Morten Lammert

The CORE Diabetes Model: Projecting Long-term Clinical Outcomes, Costs and Cost- effectiveness of Interventions in Diabetes Mellitus (Types 1 and 2) to Support Clinical and Reimbursement Decision-making

SUMMARY Objectives: We have developed an Internet-based, interactive computer model to determine the longterm health outcomes and economic consequences of implementing different treatment policies or interventions in type 1 and type 2 diabetes mellitus. The model projects outcomes for populations, taking into account baseline cohort characteristics and past history of complications, current and future diabetes management and concomitant medications, screening strategies and changes in physiological parameters over time. The development of complications, life expectancy, quality-adjusted life expectancy and total costs within populations can be calculated. Methods: The model is based on a series of sub-models that simulate important complications of diabetes (cardiovascular disease, eye disease, hypoglycaemia, nephropathy, neuropathy, foot ulcer, amputation, stroke, ketoacidosis, lactic acidosis and mortality). Each sub-model is a Markov model using Monte Carlo simulation incorporating time, state, time-in state, and diabetes type-dependent probabilities derived from published sources. Analyses can be performed on cohorts with type 1 or type 2 diabetes. Cohorts, defined in terms of age, gender, baseline risk factors and pre-existing complications, can be modified or new cohorts defined by the user. Economic and clinical data in the model can be edited, thus ensuring adaptability by allowing the inclusion of new data as they become available; creation of country- or provider-specific versions of the model; and allowing the investigation of new hypotheses. Conclusions: The CORE Diabetes Model allows the calculation of long-term outcomes, based on the best data currently available. Diabetes management strategies can be compared in different patient populations in a variety of realistic clinical settings, allowing the identification of efficient diabetes management strategies.

Validation of the CORE Diabetes Model Against Epidemiological and Clinical Studies

OBJECTIVES The aim of this study was to assess the validity of the CORE Diabetes Model by comparing results from model simulations with observed outcomes from published epidemiological and clinical studies in type 1 and type 2 diabetes. METHODS A total of 66 second- (internal) and third- (external) order validation analyses were performed across a range of complications and outcomes simulated by the CORE Diabetes Model (amputation, cataract, hypoglycaemia, ketoacidosis, macular oedema, myocardial infarction, nephropathy, neuropathy, retinopathy, stroke and mortality). Published studies were reproduced in the model by recreating cohorts in terms of demographics, baseline risk factors and complications, treatment patterns and patient management strategies, and simulating the progress of the cohort to an equivalent time horizon. RESULTS Correlation analysis on results from 66 validation simulations produced an R2 value of 0.9224 (perfect fit = 1). A correlation plot of published study data versus values simulated by the CORE Diabetes Model had a trend line with a gradient of 1.0187 (perfect fit = 1). Validation analyses in type 1 and type 2 diabetes were associated with R2 values of 0.9778 and 0.8861 respectively. Correlation of second-order validation analyses (model predictions versus observed outcomes in studies used to construct the model) produced an R2 value of 0.9574, and the value for third-order analyses (model predictions versus observed outcomes in studies not used to construct the model) was 0.9023. CONCLUSIONS The CORE Diabetes Model provides an accurate representation of patient outcomes when compared to 66 studies of diabetes and its complications. Model flexibility ensures it can be used to compare diabetes management strategies in different cohorts across a variety of clinical settings.

Multivariate models of health-related utility and the fear of hypoglycaemia in people with diabetes

