Mrs Ally Reid (NZHTA Administrative Secretary) provided document formatting.

The Canterbury Medical Library assisted with the retrieval of articles.

NZHTA is a Research Unit of the University of Otago funded under contract to the Ministry of Health.

Disclaimer

New Zealand Health Technology Assessment (NZHTA) takes great care to ensure the information supplied within the project timeframe is accurate, but neither NZHTA, the University of Otago, nor the contributors involved can accept responsibility for any errors or omissions. The reader should always consult the original database from which each abstract is derived along with the original articles before making decisions based on a document or abstract. All responsibility for action based on any information in this report rests with the reader. NZHTA and the University of Otago accept no liability for any loss of whatever kind, or damage, arising from reliance in whole or part, by any person, corporate or natural, on the contents of this report. This document is not intended as personal health advice. People seeking individual medical advice are referred to their physician. The views expressed in this report are those of NZHTA and do not necessarily represent those of the University of Otago or the New Zealand Ministry of Health.

Copyright

Copyright © to Accident Compensation Corporation 2005. All rights reserved. No part of this report may be reproduced or distributed by any person without prior written permission and/or licence from the Accident Compensation Corporation. http://www.acc.co.nz/


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Contact details

New Zealand Health Technology Assessment (NZHTA) Department of Public Health and General Practice Christchurch School of Medicine and Health Sciences PO Box 4345 Christchurch New Zealand Tel: +64 3 364 3696 Fax: +64 3 364 3697 Email: [email protected] Web Site: http://nzhta.chmeds.ac.nz/


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Contents

Contents .................................................................................................................. iii

Executive Summary ............................................................................................... vii

Recommendations ................................................................................................ viii

Background...............................................................................................................1

Definition and measurement of obesity........................................................................1

The health consequences of obesity ..............................................................................1

Factors influencing body weight ....................................................................................2

Clinically significant weight reduction...........................................................................3

Obesity and Injury............................................................................................................3

Obesity trends in NZ.......................................................................................................3

The economic cost of obesity.........................................................................................4

Benefits associated with weight loss ..............................................................................4

Review questions ..................................................................................................... 7

Pharmacological treatments for obesity .................................................................. 9

Pharmacological interventions registered in New Zealand........................................9

Phentermine (DuromineTM, Umine Timedcaps) ..........................................................9 Diethylpropion hydrochloride (Tenuate Dospan) .....................................................10 Sibutramine hydrochloride (Reductil®, Meridia®) ......................................................11 Orlistat (Xenical®)...........................................................................................................12 Meal replacement plans..................................................................................................14

Methodology ........................................................................................................... 15

Systematic review............................................................................................................15

Search strategy and information sources ....................................................................16

Study selection criteria ...................................................................................................17

Methods of the review...................................................................................................17

Levels of evidence ..........................................................................................................18

Results..................................................................................................................... 19

Meal replacement plans: weight loss and co-morbidity risk reduction...................19

Phentermine hydrochloride: weight loss and co-morbidity risk reduction............20

Diethylpropion: weight loss and co-morbidity risk reduction.................................22

Orlistat: weight loss and co-morbidity risk reduction...............................................23

Sibutramine: weight loss and co-morbidity risk reduction.......................................28

Comparative drug studies..............................................................................................34

Combined drug studies..................................................................................................39

Safety/Side effects ..................................................................................................41

Safety and side effects of sibutramine therapy...........................................................41

Safety and side effects of orlistat therapy ...................................................................42

Safety and side effects of phentermine therapy .........................................................43


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Safety and side effects of diethylpropion therapy......................................................43

Summary of potential harms of pharmacotherapy intervention .............................44

Safety and side effects of meal replacement programs .............................................44

Practice recommendations and guidelines ............................................................47

National Institute of Health, USA...............................................................................47

The National Institute for Clinical Excellence (NICE), UK ...................................47

High profile clinical trials .......................................................................................49

Completed studies ..........................................................................................................49

Childhood obesity ..........................................................................................................49

Ongoing trials..................................................................................................................50

Other anti-obesity therapies ...................................................................................51

Horizon Scan ..........................................................................................................53

Economic considerations .......................................................................................55

The direct cost of medication.......................................................................................55

Economic analysis ..................................................................................................57

Economic evaluations of orlistat ..................................................................................57 Economic evaluations of sibutramine .........................................................................58 Economic evaluations of phentermine........................................................................63 Economic evaluations of diethylpropion ....................................................................63

Discussion...............................................................................................................65

Criteria for the evaluation of medication for the treatment of obesity ..................65

Expected weight loss and duration of weight loss.....................................................66 Potential barriers to use .................................................................................................66

Evidence Summary and Conclusions .....................................................................67

Clinical effectiveness and circumstances of use.........................................................67

Safety and side effects....................................................................................................72

Ethnic groups..................................................................................................................73

Economic considerations..............................................................................................73

Evidence Tables......................................................................................................75

Appendices............................................................................................................ 105

References............................................................................................................. 113


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Tables

Table 1. Classification of body weight.............................................................................................. 1 Table 2. Obesity related co-morbidities and risk............................................................................. 2 Table 3. Inclusion and exclusion criteria for review studies........................................................17 Table 4. Scottish Intercollegiate Guidelines Network Evidence levels .....................................18 Table 5. Weight loss results at three months and one year for an unstratified and stratified study population .................................................................................................................19 Table 6a. Phentermine effectiveness studies ...................................................................................21 Table 6b. Phentermine vs. placebo post treatment outcomes, Haddock et al., 2002 ................21 Table 7. Diethylpropion effectiveness studies, Glazer et al., 2001.............................................22 Table 8. Diethylpropion vs. placebo post treatment outcomes, Haddock et al., 2002............23 Table 9. Summary of publications reporting the effectiveness of orlistat for weight loss in overweight and obese participants ...................................................................................24 Table 10. Meta-analysis of RCTs for Orlistat, long-term studies ≥ 1 year (NICE HTA, ............

Avenell, May 2004).............................................................................................................25 Table 11. Orlistat 120 mg/d weight loss in otherwise healthy obese populations .....................26 Table 12. Orlistat 30-120 mg/d weight loss in patients with hypercholesterolemia, results after one year........................................................................................................................27 Table 13. Weight loss with orlistat: results of 1 year clinical trials, European Medicine

Evaluation Agency..............................................................................................................27 Table 14. Orlistat 120 mg/d in diabetic patients or patients with glucose intolerance..............27 Table 15. Eligible studies reporting the effectiveness of sibutramine ..........................................28 Table 16. Meta-analysis of RCTs for Sibutramine, long-term studies ≥ 1 year (NICE HTA, Avenell May 2004)...............................................................................................................30 Table 17. Studies reporting the effectiveness of sibutramine in otherwise healthy overweight individuals ........................................................................................................32 Table 18. Studies reporting the effectiveness of sibutramine in individuals with type 2 diabetes .................................................................................................................................32 Table 19. Sibutramine dose ranging studies. Bray 1999 reported in Leung et al., 2003.............34 Table 20. Eligible studies comparing two or more review drugs ..................................................34 Table 21. Summary of the comparative effectiveness of orlistat, sibutramine and low fat diets that may include meal replacements........................................................................35 Table 22. Summary of short-term weight loss trials of sibutramine and orlistat not otherwise reported in systematic reviews and HTAs.....................................................35 Table 23. A comparison of the effectiveness of sibutramine, orlistat, phentermine and diethylpropion (Glazer et al., 2001) ..................................................................................37 Table 24. A comparative study of the effectiveness of sibutramine, orlistat, phentermine and diethylpropion (Haddock et al., 2002) ......................................................................37 Table 25. Weight loss drugs trade off between benefit and harm.................................................38 Table 26. The effect of sibutramine on blood pressure and heart rate; results from 20 studies (Nisoli and Carruba, 2003)....................................................................................41 Table 27. NZ Drug pricing according to MIMS, 2004 ...................................................................55 Table 28. The estimated cost of a course of anti-obesity treatment .............................................55 Table 29. Studies reporting on the cost or cost effectiveness of sibutramine, orlistat, phentermine and diethylpropion.......................................................................................57 Table 30. Sensitivity analysis around two base estimates of the cost effectiveness of sibutramine when different utilities are assigned to weight loss...................................59 Table 31. Economic evaluations of orlistat, sibutramine and phentermine.................................61


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Evidence Table 1. Meal replacement, Heymsfield, 2003 ............................................ 76 Evidence Table 2. Meal replacement, Allison et al., 2003........................................... 77 Evidence Table 3. Orlistat, Torgerson et al., 2004....................................................... 78 Evidence Table 4. Orlistat, Rissanen et al., 2001 ......................................................... 79 Evidence Table 5. Orlistat, Muls et al., 2001 ................................................................ 80 Evidence Table 6. Orlistat, Foxcroft et al., 2000 ......................................................... 81 Evidence Table 7. Orlistat, Derosa et al., 2003 ............................................................ 82 Evidence Table 8. Orlistat, Hanefield et al., 2002........................................................ 83 Evidence Table 9. Orlistat, Halpern et al., 2003........................................................... 84 Evidence Table 10. Orlistat, Leung et al., 2003.............................................................. 85 Evidence Table 11. Orlistat, Heymsfield et al., 2000..................................................... 86 Evidence Table 12. Orlistat, O’Meara et al., 2001.......................................................... 87 Evidence Table 13. Orlistat, Padwal et al., 2004 ............................................................ 89 Evidence Table 14. Sibutramine, O’Meara et al., 2002.................................................. 90 Evidence Table 15. Sibutramine,Tambascia et al., 2003 ............................................... 91 Evidence Table 16. Sibutramine, Padwal et al., 2004 .................................................... 92 Evidence Table 17. Sibutramine, Leung et al., 2003 ..................................................... 93 Evidence Table 18. Sibutramine, Nisoli and Carruba, 2003......................................... 94 Evidence Table 19. Sibutramine, Berkowtitz et al., 2003.............................................. 95 Evidence Table 20. Sibutramine, Hazenberg et al., 2000.............................................. 96 Evidence Table 21. Sibutramine, Gokcel et al., 2001 .................................................... 97 Evidence Table 22. Sibutramine, Kim et al., 2003 ......................................................... 98 Evidence Table 23. Sibutramine, Hauner et al., 2003.................................................... 99 Evidence Table 24. Sibutramine, McNulty et al., 2003 ............................................... 100 Evidence Table 25. Sibutramine, Wadden et al., 2000 ................................................ 101 Evidence Table 26. Comparative drug study, Poston et al., 2001 ............................. 102 Evidence Table 27. Comparative drug study, Haddock et al., 2002.......................... 103


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Executive Summary

Obesity is a chronic, relapsing disease which increases the risk of a number of other serious diseases including diabetes, heart disease, hypertension, stroke and some cancers. Even a modest weight loss in obese individuals may be associated with significant health benefits arising from improvements in blood pressure, blood glucose and cholesterol levels.

Anti-obesity drug treatment is perceived as an adjunct to other weight loss strategies in an overall program of supervised weight reduction, weight loss maintenance or management. Co-interventions are typically a calorie controlled diet, behavioural therapy and/or physical exercise.

Weight loss drugs currently available in New Zealand include phentermine, diethylpropion, orlistat and sibutramine. Meal replacement products are readily available and popular non-pharmacological weight loss adjuncts.

The evidence suggests that phentermine, diethylpropion, orlistat, sibutramine and specified meal replacement plans/products are all effective at achieving a moderate weight loss in obese individuals. On average, an additional weight loss of approximately 4.0 kilograms may be achieved when these products are used as part of an appropriate weight loss program. Clinically important weight loss is considered to be a loss of ≥ 5% of initial body weight; a substantial proportion of patients were reported to have achieved this goal with the aid of weight loss drugs.

In comparative studies, the newer weight loss drugs orlistat (Xenical®) and sibutramine (Reductil®) are reported to be safer, more acceptable and more effective weight loss agents than the earlier amphetamine related drugs, phentermine and diethylpropion. They can be prescribed for longer periods than the older drugs and both orlistat and sibutramine are currently being tested in adolescents. Sibutramine use has been cautioned in this age group outside a clinical trial while orlistat has recently been approved by the Food and Drug Administration (FDA) for use in adolescents.

Sibutramine may result in a higher weight loss than orlistat but with side effects that may limit its use in patients with hypertension or cardiovascular disease. For these patients, orlistat may provide a useful alternative although the accompanying gastrointestinal (GI) side effects may not be acceptable to all patients. Meal replacement plans may be useful for patients who cannot tolerate or do not respond to either of these medications.

Sibutramine is reported to be cost-effective under most scenarios, with a lower estimated cost per quality adjusted life year (QALY) gained in patient groups with significant obesity related co-morbidities such as diabetes. The cost per QALY gained with orlistat is reported to be high and for healthy obese patients orlistat may not be cost-effective. However, for patients with obesity related co-morbidities such as hypertension and/or hypercholesterolemia, orlistat may be considered to be good value for money.

It is not clear if phentermine, diethylpropion or meal replacement plans are cost-effective treatments for obesity as no economic analyses of these therapies were identified, however, the direct cost of a course of phentermine or diethylpropion is much lower than the cost of orlistat or sibutramine.


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Recommendations

The weight loss drugs sibutramine and orlistat are effective adjuncts to an appropriate clinical program of weight loss for obese ACC claimants. Short-term treatment of up to six months should be considered for maximum weight loss. Longer-term treatment – i.e., up to two years should be considered if weight loss is to be maintained.

Patients with uncontrolled hypertension or cardiovascular disease may not be suitable candidates for sibutramine therapy; in these patients orlistat should be considered.

Meal replacement products should be considered for patients who are unable to tolerate these medications or who have not had an appropriate response. There is insufficient evidence to enable any specific product recommendations to be made.

Each of these interventions should be part of a medically monitored comprehensive regimen of weight reduction based on a calorie controlled diet, behaviour modification and where possible, physical exercise and lifestyle modifications.

Individuals with a body mass index (BMI) ≥ 30kg/m2 are generally considered to be obese and should be considered for weight loss therapy. Claimants who have a BMI of ≥ 27kg/m2 and obesity related co-morbidities including diabetes, hypertension and sleep apnoea may also benefit from medical assistance with weight loss and should be considered.

Consideration should also be given to the differing recommendations for obesity thresholds in non-Caucasian populations. The World Health Organisation (WHO) has defined a lower

obesity threshold (BMI ≥ 25kg/m2) for use in Asian populations and a higher threshold (BMI ≥ 32kg/m2) for Polynesians.


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Background

Definition and measurement of obesity

Obesity is a chronic, relapsing disease in which there is an abnormal accumulation of body fat. Definitions and measurement of obesity vary but most researchers currently use BMI 1 to classify individuals in terms of weight; individuals with a BMI of ≥ 30kg/m2 are generally considered to be obese, see Table 1.

Table 1. Classification of body weight

BMI (kg/m2)

Weight Class % Above

Ideal weight Caucasian Asian* PI*

Normal 0% 18.5-24.9 18.5-22.9 18.5-22.9 Overweight 20% 25.0-29.9 23.0-24.9 26.0-31.9

Class I (mild) 20-40% 30.0-34.9 25-29.9 ≥32.0 Class II (moderate) 400-100% 35.0-39.9 ≥30.0

Obesea Class III (severe- morbid) >100% ≥40.0 - - *Figures taken from WHO, The Asia-Pacific Perspective: Redefining Obesity and its treatment. PI= Pacific Islander. a person with a BMI over 30 is considered to be obese and this is an arbitrary value obtained from epidemiological studies showing that a relationship between mortality and BMI follows a J-shaped curve and that mortality increases by 50-100% at BMI value above 30kg/m.

Generally BMI correlates well with body fat, however, BMI is not a foolproof guide to morbid fat accumulation, as it does not take into account body frame size, proportion of lean mass, age, gender or ethnic differences. Misclassification can occur when a BMI =30kg/m2 threshold is used to define obesity in non-Caucasian populations. Polynesians tend to have a lower fat percentage than Caucasians for any given BMI and the threshold for obesity in Polynesians is BMI ≥ 32kg/m2. Asian populations, however, have more fat and co-morbidities for any given BMI than Caucasians and a lower obesity threshold of BMI=26kg/m2 has been suggested (Proietto and Baur 2004).

Other useful, but less commonly used, obesity indices include waist to hip ratio and waist circumference. These measures may provide additional useful information regarding risk factors associated with weight gain. In Caucasians, a WHR>1.02 for men and a WHR >0.88 for women is used to identify obesity and abdominal fat accumulation (NHANES III); this may be a better predictor of weight related cardiovascular risk than BMI.

Genetic disorders such as Alstrom’s syndrome and endocrine disorders such as hypothyroidism and Cushing’s disease must be ruled out before diagnosing obesity (Leung et al. 2003).

The health consequences of obesity

The 1997 New Zealand National Nutrition Survey (Wilson et al. 2001) estimated that the health risks associated with obesity were equivalent to a number of high-risk, chronic diseases including type 2 diabetes, heart disease, hypertension, stroke, gallstones and some cancers.

1 BMI= weight in kilograms divided by height in metres squared (kg/m2).


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The distribution of body fat is an important determinant of the type of associated health risk; abdominal or visceral fat (android obesity) is associated with increased risk of cardiovascular mortality, hypertension and non-insulin dependent diabetes.

Increased health risks for conditions associated with obesity vary from a substantial to moderately raised risk for diabetes, heart disease, hypertension and a number of other metabolic disturbances (Brown et al. 2000; Carey et al. 1997; Chan et al. 1994; Manson et al. 1990; Rimm et al. 1995) to a slightly raised risk for some cancers and lower back pain (Bergstrom et al. 2001a; Bergstrom et al. 2001b; Calle et al. 2003; Oliveria et al. 1999). There is also an increased risk of adverse events from anaesthesia in obese patients, see Table 2.

Table 2. Obesity related co-morbidities and risk

Substantial Risk Increase (RR>3) Moderate Risk Increase (RR=2-3) Slight Risk Increase (RR= 1-2)

Type II diabetes Coronary heart disease Breast, endometrial, colon cancers

Gall bladder Hypertension Reproductive hormone abnormalities

Dyslipidaemia Osteoarthritis of the knee and hips Polycystic ovary syndrome

Metabolic syndrome Hyperuricemia Impaired fertility

Sleep apnoea Gout Low back pain

Breathlessness Increased anaesthetic risk

Foetal defects (maternal obesity) RR= relative risk is the probability of an event in the treatment group divided by the probability of the event in the control group.

Psychological problems such as clinical depression are also associated with obesity. These problems may impact on quality of life and result in job discrimination and other employment difficulties.

Factors influencing body weight

A number of factors influence body weight and fat levels making some individuals more susceptible to obesity. Known contributors are:

• ethnicity

• gender

• age

• hormonal state

• genetic make-up.

People from southern Asia are at a greater risk of developing central obesity and their cardiovascular risk increases rapidly at lower levels of obesity relative to western standards. For this ethnic group increased cardiovascular risk starts at a BMI of 21-23kg/m2.. The WHO2 has proposed new obesity guidelines for Asian populations with an obesity threshold defined as a

BMI ≥25kg/m2. Individuals with certain learning disabilities such as Down’s syndrome are also at higher risk of obesity (NHS Centre for Reviews and Dissemination 1997).

2 WHO 2000, Redefining obesity and its treatment.


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Clinically significant weight reduction

Most obese individuals would need to shed 30% of their body weight to reach their “ideal weight”. Such goals are generally unrealistic. However, much smaller reductions in weight can be accompanied by substantial health gains. A clinically significant weight reduction can be achieved with a body weight loss of 5-10% within six months. Many obese people experience difficulty in achieving this amount of weight loss in the timeframe through diet and exercise alone (Derosa et al. 2003). These people may benefit from the pharmacological interventions reviewed here.

Obesity and Injury

Weight loss may be viewed as a modality to improve general health as well as an aid to treatment and recuperation from accident or injury. A number of obesity associated health problems may be present at the time of accident or injury, or acquired afterwards, as a result of mobility and lifestyle changes. Such problems may impede recovery and rehabilitation and impede or limit the effectiveness of treatment.

For individuals recovering from accidents and injury, obesity related problems may significantly interfere with treatment and recovery. Obese claimants may be refused surgical treatment because of increased risks associated with anaesthesia. Existing obesity or obesity arising from lack of mobility, activity and exercise after an accident or injury may interfere with a claimant’s return to independence or full employment. It may also substantially increase the claimant’s recuperation period. Personal care requirements may also increase, particularly in relation to attendant care and additional health interventions may be required for co-morbid conditions, which may be initiated or exacerbated as a consequence of obesity.

Obesity trends in NZ

A substantial proportion of the New Zealand population is obese. In 1997, the National Nutrition Survey reported that more than half of New Zealand adults were overweight with 17% classified as obese; it is estimated that by 2011 this will have risen to 29% (Wilson et al. 2001). Obesity rates in Maori and Pacific Islanders are higher than for the general New Zealand population with 27% of Maori men, 26% of Pacific men, 28 % of Maori women and 47% of Pacific woman reported as obese by the 1997 survey. Obesity in New Zealand children is also increasing and is of some concern.

Given these statistics it is highly likely that a significant number of ACC claimants will be obese or at risk of obesity at the time of accident or injury. Since some ethnic groups are more at risk of obesity than others, a correspondingly greater proportion of obese claimants, or claimants with recovery related obesity risk, may be expected in these susceptible groups. It is estimated that 75% of Pacific peoples in New Zealand are overweight; an immobilising accident or injury could put these claimants at risk of becoming obese while recovering from an accident or injury.


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The economic cost of obesity

The high prevalence of obesity in New Zealand and its associated co-morbidities suggests that obesity is likely to command a significant portion of the total health care costs incurred by any government agency.

Three component costs have been identified:

• the direct treatment cost to the individual and the service provider

• the opportunity costs to the individual and society arising from premature death or attributable morbidity

• the indirect costs to the individual and society of lost work production due to absenteeism from work and premature death.

An overall assessment of the economic cost of obesity by the WHO suggested that it accounts for between 2-7% of total health care costs in developed countries. As a significant proportion of ACC claimants are likely to be obese or overweight at the time of injury or accident, additional costs arising from obesity related complications may be expected. The additional cost may be expected to arise from the:

• direct cost of obesity treatment

• indirect costs associated with delays in returning the claimant to full employment as a result of obesity-related co-morbidities or treatment and rehabilitation problems arising from morbid obesity.

Benefits associated with weight loss

Even a modest weight loss of 5-10% has been associated with significant health benefits in the obese patients. These benefits arise from improvements in obesity related co-morbidities including blood pressure, blood glucose and cholesterol levels. It has been estimated that for every one kilogram reduction in body weight there is a:

• 0.05mmol/l decrease in total cholesterol

• 0.02mmol/l decrease in low density lipoprotein cholesterol (LDL-cholesterol)

• 0.015mmol/l decrease in triglycerides

• 0.007mmol/l increase in high density lipoprotein cholesterol (HDL-cholesterol).

Weight loss and dietary fat modification appear to have independent and additive effects on the reduction in serum lipids: the net favourable effect of weight loss seems to be greater than that of dietary fat modification as weight loss per se is only responsible for about 60% of the fall in LDL-cholesterol and 70% of the fall in triglycerides (Muls et al. 2001). Every 1% reduction in glycated haemaglobin (HbA1c) decreases cardiac complications from 9-40% depending upon the population and diabetes type (Gokcel et al. 2001).


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Higher weight losses have greater benefits (Jung 1997); a 10kg weight loss may be expected to incur:

• 10mmHg decrease in systolic blood pressure (SBP)

• 20mmHg decrease in diastolic blood pressure (DBP)

• 91% reduction in angina symptoms

• 33% raise in exercise tolerance

• 10% fall in total cholesterol

• 15% fall in LDL-cholesterol

• 30% fall in triglycerides

• 8% increase in HDL-cholesterol

• >50% reduction in the risk of developing diabetes

• 30-50% fall in fasting blood glucose

• 15% fall in HbA1c.


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Review questions

The following questions guided the current review:

• What are the most appropriate measures used to classify obesity and how is obesity defined across different ethnic and age groups – is the BMI of >35, as set out in ACC's 2001 guidance, still an appropriate definition of obesity for all claimants?

• What is the relative effectiveness of phentermine, diethylpropion, orlistat, sibutramine and meal replacement plans for claimants requiring treatment to aid weight loss and what degree of weight loss can be expected and maintained with each product?

• How long do the products take to achieve a clinically important weight loss and what are appropriate time limits for treatment with the various product regimes?

• What are the circumstances in which the various products should be used and what are the potential barriers to implementation?

• How do the specified products compare in terms of safety, contraindications and patient acceptability?

• What is the relative cost-effectiveness of specified products for claimants requiring treatment to aid weight loss?

• Do the effectiveness and cost-effectiveness of the various products vary according to patients’ ethnicity, and if so, how?


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Pharmacological treatments for obesity

Pharmacological treatments for obesity are limited. Most have the potential to produce undesirable side effects, additionally, amphetamines administered for the purposes of weight loss may have euphoric actions and carry the potential for abuse (Silverstone 1992). Some previously available products have recently been withdrawn from the market in a number of countries, for example:

• phenylpropanolamine, an appetite suppressant, has been associated with increased haemorrhagic stroke in women and withdrawn in the USA

• fenfluramine and dexfenfluramine – two centrally acting appetite suppressants acting predominantly by releasing serotonin, were also withdrawn from the market recently because of an association with pulmonary hypertension and coronary valve damage (Gardin et al. 2000).

Pharmacological interventions registered in New Zealand

There are currently four generic drugs prescribed for the treatment of obesity in New Zealand:

• phentermine

• diethylpropion

• orlistat

• sibutramine.

Other non-pharmacological interventions include meal replacement products and plans and bariatric surgery. Surgery for obesity is not considered in this review.

Phentermine (DuromineTM, Umine Timedcaps3)

Phentermine has been available since the 1960s with a reported worldwide exposure of more than 50 million prescriptions (Glazer 2001). It is available in New Zealand as a resin under the brand name Duromine (15 or 30mg) or in a sustained release hydrochloride form under the brand name of Umine Timedcaps (30mg).

Phentermine is an appetite suppressant chemically related to amphetamine. It has its main effect on the dopaminergic and noradrenergic nervous systems and its actions include central nervous system (CNS) stimulation and blood pressure elevation. The resin complex (Duromine) is insoluble until it reacts with the GI fluids; phentermine is then released from the resin throughout the GI tract over a period of 10-14 hours. Phentermine HCL sustained release capsules (Umine) has peak concentrations at 2.4 hours after ingestion. There is almost complete absorption of the drug but eventually 70-80% of the oral dose is excreted unchanged in the urine with the remainder metabolised by the liver. The half-life of phentermine is about 25 hours.

3 Also marketed under the product names Ionamine, Fastin, Adipex in the USA.


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Phentermine use in children under 12 years, elderly patients and pregnant or breastfeeding women is not advised as safety and efficacy in these populations has not been established.

Dosage and administration: the starting dose is usually 30mg/d (milligrams per day), however, in light framed patients or those who have suffered side effects a dose of 15mg/d may be prescribed. Failure to achieve a weight reduction of 5% within 12 weeks of starting phentermine therapy is an indication for discontinuation of treatment. In order to reduce the risk of dependence, the maximum continuous period of treatment should not exceed 4-8 weeks.

Circumstances of use: phentermine may be used as a short-term adjunct in a medically monitored comprehensive regimen of weight reduction based on exercise, calorie controlled diet and behaviour modification in patients with a BMI ≥30kg/m2 who have not had an appropriate clinical response to an appropriate weight reduction program alone. Patients with obesity related co-morbidities such as sleep apnoea, insulin resistant diabetes mellitus, pre diabetes mellitus or impaired glucose tolerance (IGT) or high cardiovascular risk status, and have a BMI of less than 30kg/m2 may also be considered for treatment with phentermine.

Mode of action: phentermine is an amphetamine which operates by stimulating the release of noradrenaline and dopamine; it also inhibits monoamine oxidase (Lean 2001). Its central catecholamine mechanisms cause appetite suppression for 12-14 hours (Thearle and Aronne 2003).

Indications: phentermine 15mg and 30mg are indicated as a short-term adjunct in a medically monitored regime of weight reduction in obese patients that includes a calorie controlled diet, exercise and behaviour modification. It may also be appropriate to use phentermine in overweight patients with an increased risk of morbidity from other medical conditions including sleep apnoea, insulin resistant diabetes or IGT and cardiovascular disease.

Contraindications: patients with pulmonary artery hypertension, heart valve abnormalities or heart murmur, moderate to severe hypertension, cerebrovascular or cardiac disease, hypersensitivity to sympathomimetic drugs, hyperthyroidism, agitated states or psychiatric illness, depression, major eating disorder, glaucoma and patients with a history of substance abuse or dependence (Medsafe 2003).

Warning and precautions: serious cardiac valvular disease and primary pulmonary hypertension (PPH) has been reported in patients who have taken phentermine and fenfluramine or dexfenfluramine combinations (“phen-fen”) for weight loss. There have been no reported cases of valvular disease and only very rare cases of PPH in patients taking phentermine alone. There is also a theoretical risk of cardiac valvular disease if phentermine is combined with selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine, ergot derived drugs and clomipramine. Phentermine should not be administered with monoamine oxidase inhibitors and should be used with caution in patients with mild hypertension and patients under treatment with hypertensive agents as it may cause some loss of blood pressure control. The ability to perform activities requiring mental alertness such as driving and operating machinery may be impaired while taking phentermine (Medsafe 2003).

Diethylpropion hydrochloride (Tenuate Dospan)

Diethylpropion is an appetite suppressant or anorexiant. It is rapidly absorbed after oral administration with 75-100% of the dose excreted in the urine as diethylpropion hydrochloride or its metabolites. The half-life of diethylpropion in the plasma is about two hours and the excretory half-life of the drug and its metabolites is approximately 10 hours.


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The use of diethylpropion in children younger than 18 years and pregnant or breastfeeding women is not advised as safety and efficacy in these populations has not been established. Secondary organic causes of obesity should be excluded by diagnosis.

Dosage and administration: the recommended dose of sustained-release diethylpropion is 75mg once daily, one hour before meals. It is intended for short-term intermittent use only. Courses may be given over a period of up to 12 weeks with intervening period of at least one month without treatment. To limit unwanted exposure, treatment should be continued only if there is satisfactory weight loss within the first four weeks of treatment. Insulin requirements may need to be altered.

Circumstances of use: diethylpropion may be used as a short-term adjunct in a medically monitored comprehensive regimen of weight reduction based on exercise, calorie restriction and behaviour modification in obese patients with a BMI ≥ 30kg/m2 who have not had an adequate response to an appropriate weight loss program of diet and/or exercise alone. Patients with a BMI of less than 30kg/m2 with co-morbidities including sleep apnoea, insulin resistant diabetes mellitus, pre diabetes mellitus or IGT or high cardiovascular risk status, may require medical assistance with weight loss. Such patients may also be considered for treatment with diethylpropion.

Mode of action: diethylpropion is a sympathomimetic amine, it acts as a CNS stimulant, increasing the heart rate, raising blood pressure and decreasing the appetite.

Indications: diethylpropion is indicated as a short-term adjunct in a medically monitored comprehensive weight loss program based on calorie restricted diet, exercise and behaviour modification in obese patients who have not achieved an adequate weight reduction using diet and exercise alone. Overweight patients with sleep apnoea, insulin-resistant diabetes, IGT or with a high risk of cardiovascular disease may also be considered for treatment.

Contraindications: severe hypertension or pulmonary artery hypertension, advanced arteriosclerosis, hyperthyroidism, known hypersensitivity to sympathomimetic amines, glaucoma, agitated states and patients with a history of drug abuse. Failure to achieve a weight reduction of 5% in a period of 12 weeks is an indication for discontinuation of treatment. Use in conjunction with other anorectic agents is contraindicated (Medsafe 2004b).

Warning and precautions: diethylpropion should not be given during or within 14 days of monoamine oxidase inhibitors. It is not recommended for patients who have taken any anorectic agents within the prior year or for patients with a heart murmur or valvular heart disease. The use of anorexiants has been associated with PPH and an increased risk of PPH with repeated courses of therapy cannot be excluded. Epileptic patients should be carefully monitored. Diethylpropion should be used with caution in patients undergoing general anaesthesia (Medsafe 2003).

Sibutramine hydrochloride (Reductil®, Meridia®)

Sibutramine is an orally administered drug that promotes satiety after eating and stimulates energy expenditure (Lean 2001; Nisoli and Carruba 2003). It is the first product of its type to be used for the management of obesity (Medsafe, sibutramine data sheet). The drug is rapidly absorbed following ingestion with maximal plasma concentrations at one hour and an elimination half-life of about one hour. Most (77%) of the drug is absorbed from the GI tract and up to 85% of the oral dose is excreted in the urine and faeces.


12

Sibutramine and its metabolites do not enhance dopamine release and have not been shown to have a potential for abuse (Schuh et al. 2000).

The long-term effects of sibutramine on the mortality and morbidity associated with obesity have not been established. Its use in obese children under 18 years, patients over 65 years and pregnant or breastfeeding women is not advised as safety and efficacy in these populations has not been established.

Dosage and administration: the recommended starting dose is 10mg once daily with or without food; in clinical trials sibutramine was given in the morning. If there is less than 2kg weight loss after four weeks and the 10mg dose is well tolerated the daily dose may be increased to 15mg. Patients usually achieve maximum weight loss – i.e., 5-10% of initial body weight, after six months of treatment. The European Union label states that patients responding well may be treated for up to a year, in the USA treatment may be maintained for up to two years (Astrup and Toubro 2001). The frequency of adverse events may be reduced if sibutramine is administered intermittently – i.e., alternating with placebo or drug free periods (Wirth and Krause 2001).

Circumstances of use: sibutramine may be used for the management of obesity including weight loss and weight maintenance in patients with a BMI ≥ 30kg/m2 or a BMI of ≥ 27kg/m2 in patients who have diabetes, dyslipidaemia or hypertension. It is intended for use when patients have not adequately responded to appropriate weight-reducing therapy such as hypocaloric diet and/or exercise alone – e.g., patients having difficulty in achieving or maintaining a 5% weight loss within three months.

Mode of action: sibutramine is a centrally acting monoamine reuptake inhibitor which blocks the pre-synaptic reuptake of serotonin and noradrenaline thereby potentiating the anorexic effect of these two neurotransmitters in the CNS.

Indications: sibutramine 10mg and 15mg is indicated as adjunctive treatment within a weight management program for patients between 18-65 years with a BMI of 30kg/m2 (i.e., obese) or patients with a BMI of 27kg/m2 (i.e., overweight) who also have type 2 diabetes or dyslipidemia. Patients must have failed to lose weight on diet and exercise in the past.

Contraindications: patients with severe hepatic or renal dysfunction, hypersensitivity to sibutramine, organic obesity or history of major eating disorders, patients with psychiatric illness, drug or alcohol abuse, inadequately controlled hypertension or history of cardiovascular disease, narrow angle glaucoma, hyperthyroidism, benign prostatic hyperplasia with urinary retention and phaeochromocytoma (Medsafe 2004a).

Warning and precautions: blood pressure and pulse rate should be monitored while patients are taking sibutramine. The ability to drive a vehicle or operate hazardous machinery may be impaired when taking sibutramine (Medsafe 2004a).

Orlistat (Xenical®4)

Orlistat is a novel anti-obesity agent that inhibits the digestion of fat. Undigested trigylcerides are excreted in the faeces 24 to 48 hours after administration resulting in a calorific deficit that has a positive effect on weight control.

4 Xenical®, Hoffman-Roche.


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Orlistat is minimally absorbed into the systemic circulation with approximately 97% of the administered dose excreted in the faeces, 83% is unchanged orlistat (Medsafe 2004c). The time to complete excretion is three to five days.

The long-term effects of orlistat on the mortality and morbidity associated with obesity have not been established. Its use in children, adolescents below the age of 18 years, patients over 65 years and pregnant or breastfeeding women is not advised as safety and efficacy in these populations has not been established.

Dosage, administration: the recommended dose of orlistat is 120mg three times a day (t.i.d.) with each main meal. Higher doses have not been shown to provide additional benefit. The greatest weight loss occurs within the first six months of treatment. In the USA, treatment may be maintained for up to two years (Astrup and Toubro 2001).

Circumstances of use: orlistat may be used for weight loss, weight maintenance and prevention of weight regain in adults with a BMI ≥ 30kg/m2. It should be used in conjunction with a low fat calorie controlled diet that is nutritionally balanced, rich in fruit and vegetables and contains approximately 30% of calories from fat distributed over three meals.

Mode of action: orlistat is a synthetic derivative of lipstatin a naturally occurring lipase inhibitor produced by Streptomyces toxytricini. It is a potent and specific irreversible inhibitor of pancreatic and gastric lipases that acts by bonding at the active site of lipases in the lumen of the GI tract. The inactivated enzyme is unable to hydrolyse ingested triglycerides into free fatty acids and monoglycerides for absorption. At the recommended dose and when diet contains approximately 30% of calorific intake from lipids, about 20g (180kcal) of fat is excreted in the daily stool. Orlistat may also influence dietary choices as high fat meals can lead to more severe GI adverse events.

Indications: orlistat is indicated as adjunctive treatment within a low fat calorie controlled program for obese patients between 18-65 years with a BMI of 30kg/m2. Patients must have demonstrated weight loss of 2.5kg one month before its use.

Contraindications: patients with chronic malabsorption syndrome, cholestasis, known hypersensitivity to orlistat or any of its components (Medsafe 2004c).

Warning and precautions: because of a possibility of a decreased absorption of fat soluble vitamins A, D, E, K and beta-carotene, the use of multivitamin supplements may be considered while patients are taking orlistat. High fat meals are likely to increase the possibility of GI events and patients should adhere to dietary fat intake guidelines. A reduction of plasma levels of cyclosporine5 is possible after orlistat administration; the effect of amiodarone may also be reduced. Coagulation parameters of patients on concomitant oral anticoagulants should be monitored. There is no information relating to effects on ability to drive and used machines (Medsafe, orlistat data sheet). The additive GI effects of concomitant use of orlistat and olestra, a non-absorbable dietary fat substitute commonly available in snack foods such as potato chips, has been reported (Heck et al. 2002).

5 Cyclosporine absorption may be reduced by approximately one third (Zhi et al., 2003).


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Meal replacement plans

Low calorie diets (LCDs) – i.e., diets in the range of 1200-1600kcal/day, are the cornerstone of modern weight control efforts. Meal replacement strategies and products are used by millions of consumers worldwide, however, there are no established definitions of meal replacement or partial meal replacement (PMR) plans, (Heymsfield et al. 2003).

The term ‘meal replacement’ is generally used in the scientific literature to cover beverages, pre-packaged shelf-stable and frozen entities and meal or snack bars. Most of these products are fortified with vitamins and minerals designed to be consumed in place of one or more regular meals. They may be an adjunct in a LCD. Eating, behaviour modification and physical exercise advice usually accompany commercial meal replacement programs.

Meal replacement nutritional supplements may be a useful weight loss therapy in obese individuals who:

• do not want to use weight loss drugs

• cannot tolerate the side effects of weight loss drugs

• cannot maintain eating habit change

• do not respond to weight loss drugs.


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Methodology

The main methodological tools for this review include a comprehensive literature search for published studies that fulfil pre-determined criteria, a systematic review of eligible studies and a synthesis of the evidence guided by specific review questions (see page 7).

Systematic review

A systematic review is a carefully defined process that involves systematically locating, appraising and synthesising evidence from scientific studies in order to obtain a reliable overview. The literature search is comprehensive involving as many relevant sources as possible being accessed; the study selection, data extraction and data pooling are performed according to pre-set criteria. The adherence to scientific principles sets the systematic review apart from traditional literature reviews making it less biased and more objective (O'Meara et al. 1998).


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Search strategy and information sources

Search strategy

A comprehensive literature search of major relevant bibliographic and review databases was undertaken together with additional searches for clinical trials, guidelines, government, and other evidence-based materials. A range of subject headings and keyword searches were used to search indexed databases (see Appendix II). The search was not restricted by date, but was restricted to English language articles. In addition, a methodology filter was used to identify systematic reviews, randomised controlled trials (RCTs), and economic studies. This comprehensive strategy identified 777 potentially relevant journal references. After screening the abstracts of these references, 211 full text articles from peer-reviewed journals were retrieved for analysis. All relevant health technology assessment (HTA) resources were also examined and five international HTA reports of pharmacological treatment of obesity were retrieved.

Principal sources of information

The following databases were searched using the search strategy outlined in Appendix II. The searches were carried out during June and July 2004.

Bibliographic databases

Medline

Cinahl

Embase

Web of Science

Current Contents

Toxnet

Cochrane Controlled Trials Register

Review databases

Cochrane Database of Systematic Reviews

Database of Abstracts of Reviews of Effects

Health Technology Assessment Database

NHS Economic Evaluation Database


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Study selection criteria

The FDA guidelines for the clinical evaluation of weight-control drugs and the selection criteria set out in the recent HTAs of obesity treatment guided the determination of inclusion and exclusion criteria for this review. All studies of pharmacological agents included in the review were required to be randomised, placebo or active control double-blind studies with weight loss as the primary outcome and obese participants as the primary study population. Additionally, studies had to be written in English and published between 1996-2004.

Table 3. Inclusion and exclusion criteria for review studies

Inclusion Criteria

Study design Randomised placebo or active control, double-blind studies or HTAs or systematic reviews or meta-analyses of randomised, placebo-controlled, double-blind trials or RCTs, double blind, comparative drug trials, OR for meal replacement, a RCT against standard meal or diet plan.

Primary study purpose Weight loss Study size Unrestricted Study duration/ length of follow-up Any duration of treatment. Follow–up of at least 12 months for long-term benefits, any follow-

up length for short-term benefits. Participants Individuals with a BMI of at least 30kg/m2, no age restriction. Interventions Licensed drugs, sibutramine, orlistat, phentermine, diethylpropion or meal replacement

plans/products with or without co-interventions such as diet counselling, deficit diets, dietary advice sheets, education and encouragement to exercise if appropriate.

Outcome measures/endpoints Primary endpoints - actual weight loss, relative weight loss (% of body weight or % excess over ideal weight or change in BMI), changes in central obesity. Secondary endpoints - measurement of obesity related risk factors – e.g., lipids, blood pressure and glucose tolerance.

Health economics All economic and cost evaluations Language English language or English translation available Study dates/publication date Jan 1996-July 2004 Publication type Studies published in peer-reviewed journals or manufacturer’s unpublished material if

relevant and available.

Exclusion criteria

Pregnant or breastfeeding mothers Abstracts and case reports Animal studies Non-clinical studies Preliminary exclusion of overweight +co-morbidities Quasi randomised, open label and cross-over trials Studies recruiting patients with eating disorders such as anorexia or bulimia nervosa Single RCTs with a crossover design*

* Excluded because of (i) the possibility of carry over effects and (ii) because they are excluded from most meta-analyses because of their inadequacy in terms of estimating effect size (Kim et al. 2003).

Methods of the review

Studies were not limited in duration but in the analysis of results studies were considered in two groups to reflect the primary needs of ACC claimants:

• short-term studies – i.e., treatment duration < 6 months

• long-term studies – i.e., treatment durations ≥ 6 months.


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Further stratification by co-morbidity was carried out where feasible and obese patients with:

• type 2 diabetes

• hypercholesterolemia

• hypertension

were analysed separately to assess differences in need, weight loss goals and expectations that may be required by claimants with obesity related co-morbidities.

Levels of evidence

The evidence was graded using the Scottish Intercollegiate Guidelines Network (SIGN) instrument, see Table 4.

Table 4. Scottish Intercollegiate Guidelines Network Evidence levels

Level Type of evidence/study

Ia Evidence obtained from meta-analysis of randomised controlled trials Ib Evidence obtained from at least one randomised controlled trial IIa Evidence obtained from at least one well designed controlled study without randomisation IIb Evidence obtained from at least one other type of well-designed quasi-experimental study III Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies

and case control studies. IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities.

However, only evidence from RCTs, systematic reviews, and meta-analysis of RCTs or HTAs including RCTs was considered in this review, limiting the evidence levels to Ia or Ib.

