Content uploaded by Andrew Briggs
Author content
All content in this area was uploaded by Andrew Briggs on Jun 18, 2014
Content may be subject to copyright.
Diabetologia (2005) 48: 868–877
DOI 10.1007/s00125-005-1717-3
ARTICLE
P. M. Clarke
.
A. M. Gray
.
A. Briggs
.
R. J. Stevens
.
D. R. Matthews
.
R. R. Holman
.
on behalf of the UK
Prospective Diabetes Study (UKPDS)
Cost-utility analyses of intensive blood glucose and tight blood
pressure control in type 2 diabetes (UKPDS 72)
Received: 28 August 2004 / Accepted: 3 December 2004 / Published online: 15 April 2005
# Springer-Verlag 2005
Abstract Aims/hypothesis: This study estimated the eco-
nomic efficiency (1) of intensive blood glucose control and
tight blood pressure control in patients with type 2 diabetes
who also had hypertension, and (2) of metformin therapy in
type 2 diabetic patients who were overweight. Methods: We
conducted cost-utility analysis based on patient-level data
from a randomised clinical controlled trial involving 4,209
patients with newly diagnosed type 2 diabetes conducted in
23 hospital-based clinics in England, Scotland and North-
ern Ireland as part of the UK Prospective Diabetes Study
(UKPDS). Three different policies were evaluated: inten-
sive blood glucose control with sulphonylurea/insulin; in-
tensive blood glucose control with metformin for overweight
patients; and tight blood pressure control of hypertensive
patients. Incremental cost : effectiveness ratios were calcu-
lated based on the net cost of healthcare resources asso-
ciated with these policies and on effectiveness in terms of
quality-adjusted life years gained, estimated over a lifetime
from within-trial effects using the UKPDS Outcomes Model.
Results: The incremental cost per quality-adjusted life years
gained (in year 2004 UK prices) for intensive blood glucose
control was £6,028, and for blood pressure control was £369.
Metformin therapy was cost-saving and increased quality-
adjusted life expectancy. Conclusions/interpretation: Each
of the three policies evaluated has a lower cost per quality-
adjusted life year gained than that of many other accepted
uses of healthcare resources. The results provide an econom-
ic rationale for ensuring that care of patients with type 2 di-
abetes corresponds at least to the levels of these interventions.
Keywords Cost-utility analysis
.
Hypertensive
.
Metformin
.
Overweight patients
.
Quality-adjusted life
years
.
Type 2 diabetes
.
United Kingdom Prospective
Diabetes Study
Abbreviations FPG: fasting plasma glucose
.
GP: general
practitioner
.
MI: myocardial infarction
.
QALY: quality-
adjusted life year
.
UKPDS: United Kingdom Prospective
Diabetes Study
.
UKPDS OM: UKPDS Outcomes Model
Introduction
The United Kingdom Prospective Diabetes Study (UKPDS)
established that a more intensive blood glucose control pol-
icy (aiming for a fasting plasma glucose [FPG] concen-
tration of <6.0 mmol/l) reduced the relative risk of any
diabetes-related endpoint by 12% and of microvascular com-
plications by 25% [1] in newly diagnosed patients with di-
abetes, and that the cost per year free of complications is less
than £1,200 [2]. The UKPDS also showed that tighter blood
pressure control (aiming at a blood pressure of less than
150/85 mmHg in hypertensive patients with type 2 diabetes)
reduced diabetes-related endpoints by 24% and deaths re-
lated to diabetes by 32% [3], and that the cost per life year
gained was approximately £720 [4]. Finally, the UKPDS
showed that the use of metformin for more intensive blood
glucose control in overweight patients conferred a 32%
relative risk reduction for any diabetes-related endpoint and
a 42% risk reduction for diabetes-related deaths [5], and that
the increased life expectancy associated with this interven-
P. M. Clarke (*)
.
A. M. Gray
.
A. Briggs
Health Economics Research Centre,
Department of Public Health, University of Oxford,
Old Road Campus, Headington,
Oxford, OX3 7LF, UK
e-mail: philip.clarke@dphpc.ox.ac.uk
Tel.: +44-1865-226691
Fax: +44-1865-226842
P. M. Clarke
.