ABSTRACT Aim: The aim was to statistically model the degree of fear of hypoglycaemia experienced by people with diabetes, and then model the resulting change in health-related utility associated with differing severity and frequency of hypoglycaemia. Methods: The study used pooled data from two previous postal surveys among subjects with confirmed diabetes conducted in Cardiff, UK (n = 1305 responses). The fear of hypoglycaemia was characterised using the Hypoglycaemia Fear Survey (HFS [eight question worry sub-scale only]), and health-related utility using the EQ5Dindex. The data were then analysed using univariate and multivariate analysis. Results: Following detailed preliminary analysis, a two-stage approach was used since fear was important when estimating the EQ5Dindex. Fear was then modelled as a function of the severity and frequency of hypoglycaemia while controlling for other factors such as diabetes-related complications. Each severe hypoglycaemic event resulted in a change of 5.881 units on the HFS. One or more symptomatic hypoglycaemic events over the same period results in a corresponding change of 1.773 units on the HFS. A 1 unit increase on the HFS results in a 0.008 unit decrease on the EQ5Dindex. Conclusion: While controlling for other factors, the fear of hypoglycaemia was an important determinant of health-related utility. The magnitude of fear of hypoglycaemia was associated with the severity and frequency of hypoglycaemia. Hypoglycaemia was associated with a considerable decrement in health-related utility as a function of increased fear. Measures should be taken to minimise the severity and frequency of hypoglycaemia.

Cost-Effectiveness of Intensified Versus Conventional Multifactorial Intervention in Type 2 Diabetes Results and projections from the Steno-2 study

OBJECTIVE—To assess the cost-effectiveness of intensive versus conventional therapy for 8 years as applied in the Steno-2 study in patients with type 2 diabetes and microalbuminuria. RESEARCH DESIGN AND METHODS—A Markov model was developed to incorporate event and risk data from Steno-2 and account Danish-specific costs to project life expectancy, quality-adjusted life expectancy (QALE), and lifetime direct medical costs expressed in year 2005 Euros. Clinical and cost outcomes were projected over patient lifetimes and discounted at 3% annually. Sensitivity analyses were performed. RESULTS—Intensive treatment was associated with increased life expectancy, QALE, and lifetime costs compared with conventional treatment. Mean ± SD undiscounted life expectancy was 18.1 ± 7.9 years with intensive treatment and 16.2 ± 7.3 years with conventional treatment (difference 1.9 years). Discounted life expectancy was 13.4 ± 4.8 years with intensive treatment and 12.4 ± 4.5 years with conventional treatment. Lifetime costs (discounted) for intensive and conventional treatment were €45,521 ± 19,697 and €41,319 ± 27,500, respectively (difference €4,202). Increased costs with intensive treatment were due to increased pharmacy and consultation costs. Discounted QALE was 1.66 quality-adjusted life-years (QALYs) higher for intensive (10.2 ± 3.6 QALYs) versus conventional (8.6 ± 2.7 QALYs) treatment, resulting in an incremental cost-effectiveness ratio of €2,538 per QALY gained. This is considered a conservative estimate because accounting prescription of generic drugs and capturing indirect costs would further favor intensified therapy. CONCLUSIONS—From a health care payer perspective in Denmark, intensive therapy was more cost-effective than conventional treatment. Assuming that patients in both arms were treated in a primary care setting, intensive therapy became dominant (cost- and lifesaving).

Costs of managing severe hypoglycaemia in three European countries

Abstract Objectives: To assess the costs of severe hypoglycaemic events (SHEs) in diabetes patients in Germany, Spain and the UK. Methods: Healthcare resource use was measured by surveying 639 patients aged ≥16 years, receiving insulin for type 1 (n=319) or type 2 diabetes (n=320), who experienced ≥1 SHE in the preceding year. Patients were grouped by location of SHE treatment: group 1, community (family/domestic); group 2, community (healthcare professional); group 3, hospital. Costs were calculated from published unit costs applied to estimated resource use. Costs per SHE were derived from patient numbers per subgroup. Weighted average costs were derived using a prevalence database. Results: Hospital treatment was a major cost in all countries. In Germany and Spain, costs per SHE for type 1 patients differed from those for type 2 patients in each group. Average SHE treatment costs were higher for patients with type 2 diabetes (Germany, €533; Spain, €691; UK, €537) than type 1 diabetes patients (€441, €577 and €236, respectively). Telephone calls, visits to doctors, blood glucose monitoring and patient education contributed substantially to costs for non-hospitalised patients. Conclusions: Treatment of SHEs adds significantly to healthcare costs. Average costs were lower for type 1 than for insulin-treated type 2 diabetes, in all three countries.

