|Assessment of clinical and economic benefits of weight management with sibutramine in general practice in Germany
|Brennan A, Ara R, Sterz R, Matiba B, Bergemann R
This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn.
The study examined a 1-year course of sibutramine in combination with diet and lifestyle advice for the treatment of obese patients. Sibutramine was initially given at a dosage of 10 mg/day but could be switched to 15 mg/day in the case of non-response at 1 or 3 months.
Type of intervention
Treatment and primary prevention.
The study population comprised a hypothetical cohort of patients with a body mass index of >= 30 kg/m2. Only patients without co-morbidities were considered.
The setting was primary care. The economic study was carried out in Germany.
Dates to which data relate
The effectiveness data were derived from studies published between 1983 and 2004. No dates for resource use were explicitly reported. The price year was 2003.
Source of effectiveness data
The effectiveness evidence was derived from a synthesis of published studies.
A decision tree model was constructed to model the cost-effectiveness of the two strategies for the treatment of a hypothetical cohort of 1,000 obese patients. The time horizon of the model was 5 years: 1 year of sibutramine treatment plus a further 4 years' follow-up. The model quantified three elements of benefit. These were quality of life gains due to weight loss, reduced risk of coronary heart disease (CHD), and reduced incidence of diabetes. Treatment was limited to 12 months duration for responders. Responders were defined as patients who lost 2 kg after 1 month (first hurdle) and 5% of their initial weight after 3 months (second hurdle). All patients received sibutramine 10 mg/day initially, and switched to 15 mg/day in the case of non-response at 1 month (first hurdle) or 3 months (second hurdle). The structure of the decision tree was reported.
Outcomes assessed in the review
The outcomes estimated from the literature were:
the clinical efficacy of sibutramine (weight loss and percentage of treatment responders),
the monthly weight regain,
the utility values,
the CHD risk reduction, and
relationships between weight loss, diabetes incidence and mortality.
Study designs and other criteria for inclusion in the review
The primary studies appear to have been identified selectively rather than through a systematic review of the literature. Data on the clinical effectiveness of sibutramine came from five RCTs. Specifically, the German Sibutramine Adiposity Therapy (SAT) trial, the Smith trial, the STORM trial, the INTERVAL study, and a German Post-Marketing Surveillance Study (PMOS). The SAT trial provided data on the relationship between responders to treatments and quality of life scores. The Smith trial provided data for weight losses and the proportion of responders to treatment. The STORM trial provided evidence on weight regain after the cessation of sibutramine treatment. The INTERVAL study provided evidence on weight changes for intermittent sibutramine treatment. The PMOS provided evidence on the proportion of responders to treatment included in a sensitivity analysis.
The CHD risk reduction was calculated using the Framingham risk equation. The utility data were obtained using SF-36 data from the SAT trial. Limited information on the other sources of data was provided. The main details of the RCTs, such as baseline demographics and clinical characteristics, sample size and country, were reported. Three of these clinical studies were performed in Germany (SAT, INTERVAL, PMOS). The sample size ranged from 362 (SAT) to 6,360 (PMOS).
Sources searched to identify primary studies
Criteria used to ensure the validity of primary studies
The use of RCTs to derive treatment effectiveness was appropriate and ensures a high internal validity. A further strength of the primary studies was the large sample size of most of the clinical trials.
Methods used to judge relevance and validity, and for extracting data
Number of primary studies included
Twelve primary studies provided the clinical data.
Methods of combining primary studies
Investigation of differences between primary studies
Each study appears to have provided a single estimate.
Results of the review
The proportion of treatment responders at the first hurdle was 59.6% with sibutramine and 50.6% with placebo.
Of those who passed the first hurdle, the proportion of treatment responders at the second hurdle was 65.5% with sibutramine and 66.2% with placebo.
Of those who did not pass the first hurdle, the proportion of treatment responders at the second hurdle was 44.4% with sibutramine and 25.6% with placebo.
When these data were included in the model, it was seen that, at 12 months, the proportion of treatment responders was 66.2% with sibutramine and 50.5% with placebo.
In terms of weight loss, at 12 months the difference between diet and lifestyle advice alone and additional sibutramine therapy was 5.5 kg in favour of sibutramine.
Monthly weight regain for natural history was 0.083 kg.
The average monthly rate of regain following sibutramine treatment was 0.385 kg (95% confidence interval: 0.359 to 0.411; p<0.001).
The increase in utility per kg lost was 0.00375 for the total cohort. Thus, as the average sibutramine responder loses 12 kg over the 12-month period, this equates to an average utility gain of 0.045 over 12 months.
