Cost-effectiveness of rosiglitazone combination therapy for the treatment of type 2 diabetes mellitus in the UK Beale S, Bagust A, Shearer A T, Martin A, Hulme L Record Status 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. Health technology The study compared two treatment options for patients with Type 2 diabetes. Each treatment option comprised six steps and differed in the fourth and fifth steps regarding medical treatment following the failure of metformin monotherapy. The first three steps comprised diet and exercise, metformin medium dose, and metformin high dose. After failure of metformin monotherapy: group one received metformin (high dose) plus sulfonylurea (medium dose) (fourth step), followed by metformin (high dose) and sulfonylurea (high dose) (fifth step); and group two received metformin (high dose) plus rosiglitazone (low dose) (fourth step), followed by metformin (high dose) and rosiglitazone (high dose) (fifth step). The sixth step for both groups was insulin. Type of intervention Treatment. Economic study type Cost-effectiveness analysis and cost-utility analysis. Study population The study population comprised a hypothetical cohort of 1,000 patients with Type 2 diabetes who were either obese or overweight. No further inclusion or exclusion criteria were described. Setting The setting was not explicitly stated. The economic study was carried out in the UK. Dates to which data relate The effectiveness data were derived from sources published between 1995 and 2006. The cost data were derived from various sources published between 2000 and 2003. The price year was 2003. Source of effectiveness data The effectiveness data were derived from a review and synthesis of published studies, augmented, when necessary, by authors' assumptions. Modelling Page: 1 / 6
The authors used two linked published models (Bagust et al. 2001 and 2006, see 'Other Publications of Related Interest' below for bibliographic details). The linking of a metabolic model and a long-term economic model of health care for Type 2 diabetes mellitus (the Diabetes Decision Analysis of Cost Type 2, DiDACT) allowed the authors to account for the long-term natural history, including long-term complications as well as associated costs, resource use and health outcomes. Full details of the two models were given in two previous studies. The analysis was conducted over the patients' lifetime. Post-publication, the economic model was revised and improved in two areas. The Framingham cardiovascular risk models were replaced with the risk estimations from the United Kingdom Prospective Diabetes Study (Stevens et al. 2001, see 'Other Publications of Related Interest' below for bibliographic details), and a mechanism to allow the generation of quality-adjusted life-years (QALYs) was added. Outcomes assessed in the review For the calibration of treatment effects within the model, treatments were assessed for their effects on some key metabolic parameters. The direct treatment effects of the following monotherapy and combination therapy regimens were studied: metformin intermediate dose; metformin maximum dose; metformin maximum dose plus sulfonylurea intermediate dose; metformin maximum dose plus sulfonylurea maximum dose; metformin maximum dose plus rosiglitazone 4 mg once daily; metformin maximum dose plus rosiglitazone 4 mg twice daily; elec insulin 20 units per day. The key metabolic parameters included insulin sensitivity, beta-cell function, body mass index, plasma glucose, basal insulin, systolic and diastolic blood pressure, triglycerides, high- and low-density lipoprotein cholesterol and total cholesterol. Further parameters included patient characteristics on diagnosis, the order in which treatment options were prescribed, and the rate of dose escalation. Study designs and other criteria for inclusion in the review Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Since many of the parameters used in the model were not described in detail and their source was not referenced, it is Page: 2 / 6
impossible to know the exact number of primary studies included in the review. In the present study at least 19 studies were referenced as sources of effectiveness data. Methods of combining primary studies Investigation of differences between primary studies It was unclear if the authors investigated differences between the primary studies. Results of the review Given that the two models used were published elsewhere, not all of the parameters were fully reported in this paper. It was reported that at 6 months after the initiation of rosiglitazone 4 mg once a day, insulin sensitivity improved by 5.5% and beta-cell function by 6.3%. When the dose was doubled (4 mg of rosiglitazone twice a day), insulin sensitivity improved by 11.8% and beta-cell function by 11.3%. Methods used to derive estimates of effectiveness The authors made assumptions to derive some estimates of effectiveness. Estimates of effectiveness and key assumptions The authors followed European clinical guidelines for total cholesterol and low-density lipoprotein cholesterol levels after rosiglitazone