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Comparing the Long-Term Cost-Effectiveness of Repaglinide Plus Metformin Versus Nateglinide Plus Metformin in Type 2 Diabetes Patients With Inadequate Glycaemic Control: An Application of the CORE Diabetes Model in Type 2 Diabetes

Posted on: Wednesday, 10 November 2004, 03:00 CST

Key words: Complications, costs - Cost effectiveness - HbA^sub 1c^ - Metformin - Modelling - Nateglinide Repaglinide - Type 2 diabetes

SUMMARY

Objectives: As an example application of the CORE Diabetes Model in type 2 diabetes, we simulated the cost-effectiveness of repaglinide/ metformin combination therapy versus nateglinide/ metformin for treatment of individuals with type 2 diabetes with an inadequate response to sulphonylurea, metformin, or fixed dose glyburide/metformin.

Methods: The CORE Diabetes Model was used to simulate long-term outcomes for a cohort of individuals with type 2 diabetes treated with either repaglinide/metformin or nateglinide/metformin. HbA^sup 1c^ changes for each regimen were taken from a comparative study. At the end of the study, changes in HbA^sub 1c^ from baseline were - 1.28% points and -0.67% points for repaglinide/ metformin and nateglinide/metformin, respectively. Median final doses were 5.0 mg/ day for repaglinide, 360 mg/day for nateglinide and 2000 mg/day metformin in each treatment arm. Costs were calculated as the annual costs for drugs plus costs of complications (US Medicare perspective) over a 30-year period. Life expectancy (LE) and quality- adjusted life expectancy (QALE) were calculated. Outcomes and costs were discounted at 3% annually.

Results: With repaglinide/metformin, improved glycaemic control led to projected decreases in complication rates, improvement of LE and QALE by 0.15 and 0.14 years respectively, and total cost savings of $3,662/person over the 30-year period. Repaglinide/metformin had a 96% probability that the incremental costs per quality-adjusted life year gained would be $20,000 or less, and a 66% probability that repaglinide/metformin would be cost-saving compared to nateglinide/metformin. Sensitivity analyses supported the validity and reliability of the results.

Conclusions: In the health economic context, repaglinide/ metformin combination was dominant to nateglinide/metformin. The CORE Diabetes Model is a tool to help third-party reimbursement payers identify treatments for type 2 diabetes that are good value for money.

Introduction

The direct costs of treating diabetes and its complications are colossal1-3. For example, diabetes accounts for approximately 12% of total Healthcare expenditure in the USA4, with annual per patient costs of around $1,700 for men and $2,100 for women5. When attempting to reduce the costs of diabetes, healthcare payers need to identify efficient interventions by comparing the value of different programmes that compete for the same limited healthcare budget. Healthcare bodies like the Canadian Coordinating Office for Health Technology Assessment6, the National Institute for Clinical Excellence in the UK7, the Australian Pharmaceutical Benefits Advisory Committee8 and the Academy of Managed Care Pharmacy in the US9 request or suggest the provision of evidence supporting the cost- effectiveness of new interventions. These organizations recommend the inclusion of incremental cost-effectiveness analyses, expressed in terms of costs per life year gained or costs per quality- adjusted life year gained. Most clinical studies are relatively short-term, collecting intermediate outcomes data, and are neither long enough, large enough, nor designed to compare changes in life expectancy, or long-term costs - outcomes required to calculate incremental cost-effectiveness ratios. Analysis of the efficiency (value for money) of competing interventions requires an economic analysis that considers the cost of the therapy, the cost of medical events associated or avoided with the therapy, and the costs of prolonged survival, including the potential for additional medical events related to the underlying condition. Modelling is an accepted tool used in outcomes research to estimate long-term clinical and cost consequences of new interventions, based on the best available data at the current time10-13. Previous studies have assessed short- and long-term health economic outcomes in patients with type 2 diabetes treated with repaglinide or nateglinide compared to other commonly-used oral agents, either as monotherapy or in combination with metformin14-16. However, no studies to date have directly compared the health economic outcomes of repaglinide and nateglinide in combination with metformin. In this paper, we demonstrate an application of the CORE Diabetes Model comparing the possible long- term costs, clinical consequences and value for money of two competing oral combination therapies, targeting type 2 patients who had previously shown inadequate response to monotherapy with a sulphonylurea, metformin, or low-dose glyburide plus metformin.