The main purpose of randomisation is to minimise bias, however, the quality of randomised studies can vary. Where the normal quality criteria are not met a number of biases may occur, these can be minimised in a number of ways:

• selection bias - full explanation of the method of randomisation, including concealment

• attrition bias - full reporting of the number and type of withdrawals and drop-outs

• intention to treat (ITT) analysis - preserves the baseline comparability between treatment groups achieved by randomisation

• detection bias - blinding of outcome assessor and blinding of participants.

The robustness and validity of the eligible studies was further determined from the degree of bias minimisation based on the four criteria above. The most useful and reliable study was considered to be a well designed and properly conducted randomised, placebo-controlled, double-blind clinical trial or a meta-analysis of such studies. Where blinding is not possible because of the nature of the intervention – e.g., meal replacements, a well designed and properly conducted RCT or meta-analysis was considered to be the most useful type of study for the purpose of this review.


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Results

Meal replacement plans: weight loss and co-morbidity risk reduction

Meal replacement eating plans have not been critically evaluated for safety and efficacy until very recently. The first meta-analysis evaluating RCTs of PMR plans and products was published in 2003 (Heymsfield et al. 2003). In this study a search of Medline, Embase and the Cochrane Clinical Trials Register between 1960 to January 2001 for clinical trials with meal replacements or meal plans, identified 276 potential publications of which 30 were meal replacement as defined in the protocol. Only six studies finally met the review criteria, 24 were excluded due to one or more of the following:

• lack of a control arm

• less than 12 weeks duration

• not meal intervention as defined in protocol

• inclusion of subjects <18 years

• inclusion of subjects BMI <25kg/m2

• use of the anorexic drug diethylpropion.

For the purpose of the Heymsfield meta-analysis, a PMR plan was defined as a program that:

“ includes one or more meals replaced by a commercially available, calorie-reduced product(s) that are fortified with vitamins and minerals and at least one daily meal consisting of regular foods. As a LCD, the plan’s calorie content should be >800<=1,600kcal/day.”

Primary data were available from the six eligible RCTs. These data were used in a meta-analysis and pooling analysis, see Table 5.

Table 5. Weight loss results at 3 months and one year for an unstratified and stratified study population

N=

ΛΛΛΛ (PMR-RCD)

kg(s.e.) 3 months

Significance of PMR-RCD difference

p=

N=

ΛΛΛΛ (PMR-RCD)

kg(s.e.) 12 months

Significance of PMR-RCD difference

p= Analysis of all participants - unstratified Meta-analysis Random effects 403 2.60(0.96) 0.006 219 2.43(1.65) 0.142 Meta analysis Fixed effects 403 3.01(0.33) <0.001 219 3.39(0. 72) <0.001 Pooled analysis of completers 403 2.54(0.37) <0.001 219 2.63(0.88) 0.003 Pooled analysis LOCF 485 2.39(0.35) <0.001 485 2.86(0.46) <0.001 Analysis - stratified by diabetic status Non-diabetic completers 305 2.79(0.37) <0.001 193 3.17(0.99) 0.002 Non-diabetic LOCF 367 2.67(0.35) <0.001 367 3.56(0.50) <0.001 Diabetic completers 98 2.46(1.84) 0.185 26 2.76(2.00) 0.183 Diabetic LOCF 118 2.62(1.89) 0.167 118 1.52(1.89) 0.424

Λ (PMR-RCD) = weight loss difference between the treatment (PMR) and the control (RCD) group measured from baseline body weight to body weight at the time of assessment. PMR = partial meal replacement, RCD = restricted calorie diet.


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For detailed results see Meal Replacement in Evidence Table 1, Heymsfield, 2003.

All methods of analysis indicated a significantly greater weight loss for individuals following the PMR plan than those following the conventional reduced calorie diet. On average, the PMR group lost 2.54 kilograms more than the control group after three months of treatment and 2.43 kilograms more after 12 months. The proportion of subjects losing ≥ 5% of initial body weight was 33% for the RCD group and 72% for the PMR group (p<0.001); at 12 months the proportions were 33% and 74% (p<0.001).

After stratification according to diabetic status, the non-diabetic completers lost on average 2.79 kilograms more than the control group after three months (p<0.001) and 3.17 kilograms more after 12 months (p=0.002). The much smaller diabetic completers lost on average 2.46 kilograms more than the control at three months and 2.76 kilograms more than the control at 12 months. Neither difference reached significance, however, the number of diabetic cases was small and the standard error for the group large.

All of the risk factors for obesity related co-morbidities showed improvement from their baseline values in both the treatment and control groups (p<0.001), however, there was no significant additional effect of PMR on risk factor improvement with the exception of plasma insulin (p<0.001). The authors concluded that the magnitude of the weight loss that could be achieved with PMR at 12 months was within the range observed for pharmacological agents and the range known to lower obesity related risk factors. They attributed the success of PMR to a general preference by participants for structured weight loss plans which promoted improved behavioural compliance, increased nutritional knowledge, more regular meals and less snacking. No reported adverse events were attributed to either the PMR plan or the control.

A comprehensive literature search for the current review carried out in July 2004 identified a further product and randomised trial that was eligible for inclusion. The randomised trial comprised a study of 100 overweight or obese participants (Allison et al. 2003) in which half were randomly assigned to a soy-meal replacement program and half to a 1200kcal exchange diet program. Both groups received dietary counselling and a pamphlet describing good weight loss practices. After 12 weeks, the treatment group lost significantly more weight from the baseline than the control group 7.00kg vs. 2.90kg (p<0.001, ITT analysis). Fat mass was also significantly lower in the treated group -4.3 vs -1.4 (p=0.003). Obesity related risk factors showed reductions in both groups but the magnitude of the effect was variable with large standard errors; LDL-cholesterol reductions were significantly greater at all time periods in the treatment group. Treatment was reported to be well tolerated with no serious side effects. For further details of results, see Meal Replacement in Evidence Table 2 (Allison et al. 2003).

Phentermine hydrochloride: weight loss and co-morbidity risk reduction

The efficacy and safety of phentermine has been assessed primarily in short-term studies of up to 12 weeks duration. The longest study was a randomised, double-blind, placebo-controlled study of 100 subjects undergoing phentermine therapy for 36 weeks (Munro et al. 1968) and reported in a recent systematic review by Glazer (2001). No large-scale, long-term studies of phentermine for weight loss have been performed (Thearle and Aronne 2003).

The systematic review of pharmacotherapy of obesity reported by Glazer in 2001 included a comparative analysis of all randomised, placebo-controlled, double-blind trials of nine months or more duration.


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Trials limited to diabetic patients were excluded from this comparative study. Four phentermine studies were reported (Munro 1979; Munro et al. 1968; Steel et al. 1973; Truant et al. 1972; Weintraub et al. 1984), see Table 6a.

Table 6a. Phentermine effectiveness studies

Study Year Dose Duration Weight Loss (kg)

P value†

Munro 1986 30mg 36 weeks 12.2 <0.001 4/4 36 weeks 13.0 <0.001 Weintraub 1984 20 weeks 11.3 <0.01 Truant 1972 16 weeks 8.8 <0.01 Steel 1973 36 weeks 12.0 -

4/4 =4 weeks of phentermine followed by 4 weeks not on phentermine therapy. † compared to placebo

Data from these early studies suggested that phentermine was well tolerated. Adverse events were reported as “minor” with between 3-8% of patients affected. Stimulant effects such as agitation and insomnia were noted. Overall, phentermine was reported as efficacious, with a significantly greater weight loss than the placebo group reported in each study. Weight loss relative to baseline body weight was not reported and the results of the studies were not pooled. When the percentage weight loss in excess of placebo was compared across all of the reported drugs, phentermine appeared to have a weight loss advantage (8.1% of baseline weight lost) over sibutramine (5.0% of baseline weight lost), orlistat (3.4% of baseline weight lost) and diethylpropion (-1.5% of baseline weight – i.e., weight gain). However, the high between-group variation in completion rates and other study variables make these comparisons of doubtful value.

In 2002, Haddock et al., in a meta-analysis of four decades of published randomised trials of pharmacotherapy for obesity, identified nine studies of phentermine published between 1969-1992. The resulting meta-analysis of six eligible randomised studies, comprising 386 participants with a mean follow-up of 13.2 weeks, reported a significantly greater weight loss for phentermine than the placebo (effect size <0.60). There was a mean weight loss of 2.8kg for the placebo group and 6.3kg for the group treated with phentermine. The overall difference in weight loss averaged 3.6 kilograms over the study period, see Table 6b. Most of the patients (>85%) in the reported trials were female.

Table 6b. Phentermine vs. placebo post treatment outcomes, Haddock et al., 2002

Number post test Mean Weight loss (kg) Drug

average dose

(dose range)

Studies

Subjects Duration

(Wks) Placebo

(range)

Phentermine

(range)

Placebo

(range)

Phentermine

(range)

D-P Kg

(range)

Phentermine 27.7mg/d

(15-30mg/d) 6 386 13.2 (2.24) 29.4 (12-74) 32(15-76) 2.8 (1.5-5.2) 6.3(3.6-8.8) 3.6(0.6-6.0)

When the treatment effect size for phentermine was compared to that obtained for other drugs in the study, the effect size for phentermine was second only to sibutramine and higher than either orlistat or diethylpropion. However, all confidence intervals overlapped and there were significant design differences between the studies.

There was no overall effect of treatment length for drugs evaluated in this study, suggesting an early treatment impact for most of the drugs. However, phentermine correlation results for this variable were large and it was suggested that treatment length may influence phentermine’s effect size.


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Follow-up outcome analysis, carried out after the formal study completion and treatment had stopped, reported a placebo subtracted weight losses of 2.43kg and 2.37kg for phentermine and sibutramine respectively with unweighted effect sizes of 0.81 and 1.05 respectively. These results were based on a very small number of studies. Overall, the size effect was modest (less than 0.80) and the placebo subtracted weight loss was also modest <4kg.

Phentermine combinations

In 1996, phentermine which was introduced into clinical practice more than 25 years ago, was administered with the newly introduced fenfluramine in the combination known as “Phen-Fen”. Following reports of cardio valvopathy associated with this combination fenfluramide was withdrawn from the market the following year (Rothman and Baumann 2000; Rothman et al. 2000). There was no evidence that phentermine was responsible for these serious adverse events (Hensrud et al. 2003). Studies that included this drug combination have not been included in this review.

In 1999, Bradley et al. examined the use of phentermine and bupropion in combination for weight loss. This randomised, double-blind, placebo-controlled trial recruited 44 obese (>30kg/m2) patients and ran for six months. Patients were randomly assigned in a double-blind fashion to receive either phentermine 30mg + placebo or phentermine 30mg + bupropion SR (sustained release), 150mg twice daily. Both groups followed a 1200-calorie diet which included liquid meal replacement products. After six months, both groups of patients had lost more than 12% of their initial body weight. There were no serious complications or adverse effects noted over the period. Although there was no weight loss advantage in adding bupropion to phentermine, the Beck Depression Index scores improved in the groups taking bupropion. The study investigators concluded that bupropion might be a useful adjunct to phentermine in obese patients subject to mood swings and/or sub-clinical depression.

Diethylpropion: weight loss and co-morbidity risk reduction

Diethylpropion is available as Tenuate 25mg t.i.d. and Tenuate Dospan 75mg extended release taken once a day. The longest eligible study was carried out by Silverstone in 1968 and reported in a systematic review of long-term pharmacotherapy of obesity by Glazer (2001). Two shorter trials were also reported in this comparative review, see Table 7.

Table 7. Diethylpropion effectiveness studies, Glazer et al., 2001

Weight loss kg Study Year

Follow-up

period Drug Placebo

D-P

Kg P value

Silverstone 1968 6 month 7.0 8.7 -1.7 NR 1 year 8.9 10.5 -1.5 NR Deramos 1964 6 months 7.8 1.9 5.9 >0.05 McKay 1973 6 months 11.7 2.5 9.2 <0.01

Data were reported in these trials for a total of 30 patients treated with diethylpropion for six months and five patients treated for 12 months. Results varied considerably for these small studies with one study reporting inferior weight loss for diethylpropion compared to the placebo, one reporting higher, but non-significant, weight loss for diethylpropion compared to the placebo and the other reporting significantly higher weight loss for the diethylpropion compared to the placebo (McKay 1973). Diethylpropion was reported to have few stimulant-related adverse events but weight loss beyond six months was not observed with these patients.


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Relatively rapid tolerance to the drug’s anorectic effects was reported. In a comparison of the efficacy of diethylpropion with phentermine, sibutramine and orlistat, diethylpropion was the only drug to record a weight gain. However, the between-study heterogeneity was high and the diethylpropion study comprised only five subjects making the validity of the comparison doubtful and its usefulness limited.

In 2002, Haddock et al., in an analysis of four decades of published randomised trials of pharmacotherapy for obesity, critically reviewed 13 studies of diethylpropion published between 1965-1983 (Haddock et al. 2002), see Comparative Studies in Evidence Table 27. Nine of these studies were employed in a meta-analysis, see Table 8 below.

The majority of patients were female (88%) and most studies used some form of life-style management program. Some of the studies included in the analysis had no weight loss or had weight gain against the placebo as evidenced by the negative values in the drug-placebo value range. Overall, however, diethylpropion produced a greater weight loss than the placebo with an effect size of approximately 0.6. The 95% confidence intervals for diethylpropion overlapped with sibutramine, which was the drug that produced the largest effect (i.e., > 0.80), suggesting that the effect size difference between the drugs was not significantly different.

Table 8. Diethylpropion vs. placebo post treatment outcomes, Haddock et al., 2002

Number post test Mean Weight loss (kg) Drug

(dose) Studies

Duration

(wks) Placebo DP Placebo DP

D-P

(kg)

Diethylpropion 9 17.6(6-52) 21.2(5-32) 18(4-29) 3.5 (-04-10.5) 6.5(1.9-13.1) +3.00

(-1.6-11.5)

DP=diethylpropion, D-P=drug minus placebo

When compared with 12 weeks of phentermine treatment (n=50), diethylpropion (n=49) patients lost 6.3kg against 8.3kg for phentermine (ns) with an effect size of 0.574. An analysis incorporating all drugs suggested that increasing length of treatment did not lead to more weight loss and overall, weight loss attributed to pharmacological intervention for obesity was considered to be modest – i.e., <4.0kg. No data were reported on the effect of diethylpropion of obesity related co-morbidities in this study.

Orlistat: weight loss and co-morbidity risk reduction

A comprehensive literature search for randomised, placebo controlled, double-blind trials or systematic reviews, meta-analyses or HTAs of such studies published between January 1996-July 2004 identified 10 systematic reviews (Arterburn and Hitchcock 2001; Avenell et al. 2004; Foxcroft and Milne 2000; Glazer 2001; Haddock et al. 2002; Hensrud et al. 2003; Heymsfield et al. 2000; Leung et al. 2003; O'Meara et al. 2001; Padwal et al. 2004) and seven additional trials not included in the systematic reviews (Derosa et al. 2003; Halpern et al. 2003; Hanefeld and Sachse 2002; Krempf et al. 2003; Muls et al. 2001; Rissanen et al. 2001; Torgerson et al. 2004), see Table 9 (overleaf). These studies are further summarised in Evidence Tables 3-13, 26 and 27.

There was a good deal of overlap between the systematic reviews and HTAs in terms of the studies reviewed. All limited their reviews to randomised, placebo-controlled, double-blind trials of obese or overweight and obese individuals. The trials comprised mixed risk populations including healthy obese, diabetic and hypertensive patients. Two of the reviews permitted studies of any duration to be included in the review (Hensrud et al. 2003; O'Meara et al. 2001).


24

Table 9. Summary of publications reporting the effectiveness of orlistat for weight loss in overweight and obese participants

Study Size Study population Studies* Patients Study type Code Duration Health technology assessment, systematic reviews, Cochrane reviews, meta-analyses Avenell 2004 Obese Mixed 8 3885 HTA LT At least 1 year Padwal 2004 Obese Mixed 11 6021 CR LT At least 1 year Hensraud 2003 Obese Mixed 10 NR HTA MT Any Arterburn 2003 Obese mixed 6 1836 SR MT Any Leung 2003 Obese mixed 7 1830 SR MT More than 6 months Glazer 2001 Obese mixed 5 742 SR LT At least 9 months treatment Haddock 2001 Obese mixed 6 NR MA ST 48 weeks O’Meara 2001 Obese Mixed 11 5124 SR MT Any Foxcroft 2000 Obese mixed 3 551 SR LT More than 1 year Heymsfield 2000 Obese mixed 3 675 SR/MA LT 2 year follow-up Randomised, placebo-controlled, double-blind clinical trials Torgeson 2004 Obese diabetic 1 3305 RPCDBT LT 4 years Halpern 2003 Obese1 diabetic 1 365 RPCDBT ST 24 weeks Krempf 2003 Health obese 1 696 RPCDBT LT 10 months Dersosa 2003 Obese hypercholesterolemic 1 99 RPCDBT LT 1 year Rissanen 2001 Healthy obese 1 55 RBCDBT LT 1 year Hanefield 2002 Obese diabetic 1 492 RPCDBT ST 48 weeks Muls 2001 Obese hypercholesterolemic 1 441 RPCDBT ST 24 weeks + 24 weeks

* Published studies, LT=long-tern, ST=short-term, MT=mixed term, RPCDBT=randomised placebo-controlled, double-blind trial, CR=Cochrane review, SR=systematic review, MA=meta-analysis, HTA=health technology assessment.

Most of the reviews were interested in the long-term effects of orlistat in the treatment of obesity and therefore restricted their studies by duration of treatment or follow-up. Most required participants to be treated for at least one year.

The patient populations varied considerably between studies, as did the reporting of results. Most studies reported absolute weight loss or % change from baseline rather than the more clinically useful weighted mean difference between treatment and control and the proportion of patients with ≥ 5% and ≥ 10% weight loss. Later studies intended to report clinically useful endpoints more often than earlier studies. Study results were reported for three patients groups:

• otherwise healthy overweight/obese patients

• patients with type 2 diabetes/glucose intolerance

• patients with hypercholesterolemia.

One study was a Cochrane Review (Padwal et al. 2004) and one was a National Institute for Clinical Effectiveness (NICE) HTA (O'Meara et al. 2001). The three most recent reviews (Avenell et al. 2004; O'Meara et al. 2001; Padwal et al. 2004) assessed the evidence presented in a large number of randomised, placebo-controlled, double-blind trials with total populations of 3,885, 5,124 and 6,021 respectively.

Overall effectiveness of orlistat in obese patients (mixed risk)

The most recent meta-analysis of nine randomised placebo-controlled, double-blind studies of the effect of orlistat for the treatment of obesity was conducted by Avenell et al., (2004) for the NHS R&D HTAprogram in the UK. The results of the meta-analysis of these studies are summarised in Table 10 (overleaf).

EV

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25

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fixe

d e

ffec

ts (

95%

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ear

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TC

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27 (p

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53 (p

=0.7

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0.00

001)

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= 24

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399

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23 (p

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ll ef

fect

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01)

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–0.1

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= 13

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(p=0

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001)

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= 19

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001)

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= 5.

92 (p

=0.0

5)

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stat

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55

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36

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dies

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fect

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= 0.

31 (p

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6)

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cebo

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37

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dies

=3

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est f

or o

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ll ef

fect

z=

1.84

(p<0

.07)

-0

.04

(95%

CI,

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7 to

–0.0

05)

Π2

= 10

.14

(p=0

.006

) O

rlist

at n

=557

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lace

bo n

=537

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tudi

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t for

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68(p

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R

-0

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(95%

CI,

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4 to

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= 4.

15 (p

=0.1

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stat

n=5

57

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dies

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est f

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ll ef

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(p=0

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(95%

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8 to

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= 9.

39 (p

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02)

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stat

n=4

51

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cebo

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dies

=2

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est f

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ll ef

fect

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=0.0

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(95%

CI,

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8 to

–0.

24)

Π2

= 0.

22(p

=0.6

4)

Orli

stat

n=4

51

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cebo

n=4

48

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dies

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est f

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ll ef

fect

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09)

¥ =

decr

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in H

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ent g

roup

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urs

the

cont

rol g

roup

.


26

Over a period of 12 months, obese patients treated with orlistat lost on average 3.01 kilograms more than the placebo group. The difference between the two groups increased slightly at 24 months with orlistat treated patients losing on average 3.26 kilograms more than the placebo group; at both time points the difference was significant.

At 12 months, there was also significant and favourable differences reported for the orlistat treated group in terms of total cholesterol, LDL-cholesterol, blood pressure, HbA1c and fasting plasma glucose. A non-significant decrease in triglycerides was reported in favour of the treatment group and an unfavourable decrease in HDL-cholesterol. This pattern was repeated in the assessments undertaken at 24 months with the exception that SBPreduction was less marked and did not reach significance. HbA1c was not reported at 24 months.

A chi squared test for between-study heterogeneity revealed significant heterogeneity in weight loss, triglyceride, HbA1c, fasting plasma glucose and DBP at the 12-month assessment. This heterogeneity persisted between a much smaller number of studies for triglycerides and DBP at 24 months. The high between-study heterogeneity is likely to have arisen as a consequence of the inclusion of some studies with diabetic and hypercholesterolemic participants as well as studies comprising only healthy obese participants. Where possible, these sub-groups have been reported separately in the current review.

Clinical-effectiveness of orlistat in otherwise healthy populations

Three studies (two RCTs and a meta-analysis of three RCTs) reported differences in weight loss between orlistat and the placebo in healthy obese populations. All of the studies reported the difference in mean weight loss or % weight lost from baseline between the treatment and placebo groups. In addition, two studies (Krempf et al. 2003; Torgerson 2004) reported the proportion of patients with clinically important weight loss – i.e., weight loss ≥ 5% and ≥ 10% of their original weight. The reported results are shown in Table 11.

Table 11. Orlistat 360mg/d weight loss in otherwise healthy obese populations

Study Year No of studies

No of subjects

Mean difference in % change

Mean Difference WL (kg)

% with WL≥5%

% with WL≥10%

-2.6* -2.9* NR NR Krempf (RCT) 2003 1 95 -3.5** -3.6** 58 NR

NR -4.4a 73a 41a Torgerson (RCT) 2004 1 3305 NR NR 53b 26b

Heymsfield (MA) 2000 3 675 -2.9* -2.5* NR NR * at one year, intention to treat (ITT) ** 18 months ITT, a difference at one year non-diabetic b difference at four years WL =weight loss

Reporting was variable across the three studies and no study reported all of the relevant weight loss parameters. Participants treated with orlistat lost a larger proportion of their original weight (2.6-2.9% at 12 months, 3.5% at 18 months) than those treated with the placebo, they also lost a greater amount of weight overall. Only two of the studies reported the proportion of patients who lost ≥ 5% of their original weight (Krempf et al. 2003; Torgerson et al. 2004). At one year, 58-73% of treated patients had lost 5% or more of their baseline weight this was a significantly higher proportion than the placebo treated group.

Clinical effectiveness of orlistat in patients with hypercholesterolemia

Two RCTs, not reported in the systematic reviews, examined the effectiveness of orlistat in reducing lipid and blood pressure parameters in patients with hypercholesterolemia, see Table 12 (overleaf).


27

The approach to the reporting of the results and the number of parameters reported differed in the two studies with one reporting mean placebo minus drug differences, the other reporting differences for each group from the baseline value. However, both studies indicated a significant improvement in LDL-cholesterol, and total cholesterol. There was also evidence of a significant improvement in systolic and diastolic blood pressure. There was no evidence for improvement in the trigylceride and HDL-cholesterol profiles.

Table 12. Orlistat 360mg/d weight loss in patients with hypercholesterolemia, results after one year

Study Year No of

Studies (subjects)

Group Weight loss

LDL-C mg/dl

HDL-C mg/dl

Total-C mg/dl

TG mg/dl

SBP mmHg

DBP mmHg

LMS difference from placebo on % difference from baseline Muls RCT

2001 1 (411) P-O -3.03kg* -10.00 -7.56 -8.37 -0.63 NR NR

Mean % change from baseline for each group 1(23) Placebo -7.6kg** -10.8 +2.4 -12.1 -14.8 -3.0% -2.4%

Derosa RCT 2003

1(25) Orlistat -8.6kg** -19.0 +2.3 -15.0 26.5 -4.6% -4.7% Bold = significant difference from placebo *difference Placebo-Orlistat ** from baseline, LMS = least mean square

Patients with type 2 diabetes or impaired glucose intolerance

A European Medicine Evaluation Agency (EMEA) report of orlistat, comprised a meta-analysis of seven randomised, double blind, placebo-controlled trials of one to two years involving 4,188 diabetic and non-diabetic patients, see Table 13. A higher proportion of diabetic and non-diabetic patients receiving orlistat treatment experienced clinically significant weight loss (≥ 5% or ≥ 10% of baseline weight) than the placebo group. This difference was significant in all comparisons except for a weight loss of ≥ 10% for diabetic patients receiving orlistat vs. placebo. Overall, diabetic patients consistently lost less weight than their non-diabetic counterparts regardless of the treatment they received.

Table 13. Weight loss with orlistat: results of 1 year clinical trials, European Medicine Evaluation Agency.

Non-diabetic Type2 diabetes

Weight loss Orlistat* + diet

N=1561

Placebo+ diet

N=1119 P value

Orlistat* + diet

N=163

Placebo+ diet

N=159 P value

≥5% weight loss 45.3% 23.4% <0.001 30.2% 13.2% <0.001 ≥10% weight loss 20.2% 8.3% <0.001 9.3% 4.4% ns * 360mg/d

Weight loss in diabetic and non-diabetic participants was also reported in a systematic review by O'Meara et al. (2001). In a pooled analysis, non-diabetic participants who had taken orlistat 360mg/d had a mean weight loss difference (placebo minus drug) of 2.9kg compared to 1.8kg for the diabetic group; both groups lost significantly more weight than the placebo group.

A meta-analysis of studies examining glucose tolerance and changes in status from randomisation reported the weight loss achieved with orlistat 360mg/d (Heymsfield et al. 2000), see Table 14.

Table 14. Orlistat 360mg/d in diabetic patients or patients with glucose intolerance

Study Year Studies

(no subjects)

Glucose intolerant

Participants

WL - Change from baseline (kg)

% Progressing

% Improvement

IGT-NGT

Heymsfield Meta-analysis

2000 2 (675) Placebo group Orlistat group

3.79(±4.1) 6.27(±0.41)

7.6 3.0

49 72

WL=weight loss, IGT=impaired glucose tolerance, NGT=normal glucose tolerance, kg=kilogram


28

Both placebo and orlistat treated groups exhibited a significant change in weight from their baseline body weight. The treatment group, however, had a much higher total weight change, a higher proportion of patients improving their glucose tolerance and only half as many patients with IGT at baseline progressing to diabetic status.

Two short-term RCTs not otherwise reported in the systematic reviews, examined the effects of orlistat in obese diabetics (Halpern et al. 2003; Hanefeld and Sachse 2002), see Evidence Tables 8 and 9. In a 24-week study of 365 obese, non-insulin dependent diabetic patients (Halpern et al. 2003), the difference in weight loss between the orlistat and placebo group was 1.6kg (least squares mean difference, p=0.0003, ITT analysis) with 30% of orlistat and 17% of placebo patients losing ≥ 5% of their initial body weight (p=0.003). There were also significant differences (least square, mean difference, orlistat minus placebo) in total cholesterol (p=0.0001) and LDL-cholesterol (p=0.0002). HDL-cholesterol levels improved in the placebo group but not in the orlistat group (p=0.038). There was significant improvement in glycaemic control in the orlistat group with significant decreases in HbA1c (p=0.04), fasting plasma glucose (p=0.036) and post prandial glucose (p=0.05).

In a 48 week study of 492 overweight patients with type 2 diabetes treated with sulphonylurea therapy, Hanefeld et al., (2002) reported a weight loss of 4.6kg in the placebo group and 6.3kg in the orlistat group (p=0.07). Significantly more patients achieved a weight loss of ≥ 5% with orlistat than placebo (51.3% vs. 31.6% p=0.0001). There were also significantly higher improvements in HbA1c (p=0.001), fasting glucose (p=0.004), post prandial glucose (p=0.003) and LDL-cholesterol (p<0.05) in the patients treated with orlistat. There were no significant between-group differences in trigylcerides or a reduction in blood pressure. HDL-cholesterol did not change in the orlistat group, the placebo group showed an improvement over its baseline level (p=0.02).

Sibutramine: weight loss and co-morbidity risk reduction

A comprehensive literature search for randomised, placebo controlled, double-blind trials or systematic reviews, meta-analyses or HTAs of such studies, published between January 1996-July 2004 identified 10 systematic reviews (Avenell et al. 2004; Glazer 2001; Haddock et al. 2002; Hensrud 2004; Kim et al. 2003; Leung et al. 2003; McTigue et al. 2003; Nisoli and Carruba 2003; O'Meara et al. 2002; Padwal et al. 2004) and seven additional randomised trials not included in the systematic reviews (Berkowitz et al. 2003; Gokcel et al. 2001; Hauner et al. 2003; Hazenberg 2000; McNulty et al. 2003; Tambascia et al. 2003; Wadden et al. 2000), see Table 15 below. These studies are summarised in Evidence Tables 14-27.

Table 15. Eligible studies reporting the effectiveness of sibutramine

Study Size Study population Studies* Patients Study type Code Duration Health technology assessment, systematic reviews, Cochrane reviews, meta-analyses Avenell 2004 Obese Mixed 5 1455 HTA LT At least 1 year Padwal 2004 Healthy obese 3 929 CR LT At least 1 year Hensraud 2003 Obese Mixed 11 >1924 HTA MT Any Arterburn 2003 Obese mixed 6a 1975 SR MT Any Leung 2003 Obese mixed 10 3150 SR MT More than 6 months Glazer 2001 Obese mixed 1* 160 SR LT At least 9 months treatment Haddock 2001 Obese mixed 4 NR MA ST 8-26 weeks, mean=15.5 O’Meara 2002 Obese Mixed 11 2037 HTA MT Any McTigue 2003 Obese Mixed 7 2815 MA MT 6-12 months Nisoli 2003 Obese Mixed, safety 19 4039 SR MT 8-52 weeks** Kim 2003 Obese mixed 21(31a) 4528 MA MT 8-52 *in period and reported elsewhere, ** 1 study =5.5 hrs, a 21 published studies with 31 separately reported groups Randomised, placebo-controlled, double-blind clinical trials McNulty 2003 Obese diabetic 1 195 RPCDBT LT 12 months Gokcel 2001 Obese diabetic 1 60 RPCDBT ST 6 months Hazenberg 2000 Obese hypertensive 1 127 RPCDBT ST 12 weeks Berkowitz 2003 Healthy Obese adolescents 1 82 RPCDBT LT 12 months


29

Table 15. Eligible studies reporting the effectiveness of sibutramine (continued)

Study Size Study population Studies* Patients Study type Code Duration Randomised, placebo-controlled, double-blind clinical trials Tambascia 2003 Healthy obese 1 40 RPCDBT ST 24 weeks Hauner 2004 Healthy obese 1 389 RPCDBT LT 54 weeks Sibutramine and orlistat Wadden 2000 Obese mixed 1 34 RPCDBT ST 16 weeks

ST=short-term, LT=long-term, MT=mixed term, HTA = health technology assessment, CR = Cochrane review, SR = systematic review, MA = meta-analysis, RPCDBT = Randomised placebo controlled, double blind trial.

The patient populations varied considerably between trials as did the study size and duration. Study populations included healthy overweight and obese adults, mixed male and female participants, female only participants, healthy overweight adolescents, obese patients with poorly and well regulated type 2 diabetes, and obese hypertensive patients, patients with dyslipidemia. One study was carried out solely in a primary care setting.

Studies size varied between 34-389 for RCTs and 160-4,528 for systematic reviews, meta-analyses and HTAs. Reporting parameters also varied, some studies reported weight loss in kilograms and % weight loss from baseline weight for placebo and sibutramine, others reported the difference in weight change between the two. The reporting of clinically important weight loss – i.e., weight loss of ≥ 5% was variable.

One systematic review focussed attention on adverse events and side effects reported in 19 RCTs of sibutramine (Nisoli and Carruba 2003), two were NICE Health Technology Reviews (O'Meara et al. 2002) and one was a Cochrane Review (Padwal et al. 2004). The 2003 review of safety and side effects is reported separately in the section on safety and side effects of sibutramine therapy (see page 41). The most recent high quality HTA (Avenell et al. 2004) reported results obtained in a primary care setting.

There was considerable duplication of studies and reporting overlap between the systematic reviews, HTAs and MAs; this overlap and the heterogeneity of the reported parameters made it difficult to summarise and compare these studies.

The most recent HTA (Avenell et al. 2004) reported on five long-term studies including the Sibutramine Trial in Obesity Reduction and Maintenance (STORM), see Table 16 (overleaf). This was one of the most consistently reported studies with weighted mean differences between sibutramine reported for weight loss and risk factors. It was also a multi-therapy study which allowed direct comparison to be made between sibutramine and a number of other weight loss strategies including orlistat, see Table 17 and Table 21.

Over a period of 12 months, obese patients treated with sibutramine lost on average 4.12 kilograms more than the placebo group (p<0.00001). There was also a significant difference in favour of sibutramine treatment reported for HDL-cholesterol (p=0.0004) and triglyceride levels (p=0.004) together with non-significant differences favouring sibutramine for LDL-cholesterol, HbA1c and fasting glucose levels. There were overall differences in diastolic and SBP levels that favoured the placebo group; the difference was significant for DBP (p=0.0005). In both instances, blood pressure levels on average rose during the treatment period. There was no significant between-study heterogeneity at 12 months.

Results were reported for the STORM study at 18 months. Significant differences in favour of treatment were reported for weight loss (3.40kg, p<0.00001), triglycerides (p=0.02) and HDL-cholesterol (p=0.002). Differences in total cholesterol, LDL-cholesterol, HbA1c and fasting glucose levels also favoured treatment but the differences did not reach statistical significance. Blood pressure at 18 months was not reported.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

30

Tab

le 1

6.

Met

a-an

alys

is o

f R

CT

s fo

r S

ibut

ram

ine,

lon

g-t

erm

stu

die

s ≥

1 y

ear

(NIC

E H

TA

, Ave

nel

l May

200

4)

T

ota

l Wei

gh

ted

Mea

n D

iffe

ren

ce b

etw

een

dru

g a

nd

pla

ceb

o, o

ver

all s

tud

ies,

fix

ed e

ffec

ts (

95%

CI)

Stu

dy/

Y

ear

∆ W

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=0.0

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utra

min

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57 (p

=0.1

2)

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62(p

=0.5

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32

Sibutramine therapy for otherwise healthy overweight individuals

Three studies enabled an assessment of the effect of sibutramine in participants without significant obesity related co-morbidities, see Table 17. The mean difference in the percentage weight loss between sibutramine and placebo-treated patients was between 3% and 5% more in sibutramine treated patients (p=<0.05), a similar pattern was apparent for absolute weight loss.

Two of the three studies reported the proportion of patients with ≥ 5 % and ≥ 10% weight loss with difference between the treatment and placebo groups ranging from 21-34% for patients losing ≥ 5% and 15-21% losing ≥ 10% of their initial body weight. In both instances, the difference was significant. These results differ little from the overall picture obtained from the meta-analysis of trials with both low and high risk participants, see Table 17.

Table 17. Studies reporting the effectiveness of sibutramine in otherwise healthy overweight individuals

Study Year No of

studies (subjects)

Duration Dose Mg/d

Mean difference

in % change (s.d.)

Mean difference

Weight loss kg (s.d.)

% Difference WL ≥5%

(s.d.)

% Difference WL ≥10%

(s.d.) Padwal (SR) 2004 3(929) ≥1 years 15-20 4.6(3.8-5.4) a 4.3 (3.6-4.9) a 34(28-40) 15(4-27)

10 -6.1b -5.6b NR NR Tambascia (RCT) 2003 1(40) 24 weeks

- +1.1c +0.9c NR NR Hauner (RCT) 2003 1(389) 54 weeks 15 3.4 3.0(-1.4t o-4.6) a 21.2c 21.8a

a difference from placebo, b difference from baseline in sibutramine group, c difference from placebo. RCT=randomised controlled trial. WL=weight loss. Bold = a significant difference, s.d. = standard deviation.

Sibutramine therapy for patients with type 2 diabetes

Two RCTs reported the effects of sibutramine treatment on weight loss, metabolic control and blood pressure in patients with type 2 diabetes, see Table 18.

Table 18. Studies reporting the effectiveness of sibutramine in individuals with type 2 diabetes

Mean difference placebo-drug, bold = significant difference Study Year

Dose Mg/d

N= ≥5%

WL ≥10% WL

LDL-C mg/dl

HDL-C mg/dl

Total-C mg/dl

TG mg/dl

SBP mmHg

DBP mmHg

Pulse rate

15 46 14 0.0 0.1 0.0 -0.2 4.6 2.8 5.9 McNultya

(RCT) 2003

20 195

65 27 0.1 0.1 0.1 -0.3 -1.3 0.0 5.8 Gokcel 2001 10 60b NR NR 7.6 0.96 20.4 46.4 ns SR SR

a study patients were receiving metformin b females with poorly regulated diabetes. NR=not reported, SR=significant reduction no data reported.

Significantly more patients in the sibutramine group lost ≥ 5% and ≥ 10% of their initial body weight than the control group. Triglycerides were significantly reduced in the treatment group in one study (McNulty et al. 2003), differences between the groups in terms of cholesterol levels were not significant. Blood pressure and pulse rate increased significantly in the treatment group at a dose level of 15mg/d; in a few individuals blood pressure increases were particularly marked. The authors noted that blood pressure increase tended to be offset by weight loss; only 37% of patients who achieved a ≥ 10% weight loss showed a rise of ≥ 5mmHg in SBP.

A sibutramine dose-response effect was observed in one study (McNulty et al. 2003) with doses between 15-20mg/d eliciting increases in the proportion of participants losing 5% and 10% of their body weight.

In an earlier study, Gokcel et al. (2001) reported a 8.7kg greater weight loss for sibutramine after six months of treatment (drug-placebo, p<0.0001). All risk parameters, except SBP, significantly improved with treatment.


33

A number of other eligible studies (Leung et al. 2003) reported stratification and sub-group analyses that included diabetic patients; all reported significant weight loss differences between sibutramine and placebo treated participants.

Sibutramine therapy for patients with hypertension

The effectiveness of sibutramine in a patient population of mild to moderately obese hypertensive patients was examined in one RCT (Hazenberg 2000). After 12 weeks of treatment with 10mg sibutramine, the treatment groups had lost 2.4% more of their baseline body weight than the placebo group (p=0.002). In addition, 44% of treated patients had lost more than 5% of their baseline body weight compared to 17% in the placebo group (p=0.01). Blood pressure reductions of 4-5mmHg were observed in both groups. Sibutramine patients showed a slightly lower mean improvement than the placebo group; differences between the groups were not significant.

A meta-analysis of 21 randomised, placebo-controlled, double-blind trials to determine the effect of >5mg/d sibutramine on weight loss and blood pressure was carried out by Kim et al., in 2003. The patient population was extremely heterogeneous and co-morbidities of diabetes, hypertension, hyperlipidemia were allowed. Sibutramine had a significant effect on weight loss with an effect size6 of -1.0 (range, -1.17 to -0.84) but increased blood pressure significantly. The net increase in blood pressure attributable to sibutramine was 1.6mmHg and 1.8mmHg for SBP and DBP respectively. Larger increases in blood pressure were observed in heavier and/or younger participants with an effect size of 0.16 (0.08-0.24) and 0.26 (0.18-0.33) respectively. The small increases in blood pressure observed were not considered to be important in normotensive patients or patients with well controlled hypertension being treated in a clinical setting. However, the increase was considered to be clinically important in patients who had borderline or high blood pressure.

Most other studies of sibutramine actually excluded patients with hypertension or cardiovascular disease, others only allowed well-controlled hypertension (Berkowitz et al. 2003; Gokcel et al. 2001; Hauner et al. 2003; McNulty et al. 2003; Padwal et al. 2004).

The use of sibutramine in adolescents

A recent dose ranging, randomised trial of sibutramine and behaviour therapy in obese adolescents aged 13-17 years reported an average weight loss of 7.8kg (s.d.=6.3kg) and 8.5% (s.d.=6.8 %) in an ITT analysis at six months (Berkowitz et al. 2003). The sibutramine treated children lost significantly more weight than the placebo treated group. Medication was reduced in 23 cases and discontinued in 10 cases to manage increases in blood pressure, pulse rate and other symptoms. The investigators concluded that medications for weight loss in children should only be employed in the context of a clinical trial until more extensive safety and efficacy data were available, see Evidence Table 19.

Sibutramine dose ranging studies

The dosage of sibutramine used in most of the studies included in this review varied between 5-30mg/d. In some cases a sub-group analysis was carried out for different dose levels, this was however uncommon. One dose ranging study (Bray et al. 1999), was identified in a systematic review of 10 RCTs by Leung et al., (2003).

6 Effect size = the standardised difference of changes in weight loss from baseline between the treatment and control group. An effect size of >0.80 in this context may be considered to be moderate, and effect size >1.0 may be considered to be large, however, interpretations of effect size importance may vary.


34

Doses of sibutramine ranging from 1-30mg/d in 1047 obese patients produced a significant dose related weight loss at six months, see Table 19.

Table 19. Sibutramine dose ranging studies. Bray 1999 reported in Leung et al., 2003

% losing at least 5 or 10 % of base weight

Treatment group Dose mg/d

% Weight loss

5%

10%

Discontinuation due to

Adverse events %

SBP Change mmHg

DBP Change mmHg

Pulse Change bpm

Placebo - 1.2 19.5 0.0 8 -0.8 1.7 0.6 1 2.7 25.3 10.5 11 0.3 1.2 0.3 5 3.9 37.4 12.1 5 2.1 2.5 3.3 10 6.1 59.6 17.2 9 2.8 4.2 6.0 15 7.4 67.3 34.7 11 2.7 3.4 6.1 20 8.8 71.9 38.5 13 4.0 5.0 7.0

Sibutramine 24 weeks N=1047

30 9.4 77.2 45.5 18 3.3 4.1 5.3 Bold = significant difference from placebo

In this study, weight loss at four weeks was found to be predicative of weight loss at six months and the proportion of patients withdrawing from the trial because of adverse events increased with increasing sibutramine dose. Blood pressure and heart rate increased with increasing doses of sibutramine up to 20mg/d. This trend was not followed in the 30mg/d group, however, it is not clear if susceptible patients had withdrawn at this stage or if there was an ITT analysis. Treatment related adverse events that resulted in discontinuation were all more common in the 30mg/d group and included hypertension, palpitations, tachycardia, insomnia and dyspepsia.

Comparative drug studies

Seven systematic reviews of pharmacotherapy for obesity between 2001 and 2004 compared the effectiveness of two or more of the drugs being examined in the current review (Arterburn et al. 2004; Avenell et al. 2004; Glazer 2001; Haddock et al. 2002; Hensrud et al. 2003; McTigue et al. 2003; Padwal et al. 2004), see Table 20.

Table 20. Eligible studies comparing two or more review drugs

Study Phentermine Diethylpropion Orlistat Sibutramine Other weight loss therapies reported Avenell, 2004 (National Institute For Clinical Effectiveness) X X 3333 3333

Metformin Selective serotonin reuptake inhibitors (SSRIs) Acarbose VLCDs LCDs Protein sparing modified fast Diet, exercise, behaviour therapy

Hensraud, 2003 (ICSI Technology Assessment Committee)

3333 x 3333 3333

Ephedrine + Caffeine

Arterburn, 2003 McTique, 2004 (US Preventative Services Task Force)

3333 3333 3333 3333

Mazindol Metformin Fluoxetine

Haddock, 2002 (USA)

3333 3333 3333 3333

Dexamphetemine Benzocaine Benzphentermine Dexfenfluramine Fenfluramine Fluoxetine Mazindol Methamphetamine Phendimetrazine Phenylpropanolamine Sertaline

Glazer, 2001 (USA)

3333 3333 3333 3333 Mazindol Fluoxetine (SSRI) Sertaline (SSRI) Fenfluramine Dexfenfluramine

Padwal, 2004 (Cochrane Review, Canada)

X X 3333 3333 None


35

Avenell et al., May 2004. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement.

