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Cost-Effectiveness of Insulin Aspart Versus Human Soluble Insulin in Type 2 Diabetes in Four European Countries: Subgroup Analyses From the PREDICTIVE Study

Posted on: Thursday, 26 June 2008, 06:02 CDT

By Palmer, James L Goodall, Gordon; Nielsen, Steffen; Kotchie, Robert W; Valentine, William J; Palmer, Andrew J; Roze, Stephane

Key words: Cost-effectiveness - Costs - Europe - Human insulin - Insulin aspart - Modeling ABSTRACT

Objectives: evaluate the long-term health economic outcomes associated with insulin aspart (IAsp) compared to human soluble insulin (HI) in type 2 diabetes patients on basal-bolus therapy in Sweden, Spain, Italy and Poland.

Methods: A published computer simulation model of diabetes was used to predict life expectancy, quality-adjusted life expectancy and incidence of diabetes-related complications. Baseline cohort characteristics (age 61.6 years, duration of diabetes 13.2 years, 45.1% male, HbA^sub 1c^ 8.2%, BMI 29.8 kg/m^sup 2^) and treatment effects were derived from the PREDICTIVE observational study. Country-specific complication costs were derived from published sources. The analyses were run over 35-year time horizons from third- party payer perspectives in Spain, Italy and Poland and from a societal perspective in Sweden. Future costs and clinical benefits were discounted at country-specific discount rates. Sensitivity analyses were performed.

Results: IAsp was associated with improvements in discounted life expectancy and quality-adjusted life expectancy, and a reduced incidence of most diabetes-related complications versus HI in all four settings. IAsp was associated with societal cost-savings in Sweden (SEK 2470), direct medical cost-savings in Sweden and Spain (SEK 8248 and euro1382, respectively), but increased direct costs in Italy (euro2235) and Poland (euro743). IAsp was associated with improved quality-adjusted life expectancy in Sweden (0.077 QALYs), Spain (0.080 QALYs), Italy (0.120 QALYs) and Poland (0.003 QALYs).

Conclusions: IAsp was dominant versus HI in both Sweden and Spain, would be considered cost-effective in Italy with an incremental cost-effectiveness ratio of euro18597 per QALY gained, but would not be considered cost-effective in Poland.

Introduction

Patients with diabetes mellitus are at increased risk of morbidity and mortality compared to the general population. Due to the broad range of complications associated with the disease, patients with diabetes contribute to an increased burden on the healthcare budgets of both governments and private insurers worldwide. Patients with diabetes are at least three times more likely to be hospitalized than the general population1, and have a higher risk of hospitalization for costly interventions such as renal replacement therapy, where type 2 diabetes is the leading cause of end-stage renal disease (ESRD) in Europe2.

In the eight European countries included in the CODE-2 study (Belgium, France, Germany, Italy, Netherlands, Spain, Sweden and the UK), more than ten million people were estimated to have type 2 diabetes, with associated direct medical costs of euro29 billion per annum (an average yearly cost of euro2834 per patient)3. The majority of these costs were accounted by hospitalization for the treatment of diabetes-related complications. In Sweden alone, three times more resources were spent on treating diabetes-related complications than on control of the disease1.

The primary goal in the treatment of diabetes is glycemic control. Landmark epidemiological studies have shown that maintaining effective glycemic control is associated with a reduced incidence of diabetes-related complications in both type 1 and type 2 diabetes4,5. The UK Prospective Diabetes Study (UKPDS) 33 demonstrated that intensive treatment resulted in a 12% reduction in the risk of experiencing any diabetes-related complication, and a 10% risk reduction for diabetes-related death compared to conventional treatment in patients with type 2 diabetes5.

The Predictable Results and Experience in Diabetes through Intensification and Control to Target: An International Variability Evaluation (PREDICTIVE) study was a large, multi-center, observational study designed to assess the safety and efficacy of insulin detemir (IDet) in 19911 patients with type 1 or type 2 diabetes6. Insulin therapy is often regarded as the final option for the treatment of type 2 diabetes after lifestyle changes (diet and exercise) and oral anti-diabetic drugs (OADs) have failed to maintain effective glycemic control. However, evidence that demonstrates the benefits of early intervention with insulin in avoiding diabetes-related complications in type 2 diabetes is accumulating7.

