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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. 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