Download 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
ISBN
ISSN
New Zealand Health Technology Assessment (NZHTA)
1-877235-70-9
1174-5142
i
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/
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
ii
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/
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
iii
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
iv
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
v
Tables
Table 1.
Table 2.
Table 3.
Table 4.
Table 5.
Table 6a.
Table 6b.
Table 7.
Table 8.
Table 9.
Table 10.
Table 11.
Table 12.
Table 13.
Table 14.
Table 15.
Table 16.
Table 17.
Table 18.
Table 19.
Table 20.
Table 21.
Table 22.
Table 23.
Table 24.
Table 25.
Table 26.
Table 27.
Table 28.
Table 29.
Table 30.
Table 31.
Classification of body weight.............................................................................................. 1
Obesity related co-morbidities and risk............................................................................. 2
Inclusion and exclusion criteria for review studies........................................................ 17
Scottish Intercollegiate Guidelines Network Evidence levels ..................................... 18
Weight loss results at three months and one year for an unstratified and stratified
study population ................................................................................................................. 19
Phentermine effectiveness studies ................................................................................... 21
Phentermine vs. placebo post treatment outcomes, Haddock et al., 2002 ................ 21
Diethylpropion effectiveness studies, Glazer et al., 2001............................................. 22
Diethylpropion vs. placebo post treatment outcomes, Haddock et al., 2002............ 23
Summary of publications reporting the effectiveness of orlistat for weight loss in
overweight and obese participants................................................................................... 24
Meta-analysis of RCTs for Orlistat, long-term studies ≥ 1 year (NICE HTA, ............
Avenell, May 2004)............................................................................................................. 25
Orlistat 120 mg/d weight loss in otherwise healthy obese populations ..................... 26
Orlistat 30-120 mg/d weight loss in patients with hypercholesterolemia, results
after one year........................................................................................................................ 27
Weight loss with orlistat: results of 1 year clinical trials, European Medicine
Evaluation Agency.............................................................................................................. 27
Orlistat 120 mg/d in diabetic patients or patients with glucose intolerance.............. 27
Eligible studies reporting the effectiveness of sibutramine .......................................... 28
Meta-analysis of RCTs for Sibutramine, long-term studies ≥ 1 year (NICE HTA,
Avenell May 2004)............................................................................................................... 30
Studies reporting the effectiveness of sibutramine in otherwise healthy
overweight individuals ........................................................................................................ 32
Studies reporting the effectiveness of sibutramine in individuals with type 2
diabetes ................................................................................................................................. 32
Sibutramine dose ranging studies. Bray 1999 reported in Leung et al., 2003............. 34
Eligible studies comparing two or more review drugs .................................................. 34
Summary of the comparative effectiveness of orlistat, sibutramine and low fat
diets that may include meal replacements........................................................................ 35
Summary of short-term weight loss trials of sibutramine and orlistat not
otherwise reported in systematic reviews and HTAs..................................................... 35
A comparison of the effectiveness of sibutramine, orlistat, phentermine and
diethylpropion (Glazer et al., 2001) .................................................................................. 37
A comparative study of the effectiveness of sibutramine, orlistat, phentermine
and diethylpropion (Haddock et al., 2002) ...................................................................... 37
Weight loss drugs trade off between benefit and harm................................................. 38
The effect of sibutramine on blood pressure and heart rate; results from 20
studies (Nisoli and Carruba, 2003).................................................................................... 41
NZ Drug pricing according to MIMS, 2004 ................................................................... 55
The estimated cost of a course of anti-obesity treatment ............................................. 55
Studies reporting on the cost or cost effectiveness of sibutramine, orlistat,
phentermine and diethylpropion....................................................................................... 57
Sensitivity analysis around two base estimates of the cost effectiveness of
sibutramine when different utilities are assigned to weight loss................................... 59
Economic evaluations of orlistat, sibutramine and phentermine................................. 61
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
vi
Evidence Table 1.
Evidence Table 2.
Evidence Table 3.
Evidence Table 4.
Evidence Table 5.
Evidence Table 6.
Evidence Table 7.
Evidence Table 8.
Evidence Table 9.
Evidence Table 10.
Evidence Table 11.
Evidence Table 12.
Evidence Table 13.
Evidence Table 14.
Evidence Table 15.
Evidence Table 16.
Evidence Table 17.
Evidence Table 18.
Evidence Table 19.
Evidence Table 20.
Evidence Table 21.
Evidence Table 22.
Evidence Table 23.
Evidence Table 24.
Evidence Table 25.
Evidence Table 26.
Evidence Table 27.
Meal replacement, Heymsfield, 2003 ............................................ 76
Meal replacement, Allison et al., 2003........................................... 77
Orlistat, Torgerson et al., 2004....................................................... 78
Orlistat, Rissanen et al., 2001 ......................................................... 79
Orlistat, Muls et al., 2001 ................................................................ 80
Orlistat, Foxcroft et al., 2000 ......................................................... 81
Orlistat, Derosa et al., 2003 ............................................................ 82
Orlistat, Hanefield et al., 2002........................................................ 83
Orlistat, Halpern et al., 2003........................................................... 84
Orlistat, Leung et al., 2003.............................................................. 85
Orlistat, Heymsfield et al., 2000..................................................... 86
Orlistat, O’Meara et al., 2001.......................................................... 87
Orlistat, Padwal et al., 2004 ............................................................ 89
Sibutramine, O’Meara et al., 2002.................................................. 90
Sibutramine,Tambascia et al., 2003 ............................................... 91
Sibutramine, Padwal et al., 2004 .................................................... 92
Sibutramine, Leung et al., 2003 ..................................................... 93
Sibutramine, Nisoli and Carruba, 2003......................................... 94
Sibutramine, Berkowtitz et al., 2003.............................................. 95
Sibutramine, Hazenberg et al., 2000.............................................. 96
Sibutramine, Gokcel et al., 2001 .................................................... 97
Sibutramine, Kim et al., 2003 ......................................................... 98
Sibutramine, Hauner et al., 2003.................................................... 99
Sibutramine, McNulty et al., 2003 ............................................... 100
Sibutramine, Wadden et al., 2000 ................................................ 101
Comparative drug study, Poston et al., 2001 ............................. 102
Comparative drug study, Haddock et al., 2002.......................... 103
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
vii
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. Cointerventions 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 nonpharmacological 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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
viii
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
1
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
Weight Class
BMI (kg/m2)
% Above
Ideal weight
Caucasian
Asian*
PI*
Normal
Overweight
Obesea
0%
18.5-24.9
18.5-22.9
18.5-22.9
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
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
2
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
3
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
4
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
5
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
6
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
7
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?
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
8
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
9
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
10
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
11
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
13
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
14
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, prepackaged 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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
15
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
16
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
17
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
Primary study purpose
Study size
Study duration/ length of follow-up
Participants
Interventions
Outcome measures/endpoints
Health economics
Language
Study dates/publication date
Publication type
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.
Weight loss
Unrestricted
Any duration of treatment. Follow–up of at least 12 months for long-term benefits, any followup length for short-term benefits.
Individuals with a BMI of at least 30kg/m2, no age restriction.
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.
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.
All economic and cost evaluations
English language or English translation available
Jan 1996-July 2004
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
18
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
Ib
IIa
IIb
III
Evidence obtained from meta-analysis of randomised controlled trials
Evidence obtained from at least one randomised controlled trial
Evidence obtained from at least one well designed controlled study without randomisation
Evidence obtained from at least one other type of well-designed quasi-experimental study
Evidence obtained from well-designed non-experimental descriptive studies, such as comparative studies, correlation studies
and case control studies.
Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities.
IV
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
19
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=
Λ (PMRRCD)
kg(s.e.)
3 months
Significance of
PMR-RCD
difference
p=
N=
Λ (PMRRCD)
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
20
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
21
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
Munro
1986
30mg
Duration
Weight
Loss (kg)
P value†
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 19691992. 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
Drug
average dose
Studies
Subjects
(dose range)
Phentermine
27.7mg/d
(15-30mg/d)
6
386
Duration
(Wks)
13.2 (2.24)
Number post test
Mean Weight loss (kg)
Placebo
Phentermine
Placebo
Phentermine
(range)
(range)
(range)
(range)
29.4 (12-74)
32(15-76)
2.8 (1.5-5.2)
6.3(3.6-8.8)
D-P Kg
(range)
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
22
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 “PhenFen”. 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
Study
Year
Silverstone
1968
Deramos
McKay
1964
1973
Followup
period
6 month
1 year
6 months
6 months
Weight loss kg
D-P
Drug
Placebo
Kg
7.0
8.9
7.8
11.7
8.7
10.5
1.9
2.5
-1.7
-1.5
5.9
9.2
P value
NR
NR
>0.05
<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 stimulantrelated adverse events but weight loss beyond six months was not observed with these patients.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
23
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.
Drug
(dose)
Diethylpropion
Diethylpropion vs. placebo post treatment outcomes, Haddock et al., 2002
Studies
9
Duration
Number post test
Mean Weight loss (kg)
D-P
(wks)
Placebo
DP
Placebo
DP
(kg)
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 1996July 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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
24
Table 9.
Study
Summary of publications reporting the effectiveness of orlistat for weight loss in overweight and
obese participants
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
∆ TC
mmol/l
∆ Weight
(kg)
Test for overall effect
z=12.53(p<0.00001)
Test for overall effect
z=9.67p(<0.00001)
Test for overall effect
z=11.28(p<0.00001)
Test for overall effect
z=1.84(p<0.07)
Test for overall effect
z=4.90(p<0.00001)
Test for overall effect
z=7.18(p<0.00001)
Test for overall effect
z=3.26p(<0.001)
-0.03¥
(95%CI, -0.07 to–0.0)
Π2 = 0.31 (p=0.86)
Orlistat n=557
Placebo n=537
Studies=3
Test for overall effect
z=2.43(p<0.01)
-0.21
-0.22
-3.26
(95%CI, -4.15 to–2.37) (95%CI, -0.34 to–0.09) (95%CI, -0.31 to–0.13)
Π2 = 0.50 (p=0.48)
Π2 = 1.04 (p=0.60)
Π2 = 5.92 (p=0.05)
Orlistat n=451
Orlistat n=557
Orlistat n=555
Placebo n=448
Placebo n=537
Placebo n=536
Studies=3
Studies=2
Studies=3
Test for overall effect
z=0.68(p=0.55)
-0.04
(95%CI, -0.07 to–0.005)
Π2 = 10.14 (p=0.006)
Orlistat n=557
Placebo n=537
Studies=3
Test for overall effect
z=0.77(p=0.44)
-0.03
(95%CI, -0.04 to–0.10)
Π2 = 24.11 (p=0.0002)
Orlistat n=1399
Placebo n=1388
Studies=6
mmol/l
∆ TG
plasma
glucose
mmol/l
∆ Fasting
∆ DBP
mmHg
∆ SBP
mmHg
NR
-0.15
-1.20
-1.42
(95%CI, -0.24 to–0.07) (95%CI, -2.28 to–0.11) (95%CI, -3.08 to–
0.24)
Π2 = 4.15 (p=0.13)
Π2 = 9.39 (p=0.002)
Orlistat n=557
Orlistat n=451
Π2 = 0.22(p=0.64)
Placebo n=537
Placebo n=448
Orlistat n=451
Studies=3
Studies=2
Placebo n=448
Studies=2
Test for overall effect
Test for overall effect
z=3.50(p=0.0005)
z=2.16(p=<=0.03)
Test for overall
effect
z=1.68 (<0.09)
-0.17
-0.24
-1.64
-2.02
(95%CI, -0.24 to–0.10) (95%CI, -0.34 to–0.14) (95%CI, -2.20 to–1.09) (95%CI, -2.87 to–
1.17)
Π2 = 8.23 (p=0.02)
Π2 = 13.02 (p=0.02)
Π2 = 19.11 (p=0.004)
Orlistat n=1399
Orlistat n=1399
Orlistat n=2056
Π2 = 10.09(p=0.12)
Placebo n=1388
Orlistat n=2056
Placebo n=1388
Placebo n=1611
Studies=6
Studies=6
Studies=7
Placebo n=1611
Studies=7
Test for overall effect
Test for overall effect
Test for overall effect
z=4.67(p<0.00001)
z=4.77(<0.00001)
z=5.80(<0.00001)
Test for overall
effect
z=4.65 (<0.00001)
%
∆ HBAIc
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
¥ =decrease in HDL in treatment group unfavourable, this result favours the control group.
Davidson, 1999
Rossner, 2000
Hauptman, 2000
mmol/l
∆ HDL-C
-3. 01
-0.34
-0.29
-0.03¥
(95%CI, -3.48 to–2.54) (95%CI, -0.41 to–0.27) (95%CI, -0.34 to–0.24) (95%CI, -0.05 to–0.01)
Π2 = 15.08 (p=0.04)
Π2 = 4.27 (p=0.64)
Π2 = 3.53 (p=0.74)
Π2 = 7.07 (p=0.22)
Orlistat n=2166
Orlistat n=1509
Orlistat n=1059
Orlistat n=1250
Placebo n=1719
Placebo n=1496
Placebo n=1496
Placebo n=1233
Studies=8
Studies=7
Studies=7
Studies=6
Orlistat, 360mg/d + diet vs. placebo + diet, 3 RCTs at 24 months
Rossner, 2000
Sjostrom, 1998
Lindgarde, 2000
Hollander, 1998
Hauptman, 2000
Finer, 2000
Davidson, 1999
Broom, 2001
mmol/l
∆ LDL-C
Total Weighted Mean Difference between drug and placebo, over all studies, fixed effects (95%CI)
Meta-analysis of RCTs for Orlistat, long-term studies ≥ 1 year (NICE HTA, Avenell, May 2004)
Orlistat, 360mg/d + diet vs. placebo + diet, 8 RCTs at 12 months
Study/
Year
Table 10.
25
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
Krempf (RCT)
2003
1
95
Torgerson (RCT)
2004
1
3305
Heymsfield (MA) 2000
3
675
* at one year, intention to treat (ITT) ** 18 months ITT,
WL =weight loss
Mean difference
in % change
a
Mean Difference
WL (kg)
% with
WL≥5%
-2.6*
-2.9*
NR
-3.5**
-3.6**
58
NR
-4.4a
73a
NR
NR
53b
-2.9*
-2.5*
NR
difference at one year non-diabetic b difference at four years
% with
WL≥10%
NR
NR
41a
26b
NR
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
Study
Orlistat 360mg/d weight loss in patients with hypercholesterolemia, results after one year
Year
Muls
RCT
Derosa
RCT
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
-3.03kg*
-10.00
-7.56
-8.37
-0.63
NR
Mean % change from baseline for each group
2003
1(23)
Placebo
-7.6kg**
-10.8
+2.4
-12.1
-14.8
-3.0%
1(25)
Orlistat
-8.6kg**
-19.0
+2.3
-15.0
26.5
-4.6%
Bold = significant difference from placebo *difference Placebo-Orlistat ** from baseline, LMS = least mean square
2001
1 (411)
P-O
NR
-2.4%
-4.7%
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 nondiabetic 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
Weight loss
Orlistat* + diet
N=1561
≥5% weight loss
≥10% weight loss
* 360mg/d
45.3%
20.2%
Placebo+ diet
N=1119
23.4%
8.3%
Type2 diabetes
P value
<0.001
<0.001
Orlistat* + diet
Placebo+ diet
N=163
N=159
30.2%
9.3%
13.2%
4.4%
P value
<0.001
ns
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)
Heymsfield
Meta-analysis
2000
2 (675)
Glucose
intolerant
Participants
Placebo group
Orlistat group
WL - Change
from baseline (kg)
%
Progressing
%
Improvement
IGT-NGT
7.6
3.0
49
72
3.79(±4.1)
6.27(±0.41)
WL=weight loss, IGT=impaired glucose tolerance, NGT=normal glucose tolerance, kg=kilogram
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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 1996July 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.
Study
Eligible studies reporting the effectiveness of sibutramine
Size
Study population
Studies*
Patients
Study type
Code
Health technology assessment, systematic reviews, Cochrane reviews, meta-analyses
Avenell
2004
Obese Mixed
5
1455 HTA
LT
Padwal
2004
Healthy obese
3
929 CR
LT
Hensraud
2003
Obese Mixed
11
>1924 HTA
MT
Arterburn
2003
Obese mixed
6a
1975 SR
MT
Leung
2003
Obese mixed
10
3150 SR
MT
Glazer
2001
Obese mixed
1*
160 SR
LT
Haddock
2001
Obese mixed
4
NR MA
ST
O’Meara
2002
Obese Mixed
11
2037 HTA
MT
McTigue
2003
Obese Mixed
7
2815 MA
MT
Nisoli
2003
Obese Mixed, safety
19
4039 SR
MT
Kim
2003
Obese mixed
21(31a)
4528 MA
MT
*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
Gokcel
2001
Obese diabetic
1
60 RPCDBT
ST
Hazenberg
2000
Obese hypertensive
1
127 RPCDBT
ST
Berkowitz
2003
Healthy Obese adolescents
1
82 RPCDBT
LT
Duration
At least 1 year
At least 1 year
Any
Any
More than 6 months
At least 9 months treatment
8-26 weeks, mean=15.5
Any
6-12 months
8-52 weeks**
8-52
12 months
6 months
12 weeks
12 months
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
29
Table 15.
Study
Eligible studies reporting the effectiveness of sibutramine (continued)
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, metaanalyses 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 LDLcholesterol, 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 HDLcholesterol (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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
∆ TC
mmol/l
∆ Weight
(kg)
mmol/l
∆ LDL-C
%
∆ HbA1c
plasma
glucose
mmol/l
∆ Fasting
∆ DBP
mmHg
∆ SBP
mmHg
-0.08
3.30
1.20
(95%CI, -0.49 to 0.33) (95%CI, 0.91-5.69) (95%CI, -2.45 to 4.85)
Studies=1
Studies=1
Studies=1
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
-3.90
0.04
0.08
0.02
-0.18
(95%CI, -5.75 to–2.05) (95%CI, -0.29 to0.37) (95%CI, -0.01to0.17) (95%CI,-0.21to0.25) (95%CI,-0.47to0.11)
STORM, 2000
Studies=1
Studies=1
Studies=1
Studies=1
Studies=1
† Weight maintenance STORM 2000, ‡ increased blood pressure in treatment group unfavourable.
NR
Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect
z=0.16(p=0.87)
z=1.09 (p=0.28)
z=3.57 (p=0.0004)
z=2.87 (p=0.004)
z=0.76 (p=0.45)
z=0.47 (p=0.64)
z=3.47(p=0.0005)
z=9.44(p<0.00001)
z=1.29(p=0.20)
Sibutramine + diet vs. placebo + diet, 1 RCTs at 12 months, weight maintenance, hypertensive patients
Smith, 2001b
Smith,2001a
Sibutramine n=530 Sibutramine n=378 Sibutramine n=212 Sibutramine n=214 Sibutramine n=459 Sibutramine n=265 Sibutramine n=378 Sibutramine n=445 Sibutramine n=445
Placebo n=287
Placebo n=136
Placebo n=137
Placebo n=365
Placebo n=77
Placebo n=287
Placebo n=375
Placebo n=461
Placebo n=375
Studies=3
Studies=2
Studies=2
Studies=4
Studies=1
Studies=3
Studies=3
Studies=4
Studies=3
mmol/l
∆ TG
Sibutramine
Placebo
Sibutramine
Sibutramine
Sibutramine
Sibutramine
Sibutramine
Placebo
Placebo
-4.12
0.01
-0.08
0.10
-0.16
-0.07†
-0.05
2.04‡
1.16‡
(95%CI, -4.97 to–
Apfelbaum, 1999
(95%CI, -0.15 to 0.18) (95%CI, -0.23 to–0.07) (95%CI, 0.04 to 0.15) (95%CI, -0.26 to–0.05) (95%CI, -0.25 to 0.11) (95%CI, -0.26 to 0.16) (95%CI, 0.89 to3.20) (95%CI, 0.60 to2.39)
3.26)
Π2 = 1.36 (p=0.24) Π2 = 0.27 (p=0.60) Π2 = 1.10 (p=0.78)
Π2 = NA
Π2 = 0.03 (p=0.98) Π2 = 2.99 (p=0.22) Π2 = 0.12 (p=0.94)
McMahon, 2000 Π2 = 5.96 (p=0.11) Π2 = 0.03 (p=0.98)
FAVOURS
mmol/l
∆ HDL-C
Total Weighted Mean Difference between drug and placebo, over all studies, fixed effects (95%CI)
Meta-analysis of RCTs for Sibutramine, long-term studies ≥ 1 year (NICE HTA, Avenell May 2004)
Sibutramine + diet vs placebo + diet, 4 RCTs at 12 months, weight reduction
Study/
Year
Table 16.