Insulin aspart (IAsp) is a modern insulin that has a faster onset and reduced duration of action compared to animal and human insulin formations. Modern insulins have thus far demonstrated equivalent reductions of glycosylated hemoglobin (HbA^sub 1c^) with reduced intrapatient blood glucose variability compared to older human insulins8,9. In a randomized clinical trial that enrolled 394 patients with type 2 diabetes, IDet plus IAsp was associated with non-significant improvements in HbA^sub 1c^ and hypoglycemia versus NPH plus regular human insulin10. However, in clinical trial settings modern insulin has not yet demonstrated significant improvements in HbA^sub 1c^ and hypoglycemia compared to human insulin in type 2 diabetes patients. A subset of type 2 diabetes patients in the PREDICTIVE study received IAsp or human soluble insulin (HI) as the bolus component of a basal-bolus insulin regimen to meet postprandial insulin requirements, where IDet was the basal component. In PREDICTIVE, patients on IAsp benefited from greater reductions in (HbA^sub 1c^) and body mass index (BMI) than patients on HI (Table 1).

Table 1. Summary of treatment effects based on the findings of the PREDICTIVE study

The aim of this study was to evaluate the long-term economic and clinical implications of IAsp treatment for type 2 diabetes in Sweden, Spain, Italy and Poland, compared to HI based on data from the PREDICTIVE study.

Methods

A computer simulation model was used to project the long-term clinical and economic outcomes associated with IAsp treatment with and without concurrent OAD usage in type 2 diabetes patients in the Swedish, Spanish, Italian, and Polish settings. Treatment effects for IAsp were taken from the European sub-set of PREDICTIVE, while cost data and the background prevalence of diabetes-related complications were taken from country-specific sources.

Model

A brief overview of the CORE Diabetes Model is provided here, but the interested reader is referred to previously published articles by Palmer et al.11,12. The model is a non-product-specific diabetes policy analysis tool which takes into account intensive or conventional insulin therapy, OAD usage, screening and treatment strategies for microvascular complications, treatment strategies for end-stage complications and multifactorial interventions. Disease progression is based on a series of inter-dependent sub-models that simulate progression of disease-related complications (angina, myocardial infarction, congestive heart failure, stroke, peripheral vascular disease, diabetic retinopathy, macula edema, cataract, hypoglycemia, ketoacidosis, lactic acidosis, nephropathy and end- stage renal disease, neuropathy, foot ulcer and amputation) as well as mortality from other causes. Each sub-model uses time, state, time in state and diabetes type-dependent probabilities derived from published sources. The reliability of simulated outcomes has been tested, with results validated against those reported by clinical trials and epidemiological studies12.

Simulation cohorts

A cohort was defined for each country setting, with baseline age, duration of diabetes and HbA^sub 1c^ based on PREDICTIVE data (Table 2}. Additional information was obtained to reflect patient co- morbidities, with the frequency of existing complications (cardiovascular, renal, etc.) and additional baseline risk factors (systolic blood pressure, serum lipids, etc.) derived from country- specific sources for each setting13-23. The simulated cohort for the Polish setting had a higher prevalence of most diabetes-related complications compared to the other three country cohorts.

Treatment effects

Treatment effects for IAsp and HI were taken from the European subgroup of the PREDICTIVE study, where both treatments were associated with reductions in HbA^sub 1c^ and BMI (Table 1). Patients who received insulin therapy only and those prescribed OADs in addition to insulin were included in the analyses. Improvements in HbA^sub 1c^ were modeled as an initial decrease from baseline levels followed by a natural progression in line with that observed in the UKPDS. BMI changes and hypoglycemic event rates recorded during the PREDICTIVE Study (in terms of events per 100 patient years) were also applied in the simulations.