R. J. Stevens
.
D. R. Matthews
.
R. R. Holman
Diabetes Trials Unit,
Nuffield Department of Clinical Medicine,
University of Oxford,
Oxford, UK
P. M. Clarke
Australian Centre for Diabetes Strategies,
Prince of Wales Hospital,
Sydney, Australia
R. J. Stevens
.
D. R. Matthews
.
R. R. Holman
Oxford Centre for Diabetes,
Endocrinology and Metabolism,
University of Oxford,
Oxford, UK
tion was accompanied by net expenditure savings over the
trial due to lower complication costs [6].
In comparison with many other well-accepted health
interventions, these diabetes interventions are highly cost-
effective and implementing them would increase the total
health benefits obtained from the current healthcare budget.
However, such comparisons are restricted by the fact that
the results reported to date from the UKPDS have only
measured outcomes in terms of life years gained [ 4, 6]or
endpoint-free time [2].
Maximum comparability will be obtained if the out-
comes of all interventions can be expressed in the same
units of measurement, and the measure that has gained most
currency amongst health economists has been the quality-
adjusted life year (QALY), a composite measure that aims
to incorporate survival and quality of life in a single index
[7]. Economic evaluations using QALYs as the principal
measure of outcome—often termed cost-utility studies—
have become increasingly popular in the literature and have
also been adopted by a number of health technology assess-
ment agencies as the methodology of choice [8]. We report
here the cost-utility in type 2 diabetes of each of the three
major UKPDS interventions: intensive blood glucose con-
trol with sulphonylureas/insulin, intensive blood glucose
control with metformin therapy in overweight patients, and
tight blood pressure control in hypertensive patients.
We make use of primary data on resource use and com-
plications during the trial follow-up period, coupled with
estimates modelled from UKPDS data on the immediate
and long-term quality of life effects and cost implications of
microvascular and macrovascular diabetes-related compli-
cations, to estimate the lifetime costs and effects of these
interventions in terms of the cost per QALYs gained.
Materials and methods
Patients, setting and comparison The UKPDS has been
described previously [9]. Briefly, between 1977 and 1991, a
total of 5,102 patients with newly diagnosed type 2 diabetes
aged 25–65 years, who were shown subsequently to have an
FPG >6.0 mmol/l on two occasions, were recruited to the
study. Following a dietary run-in period, 4,209 patients had
FPG concentrations of 6.1–15 mmol/l without symptoms of
hyperglycaemia. Of these, 3,867 were randomised either to
a conventional glucose control policy (mainly through diet,
1,138 patients), or to an intensive glucose control policy
with insulin (1,156) or sulphonylureas (1,573). A further
342 overweight patients (>120% ideal body weight), as-
signed to an intensive glucose control policy with metfor-
min, were compared with 411 overweight patients assigned
to the conventional glucose control policy [ 5]. The aim of
the conventional policy was to maintain patients with an
FPG <15 mmol/l without symptoms of hyperglycaemia
while trying to obtain the lowest FPG attainable with diet
alone. The intensive policy aimed for FPG <6.0 mmol/l and,
in patients treated with short-acting in addition to long-
acting insulin, pre-meal glucose concentrations of 4–7
mmol/l.
An embedded study randomised 1,148 hypertensive pa-
tients to a less tight blood pressure control policy (n=390,
aiming to maintain blood pressure <200/<105 mmHg, modi-
fied in 1992 to <180/<105 mmHg) or to a tightbloodpressure
control policy (n=758, aiming for <150/85 mmHg) using an
ACE inhibitor (captopril) or a beta blocker (atenolol). If
blood pressure control criteria were not met, additional anti-
hypertensive agents were added in a predefined stepwise
fashion.
The study design and protocol amendments, which con-
form to the guidelines of the Declarations of Helsinki as
revised in 2000, were approved by the Central Oxford Re-
search Ethics Committee and by the equivalent committees at
each centre. Each patient gave informed witnessed consent.
Economic evaluation Incremental cost-effectiveness ana-
lyses were undertaken for each intervention in which the
incremental net cost and net effectiveness were calculated in
relation to the comparator, and expressed as a ratio. As the
economic evaluation perspective was that of the healthcare
purchaser, only direct health service costs were included.