30
mmol/l
(kg)
Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect Test for overall effect
z=1.22(p=0.22)
z=1.51 (p=0.13)
z=3.12 (p=0.002)
z=2.39 (p=0.02)
z=1.57 (p=0.12)
z=0.62(p=0.54)
plasma
glucose
mmol/l
∆ Fasting
Test for overall effect
z=6.33(p<0.00001)
%
∆ HbAIc
Sibutramine n=222 Sibutramine n=222 Sibutramine n=222 Sibutramine n=222 Sibutramine n=222 Sibutramine n=222
Placebo n=62
Placebo n=62
Placebo n=62
Placebo n=62
Placebo n=62
Placebo n=62
Studies=1
Studies=1
Studies=1
Studies=1
Studies=1
Studies=1
mmol/l
∆ TC
Sibutramine n=350
Placebo n=114
Studies=1
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
† Weight maintenance STORM 2000. ¥ decrease in HDL is unfavourable, this result favours the control group.
Maintenance
Weight
STORM, 2000
mmol/l
∆ HDL-C
-0.19
-0.16
-0.13¥
-0.33
-0.16
-0.12
(95%CI,-0.49 to–0.11) (95%CI,-0.37 to–0.05) (95%CI,-0.05 to–0.21) (95%CI,-0.60 to–0.06) (95%CI,-0.36 to–0.04) (95%CI,-0.50 to–0.26)
Π2 = NA
Π2 = NA
Π2 = NA
Π2 = NA
Π2 = NA
Π2 = NA
mmol/l
∆ LDL-C
-3.40
(95%CI, -4.45 to–2.35)
Π2 = NA
Sibutramine + diet vs. placebo + diet, 1 RCT at 18 months
∆ TC
∆ Weight
Total Weighted Mean Difference between drug and placebo, over all studies, fixed effects (95%CI)
Meta-analysis of RCTs for Sibutramine, long-term studies ≥ 1 year (NICE HTA, Avenell May 2004) (continued)
Study/
Year
Table 16.
NR
∆ DBP
mmHg
NR
mmHg
∆ SBP
31
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)
Padwal (SR)
2004
3(929)
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.)
≥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
+0.9c
NR
NR
+1.1c
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.
Study
Studies reporting the effectiveness of sibutramine in individuals with type 2 diabetes
Year
Dose
Mg/d
Mean difference placebo-drug, bold = significant difference
≥5% ≥10% LDL-C HDL-C Total-C TG
SBP
DBP
Pulse rate
WL
WL
mg/dl mg/dl
mg/dl
mg/dl mmHg mmHg
a
2003
McNulty
15 195
46
14
0.0
0.1
0.0
-0.2
4.6
2.8
5.9
(RCT)
20
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.
N=
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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
Treatment group
Dose
mg/d
% Weight loss
% losing at least 5 or 10
% of base weight
5%
19.5
25.3
37.4
59.6
67.3
71.9
77.2
Placebo
1.2
1
2.7
5
3.9
Sibutramine
10
6.1
24 weeks
15
7.4
N=1047
20
8.8
30
9.4
Bold = significant difference from placebo
10%
0.0
10.5
12.1
17.2
34.7
38.5
45.5
Discontinuation
due to
Adverse events
%
8
11
5
9
11
13
18
SBP
Change
mmHg
DBP
Change
mmHg
Pulse
Change
bpm
-0.8
0.3
2.1
2.8
2.7
4.0
3.3
1.7
1.2
2.5
4.2
3.4
5.0
4.1
0.6
0.3
3.3
6.0
6.1
7.0
5.3
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
Avenell, 2004
(National Institute
For Clinical
Effectiveness)
Hensraud, 2003
(ICSI Technology
Assessment
Committee)
Arterburn, 2003
McTique, 2004
(US Preventative
Services Task Force)
Haddock, 2002
(USA)
Phentermine
Diethylpropion
Orlistat
Sibutramine
X
X
✓
✓
✓
x
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
✓
X
X
✓
✓
Glazer, 2001
(USA)
Padwal, 2004
(Cochrane Review,
Canada)
Other weight loss therapies reported
Metformin
Selective serotonin reuptake inhibitors (SSRIs)
Acarbose
VLCDs
LCDs
Protein sparing modified fast
Diet, exercise, behaviour therapy
Ephedrine + Caffeine
Mazindol
Metformin
Fluoxetine
Dexamphetemine
Benzocaine
Benzphentermine
Dexfenfluramine
Fenfluramine
Fluoxetine
Mazindol
Methamphetamine
Phendimetrazine
Phenylpropanolamine
Sertaline
Mazindol
Fluoxetine (SSRI)
Sertaline (SSRI)
Fenfluramine
Dexfenfluramine
None
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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, placebocontrolled, 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
Weight change
from baseline
(kg)
Sibutramine + diet
18 months
-3.40
Orlistat + diet
24 months
-3.26
Low Fat diets*
12 months
-5.31
* Can include meal replacement programs
Therapy
Assessed at
95%
Confidence
Interval
-4.45 to –2.35
-4.15 to –2.37
-5.86 to –4.77
Change in risk factors
Beneficial except for DBP
Beneficial
Beneficial
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)
Sibutramine + diet
Orlistat + diet
12-52 weeks
12 months
24 months
-2.4-to -16.6
-3.9 to –10.3
-5.0 to –7.4
% of participants
with a loss of
≥5% of initial
body weight
27-88%
33-69%
NR
% of participants
with a loss of
≥10% of initial
body weight
6-76%
10-39%
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
37
Table 23.
A comparison of the effectiveness of sibutramine, orlistat, phentermine and diethylpropion
(Glazer et al., 2001)
Therapy
Sibutramine
Orlistat
Phentermine
Diethylpropion
a
Weight loss
attributable
to drugs
(kg)
4.3
3.4
7.9
-1.5
Weight loss
attributable
to druga
(%)
5.0
3.4
8.1
-1.5
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)
Number at
Weight loss
Mean
post test
attributable
effect
placebo
to druga
sizec
(range)
kg (range)
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.
Therapy
Dosage
Per day
(mg)
Weeks of
any treatment
(range)
Number at
post-test
drug (range)
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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 tradeoff 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
Orlistat
Phentermine
Sibutramine
Fluoxetine
Mazindol
Drugs included in the current review
Sibutramine + orlistat
Dexfenfluramine
Fenfluramine
Fenfluramine + phentermine
Phenylpropanolamine
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
40
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
Trial
The effect of sibutramine on blood pressure and heart rate; results from 20 studies (Nisoli and
Carruba, 2003)
Dose
mg/d
Study
Length
Obese subjects
Apfelbaum
10 52wk
Fanghanel
10 24wk
Hanotin
10 12wk
Cuellar
15 24wk
Walsh
15 12 wk
Hanotin
5,10,15 12wk
Weintraub
5,20 8wk
James
10,20 72wk
McNulty
10,20 12wk
Seagle
15,30 8wk
Hanson
30 5.5h
Patients with type 2 diabetes
Knoll
10,20 52wk
Knoll
15 NR
Knoll
15,20 NR
Bray
1.5-30 24wk
Fujioka
5,20 24wk
Gokcel
10 24wk
Serrano15 24wk
Rios
Finer
15 12wk
Sibutramine use in children
Berkowitz
5,10,15 24wk
a drop-out
P
S
P
S
P
S
P
S
No Patients
reporting
AEs
P
S
78
54
114*
34
9
59
20
115
64
15
11
82
55
112
35
10
177
40
352
130
29
11
NR
-4.0
+0.6
NR
NA
NR
NR
-2.4
-0.2
NR
+5.0
NR
+1.7
+0.9
NR
NA
NR
NR
+1.9
+1.5
NR
+8.6
-1.9
-1.5
-0.1
NR
NA
NR
NR
-.05
+0.5
NR
+1.4
+1.5
+0.3
+0.4
NR
NA
NR
NR
+3.4
+1.9
NR
-4.3
+1.0
-2.2
-0.9
NR
NR
-1.6
NR
+0.2
-0.8
NR
+2.8
+8.0§
+0.1
+3.6
NR
NR
+3.2
NR
+4.6
+5.0
NR
+11.24
63
23
90
16
NR
42
NR
5
NR
NR
NA
163
122
64
148
86
30
65
332
114
131
899
89
30
69
-0.5
NR
NR
-0.8
+2.4
NR
-1.1
+0.7
NR
NR
+2.5
+3.9
NR
+0.5
-0.9
NR
NR
+1.7
+1.4
NR
NR
+0.8
NR
NR
+2.9
+2.6
NR
NR
+0.1
NR
NR
+0.6
+0.7
NR
NR
+2.7
NR
NR
+4.6
+6.6
NR
+2.4
44
47
NR
NR
NR
NR
+0.2
39
43
+4.0
+0.1
2.0
No
Subjects
∆SBP
(mmHg)
∆DBP
(mmHg)
+0.6
+1.8
∆Heart rate
(beats/min)
No of dropouts
P
S
72
31
84
23
NR
126
NR
48
NR
NR
NA
5a
10
19
25
NR
12
1
58
18
NR
NA
2a
15
10
13
NR
29
4
148
32
NR
NA
NR
NR
NR
12
68
NR
34
NR
NR
NR
101
70
NR
42
83
12a
5A
61
25
5
8
146
9a
14A
303
29
1
16
+7.5
45
42
4
4
+5.4
NR
NR
5
3
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
46
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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
17
The XENDOS trial of orlistat has recently reported on its safety and efficacy at four years.
This guidance is to be reviewed in September 2004.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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 comorbidities (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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
51
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).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
52
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
54
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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†
Proprietary
Drug name
Drug
Phentermine
C5controlled drug
Durominea
Diethylpropion
Sibutramine
Umine
Tenuate Dospan b
Reductil
Orlistat
Xenical
Pack
Manufacturer
Price
NZ$
(per tablet)
Patient
Charge
NZ$
21.52
24.58
35.90
94.88
103.35
119.10
112.00
37.12
42.40
61.93
163.67
178.28
205.45
193.20
15mg [30]
30mg [30]
30mg[100]
75mg[100]
10mg[30]
15mg[30]
120mg[84]
Cost per
Tablet
NZ$
Recommended
Daily dosed
1.24
1.41
0.62
1.64
5.94
6.83
2.30
Cost‡
per patient
per month
NZ$
15mg/d
30mg/d
30mg/d
75mg/d
10mg/d
15/mg/d
360mg/d
37.82
43.01
18.91
50.02
181.17
208.32
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
Drug
Phentermine
C5controlled drug
Proprietary
Drug name
Daily
Dose
Durominea
15mg
30mg
30mg
75mg
10mg
Maximum permitted
Prescribed period
Time Period
Cost
Minimum period
Maximum weight loss
Time Period
Cost
3 months
$113.46
3 months
$129.03
Umine
3 months
$56.73
Diethylpropion
Tenuate Dospan b
3 months
$150.06
Sibutramine
Reductil
1 yr $2,174.04
2 yr $4,348.08
15mg
1 yr $2,499.84
2 yr $4,999.68
Orlistat
Xenical
360mg
1 yr $2,525.40
2 yr $5,050.80
† not reported but assumed to be maximum continuous prescription period allowed.
3 months†
3 months†
3 months†
3 months†
6 months
$113.46
$129.03
$56.73
$150.06
$1,087.02
6 months
$1,249.92
6 months
$1,262.70
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
56
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
57
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
Avenell 2004
Sibutramine
Orlistat
Hensraud 2003
Orlistat
O’Meara 2002
O’Meara 2001
Sibutramine
Orlistat
Phentermine
Sibutramine
Orlistat
Glazer 2001
Reported data from
O’Meara 2001
O’Meara 2002
Foxcroft 1999
Foxcroft 2000
Lamotte 2002
BASF Pharma/Knoll 2000
Foxcroft 2000 (rapid review)
Lamotte 2002 (HE model)
BASF Pharma/Knoll 2000
Foxcroft 2000 (rapid review)
Pharmacy chain average retail price
Economic analysis
Cost-effectiveness
Cost-effectiveness
Cost-effectiveness
Cost-effectiveness
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:
20
•
the initial consultation
•
laboratory tests
BASF Pharma Knoll (2000). Unpublished study of economic analysis of Sibutramine reported in O'Meara (2002).
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
58
•
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
59
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‡
WL benefits only
WL and CHD benefits only
WL and diabetes benefits only
Utility per kg WL = lower CI
Utility per kg WL= upper CI
Worst case
Best case
Compliance = 30%
Compliance =50%
Compliance =75%
Adverse events not included
Placebo=no monitoring costs
UK Cost per QALY
Central Estimate A
SAT trial
£4,780
UK Cost per QALY
Central Estimate B
SAMSA analysis†
£10,530
£6,341
£5,403
£5,567
£14,072
£3,001
£20,602
£2,950
£8,605
£7,077
£5,738
£4,769
£9,034
£19,125
£12,952
£14,664
£16,682
£5,965
£34,260
£5,809
£34,905
£21,482
£14,271
£10,505
£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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
60
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
61
Table 31.
Study
Economic evaluations of orlistat, sibutramine and phentermine
Type of study
Type of analysis
ORLISTAT
Foxcroft
Rapid review
2000
Cost-effectivenessd
Glazer
2001
Systematic review of
effectiveness which
included a comparison of
drug cost
ORLISTAT
Lamotte
Primary research report
2002
Cost effectiveness
Markov model
Maetzel
2003
Primary research paper
Markov state transition
model of obese
individuals with type 2
diabetes
SIBUTRAMINE
Glazer
Systematic review of
2000
effectiveness which
included a comparison of
drug cost
Costs and assumptions
Economic analysis
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
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$433
Assumptions
WMD Drug-placebo %=3.4, kg=3.4
Base case analysis
Cost utility per QALY gained = £45,881
(range £19,452 - £55,391)
Drug cost
Per patients per year = €881
Incremental costs Drug-placebo
1.Event free diabetes = €1,608
2.Hypercholesterolemia= €1,514
3.AHT= €1,678
4. Hypercholesterolemia+ AHT= = €1,641
Life years gained
1.Event free diabetes = 0.08
2.Hypercholesterolemia= 0.204
3.AHT= 0.227
4. Hypercholesterolemia+ AHT= = 0.474
Assumptions
Effectiveness data from Clark 1998 (1.=9.462,
2.=9.401,3.=8.93,4.=8.74)
public health perspective
Metformin base treatment = 119 euro per patient per year. 4.2%
of patients could stop taking oral medication for diabetes and
10% could reduce their medication by approx 25%.
Cost estimates (2001 values: US$)
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
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
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
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
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
No analysis
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
62
Table 31.
Study
Economic evaluations of orlistat, sibutramine and phentermine (continued)
Type of study
Type of analysis
SIBUTRAMINE
O’Meara Systematic review
2002
Modellingc
cost utility analysis
BASF Pharma /Knoll
UK British £
Warren
2004
Primary research
publication
Economic modelling
based
Costs and assumptions
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
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
Economic analysis
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)
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
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
PHENTERMINE
Glazer
2000
Costs
No analysis
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
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 costeffectiveness 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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
63
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 19962004 for meal replacement products or plans.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
64
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
66
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
67
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
68
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
69
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 comorbidity 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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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 34389 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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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 12001600kcal/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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
75
Evidence Tables
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Study design
Meta-analysis of six
RCTs
Heymsfield,
2003
Note: 2 meals a day
were replaced in the
exposure during the
weight loss phase, one
meal a day during the
weight maintenance
phase.
Location
USA (n=5)
Germany (n=1)
Duration
3-51 months, median 12
months
Exclusion
Studies with self
reported data.
Comparison (RCD)
Traditional LCD plan
(LCD) with the same
caloric composition as
the exposure.
Risk factors ⊥
Glucose (mg/dl)
SBP (mmHg)
DBP (mmHg)
Insulin (ΦU/ml)
Cholesterol (mmol/l)
HDL (mmol/l)
LDL (mmol/l)
TG (mmol/l)
Results at 3 months
Meta-analysis fixed effects
Meta-analysis random effects
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
>=5% weight loss RCD=34%,
PMR=72%
Non-diabetic
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
Diabetic
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
Results at 1 year (RCD N=4, PMR
N=5)
Meta-analysis fixed effects
Meta-analysis random effects
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
>=5% weight loss RCD=33%
PMR=74%
Non-diabetic
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
Diabetic
Pooled analysis of completers
Pooled analysis LOCF
Pooled analysis MI
Exposure (PMR)
PMR – i.e., one or
more meals replaced
by a commercially
available, caloriereduced product(s)
that are fortified with
vitamins and minerals
and at least one daily
meal consisting of
regular foods, acting
as a LCD and
providing
>800<=16000kcal/day
Participants N=487
Male= 25%
Female: =75%,
Mean age 46.1 years
Mean BMI at baseline
=31
Diabetic N=119 (24%)
Non-diabetic
N=368(76%)
Inclusion
Randomised trial
comparing PMR to a
traditional LCD
Study duration >
3months
Subjects >18 years
Outcomes
Exposure/
Comparison
Participants
Inclusion
Exclusion
Meal replacement, Heymsfield, 2003
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 moWL p=
0.009
<0.001
ns
ns
<0.001
ns
0.001
0.011
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 moWL p=
0.028
<0.001
ns
ns
ns
ns
0.039
0.014
s.e.
3.01
2.60
2.54
2.39
2.23
Wt-loss dif§
PMR-RCD p=
ns
ns
ns
<0.001
ns
ns
ns
ns
ns
ns
ns
0.002
<0.001
<0.001
<0.001
0.142
0.003
<0.001
0.119
<0.001
ns
ns
ns
<0.001
<0.001
<0.001
<0.001
0.006
<0.001
<0.001
<0.001
<0.001
p value
Effect Size & Precision
(Mean change from baseline)
Baseline comparison
PMR and RCD differed
significantly in one factor –
baseline glucose.
Drop-out rate
3 months (ns)
Exposure = 16%
Control=19%
1 year (p<0.001)
Exposure=47%
Control=64%
None of the drop-out reported
program or product-related
adverse events.
Heterogeneity
Estimates of weight loss and
effectiveness of both groups
from the individual studies
were heterogeneous
(p=<0.001).
Quality
The quality of all studies as
assessed by the Jadad criteria
= moderate.
Blinding was not possible due
to the nature of the
interventions.
Blinding of the outcome
assessor was not described.
Randomisations description
was included in all protocols
and all studies provided details
of dropouts.
Validity/Applicability
Safety
The first systematic evaluation of
RCTs evaluating PMR plans for
weight management suggests that
they can safely and effectively
produce significant weight loss.
There was no support for
publication bias.
Note: % weight loss at 3 months
RCD=4%, PMR=7%. % weight
loss at 1 year RCD. 3-7%,
PMR.7-8%
PMR groups lost significantly
more weight than the control
group.
All six studies resulted in
significant weight loss from
baseline in both groups.
Four studies enrolled subjects
with no co-morbidities, the other 2
were designed for patients with
type 2 diabetes.
Within the context of a clinical
trial, PMR appears to promote
significantly greater weight loss
than a corresponding RCD plan.
The overall magnitude of the
weight loss in a pooled analysis at
1 year was in the range reported
in some pharmacological weight
control studies (Glaser 2000) and
is at the level known to lower
disease risk.
Conclusions
Comments
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
*One trial >=30 years ** same study populations ns= no significant difference between groups § PMR = partial meal replacement, RCD= reduced calorie diet. Note: All risk factor values for both groups were significantly different from baseline values at 3 and 6 months,
3moWL= 3 month weight loss, 6moWL= 6 month weight loss. MI=multiple impatation, LOCF=last observation carried forward.