Costs and perspective

Both societal and third-party payer perspectives were used for the Swedish analysis. Direct medical costs only were accounted in the Spanish, Italian and Polish settings. Direct medical costs were accounted in 2005 Swedish Kroner for Sweden and 2006 euros for Spain, Italy and Poland (where Polish Zloty were converted to euros). Costs associated with the treatment of diabetes-related complications were obtained from country-specific published sources (Table 3). In the base case analysis medication costs for each treatment arm included administration devices and blood glucose monitoring and took into account OAD usage and variations in insulin doses as noted in the trial. Pharmacy costs were accounted using pharmacy list prices excluding value-added tax (if applicable]. Quality of life utilities

Quality-adjusted life expectancy was incorporated into the analysis using diabetes-related health state utility and event disutility values published by Palmer et al.24 To capture reduced utility associated with minor hypoglycemic events (such as those not requiring hospitalization), a disutility of -0.0035 was applied to each event recorded in the simulation. To capture reduced utility associated with major hypoglycemic events (requiring third-party assistance), a disutility value of -0.0118 was applied. These values were derived from a multivariate model of disutility published by Currie et al.25

Discounting and time horizon

For the Swedish base case analysis, a discount rate of 3% per annum was applied to future costs and clinical benefits as recommended by the Swedish Pharmaceutical Benefits Board26. Discount rates for both costs and clinical benefits of 6%, 3% and 5% per annum were used in the Spanish, Italian and Polish analyses, respectively. The time horizon was set to 35 years for all countries in the base case analysis to capture all complications and deaths over patient lifetimes.

Sensitivity analyses

Several one-way sensitivity analyses were performed to assess the effect of varying key parameters on cost and clinical outcomes. The impact of discounting on outcomes was assessed by varying the discount rates applied to costs and clinical benefits. The time horizons were also varied for each country between 1 and 35 years to assess the projected cost and clinical outcomes over periods shorter than patient lifetimes. A further sensitivity analysis was performed where the improvement in HbA^sub 1c^ associated with IAsp treatment was set to the same as that for HI seen in PREDICTIVE to determine the effect of this parameter on outcomes. Patients who received IAsp had a higher incidence of hypoglycemia than those administered HI, despite lower insulin dosage (72.65 IU [international units] versus 83.36IU per day). This observation may have been a reflection of higher baseline hypoglycemic event rates for patients switched to IAsp in PREDICTIVE, representing 'difficult to treat' patients (Table 1). For this reason a sensitivity analysis was performed to investigate the effect of the difference in hypoglycemia rates on outcomes by setting the same hypoglycemia event rate for IAsp treatment as for HI. Finally, to investigate the uncertainty around patient characteristics and treatment effects, probabilistic sensitivity analysis was performed where values were sampled from a normal distribution around the mean values of parameters where standard deviations were available.

Table 2. Baseline patient characteristic and complications

Table 3. Management and complication costs

Only the results of the sensitivity analyses performed in the Swedish setting are reported in this paper (for conciseness). Additional results in other settings are available on request.

Statistical methodology

A simulated cohort of 1000 patients were run through the model 1000 times for each simulation using a nonparametric bootstrapping approach and mean values and standard deviations were generated27. Data was used to generate acceptability curves in all four country settings.

Results

Clinical outcomes

Model projections indicated that IAsp was associated with improvements in life expectancy in four European countries (Table 4). In Sweden, IAsp was associated with an increase in discounted life expectancy of 0.136 years compared to HI (9.312 +- 0.162 vs. 9.176 +- 0.153, respectively). IAsp was associated with improvements in discounted life expectancy of 0.101 years in Spain and 0.164 years in Italy versus HI.

Capturing quality of life in the analysis showed further clinical benefits for IAsp. In Sweden, IAsp was associated with an increase in quality-adjusted life expectancy of 0.077 quality-adjusted life years (QALYs) versus HI (5.931 +- 0.107 vs. 5.854 +- 0.101). IAsp was also associated with improvements in quality-adjusted life- expectancy of 0.080 QALYs in Spain and 0.120 QALYs in Italy versus HI.