These included treatment costs, visits to a nurse or a general
practitioner (GP) based on ‘standard practice’ assumptions
(see below) and the costs of treating diabetic complications.
Not included in this analysis were non-medical costs such
as out-of-pocket expenses incurred when visiting clinics,
cost of informal care provided by family members and pro-
duction losses resulting from work absences, long-term dis-
ability or premature death, information on which was not
readily available. We adopted the QALY [7] as this measure
captures both increases in life expectancy and improved
quality of life which result from prevention of complica-
tions, providing a composite outcome measure of fatal and
non-fatal events that permits comparison between many
health interventions.
We compared the following treatment policies: (1) con-
ventional vs intensive blood glucose control (with insulin or
sulphonylureas); (2) conventional vs intensive blood glu-
cose control (with metformin) in overweight patients; and
(3) less tight blood vs tight blood pressure control (with
ACE inhibitors or beta blockers) in hypertensive patients. In
our main analyses we treated each of these interventions as
an independent policy.
Resource data and costs For each patient, doses of allocated
medications for blood glucose and blood pressure lowering
were collected routinely. Patients were asked also on a
regular basis if they were taking aspirin, hormone replace-
ment therapy, antidepressants, steroids, or other drugs. To
measure hospital inpatient episode costs, the date and dura-
tion of any admissions were collected at each clinic visit and
the costs estimated using previously reported methods [2].
The use of non-inpatient healthcare resources was estimated
using data from a cross-sectional survey conducted between
January 1996 and September 1997, which collected informa-
tion on domiciliary, clinic and telephone contacts with GPs,
nurses, podiatrists, opticians, dieticians and with eye and
other hospital clinics over the previous 4 months.
869
Table 1 summarises the main sources of information on
therapy unit costs, taken from UK national statistics [10,
11]. To obtain a cost per patient within the trial period, the
resource volumes used by each patient were multiplied by
these unit costs. We used previously reported equations [12]
to estimate the immediate (year of occurrence) and long-
term (all subsequent years) cost of major diabetes-related
complications, some of which are reproduced in Table 1.
The estimated immediate inpatient cost for a typical indi-
vidual ranged from £1,366 for a fatal myocardial infarction
(MI) event to £10,029 for an amputation. In all subsequent
years—that is, for patients with a history of these conditions
—hospital costs were elevated by £550 and £358, respec-
tively. Similarly, estimates for the increase in average annual
non-inpatient costs associated with any macrovascular com-
plications were £373 in the year of occurrence and £306 in
subsequent years, while for microvascular complications
the increased cost was £324 and £242, respectively.
Undiscounted costs are reported as well as net present
values using the UK Treasury recommended 3.5% discount
rate [13]. The effect of either a higher or lower discount rate
was examined in the sensitivity analysis. All costs are
reported in year 2004 values of pounds sterling (£1=∼€1.5).
All patients participating in the UKPDS, regardless of
their randomised allocation, attended clinics four or three
times a year. As the pattern of visits is likely to be different
in routine practice—especially for the conventional group
—we have reported incremental costs removing UKPDS
protocol-driven elements and using a pattern of clinic visits
reflecting a previously reported survey of GP and specialist
clinical opinion on the implementation of intensive policy
and blood pressure policy [11]. The cost of implementation
by policy and type of therapy is listed in Table 1. The effects
of higher implementation costs are considered in the sen-
sitivity analyses. The incremental annual cost of intensive
blood glucose control over conventional therapy was £111
when the patient was on tablets and £266 on insulin. Using a
similar method it was estimated that patients on tight blood
pressure control cost an additional £49 per annum regard-
less of their glucose policy.
