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Alastair Gray a Health Economics
Research Centre, Department of Public Health, University of Oxford,
Institute of Health Sciences, Headington OX3 7LF, b Department of Economics, City
University, London EC1V 0HB, c Business School, University of Nottingham,
Nottingham NG7 2RD, d Diabetes Research
Laboratories, Nuffield Department of Clinical Medicine, University of
Oxford, Oxford OX2 6HE, e Diabetes Trials Unit, Nuffield Department
of Clinical Medicine
Correspondence to: A Gray alastair.gray{at}ihs.ox.ac.uk
Abstract |
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Abstract Introduction Methods Results Discussion References |
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Objective:
To estimate the cost effectiveness of
conventional versus intensive blood glucose control in patients with
type 2 diabetes.
Improved blood glucose control is known to decrease progression of
microvascular disease in patients with type 1 diabetes, and the cost
effectiveness of this policy has been reported using data from the
diabetes control and complications trial.1 Without information on clinical treatments and their long term impact on
disease progression it has not been possible to assess the cost
effectiveness of similar strategies in patients with type 2 diabetes.
Previous economic evaluations have used existing knowledge of the
disease epidemiology to consider specific aspects of disease progression such as retinopathy.
2 3
Model-based
evaluations have also been reported, the most inclusive of which
predicted rates of microvascular complications, cardiovascular disease, and mortality.
4 5
The United Kingdom prospective diabetes study provides, for the first time, the necessary clinical information on both microvascular and macrovascular complications to allow the cost
effectiveness of an improved glucose control policy in people with
type 2 diabetes to be analysed. The median 10 year follow up in the
study makes it possible to estimate long term resource implications of
type 2 diabetes and its complications directly from trial
data.6
Participants and comparisons
Type of evaluation and perspective
Resource data
Design:
Incremental cost effectiveness analysis
alongside randomised controlled trial.
Setting:
23 UK hospital clinic based study centres.
Participants:
3867 patients with newly diagnosed type
2 diabetes (mean age 53 years).
Interventions:
Conventional (primarily diet) glucose
control policy versus intensive control policy with a sulphonylurea or insulin.
Main outcome measures:
Incremental cost per event-free
year gained within the trial period.
Results:
Intensive glucose control increased trial treatment costs by £695 (95% confidence interval £555 to £836) per
patient but reduced the cost of complications by £957 (£233 to
£1681) compared with conventional management. If standard practice visit patterns were assumed rather than trial conditions, the incremental cost of intensive management was £478 (£275 to £1232) per patient. The within trial event-free time gained in the intensive group was 0.60 (0.12 to 1.10) years and the lifetime gain 1.14 (0.69 to
1.61) years. The incremental cost per event-free year gained was £1166
(costs and effects discounted at 6% a year) and £563 (costs
discounted at 6% a year and effects not discounted).
Conclusions:
Intensive blood glucose control in
patients with type 2 diabetes significantly increased treatment costs
but substantially reduced the cost of complications and increased the
time free of complications.
Introduction
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Abstract
Introduction
Methods
Results
Discussion
References
Methods
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Abstract
Introduction
Methods
Results
Discussion
References
A total of 5102 newly diagnosed patients with type 2 diabetes,
defined as fasting plasma glucose above 6 mmol/l on two occasions,
aged 25-65 years (mean age 53) were recruited in 23 centres. After
initial dietary treatment, 4209 patients had fasting plasma glucose
concentrations of 6.1-15 mmol/l without symptoms of hyperglycaemia. Of
these, 342 overweight patients were randomised to metformin, leaving
3867 patients who entered the main randomisation and were allocated
either to conventional management (mainly through diet, 1138 patients),
or to intensive management with insulin (1156) or sulphonylureas
(1573). The aim of the conventional policy was to maintain patients
free of diabetic symptoms and with a fasting plasma glucose
concentration below 15 mmol/l, whereas the intensive policy was aimed
at a fasting plasma glucose concentration below 6 mmol/l. All patients
in the main randomisation were included in this economic evaluation. The median follow up period to death, the last known date at which survival was known, or to the end of the trial was 10 years. The main
clinical end points analysed were death or the development of diabetic
complications, including coronary heart disease, cerebrovascular disease, amputation, laser treatment for retinopathy, cataract extraction, and renal failure. All analyses and comparisons were performed on an intention to treat basis.
We performed an incremental cost effectiveness analysis in which
the net costs and net effectiveness of intensive compared with
conventional management were calculated and expressed as a ratio. The
main perspective of the economic evaluation was that of healthcare
purchasers. Only direct health service costs were analysed. These costs
covered conventional and intensive treatments, visits to diabetic
clinics and tests, and treatment of diabetic complications, including
inpatient stays and outpatient health care. We also compared the
costs of conventional policy with the insulin and sulphonylurea
intensive policies separately.