Table 4. Summary of clinical and cost outcomes

The clinical benefit of IAsp was not as pronounced in Poland, where IAsp was associated with an improvement in life expectancy of 0.028 years and an improvement in quality-adjusted life expectancy of 0.003 QALYs versus HI. The reduced benefit of IAsp in Poland was attributable to a higher prevalence of baseline complications in the simulated Polish cohort (Table 2).

In Sweden, patients receiving IAsp had a reduced cumulative incidence of most diabetes-related complications compared to HI (Table 5). There were notable reductions in the incidence of microvascular and cardiovascular complications for IAsp. The incidence of end-stage renal disease, one of the most costly complications of diabetes, was reduced by more than 14%, and severe vision loss was 7% less frequent for patients receiving IAsp compared to patients receiving HI. The lifetime cumulative incidence of stroke was 2.52% higher for patients receiving IAsp compared to patients receiving HI (15.50% +- 1.19 vs. 15.12% +- 1.13). This higher incidence of stroke was due to the survival paradox, whereby patients on IAsp live longer and are exposed to the risk of stroke for a longer period of time, and the fact that stroke risk is driven largely by age and not by markers of glycemic control28.

Similar patterns were observed in Spain and Italy, where IAsp was associated with a reduced cumulative incidence of diabetes-related complications compared to HI, with the exception of stroke (data not shown). In Poland, whilst a benefit was observed for IAsp versus HI, the projected cumulative incidence of diabetes-related complications was substantially higher than the other countries.

Cost outcomes

Projections of direct costs over patient lifetimes indicated that IAsp would be associated with cost-savings in Sweden and Spain (Table 4). In Sweden, IAsp was associated with direct cost-savings of SEK 8248 per patient versus HI (SEK 405910 +- 16358 vs. SEK 414 158 +- 15544). In Spain, IAsp was associated with direct medical cost-savings of euro1382 per patient versus HI (euro45 805 +- 12915 vs. euro47 187 +- 12470). In Italy and Poland IAsp was associated with increased lifetime direct costs versus HI of euro2235 and euro743, respectively.

Table 5. Cumulative incidence of diabetes-related complications in Sweden

In Sweden, a breakdown of direct medical costs for each treatment showed that medication and management costs (concomitant medications, eye and renal screening, foot ulcer prevention programs, etc.) contributed to 31.1% and 28.9% of direct medical costs for patients receiving IAsp and HI, respectively. IAsp was associated with cost-savings (SEK 14 886) in the treatment of diabetes-related complications versus HI in Sweden. IAsp was also associated with similar patterns of reduced complication costs in Spain, Italy, and Poland (data not shown).

The inclusion of indirect costs in the Swedish analysis indicated that IAsp was associated with societal cost savings of SEK 10717 over patient lifetimes when compared with HI (SEK 521 538 +- 22 106 vs. SEK 532 256 +-21 342]. A reduction in indirect costs for IAsp versus HI was projected despite the short time until cohort retirement.

Evaluation of cost-effectiveness

Treatment with IAsp was associated with improved clinical outcomes versus HI in the Swedish setting and would be considered cost-saving from both societal and third-party payer perspectives (Table 4). In Spain, treatment with IAsp was associated with improved clinical outcomes and cost-savings from a third-party payer perspective versus HI. In Italy, treatment with IAsp was associated with incremental cost-effectiveness ratios (ICERs) of euro13627 per life year gained and euro18597 per QALY gained from thirdparty payer perspectives, and would have a 63.7% likelihood of being considered cost-effective with a willingness to pay threshold of euro30 000 per QALY gained (Figure 1). In Poland, treatment with IAsp was associated with an ICER of euro22 091 per life year gained and euro29 0486 per QALY gained from third-party payer perspectives, and would have a 37.6% likelihood of being considered cost-effective with a willingness to pay threshold of euro30 000 per QALY gained.