Studies N=6
Ditchuneit et al.,
1999**
Fletcher-Mors et al.,
2000**
Rothacker 2001
Yip 2001
Hensrud 2001
Ashley 2001
Ahrens 2000
Objective
To assess the
safety and
effectiveness of
meal replacement
therapy
Study Design
Objective
Studies
Duration
Study
authors
and year
Evidence Table 1.
76
Study Design
RCT
Allison et al.,
2003
Recruitment
Details not given.
Exclusion
Weight loss of >5kg in
the past 3 months
Use of weight loss drugs
in the last 6 weeks.
Scores above the 90th
percentile on the Brief
Symptom inventory
Disease not believed to
be at least partially the
result of obesity and
treatable by weight
reduction. Medical or
psychological
contraindications
Known hypersensitivity to
any of the ingredients of
the formula.
Comparison N=50
M=10, F=40
1200kcal exchange
diet system.
A single session
dietary counselling
and a pamphlet
describing good
weight loss practices.
Exposure N=50,
M=10, F=40
Scan diet meal
replacement formula,
5 Scan diet shakes +
4 exchanges of fruit,
4 exchanges of
vegetables and one
fat exchange per day
instructions for use +
a single session
dietary counseling +
a pamphlet
describing good
weight loss practices.
Participants
N=100 (120 screened)
BMI 28-41kg/m2
Age 35-65
Male =20
Female =80
Inclusion
Overweight or obese
subjects
Medically fit for safe
weight loss
Exposure/
Comparison
Participants
Inclusion
Exclusion
Recruitment
Meal replacement, Allison et al., 2003
Note: 13 missing values for treatment
group and 13 missing values for control
group at week 12.
Adverse events (MOSES)a
As assessed at 12 weeks
Appetite: decreased/anorexia
Constipation
Diarrhoea
Drooling/salivation
Gas/indigestion
Taste: abnormal/metallic
Lethargy/no movement
Sleep: excessive
Urinary: enuresis/nocturesis
Weight gain
Weight loss
**All assessments at 4 and 8 weeks
were ns except for:
Fat mass at 8 weeks p=0.011,total
cholesterol at 4 weeks p=0.002, 8
weeks p=0.0001,LDL cholesterol at 4
and 8 weeks p=<0.0001
12 week assessment (ITT)*
Weight change (kg)
Total body fat mass (%)
Fat mass (kg)
Waist circumference (cm)
Total cholesterol (mg/dl)
LDL cholesterol (mg/dl)
HDL cholesterol (mg/dl)
DBP (mmHg)
SBP (mmHg)
Outcomes
(including adverse events)
0.89
0.51
0.27
0.03
1.59
0.30
0.19
0.11
0.16
0.08
1.30
Treatment
mean
-7.0(4.6)
-1.5(3.6)
-4.3(4.0)
-6.0(4.2)
-22.5(30.2)
-21.2(23.5)
-1.5(7.8)
-1.3(11.0)
-4.8 (28.4)
0.46
0.24
0.11
0.03
0.51
0.00
0.00
0.08
0.11
0.14
0.62
Control
mean
-2.9(3.3)
-0.2(4.8)
-1.4(4.8)
-2.9(3.7)
-6.8(24.7)
-7.1(19.1)
-0.5(10.6)
0.9(6.6)
-1.5(12.3)
ns
0.04
ns
ns
0.0009
0.0223
0.0426
ns
ns
ns
0.0208
p- value
0.001
ns
0.003
0.003
0.013
0.009
ns
ns
ns
Effect Size & Precision
(Mean change from baseline)
Treatment
Control
∈T-C
(s.d.)
(s.d.)
P=
Withdrawals N=5
Diarrhoea =3 (1 with nausea)
Gastric reflux=1
Other=1
Eligibility - 115/120 screened patients were
eligible
Randomisation - 15/115 were not
randomised. 6= BMI out of range,
4=BSI>90%, 1= taking anti-obesity
medication, 1= non-compliant, 3= medical
conditions
Missing data - handled via multiple
imputation rather than LOCF
Between group differences
The protein, carbohydrate, fat proportions
between groups differed
Exposed = 33%: 52%: 15%
Control = 23%: 56%: 21%
Baseline comparison= ns
Primary analysis ITT.
Completers only analysis also undertaken,
completers = 37/50 (74%) in each group.
Validity/Applicability
Safety
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
DBP=diastolic blood pressure, SBP=systolic blood pressure, ITT=intention to treat analysis, MOSES= monitoring of side effects scale (MOSES; Kalachnick, 1985) higher values are indicative of greater symptom severity.
Duration
12 weeks
Study location(s)
USA
Objective
To assess the efficacy
and safety of a low
calorie soy-based
meals replacement
program for the
treatment of obesity.
Study Design
Objective
Study Location(s)
Duration
Study
authors
and year
Evidence Table 2.
Conclusion
Soy protein meal
replacement LCD
reduces body weight;
total and LDL
cholesterol significantly
more than a LCD
without a meal
replacement product.
The study was not
powered to pick up rare
adverse events.
25% of the participants
did not complete.
Food records were not
kept and compliance
was not checked in the
control group.
Data collection on side
effects was collected
according to a
standardised protocol.
Conclusions
Comments
77
Study Design
Randomised, double
blind, placebo
controlled multicentre
study
Torgerson et al.,
2004
Exclusion
Diabetes
Ongoing/ active
cardiovascular disease
Ongoing/active GI disease
Inclusion
Age 30-60 years
BMI >=30kg/m2
Non-diabetic glucose
tolerance or IGT (fasting
venous plasma glucose
<7.8mmo;/l and 2 hr plasma
glucose 7.8-11.1mmol/l)
Exposure
Orlistat 120mg t.i.d. +
reduced calorie diet
(800kcal/day deficit).
Participants
N=3305 (placebo=1637,
orlistat =1640)
Male=45%
Female=55%
Mean age 43.7 years
(placebo), 43.0 years (orlistat).
Normal glucose tolerance
=79%
IGT = 21%
Comparison
Placebo + reduced
calorie diet
(800kcal/day deficit).
Exposure/
Comparison
Participants
Inclusion
Exclusion
Orlistat, Torgerson et al., 2004
Weight change at 1 yr (kg)
Weight change at 4 yr (kg)
Completers only 1 yr (kg)
Completers only 4 yr (kg)
>=5% weight loss 1 yr (%)
>=5% weight loss 4 yr (%)
>=10% weight loss 1 yr (%)
>=10% weight loss 4 yr (%0
Cardiovascular risk factors (yr 1)
DBP (mmHg)
SBP (mmHg)
Total cholesterol (%)
LDL cholesterol (%)
HDL cholesterol (%)
LDL-HDL ratio
Triglycerides (%)
Waist circumference (cm)
Fasting whole blood* glucose (mmol/l)
Fasting serum insulin (mmol/l)
Fibrinogen (µ mol/l)
Plasminogen activator inhibitor-1 (U/ml)
Cardiovascular risk factors (yr 4)
DBP (mmHg)
SBP (mmHg)
Total cholesterol (%)
LDL cholesterol (%)
HDL cholesterol (%)
LDL-HDL ratio
Triglycerides (%)
Waist circumference (cm)
Fasting whole blood* glucose (mmol/l)
Fasting serum insulin (pmol/l)
Fibrinogen (µ mol/l)
Plasminogen activator inhibitor-1 (U/ml)
Outcome
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
<0.01
<0.01
<0.01
<0.01
<0.01
<0.01
<0.051
<0.01
<0.012
<0.01
ns
<0.01
<0.01
<0.01
<0.01
<0.01
<0.013
<0.01
ns
<0.01
<0.014
<0.01
<0.014
<0.01
-3.6
-7.3
-8.8
-11.4
3.4
-0.5
-6.2
-9.6
0.1
-26.5
0.2
-7.1
-2.6
-4.9
-7.9
-12.8
6.5
-0.6
2.4
-6.4
0.1
-32.0
-0.4
-3.0
-2.6
-5.2
-1.3
-1.6
8.5
-0.3
-6.3
-7.0
0.2
-17.0
0.1
-3.0
-1.9
-3.4
-2.3
-5.1
9.1
-0.4
2.9
-4.4
0.2
-20.6
-0.5
0.1
p=**
10.6
5.8
11.4
6.9
72.8
52.8
41.0
26.2
O
6.2
3.0
7.5
4.1
45.1
37.3
20.8
15.6
P
Effect Size & Precision
(Mean change from baseline)
Safety
Orlistat was well tolerated
and the overall incidence of
adverse events was the
same in both groups except
for GI events. Most GI events
were mild to moderate and
occurred during the early
phase of treatment.
Over the four-year period
both groups had at least one
serious adverse event (13%
placebo, 15% orlistat).
Overall 4% of placebo and
8% of orlistat patients
withdrew because of adverse
events primarily GI events.
There were significant
decreases in fat-soluble
vitamins (A, D, E and K1)
after 4 years in the orlistat
group.
Adherence
Placebo=92.8
Orlistat= 93.3%
Completers and noncompleters were not
significantly different.
Withdrawals
Refusal of treatment,
placebo=20%
orlistat=14%. Withdrawals
due to insufficient therapeutic
response, placebo=19%,
orlistat=8%.
Compliance was determined
by counting the number of
capsules returned.
Validity/Applicability
Safety
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
*venous blood, LOCF = last observation carried forward, BLCF =baseline observation carried forward, ITT=intention to treat.
** Between treatment p values for analyses, for cardiovascular risk factors analyses by LOCF ITT, BLCF ITT and observed data except where indicated. 1 =LOCF and observed,2 BLCF p<0.053 LOCF and BLCF =NS, 4 BCLF =NS.
Duration
Four years
Study location(s)
Sweden
Objective
To determine the effect
of adding orlistat to
lifestyle changes on
body weight and the
incidence of type 2
diabetes.
Study Design
Objective
Study Location(s)
Duration
Study
authors
and year
Evidence Table 3.
78
Only 52% of the treatment group
and 34% of the placebo group
were retained to the 4th year.
The difference in weight loss was
the same whether assessed by
LOCF or BLCF analysis.
During 4 years of treatment
orlistat + lifestyle changes
significantly decreased the
progression to type 2 diabetes
compared with placebo + lifestyle
change (log-rank p=0.0032).
There was a 37.3% decrease in
the risk of developing diabetes
with orlistat compared to placebo.
The long-term safety or orlistat
was demonstrated.
The beneficial effect of orlistat in
preventing diabetes was primarily
due to a beneficial effect in IGT
patients.
Compared with lifestyle changes
alone orlistat + lifestyle changes
resulted in a greater reduction in
weight and a greater reduction in
the incidence of type 2 diabetes
over 4 years.
Conclusions
Comments
Study design
Randomised,
placebo controlled,
double blind trial.
Rissanen et al.,
2001
Duration
12 months
Location
Finland
Objective
To study the effect of
weight loss on blood
coagulability and
fibrinolysis in health
obese women.
Study Design
Objective
Study Location(s)
Duration
Study
authors
and year
Evidence Table 4.
Inclusion
See Sjostrom
Placebo vs. orlistat weight loss at 12
months (7.2kg vs. 13.0kg) was not
significant and the results of orlistat and
placebo were pooled.
-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)
Weight (kg)
BMI (kg/m2)
Body fat (kg)
Lean body mass (kg)
DBP (mmHg)
SBP (mmHg)
S- total cholesterol (mmol/l)
S-LDL-cholesterol (mmol/l)
S-HDL-cholesterol (mmol/l)
S-Triglycerides (mmol/l)
S-insulin (mU/l)
Exposure
Orlistat 120mg t.i.d.
+ hypoenergetic diet
Comparison
Placebo +
hypoenergetic diet
Hypocaloric diet
Designed to cause a
weight loss of 0., 250.5kg/wk with 30%
fat, 50%
carbohydrate, and
20% protein.
A maximum of
300mg/day
cholesterol was
distributed in 3 main
meals and a low fat
snack. Alcohol
consumption limited
to 150g per week.
Further reduction of
300kcal/d after 6
months.
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
ns
ns
ns
ns
<0.001
Effect Size & Precision
(pooled Mean change
from baseline at 1 year)
Change
P
(±sem)
Outcomes
(including adverse events)
Exposure/
Comparison
Weight loss was
not the primary
outcome, drug
and placebo
results pooled.
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Participants
55 healthy obese women
(51 completers)
Mean age =44 ±0.7
years
Mean BMI= 36±0.5kg/m2
Smokers =37
Non-smokers=14
Participants
Inclusion
Exclusion
Orlistat, Rissanen et al., 2001
There were beneficial changes in
fibrinolysis and coagulation persisted
for one year if weight loss was
maintained.
Conclusions
Comments
79
Study Design
Randomised, placebo
controlled, double blind,
multicenter trial.
Muls et al., 2001
Exclusion
Serious disease, diabetes
or uncontrolled
hypertension
Women of childbearing
potential without
adequate contraception
Previous bariatric surgery
Use of appetite
suppressants or lipid –
lowering agents
Evidence of alcohol or
substance abuse.
Inclusion
BMI 27-40kg/m2
Age 18-70 years
Fasting LDL-C 4.1 to
6.7mmol/l and
TG<4.5mmol/l
(<400mg/dl)
Exposure
Orlistat 120mg t.i.d.
+ diet (-600kcal/day) with <=30%
calories from fat
Participants
N=441 recruited
N=294 randomised
N=255 completers
Male 19%, Female 81%
Mean age 48(P) and
50(O) years
Comparison
Placebo. + diet (-600kcal/day) with
<=30% calories from fat.
Exposure/
Comparison
Participants
Inclusion
Exclusion
Liquid stools (%)
Increased defecation (%)
Loose stools (%)
Decreased defecation (%)
Bronchitis (%)
Adverse events
GI events
Overall AEs
Data analysis
Analysis was based primarily on
the ITT population for whom
follow-up was available. Last
observation carried forward
data was included.
Weight loss (kg)
Total cholesterol (mmol/l)
LDL cholesterol (mmo;/l)
HDL cholesterol (mmo;/l)
Triglycerides (mmol/l)
LDL-C/HDL-C ratio
Lp(a) (mg/l)
Outcome
(including adverse events)
8
5
3
12
6
38
67
-1.88±4.46
0.14±0.85
-0.09±0.80
0.17±0.24
0.14±9.55
-0.46±0.70
-6.50±26
P
23
22
16
3
11
0.016
<0.001
<0.001
<0.001
<0.001
0.896
0.294
0.225
64
80
p=**
O
-4.66±3.77
0.42±0.75
-0.53±0.65
0.07±0.22
0.08±0.72
-0.54±0.67
3.00±25
Effect Size & Precision
(Mean change from baseline at
24 weeks± s.d., LOCF)
Note:
Limited reporting of weight
loss parameters (BMI, %%
10% not reported).
A 2.6% difference between
placebo and treatment group
was judged to be clinically
relevant. A sample size
calculation determined that a
sample size of 100 in each
arm would be required for
there to be an 80%
probability of showing a
2.6% difference (effect size
of 0.4) at the 5% significance
level. It was estimated that
30% of patients would not be
fully evaluable and that there
would be a 20% withdrawal
rate in the placebo lead-in
period. The total number
required to be randomised
was estimated to be 284.
Patients were stratified by
study centre and weight loss
category during run-in
(<=2.00 vs. >2.0kg).
Validity/Applicability
Safety
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
LDL-C = low density lipoprotein cholesterol, P=placebo, O=orlistat, **=difference from placebo. LOCF=last observation carried forward.
Duration
24 weeks followed by an
optional 24-week open
label orlistat extension
phase.
Study location(s)
Belgium
Objective
To assess the effect of
orlistat 120mg t.i.d.
versus placebo on
weight loss and serum
lipids in obese
hypercholesterolemic
patients.
Study Design
Objective
Study Location(s)
Duration
Orlistat, Muls et al., 2001
Study
authors
and year
Evidence Table 5.
80
Run-in weight loss and weight
loss during the first 4 weeks
were predictors of longer-term
weight loss at 24 weeks.
Conclusion
Orlistat as an adjunct to
dietary intervention promotes
clinically significant weight loss
and LDL-C beyond the effect
of weight loss in overweight or
obese patients with
concomitant
hypercholesterolemia.
Conclusions
Comments
Study design
Rapid systematic review
of RCTs.
Foxcroft et al.,
2000
Studies included
Sjostrom et al., 1998
Davidson et al., 1999
Hollander et al., 1998
Objective
To clarify the potential
benefits, disbenefits and
costs of orlistat in the
treatment of obesity.
Study Design
Objective
Study Reference
Study
authors
and year
Evidence Table 6.
Exposure
Orlistat
Participants
Exposure/
Comparison
Outcomes for weight loss reported in
other systematic reviews.
Quality of life
Estimated QALYs gained in a year
of orlistat treatment (based on 100
persons starting treatment with
responders those who lost and
maintained >10% of their initial body
weight over 2 years).
Cost data
Price of a patient consultation (NHS
1998)
Monthly cost of orlistat 120 tds.
Average number of consultations per
year.
GP consultation cost per visit.
Drop-out year 1
Drop-out year 2
Average cost per year for 100
patients treated for 2 years.
The cost /QALY of orlistat treatment
(extreme value sensitivity analysis)
The cost/QALY in primary care
setting (extreme value sensitivity
analysis)
Outcomes
(including adverse events)
£26,635 (9,779 –66,505)
£45,000 (13,541-131,918) per
QALY gained
£16.00
27%
23%
£ 73,436
£45.00
4
£118.00
1.60QALY per year of orlistat
treatment
10kg weight reduction over 2
years as an adjunct to diet
(NNT=12 95% CI 7-37)
Effect Size & Precision
EMEA prescription indications for
orlistat do not coincide with the
published trial information.
Only the “most plausible” results
were used for further analysis.
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Phase II clinical trials
Not stated but only 3/109 studies or
papers were included.
Inclusion
Systematic reviews or RCTs of orlistat
in the treatment of obesity
Efficacy or cost effectiveness
Human subjects only.
Only phase III clinical trials included.
Participants
Inclusion
Exclusion
Orlistat, Foxcroft et al., 2000
There was no evidence that the shortterm weight loss would have a longerterm impact on morbidity and
mortality.
The estimated cost utility of orlistat
was £46,000 per QALY gained.
On average orlistat results in obese
people losing an additional 3-4% of
their initial body weight over diet
alone over a 2-year period.
Conclusions
Comments
81
Study design
Randomised, double
blind placebo-controlled
Derosa et al.,
2003
Exclusion
Smokers
Abnormal thyroid
function
Patients taking
diuretics or beta
blockers
Inclusion
BMI> 30kg/m2
Age>40 years
Total cholesterol
>=240mg/dl
SBP>140mg Hg
DBP<90mm Hg
Participants
N=99
Obese patients with
hypercholesterolemia
M=48
F=51
Mean age =51 years
(SD=9)
Participants
Inclusion
Exclusion
Diet: 1500kcal, 54%
carbohydrate, 24%
protein, 22% fats, 108mg
cholesterol, 35g fiber
during placebo lead-in
period. Food diaries were
kept. Diet instruction every
3 months.
All participants undertook
>=30mins aerobic activity
4 days a week
Orlistat 120mg t.i.d. +
Fluvastatin 80mg/d +
controlled energy diet
Fluvastatin 80mg/d +
controlled energy diet
Placebo + controlled
energy diet
Exposure/Comparison
Orlistat 120mg t.i.d.+
controlled energy diet
Participants
Exposure/
Comparison
Safety
Orlistat and fluvastatin were
well tolerated. 3% of patients
experienced side effects.
There were no serious
adverse events.
