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What Impact Would Pancreatic Beta-Cell Preservation Have on Life Expectancy, Quality-Adjusted Life Expectancy and Costs of Complications in Patients With Type 2 Diabetes? A Projection Using the CORE Diabetes Model

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

Key words: Beta-cell function - Costs - Diabetes - Glucagon-like peptides - Health economics - Life expectancy - Modelling - Thiazolidinediones

SUMMARY

Objective: Type 2 diabetes is characterised by progressive failure of pancreatic beta-cell function against a background of insulin resistance. Multifactorial interventions, including intensive glycaemic and blood pressure control, reduce the risk of onset and progression of complications. However, current management of type 2 diabetes focuses on treatment of signs and symptoms of disease instead of targeting underlying causes. A number of newer pharmacological interventions, including thiazolidinediones and glucagon-like peptides, have shown early promise in preserving pancreatic beta-cell function. The aim of this study was to investigate the impact of stabilising beta-cell function on long- term outcomes in patients with type 2 diabetes.

Methods: The CORE Diabetes Model was used to project life expectancy (LE), quality-adjusted LE (QALE) and total lifetime complication costs (TC) for a cohort of newly-diagnosed patients with type 2 diabetes, either with a typical increase of HbA^sub 1c^ over time as observed in the UKPDS, or assuming stabilisation of HbA^sub 1c^ after diagnosis with a hypothetical new treatment, representing beta-cell function stabilisation. Costs due to diabetes- related complications (from a US third-party payer perspective), were discounted at 3% annually. Both non-discounted and discounted (at 3% annually) LE and QALE were calculated. Sensitivity analyses were performed to test the robustness of results.

Results: Over a time period of 50 years, in a cohort with no increase of HbA^sub 1c^ over time, LE and QALE were improved by mean (SD) 1.02 (0.36) and 0.96 (0.25) years, and total costs of complications were reduced by $6,377 (2,568) per patient compared to the cohort with a typical increase in HbA^sub 1c^ over time. Results were robust under a wide range of plausible assumptions.

Conclusions: New interventions that stabilise pancreatic beta- cell function may have an important impact on length and quality of life, and lead to reduced costs of complications in patients with type 2 diabetes.

Introduction

Type 2 diabetes mellitus is characterised by progressive failure of pancreatic beta-cell function against a background of insulin resistance, with pancreatic beta-cells becoming increasingly unable to produce sufficient insulin to overcome insulin resistance in the muscles and liver1. Multifactorial interventions, including intensive glycaemic and blood pressure control, reduce the risk of onset and progression of diabetes complications2,3. However, current management of type 2 diabetes focuses on treatment of the signs and symptoms of disease instead of targeting possible underlying causes4. While lifestyle changes, including improvements in diet and increased exercise, are the foundation of therapy for type 2 diabetes4, most patients ultimately require increasingly complex pharmacological therapy as beta-cell function declines over time5,6.

The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated a gradual and inexorable increase in HbA^sub 1c^ over time following the onset of type 2 diabetes. HbA^sub 1c^ increased by approximately 0.15% per year over the course of the UKPDS, despite treatment with increasingly complex regimens over time, and was independent of treatment received6,7. This increase in HbA^sub 1c^ was attributed to gradual beta-cell function failure associated with disease progression.

A number of newer compounds, including thiazolidinediones (TZDs) and glucagon-like peptides (GLPs) have been demonstrated to stabilise or improve beta-cell function in animals and human subjects8-16. We hypothesise that newer agents may stabilise beta- cell function and this will have an important impact on the long- term clinical and economic outcomes of patients with type 2 diabetes. The present study was designed to investigate the long- term clinical outcomes and cost of complications in a cohort receiving a hypothetical intervention that stabilises beta-cell function (and therefore HbA^sub 1c^ levels) over time compared to a cohort with diminishing beta-cell function and a typical increase of HbA^sub 1c^ over time (as observed in the UKPDS).