For each patient, data were collected at three monthly
clinic visits on the doses of all drugs used for treating diabetes
(insulin, sulphonylureas, metformin); the number of home blood glucose
tests; the dose of the three main drugs for hypertension (captopril,
atenolol, nifedipine); whether the patient was taking diuretics,
methyldopa, calcium channel blockers, vasodilators, or other
antihypertensive drugs; and whether the patient was taking aspirin,
antidepressant drugs, hormone replacement therapy, anxiolytics, or any
other drugs. When treatment doses were not recorded, missing values
were replaced by extrapolation from adjacent values for that patient.
Last observation carried forward was used to impute missing data when necessary.
Costs
Unit costs for all resources used by trial patients were obtained
from national statistics and from centres participating in the trial
(table 1). These unit costs were combined with the resource volumes to
obtain a net cost per patient over their time in the trial. Mean net
costs and associated 95% confidence intervals were calculated for each
arm of the study. Costs are reported both undiscounted and in net
present values using the UK Treasury approved 6% annual discount
rate.8 All costs are reported in 1997 values
(£s).
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Outcomes
Diabetes related end points were defined as in the clinical
trial.6 The trial showed that intensive blood glucose
control significantly reduced (P=0.029) the risk of any diabetes
related end point by 12% but did not significantly reduce diabetes
related deaths or all cause mortality. Consequently, the current
analysis measures outcomes in terms of time to first event (myocardial
infarction, congestive heart failure, stroke, renal replacement
therapy, amputation, cataract extraction, vitreous haemorrhage, or
death from any cause).
Models
The model used in the simulation described above was a twofold
competing risk model. In the first component, risk of a diabetes
related event increases with age at diagnosis of diabetes and with
duration of diabetes. In the second component, risk of other death (any
death except myocardial infarction, sudden cardiac death, stroke)
increases with the age of the patient. For simplicity, the last
category includes several causes of death that may be considered
diabetes related (hyperglycaemic or hypoglycaemic episodes, renal
death, and death from peripheral vascular disease) but occurred too
infrequently to be modelled individually (total 26 deaths). The methods
used to test the model's validity are given on the
BMJ 's website.
Analysis
All comparisons were carried out on an intention to treat
basis. All results are reported as mean values with standard deviations; mean differences are reported with 95% confidence intervals. When descriptive statistics suggested the possible presence
of skewness, 1000 bootstrap replications of the original data were
performed and the resulting means, mean differences, and intervals were
compared. For all reported costs, parametric confidence intervals for
the cost differences were compared with the bootstrap confidence
intervals and were found to be robust; parametric confidence intervals
are therefore reported. Confidence intervals for the mean cost
effectiveness ratios were calculated by Fieller's
method.
9 10
The effect of assumptions on our main results
was examined by sensitivity analyses. All data were analysed with SPSS
8.0 and Microsoft Excel 97; the modelling work was carried out in C language.
Results |
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Abstract Introduction Methods Results Discussion References |
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Table 3 shows the associated mean cost per patient over the duration of the study by category of cost and allocation. The intensive glucose control policy increased the costs of antidiabetic treatment for each patient by an average of £659 (95% confidence interval £580 to £739) compared with conventional glucose control. There were no significant differences between patients in the conventional and intensive glucose control policy groups in the costs of antihypertensive drugs, other drugs, or trial clinic visits. Total routine treatment costs were £3655 per patient in the conventional group and £4350 in the intensive group (mean difference £695, 95% confidence interval £555 to £836). When trial visit and test costs were replaced by the estimates of standard clinical practice visit and test patterns, as shown in table 2, total treatment costs were £1658 in the conventional group and £3091 in the intensive group (mean difference £1435, £1332 to £1539).
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Complication costs
Hospital admissions formed the largest element of complication
costs (table 3). The mean cost of all hospital admissions was £4266 in
the conventional group and £3494 in the intensive group (mean
difference £772, £159 to £1385). The 18% reduction in cost with
intensive management is primarily the result of differences in the
length of stay (9.7 days in conventional group v 8.4 in
intensive group; mean difference 1.3, 0.2 to 2.3) combined with small
differences in the number of admissions (mean 1.5 episodes in
conventional group v 1.4 in intensive group; mean difference
0.1 (0.1 to 0.2, not significant)).
Total costs
The increased costs of antidiabetic treatment among the intensive
group were counterbalanced by reduced costs of complications so that
the net trial costs per patient did not differ between the two groups
(£9869 in the conventional group and £9608 in the intensive group).
