What is the clinical effectiveness and cost-effectiveness of using drugs in treating obese patients in primary care? A systematic review.

BACKGROUND: Obesity [defined as a body mass index (BMI) ≥ 30 kg/m(2)] represents a considerable public health problem and is associated with a significant range of comorbidities and an increased mortality risk. The primary aim of the management of obesity is to achieve weight reduction in the interests of health. For obese patients who cannot achieve or maintain a healthy weight by non-pharmacological means, drug therapy is recommended in combination with non-pharmacological interventions such as dietary modifications and exercise. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of three pharmacological interventions in obese patients. DATA SOURCES: Clinical effectiveness data used in the meta-analysis were sourced from articles identified in a systematic review of the literature. Data used to inform transitions to obesity-related comorbidities were derived from the General Practice Research Database (GPRD). The results of the meta-analysis and GPRD analyses informed the economic model supplemented by data from the Health Survey for England and other UK-specific data sourced from the literature. REVIEW METHODS: A systematic literature review was conducted of the clinical effectiveness and cost-effectiveness of orlistat, sibutramine and rimonabant within their licensed indications for the treatment of obese patients. Electronic bibliographic databases including MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases and Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched in January 2009, and the reference lists of relevant articles were checked. Studies were included if they compared orlistat, sibutramine or rimonabant with lifestyle and/or exercise advice (standard care), placebo or metformin. RESULTS: Overall, 94 studies involving 24,808 individuals were included in the clinical meta-analysis. Eighty-three trials included data on weight change, 41 included data on BMI change and 45 and 36 studies reported on 5% and 10% body weight loss, respectively. Overall, the results show that the active drug interventions are all effective at reducing weight and BMI compared with placebo. In the case of sibutramine, the higher dose (15 mg) resulted in a greater reduction than the lower dose (10 mg). Generally, the data quality of the trials included was low with poor reporting of standard errors and standard deviations. Results from the BMI risk models derived from the GPRD showed consistent increases in risk with increasing BMI. Adjustments for key confounders, such as age, sex and smoking status, were found to be statistically significant at the 5% level, in all risk models. Applying linear models to estimate BMI trajectories, for the diabetic cohort, an average increase in BMI of 0.040 per year for both men and women was observed. The non-diabetic cohort model showed an increase in BMI of 0.175 per year for women and 0.145 per year for men. The results of the cost-effectiveness analyses suggest that sibutramine 15 mg dominates the other three active interventions and the net benefit analyses show that sibutramine 15 mg is the most cost-effective alternative for thresholds > £2000 per quality-adjusted life-year (QALY). However, both sibutramine and rimonabant have been withdrawn because of safety concerns relating to potential treatment-induced fatal adverse events. If the proportion of patients who experienced a fatal adverse event was > 1.8% (1.5%, 1.0%) for sibutramine 15 mg (sibutramine 10 mg, rimonabant) the treatment would not be considered cost-effective when using a threshold of £20,000 per QALY. LIMITATIONS: The clinical review did not include all possible lifestyle comparators, with the inclusion limited to only those trials included one of the active drug interventions. We also excluded all studies not reported in English. Although the clinical review included data from 94 studies, the quality of data was generally low, particularly in terms of the reporting of standard deviation. There was also inconsistency between the results of the mixed-treatment comparison (MTC) and the pair-wise analyses. CONCLUSION: The MTC of anti-obesity treatments shows that all the active treatments are effective at reducing weight and BMI. The economic results show that, compared with placebo, the treatments are all cost-effective when using a threshold of £20,000 per QALY, and, within the limitations of the data available, sibutramine 15 mg dominates the other three interventions. This work has highlighted many areas of methodological research that could be explored, including assessing inconsistencies within a network to determine differences between the results of pair-wise and MTC analyses; the use of meta-regression methods to look for effect modifiers; exploring the effect of local publication bias; and the use of joint models to analyse the repeated measures of BMI and the time-to-event processes simultaneously. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Cost-effectiveness of pharmacotherapy to reduce obesity.