Figure 1. Changes in HbA^sub 1c^ over time. Changes in HbA^sub 1c^ over time assuming typical changes of time, similar to those seen in the UKPDS5,6 are represented as a dark solid line, and assuming effects on HbA^sub 1c^ of a hypothetical intervention that leads to beta-cell function stabilisation represented as a light dotted line

Methods

The CORE Diabetes Model, a documented, validated simulation model of type 1 and type 2 diabetes17,18, was used to project the cumulative incidence of diabetes-related complications, life expectancy, quality-adjusted life expectancy and total lifetime costs of diabetes-related complications in cohorts of newly- diagnosed patients with type 2 diabetes similar to those of the UKPDS7. The CORE Diabetes Model has been previously validated against 66 published studies, including external (third-order) validation of simulations of type 2 diabetes18.

One simulation was performed by assuming that the increase in HbA^sub 1c^ due to beta-cell failure over time was the same as that in the UKPDS (i.e. starting at approximately 7.0% HbA^sub 1c^ at baseline, and progressing to approximately 9.25% after 15 years, which corresponds to a 0.15% increase per year)7. A second 'what-if ' simulation was performed assuming that HbA^sub 1c^ did not increase over time from diagnosis (i.e. HbA^sub 1c^ remained at 7.0%), representing a stabilisation of beta-cell function19 (Figure 1). Baseline cohort characteristics included 61% male, 81% Caucasian, 8% Black and 1% Hispanic, mean age 53 years, newly- diagnosed with diabetes, mean total cholesterol 206.6 mg/dL, mean high-density lipoprotein 40.94 mg/dL, mean low-density lipoprotein 133.9 mg/dL, mean triglyceride levels 207 mg/dL, mean body mass index (BMI) 27.5 kg/m^sup 2^, and were based on the UKPDS general cohort7.

Transition probabilities, costs of complications and health state utilities/event disutilities used in the model have been detailed elsewhere17. For costs of complications, a US third-party payer perspective was taken. Only direct medical costs of complications were included in the analysis. Costs of day-to-day management of diabetes were not included, nor were indirect costs. A 50-year (lifetime) horizon was used to ensure that the development of all relevant complications were captured. Future costs were discounted at 3% annually. Both discounted (at 3% annually) and undiscounted life expectancy and quality-adjusted life expectancy were calculated.

Sensitivity analysis was performed on the degree of stabilisation of beta-cell function, assuming either 30% or 70% stabilisation of beta-cell function, compared to the base-case scenario in which 100% stabilisation was assumed, and on the rates of re-increase in HbA^sub 1c^ over time in the 'typical increase in HbA^sub 1c^' scenario, using either 1.0% or 2.0% per year increase in HbA^sub 1c^, compared to the 1.5% per year that was used in the base-case analysis.

Figure 2. Cumulative incidence of eye complications, assuming HbA^sub 1c^ stabilised over time, or with the increase in HbA^sub 1c^ over time

Results

A hypothetical stabilisation of beta-cell function (represented by a constant HbA^sub 1c^ level over the lifetime of patients) led to reductions in the cumulative incidence of major diabetes-related complications (Figures 2 to 6), including eye disease, renal disease, foot ulcers/amputation, cardiovascular disease and neuropathy. Moreover, substantial increases in life expectancy and quality-adjusted life expectancy, accompanied by a marked reduction in lifetime costs of complications per patient, were projected (Table 1).