Discounted at 6% a year to present values these costs become £7170 in
the conventional group and £6958 in the intensive group.
Costs over time
The costs reported above are aggregated per patient over the whole
trial period. Because of the nature of the disease costs will increase
over time. To illustrate this, figure 1 shows the mean undiscounted
costs per patient by year from their date of randomisation. There were
no significant differences in the mean treatment costs per patient
between conventional and intensive patients when considering
antihypertensive drugs, other drugs, or trial clinic visits. Although
we found some differences in the costs associated with the treatment of
eye and kidney disease over time, these differences arose from such a
small number of events that, as indicated in table 3, the mean cost
difference per patient over the whole trial was not significant. These
are therefore not included in figure 1.
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Outcomes
The main measure of effectiveness in this analysis is time to
first event. The conservative estimate was 14.29 years in the
conventional group and 14.89 years in the intensive group, a difference
of 0.60 (0.12 to 1.10) years (table 3). Discounted to present values at
6% a year, mean time to event was 8.88 years in the conventional group
and 9.17 years in the intensive group (0.29, 0.06 to 0.53 years).
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Cost effectiveness
The primary measure of cost effectiveness is the incremental cost
per event-free year gained. Discounting both costs and effects to
present values at 6% a year, the intervention is more effective and
cost saving based on resource use according to the trial protocol. If
the standard practice volumes are used rather than the protocol driven
volumes the cost per event-free year gained, with both costs and
effects discounted at 6%, is £1166 (£692 to £8819). With the
costs discounted at 6% a year and the effects undiscounted, the cost
per event-free year gained is £563 (£344 to £5632).
Sensitivity analysis
Sensitivity analysis was performed on the cost effectiveness ratio
resulting from the main analysis, in which both the incremental net
costs and incremental effect were discounted at 6% a year and the
study visits reflected standard practice. The analysis focused on
variation in the likely pattern and cost of visits and blood glucose
test schedules in standard practice from the baseline values in table
2. If the frequency of the visits to a doctor at a diabetes hospital
clinic increased from once to twice a year for the intensive policy
group treated with insulin and from 0.5 to once a year for the
intensive policy group treated with oral drugs, the difference in cost
between the intensive and conventional policies would become £625
(£81 to £1168), and the incremental cost per event-free year would increase from £1166 to £2155. If the frequency of the visits to a
specialist nurse increased from once to twice a year for the conventional policy group receiving insulin and from none to once a
year for the conventional policy group receiving oral drugs, the
difference in the cost between the policies would be £165 (£379 to
£710). The resulting incremental cost per event-free year would
decrease to £572.
Discussion |
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Abstract Introduction Methods Results Discussion References |
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Our economic analysis of treatment options in blood glucose control for people with type 2 diabetes is based directly on clinical trial information. The data are therefore less prone to the sources of bias, confounding, and uncertainty that are likely to affect non-randomised study designs. Secondly, because of the long follow up in the UK prospective diabetes study, the full range of costs arising from diabetic complications under conventional and intensive management could be assessed empirically. The relation between glycaemia and outcome is complex, but the UK prospective diabetes study has shown that improved glucose control reduces the risk of the diabetic complications that cause morbidity and suggested the mechanisms by which this might occur.6
Our economic analysis shows that the additional costs of intensive management are largely offset by significant reductions in the costs of treating complications of diabetes. If the prevalence of type 2 diabetes is 1.0-1.9% in the general population, a practice with a list of 10 000 patients will typically have 100-190 patients with type 2 diabetes at any time. Under our assumed clinical conditions an intensive policy costs an additional £1435 per patient (about £140 a year), which would be £14 000-£27 000 for a practice. These costs would be offset by £10 000-£18 000 in savings on complications.
Further research
Further evaluations will be needed to examine different ways in
which an intensive blood glucose control policy can be translated into
standard practice and the role of new drugs. Future studies could also
cast further light on the non-hospital costs of diabetic complications,
which we assessed using cross sectional data obtained towards the end
of the study. We did not include any potential difference between trial
groups in productivity losses to individuals and society or costs
directly incurred by patients or their families. As intensive blood
glucose control was associated with shorter hospital admissions, it may
result in fewer such indirect costs.
What is already known on this topic
Intensive blood glucose control in patients with type 2 diabetes significantly reduces the risk of diabetes related complications Intensive control has been shown cost effective in type 1 diabetes but data are lacking for type 2 diabetes What this study addsThe increased therapy costs of intensive blood glucose control in type 2 diabetes are largely offset by significantly reduced costs of complications In a typical general practice, the net cost of intensive blood glucose control for all type 2 diabetic patients is likely to be £4000-£9000 annually The cost per event-free year of intensive blood glucose control is about £1166 |
Acknowledgments |
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We thank the patients and staff at the study centres for their cooperation and Andrew Briggs, Philip Bassett, Valeria Frighi, and Ziyah Mehta for their contributions.