Patient preferences for diabetes management among people with type 2 diabetes in Denmark – a discrete choice experiment

Abstract Objectives: To study patient preferences for diabetes-treatment related attributes among people with type 2 diabetes. Research design and methods: Participants were recruited from three diabetes out-patient clinics and two general practitioner surgeries. Data were collected electronically and results were analysed using a standard statistical model designed for choice sets (conditional logit). Six characteristics relating to treatment of diabetes were examined: glycated haemoglobin level (HbA1c), weight (gain or loss), hypoglycaemic events, need for injections, transient nausea and need for blood glucose testing. Results: Two hundred and seventy participants with type 2 diabetes (178 males; 92 females) were included. Patients placed the most value on losing weight and were willing to pay the most to lose 6 kg of weight. Loss of 3 kg of weight was the next highly valued, followed by dropping one percentage point in HbA1c level. Avoidance of nausea and a reduction in hypoglycaemic events from two per month to none was also highly valued. Patients were willing to accept one injection per day if they, for instance, simultaneously lost 1.4 kg. A limitation of the study is that the survey was web-based and response rates for such surveys can be extremely variable. Conclusion: Patients with type 2 diabetes in Denmark were willing to pay for the health benefits associated with improved diabetes treatment, the most important of these being weight loss or avoidance of weight gain, and reduction of HbA1c and of hypoglycaemic events.

Overview of costs of stroke from published, incidence-based studies spanning 16 industrialized countries.

ABSTRACT Objective: The aim of this review is to summarize published data (based on a search of Medline sources, 1993–October 2003) from the last 10 years on the costs of stroke. With the recent encouraging evidence of interventions that reduce the incidence of stroke, the primary focus is on incidence-based cost of stroke studies to identify important factors for future cost-effectiveness analyses on stroke interventions. Findings: Lifetime costs per patient were in the range USD 11 787 for ‘unclassified’ stroke in Australia to USD 3 035 671 in stroke patients with untreated non-rheumatic atrial fibrillation in a UK setting (costs inflated to 2003 values). For the lifetime costs of ischemic stroke only, the range narrowed to USD 41 257 in Australia and USD 104 629 in the UK. These data confirm that stroke management is associated with a vast economic burden. No correlation of lifetime cost of stroke with specific cost components or time horizon was identified. The cost of stroke is influenced by severity (more severe strokes cost more due to extended hospitalization), age (costs were greater in younger stroke patients) and gender (direct costs were greater for women, but indirect costs were greater in men). Conclusion: Conducting research according to methodological consensus would markedly improve the quality of data from future studies of stroke and support identification of the main cost drivers in different country-specific settings.

Willingness to pay for health improvements associated with anti-diabetes treatments for people with type 2 diabetes

Abstract Objectives: This study aimed to investigate the most important consequences of diabetes medication, as measured by the patients’ willingness to pay (WTP). Research design and methods: People in Sweden were recruited using existing nationwide e-mail panels if they were adults (≥18 years) with type 2 diabetes and were receiving pharmacological anti-diabetes treatment(s). Data were collected electronically and results were analysed using a standard statistical model designed for choice games (conditional logit). Six characteristics relating to treatment of diabetes were examined: weight (gain or loss), mean glycated haemoglobin level (HbA1c), hypoglycaemic events, nausea, need for injections (with or independently of meals), and blood glucose testing. Results: A total of 461 people with type 2 diabetes (291 males; 170 females) completed an internet questionnaire and were eligible for inclusion. Participants placed high value on weight loss and nausea avoidance; they would pay 176 Swedish Krona (SEK)/€15.61 per month to lose 1 kg, and would pay SEK 560 (€49.67) per month to avoid nausea completely. Patients wanting to reduce the number of hypoglycaemic events from three per month to none were willing to pay SEK 419 (€37.17) per month. Patients valued a 1 percentage point reduction in HbA1c at SEK 414 (€36.72) per month. Participants preferred taking tablets to injections and required a compensation of SEK 376 (€33.35) to accept one injection/day. Injections independent of meals were preferred to injections with meals (WTP: SEK 140/€12.42 per month). Potential limitations of this study are that the preferences expressed may not match preferences in real-life situations, and bias through the use of electronic questionnaire, which restricted participation to those with access to, and experience with, the internet. Conclusion: People with type 2 diabetes were willing to pay a considerable amount of money each month to lose weight, reduce or avoid hypoglycaemic events and reduce HbA1C.