treatment. They assumed that an additional 25% of patients receiving rosiglitazone would necessitate complementary lipid-lowering therapy to keep up with the suggested total cholesterol levels. For the combination treatment options of metformin and rosiglitazone, the authors assumed that the two drugs would result in an additive effect without interactions. This assumption was based on the fact that the modes of action for these two drugs are independent. However, the authors explicitly stated that there was no clinical evidence available to oppose this assumption. Measure of benefits used in the economic analysis The measures of benefit used were the health utility (QALYs) and life-years gained (LYG). The authors used data on health-related quality of life (using the EuroQol EQ5D instrument), gathered from another study (CODE-2), to construct a statistical predictive model of utility score related to health states and complications of Type 2 diabetes. Direct costs The following health service costs were included in the analysis: inpatient costs (admission cost and hospital bed per day cost) of primary diagnosed complication (i.e. diabetes, nephropathy, retinopathy, neuropathy/ skin infection, heart disease, stroke, cancer, cataract, and other diseases not specifically mentioned); the cost per outpatient visit (anaesthetics, cardiology, cardiothoracic surgery, clinical pharmacology, dermatology, ear nose and throat, general medicine, general surgery, gynaecology, haematology, mental handicap, mental illness, neurology, neurosurgery, obstetrics, ophthalmology, palliative medicine, plastic surgery, radiotherapy, rehabilitation, rheumatology, thoracic medicine, trauma and orthopaedic and urology); the cost of dialysis (hospital and home haemodialysis and peritoneal); and Page: 3 / 6
the cost of community and primary-care attendance (including general practitioner visit, chiropodist visit, dietician visit, practice nurse visit). The economic analysis included medication costs for: sulfonylurea, intermediate (5 mg once daily) and maximum (5 mg twice daily) doses; metformin, intermediate (850 mg twice daily)and maximum (850 mg three times daily) doses; rosiglitazone, intermediate dose (4 mg once daily) and maximum (4 mg twice daily); simvastatin, 20 mg daily (administered with rosiglitazone); and insulin 40 IU ("20 IU three times a day, including needles"). The unit costs were reported. All costs were derived from official sources and were appropriately inflated to reflect 2003 prices. As costs were incurred over more than 2 years, the costs were appropriately discounted. Statistical analysis of costs The costs were treated deterministically. Indirect Costs Inline with the perspective adopted, the indirect costs were not included in the analysis. Currency UK pounds sterling (). Sensitivity analysis The authors conducted numerous one-way sensitivity analyses to assess the robustness of the results to variability in the data. The threshold for HbA1c was changed from 7.5 to 8% in a sensitivity analysis. A discount rate of 3.5% was used for both costs and outcomes in the base-case analysis, while in the sensitivity analysis a discount rate of 6% was used for the costs and 1.5% for the outcomes. In addition, the mean body mass index of the cohort at diagnosis was decreased and increased by 1 kg/m2. The ranges used in the sensitivity analysis appear to have been derived mainly from the literature. Estimated benefits used in the economic analysis Only incremental benefits were reported. The incremental discounted QALYs and LYG for the alternative treatment option (combination of metformin plus rosiglitazone) compared with the conventional treatment option (metformin plus sulfonylurea) were 99 (QALYs) and 78 (LYG), respectively, for the obese patient cohort (1,000 patients) and 148 and 86 for the overweight patient cohort (1,000 patients). Cost results An incremental analysis was performed. The incremental discounted costs for the alternative treatment option were 1.65 million for the obese cohort and 1.72 million for the overweight cohort (1,000 patients with Type 2 diabetes in each cohort). Synthesis of costs and benefits An incremental cost-effectiveness analysis was performed. The alternative treatment strategy resulted in discounted, incremental cost-effectiveness ratios (ICERs) of 16,700 per QALY and 21,300 per LYG in the obese cohort of Page: 4 / 6