At 6 months
BMI (kg/m2)
WCR (cm)
BWL (kg)
At 1 year
BMI (kg/m2)
WCR (cm)
BWL (kg)
At 6 months
SBP (mm Hg)
DBP (mm Hg)
TC
LDL-C
HDL-C
TGs
At 1 year
SBP (mm Hg)
DBP (mm Hg)
TC
LDL-C
HDL-C
TGs
Outcomes
(including adverse events)
p<0.01
p<0.01
p<0.05
p<0.05
p<0.05
p<0.02
P<0.05
P<0.05
P<0.02
P<0.02
P<0.02
P<0.05
P<0.05
P<0.05
P<0.05
P<0.05
NS
P<0.02
NS
NS
P<0.05
P<0.05
NS
NS
NS
NS
p<0.02
p<0.02
p<0.02
p<0.05
NS
NS
NS
NS
NS
NS
NS
NS
P<0.05
P<0.05
NS
NS
P<0.02
P<0.0
P<0.02
NS
NS
NS
NS
NS
NS
p<0.05
p<0.05
p<0.05
p<0.01
p<0.01
p<0.01
NS
NS
NS
OF
N=24
P<0.05
P<0.05
P<0.05
NS
NS
NS
NS
P<0.05
P<0.05
NS
NS
NS
P
N=23
Effect Size & Precision
(% change from baseline)
O
F
N=25
N=24
Vitamin D levels were not measured.
96 (97%) completers, 3 subjects
dropped out due to adverse reactions
(orlistat),
Both groups comparable at baseline
Randomisation envelopes used
Compliance assessed through tablet
counting
Validity/Applicability
Lipid profiles were
significantly better at 6
months for all
parameters in the
combined treatment
group. All groups
showed significant
improvements at 1 year
for total cholesterol and
low-density lipoprotein
cholesterol. Again the
combined treatment
group had the greatest
improvements for each
parameter at 6 months
and 1 year.
No significant changes
in BP in any group at 6
months, but there was a
significant improvement
in the treatment groups
singly and combined at
1 year. The greatest
reductions in BP were in
the combined treatment
groups.
Significant decreases in
weight, BMI and waist
circumference was
found only in the
orlistat+fluvastin group
at 6 months and in all
groups apart from BMI
in the placebo group at
1 year. The combined
treatment groups
showed the greatest
reductions.
Conclusions
Comments
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
BMI = body mass index, WCR = waist circumference reduction, BWL= body weight loss, P= placebo group, O=orlistat 120mg t.i.d. group, F=fluvastatin 80mg/d group, OF= orlistat 120 t.i.d.+fluvastatin 80mg/d group. TC=total cholesterol, LDL-C=low density lipoprotein
cholesterol, HDL-C+high-density lipoprotein cholesterol, TGs = triglycerides. Bold = raised values, normal=decreased values.
Duration
One year
Objective
To assess obese
patients with
hypercholesterolemia
who were prescribed a
standardised diet,
comparing the action of
orlistat, fluvastatin,
orlistat with fluvastatin
and placebo on
anthropometric
measurements, blood
pressure and lipid
profile.
Study Design
Objective
Study Duration
Orlistat, Derosa et al., 2003
Study
authors
and year
Evidence Table 7.
82
Reasons for discontinuation
Pre randomisation drop-out =109
Violation of selection criteria=59
Other protocol violation=16
Refused treatment =10
Failure to return=10
Did not co-operate=8
Adverse event=3
Other=3
Weight loss after 1 yr of treatment
Body weight (kg)
Body weight (%)
Weight loss >=5%
Diabetic metabolic parameters after 48 weeks of
treatment**
HbA1c
Fasting glucose (mmol/l)
Post prandial glucose(mmol/l)
Triglycerides(mmol/l)
Diabetic metabolic parameters after 1yr*
HbA1c
Fasting glucose (mmol/l)
Post prandial glucose (mmol/l)
Lipid profile at 48 weeks
Total cholesterol
LDL-cholesterol (mmol/L)
HDL-cholesterol (mmol/L)
Lipid profile at 1yr
Total cholesterol
LDL-cholesterol (mmol/L)
HDL-cholesterol (mmol/L)
Other CHD risk actors
Triglycerides(mmol/l)
SBP mmHg
DBP mmHg
Anthropomorphic indices
Waist circumference (cm)
Outcomes
(including adverse events)
-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
-4.80
-5.5±5.3
-0.4±1.5%
-0.7±3.2
-0.5±4.6
0.0±1.4
+0.01±1.2
+0.07±0.2
+1.8±22.0%
+5.1±34.3%
+6.4±24.5%
NR
-4.96
-4.78
-3.0±5.6
<0.01
ns
ns
ns
<0.01
<0.05
<0.01
0.07
0.12
0.02
0.0003
0.004
0.003
0.47
0.08
0.45
0.12
0.006
0.006
0.0001
p=†
Post randomisation drop-out =119
Adverse events =28 (orlistat =16,
placebo=12)
Withdrawal of consent=35 (orlistat =13,
placebo=22)
Lost to FU =24 (orlistat=13, placebo-11)
Protocol violation=14 (orlistat=9, placebo
-0.9±1.1
-1.7±2.1
-1.4±3.5
-0.1±1.4
5.3±5.1
5.4±5.0
51.3%
O
-0.6±1.6
-0.9±2.8
-0.7±4.5
-0.2±3.8
3.4±5.3
3.6±5.7
31.6%
P
Effect Size & Precision
(Mean change from baseline)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
† = Change vs placebo, ITT = intention to treat analysis, LOCF= last observation carried forward, GCP=good clinical practice.
Treatment
Duration
48 weeks
Objective
To assess the longterm effect of
orlistat on body
weight, glycaemic
control and
cardiovascular risk
factors in
overweight patients
with type 2
diabetes.
Exclusion
Diabetic patients treated with
antidiabetic drugs other than
sulphonylureas
Patients treated with medications
known to affect body weight, serum
lipids or vitamins.
Patients with proliferative
retinopathy, papilloedema,
uncontrolled hypertension
(DBP>120mmHg), hypo or
hyperthyroidism, secondary type 1
diabetes, cardiac insufficiency, or
presence or history of cancer or any
significant appetite, renal, hepatic,
GI, psychiatric, immunological or
metabolic disorders. Female
patients were excluded if they were
pregnant, lactating or for
childbearing potential and not taking
adequate contraceptive measures.
Comparison
Placebo t.i.d. + a 600
calorie reduced diet
(30% fat, 50%
carbohydrate, 20%
protein, max 300mg/d
cholesterol)
Inclusion
Age 18-70 years
BMI>=28kg/M2
HbA1c =6.5-11%
Diagnosis of type 2 diabetes treated
with sulphonylureas for at least 2
months before screening or were
diagnosed with diabetes but not yet
treated with antidiabetic medication.
Run in period
4 week placebo +
diet run in period.
Exposure
Orlistat 120mg t.i.d.+ a
600 calorie reduced diet
(30% fat, 50%
carbohydrate, 20%
protein, max 300mg/d
cholesterol)
Participants
N= 492 enrolled
N=383 randomised
N=369 ITT population
Male 181, Female= 188
Average Age 56-57
Average BMI= 34kg/m2
Study Design
Randomised,
placebo controlled,
double blind clinical
trial.
Hanefield et
al., 2002
Location
Germany
(Primary
care and
outpatient
clinics)
Exposure/
Comparison
Participants
Inclusion
Exclusion
Study Design
Objective
Duration
Orlistat, Hanefield et al., 2002
Study/Year
Location
Evidence Table 8.
Analysis
Efficacy assessed on an
ITT basis, ITT analysis:
orlistat=189,
placebo=180
LOCF model was used
for missing data
=5)
External validity
Notes
1.Study conducted
according to GCP
guidelines
2.Compliance assessed
by capsule count
3.Trained monitor
checked protocol
adherence
4.Study audit performed
throughout the study
5.Study sponsored by
Hoffmann-La-Roche
Validity/Applicability
Results were reported
from the start of
randomisation (48
weeks) in the main
table but from the start
of study (1 year) in the
summary and
conclusion. A number
of significant
differences at 1 year
were ns from the point
of randomisation
The run-in period was
included in the
reported conclusions,
ideally the results
during the
randomisation period
should have been
reported
Comments
Effect was calculated
from start of study –
i.e., including run in
period and from
randomisation.
Study conclusions
Orlistat + diet resulted
in significant weight
loss, improved
glycaemic control and
cardiovascular risk
factor profile in
overweight patients
with type 2 diabetes.
Conclusions
Comments
83
Exclusion
History of recent MI, uncontrolled
hypertension, significant cardiac,
renal, hepatic, GI, respiratory,
neurological, psychiatric or endocrine
disease, GI bariatric surgery, post
surgical adhesion, history of
carcinoma, bulimia, laxative abuse,
clinical symptoms of fat-soluble
vitamin deficiencies, substance abuse,
appetitive suppressants, insulin,
retinoids, systemic steroids other than
HRT, acarbose (wash-out =2 months),
pregnant lactating and child-bearing
potential women not taking
contraceptive measures.
Inclusion
Age 18-70 years
BMI>27kg/m2
Dx of NIDDM (WHO)
HbA1c 6.0-11.0%
Negative pregnancy test
adequate contraception in women of
child bearing potential
Exposure
Orlistat 120mg
t.i.d. +
hypocaloric diet +
behavioural
counselling
Participants
N=365 enrolled
N=343 randomised
N=280 completed the study
Orlistat N= 164
Placebo N=174
Male=104
Age=51 years
BMI=35
Caucasian = 60%
Weight loss
ITT pop % WL
Orlistat LMS diff P-O (kg)
Completers pop %WL
Completers pop WL (kg)
>=5% WL
>=10% WL
Diabetic metabolic parameters (DMP), 24
weeks
Mean decrease in glucose levels
Fasting plasma glucose LSM diff P-O
ITT pop decrease HbA1c %
Completers pop decrease HbA1c %
Blood pressure at 24 wks
SBP
DBP
Lipid profile at 24 weeks
Total cholesterol (mmol/l)
LDL-Cholesterol (mmol/l)
HDL-cholesterol (mmol/l)
Fasting TGs (mmol/l)
Post prandial TGs (mmol/l)
Anthropomorphic indices
High mean waist circumference cm
Adverse events
Overall adverse events(%)
Serious adverse events
Patients withdrawn from study because of GI
adverse events
Most common GI events
Overall
Fatty/oily stool
Increased defecation
Liquid stools
Oily evacuation
Flatulance with discharge
Abdominal pain
Outcomes
(including adverse events)
ns
ns
0.0001
0.0002
0.038
0.217
0.379
values NR
values 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)
110(65%)
77(45.6%)
68(40.2%)
17(10.1%)
17(10.1%)
13(7.7%)
13(7.7%)
-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(10.4%)
19(11.0%)
8(4.6%)
0(0.0%)
3(1.7%)
6(3.5%)
0.032
NR
0.036
0.06
0.04
NR
0.0003
NR
0.0003
0.003
0.072
P=
1.0±0.34
0.85
0.61∀0.15
-0.64∀0.16
0.01±0.30
0.22∀0.14
0.13∀0.14%
values NR
values NR
4.7 ±0.5%
1.6kg
-4.9 ±0.7%
4.24±0.23
30%
7%
O
Effect Size & Precision
3.0± 1.3%
NR
-3.1±1.0%
2.58±1.4kg
17%
3%
P
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Comparison
Placebo t.i.d. +
hypocaloric diet +
behavioural
counselling
Exposure/
Comparison
Participants
Inclusion
Exclusion
ITT= intention to treat, LMS=least mean squares, WL=weight loss.
Duration
24 weeks
Objective
To determine if noninsulin dependent
diabetic patients lose
more weight when
treated for 24 weeks
with orlistat in
conjunction with a
hypocaloric diet +
behavioural
counselling than
placebo t.i.d +
hypocaloric diet +
behavioural
counselling.
Study Design
Randomised, double
blind, placebo
controlled multi-centre,
clinical trial
Run in period
2-week open, placebo
period prior to
randomisation
Halpern et al.,
2003
Location
Latin America:
Brazil, Columbia,
Costa Rica
Mexico
Study Design
Objective
Duration
Orlistat, Halpern et al., 2003
Study/Year
Location
Evidence Table 9.
84
High drop-out rate
Drop-out causes not
specified
External validity
Highly selected patients
many co-morbidities
excluded.
Validity/Applicability
Comments
Weight loss began
to slow at between
16-20 weeks
Study
conclusions
Orlistat is a safe
adjunct to dietary
intervention and
conventional
antidiabetic
pharmacotherapy
in the global
treatment of obese
diabetic patients. It
promotes a
clinically
significant weight
loss and improved
glycaemic control
and lipid profile.
Conclusions
Comments
Study type
Systematic review
Leung et al.,
2003
Included studies
Orlistat
Davidson, 1999
Finer, 2000
Hauptman, 2000
Hill, 1999
Hollander, 1998
Rossner, 2000
Sjostrom, 1998
Objective
To describe the
pharmacological
management of obesity
concentrating on orlistat
Study Design
Objective
Study Reference
Study
authors
and year
Weight reduction with orlistat associated with a significant
improvement in control of cardiovascular risk factors.
Exposure
Orlistat 30-120mg
t.i.d.
Comparison
Placebo
Patients with type 2 diabetes
Weight loss Orlistat + hypocaloric diet vs. placebo
Improved glycaemic control orlistat vs. placebo
Patients with IGT
Normalisation of glucose levels, orlistat vs. placebo.
Reduction on rate of progression to diabetes, orlistat vs. placebo
Adverse events
Mild – moderate GI effects, orlistat vs. placebo
Low plasma levels of fat-soluble vitamins and beta carotene in the
orlistat group
Interactions reported with cyclosporine and warfarin
Patient with hypercholesterolemia
Total cholesterol orlistat vs. placebo
LDL cholesterol, orlistat vs. placebo
Plasma insulin at the end of 2 years, orlistat vs. placebo (one study)
Systolic blood pressure after one year, orlistat vs. placebo
Diastolic blood pressure after one year, orlistat vs. placebo.
Outcomes
(including adverse events)
Exposure/
Comparison
p<0.05
8-27% (yr 1)
6-22%(yr2)
71.6% vs. 49.1%p=0,04
3.0% vs. 7.6%p=0.04
6.2 vs. 4.3kg p<0.001
p<0.001
11.9% vs. 4.0%, p<0.001
17.6% vs. 7.6%, p<0.001
66.5 vs. 86.3pmol/L, p<0.04127mm
Hg vs. 129mmHg -=0.001980mm
Hg vs. 82mmHg, p=0.002
P<0.05
Effect Size & Precision
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Inclusion
Studies between 1966February 2002
RCTs of > 6 months
duration reporting the
efficacy of
orlistat
Participants
Inclusion
Exclusion
Evidence Table 10. Orlistat, Leung et al., 2003
Orlistat and
sibutramine
demonstrated a
favourable efficacy
and safety profile in
RCTs.
Withdrawal rate not
reported
Current evidence
supports their use as
adjuncts to lifestyle
modifications in the
treatment of obesity
Conclusions
Comments
Validity/Applicability
85
Study design
Meta-analysis of three
randomised, double-blindplacebo-controlled,
multicentre clinical trials.
Heymsfield et al.,
2000
Exposure
Orlistat, 120mg t.i.d.
Comparison
Placebo. t.i.d.
Concomitant
mildly low energy diet for 1
year
Inclusion
Meta-analysis
Randomised, double blind,
placebo controlled trial
At least 1 follow-up assessment of
glucose tolerance
Follow-up of at least 2 full years
Individual trials
Age >18 years
BMI 30-34
Absence of weight loss >4kg in
last 3 months
Exclusion
Meta analysis
Individual trials
Subjects who had stopped
smoking in the last 6 months
Subjects with significant cardiac,
renal, hepatic, GI, psychiatric or
endocrine disorders,
Subjects with drug-treated type 2
diabetes, history or presence of
substance abuse, excessive intake
of alcohol or concomitantly used
medications that alter appetite or
lipid levels.
Participants
N=675
Obese (BMI 30-43)
39 centers in Europe and USA
between 1992-1995.
Exposure/
Comparison
Concomitant treatment
Participants
Participants
Inclusion
Exclusion
Fasting glucose levels impaired
orlistat vs. placebo
Fasting glucose levels normal
orlistat vs. placebo
Improvement in insulin area under
curve for subjects with normal glucose
tolerance at baseline
Orlistat vs. placebo
Change from IGT to NGT
(IGT at baseline improved to NGT at
end of treatment)
orlistat
placebo
p-value
Glucose tolerance
(% of patients progressing to diabetic
status )
Orlistat
Placebo
p-value
Weight loss change from initial weight
Orlistat
Placebo
Outcomes
(including adverse events)
p=0.01
p=0.02
p=0.03
71.6%
49.1%
0.04
3.0%
7.6%
0.04
6.27 ∀0.41kg
3.79 ∀4.1kg
p<0.001
Effect Size &
Precision
Similar at baseline
ITT analysis
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
EGO =Exposure Group Occurrence, CGO = Control Group Occurrence, RR = Relative Risk, RD = Risk Difference, NNT = number needed to treat, N/S = Not Stated, ITT= intention to treat
Included publications
Sjostrom ,1998
Hauptman , 2000
Objective
To test the hypothesis
that orlistat combined with
dietary intervention
improves glucose
tolerance status and
prevents worsening
diabetes status more
effectively than placebo.
Study Design
Objective
Study References
Study
authors
and year
Evidence Table 11. Orlistat, Heymsfield et al., 2000
86
100%
% of studies
Modest pharmacologically
facilitated weight loss
produces important
metabolic benefits.
Data from the reported
studies suggest that
improvements in glucose
tolerance depend upon
relatively small changes in
body weight and that
modest weight loss may
reduce the risk of
developing diabetes in
obese subjects.
Conclusions
Comments
Study type
O’Meara et al.,
2001
Studies included
(N=11)
Davidson et al., 1999
Drent & van der Veen,
1993
Drent et al., 1995
Finer et al., 2000
Hauptman et al., 2000
Hill et al., 1999
Hollander et al., 1998
Micic et al., 1999
Rossner et al., 2000
Sjostrom et al., 1998
Van Gaal et al., 1998
Objective
To systematically assess
the evidence for the
clinical effectiveness and
cost-effectiveness of
orlistat in the
management of obesity
Study Design
Objective
Study Reference
Study
authors
and year
Orlistat
Inclusion
RCTs
Primary outcomes
Weight change
12 weeks, 2 trials (50-60mg t.i.d)
24 weeks, 2 trials
1- and 2- year endpoints (120mg t.i.d) All
trials (n=4)
From start of run-in period (n=2)
From double blind phase (n=2)
At 1 year (n=2, 120mg t.i.d.)
At 2 years (n=2, 120mg t.i.d.)
Change in % of body weight at 2 years (n=2,
120mg t.i.d.)
% weight loss relative to initial weight at 24
weeks
30mg orlistat t.i.d.
60mg orlistat t.i.d.
120mg orlistat t.i.d.
240mg orlistat t.i.d.
Placebo
% of patients losing >10% of body weight at
24 weeks (n=2),
30mg orlistat t.i.d.
60mg orlistat t.i.d.
120mg orlistat t.i.d.
240mg orlistat t.i.d.
Placebo
Reduction in waist circumference at 24
weeks (n=2)
30mg orlistat t.i.d.
60mg orlistat t.i.d.
120mg orlistat t.i.d.
240mg orlistat t.i.d.
Placebo
RR of failure to achieve at least 5% loss of
initial weight at 1 year (orlistat, 120mg t.i.d,
n=4)
RR of failure to achieve at least 10% loss of
initial weight at 1 year (orlistat, 120mg t.i.d,
n=5)
RR of failure to achieve at least 10% loss of
initial weight at 2 year (orlistat, 120mg t.i.d,
n=3)
Outcomes
(including adverse events)
RR=0.86(0.79-0.93), p=0.0001
RR=0.85 (0.80-0.91), p<0.00001
3.5cm
5.1cm
5.9cm
6.3cm
6.0cm
RR=0.72 (0.63-0.82), p<0.00001
28%
28%
37%
38%
19%
8.5%
8.8%
9.8%
9.3%
6.6%
-2.4kg(-3.62 to –1.47), p<0.00001
-3.35kg(-4.44 to –2.27), p<0.00001
-2.38kg (-3.45 to –1.31) ,p<0.00001
-3.19kg(-4.25 to – 2.12), p=0.00001
-3.23kg (-4.77 to –1.69), p=0.00001
-1.24kg (-2.65 to 0.16), p=0.08
-10.75kg orlistat, -7.34 placebo
-2.9kg (-3.61 to – 2.19) p=<0.00001
Effect Size & Precision
Weighted mean difference †
Randomised method
described (n=11)
Concealed randomisation
Similar at baseline,
Patients blinded
Carers blinded
Blind outcome assessment
Intention to treat analysis
Patient adherence assessed
Withdrawals reported
Selection criteria
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Trials recruiting
people with eating
disorders such as
anorexia nervosa,
and bulimia
nervosa.