Contributors: AG helped plan and design the health economics study, supervised and participated in the analysis, coordinated the writing of the paper, and is the guarantor. MR compiled, maintained, and analysed the economic data and participated in interpreting the results and writing the paper. AMcG helped plan and design the health economics study and participated in supervising analysis, interpreting results, and writing the paper. PF helped plan and design the health economics study and participated in supervision and interpretation of results and revising the paper. RS developed the simulation model and participated in interpreting the results and writing the paper. CC was responsible for maintenance of the database, prepared trial data for analysis, discussed statistical aspects of the analysis, and participated in revising the paper. IS participated in data preparation, interpretation, and revision of the paper. AA helped to develop the simulation model and participated in interpreting the results and revising the paper. RH was a principal clinical investigator in the UK prospective diabetes study and participated in data preparation, analysis, and interpretation and revising the paper. RT was a principal clinical investigator in the clinical study, helped plan and design the study, and participated in interpreting the results and initial drafting of the paper. He died in August 1999.
Footnotes |
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Funding: Glaxo Wellcome, SmithKline Beecham, Pfizer, Zeneca, Pharmacia Upjohn, Novo Nordisk, Bayer, Roche, and UK Department of Health. RS is supported by a Wellcome Trust fellowship (grant No 054470/Z/98/Z/DG/NOS/FH). The main study was supported by grants from the UK Medical Research Council, British Diabetic Association, UK Department of Health, US National Eye Institute and National Institute of Diabetes, Digestive and Kidney Disease in the National Institutes of Health, British Heart Foundation, Novo Nordisk, Bayer, Bristol-Myers Squibb, Hoechst, Lilly, Lipha and Farmitalia Carlo Erba.
Competing interests: RH has received research for members of staff and fees for consulting and speaking, CC has received support for the cost of attending conferences, and AA has received fees for consulting from many of the companies who supported the study. AG has received support for attending conferences from Lipha.
The centres of the UK Prospective Diabetes Study Group, methods used to test model validity, and results of secondary analysis are given on the BMJ's website
References |
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1. | The Diabetes Control and Complications Trial Research Group (DCCT). Lifetime benefits and costs of intensive therapy as practiced in the diabetes control and complications trial. JAMA 1996; 276: 1409-1415[Abstract]. |
2. | Buxton M, Sculpher M, Ferguson B, Humphreys JE, Altman JF, Spiegelhalter DJ, et al. Screening for treatable diabetic retinopathy: a comparison of different methods. Diabetic Med 1991; 8: 371-377[Medline]. |
3. | Sculpher M, Buxton M, Ferguson B, Spiegelhalter D, Kirby A. Screening for diabetic retinopathy: a relative cost-effectiveness analysis of alternative modalities and strategies. Health Economics 1992; 1: 39-52[Medline]. |
4. | Eastman RC, Javitt JC, Herman WH, Dasbach EJ, Zbrozek AS, Dong F, et al. Model of complications of NIDDM. 1. Model of construction and assumptions. Diabetes Care 1997; 20: 725-734[Abstract]. |
5. | Eastman RC, Javitt JC, Herman WH, Dasbach EJ, Copley MC, Maier W, et al. Model of complications of NIDDM. 2. Analysis of the health benefits and cost-effectiveness of treating NIDDM with the goal of normoglycemia. Diabetes Care 1997; 20: 735-744[Abstract]. |
6. | UK Prospective Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837-853[CrossRef][Medline]. |
7. | Netten A, Dennett J. Unit costs of community care. Canterbury: Personal Social Services Research Unit, University of Kent, 1998. |
8. | Treasury. Appraisal and evaluation in central government. London: Stationery Office, 1997. |
9. | Willan AR, O'Brien BJ. Confidence intervals for cost-effectiveness ratios: an application of Fieller's theorem. Health Economics 1996; 5: 297-305[CrossRef][Medline]. |
10. | Chaudhary MA, Stearns SC. Estimating confidence intervals for cost-effectiveness ratios: an example from a randomized trial. Stat Med 1996; 15: 1447-1458[CrossRef][Medline]. |
11. | Van Hout BA, Al MJ, Gordon GS, Rutten FF. Costs, effects and c/e-ratios alongside a clinical trial. Health Economics 1994; 3: 309-319[Medline]. |
12. |
UK Prospective Diabetes Study Group.
Quality of life in type 2 diabetic patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control (UKPDS 37).
Diabetes Care
1999;
22:
1125-1136 |
(Accepted 7 February 2000)
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