patients, and 11,600 per QALY and 20,000 per LYG in the overweight cohort of patients. Sensitivity analyses demonstrated that when the therapy-switching threshold increased to 8% HbA1c, the ICER per QALY was decreased to 11,800 in the obese cohort and to 9,900 in the overweight cohort, while the ICER per LYG was reduced to 14,200 in the obese cohort and to 12,600 in the overweight cohort. In the sensitivity analysis using a discount rate of 6% for the costs and 1.5% for the outcomes, the ICERs for QALYs and LYG were reduced in both cohorts of patients. The sensitivity analysis demonstrated the robustness of the results to changes in the mean body mass index of the cohort at diagnosis. Authors' conclusions The authors concluded "the model predicts that rosiglitazone in combination with metformin is a cost-effective treatment in the UK for both obese and overweight patients failing on metformin monotherapy, compared with conventional therapy using metformin in combination with sulfonylurea". CRD COMMENTARY - Selection of comparators An explicit justification was given for the comparators used. The combination treatment of metformin plus sulfonylurea would appear to represent current practice in the authors' setting. You should decide if this represents a widely used technology in your own setting. Validity of estimate of measure of effectiveness It was reported that estimates of effectiveness used in the two linked models were derived from a published systematic review. However, it was not possible to comment on the methodology and conduct of the review since the authors referred to a separate paper for details of the review. Some estimates of effectiveness were based on authors' assumptions, but it is not clear if the justification provided was well founded. To fully assess the internal validity of the effectiveness parameters, the reader is referred to the previous papers (see 'Other Publications of Related Interest' below for bibliographic details. Validity of estimate of measure of benefit The measure of benefit was health utility (QALYs), which was measured using the EuroQol EQ5D instrument, and LYG, which were derived directly from the model. The use of a QALY measure will aid comparisons with other health interventions. Validity of estimate of costs The analysis was performed from the perspective of the UK NHS paying for the treatment. It appears that all the relevant categories of costs have been included in the analysis. The unit costs were reported, thereby enhancing the reproducibility of the study in other settings. The costs were derived from published sources and, when necessary, appropriately adjusted. No sensitivity analysis of the costs or quantities was performed to assess the robustness of the estimates used. Inflation adjustments and discounting were appropriately conducted, and the price year was reported. Overall, the estimation of the costs appears to have been well conducted and thorough. Other issues Given the lack of available studies in the same area, the authors compared their findings with studies that used pioglitazone (instead of rosiglitazone) in combination with metformin, which is a different drug in the thiazolidinediones class of antidiabetic drugs. The comparison demonstrated that their findings were in agreement with other studies. The issue of generalisability of the results to other settings was not directly addressed. As the authors conducted an incremental cost-effectiveness analysis, they only reported incremental costs and benefits. The study Page: 5 / 6
Powered by TCPDF (www.tcpdf.org) enrolled obese and overweight patients with Type 2 diabetes, and this was reflected in the authors' conclusions. The authors acknowledged, as a limitation to their study, that uncertainty in individual treatment modules and surrounding cost estimates was not investigated, partially due to the lack of available data in the literature. However, this may limit the interpretation of the study findings. Implications of the study The authors did not make explicit recommendations for changes in policy or practice, or the need for further research. However, their discussion indicated areas where more information is needed. Source of funding Supported by GlaxoSmithKline. Bibliographic details Beale S, Bagust A, Shearer A T, Martin A, Hulme L. Cost-effectiveness of rosiglitazone combination therapy for the treatment of type 2 diabetes mellitus in the UK. PharmacoEconomics 2006; 24 (Supplement 1): 21-34 PubMedID 16800160 Other publications of related interest Bagust A, Hopkinson PK, Waier W, et al. An economic model of the long-term health care burden of type II diabetes. Diabetologia 2001;44:2140-55. Bagust A, Evans M, Beale S et al. A model of long-term metabolic progression of type 2 diabetes mellitus for evaluating treatment strategies. Pharmacoeconomics 2006;24 Suppl 1:5-19. Bagust A, Beale S. Modelling EuroQol health-related utility values for diabetic complications from CODE-2 data. Health Econ 2005;14:217-30. Stevens RJ, Kothari V, Adler AI, et al. The UKPDS risk engine:a model for the risk of coronary heart disease in type II diabetes (UKPDS 56). Clin Sci 2001;101:671-9. Indexing Status Subject indexing assigned by NLM MeSH Combined Modality Therapy; Cost-Benefit Analysis; Diabetes Complications; Diabetes Mellitus, Type 2 /drug therapy /economics; Drug Therapy, Combination; Economics, Pharmaceutical; Female; Great Britain; Hemoglobin A, Glycosylated /drug effects; Humans; Hypoglycemic Agents /economics /therapeutic use; Male; Metformin /therapeutic use; Models, Economic; Obesity /complications /economics; Quality-Adjusted Life Years; Thiazolidinediones /economics /therapeutic use AccessionNumber 22006008098 Date bibliographic record published 30/11/2006 Date abstract record published 30/11/2006 Page: 6 / 6