AIMS: Obesity causes a high disease burden in Australia and across the world. We aimed to analyse the cost-effectiveness of weight reduction with pharmacotherapy in Australia, and to assess its potential to reduce the disease burden due to excess body weight. METHODS: We constructed a multi-state life-table based Markov model in Excel in which body weight influences the incidence of stroke, ischemic heart disease, hypertensive heart disease, diabetes mellitus, osteoarthritis, post-menopausal breast cancer, colon cancer, endometrial cancer and kidney cancer. We use data on effectiveness identified from PubMed searches, on mortality from Australian Bureau of Statistics, on disease costs from the Australian Institute of Health and Welfare, and on drug costs from the Department of Health and Ageing. We evaluate 1-year pharmacological interventions with sibutramine and orlistat targeting obese Australian adults free of obesity-related disease. We use a lifetime horizon for costs and health outcomes and a health sector perspective for costs. Incremental Cost-Effectiveness Ratios (ICERs) below A$50 000 per Disability Adjusted Life Year (DALY) averted are considered good value for money. RESULTS: The ICERs are A$130 000/DALY (95% uncertainty interval [UI] 93 000-180 000) for sibutramine and A$230 000/DALY (170 000-340 000) for orlistat. The interventions reduce the body weight-related disease burden at the population level by 0.2% and 0.1%, respectively. Modest weight loss during the interventions, rapid post-intervention weight regain and low adherence limit the health benefits. CONCLUSIONS: Treatment with sibutramine or orlistat is not cost-effective from an Australian health sector perspective and has a negligible impact on the total body weight-related disease burden.

Cost-effectiveness of pharmacological anti-obesity treatments: a systematic review.

AIM: To review economic evaluations of weight loss drugs and compare reported incremental cost-effectiveness ratios (ICERs). METHODS: A literature search was conducted for cost-effectiveness (CEAs) and cost-utility analyses (CUAs) of sibutramine, orlistat and rimonabant. RESULTS: Fourteen unique articles were identified (11 CUAs and 3 CEAs; 9 orlistat, 4 sibutramine and 1 rimonabant). All used diet and exercise as comparator, whereas none included indirect costs. Time horizons varied from treatment period only (1-4 years) to 80 years (median 7.5 years). Longer studies modeled effects on diabetes, micro- and macrovascular complications, coronary heart disease and death. Of the CUAs, the median ICER was 16,000 euro(2007)/QALY (quality-adjusted life-year; range 10,000-88,000), with the worst cost-effectiveness when recommended stop rules for non-responding patients were not applied. All studies but three were funded by the manufacturing company, and the median ICER was considerably higher for independent than for sponsored analyses (62,000 euro vs 15,000 euro/QALY). However, two of the three independent CUAs did not use recommended stop rules, as compared with one of eight manufacturer-sponsored analyses. The results were most sensitive to assumptions regarding weight loss sustainability and utility per kilogram lost. Side effects and dropout because of reasons other than lack of efficacy were generally not incorporated. CONCLUSION: Published economic evaluations indicate that orlistat, sibutramine and rimonabant are within the range of what is generally regarded as cost-effective. Uncertainty remains about weight loss sustainability, utility gain associated with weight loss and extrapolations from transient weight loss to long-term health benefits. Modeling of head-to-head comparisons and attrition is needed, as are analyses conducted independently of manufacturing companies.

The cost-effectiveness of sibutramine in non-diabetic obese patients: evidence from four Western countries.

This paper aims to assess the cost-effectiveness of sibutramine in treating obese patients in the Western countries. The model estimates the costs and quality of life benefits directly associated with weight losses combined with the costs and benefits associated with the reduced incidence of coronary heart disease (CHD) and diabetes. The pivotal effectiveness evidence is derived from a German multicentre, double-blind, randomized clinical trial on obese (body mass index >/= 30 Euro kg m(-2)) patients. The incremental cost per quality-adjusted life year ranges from 10,734 Euro in Switzerland to 13,707 Euro in Germany. The total number of CHD events avoided ranges from 1.96 for the UK to 4.49 for Switzerland. The number of diabetes cases avoided is in the region of 3.0 (ranges from 2.58 for Germany to 3.28 for Switzerland). The majority of costs and benefits are accrued through sibutramine treatment and monitoring. Univariate sensitivity analyses show that results are sensitive to changes in the utility directly attributable to weight losses. The results demonstrate that the benefits associated with sibutramine-induced weight losses are obtained at a reasonable cost in each of the settings explored and suggest that sibutramine treatment could be considered as a viable option for pharmacotherapy treatment alongside diet and exercise.