This extensive and well-reported review included a meta-analysis of all randomised, placebo-controlled, double-blind, efficacy trials of obesity therapy with a follow-up of at least one year. Pharmacological and non-pharmacological interventions were examined. The objective of the review was to identify therapies that achieved weight reduction, risk factor modification or improved clinical outcomes. A summary of the effects of sibutramine and orlistat resulting from a meta-analysis of eligible trials is shown in Table 21. Phentermine and diethylpropion were not included in this review, as they are no longer recommended for anti-obesity therapy in the UK. The reported results for low fat diets (LFDs) are also included as they can include meal replacement programs.

Table 21. Summary of the comparative effectiveness of orlistat, sibutramine and low fat diets that may include meal replacements

Therapy Assessed at Weight change from baseline

(kg)

95% Confidence

Interval Change in risk factors

Sibutramine + diet 18 months -3.40 -4.45 to –2.35 Beneficial except for DBP Orlistat + diet 24 months -3.26 -4.15 to –2.37 Beneficial Low Fat diets* 12 months -5.31 -5.86 to –4.77 Beneficial

* Can include meal replacement programs

Weight loss from baseline was greatest with LFD followed by sibutramine and orlistat. However, treatment duration varied between 12-24 months making it difficult to make a valid comparison of performance. A beneficial change in risk factors was reported for all three therapies with the exception of sibutramine and DBP. A weight loss of 10 kilograms was reported to be associated with a fall in total cholesterol of 0.25mmol/l and a fall in DBP of 3.6mmHg; a 10% weight loss was associated with a fall in SBP of 6.1mmHg.

Hensud, 2003. Pharmacological approaches to weight loss in adults. Institute for Clinical Systems Improvement, Technology Assessment Report, February 2003.

Most of the long-term trials reported in this HTA have been reported elsewhere in the current report. However, the inclusion of some short-term trials of orlistat and sibutramine not reported elsewhere and a comparative summary of changes associated with a wide range of obesity-related risk factors merits its inclusion here. The reported weight change from baseline and the proportions of patients losing clinically significant amounts of weight with the two drugs are shown in Table 22.

Table 22. Summary of short-term weight loss trials of sibutramine and orlistat not otherwise reported in systematic reviews and HTAs.

Therapy Assessed at Weight change from baseline

(kg)

% of participants with a loss of ≥5% of initial body weight

% of participants with a loss of ≥10% of initial body weight

Sibutramine + diet 12-52 weeks -2.4-to -16.6 27-88% 6-76% Orlistat + diet 12 months -3.9 to –10.3 33-69% 10-39% 24 months -5.0 to –7.4 NR NR

Overall, 5-25% of participants failed to complete the pre-randomisation run-in phase of the studies and 9-54% of those randomised failed to complete the study (orlistat, sibutramine and placebo groups). The greatest benefits were reported for patients with co-morbidities such as


36

diabetes, these participants experienced less weight loss but important physiological benefits based on Class A and M levels of evidence7.

The type of weight loss programs that led to high proportions of patients achieving clinically important levels of weight reduction (>50% of patients losing ≥ 5% of their initial body weight and >30% of patients losing ≥ 10% of their initial body weight) were examined for predictors of this outcome. High performing programs were characterised by a number of features notably:

• a placebo run-in period that identified individuals that were willing and able to make changes in their nutritional and activity patterns

• regular monitoring in a clinical setting

• exclusion of patients with serious disease, major depression or substance abuse

• information on behaviour modification

• changing nutritional choices

• increasing physical activity.

Padwal et al., August 2003. Long-term pharmacotherapy for obesity and overweight. Cochrane Review.

Eight anti-obesity agents were reviewed in this study but only orlistat and sibutramine studies met the review inclusion criteria. All of the studies included in this review were also reviewed elsewhere but not necessarily in the same review and not reported in the same way.

On average, orlistat treated patients lost 2.7kg (95% CI: 2.3 to 3.1kg) or 2.9% (95% CI: 2.3 to 3.4%) and sibutramine patients 4.3kg (95% CI: 3.6 to 4.9kg) or 4.6% (95% CI: 3.8 to 5.4%) more weight than the placebo group. The number of patients who achieved at least 10% weight loss was 12% (95% CI: 8 to 16%) higher with orlistat than placebo and 15 % (95% CI: 4 to 27%) higher with sibutramine than placebo. Orlistat and sibutramine were reported as being “modestly effective in promoting weight loss” but with “interpretation limited by high attrition rates”.

Glazer, 2001. Long-term pharmacotherapy of obesity, 2000.

This systematic review included a comparative analysis of all of the drugs examined in the current review – i.e., phentermine, diethylpropion, orlistat and sibutramine. In addition, it evaluated some early studies of phentermine and diethylpropion not included in other reviews. The studies identified for review were considered to be too few and too heterogeneous to warrant a meta-analysis of their findings and an average weight loss was reported for each of the drugs across the relevant studies. Trials lasted between 36 to 52 weeks. Three of the four drugs reviewed in the current report, sibutramine, orlistat and phentermine, were considered to have shown weight loss efficacy in long-term trials, see Table 23 (overleaf).

7 Class A = randomised controlled trial, Class M = meta-analysis or systematic review.


37

Table 23. A comparison of the effectiveness of sibutramine, orlistat, phentermine and diethylpropion (Glazer et al., 2001)

Therapy

Weight loss attributable

to drugs

(kg)


to druga (%)

Sibutramine 4.3 5.0 Orlistat 3.4 3.4 Phentermine 7.9 8.1 Diethylpropion -1.5 -1.5

a weight loss in excess of placebo

Patients receiving phentermine and sibutramine achieved a clinically important weight loss – i.e., weight loss of ≥ 5%, orlistat patients achieved a more modest weight loss while patients treated with diethylpropion on average gained weight. The magnitude of the weight loss was supported by Level I evidence8 for orlistat (2 studies) and sibutramine (1 study) and by Level I/II/III evidence9 for phentermine. With the exception of one short-term study, the level of evidence reported for phentermine was below the standard required for the present report. The authors concluded that while the weight loss achieved with the aid of medication was modest, it was associated with important health and psychological benefits.

Haddock et al., 2002. Pharmacotherapy for obesity: a quantitative analysis of four

decades of published randomised clinical trials

This review considered 15 FDA approved medicines used for weight loss in the USA that included phentermine, diethylpropion, orlistat and sibutramine. The results of the meta-analysis of studies reported between 1960 and 1999 are shown in Table 24.

Table 24. A comparative study of the effectiveness of sibutramine, orlistat, phentermine and diethylpropion (Haddock et al., 2002)

Therapy Dosage Per day

(mg)

Weeks of any treatment

(range)

Number at post-test

drug (range)

Number at post test placebo (range)


to druga kg (range)

Mean effect sizec

Sibutramine 14.0 (10.0-20.0) 14.5(8-26) 27.3(15-52) 26.8(15-49) 3.5(2.4-5.1) 1.0 Orlistat 302.9 (190-360) 47.5(16-76) 236.9(46.7-657) 164.5(46-340) 2.08(0.30-4.2) 0.50 Phentermine 27.5 (15-30) 13.2 (2-24) 32(15-76) 29.4 (12-74) 3.6(0.6-6.0) 0.62 Diethylpropion 75 (75-75) 17.6(6-52) 21.2(5-32) 18(4-29) 3.0(-1.6 b -11.5) 0.60

a Drug-placebo b negative numbers for kilo changes indicate a weight gain. c reported in a figure and without consideration of study design differences, values in table approximate only. 0=no treatment effect.

Sibutramine produced the largest mean effect size in the meta-analysis with a significantly better weight loss than the other drugs. However, the 95% confidence intervals for the sibutramine estimate overlapped with diethylpropion and phentermine suggesting that there were no statistically significant differences between the effect sizes of these three drugs. Post treatment follow-up studies were reported for phentermine and sibutramine, patients treated with both drugs sustained a placebo subtracted weight loss of 2.43kg and 2.37kg and large effect sizes of 0.810 and 1.0510 respectively.

8 Level I evidence = randomised, double blind, placebo-controlled studies.

9 Level II/III evidence = double-blind, placebo-controlled study/blind comparison.

10 Effect sizes >0.80 produced by meta-analysis are considered to be in the “large” effects range.


38

None of the 15 drugs included in the meta-analysis exceeded a placebo subtracted weight loss of 4.0kg and none of the drugs were considered by the authors to have a demonstrated clear supremacy as an anti-obesity medication.

Arterburn, 2004. Obesity: What are the effects of drug treatment in adults?

An overview of RCTs and systematic reviews of RCTs, for nine drug treatments for obesity including phentermine, diethylpropion, orlistat and sibutramine was recently published by the British Medical Journal (Arterburn et al. 2004). All of the RCTs and systematic reviews assessed in the overview have been reported elsewhere and summarised in this review in the appropriate evidence tables. However, the study reported a useful summary of the evidence for effectiveness, harm and benefit for the study drugs and a number of key messages:

• no studies used the primary outcomes of functional morbidity or mortality and therefore the long-term effect of obesity drugs was not known

• in many studies there was insufficient evidence of effect because of high drop-out rates

• that overall diethylpropion, orlistat, phentermine and sibutramine had a favourable trade-off between benefits and harms, see Table 25.

Table 25. Weight loss drugs trade off between benefit and harm

Favourable trade off between benefits and harms

Unknown effectiveness Likely to be ineffective or harmful

� Diethylpropion Sibutramine + orlistat Dexfenfluramine � Orlistat Fenfluramine � Phentermine Fenfluramine + phentermine �Sibutramine Phenylpropanolamine Fluoxetine Mazindol

� Drugs included in the current review

McTique et al., 2003. Summary of the evidence for the US Preventive Services Task

Force (USPSTF) on obesity

An overview of the health outcomes from systematic reviews and RCTs of obesity drugs, was carried out by the US Preventive Services Task Force on obesity. Studies with at least one-year follow-up were identified by Medline and Cochrane Library searches for the period 1994-2003. Phentermine, diethylpropion, sibutramine and orlistat were amongst the drugs compared.

All of the reported systematic reviews (Arterburn and Hitchcock 2001) and RCTs (18 additional RCTs meeting the eligibility criteria) which included phentermine, diethylpropion, orlistat or sibutramine have been reported in separate studies elsewhere in this review and only the comparative efficacy observations are reported here:

• sibutramine and orlisat had high response rates, similar efficacy and promoted modest but significantly higher weight loss (3-5kg) than their controls

• in a single multi-drug trial, participants treated with sibutramine lost significantly more weight than those treated with orlistat (13.4kg vs. 8kg)

• prolonged treatment with sibutramine and orlistat helped to sustain weight loss for up to two years


39

• phentermine had short-term efficacy – i.e., promoted modest weight loss, but was not approved for long-term use

• efficacy of diethylpropion was more limited and variable than the other reported drugs

• modest weight loss improved clinical outcomes

• a high number of patients can achieve a clinically significant (5%-10%) weight loss

• discontinuation of treatment may lead to rapid weight regain.

Combined drug studies

A single randomised trial examining the effectiveness of combined therapy with two weight loss drugs with different modes of action was identified (Wadden et al. 2000).

Wadden et al., 2000. Does adding orlistat to sibutramine induce further weight loss?

The effect of adding orlistat to weight loss therapy with sibutramine was examined in a trial of 34 obese, female volunteers. The participants had already lost weight on sibutramine therapy and were continuing to take the drug at a dosage of 10-15mg/d. At the end of a 16 week combined treatment period, body weight remained essentially unchanged in both the sibutramine + orlistat and the sibutramine + placebo group.

In a sub-group analysis, participants who had lost > 10% of their initial body weight in the previous period of sibutramine treatment gained weight in the extension study – regardless of whether they received orlistat or placebo. Patients who lost < 10 % of their initial body weight in the previous period of sibutramine treatment lost further amounts of weight when orlistat was added to their treatment. These participants lost more weight than those taking sibutramine alone; however, the difference did not reach a significance level of <0.05.

The authors suggested that most obese participants have a limit of 10-15% weight loss with further loss thwarted by a number of regulatory physiological processes including compensatory mechanisms that decrease energy expenditure.


40


41

Safety/Side effects

Safety and side effects of sibutramine therapy

Sibutramine is currently being monitored by the New Zealand Intensive Medication Monitoring Program (IMMP)11.

A systematic review of the benefits and risks associated with the use of sibutramine in the management of obesity was carried out by Nisoli and Carruba (2003), see Table 26.

Table 26. The effect of sibutramine on blood pressure and heart rate; results from 20 studies (Nisoli and Carruba, 2003)

No Subjects

∆∆∆∆SBP (mmHg)

∆∆∆∆DBP (mmHg)

∆∆∆∆Heart rate (beats/min)

No Patients reporting

AEs

No of drop-outs Trial

Dose mg/d

Study Length

P S P S P S P S P S P S Obese subjects Apfelbaum 10 52wk 78 82 NR NR -1.9 +1.5 +1.0 +8.0§ 63 72 5a 2a

Fanghanel 10 24wk 54 55 -4.0 +1.7 -1.5 +0.3 -2.2 +0.1 23 31 10 15 Hanotin 10 12wk 114* 112 +0.6 +0.9 -0.1 +0.4 -0.9 +3.6 90 84 19 10 Cuellar 15 24wk 34 35 NR NR NR NR NR NR 16 23 25 13 Walsh 15 12 wk 9 10 NA NA NA NA NR NR NR NR NR NR Hanotin 5,10,15 12wk 59 177 NR NR NR NR -1.6 +3.2 42 126 12 29 Weintraub 5,20 8wk 20 40 NR NR NR NR NR NR NR NR 1 4 James 10,20 72wk 115 352 -2.4 +1.9 -.05 +3.4 +0.2 +4.6 5 48 58 148 McNulty 10,20 12wk 64 130 -0.2 +1.5 +0.5 +1.9 -0.8 +5.0 NR NR 18 32 Seagle 15,30 8wk 15 29 NR NR NR NR NR NR NR NR NR NR Hanson 30 5.5h 11 11 +5.0 +8.6 +1.4 -4.3 +2.8 +11.24 NA NA NA NA Patients with type 2 diabetes Knoll 10,20 52wk 163 332 -0.5 +0.7 -0.9 +0.8 +0.1 +2.7 NR NR 83 146 Knoll 15 NR 122 114 NR NR NR NR NR NR NR NR 12a 9a

Knoll 15,20 NR 64 131 NR NR NR NR NR NR NR NR 5A 14A

Bray 1.5-30 24wk 148 899 -0.8 +2.5 +1.7 +2.9 +0.6 +4.6 12 101 61 303 Fujioka 5,20 24wk 86 89 +2.4 +3.9 +1.4 +2.6 +0.7 +6.6 68 70 25 29 Gokcel 10 24wk 30 30 NR NR NR NR NR NR NR NR 5 1 Serrano-Rios

15 24wk 65 69 -1.1 +0.5 NR NR NR +2.4 34 42 8 16

Finer 15 12wk 44 47 NR NR NR NR +0.2 +7.5 45 42 4 4 Sibutramine use in children Berkowitz 5,10,15 24wk 39 43 +4.0 +0.1 +0.6 +1.8 2.0 +5.4 NR NR 5 3

a drop-out for adverse events, *comparison with dexfenfluramine § difference significant only at 6 months. P = Placebo, S = sibutramine

In general, the methodological quality of the reported trials was considered to be good. Double blinding, selection criteria and group comparability at baseline was reported for all trials. However, none of the trials included methods to determine if blinding had been successful and relatively few trials reported the use of a priori power calculation to estimate the required sample size.

All trials followed a similar protocol comprising a 1-3 week pre-randomisation run-in period, followed by a randomised assignment to sibutramine or placebo during a treatment period of between 8-52 weeks. In all trials adjunctive therapy comprising diet, exercise and behavioural modification advice was included in varying intensities.

11 IMMP is part of the NZ Pharmacological Vigilance Centre (formerly CARM), Department of Preventive and Social Medicine, Dunedin School of Medicine, University of Otago.


42

Adverse events

The most commonly reported adverse events of sibutramine were headache, constipation and nausea. Certain adverse events associated with the nervous system including dizziness, dry mouth and insomnia were reported by >5% of patients.

The two most clinically important side effects reported for sibutramine were increased blood pressure and tachycardia; these were generally seen in the first eight weeks of treatment, see Table 26. Heart rate increases between 4-11 beats per min were reported for sibutramine against slightly decreased and increased rates (-2 to +3 beats per min) for the placebo. In a number of instances the difference was significant, however, overall heart rate did not change dramatically during the course of treatment. A similar trend could be discerned in sub-groups with type 2 diabetes with increased heart rates of 3-7 beats per minute for diabetic patients treated with sibutramine and +0.1 to +0.7 beats per minute for the placebo treated diabetic group.

Blood pressure changes

The effect of sibutramine on blood pressure is the consequence of a reducing effect due to its action on body weight and a stimulating effect based on noradrenaline reuptake inhibition. Therapeutic doses of sibutramine have been associated with increased blood pressure in a dose dependent manner (Weintraub et al. 1991), see Table 19.

SBP was higher in all studies in sibutramine patients (median +1.7mmHg, range +0.50 to +8.6) than those who had the placebo (median -0.5mmHg, range -4.00 to +5.00mmHg). Diastolic blood pressure followed the same pattern (sibutramine median =+1.5mmHg, range -4.3 to +3.4, placebo median =0.05mm Hg, range -1.9 to +1.7).

In a trial of obese hypertensive patients (Hazenberg 2000), the mean reduction in supine DBP was numerically but not statistically greater in the placebo group compared with the sibutramine group (5.7mmHg vs. 4.0mmHg; p=0.21). Similar reductions were reported in SBP.

In March 2002, the Italian Ministry of Health approached the EMEA for a reassessment of the benefit/risk ratio of sibutramine after 51 adverse events and two deaths were reported in a period of one year. Reporting incidence by number of fatal cases was calculated at 2.40-2.86 fatal events per 100,000 treatment years, which was lower than the estimated rate for the best available control population. EMEA reaffirmed a positive benefit risk profile for sibutramine based on these data.

Safety and side effects of orlistat therapy

No systematic review of the safety of orlistat and its side effects was identified. However, all of the studies reviewed reported on safety aspects of therapy and the adverse events associated with orlistat treatment.

The main adverse events reported by patients taking orlistat were GI in keeping with the local action of the drug. They included:

• fatty/oily stools

• liquid stools


43

• faecal urgency

• faecal incontinence

• flatulence

• lower serum levels of fat-soluble vitamins A, D, E and K1.

These adverse effects were generally mild to moderate and most events occurred early in the course of treatment. Although orlistat treated patients generally had significantly more adverse events than the control group, few serious adverse events were reported.

In the overview of systematic reviews and RCTs by McTigue (2003), it was noted that GI side effects were reported in 22-95% of orlistat users and that in addition to reduced vitamin absorption there was a reduced absorption of contraceptive pills (Arteburn, 2001). Reductions in plasma levels of warfarin and cyclosporine have been reported when co-administered with orlistat. There is insufficient evidence on weight regain and long-term safety for orlistat (Arterburn and Hitchcock 2001).

Safety and side effects of phentermine therapy

No systematic reviews of the safety and side effects of phentermine were identified. However, all efficacy studies reviewed reported on safety aspects of therapy and the adverse events associated with phentermine treatment. Most of the studies published between 1996-2004 were of short duration with small numbers of patients. There is little or no data on the effects of phentermine on obesity related co-morbidities reported in these studies. No serious adverse events were reported in earlier studies of phentermine reported by McTigue et al. (2003).

In 1996, phentermine was administered with the newly introduced fenfluramine in the combination known as “Phen-Fen”. Following reports of cardio valvopathy in patients treated with this combination fenfluramide was withdrawn from the market (Hensrud 2000; Rothman and Baumann 2000).

There was no evidence that phentermine was responsible for the valvopathy (Hensrud et al. 2003) and patients treated with phentermine alone had no reported adverse reaction of this type. Nonetheless, the Medicines Control Agency (MCA) warned that a link between phentermine and heart and lung problems could not be ruled out (Medicines Control Agency Committee on Safety in Medicines, 2004). Phentermine remains available for use in Europe, however, it is not recommended for use by the Royal College of Physicians (Wilding 2004).

Safety and side effects of diethylpropion therapy

No systematic reviews of the safety of diethylpropion and its side effects were identified. However, all of the studies reviewed reported on safety aspects of therapy and any adverse events associated with diethylpropion treatment. Data on the safety of diethylpropion is limited as published studies are generally of short duration (<3 months) in keeping with its conditions of use. Reported side effects include palpitations, tachycardia, elevated blood pressure and arrhythmia together with various adverse reactions associated with CNS stimulation – e.g., nervousness, restlessness, dizziness, euphoria and insomnia. As with amphetamine and other amphetamine derivatives, diethylpropion has a potential to induce dependence.


44

Case reports of pulmonary hypertension have been reported and the European Medicines Control Agency warned that a link between diethylpropion and heart and lung problems could not be ruled out (Medicines Control Agency Committee on Safety in Medicines, 2004). Although diethylpropion still has a licence for use as an anti-obesity treatment in the UK, its use is no longer recommended for this purpose by the MCA or the Royal College of Physicians (Wilding 2004).

Summary of potential harms of pharmacotherapy intervention

Overall, pharmacotherapy for obesity when carried out as indicated, is reasonably safe. Clinically significant adverse events were reported for sibutramine and orlistat in studies of one to two years; however, the longer-term effects of these drugs is not known. Orlistat has predominantly GI side effects while sibutramine may cause clinically significant rises in blood pressure in some patient groups. Both of these drugs are reported to have clinically significant benefits in the treatment of obesity and its related co-morbidities and a positive trade off between benefits and harm.

Phentermine and diethylpropion are only indicated for short-term therapy. Their adverse events profile were somewhat sketchy in the studies reviewed, possibly because of the limits set on the publications dates for study inclusion for this review12. Phentermine in combination with fenfluramide (“Phen-Fen”) was reported to be responsible for a number of cases of cardio valvopathy and although no cases have been reported in patients taking phentermine alone, it is no longer recommended for use by the Royal College of Physicians in the UK. Diethylpropion has been linked in a number of case reports with pulmonary hypertension and the European MCA have noted that a link between the two cannot be ruled out. Diethylpropion is no longer recommended for the treatment of obesity by the MCA or the UK Royal College of Physicians.

Safety and side effects of meal replacement programs

Meal replacement programs have not been critically evaluated until recently and there are few reports of their safety. In the two studies evaluated in the current review (Allison et al. 2003; Heymsfield et al. 2003), there were few reported adverse events and their impact was limited.

A lack of adverse events reporting in any study patients, including PMR treated diabetics was noted by Heysfield et al., (2003) in a systematic review of six studies examining meal replacement strategies. On the other hand, an unblinded RCT of a novel soy-based meal replacement formula for weight loss in 100 obese volunteers (Allison et al. 2003) reported a large number of adverse events13 including:

• decreased appetite/anorexia

• constipation

• diarrhoea

12 Eligibility criteria limited studies to the period 1996-2004; most studies reporting on these drugs were published much earlier.

13 Assessed by the monitoring of side effects system (MOSES).


45

• drooling/salivation

• gas/indigestion

• abnormal taste

• lethargy

• excessive sleep

• enuresis/nocturesis

• weight gain

• weight loss.

For five of the events (constipation, gas or indigestion, abnormal or metallic taste, lethargy and weight loss), there was a significantly higher incidence in the meal replacement group. Generally however, treatment was reported to be well tolerated and free of serious side effects by the study authors.


46


47

Practice recommendations and guidelines

National Institute of Health, USA

General guidelines for incorporating weight loss medicines into the overall treatment plan for overweight and obese individuals were published by the National Institute of Health in 2000. It was recommended that:

1. Therapy should be initiated with lifestyle changes (diet and behaviour modification and exercise) and that if these failed to promote a 10% weight loss (or at least 0.5kg/wk) over six months that pharmacotherapy should be considered.

2. Only individuals with a BMI ≥ 30kg/m2 and no obesity related risk factors, or ≥ 27kg/m2 if the patient also has hypertension, dyslipidemia, coronary artery disease, type 2 diabetes or sleep apnoea, should be eligible for treatment.

3. If the patient does not lose at least 2kg in the first month of therapy, the likelihood of response to that medication is low and an adjusted dose, discontinuation of the drug or changing the medication is advised.

4. If significant weight loss occurs with the medication or the initial weight loss is maintained, medication may be continued as long as it remains effective and the side effects tolerable.

In addition, it was suggested that drugs that were limited by the FDA to a maximum period of administration of 12 weeks would be best administered in the setting of a clinical trial.

The National Institute for Clinical Excellence, UK

NICE published best practice guidelines for the use of orlistat and sibutramine in 2001.14

Orlistat

• Orlistat should only be prescribed for obese patients who fulfil the licensing criteria and have lost at least 2.5kg15 by dietary control and increased physical activity in the month prior to treatment.

• When treatment is offered trained practice nurses and dietitians should be available to offer advice, support and counselling on diet, physical exercise and behavioural strategies.

• Continuation of orlistat therapy beyond three months should be supported by evidence of at least 5% body weight loss since the start of treatment.

14 http://www.nice.org.uk.

15 The FDA guidelines do not require prior weight loss using diet and exercise alone and continuation of treatment beyond 3 and 6 months does not require weight loss of 5% and 10% respectively (Ballinger et al 2002).


48

• Continuation of orlistat therapy beyond six months should be supported by evidence of at least 10% weight loss from the start of treatment.

• Treatment should not usually be continued beyond 12 months and never beyond 24 months16.

Sibutramine

• Sibutramine should be prescribed only as part of an overall treatment plan for the management of obesity for people aged 18-65 years.

• When people are prescribed sibutramine, they should also be offered advice, support and counselling on diet, exercise and behaviour changes.

• It should be prescribed for the management of obesity in people who have a BMI of 30kg/m2 or more, or who have a BMI of 27kg/m2 or more together with significant disease – e.g., type 2 diabetes, high cholesterol.

• Sibutramine should not be prescribed unless the person taking it is monitored for side effects.

• Treatment should only be continued for more than four weeks if patients have lost 2kg in weight and should only continue treatment beyond three months if they have lost at least 5% (5kg for each 100kg) of their body weight from the start of drug treatment.

• Sibutramine should be stopped if patients do not lose weight as described.

• Blood pressure should be checked regularly. Increases in blood pressure may be a reason to stop treatment.

• Sibutramine is not recommended for patients who already have high blood pressure – i.e., 145/90 or above.

• Treatment is not recommended beyond 12 months.17

• There is no evidence to show that prescribing sibutramine with other drugs used to treat obesity is beneficial.

16 The XENDOS trial of orlistat has recently reported on its safety and efficacy at four years.

17 This guidance is to be reviewed in September 2004.


49

High profile clinical trials

Completed studies

Although there are a number of recently completed trials relating to the management of adult obesity (for a summary see Avenell et al., 2004, Appendix 9), most have little relevance to the ACC claimant population and/or do not involve any of the medications reviewed in the current report. Two high profile clinical trials of the newer weight loss drugs are notable exceptions. Their clinical outcomes have been reported in earlier sections of this review, they are examined individually here to describe the particular circumstances and goals of each trial and to highlight their contribution to this field of study.

STORM: STORM has been widely reported (Astrup and Toubro 2001; Hansen et al. 2001; James et al. 2000; James 2001) and its results incorporated in the recent systematic review by Avenell et al., (2004). This was a randomised double-blind, placebo-controlled, multi-centre European study of sibutramine for the induction and maintenance of weight loss in obese subjects. A total of 605 male and female obese patients were treated for 24 months with sibutramine 10mg/d and a 600kcal deficit diet. If weight regain occurred sibutramine was increased to 20mg/d. At the time of the study, the European Union licence only permitted continuous treatment with sibutramine for up to one year, the STORM study led the US FDA to extend its clearance of sibutramine therapy to two years.

XENDOS: this prospective trial built upon a number of earlier diabetes prevention studies in overweight subjects with IGT (e.g., the STOP-NIDDM, DPP, DPS and TRIPOD studies). Xendos was a randomised, double-blind, placebo-controlled, prospective, four year trial designed to determine the long-term diabetes-preventing and weight reducing effect of orlistat in combination with lifestyle changes in obese patients. Three thousand, three hundred and five obese patients were randomly assigned to orlistat 120mg t.i.d. or placebo. All patients had an energy-reduced diet (reduced by up to 800kcal/day) with 30% fat intake. Patients were instructed to walk 1km a day above their normal level of physical activity.

At four years the orlistat treated patients had lost 5.8kg compared with 3.0kg in the placebo groups (p=<0.001). In IGT patients, the values were 5.7kg and 3.0kg respectively. The cumulative incidence of diabetes over the period of the study was orlistat 6.2 vs. placebo 9.0 (p=0.003) – i.e., 37% reduction of risk of developing diabetes. The orlistat group also experienced significantly greater four year improvements in SBP and DBP, total-LDL and HDL-cholesterol and the LDL/HDL ratio as well as waist circumference, fibrinogen and plasminogen activator inhibitor-1 levels. It is not known if the effect would be greater if orlistat was combined with metformin and/or acarbose (Torgerson 2004; Torgerson et al. 2004).

Childhood obesity

A number of studies of the use of Xenical in children and adolescents are soon to be published – i.e., in the latter months of 2004.


50

Ongoing trials

Although there are a large number of recently completed and new trials relating to the management of obesity (for a summary see Avenell et al., 2004, Appendix 9), most have little relevance to the ACC claimant population and/or do not involve any of the medications reviewed in the current study. Two ongoing studies are, however, worthy of mention as follows:

SCOUT: a large cardiac outcomes study of sibutramine has been planned in response to a request by the European Committee for Proprietary Medicinal Products (CPMP) for a post approval commitment (Nisoli and Carruba 2003). The Sibutramine Cardiovascular Outcome Trial (SCOUT) is a placebo-controlled, double-blind, global multi-centre study with the objective of comparing the effect of sibutramine and standard care for weight management to that of placebo on the incidence of a composite cardiovascular outcome. It is hoped that the trials will recruit 9,000 subjects ≥ 55 years with a BMI ≥ 27kg/m2 and < 45kg/m2 or BMI ≥ 25kg/m2 and <27kg/m with a waist circumference of ≥ 102cm in males or ≥ 88cm in females, at risk of a cardiovascular event.

The NICHD18 trial of Xenical in children and adolescents with obesity related diseases – this is a phase II clinical trial designed to determine the safety, tolerability and efficacy of orlistat in African American and Caucasian children aged 12-17 years with one or more obesity related co-morbidities (hypertension, hyperlipidemia, hepatic steatosis, insulin resistance, IGT, type II diabetes or sleep apnoea syndrome). The trial is expected to recruit 370 children19.

18 National Institute of Child Health and Human Development. http://clinicalstudies.info.nih.gov/cgi/detail.cgi?A_1998-CH-0111.html.

19 As this report was being written, the FDA announced that it had approved the use of Xenical in children.


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Other anti-obesity therapies

A number of additional anti-obesity therapies not considered in the current review have recently been reviewed by NICE (Avenell et al. 2004) and by the US Preventative Services Task Force (McTigue et al. 2003). The full list of therapies considered in each of these reviews is listed in Table 20.

Therapies that may be of particular interest to the ACC include:

• Acarbose

• Metformin

• Very low calorie diets (VLCD)

• LCDs other than those contained meal replacement products

• Mazindol (appetite suppressant)

• Fluoxetine (anti depressant, SSRI).


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53

Horizon Scan

There are a number of potential future therapies for obesity:

• Leptin: is a hormone released from adipocytes which signals energy availability to the brain. Its deficiency leads to severe obesity and most obese individuals have been found to have elevated leptin levels. However, like most diabetics most obese people are leptin resistant (Brower 2002). There have been a number of phase 2 trials of this agent with disappointing results to date (Thearle and Aronne 2003).

• Axokine: is recombinant human ciliary neurotrophic factor which has been observed to cause weight loss and, in rodents, does not lead to rebound weight gain upon cessation. Early phase trials have indicated that weight loss in excess of placebo is obtained and that weight loss is maintained after treatment has ceased (Brower 2002, Ettinger 2003).

• Topiramate: is an anti-epilepsy drug that has been evaluated for weight loss (Bray et al. 2003, McElroy et al. 2003). A recent dose ranging study has suggested that a clinically significant weight loss and improvement in obesity associated risk factors may be obtained with the therapy but longer and larger studies are required to fully assess its efficacy and safety (Thearle and Aronne 2003).

• Bupropion: is a peptide analogue of the fragment of human growth hormone that causes lipolysis.


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55

Economic considerations

The direct cost of medication

The cost of treating a single patient for a month at the recommended dose for each of the drugs considered in the current review is shown in Table 27.

Table 27. NZ Drug pricing according to MIMS, 2004†

Drug Proprietary Drug name

Pack

Manufacturer Price NZ$

(per tablet)

Patient Charge

NZ$

Cost per Tablet NZ$

Recommended Daily dosed

Cost‡ per patient per month

NZ$ Phentermine C5controlled drug

Durominea Umine

15mg [30] 30mg [30] 30mg[100]

21.52 24.58 35.90

37.12 42.40 61.93

1.24 1.41 0.62

15mg/d 30mg/d 30mg/d

37.82 43.01 18.91

Diethylpropion Tenuate Dospan b 75mg[100] 94.88 163.67 1.64 75mg/d 50.02 Sibutramine Reductil 10mg[30]

15mg[30] 103.35 119.10

178.28 205.45

5.94 6.83

10mg/d 15/mg/d

181.17 208.32

Orlistat Xenical 120mg[84] 112.00 193.20 2.30 360mg/d 210.45 † Propharma wholesalers may quote lower prices for these drugs. a = 3M New Zealand Ltd. b = Douglas Pharmaceutical Ltd.

d based on the manufacturer’s price. ‡ calculated using patient charges.

The estimated direct drugs costs of a course of treatment are shown in Table 28.

Table 28. The estimated cost of a course of anti-obesity treatment

Maximum permitted Prescribed period

Minimum period Maximum weight loss Drug

Proprietary Drug name

DailyDose

Time Period Cost Time Period Cost Phentermine C5controlled drug

Durominea Umine

15mg 30mg 30mg

3 months 3 months 3 months

$113.46 $129.03

$56.73

3 months† 3 months† 3 months†

$113.46 $129.03

$56.73 Diethylpropion Tenuate Dospan b 75mg 3 months $150.06 3 months† $150.06 Sibutramine Reductil 10mg

15mg

1 yr 2 yr 1 yr 2 yr

$2,174.04 $4,348.08 $2,499.84 $4,999.68

6 months

6 months

$1,087.02

$1,249.92

Orlistat Xenical 360mg 1 yr 2 yr

$2,525.40 $5,050.80

6 months $1,262.70

† not reported but assumed to be maximum continuous prescription period allowed.

The cost of monthly general practitioner (GP) and or nurse consultations, dietary modifications, ancillary monitoring of obesity related co-morbidities, laboratory tests and dietitians services have not been estimated.


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Economic analysis

Obesity is a major risk factor for a number of different health conditions and the economic implications of obesity are therefore significant. Cost of illness studies in the USA suggest that obesity accounts for 5.5-7.0% of national healthcare expenditure (Hensrud et al. 2003).

A comprehensive search of the literature for the present review identified five systematic reviews examining the economics of treating obesity with one or more of the review drugs. Upon inspection these reviews all drew upon data from a relatively small pool of studies20 (Foxcroft and Milne 2000; Lamotte et al. 2002), see Table 29.

Table 29. Studies reporting on the cost or cost effectiveness of sibutramine, orlistat, phentermine and diethylpropion

Systematic review/HTA Drug Reported data from Economic analysis

Avenell 2004 Sibutramine Orlistat

O’Meara 2001 O’Meara 2002 Foxcroft 1999 Foxcroft 2000 Lamotte 2002 BASF Pharma/Knoll 2000

Cost-effectiveness

Hensraud 2003 Orlistat Foxcroft 2000 (rapid review) Lamotte 2002 (HE model)

Cost-effectiveness

O’Meara 2002 Sibutramine BASF Pharma/Knoll 2000 Cost-effectiveness O’Meara 2001 Orlistat Foxcroft 2000 (rapid review) Cost-effectiveness

Glazer 2001 Phentermine Sibutramine Orlistat

Pharmacy chain average retail price Comparative cost

HE=health economics

A single new economic analysis of sibutramine (Warren et al. 2004) was identified in the comprehensive search carried out for this review.

Economic evaluations of orlistat

Two systematic reviews (Foxcroft and Milne 2000; O'Meara et al. 2001) used effectiveness from three RCTs (Davidson 1999; Hollander et al. 1998; Sjostrom et al. 1998) reporting on interventions with 120mg of orlistat three times a day in combination with a hypocaloric diet and compared to placebo plus diet to evaluate the cost-effectiveness of orlistat. The follow-up period was one to two years and outcomes were focussed on patients who lost ≥ 5% of their initial body weight.

The perspective adopted for the economic analyses was that of the health service provider and the cost estimates included:

• the initial consultation

• laboratory tests

20 BASF Pharma Knoll (2000). Unpublished study of economic analysis of Sibutramine reported in O'Meara (2002).


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• outpatient consultations (4 per year)

• drug costs.

The incremental cost per QALY gained was estimated to be £45,888 (range £19,425-£55,391). It was noted that the trial data were not consistent with the EMEA prescription indication for orlistat21 and that the reported costs may differ from those obtained in clinical practice. It was not clear if the estimated cost of £45,888 was considered by the authors of the report to be cost-effective; however, an economic analysis conducted in 2004 (Warren 2004) suggested a cost-effectiveness threshold of approximately £20,000 for another anti-obesity drug. Using this threshold, orlistat would not be a cost-effective option in this group of patients.

A study by Lamotte et al., (2002) reported in European Euros (€) and funded by Roche Pharmaceuticals focussed on obese patients with type 2 diabetes. Using an economic modelling approach, the incremental cost-effectiveness of orlistat for two years in patients with diabetes but free of clinical events and without hypertension or hypercholesterolemia was estimated to be €19,986 22. This was just considered to be cost-effective against a threshold of approximately €20,000 per QALY but lacking robustness. The cost per life year saved decreased in patients with complications such as hypercholesterolemia and AHT, with the cost per life year saved reducing to €3,462 in patients with both hypercholesterolemia and AHT (see Table 30). Sensitivity analysis with inputs assuming that all weight is regained in 2.5 years rather than 5 years, increased the costs from €19,986 to €26,527 for event free patients and from €3,462 to €4,565 for patients with hypercholesterolemia. Treating only patients with hypertension and or hypercholesterolemia was considered to be good value for money, these results were robust under sensitivity analysis.

A study by Glazer (2001) reported only drug costs and direct costs per kg lost or 1% of base weight lost. However, these parameters were also reported for sibutramine and phentermine allowing a snapshot of comparative costs at a single point of time in the USA. The drug costs per kg weight loss were US$433, US$323 and US$91 for orlistat, sibutramine and phentermine respectively. The cost per 1% weight loss was US$433, US$268, US$89 for orlistat, sibutramine and phentermine respectively. These results suggest that orlistat and sibutramine will cost more than phentermine to reduce weight by a similar amount or by a similar proportion of initial body weight. The relative benefits and harms of therapy were not considered.

Economic evaluations of sibutramine

HTAs of sibutramine in 2002 and 2004 (Avenell et al. 2004; O'Meara et al. 2002) did not identify any published economic evaluations of sibutramine. A more recent comprehensive search for the present review (June/July 2004) identified one published economic analysis (Warren et al. 2004) and a simple comparative analysis of direct costs of a number of drugs including sibutramine by Glazer (2001). An unpublished cost utility analysis was submitted to NICE by the manufacturer BASF Pharma/Knoll (2000) and critiqued by O’Meara et al., (2002), see Table 29.

21 European Medicine’s agency prescription indication = loss of >2.5kg by diet in four weeks previous treatment and a loss of ≥ 5% body weight after 12 weeks of treatment.

22 Year 2000 Euros.


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A recent economic analysis by Warren et al., (2004) estimated the incremental cost-utility of 12 months of sibutramine therapy at a dose of 10mg/d combined with diet and lifestyle advice compared to diet and lifestyle advice alone in “healthy obese” individuals.

The clinical pathways modelled in this study were consistent with the European licensing for sibutramine23. The overall incremental cost per QALY was estimated at £4,780 based on the results of the sibutramine adiposity therapy (SAT) trial (central Estimate A, Table 29). The marginal gain for the cohort of 1,000 patients in this report was 48.15QALYs (0.048QALYs per patient). Sensitivity analyses showed that this value was sensitive to a number of parameters – particularly the utility associated with weight loss and the frequency of monitoring during and after treatment, see Table 30.

Table 30. Sensitivity analysis around two base estimates of the cost-effectiveness of sibutramine when different utilities are assigned to weight loss

Scenario‡

UK Cost per QALY Central Estimate A

SAT trial £4,780

UK Cost per QALY Central Estimate B SAMSA analysis†

£10,530 WL benefits only £6,341 £19,125 WL and CHD benefits only £5,403 £12,952 WL and diabetes benefits only £5,567 £14,664 Utility per kg WL = lower CI £14,072 £16,682 Utility per kg WL= upper CI £3,001 £5,965 Worst case £20,602 £34,260 Best case £2,950 £5,809 Compliance = 30% £8,605 £34,905 Compliance =50% £7,077 £21,482 Compliance =75% £5,738 £14,271 Adverse events not included £4,769 £10,505 Placebo=no monitoring costs £9,034 £19,899

Estimate A is based on the utility gain per kg of weight lost reported in the SAT trial.

Estimate B is based on the utility gain per kg of weight lost reported in the Samsa analysis.

† used in the NICE report ‡ Estimates for a cohort of 1,000 patients receiving 12 months treatment with

sibutramine.

The effect of differing assumptions and utilities on the estimated cost of sibutramine is also evident in the cost per QALY reported using the different utilities assumed in an economic analysis reported by Samsa et al., (2001), see Table 29. Sensitivity analyses on the central estimates of the cost per QALY for sibutramine vs. placebo based on the utilities reported in the two trials showed large variations in the estimated cost per QALY.

The basic model used in this analysis assumes coronary heart disease (CHD) and diabetes benefits in addition to weight loss and the effect of removing these effects from the model is shown for CHD and diabetes. They both appear to have effects of similar magnitude on the cost per QALY and when the effect of both is removed the cost rises from£4,780 to £6,341 for the estimates based on the SAT utilities and from £10,530 to £19,125 for estimates based on the Samsa utilities.

23 The European licensing for sibutramine only allows continued treatment for “responders” – i.e., patients who lose 2kg after one month and 5% of their initial weight after three months.


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Overall, cost was most sensitive to the utility24 attached to each kg of weight lost, however, even at the lower confidence interval of this variable, sibutramine was considered by the authors to be cost-effective by both analyses. Removing the effect of adverse events from the model makes very little difference to either estimate of the cost per QALY.

Only two obesity related co-morbidities, CHD and diabetes, were included in the analysis; however, the authors noted that if all co-morbidities were included in the model the cost per QALY of sibutramine would decrease.

It may be concluded from these analyses that the cost-effectiveness of sibutramine is dependent not only on the amount of weight lost but also on the effect the weight loss has on obesity related co-morbidities. Further calculations were carried out to identify the cost of treating sibutramine-induced side effects that would make treatment no longer a cost-effective option. For Estimate A, it was calculated that side effects that cost £900 per sibutramine patient would be required. Given the fact that sibutramine is well tolerated and that the most common side effects reported are constipation and dry mouth, it was considered unlikely that such a high cost would be incurred in the treatment of side effects.