Outcomes We estimated the difference in QALYexpectancy
for the different treatment policies. The QALY adjusts
length of life for quality of life by assigning a value or health
utility (where zero represents death and one represents full
health) for each year of life. Complications have been
Table 1 Main unit costs
for therapies and cost of
complications
a
All costs for complications are
for a representative individual
(set to the UKPDS mean popu-
lation values, i.e. a 58.63-year-
old male)
Item Unit cost £s 2004 Source
Therapy costs
Metformin (500 mg/850 mg tablet) 0.03/0.04 Drug tariff 2004
Chlorpropamide (100 mg/250 mg) 0.09/0.10 Drug tariff 2004
Glibenclamide (2.5 mg/5 mg) 0.03/0.05 Drug tariff 2004
Glipizide (2.5 mg/5 mg) 0.05/0.08 Drug tariff 2004
Ultralente insulin 1,000-unit
vial/750-unit cartridge
9.80 Drug tariff 2004
Soluble insulin 1,000-unit
vial/750-unit cartridge
9.80/10.20 Drug tariff 2004
Atenolol (25/50/100 mg) 0.06/0.07/0.09 Drug tariff 2004
Captopril (12.5/25/50 mg) 0.04/0.06/0.07 Drug tariff 2004
Other drugs Cost per item Drug tariff 2004
Implementation unit costs
General practitioner (clinic visit) 23 Netten and Curtis 2003 [10]
Practice nurse (home visit/surgery visit) 10/8
Dietician 9
Hospital eye clinic 42
Estimated standard practice costs by treatment
Conventional primarily on diet/or tablets 57 Unit costs multiplied by average
resource use reported in Table 3
of UKPDS 63 [11]
Conventional on Insulin 140
Intensive on tablets 168
Intensive on insulin 405
Immediate (subsequent years) costs of selected complications
a
Hospital costs
Fatal myocardial infarction 1,366 UKPDS 65 [12] adjusted for
inflation using the Hospital &
Community Services Pay And
Price Index
Non-fatal myocardial infarction 4,825 (550)
Non-fatal stroke 2,806 (295)
Amputation 10,029 (358)
Non-hospital costs
Macrovascular events 373 (306)
Microvascular events 324 (242)
870
shown to affect the quality of life of patients with type 2
diabetes [14]. Unlike previous evaluations of treatment for
diabetes that have used reference values for a limited num-
ber of complications [15], we estimated the effect of com-
plications using health utilities measured using the EQ-5D
health status questionnaire in a survey of 3,192 patients still
participating in the UKPDS in 1997 [16]. Using these data
the mean utility for a patient with diabetes who was free of
microvascular and macrovascular complications was found
to be 0.79, which is similar to people of the same age who do
not have diabetes. Patients with a history of complications
were found to have lower utility, and the following decre-
ments were estimated: −0.06 for an MI; −0.09 for other
ischaemic heart disease or angina; −0.16 for stroke; −0.11
for heart failure; −0.28 for amputation; and −0.07 for blind-
ness in one eye [16]. It was assumed that the occurrence of
multiple complications has an additive effect on utility and
the same decrements were applied to patients with compa-
rable health states regardless of their treatment policy.
For each patient available at the end of follow-up, the
UKPDS Outcomes Model (UKPDS OM), a newly devel-
oped simulation model which has been fully documented
elsewhere [17], was used to estimate the time from end of
follow-up to the first occurrence of each of the seven dia-
betes-related endpoints (MI, angina, stroke, heart failure,
amputation, renal failure and blindness in one eye) and to
death in order to estimate expected QALYs. In brief, the
UKPDS OM is based on an integrated system of parametric
equations which predict the annual probability of any of the
above endpoints occurring and Monte Carlo methods to
predict the occurrence of events. A key aspect of this model
is its ability to capture the clustering or interaction of dif-
ferent types of complications at the individual patient level.
This may arise not only because many events share com-
mon risk factors, but also due to event-related dependence,
i.e. when the occurrence of an event substantially increases
the likelihood of another event occurring [18]. The model is
a probabilistic discrete-time illness-death model [19], rather
than a Markov model, which simulates a patient’s life ex-
perience using annual cycles to calculate the probability of
death or of experiencing any of the specified complications.
Patients start with a given health status (e.g. no complica-
tions) and can have one or more non-fatal complications and/
or die in any model cycle by comparing estimated proba-
bilities with random numbers drawn from a uniform distri-
bution ranging from zero to one to determine whether an event
occurs. When a patient experiences a complication, their util-
ity is permanently decremented such that they accumulate
QALYs at a slower rate. Trial cohorts were run through the
model until all patients had died. For further details of the
model see http://www.dtu.ox.ac.uk/Outcomesmodel.