Other data were not reported.
Measure of benefits used in the economic analysis
The summary benefit measure used was the expected number of quality-adjusted life-years (QALYs). These were estimated by combining utility weights and life expectancy, as derived from the published literature. The utility weights were obtained from German patients in the SAT trial. An annual discount rate of 5% was applied to the QALYs. The reductions in the number of CHD-related deaths and nonfatal CHD events, and diabetes incidence were also reported as model outputs.
The analysis of the costs was carried out from the perspective of the third-party payer. It included the costs associated with monitoring (for responders and non-responders), annual management of diabetes, fatal and nonfatal CHD events, and sibutramine. The unit costs were presented separately from the resource quantities for only some items. Other costs were presented as macro-categories. The costs of fatal and nonfatal CHD events were derived from published studies. The drug costs were derived from Red Book prices. No mandatory rebate was considered. Physician services were based on the German physician's fee schedule for statutory health insurances. Resource use was derived from a survey conducted with seven German practitioners specialising in obesity treatment. Some authors' assumptions were also made to derive specific treatment patterns such as the number of visits. Discounting was relevant, as the costs were incurred during longer than 2 years, and an annual rate of 5% was used. All costs were inflated to 2003 values using the German overall Consumer Price Index.
Statistical analysis of costs
The costs were treated deterministically.
The indirect costs were not considered.
A univariate sensitivity analysis was carried out to assess the robustness of the cost-utility ratio to variations in model inputs such as different costs, utility weights and clinical inputs. The discount rate was also varied and some subgroup analyses were carried out (i.e. all females, all males). Alternative sources of values were either based on published data or on authors' opinions.
Estimated benefits used in the economic analysis
The expected 5-year QALYs relating only to weight loss in a hypothetical cohort of 1,000 patients were 10 with placebo and 41 with sibutramine (difference 31).
The cumulative lifetime QALYs relating to weight loss, diabetes and CHD in a hypothetical cohort of 1,000 patients were 20,238 with placebo and 20,290 with sibutramine (difference 51.5).
The use of sibutramine led to a reduction of 138 CHD-related deaths, 280 nonfatal CHD events, and 258 cases of diabetes for every 100,000 patients compared with placebo.
The expected 5-year costs relating only to weight loss in a hypothetical cohort of 1,000 patients were EUR 435,384 with placebo and EUR 1,341,877 with sibutramine (difference EUR 906,493).
The expected costs relating to weight loss, diabetes and CHD in a hypothetical cohort of 1,000 patients were EUR 1,596,320 with placebo and EUR 2,302,468 with sibutramine (difference EUR 706,148).
Synthesis of costs and benefits
An incremental cost-utility ratio was calculated in order to combine the costs and benefits of the alternative strategies.
The incremental cost per QALY gained with sibutramine over placebo was EUR 29,351 when considering the costs and benefits associated only with weight loss.
The incremental cost per QALY gained was EUR 13,706 when considering the costs and benefits associated with not only weight loss but also reductions in diabetes and CHD cases.
The sensitivity analysis showed that the model input with the greatest impact on cost-utility ratios was the proportion of responders to sibutramine treatment.
Using the confidence interval derived from published studies, the incremental cost per QALY ranged from EUR 9,720 to EUR 30,790 depending on the extreme values used.
The most unfavourable cost-utility ratio (EUR 51,027 per QALY) was obtained when using the mean rate weight regain observed in an alternative study (the INTERVAL trial).
The model was also sensitive to delaying weight regain. When the weight loss was held constant for 6 months, as observed in an alternative study, the cost per QALY decreased to EUR 8,235.
The results were more favourable for males than for females since males have a high risk of CHD.
The model was somewhat sensitive to the utility gained directly from weight losses. When the lower value of the confidence interval for this variable was used, the incremental cost per QALY gained rose to EUR 24,459. However, the incremental cost per QALY for 12-month treatment with sibutramine compared with placebo was always lower than EUR 50,000 per QALY.
One-year of sibutramine treatment, administered according to the published protocol for use, was a cost-effective strategy compared with the diet and lifestyle interventions currently received by obese patients in Germany.
CRD COMMENTARY - Selection of comparators
The rationale for the choice of the comparator was clear in that diet and lifestyle interventions reflected the current pattern of care for obese patients. The dosage of sibutramine reflected recommended modalities of drug administration. You should decide whether these are valid comparators in your own setting.