Sensitivity analyses

Results of the one-way sensitivity analyses performed in the Swedish setting revealed that even after changes in discount rates and most time horizons, treatment with IAsp would result in improved clinical outcomes and cost-savings versus HI from a societal perspective (Table 6). Reduced time horizons continued to demonstrate cost-savings for IAsp; a reduction in the time horizon to 10 and 5 years reduced the cost-savings versus HI from SEK 10717 in the base case to SEK 5285 and SEK 2968, respectively. When the improvement in HbA^sub 1c^ associated with IAsp treatment was reduced to the value of that observed for HI in PREDICTIVE (i.e., a change of -0.55% from baseline levels), IAsp was projected to be both more expensive and less effective than HI, due to increased pharmacy costs, no projected reductions in diabetes-related complications and higher hypoglycemic event rates, which are associated with reduced quality of life. When hypoglycemic event rates in the IAsp treatment arm were assumed equal to those in the HI arm, IAsp was calculated to be even more effective than HI, with 0.112 QALYs gained in this scenario versus 0.077 QALYs gained in the base case.

Figure 1. Acceptability curves for 1Asp versus HI. 1Asp, insulin aspart; HI, human soluble insulin; euro, euros. All values calculated in local currencies with Swedish Kroner and Polish Zloty convened to euros

Discussion This study identified that treatment with 1Asp as the bolus component of a basal-bolus insulin regimen was both more effective and cost-saving versus HI in the Swedish and Spanish settings, and may be considered cost-effective in the Italian setting. The accounting of indirect costs in the Swedish setting suggested that 1Asp would also be regarded as cost-saving from a societal perspective. However, 1Asp was not found to be cost- effective in Poland, where the projected gain in quality-adjusted life expectancy was not as large as the improvements projected in the other three settings, due to a high background prevalence of diabetes-related complications in the simulated Polish cohort.

Table 6. Sensitivity analyses performed in the Swedish setting

There may be a number of reasons for the high prevalence of complications in patients with type 2 diabetes in Poland. A lack of national diabetes treatment guidelines, late diagnosis of the disease, poor complication management practices and late initiation of insulin therapy could provide valid explanations. A particularly high baseline incidence of cardiovascular complications may indicate that better management of cardiovascular risk factors is required in Poland.

Sensitivity analyses revealed that the outcomes projected by the model were most sensitive to the time horizon and the effects of IAsp treatment on HbA^sub 1c^ levels. Model simulations over reduced time horizons (5- and 10-year time horizons) might not capture the development of serious complications of type 2 diabetes, such as cardiovascular disease and end-stage renal disease. These complications are usually accompanied by significant morbidity, mortality and costs and can therefore influence outcomes greatly. The treatment benefit of IAsp over HI was reduced from 0.077 QALYs gained in the base case to 0.021 QALYs gained when time horizon was set to 10 years, although IAsp remained costsaving from a societal perspective. When the HbA^sub 1c^ reduction observed in PREDICTIVE for IAsp was assumed equal to the reduction observed for HI, IAsp was both less effective, due to a greater number of hypoglycemic events, and more costly than HI due to higher pharmacy costs. The results of this sensitivity analysis suggest that the health economic argument for IAsp is based on the superior reduction in HbA^sub 1c^ levels versus HI as observed in PREDICTIVE, and the associated reduction in diabetes-related complications.

When the hypoglycemic event rate for IAsp was set equal to the rate for HI in a one-way sensitivity analysis, the increase in quality-adjusted life expectancy for IAsp was greater than in the base case, as hypoglycemic events are associated with reduced quality of life25. The higher frequency of hypoglycemic events seen in the IAsp arm of the PREDICTIVE observational study did not correspond to observations made in randomized controlled trials comparing modern versus human insulin, where lower hypoglycemic event rates have been observed for modern analog insulins10, 29. Randomization for baseline hypoglycemia was not performed in PREDICTIVE, thus the one-way sensitivity analysis that tested the impact of equal hypoglycemic event rates is a relevant scenario.