An economic assessment of analogue basal-bolus insulin versus human basal-bolus insulin in subjects with type 1 diabetes in the UK

ABSTRACT Background: A recent study demonstrated that treatment of type 1 diabetes with an analogue basal–bolus insulin regimen was associated with improved glycaemic control (HbA1c –0.22% points, p < 0.001), reduced risk of hypoglycaemic events (–21%, p = 0.036) and reduction in body mass index (–0.30 kg/m2, p < 0.001) compared to a human basal–bolus regimen after 18 weeks. Methods: A published and validated computer simulation model was used to project long-term economic and clinical outcomes in a simulated cohort of type 1 diabetes patients treated with either insulin detemir plus insulin aspart (analogue) or Neutral Protamine Hagedorn plus human soluble insulin (human), in a UK setting. Probabilities of complications and HbA1c-dependent adjustments were derived from major clinical and epidemiological studies. Complication and treatment costs were projected over patient lifetimes from a National Health Service perspective. Costs and clinical benefits were discounted at 3.5% annually. Results: Quality-adjusted life expectancy (QALE) was 0.66 quality-adjusted life years (QALY) higher in the analogue insulin versus the human insulin group (mean ± SD) (7.65 ± 0.09 versus 6.99 ± 0.08). Direct lifetime costs were £1654 greater with analogue versus human insulin treatment (£40 876 ± 1119 versus £39 222 ± 1141), producing an incremental cost effectiveness ratio (ICER) of £2500 per QALY gained. Sensitivity analyses showed the results were robust under a range of plausible scenarios. Conclusions: Treatment with analogue insulin was associated with a decreased incidence of long-term complications and improved QALE, but slightly higher treatment costs compared to human insulin therapy. Analogue insulin treatment had an ICER within the range generally considered to represent good value for money in the UK.

Willingness to Pay for Improvements in Chronic Long-Acting Insulin Therapy in Individuals With Type 1 or Type 2 Diabetes Mellitus

BACKGROUND Long-acting insulin treatments with varying clinical benefits are currently available for patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). The current evidence base demonstrates the efficacy of treatments, but it is critical also to understand patient preferences regarding treatments and how they are determined. OBJECTIVE This study aimed to measure the willingness to pay (WTP) of individuals with diabetes in the United Kingdom for different attributes of long-acting insulin therapy. METHODS A survey based on discrete choice experiment methodology was developed to elicit the preferences and values of adults with T1DM or insulin-dependent T2DM regarding different aspects of their therapy. Participants were presented with a series of 27 paired choices and asked which they preferred. WTP values were calculated for relevant attribute levels. RESULTS A total of 252 participants completed the questionnaire (52% response rate); 143 had T1DM and 109 had insulin-treated T2DM. The highest WTP values in participants with T1DM were avoiding 2-kg or 4-kg weight gain (£29 and £58, respectively), avoiding major difficulties with the injection device (£49), increasing the number of days per week when blood glucose levels are in the target range from 2 to 6 (£40), reducing the number of daily injections from 3 to 1 (£39), and avoiding nighttime hypoglycemia (£33). In participants with T2DM, similar factors had the highest WTP. CONCLUSIONS This is the first study to assess WTP for long-acting insulin therapy and could have implications for future guidelines on diabetes management, however some limitations, notably in sample selection, could affect generalizability of the results. In both T1DM and T2DM, the highest WTP values were for avoidance of weight gain, and reduction in the number of injections and hypoglycemia.