Assuming the increase in HbA^sub 1c^ that was seen in the UKPDS, mean (standard deviation) non-discounted life expectancy from baseline age of 53 years and quality-adjusted life expectancy were projected to be 17.48 (0.28) and 12.34 (0.19) years respectively, and total costs of complications were $49,378 (2,038) per patient. Discounted life expectancy and quality-adjusted life expectancy were 12.82 (0.17) and 9.23 (0.12) respectively. Assuming a stabilisation of HbA^sub 1c^ after diagnosis (i.e. HbA^sub 1c^ maintained at 7.0% indefinitely), life expectancy and quality-adjusted life expectancy were projected to be 18.50 (0.30) and 13.30 (0.22) years respectively, and total costs of complications were $43,002 (1,908) per patient. Discounted life expectancy and quality-adjusted life expectancy were 13.30 (0.18) and 9.72 (0.13) respectively. Undiscounted life expectancy was improved by 1.02 (0.36) years, quality-adjusted life expectancy by 0.96 (0.25) years, and costs of complications were reduced by $6,377 (2,568) per patient. Discounted life expectancy and quality-adjusted life expectancy were improved by 0.48 (0.21) and 0.50 (0.16) years, respectively.

Figure 3. Cumulative incidence of renal complications, assuming HbA^sub 1c^ stabilised over time, or with the increase in HbA^sub 1c^ \over time

Figure 4. Cumulative incidence of foot ulcers and amputations, assuming HbA^sub 1c^ stabilised over time, or with the increase in HbA^sub 1c^ over time

Figure 5. Cumulative incidence of cardiovascular complications, assuming HbA^sub 1c^ stabilised over time, or with the increase in HbA^sub 1c^ over time

Figure 6. Cumulative incidence of peripheral neuropathy, assuming HbA^sub 1c^ stabilised over time, or with the increase in HbA^sub 1c^ over time

Table 1. Summary of results for cohorts with normal increase of HbA^sub 1c^ over time, or under a hypothetical treatment that leads to beta-cell function stabilisation and subsequent stabilisation of HbA^sub 1c^ over time. Values shown are means (standard deviation) of life expectancy, quality-adjusted life expectancy and total costs of complications. LE = life expectancy [non-discounted); QALE = quality-adjusted life expectancy (non-discounted); TC = total costs of complications over the simulation period per patient ($US, 2003 values, discounted 3% annually); Δ = difference between beta- cell stabilisation versus normal HbA^sub 1c^ increase over time

Table 2. Sensitivity analysis, comparing outcomes under a hypothetical treatment that leads to 100% beta-cell function stabilisation and subsequent stabilisation of HbA^sub 1c^ over time versus no treatment, varying the rate of increase in HbA^sub 1c^ over time. Values shown are means (standard deviation) of life expectancy, quality-adjusted life expectancy and total costs of complications. LE = life expectancy (non-discounted); QALE = quality- adjusted life expectancy (non-discounted); TC = total costs of complications over the simulation period per patient ($US, 2003 values, discounted 3% annually); Δ = difference between 100% beta-cell stabilisation (i.e. no increase in HbA^sub 1c^ over time) versus various assumptions about the rate of HbA^sub 1c^ increase over time

Sensitivity analysis of the degree of stabilisation of beta-cell function, assuming either 30% or 70% stabilisation of beta-cell function, compared to the base-case scenario in which 100% stabilisation was assumed, revealed that beta-cell function stabilisation of even 30% still led to important increases in life expectancy and quality-adjusted life expectancy, as well as decreases in the long-term costs of complications (Table 1).

Sensitivity analysis of the rates of re-increase in HbA^sub 1c^ over time in the 'typical increase in HbA^sub 1c^' scenario, using either 0.10 or 0.20% per year increase in HbA^sub 1c^, compared to the 0.15% per year that was used in the base-case analysis, revealed that even with a 33% lower rate of increase of HbA^sub 1c^ over time than observed in the UKPDS (i.e. 0.10% per year versus 0.15%), an intervention that led to 100% stabilisation of beta-cell function and no subsequent increase in HbA^sub 1c^ over time would still lead to major improvements in long-term outcomes (Table 2). If the rate of increase of HbA^sub 1c^ was higher in the non-beta-cell- stabilised arm, the improvements in long-term outcomes were even greater than those forecast in the base-case analysis.