Methods

CORE Diabetes Model

Previous articles have outlined the structure, data inputs and validation of the CORE Diabetes Model17,18; however, a brief outline is included here. The model is based on a series of sub-models that simulate the major complications of diabetes (angina, myocardial infarction, heart failure, peripheral vascular disease, stroke, neuropathy, foot ulcer, amputation, renal disease and eye disease). Each sub-model is a Markov-based Monte Carlo simulation using probabilities derived from published sources. HbA^sub 1c^-dependent adjustments for the risks of developing complications in type 2 diabetes were derived from the United Kingdom Prospective Diabetes Study (UKPDS)19,20. The CORE Diabetes Model has been previously validated against 66 published studies, including external (third- order) validation of simulations of type 2 diabetes.

The Interventions Compared

A multifactorial approach to management may be optimal in type 2 diabetes21. As a key element of the multifactorial approach, improved glycaemic control delays or prevents complications21-23. Long-term monotherapy with oral hypoglycaemic agents has a high failure rate24, and combination therapy with oral agents is a common approach following failure of oral agent monotherapy. For example, UKPDS 49 reported failure rates (HbA^sub 1c^ not less than 7.0%) of 72% for patients receiving insulin and 76% for those on sulphonylurea24. Since the pathophysiology of type 2 diabetes involves both insulin resistance and beta-cell dysfunction, combination therapy with an insulin secretagogue and an insulin sensitiser is a logical and effective treatment approach. Meglitinide analogues are a new family of insulin secretagogues which stimulate insulin release through inhibition of ATP-sensitive potassium channels of the beta-cell membrane25. A recent study compared glycaemic control under combination therapy with repaglinide (a meglitinide analogue, short-acting insulin secretagogue) and metformin versus nateglinide and metformin26, and is the first and only published head-to-head comparison of these two regimens. It was a 16-week, open-label, parallel-group, randomised, multicentre trial conducted to compare the efficacy and safety of repaglinide versus nateglinide (an amino acid derivative, short- acting insulin secretagogue), each used in a combination regimen with metformin for treatment of type 2 diabetes. Enrolled patients (n = 192) had HbA^sub lc^ > 7% and ≤ 12% under previous treatment with a sulphonylurea, metformin, or low-dose glyburide (≤ 2.5mg) plus metformin (≤ 500mg). Dose titration of repaglinide and nateglinide was carried out according to product labelling of each secretagogue. Median final doses were 5.0mg/day for repaglinide and 360 mg/day for nateglinide. The median metformin dose was 2,000 mg/day in both groups.

Table 1. HbA^sub 1c^ effects of repaglinide/metformin versus nateglinide/metformin combination therapy24

The short-term effects of the combination therapies on HbA^sub 1c^ were taken from the head-to-head comparative study26 (Table 1). Repaglinide/metformin therapy showed significantly greater mean reductions of HbA^sub 1c^ from baseline (1.28% vs. 0.67%; P < 0.001). Tolerability was comparable for the two regimens, with no patients suffering any major hypoglycaemic events in either treatment arm. Long-term changes in HbA1c were assumed to follow the pattern seen in UKPDS patients, with an annual re-increase (following the initial treatment arm-dependent decrease from baseline seen in the first year) of HbA^sub 1c^ of approximately 0.15 percentage points/year, independent of treatment type23.

Cohort

A theoretical cohort of 10,000 patients was defined with similar baseline demographics, risk factors and pre-existing complications as the clinical trial population (mean age 55.8 years, duration of diabetes 7 years, BMI 33 kg/m^sup 2^, baseline HbA^sub 1c^ 8.4%, systolic blood pressure 149mmHg, total cholesterol 234 mg/dL, high- density lipoprotein (HDL) cholesterol 46 mg/dL, low-density lipoprotein (LDL) cholesterol 157 mg/dL, triglyceride 162 mg/dL)26. Where relevant data were not reported in the trial, other data were retrieved from typical US type 2 populations to fill the data gaps (Table 2).

Costs and Perspective

A third-party (Medicare) payer perspective was taken. All costs were adjusted (if necessary) to 2003 values using the consumer price index for the healthcare sector27. Costs of medications were take\n from the average wholesale price (AWP), and the costs of treating diabetes-related complications have been detailed by Palmer et al." Yearly medication costs per patient of $2,254.20 in the repaglinide/ metformin treatment arm were calculated from the median dose of 5 mg repaglinide per day (1 x 1 mg tablet @ $0.9296 per tablet AWP, plus 2 x 2mg tablets @ $0.9296 per tablet AWP) plus 2,000 mg per day metformin (2 x 1,000mg tablets @ $1.2508 AWP per tablet). Yearly medication costs per patient of $2,300.40 in the nateglinide/ metformin treatment arm were calculated from the median dose of 360 mg nateglinide per day (3 x 120mg tablet @ $1.1336 per tablet AWP) plus 2,000 mg per day metformin (2 x 1,000mg tablets @ $1.2508 AWP per tablet).