Validity of estimate of measure of effectiveness
The effectiveness data were estimated from published studies, but the authors did not state whether these were identified by means of a systematic review of the literature. However, the selective inclusion of the most recent RCTs appears to have been appropriate in order to include the most relevant sources of data on treatment effectiveness. The use of data from German patients and the large sample size of most clinical trials were further strengths of the analysis. The authors reported extensive information on the characteristics of the patients included in the clinical trials and other aspects of the studies. However, the issue of heterogeneity across the primary studies and their respective samples of patients was not addressed. The sensitivity analysis investigated the robustness of the results of the analysis to variations in the most uncertain clinical inputs.
Validity of estimate of measure of benefit
The benefit measure used in the analysis was appropriate as QALYs capture the impact of the interventions on the most relevant dimensions of health (i.e. survival and quality of life). Further, QALYs can be compared with the benefits of other health care interventions. Disease-specific measures were also reported but were not used in the cost-effectiveness analysis. The QALYs were estimated using quality of life data (SF-36), which represent a typical approach. The use of German patients to obtain utility weights was a strength of the analysis. Discounting was performed and the impact of changing the discount rate was investigated in the sensitivity analysis.
Validity of estimate of costs
The costs included were consistent with the perspective adopted in the study. The sources of the costs, which were reported, were also consistent with this viewpoint. Some costs were expressed as macro-categories and a detailed breakdown of the items was not reported. This will limit the possibility of replicating the analysis in other settings. The resource use data were mainly derived from published surveys and authors' opinions and these assumptions were not tested in the sensitivity analysis. The costs were treated deterministically in the base-case analysis, but extensive sensitivity analyses were performed. Discounting was performed and the impact of changing the discount rate was investigated in the sensitivity analysis. The price year was reported, which will facilitate reflation exercises in other time periods.
The authors did not report the results from other economic evaluations, nor did they compare their findings with those from other studies. In terms of the generalisability of the study results to other settings, the authors noted that most sources of data referred to the German epidemiological setting, thus caution will be required if extrapolating the results of the current analysis to other countries. However, since the effectiveness of the comparator reflected the maximum weight loss achievable through non-pharmacological care, the results of the analysis may also be valid for other settings where less intensive non-pharmacological care is provided. The authors noted that the results of the analysis were likely to have underestimated the true effect of sibutramine, owing to the conservative estimates chosen for model. Thus, more favourable cost-utility estimates could be observed in routine clinical practice. A limitation of the analysis was the assumption that all patients included in the study had no co-morbidities at baseline. This assumption was required because of the lack of data on different sub-groups of patients.
Implications of the study
The study results support the use of sibutramine treatment as part of an integrated approach including dietary and behavioural modification, as well as increased physical activity, to treat obese patients. The availability of data from the Sibutramine Cardiovascular Outcome Trial, the first prospective study to examine the role of obesity management in relation to cardiovascular disease, would help the derivation of more robust assumptions about the long-term relationship between reduction of obesity and incidence of cardiovascular disease.
Source of funding
Financial support from Abbott GmbH and Co, KG.
Brennan A, Ara R, Sterz R, Matiba B, Bergemann R. Assessment of clinical and economic benefits of weight management with sibutramine in general practice in Germany. European Journal of Health Economics 2006; 7: 276-284
Other publications of related interest
Because readers are likely to encounter and assess individual publications, NHS EED abstracts reflect the original publication as it is written, as a stand-alone paper. Where NHS EED abstractors are able to identify positively that a publication is significantly linked to or informed by other publications, these will be referenced in the text of the abstract and their bibliographic details recorded here for information.
Avenell A, Broom J, Brown TJ, et al. Systematic review of the long-term effects and economic consequences of treatments for obesity and implications for health improvement. Health Technol Assess 2004;8(21):111-82.
Warren E, Brennan A, Akehurst R. Cost-effectiveness of sibutramine in the treatment of obesity. Med Decis Making 2004;24:9-19.
Smith IG, Goulder MA. Randomized placebo-controlled trial of long-term treatment with sibutramine in mild to moderate obesity. J Fam Pract 2001;50:505-12.
Hauner H, Meier M, Wendland G, Lauterbach K. Weight reduction by sibutramine in obese subjects in primary care medicine: the SAT study group. Exp Clin Endocrinol Diabetes 2004;112:201-7.
Subject indexing assigned by NLM
Adult; Appetite Depressants /economics /therapeutic use; Coronary Disease /prevention & Cost-Benefit Analysis; Cyclobutanes /economics /therapeutic use; Diabetes Mellitus, Type 2 /prevention & Diet; Female; Germany; Humans; Life Style; Male; Quality of Life; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Weight Loss; control; control
Date bibliographic record published
Date abstract record published