Discussion

Our modelling study has shown that stabilisation of beta-cell function around the time of diagnosis of type 2 diabetes may lead to reductions in the incidence and progression of diabetes-related complications and their associated costs, and improvements in life expectancy and quality-adjusted life expectancy. The projected gain in life expectancy due to beta-cell stabilisation shortly after diagnosis in a hypothetical cohort of patients with type 2 diabetes similar to those in the UKPDS at around 1 year compares very well with other established interventions in health-care, where small fractions of years are often considered to be major improvements20- 22.

A number of current and potential new treatments for type 2 diabetes have shown promising effects on beta-cell function in animal and human studies, particularly the TZDs and the glucagon- like peptides (GLP). GLP-1 and 2 are members of the incretin class of gut hormones, which are released after meals and stimulate insulin secretion. Also under development is exenatide (synthetic exendin-4), an incretin mimetic, that mimics the glucoregulatory activities of GLP-1(10). In patients with type 2 diabetes, GLP-1 slows gastric emptying and induces satiety, stimulates insulin secretion, boosts beta-cell mass, and inhibits glucagon secretion". In animal models of diabetes, GLP-1 and exenatide increases glucose- dependent insulin secretion, enhances insulin gene transcription, increases islet cell mass, and inhibits beta-cell apoptosis13-15. GLP-1 has been demonstrated to improve function and inhibit apoptosis in freshly isolated human islets, and GLP-1 may increase beta-cell mass via stimulation of beta-cell neogenesis, stimulation of beta-cell proliferation, and suppression of beta-cell apoptosis16.

TZDs, including rosiglitazone, pioglitazone and troglitazone (troglitazone has been withdrawn from the market due to its association with a number of cases of liver failure), have also been demonstrated to improve beta-cell function in patients with type 2 diabetes, and in patients with a history of gestational diabetes8,9. In an observational, nested case-control study, troglitazone induced pancreatic beta-cell function recovery in 28 patients with type 2 diabetes8. In another study, 30-month improvement of insulin resistance with troglitazone has been shown to lead to preservation of pancreatic beta-cell function in women with a history of gestational diabetes9. This protection from type 2 diabetes in subjects who received troglitazone was associated with the preservation of pancreatic beta-cell function, possibly due to decreased demand on beta-cells through a reduction in chronic insulin resistance.

Sensitivity analysis demonstrated that these results were robust when the degree of stabilisation of beta-cell function was varied to 30% and 70% of the base-case value. Even at 30% stabilisation, increases in life expectancy and QALE, and decreases in the long- term costs of complications, were noted. In addition, variation in the rates of re-increase in HbA^sub 1c^ over time from the base- case setting demonstrated that, even with a 33% lower rate of increase of HbA^sub 1c^ over time than observed in the UKPDS, major improvements in long-term outcomes were observed (assuming 100% stabilisation of beta-cell function). If the rate of HbA^sub 1c^ increase was higher in the cohort without stabilised beta-cell function, the improvements in long-term outcomes were even greater than those forecast in the base-case analysis.

In our analysis, we considered the long-term effects of a hypothetical intervention that would stabilise beta-cell function, and as such, we did not include the costs of the intervention (medication costs, monitoring costs, etc.). These costs could have an impact on an analysis of overall costs. For example, even if costs were equivalent in both treatment arms, the analysis could potentially underestimate the costs of a treatment that extends life (longer course of treatment). However, the aim of the analysis was to investigate the long-term clinical outcomes and cost of complications associated with stabilised beta-cell function compared to diminishing beta-cell function over time, rather than the effects of a specific intervention. Separate analyses would be required for future interventions (including treatment costs) that stabilise beta- cell function to assess cost-effectiveness. Another potential shortcoming is that our analysis did not take into account any effects of beta-cell regeneration, which may lead to the effects of type 2 diabetes being reversed and, intuitively, improve long-term outcomes. It should also be noted that compliance, drop-outs and potential side effects were not included in the analysis as it was an investigation of the effect of changes in beta-cell function and not a specific intervention. In any future investigations of treatments that stabilise beta-cell function it will be important to include these factors, as they may well influence the effectiveness of the intervention and therefore affect long-term outcomes and costs.