A “comparative cost efficacy” of sibutramine, orlistat and phentermine reported by Glazer et al., (2001) estimated that the cost per kilogram of weight lost using sibutramine (US$323) was similar to that of orlistat (US$433) and higher than phentermine (US$91). The cost of each 1% weight loss with sibutramine was approximately 40% lower than a comparable weight loss with orlistat ($US268 vs. US$433) and again both of the newer drugs had higher costs than phentermine (US$89). An even weight loss over time was assumed in all calculations.

The BASF Pharma/Knoll model, Table 29, incorporated four weight loss scenarios:

• the effect of weight loss alone

• the effect of weight loss on cardiovascular risk reduction

• the effect of weight loss on diabetes risk reduction

• the combined effects of all three factors.

All weight lost was assumed to be regained after five years. There was some concern that the original estimates made by the company were based on unjustifiably high utility values resulting in an over-estimate of the likely gain in QALY per kg of weight lost.

24 Utilities are calculated from a relationship between weight loss and quality of life.


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Table 31. Economic evaluations of orlistat, sibutramine and phentermine

Study Type of study Type of analysis

Costs and assumptions Economic analysis

ORLISTAT Foxcroft 2000

Rapid review Cost-effectivenessd

Cost estimates Patient consultation + lab tests a£118 Monthly cost of orlistat 120mg tds =£45 GP consultation cost=£16 per visit Annual treatment costs=£7344 (1998) Estimated short run gain over a 2-year treatment period =0.016QALYs per year Assumptions Drop-outs treated on average for 3 months Drop-out rate 1yr=27%, 2yr 23% 4 outpatient appointments per year

Base case analysis Cost utility per QALY gained = £45,881 (range £19,452 - £55,391)

Glazer 2001

Systematic review of effectiveness which included a comparison of drug cost

Costs Cost of drug per month =US$119 Cost of drug per year=US$ 1,428 Cost per 1% weight lost=US$ 433 Cost per 1kg weight loss=US$433 Assumptions WMD Drug-placebo %=3.4, kg=3.4

No analysis

ORLISTAT Lamotte 2002

Primary research report Cost effectiveness Markov model

Drug cost

Per patients per year = €881 Incremental costs Drug-placebo

1.Event free diabetes = €1,608

2.Hypercholesterolemia= €1,514

3.AHT= €1,678

4. Hypercholesterolemia+ AHT= = €1,641 Life years gained

1.Event free diabetes = 0.08

2.Hypercholesterolemia= 0.204 3.AHT= 0.227

4. Hypercholesterolemia+ AHT= = 0.474 Assumptions Effectiveness data from Clark 1998 (1.=9.462, 2.=9.401,3.=8.93,4.=8.74) public health perspective Metformin base treatment = 119 euro per patient per year. 4.2% of patients could stop taking oral medication for diabetes and 10% could reduce their medication by approx 25%.

Cost per life year gained (LYG)

1. Event free diabetic=€19,986

2. Hypercholesterolemia =€7,407

3. AHT=€7,388

4. Hypercholesterolemia +AHT=€3.462 Cost-effectiveness Depending upon the risk profile (Lamotte)

1. Event free diabetes = €1,816

2. Hypercholesterolemia= €1,835

3. AHT= = €1,918

4. Hypercholesterolemia+ AHT= = €1,955

Maetzel 2003

Primary research paper Markov state transition model of obese individuals with type 2 diabetes

Cost estimates (2001 values: US$) ATG +Orlistat 120mg t.i.d. for 1 year =$US 19,987 ATG =$US 18,865 MI =$US 19,226 Stroke = $US 32,458 Microvascular disease =$US 1,248 Congestive heart failure= $US 4,842 Cateract =$US 2,163 Main Assumptions Orlistat treatment 120mg t.i.d. for one year All patients received standard type 2 diabetes treatment – i.e., sulphonylureas, metformin or insulin) No diabetes related complication at start of orlistat treatment Simulation continued for 11 years Male patients aged 52 years Reduction in HbA1c values directly translate to a reduction of diabetes related complications Perspective= US healthcare

Incremental cost-effectiveness ratio (CER) $US 8,327 per event free LYG Life expectancy increased by 0.13 years over an 11 year time frame by orlistat Sensitivity analysis for the base case Showed that 95% of CER fell under the threshold of cost effectiveness where the threshold was set at approximately $US 20,000 per event-free LYG. Conclusion Orlistat added to diabetes treatment is cost effective and that the CER is likely to be conservative as no account was taken of lipid parameter reductions or BP changes. CER for females was likely to be higher but still less than $US20,000 Note: shorter period of orlistat have less benefit

SIBUTRAMINE Glazer 2000

Systematic review of effectiveness which included a comparison of drug cost

Costs Cost per month =$116 Cost per year=$1,392 Cost per 1% weight lost=$268 Cost per 1kg weight loss=$323 Assumptions WMD Drug-placebo %=5.0, kg=4.3

No analysis


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Table 31. Economic evaluations of orlistat, sibutramine and phentermine (continued)

Study Type of study Type of analysis

Costs and assumptions Economic analysis

SIBUTRAMINE O’Meara 2002

Systematic review Modellingc

cost utility analysis

BASF Pharma /Knoll UK British £

BASF Pharma /Knoll Cost per QALY through: 1.Weight loss alone=£14,700 2.CHD risk reduction = £32,000 3.Diabetes risk reduction= £58,260 Combined cost per QALY gained from the three influences=£7,860 Main Assumptions 1000 BMI>30kg/m free of co-morbities at the start of the modelling period. All weight is regained in 5 years

O’Meara recalculated the cost per QALY as 1.Weight loss alone=£19,000 2.CHD risk reduction = £42,000 3.Diabetes risk reduction= £77,000 Combined cost per QALY gained from the three influences = £10,500 (£5,700 - £35,200)

Warren 2004

Primary research publication Economic modelling based

Costs Sibutramine 10mg per month=£35, 15mg £39.09 GP visit £13 per month for 1 year Nurse practitioner £7.50 per month for 4 years Marginal costs of 1000 patients receiving sibutramine over placebo I= £305,314 (WL), £298,328 (WL + CHD), £288,776 (WL+ diabetes) Cost saving from avoided CHD events Non-fatal x1 =£2,577, fatal x1 =£2,160, ongoing yearly cost of non-fatal =£6,19. Cost saving from reduced diabetes incidence Annual per capita cost of treating diabetes=£780 Main Assumptions Both arms diet and lifestyle advice Participants =“healthy obese’ WL, CHD and diabetes benefits are assumed 25SAT marginal QALY gain over 1000 patients =48.15 SAMSAT marginal QALY gain over 1000 patients =26.76 SAMSAT analysis used a smaller utility than SAM analysis Cost effectiveness threshold = £20,000 Most common AEs constipation and dry mouth

Incremental cost per QALY Combined WL, CHD , diabetes SAM estimate =£4,780 SAMSAT estimate =£10,530 WL only SAM estimate =£6,341 SAMSAT estimate =£19,125 WL and CHD SAM estimate =£5,403 SAMSAT estimate =£12,952 WL and diabetes only SAM estimate =£5,567 SAMSAT estimate =£14,664

PHENTERMINE Glazer 2000

Costs Cost per month =$60 Cost per year=$720 Cost per 1% weight lost=$89 Cost per 1kg weight loss=$91 Assumptions WMD Drug-placebo %=8.1, kg=7.9

No analysis

a (NHS, Trust 1998) b Based of trials of efficacy by Sjostrom 1998, Davidson 1999, Hollander 1998. c Smith 1994, James 1999. d Sjostrom 1998, Davidson 1999, e Diethylpropion was not considered to be effective in the only long-term trial considered and was not included in the comparison

Aes = adverse events. ATG = adherence to diabetes guidelines for the duration of the model. AHT = arterial hypertension. BP = blood pressure. CER = cost effectiveness ration. CHD = coronary heart disease. LYG = life year gained. MI = myocardial infarction. QALY = quality adjusted life year. SAT= Sibutramine Adiposity Therapy Trial, SAMSAT= the Samsa review trials. WL = weight loss. WMD = weighted mean difference.

O’Meara et al., (2002) recalculated the cost effectiveness estimates. The recalculated estimates were 20-25% higher than the original values, see Table 30, and the combined effects cost per QALY for sibutramine reported as £10,500 with a best case to worst case scenario range between £5,700-£35,200 per QALY. The cost per QALY gained through CHD reduction alone was £42,000, though diabetes incidence reduction alone was£77,000 and from weight loss alone was £19,000. The cost per QALY was again very dependent on the starting utilities and a sensitivity analysis carried out with lower utility gains per kilogram (0.00048 for sibutramine and 0.00058 for placebo), resulted in a cost per QALY of £50,400. Assuming a hypothetical cost- effectiveness threshold of £20,000 (Warren 2004), careful evaluation of the likely utility gain per kilogram of weight lost is required for treatment to be cost-effectiveness.

25 Two estimates were made with one based on the SAT utilities and another on the SAMSAT utilities, sensitivity analyses were computed around both estimates.


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Economic evaluations of phentermine

No published economic analyses of phentermine were identified for the period (1996-2004). One study reported drug cost and cost per unit of weight lost comparisons between phentermine, orlistat and sibutramine (Glazer 2001). The estimated annual cost of phentermine was $720, and, on the assumption of a weighted mean difference between phentermine and placebo weight loss of 8.1% and 7.9kg, a cost per 1% weight loss of $89 and 1kg weight loss of $91. The drugs cost and direct cost 1% weight loss for phentermine was much lower than for orlistat or sibutramine.

Economic evaluations of diethylpropion

No published economic analyses or drug cost comparisons were identified over the period (1996-2004) for diethylpropion.

Economic evaluations of meal replacement plans

No published economic analyses or cost comparisons were identified over the period 1996-2004 for meal replacement products or plans.


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65

Discussion

Criteria for the evaluation of medication for the treatment of obesity

Obesity is the result of long-term mismatches in energy balance where daily intake exceeds daily energy expenditure. It has been suggested (Halpern and Mancini 2003) that a useful medication for obesity treatment should:

1. be effective for body weight reduction and result in improvement of overweight dependent conditions

2. provide evidence that side effects are tolerable and/or transitory

3. not be addictive

4. provide proof of long-term efficacy and safety

5. have a known mechanism of action

6. be reasonably affordable.

None of the weight loss strategies included in the current review fulfil all six requirements. However, all of the pharmacological therapies examined were effective to a greater or lesser degree for body weight reduction and the amelioration of obesity associated co-morbidities and had known mechanisms of action (criteria 1 and 5).

All of the drugs except phentermine and diethylpropion were reported to be unlikely to cause addiction (criterion 3); caution is advised in the administration of phentermine which is an amphetamine and diethylpropion which is an amphetamine derivative. However, all of the drugs except orlistat were reported to have a CNS stimulatory effect and were contraindicated for patients with a history of drug or substance abuse.

All of the pharmacological interventions reported side effects that for the majority of participants appeared to be tolerable and/or transient (criteria 2). All weight loss studies reported high drop-out rates and many reported withdrawals due to drug side effects; however, clinically significant side effects or serious adverse events were rare.

More recent weight loss medications such as orlistat and sibutramine were subject to more intensive reporting of safety and side effects than earlier drugs such as phentermine and diethylpropion. Sibutramine was recently subjected to a reassessment of its safety profile in Europe and a positive risk-benefit for the drug affirmed. Reported side effects for orlistat were generally mild to moderate although a number of serious adverse events possibly related to therapy were reported. Phentermine and diethylpropion are no longer recommended for use for the treatment of obesity by the Royal College of Physicians in the UK.

There was very limited evidence upon which to judge the affordability of treatment (criterion 6). The cost per patient per month was higher for the newer drugs – i.e., orlistat and sibutramine than for phentermine and diethylpropion.


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There were conflicting estimates of the cost-effectiveness of orlistat. There is some evidence to suggest that orlistat treatment in patients with a number of co-morbidities is likely to be better value for money than treating otherwise healthy obese patients. Orlistat treatment of patients with type 2 diabetes who were free of clinical events and without hypertension or cholesterolemia was considered to be on the margin of cost effectiveness in one study while in another study, the estimated incremental cost per QALY of orlistat treatment appeared to lie beyond the UK cost-effectiveness threshold.

In contrast the cost-effectiveness of sibutramine, as estimated in two separative evaluations with differing assumptions and utilities, appeared to be within the UK threshold. However, an assumption of lower utility gains per kilo of weight lost for sibutramine resulted in costs that exceeded the threshold for UK cost-effectiveness. If the same cost-effectiveness threshold is assumed for New Zealand and ACC claimants, the circumstances of use for orlistat needs careful assessment if the treatment is to be cost-effective. Sibutramine treatment is likely to be cost-effective for a much wider range of patients, although monitoring for side effects may impact on this assumption.

Expected weight loss and duration of weight loss

Most of the studies reviewed agree that weight loss achieved with pharmacotherapy is modest. For most purposes the mean difference between placebo and each of the drugs in the current review was under 4kg and maintenance of weight loss without continued treatment problematic. However, experience from clinical trials indicates that most weight loss occurs within the first six months of treatment with weight loss at four weeks reported to be predictive of weight loss at six months for sibutramine. Discontinuation of treatment of all of the drugs reviewed is advised if reasonable weight loss does not occur within 12 weeks of starting treatment.

Potential barriers to use

Weight loss targets set by obese people are frequently unrealistic. In most clinical trials, weight loss ranges from 500g – 1kg per week for about six months before stabilising spontaneously. Highly restrictive diets (< 800kcal/d) have not proven to be more effective in the long-term than more modest dietary interventions such as meal replacement. Reduction of 500-1000kcal per day is recommended. The potential barriers to use for phentermine, diethylpropion, orlistat and sibutramine have been reported in detail in an earlier sectionof the review (see drug descriptions pages 9-13). A summary is presented in Appendix I.


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Evidence Summary and Conclusions

More than half of the New Zealand adult population is overweight or obese. The problem is increasing in children and adults and is more prevalent in lower socio-economic groups and amongst Maori and Pacific peoples. Given the prevalence of obesity and overweight amongst New Zealanders, a significant proportion of ACC clients are likely to be obese at the time of accident or injury or overweight and in danger of becoming obese as a result of lifestyle changes that may result from injury or accident. There are a number potential consequences for ACC and its clients.

Obesity is associated with a number of co-morbidities including heart disease, diabetes, stroke, high blood pressure and certain cancers. There is also an increased risk of adverse events from anaesthesia in these clients and psychological problems such as clinical depression that may result in job discrimination and other employment difficulties.

Personal care requirements may increase, particularly in relation to attendant care and additional health interventions may be required for co-morbid conditions initiated or exacerbated as a consequence of obesity. These problems may impact on quality of life and significantly interfere with treatment, recovery and rehabilitation.

Overall, obese clients are likely to require additional treatment and/or health related resources compared to clients who are not obese. The potential cost implications of the additional health care and resources that may be associated with untreated obesity are likely to be significant.

Clinical effectiveness and circumstances of use

Weight loss

For all of the drugs examined, most weight loss was achieved within the first six months of treatment and weight loss was not generally maintained when medication was withdrawn. Pharmacologically aided weight loss was generally modest but clinically important because of concomitant reductions in risk levels for obesity-associated co-morbidities. For long-term maintenance of weight loss, the evidence to date suggests that obesity requires sustained therapy in much the same manner as other chronic diseases.

All of the drugs examined were used as adjuncts to diet and or behaviour therapy, physical exercise and lifestyle changes. In most studies, the weight loss drugs were added to a calorie controlled diet or a similar diet plan. There was great heterogeneity between the individual studies in terms of these accompanying non-drug interventions.

All of the appraised studies were evidence level 1a or 1b according to the SIGN criteria.

Phentermine hydrochloride 15mg and 30mg is indicated as a short-term adjunct in a medically monitored comprehensive regimen of weight reduction based on exercise, calorie controlled diet and behaviour modification in patients with a BMI ≥30kg/m2 who have not had a clinical response to an appropriate weight reduction program alone. Patients with obesity related co-morbidities such as sleep apnoea, insulin resistant diabetes mellitus, pre diabetes mellitus or IGT or high cardiovascular risk status, and have a BMI of less than 30kg/m2 may also be considered for treatment.


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Phentermine may be prescribed for up to 12 weeks when used as an adjunct in a medically monitored regimen of weight reduction. Failure to achieve a weight reduction of 5% within 12 weeks is an indication for discontinuation. Treatment may be continued beyond 12 weeks provided the patient is monitored for weight loss and medical conditions, and as long as weight loss is maintained.

The effectiveness of phentermine has been examined in a number of studies but most significantly in a comparative meta-analysis of four decades of published randomised trials of anti-obesity treatments. Patients who were prescribed phentermine lost on average 6.3 kilograms with a placebo subtracted average weight loss of 3.6 kilograms (mean follow-up 13.2 weeks). Weight loss was maintained for an unspecified period26 after the formal study completion at a placebo-subtracted average of 2.43 kilograms. When the effect size for phentermine was compared to other anti-obesity drugs, it was second to sibutramine and higher than either orlistat or diethylpropion. However, the confidence intervals for all four drugs overlapped suggesting that there was no significant difference in average weight loss between the medications.

Diethylpropion hydrochloride 75mg is an appetite suppressant with a recommended daily dose of 75mg taken once daily, mid-morning. It is indicated for short-term, intermittent use in a medically monitored regimen of weight reduction based on exercise, calorie restriction and behaviour modification in obese patients with a BMI ≥ 30kg/m2 who have not had an adequate response to an appropriate weight loss program of diet and/or exercise alone. Patients with a BMI of less than 30kg/m2 with co-morbidities including sleep apnoea, insulin resistant diabetes mellitus, pre diabetes mellitus or IGT or high cardiovascular risk status, may also require medical assistance with weight loss. These patients may also be considered for treatment with diethylpropion. It is not recommended for children under 18 years.

Diethylpropion may be prescribed for courses of up to 12 weeks, with intervening periods of one month without treatment. Failure to achieve a weight reduction of 5% within a period of 12 weeks is an indication for discontinuation of treatment.

The effectiveness of diethylpropion was reported in a number of small studies and a single meta-analysis of four decades of randomised trials of weight loss medication. The results varied considerably with both positive and negative placebo-subtracted weight loss – i.e., superior and inferior weight loss when compared to the placebo group. In the most rigorous study, comprising a meta-analysis of nine randomised trials of diethylpropion, effectiveness varied with some studies reporting a weight gain in comparison with the placebo group. Diethylpropion produced a 3.0-kilogram greater weight loss than the placebo with an effect size of 0.57. In a comparison of the effect sizes for diethylpropion, phentermine, orlistat and sibutramine, diethylpropion had a lower reported effectiveness than sibutramine and phentermine but a higher reported effectiveness than orlistat. The weight loss achieved by all of the drugs was similar and the confidence intervals for effect size overlapped.

Orlistat 120mg is indicated as a long-term treatment for obesity, weight-loss maintenance and prevention of weight regain in adults with a BMI ≥30kg/m2. It should be used in conjunction with a low fat calorie controlled diet that is nutritionally balanced and contains approximately 30% of calories from fat distributed over three meals. The diet should be rich in fruit and vegetables. The recommended daily dose is one 120mg capsule three times a day at mealtimes.

26 Mean follow-up assessment for all drugs studies = 17.3 weeks, median=6 weeks after the formal study completion.


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The efficacy of orlistat in children27 and adolescents below the age of 18 years has not been established. There are currently no safety and efficacy data beyond two years and the duration of treatment should not extend beyond this period.

As one of two relatively new anti obesity medications with a novel mode of action, orlistat has been subjected to close scrutiny. A large number of relevant studies were identified including 10 systematic reviews and seven additional eligible RCTs. One of the systematic reviews was a Cochrane Review and two were performed as part of an overall HTA commissioned by the NHS R&D HTA Program on behalf of NICE in the UK (Avenell et al. 2004; O'Meara et al. 2001). Some studies examined the effect of treatment with orlistat over a period of up to two years.

Patient populations varied considerably between the studies. For the purposes of this review the results have been summarised for four patient populations (a) all patients, mixed co-morbidity risk (b) healthy obese patients (c) diabetic or glucose intolerant patients and (d) hypercholesterolemic patients.

For all patients (mixed risk groups), the placebo subtracted weight loss was 3.01 kilograms after 12 months treatment and 3.26 kilograms after 24 months of treatment. In studies reporting otherwise healthy patients only the placebo subtracted weight loss was similar with a 2.5 - 2.9 kilogram loss after 12 months and 3.6 kilogram loss at 18 months. Clinically important weight loss – i.e., a weight loss of ≥ 5% was reported at one year for 58-78% of healthy obese patients.

For studies reporting on weight loss in diabetic or glucose intolerant patients, a clinically significant weight loss was reported in 30% of orlistat + diet treated patients against 13% of patients treated with placebo + diet. This was however, somewhat lower than that reported for the non-diabetic group where 45% of patients achieved a clinically important weight loss. In a pooled analysis of diabetic and non-diabetic patients, one HTA reported a placebo subtracted weight loss of 1.8 kilograms and 2.5 kilograms for diabetic and non-diabetic patients respectively.

A meta-analysis of diabetic only patients reported a greater proportion (72%) of patients improving their glucose tolerance with orlistat treatment than the placebo group (49%) and less than half as many patients (3.0% vs. 7.6%) with IGT progressed to diabetic status after treatment with orlistat.

Patients with hypercholesterolemia who had been treated with orlistat were reported to have lost up to 3kg more on average than those treated with placebo with significant improvements reported in LDL- cholesterol and total cholesterol; there was also evidence of a significant reduction in SBP and DBP.

Sibutramine hydrochloride 10mg and 15mg may be used as a long-term treatment and management of obesity including weight loss and weight maintenance in patients with an BMI ≥ 30kg/m2 or ≥ 27kg/m2 in patients who have diabetes, dyslipidaemia or hypertension. It is intended for use when patients have not adequately responded to appropriate weight-reducing therapy such as hypocaloric diet and/or exercise alone – e.g., patients having difficulty in achieving or maintaining ≥ 5% weight loss within three months. The recommended starting dose is 10mg once daily with or without food; in clinical trials sibutramine was given in the morning. If there is less than 2kg weight loss after four weeks, and the 10mg dose is well

27 As this report was being completed, the FDA announced that Xenical® had been approved for use in children.


70

tolerated, the daily dose may be increased to 15mg. Sibutramine is not currently intended for general use in obese children under 18 years or in elderly patients over 65 years.

Patients who have demonstrated an adequate response – i.e., weight loss of ≥ 2kg within four weeks at a defined dose; usually achieve a maximum weight loss (5%-10% of initial body weight) after six months of continuous treatment with sibutramine. The current data sheet supports treatment for up to one year, however, the evidence of long-term safety and efficacy reported in the STORM study led to the US FDA to extend its clearance of sibutramine therapy to two years. Treatment must be discontinued in patients who have not had an adequate response – i.e., patients whose weight loss stabilises below 5% of initial body weight or whose weight loss within three months of starting treatment is less than 5% of their initial body weight. Treatment should not be continued in patients who regain 3kg or more after previous weight loss with sibutramine.

As one of two relatively new anti-obesity medications, sibutramine has been subjected to close scrutiny and a large number of relevant studies were identified including 10 systematic reviews and seven additional eligible RCTs. Patient populations varied considerably between the trials, as did the reporting of results. Study size varied considerably with RCTs varying between 34-389 participants and systematic reviews, HTAs and meta-analyses between 160-4,528 participants. There was considerable duplication and overlap between the studies and considerable heterogeneity in the reporting of results.

The most recent HTA reported a significant placebo subtracted average weight loss of 4.12 kilograms after 12 months of treatment. The STORM trial reported a placebo subtracted average weight loss of 3.4 kilograms after 18 months of treatment. For patients without significant obesity related co-morbidities a clinically significant weight loss – i.e., ≥ 5% of initial body weight was reported to be 21-34% higher for the sibutramine treated group than the placebo treated group, the placebo subtracted weight loss was between 3.0-4.3 kilograms.

For patients with type 2 diabetes, one study reported a clinically important weight loss difference between the treated groups and the placebo group of 45% at a dose of 15mg/d and 65% at a dose of 20mg/d. In another study, diabetic patients were reported to have lost 8.7 kilograms more weight than the placebo group (p<0.0001) after six months of treatment. In all other studies where stratification and sub-group analyses of diabetic patients were reported, a significant difference between the sibutramine treated diabetic group and the placebo treated diabetic groups was reported.

For patients with mild to moderate hypertension, 12 weeks of treatment with 10mg/d of sibutramine resulted in 44% of patients achieving a clinically important weight loss compared with 17% in the placebo group (p=0.01). In a meta-analysis of 21 RCTs, sibutramine showed a large effect size (-1.0, range –1.17 to -0.84) but increased blood pressure significantly. Most other studies of sibutramine actually excluded patients with hypertension or cardiovascular disease, others only allowed participants with well-controlled hypertension.

The effect of sibutramine varies with dose. The doses of sibutramine used in most studies in this review varied between 5-30mg/d. In some studies, a sub-group analysis was carried out for different dose levels, this was however uncommon. One study specifically designed to examine the effect of dose on treatment response was identified. It included a systematic review of 10 RCTs of 1,047 obese patients treated with doses of sibutramine ranging from 1-30mg/d. A significant dose response effect was reported after six months of treatment with the proportion of patients losing ≥ 5% of their initial rate varying from 25% at a dose of 1mg/d to 77% at a dose of 30mg/d. The proportion of placebo treated participants reporting a weight loss of ≥ 5% of initial body weight was 20%. The proportion of patients who withdrew because of adverse events, increased with increasing sibutramine dose levels. Treatment related adverse


71

events were more common in the 30mg/d group. Weight loss at four weeks was found to be predictive of weight loss at six months.

A recent dose ranging trial of sibutramine in obese adolescents between the ages of 13-17 years was also identified. A placebo subtracted average weight loss of 4.6 kilograms (95 % CI, 2.0-7.4, p=0.001) was reported in an ITT analysis after six months of treatment. Medication was reduced or discontinued in a significant number of sibutramine treated patients due to increases in blood pressure, pulse rate and other symptoms. Although sibutramine treatment was successful, the authors cautioned against the use of sibutramine in adolescents outside clinical trials until further efficacy and safety data were available.

Meal replacement plans

Meal replacement strategies are often included in LCDs (diets in the range of 1200-1600kcal/day), which are the cornerstone of modern weight control efforts. However, there are no established definitions of meal replacements plans. In the scientific literature, “meal replacement” is a term generally used to cover beverages, pre-packed, shelf-stable and frozen entities and meal or snack bars. Most of the products are fortified with vitamins and minerals and designed to be consumed in place of one or more regular meals.

Searches for specific meal replacement products such as Complan and Ensure did not identify any published scientific literature relating to these products between 1996-2004. A wider search for meal replacement plans revealed a similar paucity of information.

Meal replacement eating plans have only very recently been critically evaluated for safety and efficacy. The first meta-analysis evaluating RCTs of PMR plans was published in 2003. In this study of 276 potentially relevant publications, 30 were classified as meal replacement studies proper and only six of these studies met the review criteria. A meta-analysis of these studies estimated that the PMR group lost an average of 2.54 kilograms more than the control group after three months of treatment and 2.43 kilograms more than the control group after 12 months of treatment. The proportion of subjects losing ≥ 5% of initial body weight after three months was 33% for the control group and 72% for the PMR group (p<0.001).

After stratification according to diabetic status, non-diabetic completers lost on average 2.79 kilograms more than the control group after three months (p<0.001) and 3.17 kilograms more after 12 months (p=0.002). The diabetic group completers lost on average 2.46 kilograms more than the control at three months and 2.76 kilograms more than the control at 12 months; neither differences reached significance, however, the number of diabetic cases was small and the standard error for the group large.

A single additional product and RCT was identified by the comprehensive search strategy constructed for the current review. One hundred overweight or obese participants were randomly assigned to a novel soy-meal replacement program plus dietary counselling or 1200kcal exchange diet program plus dietary counselling. After 12 weeks, the treatment group lost significantly more weight than the control group (7.00kg vs. 2.90kg, p<0.001, ITT analysis). Fat mass was also significantly lower in the treated group -4.3 vs. -1.4 (p=0.003).

Obesity related risk factors

No data were reported on the effect of phentermine, diethylpropion or meal replacement therapy on obesity-related co-morbidities and their associated risk factors.

Orlistat induced weight loss was accompanied by significant and favourable changes in a number of CHD risk factors including total cholesterol, LDL-cholesterol, blood pressure and


72

glucose metabolism. When diabetic and glucose intolerant patients were treated with orlistat, a high proportion of diabetics improved their glucose tolerance and there was a reduction in the proportion of patients with IGT progressing to diabetic status.

Sibutramine treated patients also experienced significant and favourable changes in obesity related risk factors. Significant improvements were reported for HDL-cholesterol and triglyceride levels and non-significant improvements for LDL-Cholesterol, HbA1c and fasting glucose levels. However, blood pressure levels on average rose during treatment with sibutramine and in some instances there was a significant difference in favour of the control group. In patients with type 2 diabetes, blood pressure increases were reported to be offset by weight loss while in hypertensive patients blood pressure reductions were reported with sibutramine patients showing slightly lower mean improvements than the placebo group. Most studies of sibutramine excluded patients with hypertension or cardiovascular disease or only allowed well-controlled hypertension and further data may be required to determine more fully the effect of this drug on patients with raised blood pressure. In dose ranging studies, blood pressure and heart rate increased with increasing dose levels of sibutramine.

Safety and side effects

Overall, the therapies examined in this review were reported to be well tolerated and mostly without significant side effects or serious adverse events. However, safety and side effects have only been reported for highly selected patient populations in closely monitored clinical trials and the results obtained may not apply to typical clinical populations or the ACC claimant population.

Early studies of phentermine suggested that it was well tolerated with only minor adverse events reported for 3-8% of patients. Stimulant effects such as agitation and insomnia were reported. Concerns have been raised about the safety of phentermine and the drug is no longer recommended by the Royal College of Physicians in the UK.

Diethylpropion was reported to have few stimulant adverse events; rapid tolerance to the drugs anorectic effects was reported. Concerns have been raised about the safety of diethylpropion and the drug is no longer recommended by the Royal College of Physicians in the UK.

Orlistat is a locally acting drug and the main adverse events reported were gastrointestinal. Commonly reported side effects were fatty, oily or liquid stools, faecal urgency or incontinence and flatulence, reported in 22-95% of orlistat users. Most GI adverse events occurred early in the course of treatment and may be moderated by dietary adjustments, nevertheless, some of the GI side effects may be unacceptable to some groups of patients. Other undesirable effects attributed to orlistat were lower serum levels of fat-soluble vitamins and interference with the effectiveness of warfarin and cyclosporine treatment.

Sibutramine was generally well tolerated by the study populations at the recommended starting dose of 10mg/d. The most commonly reported side effects were headache, constipation and nausea. Adverse events associated with the CNS including dizziness, dry mouth and insomnia were reported by more than 5% of patients.

The two most clinically significant side effects were increased blood pressure and tachycardia. These symptoms were generally seen in the first eight weeks of treatment and although in some instances the increases reached statistical significance they were not generally considered to be clinically important in otherwise healthy obese patients. Sibutramine is contraindicated in patients with uncontrolled hypertension or cardiovascular disease.


73

After a number of adverse events and two deaths the benefit/risk ratio of sibutramine was reassessed by the EMEA in 2002; a positive benefit-risk profile for the drug was reaffirmed by the agency after further investigation.

As significant safety and efficacy data for orlistat and sibutramine does not extend beyond two years there is no evidence of their long-term safety.

There are few reports on the safety and side effects of meal replacement plans. In the two studies evaluated in the current review, one (Heymsfield et al. 2003) reported a lack of adverse events in any study patients, including treated diabetics, while the other (Allison et al. 2003) reported a large number of adverse events. In the latter study, which was an unblinded RCT of a novel soy-based meal replacement formula for weight loss, constipation, gas or indigestion, abnormal or metallic taste, lethargy and weight loss were significantly higher in the meal replacement group. Generally however, treatment was reported to be well tolerated and free of serious side effects by the study authors.

Ethnic groups

Some ethnic groups are more at risk of obesity than others and BMI thresholds for obesity are known to vary with ethnicity, as are the co-morbidity risks. However, no studies of the efficacy of phentermine, diethylpropion, orlistat, sibutramine or meal replacement in different ethnic groups were identified. Most of the participants in the reported RCTs were white Caucasian females and the results obtained and the conclusions reached may not be applicable to other ethnic groups. A higher obesity threshold is advised for Polynesians and a lower threshold for Asians.

Economic considerations

Orlistat and sibutramine monthly drug costs are similar at $210.45 and $181.17-$208.32 (depending on dosage) respectively, the cost of phentermine and diethylpropion medication are much lower at $18.91 and $37.82-$43.01 respectively. Additional direct costs including GP visits and laboratory tests are likely to be the same for each of the drugs and are unlikely to exceed the monthly drug costs.

There were no published economic analyses of phentermine or diethylpropion, however, in one comparative study the estimated cost per kilogram of weight lost for phentermine, orlistat and sibutramine was US$91, US$433 and US$323 respectively. This is roughly in line with the differential daily NZ direct cost of the drugs.

Economic evaluations of orlistat from two systematic reviews suggested that the overall cost of orlistat therapy is high with the incremental cost per QALY gained estimated to be £45,888 (range £19,425 - £55,391) in one study and approximately £31,978 in another. Overall, treating healthy obese patients was much less cost-effective than treating patients with obesity related co-morbidities. Treating only patients with obesity related hypertension and/or hypercholesterolemia was considered to be good value for money and the results of the analysis robust under sensitivity analysis.

Only one published economic analysis of sibutramine was identified. Two central estimates of cost per QALY gained were reported arising from differing assumptions and utilities associated with weight loss.


74

The costs per QALY arising from the two calculations were £4,780 and £10,530. However, the basic economic model used in both analyses assumed benefits additional to weight loss arising from associated improved risk profiles in patients with co-morbidities. The costs per QALY of weight loss alone were £6,341 and £19,125 and worst-case scenarios estimated at £20,602 and £34,260 respectively in the two models. Sibutramine was considered to be cost-effective even at the highest cost per QALY obtained in this analysis and it was noted that if all co-morbidities were included in the model, the cost per QALY would decrease.


75

Evidence Tables

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

76

Evi

den

ce T

able

1.

Mea

l rep

lace

men

t, H

eym

sfie

ld, 2

003

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

ies

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

Wt-

loss

dif§

s.

e.

p v

alue

Val

idity

/App

licab

ility

S

afet

y C

oncl

usi

ons

C

omm

ents

Hey

msf

ield

, 20

03

Stu

dy d

esig

n

Met

a-an

alys

is o

f six

R

CT

s O

bje

ctiv

e T

o as

sess

the

safe

ty a

nd

effe

ctiv

enes

s of

m

eal r

epla

cem

ent

ther

apy

S

tud

ies

N=6

D

itchu

neit

et a

l.,

1999

**

Fle

tche

r-M

ors

et a

l.,

2000

**

Rot

hack

er 2

001

Yip

200

1 H

ensr

ud 2

001

Ash

ley

2001

A

hren

s 20

00

Par

ticip

ants

N=4

87

Mal

e= 2

5%

Fem

ale:

=75

%,

Mea

n ag

e 46

.1 y

ears

M

ean

BM

I at b

asel

ine

=31

Dia

betic

N=1

19 (2

4%)

Non

-dia

betic

N

=368

(76%

) In

clus

ion

R

ando

mis

ed tr

ial

com

parin

g P

MR

to a

tra

ditio

nal L

CD

S

tudy

dur

atio

n >

3mon

ths

Sub

ject

s >1

8 ye

ars

Exc

lusi

on

Stu

dies

with

sel

f re

porte

d da

ta.

Du

ratio

n

3-51

mon

ths,

med

ian

12

mon

ths

Loc

atio

n

US

A (n

=5)

Ger

man

y (n

=1)

No

te: 2

mea

ls a

day

w

ere

repl

aced

in th

e ex

posu

re d

urin

g th

e w

eigh

t los

s ph

ase,

one

m

eal a

day

dur

ing

the

wei

ght m

aint

enan

ce

phas

e.

Exp

osu

re (P

MR

) P

MR

– i.

e., o

ne o

r m

ore

mea

ls re

plac

ed

by a

com

mer

cial

ly

avai

labl

e, c

alor

ie-

redu

ced

prod

uct(s

) th

at a

re fo

rtifie

d w

ith

vita

min

s an

d m

iner

als

and

at le

ast o

ne d

aily

m

eal c

onsi

stin

g of

re

gula

r foo

ds, a

ctin

g as

a L

CD

and

pr

ovid

ing

>800

<=16

000k

cal/d

ay

Co

mp

aris

on (R

CD

) T

radi

tiona

l LC

D p

lan

(LC

D) w

ith th

e sa

me

calo

ric c

ompo

sitio

n as

th

e ex

posu

re.

Res

ults

at 3

mon

ths

Met

a-an

alys

is fi

xed

effe

cts

Met

a-an

alys

is ra

ndom

effe

cts

Poo

led

anal

ysis

of c

ompl

eter

s P

oole

d an

alys

is L

OC

F

Poo

led

anal

ysis

MI

>=5%

wei

ght l

oss

RC

D=3

4%,

PM

R=7

2%

Non

-dia

betic

P

oole

d an

alys

is o

f com

plet

ers

Poo

led

anal

ysis

LO

CF

P

oole

d an

alys

is M

I D

iabe

tic

Poo

led

anal

ysis

of c

ompl

eter

s P

oole

d an

alys

is L

OC

F

Poo

led

anal

ysis

MI

Res

ults

at 1

yea

r (R

CD

N=4

, PM

R

N=5

) M

eta-

anal

ysis

fixe

d ef

fect

s M

eta-

anal

ysis

rand

om e

ffect

s P

oole

d an

alys

is o

f com

plet

ers

Poo

led

anal

ysis

LO

CF

P

oole

d an

alys

is M

I >=

5% w

eigh

t los

s R

CD

=33%

P

MR

=74%

N

on-d

iabe

tic

Poo

led

anal

ysis

of c

ompl

eter

s P

oole

d an

alys

is L

OC

F

Poo

led

anal

ysis

MI

Dia

betic

P

oole

d an

alys

is o

f com

plet

ers

Poo

led

anal

ysis

LO

CF

P

oole

d an

alys

is M

I R

isk

fact

ors

⊥ ⊥⊥⊥

Glu

cose

(mg/

dl)

SB

P (m

mH

g)

DB

P (m

mH

g)

Insu

lin (Φ

U/m

l) C

hole

ster

ol (m

mol

/l)

HD

L (m

mol

/l)

LDL

(mm

ol/l)

T

G (m

mol

/l)

3.

01

2.60

2.

54

2.39

2.

23

2.79

2.

67

2.47

2.

46

2.62

1.

67

3.39

2.

43

2.63

2.

86

1.62

3.

17

3.56

2.

92

2.76

1.

52

2.86

3

moW

L p

= 0.

028

<0.0

01

ns

ns

ns

ns

0.03

9 0.

014

0.

33

0.96

0.

37

0.35

0.

35

0.37

0.

35

0.33

1.

84

1.89

1.

73

0.72

1.

65

0.88

0.

46

0.98

0.

99

0.50

0.

66

2.00

1.

89

2.53

6

moW

L p

= 0.

009

<0.0

01

ns

ns

<0.0

01

ns

0.00

1 0.

011

<0

.001

0.

006

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

ns

ns

ns

<0.0

01

0.14

2 0.

003

<0.0

01

0.11

9 <0

.001

0.

002

<0.0

01

<0.0

01

ns

ns

ns

PM

R-R

CD

p= ns

ns

ns

<0

.001

ns

ns

ns

ns

Bas

elin

e co

mpa

riso

n

PM

R a

nd R

CD

diff

ered

si

gnifi

cant

ly in

one

fact

or –

base

line

gluc

ose.

D

rop

-ou

t rat

e 3

mon

ths

(ns)

E

xpos

ure

= 16

%

Con

trol=

19%

1

year

(p<0

.001

) E

xpos

ure=

47%

C

ontro

l=64

%

Non

e of

the

drop

-out

repo

rted

prog

ram

or p

rodu

ct-r

elat

ed

adve

rse

even

ts.

Het

ero

gen

eity

E

stim

ates

of w

eigh

t los

s an

d ef

fect

iven

ess

of b

oth

grou

ps

from

the

indi

vidu

al s

tudi

es

wer

e he

tero

gene

ous

(p=<

0.00

1).

Qu

ality

T

he q

ualit

y of

all

stud

ies

as

asse

ssed

by

the

Jada

d cr

iteria

=

mod

erat

e.

Blin

ding

was

not

pos

sibl

e du

e to

the

natu

re o

f the

in

terv

entio

ns.

Blin

ding

of t

he o

utco

me

asse

ssor

was

not

des

crib

ed.

Ran

dom

isat

ions

des

crip

tion

was

incl

uded

in a

ll pr

otoc

ols

and

all s

tudi

es p

rovi

ded

deta

ils

of d

ropo

uts.

With

in th

e co

ntex

t of a

clin

ical

tri

al, P

MR

app

ears

to p

rom

ote

sign

ifica

ntly

gre

ater

wei

ght l

oss

than

a c

orre

spon

ding

RC

D p

lan.

T

he o

vera

ll m

agni

tude

of t

he

wei

ght l

oss

in a

poo

led

anal

ysis

at

1 ye

ar w

as in

the

rang

e re

porte

d in

som

e ph

arm

acol

ogic

al w

eigh

t co

ntro

l stu

dies

(Gla

ser 2

000)

and

is

at t

he le

vel k

now

n to

low

er

dise

ase

risk.

F

our s

tudi

es e

nrol

led

subj

ects

w

ith n

o co

-mor

bidi

ties,

the

othe

r 2

wer

e de

sign

ed fo

r pat

ient

s w

ith

type

2 d

iabe

tes.

A

ll si

x st

udie

s re

sulte

d in

si

gnifi

cant

wei

ght l

oss

from

ba

selin

e in

bot

h gr

oups

. P

MR

gro

ups

lost

sig

nific

antly

m

ore

wei

ght t

han

the

cont

rol

grou

p.

No

te: %

wei

ght l

oss

at 3

mon

ths

RC

D=4

%, P

MR

=7%

. % w

eigh

t lo

ss a

t 1 y

ear R

CD

. 3-7

%,

PM

R.7

-8%

T

he fi

rst s

yste

mat

ic e

valu

atio

n of

R

CT

s ev

alua

ting

PM

R p

lans

for

wei

ght m

anag

emen

t sug

gest

s th

at

they

can

saf

ely

and

effe

ctiv

ely

prod

uce

sign

ifica

nt w

eigh

t los

s.

The

re w

as n

o su

ppor

t for

pu

blic

atio

n bi

as.

*One

tria

l >=3

0 ye

ars

** s

ame

stud

y po

pula

tions

ns=

no

sign

ifica

nt d

iffer

ence

bet

wee

n gr

oups

§ P

MR

= p

artia

l mea

l rep

lace

men

t, R

CD

= re

duce

d ca

lorie

die

t. N

ote:

All

risk

fact

or v

alue

s fo

r bo

th g

roup

s w

ere

sign

ifica

ntly

diff

eren

t fro

m b

asel

ine

valu

es a

t 3 a

nd 6

mon

ths,

3m

oWL=

3 m

onth

wei

ght l

oss,

6m

oWL=

6 m

onth

wei

ght l

oss.

MI=

mul

tiple

impa

tatio

n, L

OC

F=l

ast o

bser

vatio

n ca

rrie

d fo

rwar

d.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

77

Evi

den

ce T

able

2.

Mea

l rep

lace

men

t, A

lliso

n e

t al

., 20

03

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y L

ocat

ion

(s)

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

R

ecru

itmen

t

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

)

Tre

atm

ent

(s.d

.) C

ontr

ol

(s.d

.) ∈ ∈∈∈

T-C

P

=

Val

idity

/App

licab

ility

S

afet

y C

oncl

usi

ons

C

omm

ents

-7

.0(4

.6)

-1.5

(3.6

) -4

.3(4

.0)

-6.0

(4.2

) -2

2.5(

30.2

) -2

1.2(

23.5

) -1

.5(7

.8)

-1.3

(11.