Time Horizon

The simulation was run over a 30-year period, in accordance with current guidelines that recommend that the time horizon should be sufficient to capture the development of all relevant complications26. Cumulative incidence rates of complications were also reported at 10, 20 and 30 years. Exploratory simulations were run at the shorter time horizons of 5, 10 and 15 years.

Discounting

In the base-case analysis, both costs and clinical outcomes were discounted at 3% per annum, in accordance with current US recommendations26.

Table 4. Cumulative incidence of complications over time

plotted against the difference in quality-adjusted life years) calculated by sampling 1,000 mean values for incremental costs versus incremental effectiveness generated for 1,000 patients for repaglinide/metformin versus nateglinide/metformin (Figure 3), showed that the majority of points fell in the lower right quadrant, indicating that, in most simulations, repaglinide/ metformin was both more effective and cost-saving

Figure 1. Projected survival curves for patients treated with either repaglinide/metformin (solid line) or nateglinide/metformin (dotted line). Separation of the survival curves occurs after 15 years, when improved glycaemic control with repaglinide/ metformin starts to have an impact on the incidence of long-term, life- threatening complications like cardiovascular disease and end-stage renal disease

Table 3. Summary results of the base-case analysis

Results

Base-case Analysis

In the base-case analysis, repaglinide/metformin combination therapy was dominant (in the health economic sense] to nateglinide/ metformin combination therapy, with improved clinical outcomes and lower overall costs per patient (Table 3). The improved glycaemic control that was demonstrated in the clinical trial led to a separation of the survival curves after around 15 years (Figure 1), due to reduced incidence of life-threatening complications such as cardiovascular disease and end-stage renal disease (Table 4). There was an immediate and increasing separation of the cumulative cost curves over time, with lower treatment costs of repaglinide/ metformin contributing to this separation in the short-term, and decreased costs due to complications leading to further cost savings in the long-term (Figure 2). With repaglinide/metformin treatment, mean discounted life expectancy was 10.26 years, quality-adjusted life expectancy (QALE) was 6.57 years, and mean total costs were $102,979 per patient. With nateglinide/metformin, mean discounted life expectancy was 10.11 years, QALE was 6.43 years, and mean total costs were $106,641 per patient. Of the total 30-year costs per patient, treatment costs (annual costs of repaglinide/metformin) made up 25%; other management costs (statins, aspirin, eye, renal and foot screening, ACE-I costs etc.) contributed 8%, cardiovascular disease 40%, renal disease 9%, neuropathy/foot ulcer/amputation 16%, and eye disease 3%. Of the overall cost savings, 2% were due to reductions in treatment costs, 28% due to reductions in cardiovascular disease, 64% due to reductions in renal disease, and 6% due to reductions in peripheral neuropathy, foot ulcer and amputation.

The incremental cost-effectiveness scatter plot (the difference in costs between the two treatment arms plotted against the difference in quality-adjusted life years] calculated by sampling 1,000 mean values for incremental costs versus incremental effectiveness generated for 1,000 patients for repaglinide/ metformin versus nateglinide/metformin (Figure 3), showed that the majority of points fell in the lower right quadrant, indicating that, in most simulations, repaglinide/ metformin was both more effective and cost-saving compared to nateglinide/metformin. From this data, a point estimate showed a mean difference in QALE of 0.144 years (95% confidence intervals (CI] 0.134 to 0.153] and in mean difference in costs of $-3,662.27 (95% CI $-3,912.48 to 5- 3,412.OS)-Wh6n the scatter plot was converted to an acceptability curve, under the base-case assumptions repaglinide/metformin had a 96% probability that the incremental costs per qualityadjusted life year gained would be $20,000 or less, and a 66% probability that repaglinide/metformin would be cost saving (Figure 4).