National trends in the use and costs of anti-obesity medications in England 1998-2005.

BACKGROUND: To report the trends in the use and costs of anti-obesity medications in England from 1998 to 2005. METHODS: We analysed data on all community anti-obesity drug prescriptions in England collated by the prescription cost analysis system. RESULTS: Between 1998 and 2005, Orlistat prescriptions rose 36-fold from 17,880 to 646,700 and total cost increased by over 35-fold. Sibutramine prescriptions rose from 2001 to 2005 from 53,393 to 227,000, a 4-fold increase. Although prescriptions of Orlistat and Sibutramine have increased substantially since they were first introduced, the rate of growth decreased substantially in recent years until 2005, when a significant increase in the number and cost of prescriptions for orlistat occurred yet again. CONCLUSIONS: We found a large increase in the use and costs of anti-obesity prescriptions, consistent with the increased awareness of obesity amongst health care professionals and the public. Despite this large increase, there are still no head-to-head studies at a national level that directly compare all anti-obesity medication in use in the UK.

Assessment of clinical and economic benefits of weight management with sibutramine in general practice in Germany.

Obesity is associated with major health risks and a high economic burden impacting on health care systems. This study utilises the latest evidence from randomised clinical trials (RCTs) to explore and to assess the cost effectiveness of sibutramine in combination with diet and lifestyle advice compared to diet and lifestyle advice alone for the treatment of obese subjects without comorbidities at baseline in Germany. New evidence from recently published RCTs and post-marketing surveillance studies, including health economic data as well as quality of life (QoL) data, were used to model the long-term outcomes of weight management with sibutramine in German practice. German healthcare costs and new data from over 8,000 patients were analysed based on a recently published model. These new RCT data were used to model weight losses, proportion of responders to treatment, utilities by weight loss and variability in weight regain post-treatment. Costs and QoL benefits associated with weight loss (using SF-36 data from sibutramine trials), reduced incidence of coronary heart disease (using Framingham equations) and diabetes were used to estimate the cost per quality adjusted life year of sibutramine treatment. For 1,000 patients treated with sibutramine for 1 year, extrapolating outcomes over 4 further years, sibutramine is estimated to save 4.18 CHD events, 2.58 diabetes incident cases and give 51.5 more quality-adjusted life years (QALYs). The cost-utility analysis (CUA) estimates 13,706 euro per QALY gained. Results are sensitive to changes in weight loss, rate of weight regain and discounting rate. Although the non-pharmacological weight management programme in the comparator arm yielded higher weight losses than generally observed in clinical practice, these results demonstrate that additional sibutramine treatment is a cost effective therapy for an obese population without comorbidities in Germany. The CUA results are within the range generally accepted as cost effective and should be viewed as conservative when generalizing to settings offering standard non-pharmacological treatment.

Cost-effectiveness of sibutramine in the LOSE Weight Study: evaluating the role of pharmacologic weight-loss therapy within a weight management program.