0)

-4.8

(28.

4)

Tre

atm

ent

mea

n

-2

.9(3

.3)

-0.2

(4.8

) -1

.4(4

.8)

-2.9

(3.7

) -6

.8(2

4.7)

-7

.1(1

9.1)

-0

.5(1

0.6)

0.

9(6.

6)

-1.5

(12.

3)

Co

ntr

ol

mea

n

0.

001 ns

0.

003

0.00

3 0.

013

0.00

9 ns

ns

ns

p

- val

ue

Alli

son

et a

l.,

2003

S

tudy

Des

ign

R

CT

O

bje

ctiv

e T

o as

sess

the

effic

acy

and

safe

ty o

f a lo

w

calo

rie s

oy-b

ased

m

eals

repl

acem

ent

prog

ram

for t

he

treat

men

t of o

besi

ty.

Stu

dy lo

catio

n(s

) U

SA

D

ura

tion

12

wee

ks

Par

ticip

ants

N

=100

(120

scr

eene

d)

BM

I 28-

41kg

/m2

Age

35-

65

Mal

e =2

0 F

emal

e =8

0 In

clus

ion

O

verw

eigh

t or o

bese

su

bjec

ts

Med

ical

ly fi

t for

saf

e w

eigh

t los

s E

xclu

sion

W

eigh

t los

s of

>5k

g in

th

e pa

st 3

mon

ths

Use

of w

eigh

t los

s dr

ugs

in th

e la

st 6

wee

ks.

Sco

res

abov

e th

e 90

th

perc

entil

e on

the

Brie

f S

ympt

om in

vent

ory

Dis

ease

not

bel

ieve

d to

be

at l

east

par

tially

the

resu

lt of

obe

sity

and

tre

atab

le b

y w

eigh

t re

duct

ion.

Med

ical

or

psyc

holo

gica

l co

ntra

indi

catio

ns

Kno

wn

hype

rsen

sitiv

ity to

an

y of

the

ingr

edie

nts

of

the

form

ula.

R

ecru

itmen

t D

etai

ls n

ot g

iven

.

Exp

osu

re N

=50,

M

=10,

F=4

0 S

can

diet

mea

l re

plac

emen

t for

mul

a,

5 S

can

diet

sha

kes

+ 4

exch

ange

s of

frui

t, 4

exch

ange

s of

ve

geta

bles

and

one

fa

t exc

hang

e pe

r day

in

stru

ctio

ns fo

r use

+

a si

ngle

ses

sion

di

etar

y co

unse

ling

+ a

pam

phle

t de

scrib

ing

good

w

eigh

t los

s pr

actic

es.

Co

mp

aris

on N

=50

M=1

0, F

=40

1200

kcal

exc

hang

e di

et s

yste

m.

A s

ingl

e se

ssio

n di

etar

y co

unse

lling

an

d a

pam

phle

t de

scrib

ing

good

w

eigh

t los

s pr

actic

es.

12 w

eek

asse

ssm

ent (

ITT

)*

Wei

ght c

hang

e (k

g)

Tot

al b

ody

fat m

ass

(%)

Fat

mas

s (k

g)

Wai

st c

ircum

fere

nce

(cm

) T

otal

cho

lest

erol

(mg/

dl)

LDL

chol

este

rol (

mg/

dl)

HD

L ch

oles

tero

l (m

g/dl

) D

BP

(mm

Hg)

S

BP

(mm

Hg)

**

All

asse

ssm

ents

at

4 an

d 8

wee

ks

wer

e n

s ex

cep

t fo

r:

Fat

mas

s at

8 w

eeks

p=0

.011

,tota

l ch

oles

tero

l at 4

wee

ks p

=0.0

02, 8

w

eeks

p=0

.000

1,LD

L ch

oles

tero

l at 4

an

d 8

wee

ks p

=<0.

0001

A

dve

rse

even

ts (M

OS

ES

)a A

s as

sess

ed a

t 12

wee

ks

App

etite

: dec

reas

ed/a

nore

xia

C

onst

ipat

ion

Dia

rrho

ea

Dro

olin

g/sa

livat

ion

Gas

/indi

gest

ion

Tas

te: a

bnor

mal

/met

allic

Le

thar

gy/n

o m

ovem

ent

Sle

ep: e

xces

sive

U

rinar

y: e

nure

sis/

noct

ures

is

Wei

ght g

ain

Wei

ght l

oss

Not

e: 1

3 m

issi

ng v

alue

s fo

r tre

atm

ent

grou

p an

d 13

mis

sing

val

ues

for c

ontro

l gr

oup

at w

eek

12.

0.

89

0.51

0.

27

0.03

1.

59

0.30

0.

19

0.11

0.

16

0.08

1.

30

0.

46

0.24

0.

11

0.03

0.

51

0.00

0.

00

0.08

0.

11

0.14

0.

62

ns

0.

04

ns

ns

0.00

09

0.02

23

0.04

26

ns

ns

ns

0.02

08

Prim

ary

anal

ysis

ITT

. C

ompl

eter

s on

ly a

naly

sis

also

und

erta

ken,

co

mpl

eter

s =

37/5

0 (7

4%) i

n ea

ch g

roup

. B

asel

ine

com

paris

on=

ns

Bet

wee

n gr

oup

diffe

renc

es

The

pro

tein

, car

bohy

drat

e, fa

t pro

porti

ons

betw

een

grou

ps d

iffer

ed

Exp

osed

= 3

3%: 5

2%: 1

5%

Con

trol =

23%

: 56%

: 21%

M

issi

ng d

ata

- han

dled

via

mul

tiple

im

puta

tion

rath

er th

an L

OC

F

Elig

ibili

ty -

115/

120

scre

ened

pat

ient

s w

ere

elig

ible

R

ando

mis

atio

n - 1

5/11

5 w

ere

not

rand

omis

ed. 6

= B

MI o

ut o

f ran

ge,

4=B

SI>

90%

, 1=

taki

ng a

nti-o

besi

ty

med

icat

ion,

1=

non-

com

plia

nt, 3

= m

edic

al

cond

ition

s W

ithd

raw

als

N=5

D

iarr

hoea

=3

(1 w

ith n

ause

a)

Gas

tric

reflu

x=1

Oth

er=1

Dat

a co

llect

ion

on s

ide

effe

cts

was

col

lect

ed

acco

rdin

g to

a

stan

dard

ised

pro

toco

l. 25

% o

f the

par

ticip

ants

di

d no

t com

plet

e.

Foo

d re

cord

s w

ere

not

kept

and

com

plia

nce

was

not

che

cked

in th

e co

ntro

l gro

up.

The

stu

dy w

as n

ot

pow

ered

to p

ick

up ra

re

adve

rse

even

ts.

Co

nclu

sion

S

oy p

rote

in m

eal

repl

acem

ent L

CD

re

duce

s bo

dy w

eigh

t; to

tal a

nd L

DL

chol

este

rol s

igni

fican

tly

mor

e th

an a

LC

D

with

out a

mea

l re

plac

emen

t pro

duct

.

DB

P=d

iast

olic

blo

od p

ress

ure,

SB

P=s

ysto

lic b

lood

pre

ssur

e, IT

T=i

nten

tion

to tr

eat a

naly

sis,

MO

SE

S=

mon

itorin

g of

sid

e ef

fect

s sc

ale

(MO

SE

S; K

alac

hnic

k, 1

985)

hig

her

valu

es a

re in

dica

tive

of g

reat

er s

ympt

om s

ever

ity.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

78

Evi

den

ce T

able

3.

Orl

ista

t, T

org

erso

n e

t al

., 20

04

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y L

ocat

ion

(s)

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

e

P

O

p=*

*

Val

idity

/App

licab

ility

S

afet

y C

oncl

usi

ons

C

omm

ents

Tor

gers

on e

t al.,

20

04

Stu

dy D

esig

n

Ran

dom

ised

, dou

ble

blin

d, p

lace

bo

cont

rolle

d m

ultic

entre

st

udy

Ob

ject

ive

To

dete

rmin

e th

e ef

fect

of

add

ing

orlis

tat t

o lif

esty

le c

hang

es o

n bo

dy w

eigh

t and

the

inci

denc

e of

type

2

diab

etes

. S

tudy

loca

tion

(s)

Sw

eden

D

ura

tion

F

our y

ears

Par

ticip

ants

N

=330

5 (p

lace

bo=1

637,

or

lista

t =16

40)

Mal

e=45

%

Fem

ale=

55%

M

ean

age

43.7

yea

rs

(pla

cebo

), 43

.0 y

ears

(orli

stat

). N

orm

al g

luco

se to

lera

nce

=79%

IG

T =

21%

In

clus

ion

A

ge 3

0-60

yea

rs

BM

I >=3

0kg/

m2

Non

-dia

betic

glu

cose

to

lera

nce

or IG

T (f

astin

g ve

nous

pla

sma

gluc

ose

<7.8

mm

o;/l

and

2 hr

pla

sma

gluc

ose

7.8-

11.1

mm

ol/l)

E

xclu

sion

D

iabe

tes

Ong

oing

/ act

ive

card

iova

scul

ar d

isea

se

Ong

oing

/act

ive

GI d

isea

se

Exp

osu

re

Orli

stat

120

mg

t.i.d

. +

redu

ced

calo

rie d

iet

(800

kcal

/day

def

icit)

. C

om

par

ison

P

lace

bo +

redu

ced

calo

rie d

iet

(800

kcal

/day

def

icit)

.

Wei

ght c

hang

e at

1 y

r (kg

) W

eigh

t cha

nge

at 4

yr (

kg)

Com

plet

ers

only

1 y

r (kg

) C

ompl

eter

s on

ly 4

yr (

kg)

>=5%

wei

ght l

oss

1 yr

(%)

>=5%

wei

ght l

oss

4 yr

(%)

>=10

% w

eigh

t los

s 1

yr (%

) >=

10%

wei

ght l

oss

4 yr

(%0

Car

dio

vasc

ula

r ri

sk fa

cto

rs (y

r 1)

D

BP

(mm

Hg)

S

BP

(mm

Hg)

T

otal

cho

lest

erol

(%)

LDL

chol

este

rol (

%)

HD

L ch

oles

tero

l (%

) LD

L-H

DL

ratio

T

rigly

cerid

es (%

) W

aist

circ

umfe

renc

e (c

m)

Fas

ting

who

le b

lood

* gl

ucos

e (m

mol

/l)

Fas

ting

seru

m in

sulin

(mm

ol/l)

F

ibrin

ogen

(µm

ol/l)

P

lasm

inog

en a

ctiv

ator

inhi

bito

r-1

(U/m

l) C

ard

iova

scu

lar

risk

fact

ors

(yr

4)

DB

P (m

mH

g)

SB

P (m

mH

g)

Tot

al c

hole

ster

ol (%

) LD

L ch

oles

tero

l (%

) H

DL

chol

este

rol (

%)

LDL-

HD

L ra

tio

Trig

lyce

rides

(%)

Wai

st c

ircum

fere

nce

(cm

) F

astin

g w

hole

blo

od*

gluc

ose

(mm

ol/l)

F

astin

g se

rum

insu

lin (p

mol

/l)

Fib

rinog

en (µ

mol

/l)

Pla

smin

ogen

act

ivat

or in

hibi

tor-

1 (U

/ml)

6.2

3.0

7.5

4.1

45.1

37

.3

20.8

15

.6

-2.6

-5

.2

-1.3

-1

.6

8.5

-0.3

-6

.3

-7.0

0.

2 -1

7.0

0.1

-3.0

-1

.9

-3.4

-2

.3

-5.1

9.

1 -0

.4

2.9

-4.4

0.

2 -2

0.6

-0.5

0.

1

10.6

5.

8 11

.4

6.9

72.8

52

.8

41.0

26

.2

-3.6

-7

.3

-8.8

-1

1.4

3.4

-0.5

-6

.2

-9.6

0.

1 -2

6.5

0.2

-7.1

-2

.6

-4.9

-7

.9

-12.

8 6.

5 -0

.6

2.4

-6.4

0.

1 -3

2.0

-0.4

-3

.0

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

1 <0

.01

<0.0

1 <0

.01

<0.0

1 <0

.01

<0.0

51

<0.0

1 <0

.012

<0.0

1 ns

<0.0

1 <0

.01

<0.0

1 <0

.01

<0.0

1 <0

.013

<0.0

1 ns

<0.0

1 <0

.014

<0.0

1 <0

.014

<0.0

1

Com

plia

nce

was

det

erm

ined

by

cou

ntin

g th

e nu

mbe

r of

caps

ules

retu

rned

. W

ithd

raw

als

Ref

usal

of t

reat

men

t, pl

aceb

o=20

%

orlis

tat=

14%

. With

draw

als

due

to in

suffi

cien

t the

rape

utic

re

spon

se, p

lace

bo=1

9%,

orlis

tat=

8%.

Com

plet

ers

and

non-

com

plet

ers

wer

e no

t si

gnifi

cant

ly d

iffer

ent.

Ad

here

nce

Pla

cebo

=92.

8 O

rlist

at=

93.3

%

Saf

ety

Orli

stat

was

wel

l tol

erat

ed

and

the

over

all i

ncid

ence

of

adve

rse

even

ts w

as th

e sa

me

in b

oth

grou

ps e

xcep

t fo

r GI e

vent

s. M

ost G

I eve

nts

wer

e m

ild to

mod

erat

e an

d oc

curr

ed d

urin

g th

e ea

rly

phas

e of

trea

tmen

t. O

ver t

he fo

ur-y

ear p

erio

d bo

th g

roup

s ha

d at

leas

t one

se

rious

adv

erse

eve

nt (1

3%

plac

ebo,

15%

orli

stat

). O

vera

ll 4%

of p

lace

bo a

nd

8% o

f orli

stat

pat

ient

s w

ithdr

ew b

ecau

se o

f adv

erse

ev

ents

prim

arily

GI e

vent

s.

The

re w

ere

sign

ifica

nt

decr

ease

s in

fat-s

olub

le

vita

min

s (A

, D, E

and

K1)

af

ter 4

yea

rs in

the

orlis

tat

grou

p.

Com

pare

d w

ith li

fest

yle

chan

ges

alon

e or

lista

t + li

fest

yle

chan

ges

resu

lted

in a

gre

ater

redu

ctio

n in

w

eigh

t and

a g

reat

er re

duct

ion

in

the

inci

denc

e of

type

2 d

iabe

tes

over

4 y

ears

. T

he b

enef

icia

l effe

ct o

f orli

stat

in

prev

entin

g di

abet

es w

as p

rimar

ily

due

to a

ben

efic

ial e

ffect

in IG

T

patie

nts.

T

he lo

ng-te

rm s

afet

y or

orli

stat

w

as d

emon

stra

ted.

D

urin

g 4

year

s of

trea

tmen

t or

lista

t + li

fest

yle

chan

ges

sign

ifica

ntly

dec

reas

ed th

e pr

ogre

ssio

n to

type

2 d

iabe

tes

com

pare

d w

ith p

lace

bo +

life

styl

e ch

ange

(log

-ran

k p=

0.00

32).

The

re w

as a

37.

3% d

ecre

ase

in

the

risk

of d

evel

opin

g di

abet

es

with

orli

stat

com

pare

d to

pla

cebo

. T

he d

iffer

ence

in w

eigh

t los

s w

as

the

sam

e w

heth

er a

sses

sed

by

LOC

F o

r BLC

F a

naly

sis.

O

nly

52%

of t

he tr

eatm

ent g

roup

an

d 34

% o

f the

pla

cebo

gro

up

wer

e re

tain

ed to

the

4th y

ear.

*ven

ous

bloo

d, L

OC

F =

last

obs

erva

tion

carr

ied

forw

ard,

BLC

F =

base

line

obse

rvat

ion

carr

ied

forw

ard,

ITT

=int

entio

n to

trea

t. **

Bet

wee

n tr

eatm

ent p

val

ues

for

anal

yses

, for

car

diov

ascu

lar

risk

fact

ors

anal

yses

by

LOC

F IT

T, B

LCF

ITT

and

obs

erve

d da

ta e

xcep

t whe

re in

dica

ted.

1 =

LOC

F a

nd o

bser

ved,

2 B

LCF

p<

0.05

3 LO

CF

and

BLC

F =

NS

, 4 B

CLF

=N

S.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

79

Evi

den

ce T

able

4.

Orl

ista

t, R

issa

nen

et

al.,

2001

Eff

ect S

ize

& P

reci

sion

(p

oole

d M

ean

ch

ange

fr

om

bas

elin

e at

1 y

ear)

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y L

ocat

ion

(s)

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

Cha

nge

(±se

m)

P

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Ris

sane

n et

al.,

20

01

Stu

dy d

esig

n

Ran

dom

ised

, pl

aceb

o co

ntro

lled,

do

uble

blin

d tri

al.

Ob

ject

ive

To

stud

y th

e ef

fect

of

wei

ght l

oss

on b

lood

co

agul

abili

ty a

nd

fibrin

olys

is in

hea

lth

obes

e w

omen

. L

ocat

ion

F

inla

nd

Du

ratio

n

12 m

onth

s

Par

ticip

ants

55

hea

lthy

obes

e w

omen

(5

1 co

mpl

eter

s)

Mea

n ag

e =4

4 ±

0.7

year

s M

ean

BM

I= 3

6±0.

5kg/

m2

Sm

oker

s =3

7 N

on-s

mok

ers=

14

Incl

usio

n

See

Sjo

stro

m

Exp

osu

re

Orli

stat

120

mg

t.i.d

.

+ hy

poen

erge

tic d

iet

Co

mp

aris

on

Pla

cebo

+

hypo

ener

getic

die

t H

ypo

calo

ric

die

t D

esig

ned

to c

ause

a

wei

ght l

oss

of 0

., 25

-0.

5kg/

wk

with

30%

fa

t, 50

%

carb

ohyd

rate

, and

20

% p

rote

in.

A m

axim

um o

f 30

0mg/

day

chol

este

rol w

as

dist

ribut

ed in

3 m

ain

mea

ls a

nd a

low

fat

snac

k. A

lcoh

ol

cons

umpt

ion

limite

d to

150

g pe

r wee

k.

Fur

ther

redu

ctio

n of

30

0kca

l/d a

fter 6

m

onth

s.

Wei

ght (

kg)

BM

I (kg

/m2 )

B

ody

fat (

kg)

Lean

bod

y m

ass

(kg)

D

BP

(mm

Hg)

S

BP

(mm

Hg)

S

- tot

al c

hole

ster

ol (m

mol

/l)

S-L

DL-

chol

este

rol (

mm

ol/l)

S

-HD

L-ch

oles

tero

l (m

mol

/l)

S-T

rigly

cerid

es (m

mol

/l)

S-in

sulin

(mU

/l)

Pla

cebo

vs.

orli

stat

wei

ght l

oss

at 1

2 m

onth

s (7

.2kg

vs.

13.

0kg)

was

not

si

gnifi

cant

and

the

resu

lts o

f orli

stat

and

pl

aceb

o w

ere

pool

ed.

-10.

0(1.

1)

-3.8

(0.4

) -6

.9(1

.0)

-3.1

(0.5

) -7

.1(1

.3)

-7.3

(1.9

) -0

.1(0

.1)

-0.2

(0.1

) -0

.0(0

.0)

-0.1

(0.1

) -3

.4(0

.8)

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

<0.0

01

ns

ns

ns

ns

<0.0

01

Wei

ght l

oss

was

no

t the

prim

ary

outc

ome,

dru

g an

d pl

aceb

o re

sults

poo

led.

The

re w

ere

bene

ficia

l cha

nges

in

fibrin

olys

is a

nd c

oagu

latio

n pe

rsis

ted

for o

ne y

ear i

f wei

ght l

oss

was

m

aint

aine

d.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

80

Evi

den

ce T

able

5.

Orl

ista

t, M

uls

et

al.,

2001

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e at

24

wee

ks±

s.d

., L

OC

F)

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y L

ocat

ion

(s)

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

e (in

clud

ing

ad

vers

e ev

ents

)

P

O

p=*

*

Val

idity

/App

licab

ility

S

afet

y C

oncl

usi

ons

C

omm

ents

Mul

s et

al.,

200

1 S

tudy

Des

ign

R

ando

mis

ed, p

lace

bo

cont

rolle

d, d

oubl

e bl

ind,

m

ultic

ente

r tria

l. O

bje

ctiv

e T

o as

sess

the

effe

ct o

f or

lista

t 120

mg

t.i.d

. ve

rsus

pla

cebo

on

wei

ght l

oss

and

seru

m

lipid

s in

obe

se

hype

rcho

lest

erol

emic

pa

tient

s.

Stu

dy lo

catio

n(s

) B

elgi

um

Du

ratio

n

24 w

eeks

follo

wed

by

an

optio

nal 2

4-w

eek

open

la

bel o

rlist

at e

xten

sion

ph

ase.

Par

ticip

ants

N

=441

recr

uite

d N

=294

rand

omis

ed

N=2

55 c

ompl

eter

s M

ale

19%

, Fem

ale

81%

M

ean

age

48(P

) and

50

(O) y

ears

In

clus

ion

B

MI 2

7-40

kg/m

2

Age

18-

70 y

ears

F

astin

g LD

L-C

4.1

to

6.7m

mol

/l an

d T

G<4

.5m

mol

/l (<

400m

g/dl

) E

xclu

sion

S

erio

us d

isea

se, d

iabe

tes

or u

ncon

trolle

d hy

perte

nsio

n W

omen

of c

hild

bear

ing

pote

ntia

l with

out

adeq

uate

con

trace

ptio

n P

revi

ous

baria

tric

surg

ery

Use

of a

ppet

ite

supp

ress

ants

or l

ipid

–lo

wer

ing

agen

ts

Evi

denc

e of

alc

ohol

or

subs

tanc

e ab

use.

Exp

osu

re

Orli

stat

120

mg

t.i.d

. +

diet

(-60

0kca

l/day

) with

<=3

0%

calo

ries

from

fat

Co

mp

aris

on

Pla

cebo

. + d

iet (

-600

kcal

/day

) with

<=

30%

cal

orie

s fro

m fa

t.

Wei

ght l

oss

(kg)

T

otal

cho

lest

erol

(mm

ol/l)

LD

L ch

oles

tero

l (m

mo;

/l)

HD

L ch

oles

tero

l (m

mo;

/l)

Trig

lyce

rides

(mm

ol/l)

LD

L-C

/HD

L-C

ratio

Lp

(a) (

mg/

l) D

ata

anal

ysis

A

naly

sis

was

bas

ed p

rimar

ily o

n th

e IT

T p

opul

atio

n fo

r who

m

follo

w-u

p w

as a

vaila

ble.

Las

t ob

serv

atio

n ca

rrie

d fo

rwar

d da

ta w

as in

clud

ed.

Ad

vers

e ev

ents

G

I eve

nts

Ove

rall

AE

s Li

quid

sto

ols

(%)

Incr

ease

d de

feca

tion

(%)

Loos

e st

ools

(%)

Dec

reas

ed d

efec

atio

n (%

) B

ronc

hitis

(%)

-1.8

8±4.

46

0.14

±0.

85

-0.0

9±0.

80

0.17

±0.

24

0.14

±9.

55

-0.4

6±0.

70

-6.5

0±26

38

67

8 5 3 12 6

-4.6

6±3.

77

0.42

±0.

75

-0.5

3±0.

65

0.07

±0.

22

0.08

±0.

72

-0.5

4±0.

67

3.00

±25

64

80

23

22

16

3 11

<0.0

01

<0.0

01

<0.0

01

<0.0

01

0.89

6 0.

294

0.22

5 0.

016

Pat

ient

s w

ere

stra

tifie

d by

st

udy

cent

re a

nd w

eigh

t los

s ca

tego

ry d

urin

g ru

n-in

(<

=2.0

0 vs

. >2.

0kg)

. A

2.6

% d

iffer

ence

bet

wee

n pl

aceb

o an

d tre

atm

ent g

roup

w

as ju

dged

to b

e cl

inic

ally

re

leva

nt. A

sam

ple

size

ca

lcul

atio

n de

term

ined

that

a

sam

ple

size

of 1

00 in

eac

h ar

m w

ould

be

requ

ired

for

ther

e to

be

an 8

0%

prob

abili

ty o

f sho

win

g a

2.6%

diff

eren

ce (e

ffect

siz

e of

0.4

) at t

he 5

% s

igni

fican

ce

leve

l. It

was

est

imat

ed th

at

30%

of p

atie

nts

wou

ld n

ot b

e fu

lly e

valu

able

and

that

ther

e w

ould

be

a 20

% w

ithdr

awal

ra

te in

the

plac

ebo

lead

-in

perio

d. T

he to

tal n

umbe

r re

quire

d to

be

rand

omis

ed

was

est

imat

ed to

be

284.

N

ote

: Li

mite

d re

porti

ng o

f wei

ght

loss

par

amet

ers

(BM

I, %

%

10%

not

repo

rted)

.

Co

nclu

sion

O

rlist

at a

s an

adj

unct

to

diet

ary

inte

rven

tion

prom

otes

cl

inic

ally

sig

nific

ant w

eigh

t los

s an

d LD

L-C

bey

ond

the

effe

ct

of w

eigh

t los

s in

ove

rwei

ght o

r ob

ese

patie

nts

with

co

ncom

itant

hy

perc

hole

ster

olem

ia.

Run

-in w

eigh

t los

s an

d w

eigh

t lo

ss d

urin

g th

e fir

st 4

wee

ks

wer

e pr

edic

tors

of l

onge

r-te

rm

wei

ght l

oss

at 2

4 w

eeks

.

LDL-

C =

low

den

sity

lipo

prot

ein

chol

este

rol,

P=p

lace

bo, O

=orli

stat

, **=

diffe

renc

e fr

om p

lace

bo. L

OC

F=l

ast o

bser

vatio

n ca

rrie

d fo

rwar

d.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

81

Evi

den

ce T

able

6.

Orl

ista

t, F

oxc

roft

et

al.,

2000

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) E

ffec

t Siz

e &

Pre

cisi

on

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Fox

crof

t et a

l.,

2000

S

tudy

des

ign

R

apid

sys

tem

atic

revi

ew

of R

CT

s.

Ob

ject

ive

To

clar

ify th

e po

tent

ial

bene

fits,

dis

bene

fits

and

cost

s of

orli

stat

in th

e tre

atm

ent o

f obe

sity

. S

tud

ies

incl

uded

S

jost

rom

et a

l., 1

998

Dav

idso

n et

al.,

199

9 H

olla

nder

et a

l., 1

998

Incl

usio

n

Sys

tem

atic

revi

ews

or R

CT

s of

orli

stat

in

the

treat

men

t of o

besi

ty

Effi

cacy

or c

ost e

ffect

iven

ess

Hum

an s

ubje

cts

only

. O

nly

phas

e III

clin

ical

tria

ls in

clud

ed.

Exc

lusi

on

Pha

se II

clin

ical

tria

ls

Not

sta

ted

but o

nly

3/10

9 st

udie

s or

pa

pers

wer

e in

clud

ed.

Exp

osu

re

Orli

stat

Out

com

es fo

r wei

ght l

oss

repo

rted

in

othe

r sys

tem

atic

revi

ews.

Qu

ality

of l

ife

Est

imat

ed Q

ALY

s ga

ined

in a

yea

r of

orli

stat

trea

tmen

t (ba

sed

on 1

00

pers

ons

star

ting

treat

men

t with

re

spon

ders

thos

e w

ho lo

st a

nd

mai

ntai

ned

>10%

of t

heir

initi

al b

ody

wei

ght o

ver 2

yea

rs).

Co

st d

ata

Pric

e of

a p

atie

nt c

onsu

ltatio

n (N

HS

19

98)

Mon

thly

cos

t of o

rlist

at 1

20 td

s.

Ave

rage

num

ber o

f con

sulta

tions

per

ye

ar.

GP

con

sulta

tion

cost

per

vis

it.

Dro

p-ou

t yea

r 1

Dro

p-ou

t yea

r 2

Ave

rage

cos

t per

yea

r for

100

pa

tient

s tre

ated

for 2

yea

rs.

The

cos

t /Q

ALY

of o

rlist

at tr

eatm

ent

(ext

rem

e va

lue

sens

itivi

ty a

naly

sis)

T

he c

ost/Q

ALY

in p

rimar

y ca

re

setti

ng (e

xtre

me

valu

e se

nsiti

vity

an

alys

is)

10kg

wei

ght r

educ

tion

over

2

year

s as

an

adju

nct t

o di

et

(NN

T=1

2 95

% C

I 7-3

7)

1.60

QA

LY p

er y

ear o

f orli

stat

tre

atm

ent

£118

.00

£45.

00

4 £16.

00

27%

23

%

£ 73

,436

£4

5,00

0 (1

3,54

1-13

1,91

8) p

er

QA

LY g

aine

d £2

6,63

5 (9

,779

–66

,505

)

Onl

y th

e “m

ost p

laus

ible

” re

sults

w

ere

used

for f

urth

er a

naly

sis.

E

ME

A p

resc

riptio

n in

dica

tions

for

orlis

tat d

o no

t coi

ncid

e w

ith th

e pu

blis

hed

trial

info

rmat

ion.

On

aver

age

orlis

tat r

esul

ts in

obe

se

peop

le lo

sing

an

addi

tiona

l 3-4

% o

f th

eir i

nitia

l bod

y w

eigh

t ove

r die

t al

one

over

a 2

-yea

r per

iod.

T

he e

stim

ated

cos

t util

ity o

f orli

stat

w

as £

46,0

00 p

er Q

ALY

gai

ned.

T

here

was

no

evid

ence

that

the

shor

t-te

rm w

eigh

t los

s w

ould

hav

e a

long

er-

term

impa

ct o

n m

orbi

dity

and

m

orta

lity.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

82

Evi

den

ce T

able

7.

Orl

ista

t, D

ero

sa e

t al

., 20

03

Eff

ect S

ize

& P

reci

sion

(%

cha

nge

fro

m b

asel

ine)

S

tud

y

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y D

ura

tion

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) P

N

=23

O

N=2

5 F

N

=24

OF

N

=24

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Der

osa

et a

l.,

2003

S

tudy

des

ign

R

ando

mis

ed, d

oubl

e bl

ind

plac

ebo-

cont

rolle

d O

bje

ctiv

e T

o as

sess

obe

se

patie

nts

with

hy

perc

hole

ster

olem

ia

who

wer

e pr

escr

ibed

a

stan

dard

ised

die

t, co

mpa

ring

the

actio

n of

or

lista

t, flu

vast

atin

, or

lista

t with

fluv

asta

tin

and

plac

ebo

on

anth

ropo

met

ric

mea

sure

men

ts, b

lood

pr

essu

re a

nd li

pid

prof

ile.

Du

ratio

n

One

yea

r

Par

ticip

ants

N

=99

Obe

se p

atie

nts

with

hy

perc

hole

ster

olem

ia

M=4

8 F

=51

Mea

n ag

e =5

1 ye

ars

(SD

=9)

Incl

usio

n

BM

I> 3

0kg/

m2

Age

>40

year

s T

otal

cho

lest

erol

>=

240m

g/dl

S

BP

>140

mg

Hg

DB

P<9

0mm

Hg

Exc

lusi

on

Sm

oker

s A

bnor

mal

thyr

oid

func

tion

Pat

ient

s ta

king

di

uret

ics

or b

eta

bloc

kers

Exp

osu

re/C

om

par

ison

O

rlist

at 1

20m

g t.i

.d.+

co

ntro

lled

ener

gy d

iet

Pla

cebo

+ c

ontro

lled

ener

gy d

iet

Flu

vast

atin

80m

g/d

+ co

ntro

lled

ener

gy d

iet

Orli

stat

120

mg

t.i.d

. +

Flu

vast

atin

80m

g/d

+ co

ntro

lled

ener

gy d

iet

All

parti

cipa

nts

unde

rtook

>=

30m

ins

aero

bic

activ

ity

4 da

ys a

wee

k D

iet:

150

0kca

l, 54

%

carb

ohyd

rate

, 24%

pr

otei

n, 2

2% fa

ts, 1

08m

g ch

oles

tero

l, 35

g fib

er

durin

g pl

aceb

o le

ad-in

pe

riod.

Foo

d di

arie

s w

ere

kept

. Die

t ins

truct

ion

ever

y 3

mon

ths.

At 6

mon

ths

BM

I (kg

/m2 )

W

CR

(cm

) B

WL

(kg)

A

t 1 y

ear

BM

I (kg

/m2 )

W

CR

(cm

) B

WL

(kg)

A

t 6 m

onth

s S

BP

(mm

Hg)

D

BP

(mm

Hg)

T

C

LDL-

C

HD

L-C

T

Gs

At 1

yea

r S

BP

(mm

Hg)

D

BP

(mm

Hg)

T

C

LDL-

C

HD

L-C

T

Gs

Saf

ety

Orli

stat

and

fluv

asta

tin w

ere

wel

l tol

erat

ed. 3

% o

f pat

ient

s ex

perie

nced

sid

e ef

fect

s.

The

re w

ere

no s

erio

us

adve

rse

even

ts.

N

S

NS

N

S

NS

P

<0.0

5 P

<0.0

5 N

S

NS

N

S

NS

N

S

NS

N

S

NS

P

<0.0

5 P

<0.0

5 N

S

NS

N

S

NS

N

S

P<0

.02

P<0

.0

P<0

.02

NS

N

S

NS

N

S

NS

N

S

P<0

.05

P<0

.05

P<0

.05

P<0

.05

NS

P

<0.0

2

N

S

NS

N

S

P<0

.05

P<0

.05

P<0

.05

NS

N

S

P<0

.05

P<0

.05

NS

N

S

P<0

.05

P<0

.05

P<0

.02

P<0

.02

P<0

.02

P<0

.05

p<

0.05

p

<0.0

5 p

<0.0

5 p<

0.01

p

<0.0

1 p

<0.0

1 N

S

NS

p<

0.02

p<

0.02

p

<0.0

2 p<

0.05

p<

0.01

p<

0.01

p<

0.05

p<

0.05

p

<0.0

5 p<

0.02

Bot

h gr

oups

com

para

ble

at b

asel

ine

Ran

dom

isat

ion

enve

lope

s us

ed

Com

plia

nce

asse

ssed

thro

ugh

tabl

et

coun

ting

96 (9

7%) c

ompl

eter

s, 3

sub

ject

s dr

oppe

d ou

t due

to a

dver

se re

actio

ns

(orli

stat

),

Vita

min

D le

vels

wer

e no

t mea

sure

d.

Sig

nific

ant d

ecre

ases

in

wei

ght,

BM

I and

wai

st

circ

umfe

renc

e w

as

foun

d on

ly in

the

orlis

tat+

fluva

stin

gro

up

at 6

mon

ths

and

in a

ll gr

oups

apa

rt fro

m B

MI

in th

e pl

aceb

o gr

oup

at

1 ye

ar. T

he c

ombi

ned

treat

men

t gro

ups

show

ed th

e gr

eate

st

redu

ctio

ns.

No

sign

ifica

nt c

hang

es

in B

P in

any

gro

up a

t 6

mon

ths,

but

ther

e w

as a

si

gnifi

cant

impr

ovem

ent

in th

e tre

atm

ent g

roup

s si

ngly

and

com

bine

d at

1

year

. The

gre

ates

t re

duct

ions

in B

P w

ere

in

the

com

bine

d tre

atm

ent

grou

ps.

Lipi

d pr

ofile

s w

ere

sign

ifica

ntly

bet

ter a

t 6

mon

ths

for a

ll pa

ram

eter

s in

the

com

bine

d tre

atm

ent

grou

p. A

ll gr

oups

sh

owed

sig

nific

ant

impr

ovem

ents

at 1

yea

r fo

r tot

al c

hole

ster

ol a

nd

low

-den

sity

lipo

prot

ein

chol

este

rol.

Aga

in th

e co

mbi

ned

treat

men

t gr

oup

had

the

grea

test

im

prov

emen

ts fo

r eac

h pa

ram

eter

at 6

mon

ths

and

1 ye

ar.

BM

I = b

ody

mas

s in

dex,

WC

R =

wai

st c

ircum

fere

nce

redu

ctio

n, B

WL=

bod

y w

eigh

t los

s, P

= pl

aceb

o gr

oup,

O=

orlis

tat 1

20m

g t.i

.d. g

roup

, F=f

luva

stat

in 8

0mg/

d gr

oup,

OF

= o

rlist

at 1

20 t.

i.d.+

fluva

stat

in 8

0mg/

d gr

oup.

TC

=to

tal c

hole

ster

ol, L

DL-

C=l

ow d

ensi

ty li

popr

otei

n ch

oles

tero

l, H

DL-

C+

high

-den

sity

lipo

prot

ein

chol

este

rol,

TG

s =

trig

lyce

rides

. Bo

ld =

rai

sed

valu

es, n

orm

al=d

ecre

ased

val

ues.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

83

Evi

den

ce T

able

8.

Orl

ista

t, H

anef

ield

et

al.,

2002

† =

Cha

nge

vs p

lace

bo, I

TT

= in

tent

ion

to tr

eat a

naly

sis,

LO

CF

= la

st o

bser

vatio

n ca

rrie

d fo

rwar

d, G

CP

=goo

d cl

inic

al p

ract

ice.

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy/

Yea

r L

ocat

ion

S

tud

y D

esig

n

Ob

ject

ive

Du

ratio

n

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

P

O

p=†

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Wei

gh

t los

s af

ter

1 yr

of t

reat

men

t B

ody

wei

ght (

kg)

Bod

y w

eigh

t (%

) W

eigh

t los

s >=

5%

Dia

bet

ic m

etab

olic

par

amet

ers

afte

r 48

wee

ks o

f tr

eatm

ent*

* H

bA1c

Fas

ting

gluc

ose

(mm

ol/l)

P

ost p

rand

ial g

luco

se(m

mol

/l)

Trig

lyce

rides

(mm

ol/l)

D

iab

etic

met

abo

lic p

aram

eter

s af

ter

1yr*

H

bA1c

Fas

ting

gluc

ose

(mm

ol/l)

P

ost p

rand

ial g

luco

se (m

mol

/l)

Lip

id p

rofil

e at

48

wee

ks

Tot

al c

hole

ster

ol

LDL-

chol

este

rol (

mm

ol/L

) H

DL-

chol

este

rol (

mm

ol/L

) L

ipid

pro

file

at 1

yr

Tot

al c

hole

ster

ol

LDL-

chol

este

rol (

mm

ol/L

) H

DL-

chol

este

rol (

mm

ol/L

) O

ther

CH

D r

isk

acto

rs

Trig

lyce

rides

(mm

ol/l)

S

BP

mm

Hg

DB

P m

mH

g A

nth

rop

omo

rph

ic in

dic

es

Wai

st c

ircum

fere

nce

(cm

)

3.

4±5.

3 3.

6±5.

7 31

.6%

-0.6

±1.

6 -0

.9±

2.8

-0.7

±4.

5 -0

.2±

3.8

-0.4

±1.

5%

-0.7

±3.

2 -0

.5±

4.6

0.

0±1.

4 +0

.01±

1.2

+0.0

7±0.

2

+1.8

±22

.0%

+5

.1±

34.3

%

+6.4

±24

.5%

NR

-4

.96

-4.7

8

-3.0

±5.

6

5.

3±5.

1 5.

4±5.

0 51

.3%

-0.9

±1.

1 -1

.7±

2.1

-1.4

±3.

5 -0

.1±

1.4

-0.9

+1.3

%

-1.6

±2.

5 -1

.8±

3.8

-0.2

±0.

9 -0

.09±

0.7

0.0±

0.2

-2

.3±

16.3

%

-2.0

±26

.7%

+0

.6±

20.0

%

NR

-4

.98

-4.8

0

-5.5

±5.

3

0.

006

0.00

6 0.

0001

0.47

0.

08

0.45

0.

12

0.00

03

0.00

4 0.

003

0.07

0.

12

0.02

<0.0

1 <0

.05

<0.0

1 ns

ns

ns

<0.0

1

Han

efie

ld e

t al

., 20

02

Loc

atio

n

Ger

man

y (P

rimar

y ca

re a

nd

outp

atie

nt

clin

ics)

Stu

dy D

esig

n

Ran

dom

ised

, pl

aceb

o co

ntro

lled,

do

uble

blin

d cl

inic

al

trial

. R

un

in p

erio

d

4 w

eek

plac

ebo

+ di

et ru

n in

per

iod.

O

bje

ctiv

e T

o as

sess

the

long

-te

rm e

ffect

of

orlis

tat o

n bo

dy

wei

ght,

glyc

aem

ic

cont

rol a

nd

card

iova

scul

ar ri

sk

fact

ors

in

over

wei

ght p

atie

nts

with

type

2

diab

etes

. T

reat

men

t D

ura

tion

48

wee

ks

Par

ticip

ants

N

= 49

2 en

rolle

d N

=383

rand

omis

ed

N=3

69 IT

T p

opul

atio

n M

ale

181,

Fem

ale=

188

A

vera

ge A

ge 5

6-57

A

vera

ge B

MI=

34k

g/m

2

Incl

usio

n

Age

18-

70 y

ears

B

MI>

=28k

g/M

2

HbA

1c =

6.5-

11%

D

iagn

osis

of t

ype

2 di

abet

es tr

eate

d w

ith s

ulph

onyl

urea

s fo

r at l

east

2

mon

ths

befo

re s

cree

ning

or w

ere

diag

nose

d w

ith d

iabe

tes

but n

ot y

et

treat

ed w

ith a

ntid

iabe

tic m

edic

atio

n.

Exc

lusi

on

Dia

betic

pat

ient

s tre

ated

with

an

tidia

betic

dru

gs o

ther

than

su

lpho

nylu

reas

P

atie

nts

treat

ed w

ith m

edic

atio

ns

know

n to

affe

ct b

ody

wei

ght,

seru

m

lipid

s or

vita

min

s.

Pat

ient

s w

ith p

rolif

erat

ive

retin

opat

hy, p

apill

oede

ma,

un

cont

rolle

d hy

perte

nsio

n (D

BP

>120

mm

Hg)

, hyp

o or

hy

perth

yroi

dism

, sec

onda

ry ty

pe 1

di

abet

es, c

ardi

ac in

suffi

cien

cy, o

r pr

esen

ce o

r his

tory

of c

ance

r or a

ny

sign

ifica

nt a

ppet

ite, r

enal

, hep

atic

, G

I, ps

ychi

atric

, im

mun

olog

ical

or

met

abol

ic d

isor

ders

. Fem

ale

patie

nts

wer

e ex

clud

ed if

they

wer

e pr

egna

nt, l

acta

ting

or fo

r ch

ildbe

arin

g po

tent

ial a

nd n

ot ta

king

ad

equa

te c

ontra

cept

ive

mea

sure

s.

Exp

osu

re

Orli

stat

120

mg

t.i.d

.+ a

60

0 ca

lorie

redu

ced

diet

(3

0% fa

t, 50

%

carb

ohyd

rate

, 20%

pr

otei

n, m

ax 3

00m

g/d

chol

este

rol)

Co

mp

aris

on

Pla

cebo

t.i.d

. + a

600

ca

lorie

redu

ced

diet

(3

0% fa

t, 50

%

carb

ohyd

rate

, 20%

pr

otei

n, m

ax 3

00m

g/d

chol

este

rol)

Rea

son

s fo

r d

isco

ntin

uatio

n

Pre

rand

omis

atio

n dr

op-o

ut =

109

Vio

latio

n of

sel

ectio

n cr

iteria

=59

Oth

er p

roto

col v

iola

tion=

16

Ref

used

trea

tmen

t =10

F

ailu

re to

retu

rn=1

0 D

id n

ot c

o-op

erat

e=8

Adv

erse

eve

nt=3

O

ther

=3

Pos

t ran

dom

isat

ion

drop

-out

=11

9 A

dver

se e

vent

s =2

8 (o

rlist

at =

16,

plac

ebo=

12)

With

draw

al o

f con

sent

=35

(orli

stat

=13

, pl

aceb

o=22

) Lo

st to

FU

=24

(orli

stat

=13,

pla

cebo

-11)

P

roto

col v

iola

tion=

14 (o

rlist

at=9

, pla

cebo

An

alys

is

Effi

cacy

ass

esse

d on

an

ITT

bas

is, I

TT a

naly

sis:

or

lista

t=18

9,

plac

ebo=

180

LOC

F m

odel

was

use

d fo

r mis

sing

dat

a =5

) E

xter

nal

val

idity

N

ote

s 1.