Only studies
published in
English, French,
Dutch or German
were considered
for inclusion.
Obese or
overweight
patients or patients
who have
previously been
obese or
overweight wishing
to maintain weight
loss.
Any length of
follow-up*
Any duration of
therapy*
Exposure/
Comparison
Participants
Inclusion
Exclusion
Evidence Table 12. Orlistat, O’Meara et al., 2001
100%
100%
100%
100%
100%
Unclear
9%, 91%
82%
91%
9%
% of
studies
For orlistat trials that
matched the prescribing
guidelines most reported
statistically significant
results in favour of
orlistat for weight loss in
participants with and
without diabetes.
There is a lack of
information on the
effectiveness and safety
of orlistat in older people.
Most trials were single
blind, placebo with a runin period prior to double
blind trial.
The optimum regimen
was 120mg t.i.d.
In general the
methodological quality of
the trials was moderate
to good.
Comments
Conclusions
87
Study Design
Objective
Study Reference
Participants
Inclusion
Exclusion
** manufacturer’s trials had to have duration of at least 1 year.
O’Meara et al.,
2001 (Cont)
Study
authors
and year
Economic evaluation
Incremental cost-utility of
orlistat treatment per QALY
gained for WL of 3-4% during
first year of treatment.
Adverse events
Gastrointestinal adverse
events: fatty stools, increased
defecation, oily spotting.
Lower serum levels of fatsoluble vitamins.
Outcomes
(including adverse events)
GBP 45,881
(19,452-55,391)
More frequent in
orlistat group
Effect Size & Precision
Weighted mean
NNT
difference†
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Participants
Exposure/
Comparison
Evidence Table 12. Orlistat, O’Meara et al., 2001 (continued)
88
% of
studies
Conclusions
Comments
Cochrane Systematic
Review
Padwal et al.,
2004
Adverse events
Increased in orlistat group:
fatty/oily stool and oily spotting
faecal urgency (9 trials)
Faecal incontinence increase
Fasting plasma glucose reductions (9 trials,
significantly different to placebo in 5 trials)
HbA1c reduction (4 trials, high risk patients)
SBP net decrease (9 trials)
SBP net increase (2 trials)
DBP net decrease (8 trials)
75 % Caucasian
80% female
Av age = 47 years
Av weight = 96kg
Av BMI = 33.4kg/m2
High risk populations
Six trials limited enrollment
to higher risk patients, 3
with type 2 diabetes on
stable doses of oral
hypoglycemic agents or
insulin, 3 with at least one
additional CVD risk factor
(hypertension,
dyslipidemia, type 2
diabetes IGT).
Exclusion
Obesity of endocrine
origin,
diabetes mellitus,
treatment with
medication that may
alter body weight,
uncontrolled
hypertension
Six trials required a
compliance rate of
>75% in the run-in
phase
Primary outcomes
average weight loss in kg
average weight loss as % change from baseline
% with weight loss >= 5%
% with weight loss >=10%
total population
high risk group
low risk group
Comparative BMI reduction
Comparative waist circumference reduction for
Orlistat (5 trials, not pooled, p<0.05 in 4 of 5
studies)
Secondary outcomes
(10 trials)
Total cholesterol reduction greater in orlistat
group
Low-density lipoprotein reduction greater in
orlistat group (8 trials)
HDL reduction higher in orlistat group (7 trials)
Triglyceride levels reduction greater in orlistat
group
Drug; Orlistat
Dose; 120mg t.i.d
Co-interventions
Low fat hypocaloric diet (8
studies)
Dietary counselling
Exercise counselling
Food intake diaries
Educational literature or
videos
Inclusion
BMI ≥ 30kg/m2
study length ≥ 1 yr
randomised
double-blind
placebo or active
control
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
6%(5-8%)
16-40%
0.1-1.3 mmol/L
0.2% (0.2-0.3)
1.8mmHg (0.9-2.6)
0.4mm Hg (NS)
1.6mm Hg (0.7-2.4)
0.05mmol/L (0.07gain–0.17
loss)
0.02mmol/L (0.01-0.04)
0.27mmol/L (0.22-0.31)
0.33 mmol/L (0.28-0.38)
2.7(2.3-3.1)
2.9(2.3-3.4)
21(19-24)
12(8-16)
8(5-10)
17(14-21)
0.7-3.4cm
Effect Size & Precision
Average drop-out rate
Blind outcome
assessment
Double blind
33%
(14-52)
NR
100%
0%*
ITT last observation
carried forward
Note:
Levels of fat-soluble vitamins
A, D, E and beta-carotene
were reported as lowered in
the orlistat group.
Is the degree of weight loss
achieved of clinical benefit?
It may be, particularly for highrisk groups but more definitive
data are needed. Weight
reduction of 5-10% of body
weight is associated with
improvements in blood
pressure, lipid and glucose
parameters but data on the
effect of mortality and
cardiovascular events are
lacking.
All studies showed a positive
treatment effect. However
publication bias cannot be
ruled out.
The patient population studies
represent a highly selected
group of relatively healthy
obese patients who were able
to comply with study diet and
medication requirement. Most
of the patients were female
Caucasians. Extrapolation to
patients with different
demographic profile must be
made with caution.
High attrition rates were the
major methodological
limitation.
Baseline weight was
calculated from the start of the
run in period rather than the
point of randomisation –
inflating the absolute change
in weight.
18%
55%
Conclusions
Comments
% of
studies
Similar at baseline
Randomised/allocation
concealment method
described
Validity/Applicability
* all trials hampered by a high attrition rate of 14-52%, average 33%
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Included studies
Hollander et al., 1998
Sjostrom et al., 1998
Davidson et al., 1999
Finer et al., 2000
Hauptman et al., 2000
Lindgarde et al., 2000
Rossner et al., 2000
Bakris et al., 2002
Broom et al., 2002
Kelley et al., 2002
Miles et al., 2002
11 trials
6,021 participants
Objective
To assess/compare the
effects and safety of
single or combination
anti-obesity drug therapy
in clinical trials of at
least one year
Study Design/Type
Objective
Study References
Study
authors
and year
Evidence Table 13. Orlistat, Padwal et al., 2004
89
Exclusion
Trials recruiting people with eating
disorders such as anorexia nervosa,
and bulimia nervosa.
Only studies published in English,
French, Dutch or German were
considered for inclusion.
Obese or overweight patients or
patients who have previously been
obese or overweight wishing to maintain
weight loss.
Sibutramine 530mg/d
Participants
Exposure/
Comparison
Estimated cost per QALY
Best-worse case scenario
Cost per QALY gained through
CHD reduction
Cost per QALY gained through
diabetes incidence
QoL coefficient for sibutramine
Manufacturer’s cost utility
analysis (BMI<30kg/m2, free of
complications and co-morbidities,
no weight loss sustained at 56
years, costs discounted at 6%,
benefits at 1.5%))
Headaches, sleep difficulty,
irritability
Adverse events
Pulse rate, blood pressure and
heart rate
Fat content
Fat-free mass loss at eight weeks
(2 trials, sibutramine)
Fat change at eight weeks (2
trials, sibutramine)
RR of failure to achieve a weight
loss of at least 5% of initial body
weight at 24 weeks – 2 trials
(10mg/d). Note for 15mg/d dose
significant heterogeneity was
observed.
Primary outcomes
Weight change
8 weeks (3 trials, 10-20mg/d)
24 weeks (4 trials, 10mg/d)
1 year
Outcomes
(including adverse events)
£10,500 (£5,7000-£35,000)
£77,000
£42,000
0.00185/kg lost
Reported in one small trial.
Small but significant increase with
sibutramine, not considered to be
clinically significant.
-1.77kg (-2.58-0.96) p<0.00002
-1.83kg(-2.48 to –1.19)p<0.00001
RR=0.48 (0.39-0.60), p<0.00001
-3.4kg (4.22 to –2.58) p<0.00001
-4.0 to 9.1kg
-4.1 to –4.8kg
Effect Size & Precision
Weighted mean difference, RR
Intention to treat analysis
Patient adherence assessed
Withdrawals reported
Selection criteria
Patients blinded
Carers blinded
Blind outcome assessment
Randomised method described
(n=16)
Concealed randomisation
Similar at baseline, manufacturers
trials (n=5), other trials (N=11)
Validity/Applicability
69%
50%
94%
100%
100%
unclear
unclear
0%
100%
100%
19%
% of
studies
Between group
difference in BP, lipids
levels and glycaemic
control were
inconsistent.
Weight loss seems to
be dose related with
statistically significant
results reported for 1020mg doses of
sibutramine.
The differences were
small and may not be
clinically important.
Many of the trials
demonstrated a
statistically significant
difference in favour of
sibutramine in terms of
(a) absolute weight
loss (b) % of patients
achieving at least 5%
or 10% loss of initial
body weight.
Conclusions
Comments
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
EGO =Exposure Group Occurrence, CGO = Control Group Occurrence, RR = Relative Risk, RD = Risk Difference, NNT = number needed to treat, N/S = Not Stated NSD no significant difference, NS = not significant ‡individually significant data not pooled.
* manufacturer’s trials
had to have a duration of
at least 1 year
Studies from the
manufacturer (N=5)*
Wirth et al., 1998
Smith et al., 1994
James et al., 1999
Rissan et al., 1998
Williams ey al., 1999
Studies included
(N=11)
Apfelbaum et al., 1999
Bray et al., 1999
Cuellar et al., 2000
Fanghanel et al., 2000
Finer et al., 2000
Fujioka et al., 2000
Hanotin et al., 1998
Hansen et al., 1999
Seagle et al., 1998
Walsh et al., 1999
Weintraub et al., 1991
Any duration of therapy
Objective
To systematically assess
the evidence for the
clinical effectiveness and
cost-effectiveness of
sibutramine in the
management of obesity
Any length of follow-up
Inclusion
RCTs
Study type
NICE HDL
O’Meara et
al., 2002
Participants
Inclusion
Exclusion
Study Design/Type
Objective
Study References
Study
authors
and year
Evidence Table 14. Sibutramine, O’Meara et al., 2002
90
Exposure
Sibutramine 10mg/d +
dietary advice from obese
clinic
Comparison
Placebo + diet advice from
obese clinic
Participants
N=48 recruited
N=40 randomised
N=31 completers
Healthy obese, female
volunteers
Age =41.1±9.9 years
Age-range =19-58 years
BMI=34.3±2.9kg/m2
Exclusion
Psychiatric instability, history of
anti-obesity surgery, recent
change in exercise pattern,
smoking cessation within 6
months, hypertension, history of
CHD, cardiac arrhythmia,
endocrine disorders including
type 2 diabetes and glucose
intolerance, history of drug or
alcohol abuse, use of antidepressant agents, monoamine
oxidase inhibitors and use of
drugs that affect insulin
sensitivity (corticoids, diuretics,
insulin sensitisers, oestrogen
replacement.
Females were required to have a
negative serum pregnancy test,
to be post menopausal,
surgically sterilised or using a
medically accepted contraceptive
method.
Inclusion
BMI=30-40kg/m2
Exposure/
Comparison
Participants
Inclusion
Exclusion
Anthropomorphic indices
Waist circumference cm
Adverse events
Sibutramine = anorexia, dry mouth and
nausea.
Serious adverse events
Cardiac arrhythmia =1 (sibutramine)
Blood pressure at 24 wks
SBP mmHg
DBP mmHg
Heart rate (bpm)
Lipid profile at 24 weeks
Total cholesterol
HDL-cholesterol
LDL-cholesterol
Weight loss at 24 weeks
Weight loss (kg)
Weight loss (%)
Fat mass (%)
Diabetic metabolic parameters at 24
weeks
Glucose (mg/dl)
Trigylcerides
Insulin (:U/ml)
HOMA-IR
HOMA-≥
Kitt
Outcomes
(including adverse events)
+0.9
1.2
+0.4
+1.0
-8.0
-1.0
-5.0
+4.0
+1.0
+2.0
0.0
-8.0
+4.6
+0.8
+51
+0.19
P
-5.6
-6.1
-1.6
-4.0
-8.0
+2.0
-2.0
-5.0
-5.0
+5.0
-2.0
-40.0
-9.3
-2.2
-134
+1.06
S
Effect Size & Precision
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
HOMA-IR, HOMA-≥ and Kittare insulin sensitivity tests, BMP = beats per minutes, P=placebo, S=sibutramine. Bold figures = significant difference.
Duration
24 weeks
Objective
To assess the effect of
sibutramine assisted weight
reduction on insulin sensitivity
and metabolic parameters in
obese, normal glucose
tolerant individuals over a
period of 24 weeks.
Run in period
None reported
Study Design
Randomised,
Placebo-controlled, double
blind clinical trial
Tambascia et
al., 2003
Location
Brazil
Study Design
Objective
Duration
Study/Year
Location
Evidence Table 15. Sibutramine,Tambascia et al., 2003
External validity
100% female
very large number of
exclusion criteria
Reasons for
discontinuation
Adverse event =1
Pregnancy=1
Protocol
deviation=3(1S+2P)
Lack of efficacy=4
(1S+3P)
Study conclusions
The authors concluded that
sibutramine had demonstrated
efficacy in reducing weight in
non-diabetic females and
ameliorated insulin sensitivity
parameters and other metabolic
parameters.
Analysis
Compliance tests – pill
counting
Completers analysisanalysis per protocol
Only difference from
baseline computed for
each treatment
separately.
Proportion of participants
>=5% and 10% weight
loss not reported
Comments
Weak analysis
Less than 20 per group
No formal dietary intervention or
behaviour modification program
Sibutramine not administered as
per licence.
Conclusions
Comments
Validity/Applicabiilty
91
Cochrane
Systematic Review
Padwal et al.,
2004
McMahon et al 2000
Smith et al 2001
McMahon et al 2002
To assess/compare
the effects and safety
of single or
combination antiobesity drug therapy
in clinical trials of at
least one year
Study Design
Objective
Study Reference
Study
authors
and year
2 trials limited enrollment to
obese hypertensive patients
with well controlled BP, in the
remaining trial only *% had a
treated cardiovascular condition
75 % Caucasian
80% female
Av age 47 years
Av weight 96kg
Av BMI 33.4kg/m2
Co-interventions =
3 trials (2 USA, 1UK) 929
participants
Sibutramine 15-20mg daily
Participants
Exposure/
Comparison
Other AEs more common in sibutramine
arm
Insomnia
Nausea
Dry mouth
Constipation
Adverse Events
(Sibutramine)
Systolic blood pressure net increase
1.9mmHg (0.2-3.6)‡.Diastolic blood ‡
pressure 1-4mm Hg
Pulse rate increase 4-6 beats per min
(p=<0.05)
Secondary outcomes
Improved blood glucose levels (2 studies)
sibutramine treated patients
Triglycerides levels lower in sibutramine arm
Total cholesterol
Low-density lipoprotein
HDL higher in sibutramine studies (n=2)
Primary outcomes
average weight loss in kg
average weight loss % change from baseline
% of patients with weight loss of least 5%
% of patients with weight loss of at least 10%
Comparative BMI reduction
Waist circumference reduction
Outcomes
(including adverse events)
7-20%
0.08 and 0.9mmol/L (NS)
0.18-0.23 mmol/L
(p<0.05)
NSD
NSD
0.08-0.09mmol/L
(p=<0.05)
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
Effect Size & Precision
Weighted mean
difference †
Randomised method described
Similar at baseline
Intention to treat last observation
carried forward
Double blind
Blind outcome assessment
Compliance
Drop-outs<20%
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Note: one trial excluded
because 36% of randomised
patients were not included in
the analysis.
Duplicate populations
Exclusion
Obesity of endocrine origin,
diabetes mellitus, treatment
with medication that may
alter body weight,
uncontrolled hypertension
Randomisation restricted to
patients who could follow
dietary advice or had 75%
compliance during the run-in
phase.
Inclusion
BMI ≥ 30kg/m2
study length ≥1 yr
randomised
double blind
placebo or active control
Participants
Inclusion
Exclusion
Evidence Table 16. Sibutramine, Padwal et al., 2004
92
100
NR
NR
Yes (43%)
33
67
100
% of
studies
Heterogeneity in
primary outcomes
considered to be of
negligible clinical
relevance. Stratifying
into high and low risk
study populations
eliminated observed
heterogeneity.
Conclusions
Comments
Study type
Systematic review
Leung et al.,
2003
Included studies
Sibutramine
Apfelbaum, 1999
Cueller, 2000
Dujovne, 2001
Fanghanel, 2000
Fanghanel , 2001
Fujioka, 2000
James, 2000
McMahon, 2000
Smith, 2001
Wirth, 2001
Objective
To describe the
pharmacologic
management of
obesity
concentrating on
sibutramine
Study Design
Objective
Study Reference
Study
authors
and year
Exposure
Sibutramine 130mg t.i.d.
Comparison
Placebo
Inclusion
Studies between
1966-February
2002
RCTs of > 6
months duration
reporting the
efficacy of
Sibutramine
Meta analysis of 4 long-term trials
Waist circumference reduced (sibutramine)
Waist hip ratio reduced (sibutramine)
Weight loss greater in treatment group than
placebo group for
Type 2 diabetes mellitus
Dyslipidemia
Hypertension
Greater reductions with sibutramine vs. placebo
Fasting HbA1c and glucose levels, serum triglycerides
high density lipoprotein, cholesterol, urate, C-peptide
Insulin
Adverse events
Dry mouth, anorexia, insomnia, constipation, headache
Blood pressure, sibutramine vs. placebo
Heart rate, sibutramine vs. placebo
Dose related weight loss at 6 months
Sibutramine
1mg
5mg
10mg
30mg
Placebo
Outcomes
(including adverse events)
p<0.001
1-3mmHg (mean increase)
4-5 beats/min (mean increase)
p<0.001
p<0.05
p<0.001
p<0.05
p<0.05
p<0.001
p<0.02
2.5%
3.9%
6.1% p<0.05
9.4%
1.2%
Effect Size & Precision
No quality assessment
was reported
Overall withdrawal
rates
Sibutramine
Placebo
Discontinuation due to
hypertension
Sibutramine
Placebo
Discontinuation due to
tachycardia
Sibutramine
Placebo
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exposure/
Comparison
Participants
Inclusion
Exclusion
Evidence Table 17. Sibutramine, Leung et al., 2003
0.4%
0.1%
0.4%
0.4%
9%
7%
% of studies
Note: In March 2002 the Italian
Health Ministry suspended sales of
sibutramine for re-evaluation of its
safety profile after 2 deaths and 50
adverse events. After investigation
the EAEMP (June 2002) reported that
the risk-benefit profile of sibutramine
remained positive.
Conclusion
Orlistat and sibutramine
demonstrated a favourable efficacy
and safety profile in RCTs. Current
evidence supports their use as
adjuncts to lifestyle modifications in
the treatment of obesity
Conclusions
Comments
93
Study design
Systematic Review of all
trials of sibutramine
reporting unwanted side
effects of sibutramine
Nisoli and
Carruba, 2003
Included studies
Hansen et al., 1998
Walsh et al., 1999
James et al., 2000
Apfelbaum et al., 1999
Knoll 2000
Knoll2000
Knoll 2000
McNulty et al., 2003
Bray et al., 1999
Fanghanel et al., 2000
Cueller et al., 2000
Fujioka et al., 2000
Gokcel et al., 2001
Serrano-Rios et al., 2002
Hanotin et al., 1998
Finer et al., 2000
Hanotin et al., 1998
Weintaub et al., 1991
Seagle et al., 1998
Objective
A benefit-risk assessment
of sibutramine in the
management of obesity
Study Design
Objective
Included Studies
Study
authors
and year
Adjunctive therapy in the
form of diet, exercised
and behavior
modification advice in
varying intensities.