Conclusions

New interventions that potentially stabilise pancreatic beta- cell function may lead to important reductions in the incidence, progression and costs of diabetes-related complications, and improvements in the length and quality of life in patients with type 2 diabetes

Acknowledgements

This study was supported by an unrestricted research grant from Eli Lilly and Company, Inc., Indianapolis, Indiana, USA.

References

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2. UK Prospective Diabetes Study Group. Cost effectiveness analysis of improved blood pressure control in hypertensive patients with type 2 diabetes: UKPDS 40. BMJ 1998; 317:720-6.

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9. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J et al. Preservation of pancreatic beta-cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk hispanic women. Diabetes 2002; 51 (9):2796-803.

10. Rolin B, Larsen MO, Gotfredsen CF, Deacon CF, Carr RD, Wilken M et al. The long-acting GLP-1 derivative NN2211 ameliorates glycemia and increases beta-cell mass in diabetic mice. Am J Physiol Endocrinol Metab 2002; 283(4):E745-E752.

11. Farilla L, Bulotta A, Hirshberg B, Li CS, Khoury N, Noushmehr H et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003; 144(12):5149-58.

12. Fineman MS, Bicsak TA, Shen LZ, Taylor K, Gaines E, Yarns A et al. Effect on glycemic control of exenatide (synthetic exendin- 4) additive to existing metformin and/or sulfonylurea treatment in patients with type 2 diabetes. Diabetes Care 2003; 26(8):2370-7.

13. Tourrel C, Bailbe D, Lacorne M, Meile MJ, Kergoat M, Portha B. Persistent improvement of type 2 diabetes in the Goto-Kakizaki rat model by expansion of the beta-cell mass during the prediabetic period with glucagon-like peptide-1 or exendin-4. Diabetes 2002; 51(5):1443-52.

14. Tourrel C, Bailbe D, Meile MJ, Kergoat M, Portha B. Glucagon- like peptide-1 and exendin-4 stimulate beta-cell neogenesis in streptozotocin-treated newborn rats resulting in persistently improved glucose homeostasis at adult age. Diabetes 2001; 50(7):1562- 70.

15. Xu G, Stoffers DA, Habener JF, Bonner-Weir S. Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes 1999; 48(12):2270-6.

16. Li Y, Hansotia T, Yusta B, Ris F, Halban PA, Drucker DJ. Glucagon-like peptide-1 receptor signaling modulates beta-cell apoptosis. J Biol Chem 2003; 278(l):471-8.

17. Palmer AJ, Roze S, Valentine WJ, Minshall ME, Foos V, Lurati FM, Lammert M, Spinas GA. 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. Curr Med Res Opin 2004; 20(Suppl 1):S5-S26.

18. Palmer AJ, Roze S, Valentine W, Minshall ME, Foos V, Lurati F et al. Validation of the CORE Diabetes Model against epidemiological and clinical studies. Curr Med Res Opin 2004; 20(Suppl. 1).

19. Wallace TM, Matthews DR. Coefficient of failure: a methodology for examining longitudinal beta-cell function in Type 2 diabetes. Diabet Med 2002; 19(6):465-9.

20. Naimark D, Naglie G, Detsky AS. The meaning of life expectancy: what is a clinically significant gain? J Gen Intern Med 1994;9(12):702-7.

21. Wright JC, Weinstein MC. Gains in life expectancy from medical interventions - standardizing data on outcomes. N Engl J Med 1998;339(6):380-6.

22. Detsky AS, Redelmeier DA. Measuring health outcomes - putting gains into perspective. N Engl J Med 1998; 339(6): 402-4.

Andrew J. Palmer(a), Stphane Roze(a), William J. Valentine(a), Michael E. Minshall(b), Morten Lammert(a), Alan Oglesby(c), Clarice Hayes(c) and Giatgen A. Spinas(d)

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

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

c Eli Lilly and Company Inc., Indianapolis, Indiana, USA

d 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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