UNLABELLED: the cost-effectiveness of drug therapy when used in conjunction with a weight management program (WMP) for treatment of obesity. The objective was to compare the cost-effectiveness of sibutramine (Meridia) plus a structured WMP versus only a structured WMP in both overweight and obese individuals. The core WMP was a physician-supervised, multidisciplinary program for which each enrollee paid $100 out of pocket. METHODS: A cost-effectiveness analysis was performed based upon the results of a previously published randomized controlled trial conducted within a managed care organization. The target population for this study was obese or overweight persons. The perspective of the study was that of a managed care organization. The intervention consisted of subjects receiving a WMP with or without sibutramine. The primary outcomes of this study were (a) absolute change in body weight and percentage change in body weight over 12 months, (b) change in obesity-related and total medical costs from 12 months prior to enrollment through 12 months after enrollment, and (c) cost-effectiveness in terms of cost per pound of weight loss. All costs were adjusted to 2004 dollars using the respective components of the consumer price index for each medical service or medication. RESULTS: A total of 501 evaluable subjects were enrolled in the study, with 281 receiving sibutramine plus a structured WMP and 220 receiving only the structured WMP. The meanSD weight loss was significantly greater in the sibutramine (13.715.5 pounds, 4.8%) group than in the nondrug group (513.2 pounds, 2.2%) (P < 0.001). The change in obesity-related total cost was a median increase of $408 for the sibutramine group compared with $31 for the nondrug group (P < 0.001). The change in total health care cost was a median $1,279 increase in the sibutramine group compared with $271 for the nondrug group (P < 0.001). Adding sibutramine to the WMP increased the total cost by $44 per additional pound of weight loss (95% confidence interval, 42-46). Sensitivity analyses found that the results were sensitive to the price of sibutramine, whereas varying the cost of clinic visits did not substantially change the results. CONCLUSION: Patients enrolled in a WMP receiving sibutramine had greater weight loss and decrease in body mass index at greater cost than did patients enrolled in the same program who did not receive sibutramine. There were no observed savings in total health care resource utilization or cost in the sibutramine group compared with the nondrug group.

Does prior authorization of sibutramine improve medication compliance or weight loss?

OBJECTIVE: This study was designed to examine whether prior authorization for insurer reimbursement of weight loss medication affects compliance with taking sibutramine or adherence to a medical weight control program. The underlying hypothesis is that physician advocacy through prior authorization increases patient compliance and treatment outcomes. RESEARCH METHODS AND PROCEDURES: A retrospective review was conducted of 22 subjects who had received a prescription for sibutramine that was reimbursed through their health insurer by prior authorization (PAR) and compared them with 47 randomly selected subjects who were also prescribed sibutramine but did not receive reimbursement (non-PAR). Outcome measures included the percentage weight lost, visits to the clinic, and number of prescriptions received at 3, 6, 9, and 12 months. RESULTS: The proportion of subjects remaining in the clinic program, the number of clinic visits made, the number of prescriptions received, and the amount of weight lost were all significantly greater among PAR subjects than among non-PAR subjects. PAR subjects used the medication 37% longer by month 6 (2.43 vs. 1.52 prescriptions; p<0.02), visited the clinic 44% more often (72.5 vs. 40.5 visits in 12 months; p<0.0006), and achieved 38% better maximal weight loss (16% vs. 9.9% at 6 months; p<0.49) than non-PAR subjects. DISCUSSION: This study suggests that, when those medications are not included on a health insurer's formulary, the use of the prior authorization process may improve both medication and behavioral compliance.

Cost-effectiveness of sibutramine in the treatment of obesity.

BACKGROUND: This study reports incremental cost-utility of sibutramine compared to diet and lifestyle advice for the treatment of obesity. METHOD: The model estimates the costs and quality of life benefits associated with weight loss itself and the reduced incidence of coronary heart disease (CHD) and diabetes in the "healthy obese." The key source of effectiveness data is 2 randomized controlled trials over 12 months. Utility gain per kilogram lost is analyzed using Short Form-36 data from sibutramine trials. The impact on CHD is estimated using the Framingham risk equation, which relates age/sex/body mass index to risk of heart disease. The reduced incidence of diabetes due to weight loss is estimated from published literature. A life tables approach was used to calculate the cost per quality-adjusted life year (QALY) of 1 year's treatment with sibutramine compared to diet and lifestyle advice. RESULTS: The incremental cost per QALY of sibutramine is 4,780 UK pounds. Sensitivity analyses show that this result is sensitive to utility associated with weight loss and the frequency of monitoring. CONCLUSIONS: Sibutramine is a cost-effective treatment for obesity when combined with diet and lifestyle advice.