Exposure
Sibutramine
Co-intervention
Low calorie diet
Participants
Exposure/
Comparison
Adverse events
STORM trial
Data relating to blood lipids
and general metabolism
showed substantial
improvements in the
sibutramine group.
Common adverse events
associated with sibutramine
Headache
Constipation
Nausea
Nervous system (>5%)
Dizziness
Dry mouth
Insomnia
Requiring regular
monitoring
Increased blood pressure
Increased heart rate
Outcomes
(including adverse events)
Withdrawals
results form
adverse events
Sibutramine
withdrawals as a
result of BP
Insomnia
Nausea
Inc blood
pressure
Lassitude
Back pain
Adverse Event
P
0.8%
14%vs5%
8% vs. 3%
7% vs. 11%
7% vs. 9%
8% vs. 3%
7% vs. 1%
S
A few trials included an
assessment of patient’s adherence
with the trial regimen; usually
either counting returned capsules
or self-reporting (both are
potentially unreliable).
Reporting of numbers of
withdrawals per group with
reasons was variable.
None of the trials included
methods to determine the success
of blinding of patients, care givers
or outcomes assessors.
Relatively few trials described the
use of a priori power calculation to
estimate required sample size.
All trials reported participant
selection criteria and comparability
of groups at baseline.
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Inclusion
All clinical trials of sibutramine for
weight management in overweight or
obese subjects reporting unwanted
side effects of sibutramine
Participants
Inclusion
Exclusion
Evidence Table 18. Sibutramine, Nisoli and Carruba, 2003
94
The authors
concluded that the
assessment-risk
profile of
sibutramine was
positive although
the product must
be kept under
review and BP and
heart rate
monitored
especially in obese
hypertensive
patients.
Conclusions
Comments
Study design
Randomised,
double blind,
placebo
controlled trial
Berkowtitz et
al., 2003
Exclusion/
contraindications
Cardiovascular disease
Diabetes (type 1 or 2)
Major psychiatric disorders
Use of a weight loss
medication or weight loss
of 5kg or more in the
previous 6 months
Use of medications
promoting weight gain
(e.g., oral steroids)
Use of medicines
contraindicated with use of
sibutramine
Cigarette smoking
Inclusion
adolescents
13-17 years
BMI =32-44.
Phase I
Mean weight loss
% change in BMI
Waist circumference
BMI reduction>=5%
BMI reduction>=10%
BMI reduction>=15%
Systolic BP (3 mo)
Diastolic BP (3mo)
Systolic BP (6mo)
Diastolic (6mo)
Pulse rate (3mo)
Pulse rate (6mo)
Hunger reduction
19 dropouts
Systolic BP‡
Diastolic BP‡
Pulse rate
Phase I, placebo
controlled, 6months
weight loss trial
Sibutramine + behavior
therapy, N=43 or placebo
+behavior therapy, n=39
Medication protocol
Week one: all participants
received placebo. Week two:
either 5mg/d sibutramine or
placebo. Week three:
10mg/d or placebo. Week
seven: 15mg/d or placebo
Dose reduction: in subjects
with an increase in SBP or
DBP of >=10mmHg or an
increase of pulse rate of
>=15%, dose reduced in
5mg until desired rates
achieved. Sibutramine
discontinued if BP increased
20mm Hg or more.
Behavioural protocol
Weekly group sessions for
subject and separate groups
sessions for parents. Groups
were led by dietitians,
psychologists or
psychiatrists.
Diet
1200-1500kcal/d 30% fat
15% protein, 55%
carbohydrate.
Exercise
Eventual goal of walking or
similar aerobic activity
120mins per week.
Other
Daily eating and activity logs
Participants
N=146 adolescents
evaluated at clinic, 82
randomised, 64 excluded
(psychiatric conditions
(24), not interested (21),
unable to attend group
meetings (12), medical
conditions (2), other (7)).
Mean age =14.1 yrs
(SD=1.2)
Mean weight=103.6kg
(SD=15.4)
Mean BMI=37.8(SD=3.8)
Mean waist
circumference=110.8cm
(SD=10.0)
Sex= 55F: 27M
White race=45
Black race=34
Serum chemistry
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
No between group
differences
0.001
0.001
<0.001
0.02
0.02
0.02
0.02†
0.23†
0.06†
0.11†
<0.001†
0.007†
0.002
<0.001
<0.001
<0.001
+ 10mmHg
+8.6mmHg
+14.3/min
p
value
7.8kg (6.3)
8.5% (6.8)
-8.2(6.9)
27(63)
17(40)
8(19)
114.8mmHg
58.4mmHg
112.9mmHg
58.6mmHg
85.6beats/min
84.8beats/min
greater
Effect Size & Precision
Sibutramine
(s.d.)
3.2kg (6.1)
4.0%(5.4)
-2.8cm(5.6)
14(36)
6(15)
1(3)
110.7mmHg
55.7mmHg
110.3mmHg
55.3mmHg
81.6 beats/min
81.2beats/min
Placebo
(s.d.)
Phase II, maintenance
trials 7-12 months, all
subjects receive
sibutramine
Not reported here,
endpoints not relevant.
No significant
difference in
withdrawals between
groups
No significant
difference between
groups at baseline
Study powered to
detect 4% difference in
baseline BMI between
treatment groups.
ITT analysis
Taken off study
because of marked and
sustained BP increase
with sibutramine
Phase I
Completed 6 month
assessment
Placebo
Sibutramine
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
† represents the difference between treatment conditions between baseline and month 3, baseline and month 6. ‡ Increase from baseline to time of dropout
Length of
study
Intention to treat
analysis at 6
months
Study Design
Objective
Length of
study
Study
authors
and year
Evidence Table 19. Sibutramine, Berkowtitz et al., 2003
5/43 (12%)
34/39
(87%)
40/43
(93%)
Sibutramine must be
carefully monitored to
control increases in BP
and pulse rate.
Behavioural and
pharmacological
treatments appeared to
have additive effects that
maximised weight loss.
Comment
Sibutramine and
behaviour therapy
resulted in significantly
greater weight loss than
placebo and behaviour
therapy.
During Phase I
19/43(44%) participants
had dose reductions or
discontinued treatment
with sibutramine. BP and
HR results reflect a
deliberate attempt to limit
increases in BP or HR.
Conclusions
Comments
95
Study design
Randomised, double
blind, parallel-group,
placebo controlled
Hazenberg
et al., 2000
Objective
To assess weight loss,
safety and tolerability
associated with
sibutramine in mild to
moderately obese
hypertensive patients.
Study Design
Objective
Study
authors
and year
Dry mouth
Constipation
Nervousness
Adverse events
Sibutramine = 42%
Placebo =43%
Results at 12 weeks
Body weight (kg)
Body weight % reduction
BMI reduction (kg/m2)
More than 5% baseline body
weight loss (%)
Waist Hip Ratio change
Supine DBP (mm Hg)
Supine SBP (mm Hg)
Heart rate (beats/min)
Exposure
Sibutramine 10mg, N=62
Comparison
Placebo N=65
Co-interventions
Dietary advice and diet
sheet
Outcomes
(including adverse events)
Exposure/
Comparison
2
4
5
17
+0.01
-5.2
-4.2
-3.1
-2.2
+2.3
-0.8
8
6
1
44
-0.01
-3.7
-4.1
+1.8
-4.4
+4.7
-1.6
<0.01
<0.06
0.14
0.97
<0.001
0.002
<0.001
<0.01
Effect Size & Precision
(Mean change from baseline)
P
S
p=
Last observation carried forward analysis.
4 patients withdrew (2 sibutramine, 2 placebo)
because of adverse events
7 patients withdrawn in double blind phase
N=4 sibutramine (AEs =2 protocol violation =2)
n=3 placebo (AEs=2, protocol violation =1).
Withdrawals
Four patients withdrew in the run-in phase.
14 patients erroneously given active
medication during the run-in phase were
withdrawn.
Completed study
Sibutramine n=50 (81%)
Placebo n=56(86%)
Validity/Applicability
% of studies
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
More than 3kg loss in previous 3
months
Previous sibutramine
More than borderline depression
or taking any antidepressant.
Obesity of endocrine origin
Diabetes requiring insulin
Any past or present significant
illness
Risk of pregnancy
Inclusion
18-65 years
BMI in the range 27-40kg/m2
Hypertension stabilised for at least
4 weeks and medication not
changed in the period.
Participants
N=127
Age – median 48 years (19-65)
M=38
F=39
Hypertensive n=113
Participants
Inclusion
Exclusion
Evidence Table 20. Sibutramine, Hazenberg et al., 2000
96
Weight reduction has
a beneficial effect on
BP in obese
hypertensive
patients.
Sibutramine 10mg/d
is effective in
reducing body weight
in obese patients.
Conclusion
Conclusions
Comments
Study design
Randomised, double blind,
placebo controlled.
Gokcel et
al., 2001
Objective
Evaluation of the efficacy of
sibutramine in combination
with hypoglycemic drugs in
obese females with poorly
regulated type 2 diabetes.
Study Design
Objective
Study
authors
and year
Side effects (sibutramine)
Dry mouth, n=11
Constipation, n=16
Hypertension, n=1 (patients withdrew
from study)
0.91± 0.53
0.36± 0.21
0.92± 0.49
15.76± 3.89
32.88± 6.13
0.68± 0.43
0.31± 0.28
0.53± 0.01
7.68± 5.04
0.01± 1.10
13.32± 3.94
0.01± 2.58
0.36± 7.26
-9.61± 1.37
-3.92± 0.54
-8.04± 4.43
124.88± 8.58
102.24± 51.99
5.66± 0.97
7.09± 0.81
2.73± 0.01
28.08± 4.93
0.97± 1.58
20.92± 4.66
8.68± 2.58
46.76± 13.09
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.008
>0.05
>0.05
<0.02
<0.08
<0.0001
<0.0001
<0.0001
Effect Size & Precision
(Mean change from baseline)
P
S
P=
Comparable patient population at
baseline
Withdrawal - one subject withdrew
from the treatment group because
of hypertension.
Exclusion - five subjects from
placebo group suffered low
treatment efficacy and were
excluded and switched to insulin.
Validity/Applicability
% of studies
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Type 1 diabetes
Obesity of endocrine
origin
Previous weight loss
drugs or intensive weight
loss program
Uncontrolled
hypertension,
SBP>160mm Hg or DBP>
100mm Hg.
Glaucoma
Pregnant women
Patients taking betablockers, antidepressants,
monamine oxidase
inhibitors or any drug
affecting appetite or
weight.
SBP – not reported
DBP & HR significant reductions
reported but no data given
Six months
Weight loss (kg)
BMI change (kg/m2)
Waist circumference (cm)
Fasting blood glucose (mg/dl)
Postprandial blood glucose (mg/dl)
Insulin level (:U/ml)
HOMA IR
HbA1c (%)
Total cholesterol (mg/dl)
HDL cholesterol (mg/dl)
LDL cholesterol (mg/dl)
VLDL cholesterol (mg/dl)
Triglycerides (mg/dl)
Exposure n=29
Sibutramine 10mg
t.i.d.
Diet restriction
Hypoglycemic
drugs
Comparison n=25
Placebo
Diet restriction
Hypoglycaemic
drugs
Participants
N=60, obese females
Inclusion
HbA1c >8%
BMI >30kg/m2
On maximum dosage of
metformin (2,550mg/d)
and sulfonylureas
(gliclazide, 320mg/d or
glipizide, 20mg/d).
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
Evidence Table 21. Sibutramine, Gokcel et al., 2001
Sibutramine is well tolerated
and safe in this patient
population.
Conclusion
The addition of sibutramine to
oral hypoglycaemic therapy
leads to significant weight loss
and improved metabolic
parameters.
There was also a significant
positive change in the lipid
profile of the sibutramine
patients.
The significant improvement
in glycemic control in the
sibutramine group was
attributed to weight loss.
Conclusions
Comments
97
Study design
Meta-analysis of
randomised double blind
placebo controlled
trials.
Objective
A comprehensive metaanalysis of RCTs on the
effect of sibutramine on
weight loss and blood
pressure.
Kim et al.,
2003
Exclusion
Studies of patients with eating
disorders
Crossover studies
Studies that did not provide
information for estimating a size
effect of weight change.
Studies using drugs for weight
maintenance
Studies with multiple treatment
groups that did not compare each
group with the control group
independently.
The overall effect size
was significantly larger
when the sibutramine
dose was >15mg/d.
Participants with a higher
weight (>=92kg)
experienced a higher
DBP and SBP.
A greater increase in
SBP was found in
subjects <44 years of age
and in the larger trials
(n>=120).
Sibutramine showed a
large effect on weight but
increased blood pressure
significantly, particularly
in heavier and/or younger
participants. The size of
the increase in blood
pressure was small
however, it was
considered to be clinically
important in patients who
had borderline or high
blood pressure.
All studies were carried out in Western
countries, which may limit applicability.
Inclusion criteria may have led to under or
over-estimation of the effect.
Because only published studies were
employed in the analysis there is a possibility
of publication bias, however Rosenthal’s failsafe N values were approximately N= 100 for
SBP and N= 341 for DBP which makes
publication bias unlikely.
Conclusions
Comments
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
0.26 (0.18 to 0.33)
-0.11 to 0.73
1.8mm Hg
DBP
Overall size effect
Size effect range
Net increased DBP attributable
to sibutramine
-1.00 (-1.17 to -0.84)
0.16 (0.08 to 0.24)
-0.38 to 0.45
1.6mm Hg
Weight change
Overall size effect
Exposure
Sibutramine >5mg/d
Comparator
Placebo
Inclusion
Human studies
Double blind randomised, placebo
controlled trials of sibutramine
English
Full text available
Obese or overweight participants
Dosage of sibutramine > 5mg
Any duration
Co-morbidities of diabetes,
hypertension or hyperlipidemia
allowed.
Effect Size & Precision
Standardised difference of
changes from baseline between
treatment and control§ (95%
CI)
SBP
Overall size effect
Size effect range
Net increased SBP attributable
to sibutramine
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
DBP=diastolic blood pressure, SBP=systolic blood pressure
Studies included, N=21
Weintraub et al., 1991
Hanotin et al., 1998
Seagle et al., 1998
Apfebaum et al., 1999
Bray et al., 1999
Hansen et al., 1999
Cuellar et al., 2000
Fanghanel et al., 2000
Finer et al., 2000
Fujioka et al., 2000
Hazenberg et al., 2000
McMahon et al., 2000
Dujovne et al., 2001
Gokcel et al., 2001
Smith et al., 2001
Wirth et al., 2001
Faria et al., 2002
McMahon et al., 2002
Serrano-Rios et al.,
2002
Sramek et al., 2002
Zannad et al., 2002
Study Design
Objective
Studies Included
Study
authors
and year
Evidence Table 22. Sibutramine, Kim et al., 2003
98
Study design
Randomised, double
blind, placebo controlled
clinical trial
Hauner et
al., 2003
Exposure N=174
Sibutramine 15mg/day
given as an adjunct to a
standard nonpharmacological
treatment.
Comparison N=174
Placebo given as an
adjunct to a standard nonpharmacological
treatment.
Concomitant nonpharmacological therapy
Four educational sessions
on food choice, physical
activity, motivation and
behavioral modification
and diet counselling.
Subjects were also
encouraged to attend 16
further sessions.
A dietitian made individual
dietary counselling and
energy requirement
calculations. Subjects
were encouraged to record
their dietary intake for selfcontrol.
Subjects were encouraged
to increase their physical
activity such that excess
energy expenditure by
additional physical activity
should exceed 1000kcal
per week.
Exposure/
Comparison
Adverse events
310/348 (85.6%) patients of the
ITT population experienced
adverse events including:
Back pain
Bronchitis
Sinusitis
Gastritis
Ill defined experience
Headache
Infection
Pharyngitis
Accidental injury
Enteritis
Dry mouth
Surgery
Flu syndrome
Fungal dermatitis
Upper respiratory tract infection
Gastrointestinal disorder
Eczema
Hypertension
Constipation
Waist circumference (cm)
SBP (mm Hg)
DBP (mm Hg)
Heart rate (beats/min)
Total cholesterol (mg/dl)
LDL- cholesterol (mg/dl)
HDL - cholesterol (mg/dl)
Triglycerides (mg/dl)
Weight loss (kg)
Weight loss (%)
5% weight reduction (%)
10% weight reduction (%)
WHR
Outcomes
(including adverse events)
83.5%
5.1(-6.1 to –4.1)
4.9 (4.0-5.8)
41.4
19.0
-0.019
(-0.027 to –0.012)
-6.0(-7.1 to –5.0)
-1.5 (-3.9 to 0.09)
-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 49.6)
87.8%
8.1(-9.2 to –6.9)
8.3 (7.1-9.6)
62.6
40.8
-0.024
(-0.033 to –0.014)
-8.5cm (-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)
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
0.001
ns
ns
0.022
ns
ns
ns
ns
0.002
<0.01
ns
<0.001
<0.001
ns
ns
ns
ns
<0.05
ns
ns
ns
ns
Effect Size & Precision
Change in weight from baseline to 54 weeks
P-S
Placebo
Sibutramine
p=
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Serum creatinine >2mg/dl
Hypercholesterolemia
(total cholesterol
>320mg/dl)
Uncontrolled hypertension
(>160/95mmHg, mean of
3 independent
measurements)
Type 2 diabetes mellitus
Coronary heart disease
Clinically significant
dysrhythmia
Psychiatric diseases
Child bearing potential
without adequate
contraception
Use of medication that
may alter appetite.
Inclusion
Age 18-65 years
BMI 30-40kg/m2
Stable weight (±2kg)
during the preceding 3
months
Motivation and willingness
to reduce weight.
Participants
N=389, ITT population
N=348
Consecutive, GP patients
in the area of CologneDusseldorf, Germany.
Male=89 (23%),
Female=259(67%)
Mean age =42.7 ± 11.7
years
Inclusion
Exclusion
Participants
Outcome figures in bold are statistically significant
Trial duration
54 weeks
Objective
To study, in a primary
health care setting, the
effect of a standardised
non-pharmacological
program and 15mg
sibutramine or placebo
on long-term weight
reduction.
Study Design
Objective
Study
authors
and year
Evidence Table 23. Sibutramine, Hauner et al., 2003
Withdrawals
Sibutramine =66
Placebo=75
Main reasons for drop-out
poor compliance and
discontent with weight
loss, sibutramine N=38,
placebo n=43.
Adverse event
withdrawals, sibutramine
n=22, placebo n=15.
The populations were
similar at baseline except
for a significantly smaller
number of males in the
sibutramine group.
Analysis based on ITT and
at least one follow-up visits
with weight measurement.
Last observation carried
forward (LOCF) was used
for the final analysis.
There were a significantly
(p<0.05) smaller number of
males in the sibutramine
group.
Validity/Applicability
Treatment with sibutramine
proved to be safe and
particularly effective in those
obese subjects who were
less successful with the nonpharmacological program.
Adjunct treatment of obese
subjects with 15mg
sibutramine daily in
combination with a
comprehensive nonpharmacological weight
reduction program produces
additional; weight loss and
can be readily implemented
in a primary care setting.
Conclusions
Comments
99
Study design
Randomised,
placebo controlled,
double blind,
multicentre, and
multi national trial.
McNulty et al.,
2003
Adverse events
Sibutramine
Dry mouth
Constipation
Insomnia
Cardiovascular effects
SBP (mmHg)
DBP (mmHg)
Pulse rate (beats per min)
95%CI
0.3 to 8.8
0.4 to 5.3
2.5 to 9.4
-1.3 ±2.2
0.0±1.3
5.8±1.8
-5.6 to 3.1
-2.5 to 2.4
2.3 to 9.3
-0.6 to 0.0
-0.3
-0.6 to 0.1
-0.2
4.6±2.2
2.8±1.2
5.9 ±1.7
-1.0 to 0.5
-0.76 to 0.57
-30.0 to 0.0
-0.1 to 0.3
0.0 to 0.1
-0.1 to 0.3
-0.5 to 0.1
-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
95% CI
-0.2
-0.10±0.34
-18.0
0.1
0.1
0.1
-0.2
-7.8±1.0
-2.9±0.3
-6.8±1.0
-6.1± 1.0
-0.9±0.9
65
27
S20mg/d
-1.0 to 0.7
-0.99 to 0.31
-24.0 to 12.0
-0.2 to 0.3
0.0 to 0.2
-0.2 to 0.3
-0.9 to-0.2
-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
-0.2
-0.34±0.33
-6.0
0.0
0.1
0.0
-0.5
-5.1±0.9
-1.9-±0.3
-4.9±0.9
-3.0±1.0
-1.4±0.9
46
14
S15mg/d
Effect Size & Precision
(mean difference sibutramine –
placebo ± SE or medians (range)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Ischemic heart disease,
heart failure or stroke.