Table 4. Cumulative incidence of complications over time

Figure 2. Cumulative costs per patient. An immediate and increasing separation of the cumulative cost curves over time was observed, with lower treatment costs of repaglinide/metformin contributing to this separation in the short-term, and decreased costs due complications leading to further cost savings in the long- term

Figure 3. Base-case analysis scatter plot of 1,000 samples of mean incremental costs plotted against mean incremental effectiveness (quality-adjusted life years gained). The scatter plot was generated for 1,000 patients for repaglinide/metformin versus nateglinide/metformin combination therapy (base-case assumptions). The majority of the points lie in the lower right-hand quadrant, indicating cost savings and improved effectiveness for repaglinide/ metformin. Point estimate is represented by the shaded rectangle (mean difference in QALE 0.144 years [95% confidence intervals 0.134 to 0.153], mean difference in costs $-3,662.27 [95% confidence intervals $-3,912.48 to $-3,412.05]

Figure 4. ease-case analysis acceptability curve for repaglinide/ metformin versus nateglinide/metformin therapy. The curve was generated from 1,000 samples of mean incremental costs versus mean incremental effectiveness (quality-adjusted life years gained) for 1,000 patients treated with either repaglinide/metformin or nateglinide/metformin therapy. The acceptability curve shows how likely it will be that repaglinide/metformin is cost-effective for any particular willingness to pay. With a willingness to pay of $20,000 per quality-adjusted life year gained, there is a 96% probability that repaglinide/metformin will be 'costeffective' compared to nateglinide/metformin. There was a 66% probability that repaglinide/metformin will be cost-saving

Table 5. Summary results at 5-, 10- and 15-year time horizons

This analysis uses short-term clinical data to project long-term (30-year] outcomes. However, improvements in LE and cost savings with repaglinide/metformin treatment compared to nateglinide/ metformin were also observed at shorter (5-, 10- and 15-year) time horizons (Table 5). Even with a 5-year time horizon, mean QALE was improved by 0.013 years and mean cost savings of $575.06 per patient were recorded.

Sensitivity Analysis

When the 'worst case' sensitivity analysis was performed, assuming that the reduction in HbA^sub 1c^ from baseline in the repaglinide/metformin treatment arm was 1.04% points (compared to 1.28% points used in the base-case analysis) and the reduction in HbA^sub 1c^ from base-line in the nateglinide/metformin treatment arm was 0.87% points (compared to 0.67% points used in the base- case analysis), repaglinide combination therapy remained dominant to nateglinide combination therapy, i.e. it was both cost saving and improved clinical outcomes. The mean (standard deviation) discounted LE was 10.20 (0.18) years, QALE was 6.51 (0.12) years, and mean total costs were $104,067 (3,128) per patient with repaglinide/ metformin treatment, and with nateglinide/metformin, mean discounted life expectancy was 10.16 (0.18) years, QALE was 6.47 (0.12) years, and mean total costs were $105,668 (3,152) per patient; i.e. there was an improvement in life expectancy of 0.04 (0.19) years, in QALE of 0.04 (0.13) years, and in cost savings of $1,601 (3,515) per patient with repaglinide/metformin. Under these assumptions about HbA^sub 1c^ changes, there was a 77% probability that the incremental costs per quality-adjusted life year gained for repaglinide/metformin versus nateglinide/metformin would fall below $20,000, and a 37% probability that repaglinide/metformin would be cost-saving.

Varying discount rates for clinical and economic outcomes within a range 0-6% had no impact on the relative outcomes: repaglinide/ metformin was dominant to nateglinide/metformin under all combinations of discount rates.

Discussion

Our modelling study shows that the improved glycaemic control seen in the first and only head-tohead clinical trial published to date comparing repaglinide/metformin combination therapy with nateglinide/metformin may translate into reduced incidence of long- term complications, improved life expectancy and QALE, and reduced total 30-year costs in type 2 diabetes patients who have previously failed on treatment with sulphonylurea, metformin, or low-dose glyburide plus metformin. We are aware that such a regimen may require more complicated combination therapy within a few years due to beta-cell failure23,29-30.

While some debate arose about the robustness of the clinical trial results on which this modelling study was based due to concerns over pre-baseline treatments and the length of time patients received metformin before titration31,32, another direct comparison between repaglinide and nateglinide used as monotherapy in patients treated with diet and exercise for 3 monthsalso reported similar differences in HbA^sub 1c^ changes at 16 weeks of around 0.5 percentage points33. The conclusion generated from our modelling study was robust under a wide range of assumptions, suggesting that the questionmarks over the aforementioned clinical data are unlikely to affect markedly the outcomes observed in the present study.