Stu

dy c

ondu

cted

ac

cord

ing

to G

CP

gu

idel

ines

2.

Com

plia

nce

asse

ssed

by

cap

sule

cou

nt

3.T

rain

ed m

onito

r ch

ecke

d pr

otoc

ol

adhe

renc

e 4.

Stu

dy a

udit

perfo

rmed

th

roug

hout

the

stud

y 5.

Stu

dy s

pons

ored

by

Hof

fman

n-La

-Roc

he

Stu

dy c

onc

lusi

ons

Orli

stat

+ d

iet r

esul

ted

in s

igni

fican

t wei

ght

loss

, im

prov

ed

glyc

aem

ic c

ontro

l and

ca

rdio

vasc

ular

risk

fa

ctor

pro

file

in

over

wei

ght p

atie

nts

with

type

2 d

iabe

tes.

C

om

men

ts

Effe

ct w

as c

alcu

late

d fro

m s

tart

of s

tudy

–

i.e.,

incl

udin

g ru

n in

pe

riod

and

from

ra

ndom

isat

ion.

T

he ru

n-in

per

iod

was

in

clud

ed in

the

repo

rted

conc

lusi

ons,

id

eally

the

resu

lts

durin

g th

e ra

ndom

isat

ion

perio

d sh

ould

hav

e be

en

repo

rted

Res

ults

wer

e re

porte

d fro

m th

e st

art o

f ra

ndom

isat

ion

(48

wee

ks) i

n th

e m

ain

tabl

e bu

t fro

m th

e st

art

of s

tudy

(1 y

ear)

in th

e su

mm

ary

and

conc

lusi

on.

A n

umbe

r of

sig

nific

ant

diffe

renc

es a

t 1 y

ear

wer

e ns

from

the

poin

t of

rand

omis

atio

n

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

84

Evi

den

ce T

able

9.

Orl

ista

t, H

alp

ern

et

al.,

2003

Eff

ect S

ize

& P

reci

sion

S

tud

y/Y

ear

Loc

atio

n

Stu

dy

Des

ign

O

bje

ctiv

e D

ura

tion

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

P

O

P=

Val

idity

/App

licab

ility

Con

clu

sio

ns

Com

men

ts

Hal

pern

et a

l.,

2003

L

ocat

ion

La

tin A

mer

ica:

B

razi

l, C

olum

bia,

C

osta

Ric

a M

exic

o

Stu

dy D

esig

n

Ran

dom

ised

, dou

ble

blin

d, p

lace

bo

cont

rolle

d m

ulti-

cent

re,

clin

ical

tria

l R

un

in p

erio

d

2-w

eek

open

, pla

cebo

pe

riod

prio

r to

rand

omis

atio

n O

bje

ctiv

e T

o de

term

ine

if no

n-in

sulin

dep

ende

nt

diab

etic

pat

ient

s lo

se

mor

e w

eigh

t whe

n tre

ated

for 2

4 w

eeks

w

ith o

rlist

at in

co

njun

ctio

n w

ith a

hy

poca

loric

die

t +

beha

viou

ral

coun

selli

ng th

an

plac

ebo

t.i.d

+

hypo

calo

ric d

iet +

be

havi

oura

l co

unse

lling

. D

ura

tion

24

wee

ks

Par

ticip

ants

N

=365

enr

olle

d N

=343

rand

omis

ed

N=2

80 c

ompl

eted

the

stud

y O

rlist

at N

= 16

4 P

lace

bo N

=174

M

ale=

104

Age

=51

year

s B

MI=

35

Cau

casi

an =

60%

In

clus

ion

A

ge 1

8-70

yea

rs

BM

I>27

kg/m

2

Dx

of N

IDD

M (W

HO

) H

bA1c

6.0

-11.

0%

Neg

ativ

e pr

egna

ncy

test

ad

equa

te c

ontra

cept

ion

in w

omen

of

child

bea

ring

pote

ntia

l E

xclu

sion

H

isto

ry o

f rec

ent M

I, un

cont

rolle

d hy

perte

nsio

n, s

igni

fican

t car

diac

, re

nal,

hepa

tic, G

I, re

spira

tory

, ne

urol

ogic

al, p

sych

iatri

c or

end

ocrin

e di

seas

e, G

I bar

iatri

c su

rger

y, p

ost

surg

ical

adh

esio

n, h

isto

ry o

f ca

rcin

oma,

bul

imia

, lax

ativ

e ab

use,

cl

inic

al s

ympt

oms

of fa

t-sol

uble

vi

tam

in d

efic

ienc

ies,

sub

stan

ce a

buse

, ap

petit

ive

supp

ress

ants

, ins

ulin

, re

tinoi

ds, s

yste

mic

ste

roid

s ot

her t

han

HR

T, a

carb

ose

(was

h-ou

t =2

mon

ths)

, pr

egna

nt la

ctat

ing

and

child

-bea

ring

pote

ntia

l wom

en n

ot ta

king

co

ntra

cept

ive

mea

sure

s.

Exp

osu

re

Orli

stat

120

mg

t.i.d

. +

hypo

calo

ric d

iet +

be

havi

oura

l co

unse

lling

C

om

par

ison

P

lace

bo t.

i.d. +

hy

poca

loric

die

t +

beha

viou

ral

coun

selli

ng

Wei

gh

t los

s IT

T p

op %

WL

Orli

stat

LM

S d

iff P

-O (k

g)

Com

plet

ers

pop

%W

L C

ompl

eter

s po

p W

L (k

g)

>=5%

WL

>=10

% W

L D

iab

etic

met

abo

lic p

aram

eter

s (D

MP

), 24

w

eeks

M

ean

decr

ease

in g

luco

se le

vels

F

astin

g pl

asm

a gl

ucos

e LS

M d

iff P

-O

ITT

pop

dec

reas

e H

bA1c

%

Com

plet

ers

pop

decr

ease

HbA

1c %

B

lood

pre

ssur

e at

24

wks

S

BP

D

BP

L

ipid

pro

file

at 2

4 w

eeks

T

otal

cho

lest

erol

(mm

ol/l)

LD

L-C

hole

ster

ol (m

mol

/l)

HD

L-ch

oles

tero

l (m

mol

/l)

Fas

ting

TG

s (m

mol

/l)

Pos

t pra

ndia

l TG

s (m

mol

/l)

An

thro

pom

orp

hic

ind

ices

H

igh

mea

n w

aist

circ

umfe

renc

e cm

A

dve

rse

even

ts

Ove

rall

adve

rse

even

ts(%

) S

erio

us a

dver

se e

vent

s P

atie

nts

with

draw

n fro

m s

tudy

bec

ause

of

GI

adve

rse

even

ts

Mo

st c

omm

on G

I eve

nts

O

vera

ll F

atty

/oily

sto

ol

Incr

ease

d de

feca

tion

Liqu

id s

tool

s O

ily e

vacu

atio

n F

latu

lanc

e w

ith d

isch

arge

A

bdom

inal

pai

n

3.

0± 1

.3%

N

R

-3.1

±1.

0%

2.58

±1.

4kg

17%

3%

0.

01±

0.30

0.

22∀

0.14

-0.

13∀

0.14

%va

lues

NR

va

lues

NR

-0

.03∀

0.11

+0

.03∀

0.09

+0

.02∀

0.02

-0

.10∀

0.12

-0

.11∀

0.13

-3

.5∀

5.4

60

.3 4

5(2)

65

(37.

0%)

18(1

0.4%

) 19

(11.

0%)

8(4.

6%)

0(0.

0%)

3(1.

7%)

6(3.

5%)

4.

7 ±

0.5%

1.

6kg

-4.9

±0.

7%

4.24

±0.

23

30%

7%

1.

0±0.

34

0.85

0.

61∀

0.15

-0

.64∀

0.16

va

lues

NR

va

lues

NR

-0

.40∀

0.08

-0

.31∀

0.08

-0

.02∀

0.02

-0

.18∀

0.09

-0

.03∀

0.13

-5

.3∀

5.3

74 5

8(7)

11

0(65

%)

77(4

5.6%

) 68

(40.

2%)

17(1

0.1%

) 17

(10.

1%)

13(7

.7%

) 13

(7.7

%)

N

R

0.00

03

NR

0.

0003

0.

003

0.07

2 N

R

0.03

6 0.

06

0.04

ns

ns

0.

0001

0.

0002

0.

038

0.21

7 0.

379

0.03

2

Ext

ern

al v

alid

ity

Hig

hly

sele

cted

pat

ient

s m

any

co-m

orbi

ditie

s ex

clud

ed.

Hig

h dr

op-o

ut ra

te

Dro

p-ou

t cau

ses

not

spec

ified

Stu

dy

con

clu

sio

ns

Orli

stat

is a

saf

e ad

junc

t to

diet

ary

inte

rven

tion

and

conv

entio

nal

antid

iabe

tic

phar

mac

othe

rapy

in

the

glob

al

treat

men

t of o

bese

di

abet

ic p

atie

nts.

It

prom

otes

a

clin

ical

ly

sign

ifica

nt w

eigh

t lo

ss a

nd im

prov

ed

glyc

aem

ic c

ontro

l an

d lip

id p

rofil

e.

Co

mm

ents

W

eigh

t los

s be

gan

to s

low

at b

etw

een

16-2

0 w

eeks

ITT

= in

tent

ion

to tr

eat,

LMS

=lea

st m

ean

squa

res,

WL=

wei

ght l

oss.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

85

Evi

den

ce T

able

10.

O

rlis

tat,

Leu

ng

et

al.,

2003

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

Eff

ect S

ize

& P

reci

sion

V

alid

ity/A

pplic

abili

ty

C

oncl

usi

ons

C

omm

ents

Leun

g et

al.,

20

03

Stu

dy ty

pe

Sys

tem

atic

revi

ew

Ob

ject

ive

To

desc

ribe

the

phar

mac

olog

ical

m

anag

emen

t of o

besi

ty

conc

entra

ting

on o

rlist

at

Incl

uded

stu

die

s O

rlist

at

Dav

idso

n, 1

999

Fin

er, 2

000

Hau

ptm

an, 2

000

Hill

, 199

9 H

olla

nder

, 199

8 R

ossn

er, 2

000

Sjo

stro

m, 1

998

Incl

usio

n

Stu

dies

bet

wee

n 19

66-

Feb

ruar

y 20

02

RC

Ts

of >

6 m

onth

s du

ratio

n re

porti

ng th

e ef

ficac

y of

or

lista

t

Exp

osu

re

Orli

stat

30-

120m

g t.i

.d.

Co

mp

aris

on

Pla

cebo

Wei

gh

t red

uct

ion

with

orli

stat

ass

ocia

ted

with

a s

igni

fican

t im

prov

emen

t in

cont

rol o

f car

diov

ascu

lar r

isk

fact

ors.

P

atie

nt w

ith h

yper

cho

lest

ero

lem

ia

Tot

al c

hole

ster

ol o

rlist

at v

s. p

lace

bo

LDL

chol

este

rol,

orlis

tat v

s. p

lace

bo

Pla

sma

insu

lin a

t the

end

of 2

yea

rs, o

rlist

at v

s. p

lace

bo (o

ne s

tudy

) S

ysto

lic b

lood

pre

ssur

e af

ter o

ne y

ear,

orlis

tat v

s. p

lace

bo

Dia

stol

ic b

lood

pre

ssur

e af

ter o

ne y

ear,

orlis

tat v

s. p

lace

bo.

Pat

ien

ts w

ith ty

pe

2 d

iab

etes

W

eigh

t los

s O

rlist

at +

hyp

ocal

oric

die

t vs.

pla

cebo

Im

prov

ed g

lyca

emic

con

trol o

rlist

at v

s. p

lace

bo

Pat

ien

ts w

ith IG

T

Nor

mal

isat

ion

of g

luco

se le

vels

, orli

stat

vs.

pla

cebo

. R

educ

tion

on ra

te o

f pro

gres

sion

to d

iabe

tes,

orli

stat

vs.

pla

cebo

A

dve

rse

even

ts

Mild

– m

oder

ate

GI e

ffect

s, o

rlist

at v

s. p

lace

bo

Low

pla

sma

leve

ls o

f fat

-sol

uble

vita

min

s an

d be

ta c

arot

ene

in th

e or

lista

t gro

up

Inte

ract

ions

repo

rted

with

cyc

losp

orin

e an

d w

arfa

rin

P<0

.05

11.9

% v

s. 4

.0%

, p<0

.001

17

.6%

vs.

7.6

%, p

<0.0

01

66.5

vs.

86.

3pm

ol/L

, p<0

.041

27m

m

Hg

vs. 1

29m

mH

g -=

0.00

1980

mm

H

g vs

. 82m

mH

g, p

=0.0

02

6.2

vs. 4

.3kg

p<0

.001

p<0.

001

71.6

% v

s. 4

9.1%

p=0,

04

3.0%

vs.

7.6

%p=

0.04

8-

27%

(yr 1

) 6-

22%

(yr2

) p<

0.05

With

draw

al ra

te n

ot

repo

rted

Orli

stat

and

si

butra

min

e de

mon

stra

ted

a fa

vour

able

effi

cacy

an

d sa

fety

pro

file

in

RC

Ts.

C

urre

nt e

vide

nce

supp

orts

thei

r use

as

adju

ncts

to li

fest

yle

mod

ifica

tions

in th

e tre

atm

ent o

f obe

sity

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

86

Evi

den

ce T

able

11.

O

rlis

tat,

Hey

msf

ield

et

al.,

2000

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

s

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

C

onco

mita

nt t

reat

men

t P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) E

ffec

t Siz

e &

P

reci

sion

V

alid

ity/A

pplic

abili

ty

% o

f stu

die

s C

oncl

usi

ons

C

omm

ents

Hey

msf

ield

et a

l.,

2000

S

tudy

des

ign

M

eta-

anal

ysis

of t

hree

ra

ndom

ised

, dou

ble-

blin

d-pl

aceb

o-co

ntro

lled,

m

ultic

entre

clin

ical

tria

ls.

Ob

ject

ive

To

test

the

hypo

thes

is

that

orli

stat

com

bine

d w

ith

diet

ary

inte

rven

tion

impr

oves

glu

cose

to

lera

nce

stat

us a

nd

prev

ents

wor

seni

ng

diab

etes

sta

tus

mor

e ef

fect

ivel

y th

an p

lace

bo.

Incl

uded

pub

licat

ion

s S

jost

rom

,199

8 H

aupt

man

, 20

00

Incl

usio

n

Met

a-an

alys

is

Ran

dom

ised

, dou

ble

blin

d,

plac

ebo

cont

rolle

d tri

al

At l

east

1 fo

llow

-up

asse

ssm

ent o

f gl

ucos

e to

lera

nce

Fol

low

-up

of a

t lea

st 2

full

year

s In

divi

dual

tria

ls

Age

>18

yea

rs

BM

I 30-

34

Abs

ence

of w

eigh

t los

s >4

kg in

la

st 3

mon

ths

Exc

lusi

on

Met

a an

alys

is

Indi

vidu

al tr

ials

S

ubje

cts

who

had

sto

pped

sm

okin

g in

the

last

6 m

onth

s S

ubje

cts

with

sig

nific

ant c

ardi

ac,

rena

l, he

patic

, GI,

psyc

hiat

ric o

r en

docr

ine

diso

rder

s,

Sub

ject

s w

ith d

rug-

treat

ed ty

pe 2

di

abet

es, h

isto

ry o

r pre

senc

e of

su

bsta

nce

abus

e, e

xces

sive

inta

ke

of a

lcoh

ol o

r con

com

itant

ly u

sed

med

icat

ions

that

alte

r app

etite

or

lipid

leve

ls.

Par

ticip

ants

N

=675

O

bese

(BM

I 30-

43)

39 c

ente

rs in

Eur

ope

and

US

A

betw

een

1992

-199

5.

Exp

osu

re

Orli

stat

, 120

mg

t.i.d

. C

om

par

ison

P

lace

bo. t

.i.d.

C

onc

om

itan

t m

ildly

low

ene

rgy

diet

for 1

ye

ar

Wei

ght l

oss

chan

ge fr

om in

itial

wei

ght

Orli

stat

P

lace

bo

Glu

cose

tole

ranc

e (%

of p

atie

nts

prog

ress

ing

to d

iabe

tic

stat

us )

Orli

stat

P

lace

bo

p-va

lue

Cha

nge

from

IGT

to N

GT

(IG

T a

t bas

elin

e im

prov

ed to

NG

T a

t en

d of

trea

tmen

t) or

lista

t pl

aceb

o p-

valu

e Im

prov

emen

t in

insu

lin a

rea

unde

r cu

rve

for s

ubje

cts

with

nor

mal

glu

cose

to

lera

nce

at b

asel

ine

Orli

stat

vs.

pla

cebo

F

astin

g gl

ucos

e le

vels

nor

mal

or

lista

t vs.

pla

cebo

F

astin

g gl

ucos

e le

vels

impa

ired

or

lista

t vs.

pla

cebo

6.27

∀0.

41kg

3.

79 ∀

4.1k

g p<

0.00

1 3.

0%

7.6%

0.

04

71.6

%

49.1

%

0.04

p=

0.03

p=

0.02

p=

0.01

ITT

ana

lysi

s S

imila

r at b

asel

ine

100%

Dat

a fro

m th

e re

porte

d st

udie

s su

gges

t tha

t im

prov

emen

ts in

glu

cose

to

lera

nce

depe

nd u

pon

rela

tivel

y sm

all c

hang

es in

bo

dy w

eigh

t and

that

m

odes

t wei

ght l

oss

may

re

duce

the

risk

of

deve

lopi

ng d

iabe

tes

in

obes

e su

bjec

ts.

Mod

est p

harm

acol

ogic

ally

fa

cilit

ated

wei

ght l

oss

prod

uces

impo

rtant

m

etab

olic

ben

efits

.

EG

O =

Exp

osur

e G

roup

Occ

urre

nce,

CG

O =

Con

trol

Gro

up O

ccur

renc

e, R

R =

Rel

ativ

e R

isk,

RD

= R

isk

Diff

eren

ce, N

NT

= n

umbe

r ne

eded

to tr

eat,

N/S

= N

ot S

tate

d, IT

T=

inte

ntio

n to

trea

t

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

87

Evi

den

ce T

able

12.

O

rlis

tat,

O’M

eara

et

al.,

2001

Eff

ect S

ize

& P

reci

sion

S

tud

y

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) W

eigh

ted

mea

n d

iffer

ence

†

Val

idity

/App

licab

ility

%

of

stud

ies

Com

men

ts

Con

clu

sio

ns

O’M

eara

et a

l.,

2001

S

tudy

type

O

bje

ctiv

e T

o sy

stem

atic

ally

ass

ess

the

evid

ence

for t

he

clin

ical

effe

ctiv

enes

s an

d co

st-e

ffect

iven

ess

of

orlis

tat i

n th

e m

anag

emen

t of o

besi

ty

Stu

die

s in

clud

ed

(N=1

1)

Dav

idso

n et

al.,

199

9 D

rent

& v

an d

er V

een,

19

93

Dre

nt e

t al.,

199

5 F

iner

et a

l., 2

000

Hau

ptm

an e

t al.,

200

0 H

ill e

t al.,

199

9 H

olla

nder

et a

l., 1

998

Mic

ic e

t al.,

199

9 R

ossn

er e

t al.,

200

0 S

jost

rom

et a

l., 1

998

Van

Gaa

l et a

l., 1

998

Incl

usio

n

RC

Ts

Any

dur

atio

n of

th

erap

y*

Any

leng

th o

f fo

llow

-up*

O

bese

or

over

wei

ght

patie

nts

or p

atie

nts

who

hav

e pr

evio

usly

bee

n

obes

e or

ov

erw

eigh

t wis

hing

to

mai

ntai

n w

eigh

t lo

ss.

Onl

y st

udie

s pu

blis

hed

in

Eng

lish,

Fre

nch,

D

utch

or G

erm

an

wer

e co

nsid

ered

fo

r inc

lusi

on.

Exc

lusi

on

Tria

ls re

crui

ting

peop

le w

ith e

atin

g di

sord

ers

such

as

anor

exia

ner

vosa

, an

d bu

limia

ne

rvos

a.

Orli

stat

Pri

mar

y o

utc

omes

W

eigh

t cha

nge

12 w

eeks

, 2 tr

ials

(50-

60m

g t.i

.d)

24 w

eeks

, 2 tr

ials

1-

and

2- y

ear e

ndpo

ints

(120

mg

t.i.d

) All

trial

s (n

=4)

Fro

m s

tart

of ru

n-in

per

iod

(n=2

) F

rom

dou

ble

blin

d ph

ase

(n=2

) A

t 1 y

ear (

n=2,

120

mg

t.i.d

.) A

t 2 y

ears

(n=2

, 120

mg

t.i.d

.) C

hang

e in

% o

f bod

y w

eigh

t at 2

yea

rs (n

=2,

120m

g t.i

.d.)

% w

eigh

t los

s re

lativ

e to

initi

al w

eigh

t at 2

4 w

eeks

30

mg

orlis

tat t

.i.d.

60

mg

orlis

tat t

.i.d.

12

0mg

orlis

tat t

.i.d.

24

0mg

orlis

tat t

.i.d.

P

lace

bo

% o

f pat

ient

s lo

sing

>10

% o

f bod

y w

eigh

t at

24 w

eeks

(n=2

), 30

mg

orlis

tat t

.i.d.

60

mg

orlis

tat t

.i.d.

12

0mg

orlis

tat t

.i.d.

24

0mg

orlis

tat t

.i.d.

P

lace

bo

Red

uctio

n in

wai

st c

ircum

fere

nce

at 2

4 w

eeks

(n=2

) 30

mg

orlis

tat t

.i.d.

60

mg

orlis

tat t

.i.d.

12

0mg

orlis

tat t

.i.d.

24

0mg

orlis

tat t

.i.d.

P

lace

bo

RR

of f

ailu

re to

ach

ieve

at l

east

5%

loss

of

initi

al w

eigh

t at 1

yea

r (or

lista

t, 12

0mg

t.i.d

, n=

4)

RR

of f

ailu

re to

ach

ieve

at l

east

10%

loss

of

initi

al w

eigh

t at 1

yea

r (or

lista

t, 12

0mg

t.i.d

, n=

5)

RR

of f

ailu

re to

ach

ieve

at l

east

10%

loss

of

initi

al w

eigh

t at 2

yea

r (or

lista

t, 12

0mg

t.i.d

, n=

3)

-1.2

4kg

(-2.

65 to

0.1

6), p

=0.0

8 -1

0.75

kg o

rlist

at, -

7.34

pla

cebo

-2

.9kg

(-3.

61 to

– 2

.19)

p=<

0.00

001

-2.4

kg(-

3.62

to –

1.47

), p<

0.00

001

-3.3

5kg(

-4.4

4 to

–2.

27),

p<0.

0000

1 -2

.38k

g (-

3.45

to –

1.31

) ,p<

0.00

001

-3.1

9kg(

-4.2

5 to

– 2

.12)

, p=0

.000

01

-3.2

3kg

(-4.

77 to

–1.

69),

p=0.

0000

1

8.5%

8.

8%

9.8%

9.3%

6.

6%

28%

28

%

37%

38

%

19%

3.

5cm

5.

1cm

5.

9cm

6.

3cm

6.

0cm

R

R=0

.72

(0.6

3-0.

82),

p<0.

0000

1

RR

=0.8

5 (0

.80-

0.91

), p<

0.00

001

RR

=0.8

6(0.

79-0

.93)

, p=0

.000

1

Ran

dom

ised

met

hod

desc

ribed

(n=1

1)

Con

ceal

ed ra

ndom

isat

ion

Sim

ilar a

t bas

elin

e,

Pat

ient

s bl

inde

d C

arer

s bl

inde

d B

lind

outc

ome

asse

ssm

ent

Inte

ntio

n to

trea

t ana

lysi

s P

atie

nt a

dher

ence

ass

esse

d W

ithdr

awal

s re

porte

d S

elec

tion

crite

ria

9%

100%

10

0%

100%

U

ncle

ar

9%, 9

1%

82%

91

%

100%

10

0%

In g

ener

al th

e m

etho

dolo

gica

l qua

lity

of

the

trial

s w

as m

oder

ate

to g

ood.

T

he o

ptim

um re

gim

en

was

120

mg

t.i.d

. M

ost t

rials

wer

e si

ngle

bl

ind,

pla

cebo

with

a ru

n-in

per

iod

prio

r to

doub

le

blin

d tri

al.

The

re is

a la

ck o

f in

form

atio

n on

the

effe

ctiv

enes

s an

d sa

fety

of

orli

stat

in o

lder

peo

ple.

F

or o

rlist

at tr

ials

that

m

atch

ed th

e pr

escr

ibin

g gu

idel

ines

mos

t rep

orte

d st

atis

tical

ly s

igni

fican

t re

sults

in fa

vour

of

orlis

tat f

or w

eigh

t los

s in

pa

rtici

pant

s w

ith a

nd

with

out d

iabe

tes.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

88

Evi

den

ce T

able

12.

Orl

ista

t, O

’Mea

ra e

t al

., 20

01 (

con

tin

ued

)

** m

anuf

actu

rer’s

tria

ls h

ad to

hav

e du

ratio

n of

at l

east

1 y

ear.

Eff

ect S

ize

& P

reci

sion

S

tud

y au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) W

eigh

ted

mea

n

diff

eren

ce†

N

NT

V

alid

ity/A

pplic

abili

ty

% o

f st

udie

s C

oncl

usi

ons

C

omm

ents

O’M

eara

et a

l.,

2001

(Con

t)

Ad

vers

e ev

ents

G

astro

inte

stin

al a

dver

se

even

ts: f

atty

sto

ols,

incr

ease

d de

feca

tion,

oily

spo

tting

. Lo

wer

ser

um le

vels

of f

at-

solu

ble

vita

min

s.

Eco

nom

ic e

valu

atio

n

Incr

emen

tal c

ost-u

tility

of

orlis

tat t

reat

men

t per

QA

LY

gain

ed fo

r WL

of 3

-4%

dur

ing

first

yea

r of t

reat

men

t.

Mor

e fre

quen

t in

orlis

tat g

roup

G

BP

45,

881

(19,

452-

55,3

91)

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

89

Evi

den

ce T

able

13.

O

rlis

tat,

Pad

wal

et

al.,

2004

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

/Typ

e O

bje

ctiv

e S

tud

y R

efer

ence

s

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) E

ffec

t Siz

e &

Pre

cisi

on

Val

idity

/App

licab

ility

%

of

stud

ies

Con

clu

sio

ns

Com

men

ts

Pad

wal

et a

l.,

2004

C

och

rane

Sys

tem

atic

R

evie

w

Ob

ject

ive

To

asse

ss/c

ompa

re th

e ef

fect

s an

d sa

fety

of

sing

le o

r com

bina

tion

anti-

obes

ity d

rug

ther

apy

in c

linic

al tr

ials

of a

t le

ast o

ne y

ear

11 tr

ials

6,

021

parti

cipa

nts

Incl

uded

stu

die

s H

olla

nder

et a

l., 1

998

Sjo

stro

m e

t al.,

199

8 D

avid

son

et a

l., 1

999

Fin

er e

t al.,

200

0 H

aupt

man

et a

l., 2

000

Lind

gard

e et

al.,

200

0 R

ossn

er e

t al.,

200

0 B

akris

et a

l., 2

002

Bro

om e

t al.,

200

2 K

elle

y et

al.,

200

2 M

iles

et a

l., 2

002

Incl

usio

n

BM

I ≥ 3

0kg/

m2

stud

y le

ngth

≥ 1

yr

rand

omis

ed

doub

le-b

lind

plac

ebo

or a

ctiv

e co

ntro

l S

ix tr

ials

requ

ired

a co

mpl

ianc

e ra

te o

f >7

5% in

the

run-

in

phas

e E

xclu

sion

O

besi

ty o

f end

ocrin

e or

igin

, di

abet

es m

ellit

us,

treat

men

t with

m

edic

atio

n th

at m

ay

alte

r bod

y w

eigh

t, un

cont

rolle

d hy

perte

nsio

n

Dru

g; O

rlist

at

Dos

e; 1

20m

g t.i

.d

Co

-inte

rven

tions

Lo

w fa

t hyp

ocal

oric

die

t (8

stud

ies)

D

ieta

ry c

ouns

ellin

g E

xerc

ise

coun

selli

ng

Foo

d in

take

dia

ries

Edu

catio

nal l

itera

ture

or

vide

os

Av

BM

I = 3

3.4k

g/m

2

Av

wei

ght =

96k

g A

v ag

e =

47 y

ears

80

% fe

mal

e 75

% C

auca

sian

H

igh

ris

k po

pula

tions

S

ix tr

ials

lim

ited

enro

llmen

t to

hig

her r

isk

patie

nts,

3

with

type

2 d

iabe

tes

on

stab

le d

oses

of o

ral

hypo

glyc

emic

age

nts

or

insu

lin, 3

with

at l

east

one

ad

ditio

nal C

VD

risk

fact

or

(hyp

erte

nsio

n,

dysl

ipid

emia

, typ

e 2

diab

etes

IGT

).

Pri

mar

y o

utc

omes

av

erag

e w

eigh

t los

s in

kg

av

erag

e w

eigh

t los

s as

% c

hang

e fro

m b

asel

ine

% w

ith w

eigh

t los

s >=

5%

%

with

wei

ght l

oss

>=10

%

tota

l pop

ulat

ion

high

risk

gro

up

low

risk

gro

up

Com

para

tive

BM

I red

uctio

n C

ompa

rativ

e w

aist

circ

umfe

renc

e re

duct

ion

for

Orli

stat

(5 tr

ials

, not

poo

led,

p<0

.05

in 4

of 5

st

udie

s)

Sec

ond

ary

outc

omes

(1

0 tri

als)

T

otal

cho

lest

erol

redu

ctio

n gr

eate

r in

orlis

tat

grou

p Lo

w-d

ensi

ty li

popr

otei

n re

duct

ion

grea

ter i

n or

lista

t gro

up (8

tria

ls)

HD

L re

duct

ion

high

er in

orli

stat

gro

up (

7 tri

als)

T

rigly

cerid

e le

vels

redu

ctio

n gr

eate

r in

orlis

tat

grou

p S

BP

net

dec

reas

e (9

tria

ls)

SB

P n

et in

crea

se (2

tria

ls)

DB

P n

et d

ecre

ase

(8 tr

ials

) F

astin

g pl

asm

a gl

ucos

e re

duct

ions

(9 tr

ials

, si

gnifi

cant

ly d

iffer

ent t

o pl

aceb

o in

5 tr

ials

) H

bA1c

redu

ctio

n (4

tria

ls, h

igh

risk

patie

nts)

A

dve

rse

even

ts

Incr

ease

d in

orli

stat

gro

up:

fatty

/oily

sto

ol a

nd o

ily s

potti

ng

faec

al u

rgen

cy (9

tria

ls)

Fae

cal i

ncon

tinen

ce in

crea

se

2.

7(2.

3-3.

1)

2.9(

2.3-

3.4)

21

(19-

24)

12(8

-16)

8(

5-10

) 17

(14-

21)

0.7-

3.4c

m

0.33

mm

ol/L

(0.2

8-0.

38)

0.27

mm

ol/L

(0.2

2-0.

31)

0.

02m

mol

/L (0

.01-

0.04

)

0.05

mm

ol/L

(0.0

7gai

n–0.

17

loss

) 1.

8mm

Hg

(0.9

-2.6

) 0.

4mm

Hg

(NS

) 1.

6mm

Hg

(0.7

-2.4

) 0.

1-1.

3 m

mol

/L

0.2%

(0.2

-0.3

)

16

-40%

6%

(5-8

%)

Ran

dom

ised

/allo

catio

n co

ncea

lmen

t met

hod

desc

ribed

S

imila

r at b

asel

ine

ITT

last

obs

erva

tion

carr

ied

forw

ard

Dou

ble

blin

d B

lind

outc

ome

asse

ssm

ent

Ave

rage

dro

p-ou

t rat

e

18%

55

%

0%*

100%

N

R

33%

(1

4-52

)

Bas

elin

e w

eigh

t was

ca

lcul

ated

from

the

star

t of t

he

run

in p

erio

d ra

ther

than

the

poin

t of r

ando

mis

atio

n –

infla

ting

the

abso

lute

cha

nge

in w

eigh

t. H

igh

attri

tion

rate

s w

ere

the

maj

or m

etho

dolo

gica

l lim

itatio

n.

Is th

e de

gree

of w

eigh

t los

s ac

hiev

ed o

f clin

ical

ben

efit?

It

may

be,

par

ticul

arly

for h

igh-

risk

grou

ps b

ut m

ore

defin

itive

da

ta a

re n

eede

d. W

eigh

t re

duct

ion

of 5

-10%

of b

ody

wei

ght i

s as

soci

ated

with

im

prov

emen

ts in

blo

od

pres

sure

, lip

id a

nd g

luco

se

para

met

ers

but d

ata

on th

e ef

fect

of m

orta

lity

and

card

iova

scul

ar e

vent

s ar

e la

ckin

g.

All

stud

ies

show

ed a

pos

itive

tre

atm

ent e

ffect

. How

ever

pu

blic

atio

n bi

as c

anno

t be

rule

d ou

t. T

he p

atie

nt p

opul

atio

n st

udie

s re

pres

ent a

hig

hly

sele

cted

gr

oup

of re

lativ

ely

heal

thy

obes

e pa

tient

s w

ho w

ere

able

to

com

ply

with

stu

dy d

iet a

nd

med

icat

ion

requ

irem

ent.

Mos

t of

the

patie

nts

wer

e fe

mal

e C

auca

sian

s. E

xtra

pola

tion

to

patie

nts

with

diff

eren

t de

mog

raph

ic p

rofil

e m

ust b

e m

ade

with

cau

tion.

N

ote

:

Leve

ls o

f fat

-sol

uble

vita

min

s A

, D, E

and

bet

a-ca

rote

ne

wer

e re

port

ed a

s lo

wer

ed in

th

e or

lista

t gro

up.

* al

l tria

ls h

ampe

red

by a

hig

h at

triti

on r

ate

of 1

4-52

%, a

vera

ge 3

3%

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

90

Evi

den

ce T

able

14.

S

ibu

tram

ine,

O’M

eara

et

al.,

2002

Eff

ect S

ize

& P

reci

sion

S

tud

y au

tho

rs

and

yea

r

Stu

dy

Des

ign

/Typ

e O

bje

ctiv

e S

tud

y R

efer

ence

s

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) W

eigh

ted

mea

n d

iffer

ence

, RR

Val

idity

/App

licab

ility

%

of

stud

ies

Con

clu

sio

ns

Com

men

ts

O’M

eara

et

al.,

2002

S

tudy

type

N

ICE

HD

L O

bje

ctiv

e T

o sy

stem

atic

ally

ass

ess

the

evid

ence

for t

he

clin

ical

effe

ctiv

enes

s an

d co

st-e

ffect

iven

ess

of

sibu

tram

ine

in th

e m

anag

emen

t of o

besi

ty

Stu

die

s in

clud

ed

(N=1

1)

Apf

elba

um e

t al.,

199

9 B

ray

et a

l., 1

999

Cue

llar e

t al.,

200

0 F

angh

anel

et a

l., 2

000

Fin

er e

t al.,

200

0 F

ujio

ka e

t al.,

200

0 H

anot

in e

t al.,

199

8 H

anse

n et

al.,

199

9 S

eagl

e et

al.,

199

8 W

alsh

et a

l., 1

999

Wei

ntra

ub e

t al.,

199

1 S

tud

ies

from

the

man

ufa

ctu

rer

(N=5

)*

Wirt

h et

al.,

199

8 S

mith

et a

l., 1

994

Jam

es e

t al.,

199

9 R

issa

n et

al.,

199

8 W

illia

ms

ey a

l., 1

999

* m

anuf

actu

rer’s

tria

ls

had

to h

ave

a du

ratio

n of

at

leas

t 1 y

ear

Incl

usio

n

RC

Ts

Any

dur

atio

n of

ther

apy

Any

leng

th o

f fol

low

-up

Obe

se o

r ove

rwei

ght p

atie

nts

or

patie

nts

who

hav

e pr

evio

usly

bee

n

obes

e or

ove

rwei

ght w

ishi

ng to

mai

ntai

n w

eigh

t los

s.

Onl

y st

udie

s pu

blis

hed

in E

nglis

h,

Fre

nch,

Dut

ch o

r Ger

man

wer

e co

nsid

ered

for i

nclu

sion

. E

xclu

sion

T

rials

recr

uitin

g pe

ople

with

eat

ing

diso

rder

s su

ch a

s an

orex

ia n

ervo

sa,

and

bulim

ia n

ervo

sa.

Sib

utra

min

e 5-

30m

g/d

Pri

mar

y o

utc

omes

W

eigh

t cha

nge

8 w

eeks

(3 tr

ials

, 10-

20m

g/d)

24

wee

ks (4

tria

ls, 1

0mg/

d)

1 ye

ar

RR

of f

ailu

re to

ach

ieve

a w

eigh

t lo

ss o

f at l

east

5%

of i

nitia

l bod

y w

eigh

t at 2

4 w

eeks

– 2

tria

ls

(10m

g/d)

. Not

e fo

r 15m

g/d

dose

si

gnifi

cant

het

erog

enei

ty w

as

obse

rved

. F

at c

onte

nt

Fat

-free

mas

s lo

ss a

t eig

ht w

eeks

(2

tria

ls, s

ibut

ram

ine)

F

at c

hang

e at

eig

ht w

eeks

(2

trial

s, s

ibut

ram

ine)

A

dve

rse

even

ts

Pul

se ra

te, b

lood

pre

ssur

e an

d he

art r

ate

H

eada

ches

, sle

ep d

iffic

ulty

, irr

itabi

lity

Man

ufa

ctu

rer’

s co

st u

tility

an

alys

is (B

MI<

30kg

/m2 ,

free

of

com

plic

atio

ns a

nd c

o-m

orbi

ditie

s,

no w

eigh

t los

s su

stai

ned

at 5

6 ye

ars,

cos

ts d

isco

unte

d at

6%

, be

nefit

s at

1.5

%))

Q

oL c

oeffi

cien

t for

sib

utra

min

e C

ost p

er Q

ALY

gai

ned

thro

ugh

CH

D re

duct

ion

Cos

t per

QA

LY g

aine

d th

roug

h di

abet

es in

cide

nce

Est

imat

ed c

ost p

er Q

ALY

B

est-w

orse

cas

e sc

enar

io

-3.4

kg (4

.22

to –

2.58

) p<0

.000

01

-4.0

to 9

.1kg

-4

.1 to

–4.

8kg

RR

=0.4

8 (0

.39-

0.60

), p<

0.00

001

-1.8

3kg(

-2.4

8 to

–1.

19)p

<0.0

0001

-1

.77k

g (-

2.58

-0.9

6) p

<0.0

0002

S

mal

l but

sig

nific

ant i

ncre

ase

with

si

butra

min

e, n

ot c

onsi

dere

d to

be

clin

ical

ly s

igni

fican

t. R

epor

ted

in o

ne s

mal

l tria

l. 0.

0018

5/kg

lost

£4

2,00

0 £7

7,00

0 £1

0,50

0 (£

5,70

00-£

35,0

00)

Ran

dom

ised

met

hod

desc

ribed

(n

=16)

C

once

aled

rand

omis

atio

n S

imila

r at b

asel

ine,

man

ufac

ture

rs

trial

s (n

=5),

othe

r tria

ls (N

=11)

P

atie

nts

blin

ded

Car

ers

blin

ded

Blin

d ou

tcom

e as

sess

men

t In

tent

ion

to tr

eat a

naly

sis

Pat

ient

adh

eren

ce a

sses

sed

With

draw

als

repo

rted

Sel

ectio

n cr

iteria

19%

10

0%

0%

100%

10

0%

uncl

ear

uncl

ear

69%

50

%

94%

10

0%

Man

y of

the

trial

s de

mon

stra

ted

a st

atis

tical

ly s

igni

fican

t di

ffere

nce

in fa

vour

of

sibu

tram

ine

in te

rms

of

(a) a

bsol

ute

wei

ght

loss

(b) %

of p

atie

nts

achi

evin

g at

leas

t 5%

or

10%

loss

of i

nitia

l bo

dy w

eigh

t. T

he d

iffer

ence

s w

ere

smal

l and

may

not

be

clin

ical

ly im

porta

nt.

Wei

ght l

oss

seem

s to

be

dos

e re

late

d w

ith

stat

istic

ally

sig

nific

ant

resu

lts re

porte

d fo

r 10-

20m

g do

ses

of

sibu

tram

ine.

B

etw

een

grou

p di

ffere

nce

in B

P, l

ipid

s le

vels

and

gly

caem

ic

cont

rol w

ere

inco

nsis

tent

.

EG

O =

Exp

osur

e G

roup

Occ

urre

nce,

CG

O =

Con

trol

Gro

up O

ccur

renc

e, R

R =

Rel

ativ

e R

isk,

RD

= R

isk

Diff

eren

ce, N

NT

= n

umbe

r ne

eded

to tr

eat,

N/S

= N

ot S

tate

d N

SD

no

sign

ifica

nt d

iffer

ence

, NS

= n

ot s

igni

fican

t ‡i

ndiv

idua

lly s

igni

fican

t dat

a no

t poo

led.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

91

Evi

den

ce T

able

15.

S

ibu

tram

ine,

Tam

bas

cia

et a

l., 2

003

Eff

ect S

ize

& P

reci

sion

S

tud

y/Y

ear

Loc

atio

n

Stu

dy

Des

ign

O

bje

ctiv

e D

ura

tion

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

P

S

Val

idity

/App

licab

iilty

C

oncl

usi

ons

C

omm

ents

Tam

basc

ia e

t al

., 2

003

Loc

atio

n

Bra

zil

Stu

dy D

esig

n

Ran

dom

ised

, P

lace

bo-c

ontro

lled,

dou

ble

blin

d cl

inic

al tr

ial

Ru

n in

per

iod

N

one

repo

rted

Ob

ject

ive

To

asse

ss th

e ef

fect

of

sibu

tram

ine

assi

sted

wei

ght

redu

ctio

n on

insu

lin s

ensi

tivity

an

d m

etab

olic

par

amet

ers

in

obes

e, n

orm

al g

luco

se

tole

rant

indi

vidu

als

over

a

perio

d of

24

wee

ks.

Du

ratio

n

24 w

eeks

Par

ticip

ants

N

=48

recr

uite

d N

=40

rand

omis

ed

N=3

1 co

mpl

eter

s H

ealth

y ob

ese,

fem

ale

volu

ntee

rs

Age

=41

.1±

9.9

year

s

Age

-ran

ge =

19-5

8 ye

ars

BM

I=34

.3±

2.9k

g/m

2 In

clus

ion

B

MI=

30-4

0kg/

m2

Exc

lusi

on

Psy

chia

tric

inst

abili

ty, h

isto

ry o

f an

ti-ob

esity

sur

gery

, rec

ent

chan

ge in

exe

rcis

e pa

ttern

, sm

okin

g ce

ssat

ion

with

in 6

m

onth

s, h

yper

tens

ion,

his

tory

of

CH

D, c

ardi

ac a

rrhy

thm

ia,

endo

crin

e di

sord

ers

incl

udin

g ty

pe 2

dia

bete

s an

d gl

ucos

e in

tole

ranc

e, h

isto

ry o

f dru

g or

al

coho

l abu

se, u

se o

f ant

i-de

pres

sant

age

nts,

mon

oam

ine

oxid

ase

inhi

bito

rs a

nd u

se o

f dr

ugs

that

affe

ct in

sulin

se

nsiti

vity

(cor

ticoi

ds, d

iure

tics,

in

sulin

sen

sitis

ers,

oes

troge

n re

plac

emen

t. F

emal

es w

ere

requ

ired

to h

ave

a ne

gativ

e se

rum

pre

gnan

cy te

st,

to b

e po

st m

enop

ausa

l, su

rgic

ally

ste

rilis

ed o

r usi

ng a

m

edic

ally

acc

epte

d co

ntra

cept

ive

met

hod.