Seated pulse rate
>100BPM,
DBP>95mmHg
Fasting serum
triglycerides>5.6mmol/l
Fasting serum cholesterol
>7.8mmol/l
Serum creatinine
>120µ mol/l
Serum liver enzymes of
bilirubin levels x2 upper limit
of normal.
Weight change >3kg in
preceding 3 months
Pregnant or childbearing
women or childbearing
potential not taking
adequate precautions again
pregnancy.
Inclusion
Type 2 diabetes > 6 mo
BMI>=27kg/m2
Metformin treatment 3
months - 2 years
Age 25-70 years
Fasting serum glucose 715mmol/l
Weight change (kg)
BMI (kg/m2)
Waist circumference (cm)
Hip
Waist hip ratio
>=5% weight loss (%)
>=10% weight loss (%)
Exposure
Sibutramine 15mg/day
and 20mg/day and
standard diet advised by
a dietitian.
Comparison
Placebo and standard
diet advised by a
dietitian.
Participants
N=195
Male=45%, Female=55%
Mean Age=48-51years,
range 27-69years
Duration=1 year
Hypertensive =36% with
29% taking antihypertensive and 17% lipid
lowering drugs.
Metabolic changes
Fasting glucose (mmol/l)
HbA1c (%)
Fasting insulin (pmol/l)
Cholesterol (mmol/l)
HDL
LDL
Total cholesterol to HDL
cholesterol
Triglycerides (mmol/l)
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
Figures in bold = significant, S=sibutramine.
Recruitment
Eligible patients
from case notes
Objective
To evaluate the
effects of
sibutramine (15 and
20mg/day) on
weight metabolic
control and blood
pressure in
metformin obese
subjects with type 2
diabetes.
Study Design
Objective
Study
authors
and year
Evidence Table 24. Sibutramine, Mcnulty et al., 2003
100
Relatively young patient
population
Strict inclusion criteria may
limit applicability.
Validity/Applicabiilty
Sibutramine tended to
increase blood
pressure in more
patients than placebo
and a few individuals
showed marked rises.
Poorly controlled obese
type 2 diabetic patients
may gain the most from
weight loss and antiobesity medication.
Lipid changes were
modest in this study
and lower than other
studies but may be
explained by the fact
that study participants
were receiving
metformin which has
favorable moderating
effect on lipids.
Weight loss of >= 10%
conferred metabolic
and cardiovascular
benefits. No patients in
the placebo group lost
>=10-% body weight.
Average weight loss at
one year was 5.5kg
with 15mg sibutramine
and 8.0kg with 20mg –
placebo patients lost no
weight. In fact 19%
gained more than 2kg
over 1 year.
Sibutramine was an
effective anti-obesity
agent in a substantial
proportion of patients
with type 2 diabetes.
Conclusions
Comments
Study Design
Randomised, double
blind, placebo
controlled clinical trial.
Wadden et al.,
2000
Duration
16 weeks after 1 year
of sibutramine
Study location(s)
USA
Objective
To assess if adding
orlistat to sibutramine
induces further weight
loss or maintains
weight lost in patients
who have lost weight
taking sibutramine
alone and continue
taking sibutramine.
Study Design
Objective
Study Location(s)
Study
authors
and year
Combining the treatments did not appear
to result in any unexpected side effects.
The adverse events are reports for the
last week of the trial.
Adverse events (% of patients)
Soft stool
Increased bowel movement
Faecal urgency
Oily evacuation
Oily spotting
Flatus with discharge
Fatty oily stool
Liquid stool
Stomach pain/upset stomach
Faecal incontinence
Decreased bowel movement
Pellets/hard stool
Weight change in 16 week continuation
trial –Last observation carried forward
N=17
1 month
2 months
3 months
4 months
Weight change in 16 week continuation
trial –End point analysis
1 month (N=16 S+P, N=14 S+O)
2 months (N=10 S+P, N= 15 S+O)
3 months (N=12 S+P, N=15 S+O)
4 months (N=10 S+P, N=14 S+O)
Outcomes
9.1
9.1
9.1
0
9.1
0
0
9.1
9.1
0
0
18.2
-0.7±1.3
-0.3±1.6
+0.2±1.9
+0.8±2.0
-0.7±1.2
-0.5±1.4
+0.1±1.8
+0.5±2.1
50
50
42.9
42.9
28.6
28.6
28.6
14.3
14.3
7.1
7.1
7.1
-0.9±1.9
-0.7±23.1
-0.6±4.4
+0.3±4.2
-0.7±1.8
-0.7±2.9
-0.4±4.2
+0.1±4.1
0.04*
0.04*
ns
0.02*
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
ns
Effect Size & Precision
(Mean change from baseline)
S+P
S+O
P=**
Dosage
The medication dosage varied for both
treatments,
Sibutramine + placebo
10mg/d sibutramine N=7
15mg/d sibutramine N=-10
Sibutramine + orlistat
10mg/d sibutramine N=6
15mg/d sibutramine N=-11
Orlistat 120mg t.i.d.
Dose reduction of sibutramine had
been made in the previous 1 year
study because of side effects notably
insomnia, increased blood pressure
and pulse.
Blinding
84.6% of patients had guessed what
treatment they were on.
Completers (EPA) and last observation
carried forward (LOCF) analyses both
reached the same conclusions.
Not clear if ITT analysis was carried
out but a chi-squared test on the dropout showed no significant difference.
Withdrawals
Sibutramine + orlistat, n=3 (18%)
Sibutramine, n=5 (29%) difference not
significant.
Small study
Short duration
Diet modification /lifestyle therapy not
standard.
Diets may have been very low fat.
Validity/Applicability
Safety
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Overall – modest lifestyle
intervention.
Prescribed diet
1200-1600kcal/day
representing a deficit of
600-500kcal/day. Diet to
comprise 20% calories
from protein, 50%
carbohydrate <=30% fat.
Healthy eating education.
Fat intake limited to
60g/d.
Exercise/activity
Monthly activity goals with
eventual goal of 5
sessions of 30-40mins
per week.
Comparison n=17
Sibutramine (10-15mg/d)
and placebo + prescribed
diet + a daily multivitamin.
Exposure N=17
Sibutramine (1015mg/day) and orlistat +
prescribed diet + a daily
multivitamin
Participants
34 volunteers
Mean age 44.1 years
(±10.4)
Female =100%
BMI=33.9±4.9kg/m2
Inclusion
Females who had
completed 1 year
treatment with
sibutramine (1015mg/d)
Exposure/
Comparison
Participants
Inclusion
Exclusion
Recruitment
Evidence Table 25. Sibutramine, Wadden et al., 2000
The authors suggest that most
obese patients have a limit of 1015% weight loss. Further weight
loss appears to be thwarted by a
toxic environment that discourages
physical activity, encourages
consumption of high fat diet and
compensatory biological
mechanism that decrease energy
expenditure.
Further sub-group analyses of
patients thought most likely to
benefit from combination therapy
did not increase their weight loss.
However, those that lost >=10% of
their initial weight in the previous 1
year gained weight during the
second study regardless of
medication received. Those that
gained <10% in the initial study lost
a further amount of weight in the
second study with those taking
sibutramine + orlistat losing more
weight than those taking
sibutramine alone (ns).
Conclusion
Body weight remained essentially
unchanged in the two groups over
the 16-week study period.
Conclusions
Comments
101
Study design/type
Meta-analysis of
randomised, placebo
controlled double
blind trials of FDA
approved anti-obesity
agents.
Poston et al.,
2001
Studies included
N=108 independent
RCTs published in
103 articles
1960s n=10
1970s n=46
1980sn=13
1990s n=39
Objective
Evaluation of lifestyle treatments used
in published obesity
drug studies and their
contribution to weight
losses associated
with pharmacological
interventions.
Study Design
Objective
Study Reference
Study
authors
and year
49.5% vs. 26.5%
28.3%
46-54%
4.6%
25.0%
40.7%
0.9%
0%
2.8%
23.1%
3.7%
27.8%
0.9%
17.6%
82.4%
3.7%
49.1%
% of studies
N=108
Most studies were conducted with
middle-aged overweight to moderately
obese women in their 40s. Their
outcomes may not be generally
relevant to the larger population of
obesity patients who seek treatment,
particularly those with more severe
obesity.
Validity/Applicability
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
Exclusion
Experimental obesity
agents
Nutritional supplements
Weight maintenance
studies
Broad classification of components
Behavioural modification studies
Psychotherapy or cognitive behavioural
Exercise
Diet
Treatment manual for lifestyle intervention
Formal training by lifestyle interventionists
Specific classification of components
Very low calorific, pre-packaged food or Eating
management
Low-calorie diet
Balanced deficit diet
Aerobics, Callisthenics or Lifestyle exercise
Weight lifting
Walking
Self-monitoring
Stimulus control or Contingency management
%outcome due to/ lifestyle component
Trials with no lifestyle component
Trials with 1-3 lifestyle components
% weight loss attributable to specific
strategies in patients receiving drug
treatment
Diet interventions vs. no diet interventions
Included drugs
Amphetamine
Benzocaine
Benzphetamine
Dexfenfluramine
Diethylpropion
Fenfluramine
Fluoxetine
Mazindol
Methamphetamine
Orlistat
Phendimetrazine
Phentermine
Phenylpropanalamine
Sertaline
Sibutramine
Inclusion
Studies published on or
before December 1999
FDA approved obesity
medication
Randomised studies where
randomisation was not
broken
Studies that included a
direct comparison with
another anti-obesity drug or
placebo controlled.
Data were for only human
studies
English version of the study
available
Data in published reports in
peer-reviewed journals
Relevant sub-groups
identifiable
Studies with sufficient
outcome data to compute a
size effect based on weight
loss
Participants
108 independent RCTs
Outcomes
(including adverse events)
Exposure/
Comparison
Participants
Inclusion
Exclusion
Evidence Table 26. Comparative drug study, Poston et al., 2001
102
Obesity-pharmacotherapy trials do not use
life-style treatments with the frequency
expected based on the official positions of
most professional organisations concerned
with the comprehensive management of
obesity.
Lifestyle treatments, with the exception of
diets, have not been widely used in
randomised, placebo-controlled obesity drug
trials.
Conclusions
Comments
Study Design
Meta-analysis of RCTs
Haddock et
al., 2002
N=108 clinical trials
included
Exclusion
Experimental obesity
drugs
Dietary supplements
Diethylpropion (9 studies)
Orlistat (6 studies)
Phentermine (6 studies)
Sibutramine (4 studies)
Exposure
Orlistat
Sibutramine
Phentermine
Diethylpropion
Inclusion
FDA approved antiobesity drugs
Prescription or OTC or
off label
Studies published in
peer reviewed journals
Published before
December 1999
English version available
Human studies
Placebo or active
comparator
Randomised study
Outcome data available
Comparison
Placebo
Outcomes
(including adverse events)
Exposure/
Comparison
Inclusion
Exclusion
18(6-51)
48(16-76)
13(2-24)
15(8-26)
Wks
Rx
75
303(190-360)
28 (15-30)
14(10-20)
Dose
Mg/d
3.0(-1.6-11.5)
2.08(0.30-4.2)
3.6(0.6-6.0)
3.5(2.4-5.1)
Drug minus
placebo (kg)
<0.80
<0.80
0.81
1.05
Effect size
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
† withdrawn 1997, NS = not significant – i.e., p=<0.05 * ns if Bonferroni’s correction for multiple tests is used. OTC = over the counter
* current review medications
Objective
A comprehensive meta-analysis
of RCTs of medications for
obesity.
Medications
Amphetamine
(dexamphetamine)
Benzocaine
Benzphetamine
Dexfenfluramine†
Diethylpropion*
Fenfluramine†
Fluoxetine
Mazindol
Methamphetamine
Orlistat*
Phendimetrazine
Phentermine (HCL and resin)*
Phenylpropanolamine (PPA)
Sertraline
Sibutramine*
Study Design
Objective
Included Medications
Study
authors
and year
Evidence Table 27. Comparative drug study, Haddock et al., 2002
Female preponderance
Standardised mean
difference (d) based on
change scores
(reduction in weight)
used as a measure of
effect size, where:
d1 = (Xti -XcI)/ Si
Xti = mean weight loss
treatment group
Xci = mean WL control
group
Si = pooled SD of
change for both
Study weighting –
inverse function of
sample variance
Validity/Applicability
Treatment length did
not influence effect
size.
The absolute
placebo-subtracted
weight loss
associated with antiobesity drug use in
the MA did not
exceed 4.0kg (i.e.,
modest).
Sibutramine, which
was the drug with
the largest effect
size, had
overlapping CIs with
phentermine.
Only sibutramine
had an effect size
exceeding 0.90.
A large number of
studies did not
present codable
data.
Conclusions
Comments
103
104
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
105
Appendices
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
106
Appendix I.
Summary of potential barriers to use of drugs
included in the review
Potential barriers to use†
Medication
Contraindications
Phentermine
HCL
30mg
Umine
Timedcaps
!5mg & 30mg
DuromineTM
Diethylpropion
HCL
75mg
Tenutate
Dospan
Sibutramine
HCL
10mg & 15mg
Reductil®
Orlistat
120mg
Xenical®
Interactions
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
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
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 cerebrovascular 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
# MAOI inhibitors
# Other anorectic agents
# General anaesthetics
Chronic malabsorption syndrome
Cholestasis
Known hypersensitivity to orlistat or any of its
components
# Warfarin and other anti-coagulants
# 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
Additional Cautions
! 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.
! Altered anti-diabetic drug requirements
! 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.
# 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 desethylamiodarone 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
† 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
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
107
Appendix II.
Search strategies
Medline strategy
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
exp Obesity/ (56799)
(obese or obesity).tw. (56362)
weight loss/ (8738)
appetite depressants/ (2734)
appetite/de (1343)
anti-obesity agents/ (628)
or/1-6 (82997)
exp Phentermine/ (819)
duromine.tw. (3)
umine.tw. (0)
Diethylpropion/ (224)
tenuate dospan.tw. (9)
sibutramine hydrochloride.tw. (27)
Cyclobutanes/ (845)
reductil.tw. (8)
orlistat.ti. (184)
lactones/ (7467)
xenical.tw. (30)
complan.tw. (9)
Food, Formulated/ (4095)
or/8-20 (13334)
7 and 21 (1214)
randomized controlled trials/ (33133)
randomized controlled trial.pt. (191180)
random allocation/ (51130)
double blind method/ (78837)
single blind method/ (8255)
clinical trial.pt. (386534)
exp clinical trials/ (156308)
(clinic$ adj trial$).tw. (79327)
((singl$ or doubl$ or treb$ or tripl$) adj (blind$ or mask$)).tw. (75413)
placebos/ (23136)
placebo$.tw. (84981)
randomly allocated.tw. (7750)
(allocated adj2 random).tw. (607)
meta-analysis/ (5457)
(metaanaly$ or meta analy$).tw. (11523)
meta analysis.pt. (9354)
exp review, literature/ (2051)
(systematic adj (review$ or overview$)).tw. (5737)
or/23-40 (561105)
comment.pt. (253767)
letter.pt. (509370)
editorial.pt. (163392)
animal/ (3653674)
human/ (8547910)
45 not (45 and 46) (2808546)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
108
48
49
50
51
or/42-44,47 (3486417)
22 and 41 (408)
49 not 48 (390)
limit 50 to english language (348)
Medline (extra economics search)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
economics/ (23811)
"costs and cost analysis"/ (32452)
cost allocation/ (1667)
cost-benefit analysis/ (33314)
cost control/ (15851)
cost savings/ (4816)
cost of illness/ (6121)
cost sharing/ (949)
health care costs/ (11660)
direct service costs/ (677)
drug costs/ (6035)
hospital costs/ (4347)
health expenditures/ (8059)
economics, pharmaceutical/ (1367)
((low or high) adj cost$).mp. (10695)
(health?care adj cost$).mp. (864)
(fiscal or funding or financial or finance).tw. (31542)
(cost adj (estimate$ or variable$)).mp. (810)
(unit adj cost$).mp. (578)
(economic$ or pharmacoeconomic$ or price$ or pricing).tw. (68154)
or/1-20 (210993)
exp Obesity/ (56799)
(obese or obesity).tw. (56362)
weight loss/ (8738)
appetite depressants/ (2734)
appetite/de (1343)
anti-obesity agents/ (628)
or/22-27 (82997)
exp Phentermine/ (819)
duromine.tw. (3)
umine.tw. (0)
Diethylpropion/ (224)
tenuate dospan.tw. (9)
sibutramine hydrochloride.tw. (27)
Cyclobutanes/ (845)
reductil.tw. (8)
orlistat.ti. (184)
lactones/ (7467)
xenical.tw. (30)
complan.tw. (9)
Food, Formulated/ (4095)
or/29-41 (13334)
28 and 42 (1214)
comment.pt. (253767)
letter.pt. (509370)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
109
46
47
48
49
50
51
52
53
editorial.pt. (163392)
animal/ (3653674)
human/ (8547910)
47 not (47 and 48) (2808546)
or/44-46,49 (3486417)
21 and 28 and 42 (28)
51 not 50 (24)
limit 52 to english language (21)
Embase
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Diabetic Obesity/ (437)
obesity/ or morbid obesity/ (40399)
weight reduction/ (18379)
(obese or obesity).tw. (36765)
or/1-4 (62130)
Phentermine/ (751)
duromine.tn,tw. (11)
umine.tn,tw. (0)
Amfepramone/ (375)
tenuate dospan.tn,tw. (22)
Sibutramine/ (882)
reductil.tn,tw. (110)
Tetrahydrolipstatin/ (1055)
xenical.tn,tw. (323)
complan.tn,tw. (1)
complan/ (1)
reductil/ (882)
tenuate dospan/ (375)
duromine/ (103)
umine/ (0)
ensure/ (48)
(meal adj3 replace$).tw. (73)
or/6-22 (2308)
5 and 23 (1436)
exp meta analysis/ (18397)
(metaanaly$ or meta analy$).tw. (10151)
(systematic$ adj (review$ or overview$)).mp. (5300)
randomized controlled trials/ (85380)
clinical trial/ (296906)
randomization/ (10898)
single blind procedure/ (4761)
double blind procedure/ (47475)
crossover procedure/ (14990)
placebo/ (44490)
randomi?ed controlled trial$.tw. (13528)
(clinic$ adj trial$).tw. (63823)
((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (55628)
placebo$.tw. (65892)
(random$ adj allocat$).tw. (6611)
prospective study/ (38007)
or/25-40 (421878)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
110
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
case study/ (1663)
case report.tw. (66042)
abstract report/ or editorial/ or letter/ (409542)
or/42-44 (476020)
animal/ (7039)
exp animal experiment/ (644137)
46 or 47 (648030)
human/ (3829304)
48 not (48 and 49) (602008)
24 and 41 (588)
51 not 45 (554)
52 not 50 (553)
limit 53 to english language (497)
drug safety/ (67314)
drug contraindication/ (8022)
patient satisfaction/ (18988)
or/55-57 (92266)
58 and 24 and 45 (26)
54 or 59 (497)
Cinahl
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
exp obesity/ or obesity, morbid/ (5024)
Weight Reduction Programs/ (295)
weight gain/ or "altered nutrition, more than body requirements (nanda)"/ (1092)
Weight Loss/ (1966)
(obese or obesity).tw. (3954)
or/1-5 (8392)
Appetite Depressants/ (216)
(phentermine or duromine or umine).tw. (20)
diethylpropion.tw. (0)
tenuate dospan.tw. (0)
Sibutramine/ (35)
reductil.tw. (0)
orlistat.tw. (54)
xenical.tw. (8)
complan.tw. (0)
food, formulated/ (609)
or/7-16 (916)
6 and 17 (227)
Meta Analysis/ (4451)
(meta analy$ or metaanaly$).tw. (2303)
(systematic$ adj (review$ or overview$)).mp. (5227)
"literature review"/ or "systematic review"/ (3178)
exp Clinical Trials/ (26696)
clinical trial.pt. (10842)
(clinic$ adj trial$).tw. (6139)
randomi?ed controlled trial$.tw. (5128)
((singl$ or doubl$ or tripl$ or trebl$) adj (blind$ or mask$)).tw. (3569)
Placebos/ (2379)
placebo$.tw. (5466)
(random$ adj allocat$).tw. (774)
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
111
31
32
33
or/19-30 (36028)
18 and 31 (64)
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.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
112
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
113
References
Allison, D. B., Gadbury, G., Schwartz, L. G., Murugesan, R., Kraker, J. L., Heshka, S.,
Fontaine, K. R., et al. (2003). A novel soy-based meal replacement formula for weight loss
among obese individuals: a randomized controlled clinical trial. European Journal of Clinical
Nutrition, 57, 514-522.