A potential limitation of this analysis is that the PREDICTIVE study was not designed to look at the difference in outcomes for patients receiving either IAsp or HI. However the numbers of patients in each arm, 455 receiving IAsp and 1042 treated with HI, was sufficient to give the simulated clinical inputs some statistical power. Additionally, patients prescribed analogue insulin regimens in PREDICTIVE may have been 'difficult to treat', as evidenced by higher baseline hypoglycemic event rates and HbA^sub 1c^ levels for patients treated with IAsp (Table 1). Despite the fact that PREDICTIVE was designed to assess the effect of IDet, it is interesting that clinical benefits for IAsp were also observed.

Another potential criticism of this and most other modeling analyses is that it makes long-term predictions based on short-term clinical findings. This is an unavoidable consequence of almost all modeling analyses. However, in the absence of long-term clinical trial data, modeling remains a pragmatic approach to address pressing health economic questions. Validation of the computer simulation model of diabetes used to perform this analysis provides support for the long-term projections made12.

An additional criticism relevant to this modeling analysis is that the cohorts simulated in the model may not be fully representative of the PREDICTIVE patient populations. However, as patient history influences the likelihood of future diabetes- related events in the computer simulation model used, supplementation with data from other country-specific sources was necessary to ascertain prevalence of complications in comparable type 2 diabetes cohorts. Furthermore, the incorporation of information from a range of appropriate sources is acceptable when performing modeling analyses30.

An advantage of this study is that it assessed the potential health economic benefits of IAsp in four countries, with societal and third-party payer perspectives taken for Sweden. The study incorporated recent cost data for each setting and took into account clinical characteristics for patients with type 2 diabetes that were not reported in this PREDICTIVE subgroup. Thus, the study allows an overall assessment of the potential health economic benefits of IAsp in Europe and should be taken into account by policy makers in countries not included in the analysis.

Conclusions

The findings of this modeling analysis suggest that increased spending on more modern treatments for diabetes is likely to be cost- saving or cost-effective in the long term in many countries. While the treatment costs were projected to be higher for patients on IAsp, the overall cost burden from diabetes was reduced due to lower incidence of expensive diabetes-related complications such as end- stage renal disease and cardiovascular events.

Based on the findings of this modeling analysis, IAsp in combination with insulin IDet as basalbolus therapy for the treatment of patients with type 2 diabetes is likely to result in improved clinical benefits in Sweden, Spain, Italy and Poland, is associated with cost-savings from both societal and third-party payer perspectives in Sweden, is cost-saving from a third-party payer perspective in Spain, is cost-effective in Italy, but is not likely to be cost-effective in Poland.

Acknowledgments

Declaration of interest: This study was supported by an unrestricted grant from Novo Nordisk A/S. James L. Palmer, Gordon Goodall, Robert W. Kotchie, William J. Valentine, Andrew J. Palmer and Stephane Roze are current or previous employees of IMS Health, which has received consulting fees from Novo Nordisk. Steffen Nielsen is a current employee of Novo Nordisk.

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CrossRef links are available in the online published version of this article: http://www.cmrojournal.com

Paper CMRO-4353.5, 10:40-23.04.08

Accepted for publication: 11 March 2008

Published Online: 08 April 2008

doi: 10.1185/030079908X297295

James L. Palmer(a), Gordon Goodall(a), Steffen Nielsen(b), Robert W. Kotchie(c), William J. Valentine(a), Andrew J. Palmer(a) and Stephane Roze(a)

a IMS Health, Basel, Switzerland

b Novo Nordisk, Bagsvaerd, Denmark

c IMS Health, London, UK

Address for correspondence: Mr James L. Palmer, IMS Health, Gewerbestrasse 25, CH-4123 Allschwil, Switzerland. Tel.: +41 61 383 0758; Fax: +41 61 383 0759

Copyright Librapharm May 2008

(c) 2008 Current Medical Research and Opinion. Provided by ProQuest Information and Learning. All rights Reserved.

Source: Current Medical Research and Opinion

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