Exp

osu

re

Sib

utra

min

e 10

mg/

d +

diet

ary

advi

ce fr

om o

bese

cl

inic

C

om

par

ison

P

lace

bo +

die

t adv

ice

from

ob

ese

clin

ic

Wei

gh

t los

s at

24

wee

ks

Wei

ght l

oss

(kg)

W

eigh

t los

s (%

) F

at m

ass

(%)

Dia

bet

ic m

etab

olic

par

amet

ers

at 2

4 w

eeks

G

luco

se (m

g/dl

) T

rigyl

cerid

es

Insu

lin (:

U/m

l) H

OM

A-IR

H

OM

A-≥

K

itt

Blo

od p

ress

ure

at 2

4 w

ks

SB

P m

mH

g D

BP

mm

Hg

Hea

rt ra

te (b

pm)

Lip

id p

rofil

e at

24

wee

ks

Tot

al c

hole

ster

ol

HD

L-ch

oles

tero

l LD

L-ch

oles

tero

l A

nth

rop

omo

rph

ic in

dic

es

Wai

st c

ircum

fere

nce

cm

Ad

vers

e ev

ents

S

ibut

ram

ine

= an

orex

ia, d

ry m

outh

and

na

usea

. S

erio

us

adve

rse

even

ts

Car

diac

arr

hyth

mia

=1

(sib

utra

min

e)

+0

.9

1.2

+0.4

0.

0 -8

.0

+4.6

+0

.8

+51

+0.1

9 +4

.0

+1.0

+2

.0

-8.0

-1

.0

-5.0

+1.0

-5

.6

-6.1

-1

.6

-2.0

-4

0.0

-9.3

-2

.2

-134

+1

.06

-5.0

-5

.0

+5.0

-8

.0

+2.0

-2

.0

-4.0

An

alys

is

Com

plia

nce

test

s –

pill

coun

ting

Com

plet

ers

anal

ysis

- an

alys

is p

er p

roto

col

Onl

y di

ffere

nce

from

ba

selin

e co

mpu

ted

for

each

trea

tmen

t se

para

tely

. P

ropo

rtion

of p

artic

ipan

ts

>=5%

and

10%

wei

ght

loss

not

repo

rted

Rea

son

s fo

r d

isco

ntin

uat

ion

A

dver

se e

vent

=1

Pre

gnan

cy=1

P

roto

col

devi

atio

n=3(

1S+2

P)

Lack

of e

ffica

cy=4

(1

S+3

P)

Ext

ern

al v

alid

ity

100%

fem

ale

very

larg

e nu

mbe

r of

excl

usio

n cr

iteria

Stu

dy c

onc

lusi

ons

The

aut

hors

con

clud

ed th

at

sibu

tram

ine

had

dem

onst

rate

d ef

ficac

y in

redu

cing

wei

ght i

n no

n-di

abet

ic fe

mal

es a

nd

amel

iora

ted

insu

lin s

ensi

tivity

pa

ram

eter

s an

d ot

her m

etab

olic

pa

ram

eter

s.

Co

mm

ents

W

eak

anal

ysis

Le

ss th

an 2

0 pe

r gro

up

No

form

al d

ieta

ry in

terv

entio

n or

be

havi

our m

odifi

catio

n pr

ogra

m

Sib

utra

min

e no

t adm

inis

tere

d as

pe

r lic

ence

.

HO

MA

-IR

, HO

MA

-≥ a

nd K

ittar

e in

sulin

sen

sitiv

ity te

sts,

BM

P =

bea

ts p

er m

inut

es, P

=pla

cebo

, S=s

ibut

ram

ine.

Bo

ld fi

gure

s =

sig

nific

ant d

iffer

ence

.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

92

Evi

den

ce T

able

16.

S

ibu

tram

ine,

Pad

wal

et

al.,

2004

Eff

ect S

ize

& P

reci

sion

S

tud

y au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) W

eigh

ted

mea

n

diff

eren

ce †

Val

idity

/App

licab

ility

%

of

stud

ies

Con

clu

sio

ns

Com

men

ts

Pad

wal

et a

l.,

2004

C

och

rane

S

yste

mat

ic R

evie

w

To

asse

ss/c

ompa

re

the

effe

cts

and

safe

ty

of s

ingl

e or

co

mbi

natio

n an

ti-ob

esity

dru

g th

erap

y in

clin

ical

tria

ls o

f at

leas

t one

yea

r M

cMah

on e

t al 2

000

Sm

ith e

t al 2

001

McM

ahon

et a

l 200

2

Incl

usio

n

BM

I ≥ ≥≥≥ 3

0kg

/m2

stud

y le

ngth

≥1

yr

rand

omis

ed

doub

le b

lind

plac

ebo

or a

ctiv

e co

ntro

l R

ando

mis

atio

n re

stric

ted

to

patie

nts

who

cou

ld fo

llow

di

etar

y ad

vice

or h

ad 7

5%

com

plia

nce

durin

g th

e ru

n-in

ph

ase.

E

xclu

sion

O

besi

ty o

f end

ocrin

e or

igin

, di

abet

es m

ellit

us, t

reat

men

t w

ith m

edic

atio

n th

at m

ay

alte

r bod

y w

eigh

t, un

cont

rolle

d hy

perte

nsio

n N

ote:

one

tria

l exc

lude

d be

caus

e 36

% o

f ran

dom

ised

pa

tient

s w

ere

not i

nclu

ded

in

the

anal

ysis

. D

uplic

ate

popu

latio

ns

Sib

utr

amin

e 15

-20m

g d

aily

C

o-in

terv

entio

ns =

3

trial

s (2

US

A, 1

UK

) 929

pa

rtici

pant

s A

v B

MI 3

3.4k

g/m

2

Av

wei

ght 9

6kg

Av

age

47 y

ears

80

% fe

mal

e 75

% C

auca

sian

2

trial

s lim

ited

enro

llmen

t to

obes

e hy

perte

nsiv

e pa

tient

s w

ith w

ell c

ontro

lled

BP

, in

the

rem

aini

ng tr

ial o

nly

*% h

ad a

tre

ated

car

diov

ascu

lar c

ondi

tion

Pri

mar

y o

utc

omes

av

erag

e w

eigh

t los

s in

kg

av

erag

e w

eigh

t los

s %

cha

nge

from

bas

elin

e %

of p

atie

nts

with

wei

ght l

oss

of le

ast 5

%

% o

f pat

ient

s w

ith w

eigh

t los

s of

at l

east

10%

C

ompa

rativ

e B

MI r

educ

tion

Wai

st c

ircum

fere

nce

redu

ctio

n S

econ

dar

y ou

tcom

es

Impr

oved

blo

od g

luco

se le

vels

(2 s

tudi

es)

sibu

tram

ine

treat

ed p

atie

nts

Trig

lyce

rides

leve

ls lo

wer

in s

ibut

ram

ine

arm

T

otal

cho

lest

erol

Lo

w-d

ensi

ty li

popr

otei

n H

DL

high

er in

sib

utra

min

e st

udie

s (n

=2)

Ad

vers

e E

ven

ts

(Sib

utra

min

e)

Sys

tolic

blo

od p

ress

ure

net i

ncre

ase

1.9m

mH

g (0

.2-3

.6)‡

.Dia

stol

ic b

lood

‡

pres

sure

1-4

mm

Hg

Pul

se ra

te in

crea

se 4

-6 b

eats

per

min

(p

=<0.

05)

Oth

er A

Es

mo

re c

om

mon

in s

ibu

tram

ine

arm

In

som

nia

Nau

sea

Dry

mou

th

Con

stip

atio

n

4.

3(3.

6-4.

9)

4.6(

3.8-

5.4)

34

(28-

40)

15(4

-27)

1.

5kg/

m2

(1.2

-1.8

) 4-

5cm

0.08

and

0.9

mm

ol/L

(NS

) 0.

18-0

.23

mm

ol/L

(p

<0.0

5)

NS

D

NS

D

0.08

-0.0

9mm

ol/L

(p

=<0.

05)

7-

20%

Ran

dom

ised

met

hod

desc

ribed

S

imila

r at b

asel

ine

Inte

ntio

n to

trea

t las

t obs

erva

tion

carr

ied

forw

ard

Dou

ble

blin

d B

lind

outc

ome

asse

ssm

ent

Com

plia

nce

D

rop-

outs

<20%

33

67

100

10

0 N

R

NR

Y

es (4

3%)

Het

erog

enei

ty in

pr

imar

y ou

tcom

es

cons

ider

ed to

be

of

negl

igib

le c

linic

al

rele

vanc

e. S

tratif

ying

in

to h

igh

and

low

risk

st

udy

popu

latio

ns

elim

inat

ed o

bser

ved

hete

roge

neity

.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

93

Evi

den

ce T

able

17.

S

ibu

tram

ine,

Leu

ng

et

al.,

2003

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

Eff

ect S

ize

& P

reci

sion

V

alid

ity/A

pplic

abili

ty

% o

f stu

die

s C

oncl

usi

ons

C

omm

ents

Leun

g et

al.,

20

03

Stu

dy ty

pe

Sys

tem

atic

revi

ew

Ob

ject

ive

To

desc

ribe

the

phar

mac

olog

ic

man

agem

ent o

f ob

esity

co

ncen

tratin

g on

si

butra

min

e In

clud

ed s

tud

ies

Sib

utra

min

e A

pfel

baum

, 199

9 C

uelle

r, 20

00

Duj

ovne

, 200

1 F

angh

anel

, 200

0 F

angh

anel

, 20

01

Fuj

ioka

, 200

0 Ja

mes

, 200

0 M

cMah

on, 2

000

Sm

ith, 2

001

Wirt

h, 2

001

Incl

usio

n

Stu

dies

bet

wee

n 19

66-F

ebru

ary

2002

R

CT

s of

> 6

m

onth

s du

ratio

n re

porti

ng th

e ef

ficac

y of

S

ibut

ram

ine

Exp

osu

re

Sib

utra

min

e 1-

30m

g t.i

.d.

Co

mp

aris

on

Pla

cebo

Do

se r

elat

ed w

eigh

t lo

ss a

t 6 m

onth

s S

ibut

ram

ine

1mg

5mg

10m

g 30

mg

Pla

cebo

M

eta

anal

ysis

of 4

long

-ter

m tr

ials

W

aist

circ

umfe

renc

e re

duce

d (s

ibut

ram

ine)

W

aist

hip

ratio

redu

ced

(sib

utra

min

e)

Wei

gh

t los

s g

reat

er in

trea

tmen

t gro

up

than

p

lace

bo

gro

up fo

r T

ype

2 di

abet

es m

ellit

us

Dys

lipid

emia

H

yper

tens

ion

Gre

ater

red

uctio

ns

with

sib

utr

amin

e vs

. pla

cebo

F

astin

g H

bA1c

and

glu

cose

leve

ls, s

erum

trig

lyce

rides

hi

gh d

ensi

ty li

popr

otei

n, c

hole

ster

ol, u

rate

, C-p

eptid

e In

sulin

A

dve

rse

even

ts

Dry

mou

th, a

nore

xia,

inso

mni

a, c

onst

ipat

ion,

hea

dach

e B

lood

pre

ssur

e, s

ibut

ram

ine

vs. p

lace

bo

Hea

rt ra

te, s

ibut

ram

ine

vs. p

lace

bo

2.

5%

3.9%

6.

1% p

<0.0

5 9.

4%

1.2%

p<0.

001

p<0.

02

p<

0.00

1 p<

0.05

p<

0.05

p<0

.05

p<

0.00

1 p<

0.00

1 1-

3mm

Hg

(mea

n in

crea

se)

4-5

beat

s/m

in (m

ean

incr

ease

)

Ove

rall

with

dra

wal

ra

tes

S

ibut

ram

ine

Pla

cebo

D

isco

ntin

uatio

n d

ue

to

hyp

erte

nsi

on

Sib

utra

min

e P

lace

bo

Dis

con

tinua

tion

du

e to

ta

chyc

ard

ia

Sib

utra

min

e P

lace

bo

No

qual

ity a

sses

smen

t w

as re

porte

d

9%

7%

0.4%

0.

4%

0.4%

0.

1%

Co

nclu

sion

O

rlist

at a

nd s

ibut

ram

ine

dem

onst

rate

d a

favo

urab

le e

ffica

cy

and

safe

ty p

rofil

e in

RC

Ts.

Cur

rent

ev

iden

ce s

uppo

rts th

eir u

se a

s ad

junc

ts to

life

styl

e m

odifi

catio

ns in

th

e tre

atm

ent o

f obe

sity

N

ote

: In

Mar

ch 2

002

the

Italia

n H

ealth

Min

istry

sus

pend

ed s

ales

of

sibu

tram

ine

for r

e-ev

alua

tion

of it

s sa

fety

pro

file

afte

r 2 d

eath

s an

d 50

ad

vers

e ev

ents

. Afte

r inv

estig

atio

n th

e E

AE

MP

(Jun

e 20

02) r

epor

ted

that

th

e ris

k-be

nefit

pro

file

of s

ibut

ram

ine

rem

aine

d po

sitiv

e.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

94

Evi

den

ce T

able

18.

S

ibu

tram

ine,

Nis

oli

and

Car

rub

a, 2

003

S

tud

y au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e In

clud

ed S

tud

ies

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

P

artic

ipan

ts

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

)

Adv

erse

Eve

nt

S

P

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Nis

oli a

nd

Car

ruba

, 200

3 S

tudy

des

ign

S

yste

mat

ic R

evie

w o

f all

trial

s of

sib

utra

min

e re

porti

ng u

nwan

ted

side

ef

fect

s of

sib

utra

min

e O

bje

ctiv

e A

ben

efit-

risk

asse

ssm

ent

of s

ibut

ram

ine

in th

e m

anag

emen

t of o

besi

ty

Incl

uded

stu

die

s H

anse

n et

al.,

199

8 W

alsh

et a

l., 1

999

Jam

es e

t al.,

200

0 A

pfel

baum

et a

l., 1

999

Kno

ll 20

00

Kno

ll200

0 K

noll

2000

M

cNul

ty e

t al.,

200

3 B

ray

et a

l., 1

999

Fan

ghan

el e

t al.,

200

0 C

uelle

r et a

l., 2

000

Fuj

ioka

et a

l., 2

000

Gok

cel e

t al.,

200

1 S

erra

no-R

ios

et a

l., 2

002

Han

otin

et a

l., 1

998

Fin

er e

t al.,

200

0 H

anot

in e

t al.,

199

8 W

eint

aub

et a

l., 1

991

Sea

gle

et a

l., 1

998

Incl

usio

n

All

clin

ical

tria

ls o

f sib

utra

min

e fo

r w

eigh

t man

agem

ent i

n ov

erw

eigh

t or

obes

e su

bjec

ts re

porti

ng u

nwan

ted

side

effe

cts

of s

ibut

ram

ine

Exp

osu

re

Sib

utra

min

e C

o-in

terv

entio

n

Low

cal

orie

die

t A

djun

ctiv

e th

erap

y in

the

form

of d

iet,

exer

cise

d an

d be

havi

or

mod

ifica

tion

advi

ce in

va

ryin

g in

tens

ities

.

Co

mm

on a

dve

rse

even

ts

asso

ciat

ed w

ith s

ibu

tram

ine

H

eada

che

Con

stip

atio

n N

ause

a N

ervo

us s

yste

m (>

5%)

Diz

zine

ss

Dry

mou

th

Inso

mni

a R

equ

irin

g r

egu

lar

mon

itori

ng

In

crea

sed

bloo

d pr

essu

re

Incr

ease

d he

art r

ate

ST

OR

M tr

ial

Dat

a re

latin

g to

blo

od li

pids

an

d ge

nera

l met

abol

ism

sh

owed

sub

stan

tial

impr

ovem

ents

in th

e si

butra

min

e gr

oup.

A

dver

se e

vent

s

Inso

mni

a N

ause

a In

c bl

ood

pres

sure

La

ssitu

de

Bac

k pa

in

With

draw

als

resu

lts fo

rm

adve

rse

even

ts

Sib

utra

min

e w

ithdr

awal

s as

a

resu

lt of

BP

8% v

s. 3

%

7% v

s. 1

%

8% v

s. 3

%

7% v

s. 1

1%

7% v

s. 9

%

14%

vs5%

0.

8%

All

tria

ls re

porte

d pa

rtici

pant

se

lect

ion

crite

ria a

nd c

ompa

rabi

lity

of g

roup

s at

bas

elin

e.

Rel

ativ

ely

few

tria

ls d

escr

ibed

the

use

of a

prio

ri po

wer

cal

cula

tion

to

estim

ate

requ

ired

sam

ple

size

. N

one

of th

e tri

als

incl

uded

m

etho

ds to

det

erm

ine

the

succ

ess

of b

lindi

ng o

f pat

ient

s, c

are

give

rs

or o

utco

mes

ass

esso

rs.

Rep

ortin

g of

num

bers

of

with

draw

als

per g

roup

with

re

ason

s w

as v

aria

ble.

A

few

tria

ls in

clud

ed a

n as

sess

men

t of p

atie

nt’s

adh

eren

ce

with

the

trial

regi

men

; usu

ally

ei

ther

cou

ntin

g re

turn

ed c

apsu

les

or s

elf-r

epor

ting

(bot

h ar

e po

tent

ially

unr

elia

ble)

.

The

aut

hors

co

nclu

ded

that

the

asse

ssm

ent-r

isk

prof

ile o

f si

butra

min

e w

as

posi

tive

alth

ough

th

e pr

oduc

t mus

t be

kep

t und

er

revi

ew a

nd B

P a

nd

hear

t rat

e m

onito

red

espe

cial

ly in

obe

se

hype

rtens

ive

patie

nts.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

95

Evi

den

ce T

able

19.

S

ibu

tram

ine,

Ber

kow

titz

et

al.,

2003

Eff

ect S

ize

& P

reci

sion

S

tud

y au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e L

eng

th o

f st

udy

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) P

lace

bo

(s

.d.)

Sib

utr

amin

e (s

.d.)

p

valu

e

Val

idity

/App

licab

ility

Co

ncl

usi

on

s C

om

men

ts

Ber

kow

titz

et

al.,

2003

S

tudy

des

ign

R

ando

mis

ed,

doub

le b

lind,

pl

aceb

o co

ntro

lled

trial

L

eng

th o

f st

udy

Inte

ntio

n to

trea

t an

alys

is a

t 6

mon

ths

Par

ticip

ants

N

=146

ado

lesc

ents

ev

alua

ted

at c

linic

, 82

rand

omis

ed, 6

4 ex

clud

ed

(psy

chia

tric

cond

ition

s (2

4), n

ot in

tere

sted

(21)

, un

able

to a

ttend

gro

up

mee

tings

(12)

, med

ical

co

nditi

ons

(2),

othe

r (7)

).

Mea

n ag

e =1

4.1

yrs

(SD

=1.2

) M

ean

wei

ght=

103.

6kg

(SD

=15.

4)

Mea

n B

MI=

37.8

(SD

=3.8

) M

ean

wai

st

circ

umfe

renc

e=11

0.8c

m

(SD

=10.

0)

Sex

= 55

F: 2

7M

Whi

te ra

ce=4

5 B

lack

race

=34

Incl

usio

n

adol

esce

nts

13

-17

year

s B

MI =

32-4

4.

Exc

lusi

on/

con

trai

nd

icat

ions

C

ardi

ovas

cula

r dis

ease

D

iabe

tes

(type

1 o

r 2)

Maj

or p

sych

iatri

c di

sord

ers

Use

of a

wei

ght l

oss

med

icat

ion

or w

eigh

t los

s of

5kg

or m

ore

in th

e pr

evio

us 6

mon

ths

Use

of m

edic

atio

ns

prom

otin

g w

eigh

t gai

n (e

.g.,

oral

ste

roid

s)

Use

of m

edic

ines

co

ntra

indi

cate

d w

ith u

se o

f si

butra

min

e C

igar

ette

sm

okin

g

Ph

ase

I, p

lace

bo

co

ntr

olle

d, 6

mon

ths

wei

ght l

oss

tria

l S

ibut

ram

ine

+ be

havi

or

ther

apy,

N=4

3 or

pla

cebo

+b

ehav

ior t

hera

py, n

=39

Med

icat

ion

pro

toco

l W

eek

one:

all

parti

cipa

nts

rece

ived

pla

cebo

. Wee

k tw

o:

eith

er 5

mg/

d si

butra

min

e or

pl

aceb

o. W

eek

thre

e:

10m

g/d

or p

lace

bo. W

eek

seve

n: 1

5mg/

d or

pla

cebo

D

ose

redu

ctio

n: in

sub

ject

s w

ith a

n in

crea

se in

SB

P o

r D

BP

of >

=10m

mH

g or

an

incr

ease

of p

ulse

rate

of

>=15

%, d

ose

redu

ced

in

5mg

until

des

ired

rate

s ac

hiev

ed. S

ibut

ram

ine

disc

ontin

ued

if B

P in

crea

sed

20m

m H

g or

mor

e.

Beh

avio

ura

l pro

toco

l W

eekl

y gr

oup

sess

ions

for

subj

ect a

nd s

epar

ate

grou

ps

sess

ions

for p

aren

ts. G

roup

s w

ere

led

by d

ietit

ians

, ps

ycho

logi

sts

or

psyc

hiat

rists

. D

iet

1200

-150

0kca

l/d 3

0% fa

t 15

% p

rote

in, 5

5%

carb

ohyd

rate

. E

xerc

ise

Eve

ntua

l goa

l of w

alki

ng o

r si

mila

r aer

obic

act

ivity

12

0min

s pe

r wee

k.

Oth

er

Dai

ly e

atin

g an

d ac

tivity

logs

Ph

ase

I M

ean

wei

ght l

oss

% c

hang

e in

BM

I W

aist

circ

umfe

renc

e B

MI r

educ

tion>

=5%

B

MI r

educ

tion>

=10%

B

MI r

educ

tion>

=15%

S

ysto

lic B

P (3

mo)

D

iast

olic

BP

(3m

o)

Sys

tolic

BP

(6m

o)

Dia

stol

ic (6

mo)

P

ulse

rate

(3m

o)

Pul

se ra

te (6

mo)

H

unge

r red

uctio

n 19

dro

pou

ts

Sys

tolic

BP

‡

Dia

stol

ic B

P‡

Pul

se ra

te

Ser

um c

hem

istr

y

3.

2kg

(6.1

) 4.

0%(5

.4)

-2.8

cm(5

.6)

14(3

6)

6(15

) 1(

3)

110.

7mm

Hg

55.7

mm

Hg

110.

3mm

Hg

55.3

mm

Hg

81.6

bea

ts/m

in

81.2

beat

s/m

in

No

betw

een

grou

p di

ffere

nces

7.

8kg

(6.3

) 8.

5% (6

.8)

-8.2

(6.9

) 27

(63)

17

(40)

8(

19)

114.

8mm

Hg

58.4

mm

Hg

112.

9mm

Hg

58.6

mm

Hg

85.6

beat

s/m

in

84.8

beat

s/m

in

grea

ter

+ 10

mm

Hg

+8.6

mm

Hg

+14.

3/m

in

0.

001

0.00

1 <0

.001

0.

02

0.02

0.

02

0.02

† 0.

23†

0.06

† 0.

11†

<0.0

01†

0.00

7†

0.00

2 <0

.001

<0

.001

<0

.001

Ph

ase

I C

ompl

eted

6 m

onth

as

sess

men

t P

lace

bo

Sib

utra

min

e T

aken

off

stud

y be

caus

e of

mar

ked

and

sust

aine

d B

P in

crea

se

with

sib

utra

min

e IT

T a

naly

sis

Stu

dy p

ower

ed to

de

tect

4%

diff

eren

ce in

ba

selin

e B

MI b

etw

een

treat

men

t gro

ups.

N

o si

gnifi

cant

di

ffere

nce

betw

een

grou

ps a

t bas

elin

e N

o si

gnifi

cant

di

ffere

nce

in

with

draw

als

betw

een

grou

ps

Ph

ase

II, m

ain

tena

nce

tria

ls 7

-12

mo

nth

s, a

ll su

bje

cts

rece

ive

sibu

tram

ine

Not

repo

rted

here

, en

dpoi

nts

not r

elev

ant.

34/3

9 (8

7%)

40/4

3 (9

3%)

5/43

(12%

)

Dur

ing

Pha

se I

19/4

3(44

%) p

artic

ipan

ts

had

dose

redu

ctio

ns o

r di

scon

tinue

d tre

atm

ent

with

sib

utra

min

e. B

P a

nd

HR

resu

lts re

flect

a

delib

erat

e at

tem

pt to

lim

it in

crea

ses

in B

P o

r HR

. C

om

men

t S

ibut

ram

ine

and

beha

viou

r the

rapy

re

sulte

d in

sig

nific

antly

gr

eate

r wei

ght l

oss

than

pl

aceb

o an

d be

havi

our

ther

apy.

B

ehav

iour

al a

nd

phar

mac

olog

ical

tre

atm

ents

app

eare

d to

ha

ve a

dditi

ve e

ffect

s th

at

max

imis

ed w

eigh

t los

s.

Sib

utra

min

e m

ust b

e ca

refu

lly m

onito

red

to

cont

rol i

ncre

ases

in B

P

and

puls

e ra

te.

† re

pres

ents

the

diffe

renc

e be

twee

n tr

eatm

ent c

ondi

tions

bet

wee

n ba

selin

e an

d m

onth

3, b

asel

ine

and

mon

th 6

. ‡ In

crea

se fr

om b

asel

ine

to ti

me

of d

ropo

ut

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

96

Evi

den

ce T

able

20.

S

ibu

tram

ine,

Haz

enb

erg

et

al.,

2000

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) P

S

p=

Val

idity

/App

licab

ility

%

of s

tud

ies

Con

clu

sio

ns

Com

men

ts

Haz

enbe

rg

et a

l., 2

000

Stu

dy d

esig

n

Ran

dom

ised

, dou

ble

blin

d, p

aral

lel-g

roup

, pl

aceb

o co

ntro

lled

Ob

ject

ive

To

asse

ss w

eigh

t los

s,

safe

ty a

nd to

lera

bilit

y as

soci

ated

with

si

butra

min

e in

mild

to

mod

erat

ely

obes

e hy

perte

nsiv

e pa

tient

s.

Par

ticip

ants

N

=127

A

ge –

med

ian

48 y

ears

(19-

65)

M=3

8 F

=39

Hyp

erte

nsiv

e n=

113

Incl

usio

n

18-6

5 ye

ars

BM

I in

the

rang

e 27

-40k

g/m

2 H

yper

tens

ion

stab

ilise

d fo

r at l

east

4

wee

ks a

nd m

edic

atio

n no

t ch

ange

d in

the

perio

d.

Exc

lusi

on

Mor

e th

an 3

kg lo

ss in

pre

viou

s 3

mon

ths

Pre

viou

s si

butra

min

e M

ore

than

bor

derli

ne d

epre

ssio

n or

taki

ng a

ny a

ntid

epre

ssan

t. O

besi

ty o

f end

ocrin

e or

igin

D

iabe

tes

requ

iring

insu

lin

Any

pas

t or p

rese

nt s

igni

fican

t ill

ness

R

isk

of p

regn

ancy

Exp

osu

re

Sib

utra

min

e 10

mg,

N=6

2 C

om

par

ison

P

lace

bo N

=65

Co

-inte

rven

tions

D

ieta

ry a

dvic

e an

d di

et

shee

t

Res

ults

at 1

2 w

eeks

B

ody

wei

ght (

kg)

Bod

y w

eigh

t % re

duct

ion

BM

I red

uctio

n (k

g/m

2 )

Mor

e th

an 5

% b

asel

ine

body

w

eigh

t los

s (%

) W

aist

Hip

Rat

io c

hang

e

Sup

ine

DB

P (m

m H

g)

Sup

ine

SB

P (m

m H

g)

Hea

rt ra

te (b

eats

/min

) A

dve

rse

even

ts

Sib

utra

min

e =

42%

P

lace

bo =

43%

D

ry m

outh

C

onst

ipat

ion

Ner

vous

ness

-2.2

+2

.3

-0.8

17

+0

.01

-5.2

-4

.2

-3.1

2 4 5

-4.4

+4

.7

-1.6

44

-0

.01

-3.7

-4

.1

+1.8

8 6 1

0.00

2 <0

.001

<0

.01

<0.0

1 <0

.06

0.14

0.

97

<0.0

01

Com

plet

ed s

tudy

S

ibut

ram

ine

n=50

(81%

) P

lace

bo n

=56(

86%

) W

ithdr

awal

s F

our p

atie

nts

with

drew

in th

e ru

n-in

pha

se.

14 p

atie

nts

erro

neou

sly

give

n ac

tive

med

icat

ion

durin

g th

e ru

n-in

pha

se w

ere

with

draw

n.

4 pa

tient

s w

ithdr

ew (2

sib

utra

min

e, 2

pla

cebo

) be

caus

e of

adv

erse

eve

nts

7 pa

tient

s w

ithdr

awn

in d

oubl

e bl

ind

phas

e N

=4 s

ibut

ram

ine

(AE

s =2

pro

toco

l vio

latio

n =2

) n=

3 pl

aceb

o (A

Es=

2, p

roto

col v

iola

tion

=1).

Last

obs

erva

tion

carr

ied

forw

ard

anal

ysis

.

Co

nclu

sion

S

ibut

ram

ine

10m

g/d

is e

ffect

ive

in

redu

cing

bod

y w

eigh

t in

obe

se p

atie

nts.

W

eigh

t red

uctio

n ha

s a

bene

ficia

l effe

ct o

n B

P in

obe

se

hype

rtens

ive

patie

nts.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

97

Evi

den

ce T

able

21.

S

ibu

tram

ine,

Go

kcel

et

al.,

2001

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) P

S

P

=

Val

idity

/App

licab

ility

%

of s

tud

ies

Con

clu

sio

ns

Com

men

ts

Gok

cel e

t al

., 2

001

Stu

dy d

esig

n

Ran

dom

ised

, dou

ble

blin

d,

plac

ebo

cont

rolle

d.

Ob

ject

ive

Eva

luat

ion

of th

e ef

ficac

y of

si

butra

min

e in

com

bina

tion

with

hyp

ogly

cem

ic d

rugs

in

obes

e fe

mal

es w

ith p

oorly

re

gula

ted

type

2 d

iabe

tes.

Par

ticip

ants

N

=60,

obe

se fe

mal

es

Incl

usio

n

HbA

1c >

8%

BM

I >30

kg/m

2 O

n m

axim

um d

osag

e of

m

etfo

rmin

(2,5

50m

g/d)

an

d su

lfony

lure

as

(glic

lazi

de, 3

20m

g/d

or

glip

izid

e, 2

0mg/

d).

Exc

lusi

on

Typ

e 1

diab

etes

O

besi

ty o

f end

ocrin

e or

igin

P

revi

ous

wei

ght l

oss

drug

s or

inte

nsiv

e w

eigh

t lo

ss p

rogr

am

Unc

ontro

lled

hype

rtens

ion,

S

BP

>160

mm

Hg

or D

BP

> 10

0mm

Hg.

G

lauc

oma

Pre

gnan

t wom

en

Pat

ient

s ta

king

bet

a-bl

ocke

rs, a

ntid

epre

ssan

ts,

mon

amin

e ox

idas

e in

hibi

tors

or a

ny d

rug

affe

ctin

g ap

petit

e or

w

eigh

t.

Exp

osu

re n

=29

Sib

utra

min

e 10

mg

t.i.d

. D

iet r

estri

ctio

n H

ypog

lyce

mic

dr

ugs

Co

mp

aris

on n

=25

Pla

cebo

D

iet r

estri

ctio

n H

ypog

lyca

emic

dr

ugs

Six

mon

ths

Wei

ght l

oss

(kg)

B

MI c

hang

e (k

g/m

2)

Wai

st c

ircum

fere

nce

(cm

) F

astin

g bl

ood

gluc

ose

(mg/

dl)

Pos

tpra

ndia

l blo

od g

luco

se (m

g/dl

) In

sulin

leve

l (:U

/ml)

HO

MA

IR

HbA

1c (

%)

Tot

al c

hole

ster

ol (m

g/dl

) H

DL

chol

este

rol (

mg/

dl)

LDL

chol

este

rol (

mg/

dl)

VLD

L ch

oles

tero

l (m

g/dl

) T

rigly

cerid

es (m

g/dl

) S

BP

– n

ot re

porte

d D

BP

& H

R s

igni

fican

t red

uctio

ns

repo

rted

but n

o da

ta g

iven

S

ide

effe

cts

(sib

utra

min

e)

Dry

mou

th, n

=11

Con

stip

atio

n, n

=16

H

yper

tens

ion,

n=1

(pat

ient

s w

ithdr

ew

from

stu

dy)

0.91

±0.

53

0.36

±0.

21

0.92

±0.

49

15.7

6±3.

89

32.8

8±6.

13

0.68

±0.

43

0.31

±0.

28

0.53

±0.

01

7.68

±5.

04

0.01

±1.

10

13.3

2±3.

94

0.01

±2.

58

0.36

±7.

26

-9.6

1±1.

37

-3.9

2±0.

54

-8.0

4±4.

43

124.

88±

8.58

10

2.24

±51

.99

5.66

±0.

97

7.09

±0.

81

2.73

±0.

01

28.0

8±4.

93

0.97

±1.

58

20.9

2±4.

66

8.68

±2.

58

46.7

6±13

.09

<0.0

001

<0.0

001

<0.0

001

<0.0

001

<0.0

001

<0.0

001

<0.0

001

<0.0

001

<0.0

08

>0.0

5 >0

.05

<0.0

2 <0

.08

With

draw

al -

one

subj

ect w

ithdr

ew

from

the

treat

men

t gro

up b

ecau

se

of h

yper

tens

ion.

E

xclu

sion

- fiv

e su

bjec

ts fr

om

plac

ebo

grou

p su

ffere

d lo

w

treat

men

t effi

cacy

and

wer

e ex

clud

ed a

nd s

witc

hed

to in

sulin

. C

ompa

rabl

e pa

tient

pop

ulat

ion

at

base

line

The

sig

nific

ant i

mpr

ovem

ent

in g

lyce

mic

con

trol i

n th

e si

butra

min

e gr

oup

was

at

tribu

ted

to w

eigh

t los

s.

The

re w

as a

lso

a si

gnifi

cant

po

sitiv

e ch

ange

in th

e lip

id

prof

ile o

f the

sib

utra

min

e pa

tient

s.

Co

nclu

sion

T

he a

dditi

on o

f sib

utra

min

e to

or

al h

ypog

lyca

emic

ther

apy

lead

s to

sig

nific

ant w

eigh

t los

s an

d im

prov

ed m

etab

olic

pa

ram

eter

s.

Sib

utra

min

e is

wel

l tol

erat

ed

and

safe

in th

is p

atie

nt

popu

latio

n.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

98

Evi

den

ce T

able

22.

S

ibu

tram

ine,

Kim

et

al.,

2003

DB

P=d

iast

olic

blo

od p

ress

ure,

SB

P=s

ysto

lic b

lood

pre

ssur

e

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

ies

Incl

ude

d

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) E

ffec

t Siz

e &

Pre

cisi

on

Sta

ndar

dise

d di

ffere

nce

of

chan

ges

from

bas

elin

e be

twee

n tre

atm

ent a

nd c

ontro

l§ (

95%

C

I)

Val

idity

/App

licab

ility

Con

clu

sio

ns

Com

men

ts

Kim

et a

l.,

2003

S

tudy

des

ign

M

eta-

anal

ysis

of

rand

omis

ed d

oubl

e bl

ind

plac

ebo

cont

rolle

d

trial

s.

Ob

ject

ive

A c

ompr

ehen

sive

met

a-an

alys

is o

f RC

Ts o

n th

e ef

fect

of s

ibut

ram

ine

on

wei

ght l

oss

and

bloo

d pr

essu

re.

Stu

die

s in

clud

ed, N

=21

Wei

ntra

ub e

t al.,

199

1 H

anot

in e

t al.,

199

8 S

eagl

e et

al.,

199

8 A

pfeb

aum

et a

l., 1

999

Bra

y et

al.,

199

9 H

anse

n et

al.,

199

9 C

uella

r et a

l., 2

000

Fan

ghan

el e

t al.,

200

0 F

iner

et a

l., 2

000

Fuj

ioka

et a

l., 2

000

Haz

enbe

rg e

t al.,

200

0 M

cMah

on e

t al.,

200

0 D

ujov

ne e

t al.,

200

1 G

okce

l et a

l., 2

001

Sm

ith e

t al.,

200

1 W

irth

et a

l., 2

001

Far

ia e

t al.,

200

2 M

cMah

on e

t al.,

200

2 S

erra

no-R

ios

et a

l.,

2002

S

ram

ek e

t al.,

200

2 Z

anna

d et

al.,

200

2

Incl

usio

n

Hum

an s

tudi

es

Dou

ble

blin

d ra

ndom

ised

, pla

cebo

co

ntro

lled

trial

s of

sib

utra

min

e E

nglis

h

Ful

l tex

t ava

ilabl

e O

bese

or o

verw

eigh

t par

ticip

ants

D

osag

e of

sib

utra

min

e >

5mg

Any

dur

atio

n C

o-m

orbi

ditie

s of

dia

bete

s,

hype

rtens

ion

or h

yper

lipid

emia

al

low

ed.

Exc

lusi

on

Stu

dies

of p

atie

nts

with

eat

ing

diso

rder

s C

ross

over

stu

dies

S

tudi

es th

at d

id n

ot p

rovi

de

info

rmat

ion

for e

stim

atin

g a

size

ef

fect

of w

eigh

t cha

nge.

S

tudi

es u

sing

dru

gs fo

r wei

ght

mai

nten

ance

S

tudi

es w

ith m

ultip

le tr

eatm

ent

grou

ps th

at d

id n

ot c

ompa

re e

ach

grou

p w

ith th

e co

ntro

l gro

up

inde

pend

ently

.

Exp

osu

re

Sib

utra

min

e >5

mg/

d C

om

par

ato

r P

lace

bo

Wei

gh

t cha

nge

O

vera

ll si

ze e

ffect

S

BP

O

vera

ll si

ze e

ffect

S

ize

effe

ct ra

nge

Net

incr

ease

d S

BP

attr

ibut

able

to

sib

utra

min

e D

BP

O

vera

ll si

ze e

ffect

S

ize

effe

ct ra

nge

Net

incr

ease

d D

BP

attr

ibut

able

to

sib

utra

min

e

-1.0

0 (-

1.17

to -0

.84)

0.

16 (0

.08

to 0

.24)

-0

.38

to 0

.45

1.6m

m H

g 0.

26 (0

.18

to 0

.33)

-0

.11

to 0

.73

1.8m

m H

g

All

stud

ies

wer

e ca

rrie

d ou

t in

Wes

tern

co

untri

es, w

hich

may

lim

it ap

plic

abili

ty.

Incl

usio

n cr

iteria

may

hav

e le

d to

und

er o

r ov

er-e

stim

atio

n of

the

effe

ct.

Bec

ause

onl

y pu

blis

hed

stud

ies

wer

e em

ploy

ed in

the

anal

ysis

ther

e is

a p

ossi

bilit

y of

pub

licat

ion

bias

, how

ever

Ros

enth

al’s

fail-

safe

N v

alue

s w

ere

appr

oxim

atel

y N

= 10

0 fo

r S

BP

and

N=

341

for D

BP

whi

ch m

akes

pu

blic

atio

n bi

as u

nlik

ely.

Sib

utra

min

e sh

owed

a

larg

e ef

fect

on

wei

ght b

ut

incr

ease

d bl

ood

pres

sure

si

gnifi

cant

ly, p

artic

ular

ly

in h

eavi

er a

nd/o

r you

nger

pa

rtici

pant

s. T

he s

ize

of

the

incr

ease

in b

lood

pr

essu

re w

as s

mal

l ho

wev

er, i

t was

co

nsid

ered

to b

e cl

inic

ally

im

porta

nt in

pat

ient

s w

ho

had

bord

erlin

e or

hig

h bl

ood

pres

sure

. A

gre

ater

incr

ease

in

SB

P w

as fo

und

in

subj

ects

<44

yea

rs o

f age

an

d in

the

larg

er tr

ials

(n

>=12

0).

Par

ticip

ants

with

a h

ighe

r w

eigh

t (>=

92kg

) ex

perie

nced

a h

ighe

r D

BP

and

SB

P.

The

ove

rall

effe

ct s

ize

was

sig

nific

antly

larg

er

whe

n th

e si

butra

min

e do

se w

as >

15m

g/d.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

99

Evi

den

ce T

able

23.

S

ibu

tram

ine,

Hau

ner

et

al.,

2003

Eff

ect S

ize

& P

reci

sion

C

hang

e in

wei

ght f

rom

bas

elin

e to

54

wee

ks

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

)

Pla

ceb

o

Sib

utr

amin

e P

-S

p=

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Hau

ner e

t al

., 2

003

Stu

dy d

esig

n

Ran

dom

ised

, dou

ble

blin

d, p

lace

bo c

ontro

lled

clin

ical

tria

l O

bje

ctiv

e T

o st

udy,

in a

prim

ary

heal

th c

are

setti

ng, t

he

effe

ct o

f a s

tand

ardi

sed

non-

phar

mac

olog

ical

pr

ogra

m a

nd 1

5mg

sibu

tram

ine

or p

lace

bo

on lo

ng-te

rm w

eigh

t re

duct

ion.

T

rial

du

ratio

n

54 w

eeks

Par

ticip

ants

N

=389

, IT

T p

opul

atio

n N

=348

C

onse

cutiv

e, G

P p

atie

nts

in th

e ar

ea o

f Col

ogne

-D

usse

ldor

f, G

erm

any.

M

ale=

89 (2

3%),

Fem

ale=

259(

67%

) M

ean

age

=42.

7 ±

11.

7 ye

ars

Incl

usio

n

Age

18-

65 y

ears

B

MI 3

0-40

kg/m

2 S

tabl

e w

eigh

t (±

2kg)

du

ring

the

prec

edin

g 3

mon

ths

Mot

ivat

ion

and

will

ingn

ess

to re

duce

wei

ght.

Exc

lusi

on

Ser

um c

reat

inin

e >2

mg/

dl

Hyp

erch

oles

tero

lem

ia

(tota

l cho

lest

erol

>3

20m

g/dl

) U

ncon

trolle

d hy

perte

nsio

n (>

160/

95m

mH

g, m

ean

of

3 in

depe

nden

t m

easu

rem

ents

) T

ype

2 di

abet

es m

ellit

us

Cor

onar

y he

art d

isea

se

Clin

ical

ly s

igni

fican

t dy

srhy

thm

ia

Psy

chia

tric

dise

ases

C

hild

bea

ring

pote

ntia

l w

ithou

t ade

quat

e co

ntra

cept

ion

Use

of m

edic

atio

n th

at

may

alte

r app

etite

.

Exp

osu

re N

=174

S

ibut

ram

ine

15m

g/da

y gi

ven

as a

n ad

junc

t to

a st

anda

rd n

on-

phar

mac

olog

ical

tre

atm

ent.

Co

mp

aris

on N

=174

P

lace

bo g

iven

as

an

adju

nct t

o a

stan

dard

non

-ph

arm

acol

ogic

al

treat

men

t. C

onc

om

itan

t non

-p

harm

aco

log

ical

ther

apy

Fou

r edu

catio

nal s

essi

ons

on fo

od c

hoic

e, p

hysi

cal

activ

ity, m

otiv

atio

n an

d be

havi

oral

mod

ifica

tion

and

diet

cou

nsel

ling.

S

ubje

cts

wer

e al

so

enco

urag

ed to

atte

nd 1

6 fu

rther

ses

sion

s.