Arterburn, D., & Hitchcock, N. P. (2001). Obesity. BMJ, 322, 1406-1409.
Arterburn, D. E., Crane, P. K., & Veenstra, D. L. (2004). The efficacy and safety of sibutramine
for weight loss: a systematic review. Archives of Internal Medicine, 164, 994-1003.
Astrup, A., & Toubro, S. (2001). When, for whom and how to use sibutramine? International
Journal of Obesity, 25, S2-S7.
Avenell, A., Broom, I., Brown, T. J., Poobalan, A., Aucott, L., Stearns, S. C., Smith, W. C. S., et
al. (2004). Systematic review of the long-term effects and economic consequences of treatments
for obesity and implications for health improvement. Health Technology Assessment, 8.
Bergstrom, A., Hsieh, C. C., Lindblad, P., Lu, C. M., Cook, N. R., & Wolk, A. (2001a). Obesity
and renal cell cancer: a quantitative review. British Journal of Cancer, 85, 984-990.
Bergstrom, A., Pisani, P., Tenet, V., Wolk, A., & Adami, H. O. (2001b). Overweight as an
avoidable cause of cancer in Europe. International Journal of Cancer, 91, 421-430.
Berkowitz, R. I., Wadden, R. A., Tershakovec, A. M., & Cronquist, J. L. (2003). Behavior
therapy and sibutramine for the treatment of adolescent obesity: a randomized controlled trial.
JAMA, 289, 1805-1812.
Bradley, P. S., Maddox, R. R., & North, W. K. (1999). Bupropion sr with phentermine for
weight reduction, 51st Institute on Psychiatric Services: 29th October-2nd November 1999, New Orleans.
Bray, G. A., Blackburn, G. L., Ferguson, J. M., Greenway, F. L., Jain, A. K., Mendel, C. M.,
Mendels, J., et al. (1999). Sibutramine produces dose-related weight loss. Obesity Research, 7, 189198.
Bray, G. A., Hollander, P., Klein, S., Kushner, R., Levy, B., Fitchet, M., & Perry, B. H. (2003).
A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in
obesity. Obesity Research, 11, 722-733.
Brower, V. (2002). Fighting fat. New drugs against obesity in the pipeline. EMBO Reports, 3,
601-603.
Brown, C. D., Higgins, M., Donato, K. A., Rohde, F. C., Garrison, R., Obarzanek, E., Ernst, N.
D., et al. (2000). Body mass index and the prevalence of hypertension and dyslipidemia. Obesity
Research, 8, 605-619.
Calle, E. E., Rodriguez, C., Walker-Thurmond, K., & Thun, M. J. (2003). Overweight, obesity,
and mortality from cancer in a prospectively studied cohort of U.S. adults. New England Journal
of Medicine, 348, 1625-1638.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
114
Carey, V. J., Walters, E. E., Colditz, G. A., Solomon, C. G., Willett, W. C., Rosner, B. A.,
Speizer, F. E., et al. (1997). Body fat distribution and risk of non-insulin-dependent diabetes
mellitus in women. The Nurses' Health Study. American Journal of Epidemiology, 145, 614-619.
Chan, J. M., Rimm, E. B., Colditz, G. A., Stampfer, M. J., & Willett, W. C. (1994). Obesity, fat
distribution, and weight gain as risk factors for clinical diabetes in men. Diabetes Care, 17, 961969.
Davidson, M. H. (1999). Weight control and risk factor reduction in obese subjects treated for
2 years with Orlistat: a randomized controlled trial. JAMA, 281, 1174-1174.
Derosa, G., Mugellini, A., Ciccarelli, L., & Fogari, R. (2003). Randomized, double-blind,
placebo-controlled comparison of the action of orlistat, fluvastatin, or both on anthropometric
measurements, blood pressure, and lipid profile in obese patients with hypercholesterolemia
prescribed a standardized diet. Clinical Therapeutics, 25, 1107-1122.
Ettinger, M.P., Littlejohn, T.W., Schwartz, S.L., Weiss, S.R., McIlwain, H.H., Heymsfield, S.B.
(2003). Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a
randomized, dose-ranging study. JAMA, 289, 1826-1832.
Foxcroft, D. R., & Milne, R. (2000). Orlistat for the treatment of obesity: rapid review and costeffectiveness model. Obesity Reviews, 1, 121-126.
Gardin, J. M., Schumacher, D., Constantine, G., Davis, K. D., Leung, C., & Reid, C. L. (2000).
Valvular abnormalities and cardiovascular status following exposure to dexfenfluramine or
phentermine/fenfluramine. Journal of the American Medical Association, 283, 1703-1709.
Glazer, G. (2001). Long-term pharmacotherapy of obesity 2000: a review of efficacy and safety.
Archives of Internal Medicine, 161, 1814-1824.
Gokcel, A., Karakose, H., Ertorer, E. M., Tanaci, N., Tutuncu, N. B., & Guvener, N. (2001).
Effects of sibutramine in obese female subjects with type 2 diabetes and poor blood glucose
control. Diabetes Care, 24, 1957-1960.
Haddock, C. K., Poston, W. S. C., Dill, P. L., Foreyt, J. P., & Ericsson, M. (2002).
Pharmacotherapy for obesity: a quantitative analysis of four decades of published randomized
clinical trials. International Journal of Obesity, 26, 262-273.
Halpern, A., & Mancini, M. C. (2003). Treatment of obesity: an update on anti-obesity
medications. Obesity Reviews, 4, 25-42.
Halpern, A., Mancini, M. C., Suplicy, H., Zanella, M. T., Repetto, G., Gross, J., Jadzinsky, M., et
al. (2003). Latin-American trial or orlistat for weight loss and improvement in glycaemic profile
in obese diabetic patients. Diabetes, Obesity & Metabolism, 5, 180-188.
Hanefeld, M., & Sachse, G. (2002). The effects of orlistat on body weight and glycaemic control
in overweight patients with type 2 diabetes: a randomized, placebo-controlled trial. Diabetes,
Obesity & Metabolism, 4, 415-423.
Hansen, D., Astrup, A., Toubro, S., Finer, N., Kopelman, P., Hilsted, J., Rossner, S., et al.
(2001). Predictors of weight loss and maintenance during 2 years of treatment by sibutramine in
obesity. Results from the European multi-centre STORM trial. Sibutramine Trial of Obesity
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
115
Reduction and Maintenance. International Journal of Obesity & Related Metabolic Disorders: Journal of
the International Association for the Study of Obesity, 25, 496-501.
Hauner, H., Meier, M., Jockel, K. H., Frey, U. H., & Siffert, W. (2003). Prediction of successful
weight reduction under sibutramine therapy through genotyping of the G-protein beta3 subunit
gene (GNB3) C825T polymorphism. Pharmacogenetics, 13, 453-459.
Hazenberg, B. P. (2000). Randomized, double-blind, placebo-controlled, multicenter study of
sibutramine in obese hypertensive patients. Cardiology, 94, 152-158.
Heck, A. M., Calis, K. A., McDuffie, J. R., Carobene, S. E., & Yanovski, J. A. (2002). Additive
gastrointestinal effects with concomitant use of olestra and orlistat. Annals of Pharmacotherapy, 36,
1003-1005.
Hensrud, D. D. (2000). Pharmacotherapy for obesity. Medical Clinics of North America, 84, 463476.
Hensrud, D. D. (2004). Diet and obesity. Current Opinion in Gastroenterology, 20, 119-124.
Hensrud, D. D., Billington, C., Blum, H. T., & Gonzales-Campoy, J. M. (2003). Pharmacological
approaches to weight loss. Bloomington, M.N.: Institute for Clinical Systems Improvement (ICSI).
Heymsfield, S. B., Segal, K. R., Hauptman, J., Lucas, C. P., Boldrin, M. N., Rissanen, A.,
Wilding, J. P., et al. (2000). Effects of weight loss with orlistat on glucose tolerance and
progression to type 2 diabetes in obese adults. Archives of Internal Medicine, 160, 1321-1326.
Heymsfield, S. B., Van Mierlo, C. A. J., Van Der Knaap, H. C. M., Heo, M., & Frier, H. I.
(2003). Weight management using a meal replacement strategy: meta and pooling analysis from
six studies. International Journal of Obesity, 27, 537-549.
Hollander, P. A., Elbein, S. C., Hirsch, I. B., Kelley, D., McGill, J., Taylor, T., Weiss, S. R., et al.
(1998). Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year
randomized double-blind study. Diabetes Care, 21, 1288-1294.
James, W. P., Astrup, A., Finer, N., Hilsted, J., Kopelman, P., Rossner, S., Saris, W. H., et al.
(2000). Effect of sibutramine on weight maintenance after weight loss: a randomised trial.
STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet, 356,
2119-2125.
James, W. P. T. (2001). A new drug to maintain weight loss. Hospital Practice, 36, 22-23.
Jung, R.T. (1997). Obesity as a disease. British Medical Bulletin, 53, 307-321.
Kim, S. H., Lee, Y. M., Jee, S. H., & Nam, C. M. (2003). Effect of sibutramine on weight loss
and blood pressure: a meta-analysis of controlled trials. Obesity Research, 11, 1116-1123.
Krempf, M., Louvet, J. P., Allanic, H., Miloradovich, T., Joubert, J. M., & Attali, J. R. (2003).
Weight reduction and long-term maintenance after 18 months treatment with orlistat for
obesity. International Journal of Obesity & Related Metabolic Disorders: Journal of the International
Association for the Study of Obesity, 27, 591-597.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
116
Lamotte, M., Annemans, L., Lefever, A., Nechelput, M., & Masure, J. (2002). A health
economic model to assess the long-term effects and cost-effectiveness of orlistat in obese type
2 diabetic patients. Diabetes Care, 25, 303-308.
Lean, M. E. J. (2001). How does sibutramine work? International Journal of Obesity, 25, S8-S11.
Leung, W. Y., Neil Thomas, G., Chan, J. C., & Tomlinson, B. (2003). Weight management and
current options in pharmacotherapy: orlistat and sibutramine. Clinical Therapeutics, 25, 58-80.
Manson, J. E., Colditz, G. A., Stampfer, M. J., Willett, W. C., Rosner, B., Monson, R. R.,
Speizer, F. E., et al. (1990). A prospective study of obesity and risk of coronary heart disease in
women. New England Journal of Medicine, 322, 882-889.
McElroy, S.L., Arnold, L.M., Shapira, N.A., Keck, P.E., Rosenthal, N.R., Karim, M.R. (2003).
Topiramate in the treatment of binge eating disorder associated with obesity: a randomized,
placebo-controlled trial. American Journal of Psychiatry, 160, 255-261.
McKay, R. H. (1973). Long-term use of diethylpropion in obesity. Current Medical Research &
Opinion, 1, 489-493.
McNulty, S. J., Ur, E., & Williams, G. (2003). A randomized trial of sibutramine in the
management of obese type 2 diabetic patients treated with metformin. Diabetes Care, 26, 125131.
McTigue, K. M., Harris, R., Hemphill, B., Lux, L., Sutton, S., Bunton, A. J., & Lohr, K. N.
(2003). Screening and interventions for obesity in adults: summary of the evidence for the U.S.
Preventive Services Task Force. Annals of Internal Medicine, 139.
Medicines Control Agency Committtee on Safety in Medicines (2004). Important safety
message: European withdrawal of anorectic agents/appetite suppressants: new legal
developments, no new safety issues: Licences for phentermine and amfepramone being
withdrawn May 2001. Available from:
http://www.mca.gov.uk/ourwork/monitorsafequalmed/safetymessages/anorectic.htm
Medsafe (2003). Duromine™: phentermine capsules 15mg and 30mg: data sheet. Wellington: NZ,
Ministry of Health.
Medsafe (2004a). REDUCTIL®: sibutramine hydrochloride: data sheet. Wellington: NZ, Ministry of
Health.
Medsafe (2004b). Tenuate dospan: diethylpropion hydrochloride 75 mg tablet: data sheet. Wellington: NZ,
Ministry of Health.
Medsafe (2004c). Xenical®: orlistat 120mg capsules: data sheet. Wellington: NZ, Ministry of Health.
Muls, E., Kolanowski, J., Scheen, A., & Van Gaal, L. (2001). The effects of orlistat on weight
and on serum lipids in obese patients with hypercholesterolemia: a randomized, double-blind,
placebo-controlled, multicentre study. International Journal of Obesity, 25, 1713-1721.
Munro, J. F. (1979). Clinical aspects of the treatment of obesity by drugs: a review. International
Journal of Obesity, 3, 171-180.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
117
Munro, J. F., MacCusih, A. C., & Wilson, E. M. (1968). Comparison of continuous and
intermittent anorectic therapy in obesity. BMJ, 1, 352-354.
NHS Centre for Reviews and Dissemination (1997). The prevention and treatment of obesity.
Effective Health Care, 3.
Nisoli, E., & Carruba, M. O. (2003). A benefit-risk assessment of sibutramine in the
management of obesity. Drug Safety, 26, 1027-1048.
Oliveria, S. A., Felson, D. T., Cirillo, P. A., Reed, J. I., & Walker, A. M. (1999). Body weight,
body mass index, and incident symptomatic osteoarthritis of the hand, hip, and knee.
Epidemiology, 10, 161-166.
O'Meara, S., Glenny, A. M., Sheldon, T., Melville, A., & Wilson, C. (1998). Systematic review of
the effectiveness of interventions used in the management of obesity. Journal of Human Nutrition
& Dietetics, 11, 203-206.
O'Meara, S., Riemsma, R., Shirran, L., Mather, L., & ter Riet, G. (2001). A rapid and systematic
review of the clinical effectiveness and cost-effectiveness of orlistat in the management of
obesity. Health Technology Assessment, 5, 1-81.
O'Meara, S., Riemsma, R., Shirran, L., Mather, L., & ter Riet, G. (2002). The clinical
effectiveness and cost-effectiveness of sibutramine in the management of obesity: a technology
assessment. Health Technology Assessment, 6, 1-97.
Padwal, R., Li, S. K., & Lau, D. C. W. (2004). Long-term pharmacotherapy for obesity and
overweight. Cochrane Database of Systematic Reviews.
Poston, W. S. C., Haddock, C. K., Dill, P. L., Thayer, B., & Foreyt, J. P. (2001). Lifestyle
treatments in randomized clinical trials of pharmacotherapies for obesity. Obesity Research, 9,
552-563.
Proietto, J., & Baur, L. A. (2004). Management of obesity. Medical Journal of Australia, 180, 474480.
Rimm, E. B., Stampfer, M. J., Giovannucci, E., Ascherio, A., Spiegelman, D., Colditz, G. A., &
Willett, W. C. (1995). Body size and fat distribution as predictors of coronary heart disease
among middle-aged and older US men. American Journal of Epidemiology, 141, 1117-1127.
Rissanen, P., Vahtera, E., Krusius, T., Uusitupa, M., & Rissanen, A. (2001). Weight change and
blood coagulability and fibrinolysis in healthy obese women. International Journal of Obesity &
Related Metabolic Disorders: Journal of the International Association for the Study of Obesity, 25, 212-218.
Rothman, R. B., & Baumann, M. H. (2000). Neurochemical mechanisms of phentermine and
fenfluramine: therapeutic and adverse effects. Drug Development Research, 51, 52-65.
Rothman, R. B., Redmon, J. B., Raatz, S. K., Kwong, C. A., Swanson, J. E., & Bantle, J. P.
(2000). Chronic treatment with phentermine combined with fenfluramine lowers plasma
serotonin. American Journal of Cardiology, 85, 913-915.
Schuh, L. M., Schuster, C. R., Hopper, J. A., & Mendel, C. M. (2000). Abuse liability assessment
of sibutramine, a novel weight control agent. Psychopharmacology, 147, 339-346.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC
118
Silverstone, T. (1992). Appetite suppressants: a review. Drugs, 43, 820-836.
Sjostrom, L., Rissanen, A., Andersen, T., Boldrin, M., Golay, A., Koppeschaar, H. P. F., &
Krempf, M. (1998). Randomised placebo-controlled trial of orlistat for weight loss and
prevention of weight regain in obese patients. Lancet, 352, 167-172.
Steel, J. M., Munro, J. F., & Duncan, L. J. (1973). A comparative trial of different regimens of
fenfluramine and phentermine in obesity. Practitioner, 211, 232-236.
Tambascia, M. A., Geloneze, B., Repetto, E. M., Geloneze, S. R., Picolo, M., & Magro, D. O.
(2003). Sibutramine enhances insulin sensitivity ameliorating metabolic parameters in a doubleblind, randomized, placebo-controlled trial. Diabetes, Obesity & Metabolism, 5, 338-344.
Thearle, M., & Aronne, L. J. (2003). Obesity and pharmacologic therapy. Endocrinology &
Metabolism Clinics of North America, 32, 1005-1024.
Torgerson, J. S. (2004). Preventing diabetes in the obese: the XENDOS study and its context.
British Journal of Diabetes & Vascular Disease, 4, 22-27.
Torgerson, J. S., Hauptman, J., Boldrin, M. N., & Sjostrom, L. (2004). XENical in the
prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an
adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes Care,
27, 155-161.
Truant, A. P., Olon, L. P., & Cobb, S. (1972). Phentermine resin as an adjunct in medical
weight reduction: a controlled, randomized, double-blind prospective study. Current Therapeutic
Research, Clinical & Experimental, 14, 726-738.
Wadden, T. A., Berkowitz, R. I., Womble, L. G., Sarwer, D. B., Arnold, M. E., & Steinberg, C.
M. (2000). Effects of sibutramine plus orlistat in obese women following 1 year of treatment by
sibutramine alone: a placebo-controlled trial. Obesity Research, 8, 431-437.
Warren, E., Brennan, A., & Akehurst, R. (2004). Cost-effectiveness of sibutramine in the
treatment of obesity. Medical Decision Making, 24, 9-19.
Weintraub, M., Hasday, J. D., Mushlin, A. I., & Lockwood, D. H. (1984). A double-blind
clinical trial in weight control. Use of fenfluramine and phentermine alone and in combination.
Archives of Internal Medicine, 144, 1143-1148.
Weintraub, M., Rubio, A., Golik, A., Byrne, L., & Scheinbaum, M. L. (1991). Sibutramine in
weight control: a dose-ranging, efficacy study. Clinical Pharmacology & Therapeutics, 50, 330-337.
Wilding, J. (2004). Clinical evaluation of anti-obesity drugs. Current Drug Targets, 5, 325-332.
Wilson, B. D., Wilson, N. C., & Russell, D. G. (2001). Obesity and body fat distribution in the
New Zealand population. New Zealand Medical Journal, 114, 127-130.
Wirth, A., & Krause, J. (2001). Long term weight loss with sibutramine: randomized controlled
trial. JAMA, 286, 1331-1339.
EVIDENCE BASED REVIEW OF WEIGHT LOSS MEDICINES: A REPORT COMMISSIONED BY THE NEW ZEALAND ACC