Other health economic studies have investigated both the short- and long-term outcomes of patients with type 2 diabetes treated with nateglinide and repaglinide, used as monotherapy and in combination with other oral agents. The lifetime economic effects associated with adding nateglinide to metformin have been assessed16. Due to improved glycaemic control, reductions in the incidence of complications resulted in substantial cost savings of $2,742 per patient with the addition of nateglinide to metformin. The main savings were seen in nephropathy ($1,166) and macrovascular disease ($632) after the addition of nateglinide. Total costs (management + complications) were increased with nateglinide/metformin treatment versus metformin alone. Due to reductions in complications, discounted LE was improved by 0.21 years with nateglinide/metformin treatment, with incremental costs per life year gained of $43,024 per discounted life year gained, which is generally considered to be good value for money34. A retrospective analysis of 9 months' data gathered on 44,367 patients with type 2 diabetes in the United States assessed the total healthcare costs per patient treated with repaglinide, metformin, repaglinide/metformin, and glyburide/ metformin combination therapy14. Patients treated with repaglinide monotherapy had mean medical charges of $11,057 and pharmacy costs of $l,558/patient. Medical charges and pharmacy costs were similar in patients treated with metformin or metformin-glyburide combination therapy, while patients treated with repaglinide- metformin combination therapy had the lowest medical charges ($6,607), and pharmacy costs of $1,941/patient, and the lowest total costs of $8,548/patient. A Markov model was used to project short- term costs (costs of comprehensive medical care, laboratory investigations, education, medications, self-monitoring of blood glucose, and adverse events) over a 3-year period for six first- line oral agents: glipizide gastrointestinal therapeutic system, metformin immediate-release, metformin extendedrelease, glibenclamide, rosiglitazone and repaglinide15. Total costs were: glipizide gastrointestinal therapeutic system $6,106; metformin immediate-release $6,727; metformin extended-release $6,826; glibenclamide (glyburide)/metformin $7,141; rosiglitazone $7,759; and repaglinide $9,298. While repaglinide had the highest short- term costs compared to other commonly used oral agents, this study did not account for the reduced costs of complications due to complications avoided. Nor did it consider the relative costs of nateglinide versus repaglinide, or repaglinide used in combination therapy.

There were some limitations to our analysis. We assumed that the separation in HbA^sub 1c^ between the two treatment arms seen in the short-term would be maintained over the long-term - a common practice in diabetes health economic modelling. Whether or not this separation remains over the long-term should be revealed by long- term follow-up studies. In this analysis, we did not take into account treatment changes due to side effects or increasing glycaemia, which may have led to an underestimation of the ongoing treatment costs in both treatment arms. However, the side effects recorded in the clinical trial were minor and similar in both treatment arms, therefore any error due to this assumption occurred systematically in each arm in our analysis. Additionally, the improved glycaemic control seen with repaglinide/metformin combination therapy implies a lower rate of changing to more expensive therapies like triple combination therapy, due to increasing glycaemia, thus the omission of this effect led to possible biasing against the repaglinide/metformin treatment arm. The study presents costs from a Medicare payer perspective. It should be noted that this does not include non-medical costs such as lost productivity or transport costs, and therefore is likely to underestimate costs from a societal perspective. Avenues of future research that could provide valuable information in terms of expanding our knowledge in this area include long-term head-to-head clinical trials of repaglinide/metformin versus nateglinide/ metformin, and studies assessing compliance and effectiveness could provide valuable information on how the benefits observed in clinical studies might translate into the real-life setting.

Conclusions

This analysis demonstrates the use of the CORE Diabetes Model to compare costs and clinical outcomes of different treatment strategies in type 2 diabetes patients. The information given could be used to assist reimbursement agencies in their decision-making process when deciding between two competing interventions. In the example presented, the better efficacy of repaglinide/metformin combination therapy compared to nateglinide/metformin led to improved LE and QALE, and lower lifetime costs per patient.

Acknowledgements

This study was funded by an unrestricted grant from Novo Nordisk Pharmaceuticals, Inc. Princeton, New Jersey, USA.

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Andrew J. Palmer(a), Stphane Roze(a), Morten Lammert(a), William J. Valentine(c), Michael E. Minshall(b), Lars Nicklasson(c), Mari- Anne Gall(d) and Giatgen A. Spinas(e)

a CORE - Center for Outcomes Research, Binningen/Basel, Switzerland

b CORE-USA, LLC, Fishers, Indiana, USA

c Novo Nordisk Pharmaceuticals Inc., Princeton, NJ, USA

d Novo Nordisk A/S, Bagsvaerd, Denmark

e Department of Endocrinology and Diabetes, University Hospital Zrich, Switzerland

Address for correspondence: Dr Andrew J. Palmer, CORE - Center for Outcomes Research, Buendtenmattstrasse 40, 4102 Binningen/ Basel, Switzerland; Tel.: +41 61 383 0756; Fax: +41 61 383 0759; E- mail: ap@thecenter.ch

Copyright Librapharm Aug 2004

Source: Current Medical Research and Opinion

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