A d

ietit

ian

mad

e in

divi

dual

di

etar

y co

unse

lling

and

en

ergy

requ

irem

ent

calc

ulat

ions

. Sub

ject

s w

ere

enco

urag

ed to

reco

rd

thei

r die

tary

inta

ke fo

r sel

f-co

ntro

l. S

ubje

cts

wer

e en

cour

aged

to

incr

ease

thei

r phy

sica

l ac

tivity

suc

h th

at e

xces

s en

ergy

exp

endi

ture

by

addi

tiona

l phy

sica

l act

ivity

sh

ould

exc

eed

1000

kcal

pe

r wee

k.

Wei

ght l

oss

(kg)

W

eigh

t los

s (%

) 5%

wei

ght r

educ

tion

(%)

10%

wei

ght r

educ

tion

(%)

WH

R

Wai

st c

ircum

fere

nce

(cm

) S

BP

(mm

Hg)

D

BP

(mm

Hg)

H

eart

rate

(bea

ts/m

in)

Tot

al c

hole

ster

ol (m

g/dl

) LD

L- c

hole

ster

ol (m

g/dl

) H

DL

- cho

lest

erol

(mg/

dl)

Trig

lyce

rides

(mg/

dl)

Ad

vers

e ev

ents

31

0/34

8 (8

5.6%

) pat

ient

s of

the

ITT

pop

ulat

ion

expe

rienc

ed

adve

rse

even

ts in

clud

ing:

B

ack

pain

B

ronc

hitis

S

inus

itis

Gas

tritis

Ill

def

ined

exp

erie

nce

Hea

dach

e In

fect

ion

Pha

ryng

itis

Acc

iden

tal i

njur

y E

nter

itis

Dry

mou

th

Sur

gery

F

lu s

yndr

ome

Fun

gal

der

mat

itis

Upp

er re

spira

tory

trac

t inf

ectio

n G

astro

inte

stin

al d

isor

der

Ecz

ema

Hyp

erte

nsio

n C

ons

tipat

ion

5.1(

-6.1

to –

4.1)

4.

9 (4

.0-5

.8)

41.4

19

.0

-0.0

19

(-0.

027

to –

0.01

2)

-6.0

(-7.

1 to

–5.

0)

-1.5

(-3.

9 to

0.0

9)

-1.3

(-2.

8 to

0.1

) -0

.9 (-

2.8

to 0

.8)

-1.4

(-7.

0 to

4.2

) -8

.7 (-

15.0

to –

2.3)

3.

9 (2

.2 to

5.5

) 17

.1 (-

15.3

to 4

9.6)

83

.5%

8.1(

-9.2

to –

6.9)

8.

3 (7

.1-9

.6)

62.6

40

.8

-0.0

24

(-0.

033

to –

0.01

4)

-8.5

cm (-

9.7

to –

7.2)

-2

.9 (-

5.1

to –

0.7)

-0

.3(-

1.8

to 1

.3)

1.9(

0.1

to 3

.8)

-2.5

(-7.

6 to

2.6

) -6

.1 (-

10.7

to –

1.5)

5.

6 (4

.1 to

7.1

) -9

.9(-

21.1

to 1

.3)

87.8

%

<0.0

1 ns

<0.0

01

<0.0

01

ns

ns

ns

ns

<0.0

5 ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

ns

0.00

1 ns

ns

0.02

2 ns

ns

ns

ns

0.00

2

The

pop

ulat

ions

wer

e si

mila

r at b

asel

ine

exce

pt

for a

sig

nific

antly

sm

alle

r nu

mbe

r of m

ales

in th

e si

butra

min

e gr

oup.

A

naly

sis

base

d on

ITT

and

at

leas

t one

follo

w-u

p vi

sits

w

ith w

eigh

t mea

sure

men

t. La

st o

bser

vatio

n ca

rrie

d fo

rwar

d (L

OC

F) w

as u

sed

for t

he fi

nal a

naly

sis.

T

here

wer

e a

sign

ifica

ntly

(p

<0.0

5) s

mal

ler n

umbe

r of

mal

es in

the

sibu

tram

ine

grou

p.

With

draw

als

Sib

utra

min

e =6

6 P

lace

bo=7

5 M

ain

reas

ons

for d

rop-

out

poor

com

plia

nce

and

disc

onte

nt w

ith w

eigh

t lo

ss, s

ibut

ram

ine

N=3

8,

plac

ebo

n=43

. A

dver

se e

vent

w

ithdr

awal

s, s

ibut

ram

ine

n=22

, pla

cebo

n=1

5.

Adj

unct

trea

tmen

t of o

bese

su

bjec

ts w

ith 1

5mg

sibu

tram

ine

daily

in

com

bina

tion

with

a

com

preh

ensi

ve n

on-

phar

mac

olog

ical

wei

ght

redu

ctio

n pr

ogra

m p

rodu

ces

addi

tiona

l; w

eigh

t los

s an

d ca

n be

read

ily im

plem

ente

d in

a p

rimar

y ca

re s

ettin

g.

Tre

atm

ent w

ith s

ibut

ram

ine

prov

ed to

be

safe

and

pa

rticu

larly

effe

ctiv

e in

thos

e ob

ese

subj

ects

who

wer

e le

ss s

ucce

ssfu

l with

the

non-

phar

mac

olog

ical

pro

gram

.

Out

com

e fig

ures

in b

old

are

sta

tistic

ally

sig

nific

ant

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

100

Evi

den

ce T

able

24.

S

ibu

tram

ine,

Mcn

ult

y et

al.,

200

3

Eff

ect S

ize

& P

reci

sion

(m

ean

diff

eren

ce s

ibu

tram

ine

–

pla

ceb

o ±

SE

or

med

ians

(ran

ge)

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e P

artic

ipan

ts

Incl

usio

n

Exc

lusi

on

Exp

osu

re/

Com

pari

son

O

utc

om

es

(incl

udin

g a

dve

rse

even

ts)

S15

mg

/d

95%

CI

S20

mg

/d

95%

CI

Val

idity

/App

licab

iilty

C

oncl

usi

ons

C

omm

ents

McN

ulty

et a

l.,

2003

S

tudy

des

ign

R

ando

mis

ed,

plac

ebo

cont

rolle

d,

doub

le b

lind,

m

ultic

entre

, and

m

ulti

natio

nal t

rial.

Ob

ject

ive

To

eval

uate

the

effe

cts

of

sibu

tram

ine

(15

and

20m

g/da

y) o

n w

eigh

t met

abol

ic

cont

rol a

nd b

lood

pr

essu

re in

m

etfo

rmin

obe

se

subj

ects

with

type

2

diab

etes

. R

ecru

itmen

t E

ligib

le p

atie

nts

from

cas

e no

tes

Par

ticip

ants

N

=195

M

ale=

45%

, Fem

ale=

55%

M

ean

Age

=48-

51ye

ars,

ra

nge

27-6

9yea

rs

Dur

atio

n=1

year

H

yper

tens

ive

=36%

with

29

% ta

king

ant

i- hy

perte

nsiv

e an

d 17

% li

pid

low

erin

g dr

ugs.

In

clus

ion

T

ype

2 di

abet

es >

6 m

o B

MI>

=27k

g/m

2

Met

form

in tr

eatm

ent 3

m

onth

s - 2

yea

rs

Age

25-

70 y

ears

F

astin

g se

rum

glu

cose

7-

15m

mol

/l E

xclu

sion

Is

chem

ic h

eart

dise

ase,

he

art f

ailu

re o

r stro

ke.

Sea

ted

puls

e ra

te

>100

BP

M,

DB

P>9

5mm

Hg

Fas

ting

seru

m

trigl

ycer

ides

>5.6

mm

ol/l

Fas

ting

seru

m c

hole

ster

ol

>7.8

mm

ol/l

Ser

um c

reat

inin

e >1

20µ

mol

/l S

erum

live

r enz

ymes

of

bilir

ubin

leve

ls x

2 up

per l

imit

of n

orm

al.

Wei

ght c

hang

e >3

kg in

pr

eced

ing

3 m

onth

s P

regn

ant o

r chi

ldbe

arin

g w

omen

or c

hild

bear

ing

pote

ntia

l not

taki

ng

adeq

uate

pre

caut

ions

aga

in

preg

nanc

y.

Exp

osu

re

Sib

utra

min

e 15

mg/

day

and

20m

g/da

y an

d st

anda

rd d

iet a

dvis

ed b

y a

diet

itian

. C

om

par

ison

P

lace

bo a

nd s

tand

ard

diet

adv

ised

by

a di

etiti

an.

Wei

ght c

hang

e (k

g)

BM

I (kg

/m2 )

W

aist

circ

umfe

renc

e (c

m)

Hip

W

aist

hip

ratio

>=

5% w

eigh

t los

s (%

) >=

10%

wei

ght l

oss

(%)

Met

abo

lic c

han

ges

Fas

ting

gluc

ose

(mm

ol/l)

H

bA1c

(%)

Fas

ting

insu

lin (p

mol

/l)

Cho

lest

erol

(mm

ol/l)

H

DL

LDL

Tot

al c

hole

ster

ol to

HD

L ch

oles

tero

l T

rigly

cerid

es (m

mol

/l)

Car

dio

vasc

ula

r ef

fect

s S

BP

(mm

Hg)

D

BP

(mm

Hg)

P

ulse

rate

(bea

ts p

er m

in)

Ad

vers

e ev

ents

S

ibut

ram

ine

Dry

mou

th

Con

stip

atio

n In

som

nia

-5.1

±0.

9 -1

.9-±

0.3

-4.9

±0.

9 -3

.0±

1.0

-1.4

±0.

9 46

14

-0.2

-0

.34±

0.33

-6

.0

0.0

0.1

0.0

-0.5

-0

.2

4.6±

2.2

2.8±

1.2

5.9

±1.

7

-7.0

to –

3.3

-2.6

tp-1

.2

-6.7

to-3

.0

-5.0

to-1

.0

-3.1

to 0

.3

-1.0

to 0

.7

-0.9

9 to

0.3

1 -2

4.0

to 1

2.0

-0.2

to 0

.3

0.0

to 0

.2

-0.2

to 0

.3

-0.9

to-0

.2

-0.6

to 0

.1

0.3

to 8

.8

0.4

to 5

.3

2.5

to 9

.4

-7.8

±1.

0 -2

.9±

0.3

-6.8

±1.

0 -6

.1±

1.0

-0

.9±

0.9 65

27

-0

.2

-0.1

0±0.

34

-18.

0 0.

1 0.

1 0.

1 -0

.2

-0.3

-1

.3 ±

2.2

0.0±

1.3

5.8±

1.8

-9.7

to-5

.9

-3.6

to-2

.2

-8.7

to-4

.9

-8.2

to-4

.1

-2.6

to 0

.8

-1.0

to 0

.5

-0.7

6 to

0.5

7 -3

0.0

to 0

.0

-0.1

to 0

.3

0.0

to 0

.1

-0.1

to 0

.3

-0.5

to 0

.1

-0.6

to 0

.0

-5.6

to 3

.1

-2.5

to 2

.4

2.3

to 9

.3

Rel

ativ

ely

youn

g pa

tient

po

pula

tion

Stri

ct in

clus

ion

crite

ria m

ay

limit

appl

icab

ility

.

Sib

utra

min

e w

as a

n ef

fect

ive

anti-

obes

ity

agen

t in

a su

bsta

ntia

l pr

opor

tion

of p

atie

nts

with

type

2 d

iabe

tes.

A

vera

ge w

eigh

t los

s at

on

e ye

ar w

as 5

.5kg

w

ith 1

5mg

sibu

tram

ine

and

8.0k

g w

ith 2

0mg

– pl

aceb

o pa

tient

s lo

st n

o w

eigh

t. In

fact

19%

ga

ined

mor

e th

an 2

kg

over

1 y

ear.

Wei

ght l

oss

of >

= 10

%

conf

erre

d m

etab

olic

an

d ca

rdio

vasc

ular

be

nefit

s. N

o pa

tient

s in

th

e pl

aceb

o gr

oup

lost

>=

10-%

bod

y w

eigh

t. P

oorly

con

trolle

d ob

ese

type

2 d

iabe

tic p

atie

nts

may

gai

n th

e m

ost f

rom

w

eigh

t los

s an

d an

ti-ob

esity

med

icat

ion.

Li

pid

chan

ges

wer

e m

odes

t in

this

stu

dy

and

low

er th

an o

ther

st

udie

s bu

t may

be

expl

aine

d by

the

fact

th

at s

tudy

par

ticip

ants

w

ere

rece

ivin

g m

etfo

rmin

whi

ch h

as

favo

rabl

e m

oder

atin

g ef

fect

on

lipid

s.

Sib

utra

min

e te

nded

to

incr

ease

blo

od

pres

sure

in m

ore

patie

nts

than

pla

cebo

an

d a

few

indi

vidu

als

show

ed m

arke

d ris

es.

Fig

ures

in b

old

= si

gnifi

cant

, S=s

ibut

ram

ine.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

101

Evi

den

ce T

able

25.

S

ibu

tram

ine,

Wad

den

et

al.,

2000

Eff

ect S

ize

& P

reci

sion

(M

ean

cha

nge

from

bas

elin

e)

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y L

ocat

ion

(s)

Par

ticip

ants

In

clus

ion

E

xclu

sion

R

ecru

itmen

t

Exp

osu

re/

Com

pari

son

Ou

tco

mes

S+P

S

+O

P=*

*

Val

idity

/App

licab

ility

S

afet

y

Con

clu

sio

ns

Com

men

ts

-0.7

±1.

2 -0

.5±

1.4

+0.1

±1.

8 +0

.5±

2.1

-0.7

±1.

3 -0

.3±

1.6

+0.2

±1.

9 +0

.8±

2.0

-0.7

±1.

8 -0

.7±

2.9

-0.4

±4.

2 +0

.1±

4.1

-0.9

±1.

9 -0

.7±

23.1

-0

.6±

4.4

+0.3

±4.

2

ns

ns

ns

ns

ns

ns

ns

ns

Wad

den

et a

l.,

2000

S

tudy

Des

ign

R

ando

mis

ed, d

oubl

e bl

ind,

pla

cebo

co

ntro

lled

clin

ical

tria

l. O

bje

ctiv

e T

o as

sess

if a

ddin

g or

lista

t to

sibu

tram

ine

indu

ces

furth

er w

eigh

t lo

ss o

r mai

ntai

ns

wei

ght l

ost i

n pa

tient

s w

ho h

ave

lost

wei

ght

taki

ng s

ibut

ram

ine

alon

e an

d co

ntin

ue

taki

ng s

ibut

ram

ine.

S

tudy

loca

tion

(s)

US

A

Du

ratio

n

16 w

eeks

afte

r 1 y

ear

of s

ibut

ram

ine

Par

ticip

ants

34

vol

unte

ers

M

ean

age

44.1

yea

rs

(±10

.4)

Fem

ale

=100

%

BM

I=33

.9±

4.9k

g/m

2 In

clus

ion

F

emal

es w

ho h

ad

com

plet

ed 1

yea

r tre

atm

ent w

ith

sibu

tram

ine

(10-

15m

g/d)

Exp

osu

re N

=17

Sib

utra

min

e (1

0-15

mg/

day)

and

orli

stat

+

pres

crib

ed d

iet +

a d

aily

m

ultiv

itam

in

Co

mp

aris

on n

=17

Sib

utra

min

e (1

0-15

mg/

d)

and

plac

ebo

+ pr

escr

ibed

di

et +

a d

aily

mul

tivita

min

. P

resc

rib

ed d

iet

1200

-160

0kca

l/day

re

pres

entin

g a

defic

it of

60

0-50

0kca

l/day

. Die

t to

com

pris

e 20

% c

alor

ies

from

pro

tein

, 50%

ca

rboh

ydra

te <

=30%

fat.

Hea

lthy

eatin

g ed

ucat

ion.

F

at in

take

lim

ited

to

60g/

d.

Exe

rcis

e/ac

tivity

M

onth

ly a

ctiv

ity g

oals

with

ev

entu

al g

oal o

f 5

sess

ions

of 3

0-40

min

s pe

r wee

k.

Ove

rall

– m

odes

t life

styl

e in

terv

entio

n.

Wei

ght c

hang

e in

16

wee

k co

ntin

uatio

n tri

al –

Last

obs

erva

tion

carr

ied

forw

ard

N=1

7 1

mon

th

2 m

onth

s 3

mon

ths

4 m

onth

s W

eigh

t cha

nge

in 1

6 w

eek

cont

inua

tion

trial

–E

nd p

oint

ana

lysi

s 1

mon

th (N

=16

S+P

, N=1

4 S

+O)

2 m

onth

s (N

=10

S+P

, N=

15 S

+O)

3 m

onth

s (N

=12

S+P

, N=1

5 S

+O)

4 m

onth

s (N

=10

S+P

, N=1

4 S

+O)

Ad

vers

e ev

ents

(% o

f pat

ien

ts)

Sof

t sto

ol

Incr

ease

d bo

wel

mov

emen

t F

aeca

l urg

ency

O

ily e

vacu

atio

n O

ily s

potti

ng

Fla

tus

with

dis

char

ge

Fat

ty o

ily s

tool

Li

quid

sto

ol

Sto

mac

h pa

in/u

pset

sto

mac

h F

aeca

l inc

ontin

ence

D

ecre

ased

bow

el m

ovem

ent

Pel

lets

/har

d st

ool

The

adv

erse

eve

nts

are

repo

rts fo

r the

la

st w

eek

of th

e tri

al.

Com

bini

ng th

e tre

atm

ents

did

not

app

ear

to re

sult

in a

ny u

nexp

ecte

d si

de e

ffect

s.

9.1

9.1

9.1

0 9.1

0 0 9.1

9.1

0 0 18.2

50

50

42.9

42

.9

28.6

28

.6

28.6

14

.3

14.3

7.

1 7.

1 7.

1

0.04

* 0.

04*

ns

0.02

* ns

ns

ns

ns

ns

ns

ns

ns

Sm

all s

tudy

S

hort

dura

tion

Die

t mod

ifica

tion

/life

styl

e th

erap

y no

t st

anda

rd.

Die

ts m

ay h

ave

been

ver

y lo

w fa

t. W

ithd

raw

als

Sib

utra

min

e +

orlis

tat,

n=3

(18%

) S

ibut

ram

ine,

n=5

(29%

) diff

eren

ce n

ot

sign

ifica

nt.

Com

plet

ers

(EP

A) a

nd la

st o

bser

vatio

n ca

rrie

d fo

rwar

d (L

OC

F) a

naly

ses

both

re

ache

d th

e sa

me

conc

lusi

ons.

N

ot c

lear

if IT

T a

naly

sis

was

car

ried

out b

ut a

chi

-squ

ared

test

on

the

drop

-ou

t sho

wed

no

sign

ifica

nt d

iffer

ence

. D

osa

ge

The

med

icat

ion

dosa

ge v

arie

d fo

r bot

h tre

atm

ents

, S

ibut

ram

ine

+ pl

aceb

o 10

mg/

d si

butra

min

e N

=7

15m

g/d

sibu

tram

ine

N=-

10

Sib

utra

min

e +

orlis

tat

10m

g/d

sibu

tram

ine

N=6

15

mg/

d si

butra

min

e N

=-11

O

rlist

at 1

20m

g t.i

.d.

Dos

e re

duct

ion

of s

ibut

ram

ine

had

been

mad

e in

the

prev

ious

1 y

ear

stud

y be

caus

e of

sid

e ef

fect

s no

tabl

y in

som

nia,

incr

ease

d bl

ood

pres

sure

an

d pu

lse.

B

lind

ing

84

.6%

of p

atie

nts

had

gues

sed

wha

t tre

atm

ent t

hey

wer

e on

.

Co

nclu

sion

B

ody

wei

ght r

emai

ned

esse

ntia

lly

unch

ange

d in

the

two

grou

ps o

ver

the

16-w

eek

stud

y pe

riod.

H

owev

er, t

hose

that

lost

>=1

0% o

f th

eir i

nitia

l wei

ght i

n th

e pr

evio

us 1

ye

ar g

aine

d w

eigh

t dur

ing

the

seco

nd s

tudy

rega

rdle

ss o

f m

edic

atio

n re

ceiv

ed. T

hose

that

ga

ined

<10

% in

the

initi

al s

tudy

lost

a

furth

er a

mou

nt o

f wei

ght i

n th

e se

cond

stu

dy w

ith th

ose

taki

ng

sibu

tram

ine

+ or

lista

t los

ing

mor

e w

eigh

t tha

n th

ose

taki

ng

sibu

tram

ine

alon

e (n

s).

Fur

ther

sub

-gro

up a

naly

ses

of

patie

nts

thou

ght m

ost l

ikel

y to

be

nefit

from

com

bina

tion

ther

apy

did

not i

ncre

ase

thei

r wei

ght l

oss.

T

he a

utho

rs s

ugge

st th

at m

ost

obes

e pa

tient

s ha

ve a

lim

it of

10-

15%

wei

ght l

oss.

Fur

ther

wei

ght

loss

app

ears

to b

e th

war

ted

by a

to

xic

envi

ronm

ent t

hat d

isco

urag

es

phys

ical

act

ivity

, enc

oura

ges

cons

umpt

ion

of h

igh

fat d

iet a

nd

com

pens

ator

y bi

olog

ical

m

echa

nism

that

dec

reas

e en

ergy

ex

pend

iture

.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

102

Evi

den

ce T

able

26.

C

om

par

ativ

e d

rug

stu

dy,

Po

ston

et

al.,

2001

Stu

dy

auth

ors

an

d y

ear

Stu

dy

Des

ign

O

bje

ctiv

e S

tud

y R

efer

ence

Par

ticip

ants

In

clus

ion

E

xclu

sion

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) %

of s

tud

ies

N=1

08

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Pos

ton

et a

l.,

2001

Stu

dy d

esig

n/ty

pe

Met

a-an

alys

is o

f ra

ndom

ised

, pla

cebo

co

ntro

lled

doub

le

blin

d tri

als

of F

DA

ap

prov

ed a

nti-o

besi

ty

agen

ts.

Ob

ject

ive

Eva

luat

ion

of li

fe-

styl

e tre

atm

ents

use

d in

pub

lishe

d ob

esity

dr

ug s

tudi

es a

nd th

eir

cont

ribut

ion

to w

eigh

t lo

sses

ass

ocia

ted

with

pha

rmac

olog

ical

in

terv

entio

ns.

Stu

die

s in

clud

ed

N=1

08 in

depe

nden

t R

CT

s pu

blis

hed

in

103

artic

les

19

60s

n=10

19

70s

n=46

19

80sn

=13

1990

s n=

39

Incl

usio

n

Stu

dies

pub

lishe

d on

or

befo

re D

ecem

ber 1

999

FD

A a

ppro

ved

obes

ity

med

icat

ion

Ran

dom

ised

stu

dies

whe

re

rand

omis

atio

n w

as n

ot

brok

en

Stu

dies

that

incl

uded

a

dire

ct c

ompa

rison

with

an

othe

r ant

i-obe

sity

dru

g or

pl

aceb

o co

ntro

lled.

D

ata

wer

e fo

r onl

y hu

man

st

udie

s E

nglis

h ve

rsio

n of

the

stud

y av

aila

ble

Dat

a in

pub

lishe

d re

ports

in

peer

-rev

iew

ed jo

urna

ls

Rel

evan

t sub

-gro

ups

iden

tifia

ble

Stu

dies

with

suf

ficie

nt

outc

ome

data

to c

ompu

te a

si

ze e

ffect

bas

ed o

n w

eigh

t lo

ss

Exc

lusi

on

Exp

erim

enta

l obe

sity

ag

ents

N

utrit

iona

l sup

plem

ents

W

eigh

t mai

nten

ance

st

udie

s

Incl

uded

dru

gs

Am

phet

amin

e B

enzo

cain

e B

enzp

heta

min

e D

exfe

nflu

ram

ine

Die

thyl

prop

ion

Fen

flura

min

e F

luox

etin

e M

azin

dol

Met

ham

phet

amin

e O

rlist

at

Phe

ndim

etra

zine

P

hent

erm

ine

Phe

nylp

ropa

nala

min

e S

erta

line

Sib

utra

min

e P

artic

ipan

ts

108

inde

pend

ent R

CTs

Bro

ad c

lass

ifica

tion

of c

ompo

nen

ts

Beh

avio

ural

mod

ifica

tion

stud

ies

P

sych

othe

rapy

or c

ogni

tive

beha

viou

ral

Exe

rcis

e

Die

t

T

reat

men

t man

ual f

or li

fest

yle

inte

rven

tion

For

mal

trai

ning

by

lifes

tyle

inte

rven

tioni

sts

S

pec

ific

clas

sific

atio

n o

f co

mp

onen

ts

Ver

y lo

w c

alor

ific,

pre

-pac

kage

d fo

od o

r Eat

ing

man

agem

ent

Low

-cal

orie

die

t B

alan

ced

defic

it di

et

Aer

obic

s, C

allis

then

ics

or L

ifest

yle

exer

cise

W

eigh

t lift

ing

Wal

king

S

elf-m

onito

ring

Stim

ulus

con

trol o

r Con

tinge

ncy

man

agem

ent

%ou

tco

me

due

to/ l

ifest

yle

com

pon

ent

Tria

ls w

ith n

o lif

esty

le c

ompo

nent

T

rials

with

1-3

life

styl

e co

mpo

nent

s %

wei

ght l

oss

attr

ibu

tab

le to

sp

ecifi

c st

rate

gie

s in

pat

ien

ts r

ecei

ving

dru

g

trea

tmen

t D

iet i

nter

vent

ions

vs.

no

diet

inte

rven

tions

27.8

%

0.9%

17

.6%

82

.4%

3.

7%

49.1

%

4.6%

25

.0%

40

.7%

0.

9%

0%

2.8%

23

.1%

3.

7%

28.3

%

46-5

4%

49.5

% v

s. 2

6.5%

Mos

t stu

dies

wer

e co

nduc

ted

with

m

iddl

e-ag

ed o

verw

eigh

t to

mod

erat

ely

obes

e w

omen

in th

eir 4

0s. T

heir

outc

omes

may

not

be

gene

rally

re

leva

nt to

the

larg

er p

opul

atio

n of

ob

esity

pat

ient

s w

ho s

eek

treat

men

t, pa

rticu

larly

thos

e w

ith m

ore

seve

re

obes

ity.

Life

styl

e tre

atm

ents

, with

the

exce

ptio

n of

di

ets,

hav

e no

t bee

n w

idel

y us

ed in

ra

ndom

ised

, pla

cebo

-con

trolle

d ob

esity

dru

g tri

als.

O

besi

ty-p

harm

acot

hera

py tr

ials

do

not u

se

life-

styl

e tre

atm

ents

with

the

frequ

ency

ex

pect

ed b

ased

on

the

offic

ial p

ositi

ons

of

mos

t pro

fess

iona

l org

anis

atio

ns c

once

rned

w

ith th

e co

mpr

ehen

sive

man

agem

ent o

f ob

esity

.

EV

ID

EN

CE

BA

SE

D R

EV

IE

W O

F W

EIG

HT

LO

SS

ME

DIC

IN

ES

: A

RE

PO

RT

CO

MM

IS

SIO

NE

D B

Y T

HE

NE

W Z

EA

LA

ND

AC

C

103

Evi

den

ce T

able

27.

C

om

par

ativ

e d

rug

stu

dy,

Had

dock

et

al.,

2002

Stu

dy

au

tho

rs

and

yea

r

Stu

dy

Des

ign

O

bje

ctiv

e In

clud

ed M

edic

atio

ns

Incl

usio

n

Exc

lusi

on

Exp

osu

re/

Com

pari

son

Ou

tco

mes

(in

clud

ing

ad

vers

e ev

ents

) W

ks

Rx

Dos

e M

g/d

D

rug

min

us

pla

ceb

o (k

g)

Eff

ect s

ize

Val

idity

/App

licab

ility

C

oncl

usi

ons

C

omm

ents

Had

dock

et

al.,

2002

S

tudy

Des

ign

M

eta-

anal

ysis

of R

CTs

O

bje

ctiv

e A

com

preh

ensi

ve m

eta-

anal

ysis

of

RC

Ts

of m

edic

atio

ns fo

r ob

esity

. M

edic

atio

ns

Am

phet

amin

e (d

exam

phet

amin

e)

Ben

zoca

ine

Ben

zphe

tam

ine

Dex

fenf

lura

min

e†

Die

thyl

prop

ion*

F

enflu

ram

ine†

F

luox

etin

e M

azin

dol

Met

ham

phet

amin

e O

rlist

at*

Phe

ndim

etra

zine

P

hent

erm

ine

(HC

L an

d re

sin)

* P

heny

lpro

pano

lam

ine

(PP

A)

Ser

tralin

e S

ibut

ram

ine*

*

curr

ent r

evie

w m

edic

atio

ns

Incl

usio

n

FD

A a

ppro

ved

anti-

obes

ity d

rugs

P

resc

riptio

n or

OT

C o

r of

f lab

el

Stu

dies

pub

lishe

d in

pe

er re

view

ed jo

urna

ls

Pub

lishe

d be

fore

D

ecem

ber 1

999

Eng

lish

vers

ion

avai

labl

e H

uman

stu

dies

P

lace

bo o

r act

ive

com

para

tor

Ran

dom

ised

stu

dy

Out

com

e da

ta a

vaila

ble

Exc

lusi

on

Exp

erim

enta

l obe

sity

dr

ugs

Die

tary

sup

plem

ents

N

=108

clin

ical

tria

ls

incl

uded

Exp

osu

re

Orli

stat

S

ibut

ram

ine

Phe

nter

min

e D

ieth

ylpr

opio

n C

om

par

ison

P

lace

bo

Die

thyl

prop

ion

(9 s

tudi

es)

Orli

stat

(6 s

tudi

es)

Phe

nter

min

e (6

stu

dies

) S

ibut

ram

ine

(4 s

tudi

es)

18(6

-51)

48

(16-

76)

13(2

-24)

15

(8-2

6)

75

303(

190-

360)

28

(15-

30)

14(1

0-20

)

3.0(

-1.6

-11.

5)

2.08

(0.3

0-4.

2)

3.6(

0.6-

6.0)

3.

5(2.

4-5.

1)

<0.8

0 <0

.80

0.81

1.

05

Sta

ndar

dise

d m

ean

diffe

renc

e (d

) bas

ed o

n ch

ange

sco

res

(red

uctio

n in

wei

ght)

used

as

a m

easu

re o

f ef

fect

siz

e, w

here

: d 1

= (X

t i -X

c I)/

Si

Xt i

= m

ean

wei

ght l

oss

treat

men

t gro

up

Xc i

= m

ean

WL

cont

rol

grou

p S

i = p

oole

d S

D o

f ch

ange

for b

oth

Stu

dy w

eigh

ting

– in

vers

e fu

nctio

n of

sa

mpl

e va

rianc

e F

emal

e pr

epon

dera

nce

A la

rge

num

ber o

f st

udie

s di

d no

t pr

esen

t cod

able

da

ta.

Onl

y si

butra

min

e ha

d an

effe

ct s

ize

exce

edin

g 0.

90.

The

abs

olut

e pl

aceb

o-su

btra

cted

w

eigh

t los

s as

soci

ated

with

ant

i- ob

esity

dru

g us

e in

th

e M

A d

id n

ot

exce

ed 4

.0kg

(i.e

., m

odes

t).

Sib

utra

min

e, w

hich

w

as th

e dr

ug w

ith

the

larg

est e

ffect

si

ze, h

ad

over

lapp

ing

CIs

with

ph

ente

rmin

e.

Tre

atm

ent l

engt

h di

d no

t inf

luen

ce e

ffect

si

ze.

† w

ithdr

awn

1997

, NS

= n

ot s

igni

fican

t – i.

e., p

=<0

.05

* n

s if

Bon

ferr

oni’s

cor

rect

ion

for

mul

tiple

test

s is

use

d. O

TC

= o

ver t

he c

ount

er


104


105

Appendices


106

Appendix I. Summary of potential barriers to use of drugs included in the review

† For further details and information see

http://www.medsafe.govt.nz/profs/Datasheet/u/uminetimedcaps.htm http://www.medsafe.govt.nz/profs/Datasheet/d/durominecap.htm http://www.medsafe.govt.nz/profs/Datasheet/t/tenuate%20dospantab.htm http://www.medsafe.govt.nz/profs/Datasheet/r/Reductilcap.htm http://www.medsafe.govt.nz/profs/Datasheet/x/Xenicalcap.htm

Potential barriers to use† Medication

Contraindications Interactions Additional Cautions Phentermine

HCL

30mg Umine

Timedcaps

!5mg & 30mg DuromineTM

�Agitated patients �Alcoholics �Advanced arteriosclerosis �Symptomatic cardiovascular disease �Patients with a history of drug abuse �Glaucoma �Hypertension �Hyperthyroidism �Pregnant females �Valvular heart disease �Children and adolescents

# Hypotensive drugs # Thyroid hormones # MAO inhibitors # Chlorpromazine # Fenfluramine # SSRIs # Tricyclic antidepressants # Alcohol # Anaesthetics

! May impair ability to engage in potentially hazardous activities – e.g., operating machinery, driving a vehicle. ! Potential for abuse (amphetamine family of drugs) and dependence. ! Abrupt cessation after prolonged high doses may result in extreme fatigue, depression and sleep pattern changes. ! Insulin requirement in diabetics may change and strict monitoring of blood glucose is required.

Diethylpropion HCL

75mg

Tenutate Dospan

�Agitated patients �Advanced arteriosclerosis �Patients with a history of drug abuse �Glaucoma �Hypertension �Hyperthyroidism �Hypersensitivity or idiosyncrasy to the

sympthomimetic amine �Patients with pulmonary artery hypertension �Severe hypertension

# MAOI inhibitors # Other anorectic agents # General anaesthetics

! Altered anti-diabetic drug requirements

Sibutramine HCL

10mg & 15mg

Reductil®

�Hypersensitivity to sibutramine or its ingredients �Organic causes of obesity �History of major eating disorders �Psychiatric illness �Giulles de la Tourette’s syndrome �MAOI’s in the past 2 weeks �Other centrally acting drugs for the treatment of

psychiatric, weight reduction �Tryptophan for sleep disorders �History of coronary artery disease, congestive

heart failure, tachycardia, peripheral arterial occlusive disease, arrhythmia or cerebro-vascular disease.

�Inadequately controlled hypertension �Hyperthyroidism �Severe liver or renal impairment �Benign prostatic hyperplasia/urinary retention �Phaeochromocytoma �Narrow angle Glaucoma �Drug, medication or alcohol abuse �Pregnancy or breastfeeding women �Patients under 18 and over 65 years

# CNS active drugs # MAOI’s # Migraine therapy # Concomitant use of SSRI’s # Agents that may raise blood pressure or heart rate – e.g., decongestants, cough cold and allergy medications and anti-inflammatory agents # Drugs that affect cytochrome P450metabolism # Co-administrations of ketoconazole or erythromycin.Cimetidine # Alcohol excess

! Blood pressure and pulse rate should be monitored in all patients as sibutramine has caused clinically relevant increases in blood pressure in some patients. ! Caution is advised in patients taking concomitant medicines known to affect haemostasis or platelet function. ! Seizures have been reported in <0.1% of patients and sibutramine should be given with caution to patients with a history of seizures. ! Sibutramine should be given with caution to patients who have a history of motor or verbal ticks.

Orlistat 120mg

Xenical®

�Chronic malabsorption syndrome �Cholestasis �Known hypersensitivity to orlistat or any of its

components

# Warfarin and other anti-coagulants # Decreased absorption of fat-soluble vitamins D, E and beta-carotene when co-administered with orlistat. If a multivitamin is recommended it should be taken at least two hours after the administration of orlistat or at bedtime. A reduction in cyclosporine plasma levels has been observed with orlistat. Reduction in the exposure to amiodarone and des-ethylamiodarone has been recorded, but the clinical effects are unclear.

! When given with anticoagulants INR values should be monitored. ! Use of a multivitamin could be considered. ! Patients should be advised to use dietary guidelines and fat intake should be distributed over three main meals. ! Improved metabolic control in type 2 diabetes may allow dose reduction of oral hypo-glycaemic medication. ! Monitor cyclosporine levels more frequently when co-administered with orlistat ! Coagulation parameters should be monitored in patients treated with oral anticoagulants. ! There may be reduced therapeutic effects of patients on amiodarone


107

Appendix II. Search strategies

Medline strategy

1 exp Obesity/ (56799) 2 (obese or obesity).tw. (56362) 3 weight loss/ (8738) 4 appetite depressants/ (2734) 5 appetite/de (1343) 6 anti-obesity agents/ (628) 7 or/1-6 (82997) 8 exp Phentermine/ (819) 9 duromine.tw. (3) 10 umine.tw. (0) 11 Diethylpropion/ (224) 12 tenuate dospan.tw. (9) 13 sibutramine hydrochloride.tw. (27) 14 Cyclobutanes/ (845) 15 reductil.tw. (8) 16 orlistat.ti. (184) 17 lactones/ (7467) 18 xenical.tw. (30) 19 complan.tw. (9) 20 Food, Formulated/ (4095) 21 or/8-20 (13334) 22 7 and 21 (1214) 23 randomized controlled trials/ (33133) 24 randomized controlled trial.pt. (191180) 25 random allocation/ (51130) 26 double blind method/ (78837) 27 single blind method/ (8255) 28 clinical trial.pt. (386534) 29 exp clinical trials/ (156308) 30 (clinic$ adj trial$).tw. (79327) 31 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$ or mask$)).tw. (75413) 32 placebos/ (23136) 33 placebo$.tw. (84981) 34 randomly allocated.tw. (7750) 35 (allocated adj2 random).tw. (607) 36 meta-analysis/ (5457) 37 (metaanaly$ or meta analy$).tw. (11523) 38 meta analysis.pt. (9354) 39 exp review, literature/ (2051) 40 (systematic adj (review$ or overview$)).tw. (5737) 41 or/23-40 (561105) 42 comment.pt. (253767) 43 letter.pt. (509370) 44 editorial.pt. (163392) 45 animal/ (3653674) 46 human/ (8547910) 47 45 not (45 and 46) (2808546)


108

48 or/42-44,47 (3486417) 49 22 and 41 (408) 50 49 not 48 (390) 51 limit 50 to english language (348)

Medline (extra economics search)

1 economics/ (23811) 2 "costs and cost analysis"/ (32452) 3 cost allocation/ (1667) 4 cost-benefit analysis/ (33314) 5 cost control/ (15851) 6 cost savings/ (4816) 7 cost of illness/ (6121) 8 cost sharing/ (949) 9 health care costs/ (11660) 10 direct service costs/ (677) 11 drug costs/ (6035) 12 hospital costs/ (4347) 13 health expenditures/ (8059) 14 economics, pharmaceutical/ (1367) 15 ((low or high) adj cost$).mp. (10695) 16 (health?care adj cost$).mp. (864) 17 (fiscal or funding or financial or finance).tw. (31542) 18 (cost adj (estimate$ or variable$)).mp. (810) 19 (unit adj cost$).mp. (578) 20 (economic$ or pharmacoeconomic$ or price$ or pricing).tw. (68154) 21 or/1-20 (210993) 22 exp Obesity/ (56799) 23 (obese or obesity).tw. (56362) 24 weight loss/ (8738) 25 appetite depressants/ (2734) 26 appetite/de (1343) 27 anti-obesity agents/ (628) 28 or/22-27 (82997) 29 exp Phentermine/ (819) 30 duromine.tw. (3) 31 umine.tw. (0) 32 Diethylpropion/ (224) 33 tenuate dospan.tw. (9) 34 sibutramine hydrochloride.tw. (27) 35 Cyclobutanes/ (845) 36 reductil.tw. (8) 37 orlistat.ti. (184) 38 lactones/ (7467) 39 xenical.tw. (30) 40 complan.tw. (9) 41 Food, Formulated/ (4095) 42 or/29-41 (13334) 43 28 and 42 (1214) 44 comment.pt. (253767) 45 letter.pt. (509370)


109

46 editorial.pt. (163392) 47 animal/ (3653674) 48 human/ (8547910) 49 47 not (47 and 48) (2808546) 50 or/44-46,49 (3486417) 51 21 and 28 and 42 (28) 52 51 not 50 (24) 53 limit 52 to english language (21) Embase

1 Diabetic Obesity/ (437) 2 obesity/ or morbid obesity/ (40399) 3 weight reduction/ (18379) 4 (obese or obesity).tw. (36765) 5 or/1-4 (62130) 6 Phentermine/ (751) 7 duromine.tn,tw. (11) 8 umine.tn,tw. (0) 9 Amfepramone/ (375) 10 tenuate dospan.tn,tw. (22) 11 Sibutramine/ (882) 12 reductil.tn,tw. (110) 13 Tetrahydrolipstatin/ (1055) 14 xenical.tn,tw. (323) 15 complan.tn,tw. (1) 16 complan/ (1) 17 reductil/ (882) 18 tenuate dospan/ (375) 19 duromine/ (103) 20 umine/ (0) 21 ensure/ (48) 22 (meal adj3 replace$).tw. (73) 23 or/6-22 (2308) 24 5 and 23 (1436) 25 exp meta analysis/ (18397) 26 (metaanaly$ or meta analy$).tw. (10151) 27 (systematic$ adj (review$ or overview$)).mp. (5300) 28 randomized controlled trials/ (85380) 29 clinical trial/ (296906) 30 randomization/ (10898) 31 single blind procedure/ (4761) 32 double blind procedure/ (47475) 33 crossover procedure/ (14990) 34 placebo/ (44490) 35 randomi?ed controlled trial$.tw. (13528) 36 (clinic$ adj trial$).tw. (63823) 37 ((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (55628) 38 placebo$.tw. (65892) 39 (random$ adj allocat$).tw. (6611) 40 prospective study/ (38007) 41 or/25-40 (421878)


110

42 case study/ (1663) 43 case report.tw. (66042) 44 abstract report/ or editorial/ or letter/ (409542) 45 or/42-44 (476020) 46 animal/ (7039) 47 exp animal experiment/ (644137) 48 46 or 47 (648030) 49 human/ (3829304) 50 48 not (48 and 49) (602008) 51 24 and 41 (588) 52 51 not 45 (554) 53 52 not 50 (553) 54 limit 53 to english language (497) 55 drug safety/ (67314) 56 drug contraindication/ (8022) 57 patient satisfaction/ (18988) 58 or/55-57 (92266) 59 58 and 24 and 45 (26) 60 54 or 59 (497) Cinahl

1 exp obesity/ or obesity, morbid/ (5024) 2 Weight Reduction Programs/ (295) 3 weight gain/ or "altered nutrition, more than body requirements (nanda)"/ (1092) 4 Weight Loss/ (1966) 5 (obese or obesity).tw. (3954) 6 or/1-5 (8392) 7 Appetite Depressants/ (216) 8 (phentermine or duromine or umine).tw. (20) 9 diethylpropion.tw. (0) 10 tenuate dospan.tw. (0) 11 Sibutramine/ (35) 12 reductil.tw. (0) 13 orlistat.tw. (54) 14 xenical.tw. (8) 15 complan.tw. (0) 16 food, formulated/ (609) 17 or/7-16 (916) 18 6 and 17 (227) 19 Meta Analysis/ (4451) 20 (meta analy$ or metaanaly$).tw. (2303) 21 (systematic$ adj (review$ or overview$)).mp. (5227) 22 "literature review"/ or "systematic review"/ (3178) 23 exp Clinical Trials/ (26696) 24 clinical trial.pt. (10842) 25 (clinic$ adj trial$).tw. (6139) 26 randomi?ed controlled trial$.tw. (5128) 27 ((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (3569) 28 Placebos/ (2379) 29 placebo$.tw. (5466) 30 (random$ adj allocat$).tw. (774)


111

31 or/19-30 (36028) 32 18 and 31 (64) 33 limit 32 to english (64) Searches from other sources

In databases and all other sources without controlled vocabulary combinations of the index terms and additional keywords from the above strategies were used in the search.

Timing of the searches

The searches were carried out during June and July 2004.


112


113

References

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Evidence Based Review of Weight Loss Medicines