In these simulations we assume that every patient from
the end of the trial has the overall mean HbA
1
c and blood
pressure levels, regardless of randomised policy. The only
difference in hazard between the groups is due to compli-
cations experienced during the trial. The estimated QALY
gain using our model will therefore be conservative as it
assumes that there is no continuing benefit of therapy. We
report undiscounted benefits along with outcomes discount-
ed at 3.5% and 6% per year.
Analysis Results are reported as mean values and SDs or
mean differences with CIs, and as cost to effectiveness
ratios. To provide a visual representation of the results, the
costs and health outcomes are mapped onto the cost-ef-
fectiveness plane and reported as acceptability curves [20].
The effect on our main results of uncertainty surrounding
some aspects of cost and the utility values used in the study
were examined using sensitivity analyses.
Results
Costs Tables 2, 3, 4 show the mean cost per patient over the
duration of the study for each of the three interventions
considered, by category of cost and by randomised allo-
Table 2 Mean and SD costs per patient during the trial follow-up period and mean (95% CI) cost differences for conventional vs intensive
blood glucose control with insulin or sulphonylureas, by cost category (£s 2004)
Conventional Intensive Mean cost
difference (95% CI)
per patient
a
Mean SD Mean SD
Antidiabetic treatment 620 957 1,299 1,196 678 (607, 750)
Anti-hypertensive treatment 430 668 427 666 −3(−49, 43)
Cost of implementation 699 315 2,160 865 1,461 (1,424, 1,498)
Total cost of treatment 1,749 1,399 3,885 1,992 2,136 (2,009, 2,263)
Within-trial hospital inpatient costs 5,212 15,492 4,159 8,557 −1,053 (288, 1,818)
Within-trial non-hospital and outpatient costs 2,528 1,084 2,538 1,092 10 (−66, 85)
Projected hospital inpatient costs 13,322 38,052 13,476 37,428 154 (−3,265, 3,573)
Projected non-hospital and outpatient costs 3,708 3,821 3,807 3,881 98 (−259, 455)
Total cost of complications 24,771 43,276 23,980 41,106 −791 (−4,586, 3,003)
Total costs, undiscounted 26,516 43,438 27,865 41,310 1,349 (−2,455, 5,153)
Total costs, 3.5% discount rate 14,984 17,888 15,868 14,465 884 (−483, 2,250)
Total costs, 6% discount rate 11,169 13,340 11,852 9,261 683 (−230, 1,597)
a
Negative cost differences indicate cost-savings associated with more intensive therapies. Sub-totals may not sum exactly due to rounding
871
cation. The intensive blood glucose control policy increased
the antidiabetic treatment costs by £678 (95% CI 607, 7,50)
and the incremental costs of visits and self-testing in a
standard practice setting by £1,461 (1,424, 1,498), when
compared with conventional glucose control (Table 2).
However, the effect of this policy was also to reduce mean
hospitalisation cost per patient over the median 10.4 years of
follow-up, from £5,212 in the conventional policy group to
£4,159 in the intensive policy group. Simulated post-trial
hospitalisation costs were similar in the conventional and
intensive groups (£13,322 vs £13,476). When non-hospital
costs also were taken into account, the overall intensive
policy reduction in cost of complications was £791 (−4,586,
3,003). Combining both therapy costs and savings achieved,
the incremental cost of intensive blood glucose control with
insulin or sulphonylureas was £1,349 (−2,455, 5,153), or
£884 (−483, 2,250) when discounted.
Intensive blood glucose control with metformin in over-
weight patients increased therapy costs by £1,742 (1,521,
1,963) compared with those on conventional therapy, main-
ly due to the costs associated with implementing this policy
in a standard practice setting (Table 3). The cost of compli-
cations was £−2,765 (−11,695, 6,166) less per patient in the
metformin group, compared with conventional policy. As
the increased cost of metformin therapy (including standard
practice costs) is less than the reduction in the cost of com-
plications, there is on average a net cost-saving from the
intervention of £−1,023 (−9,972, 7,926) per patient.
The costs for the embedded hypertension study, which
had a shorter median duration of follow-up of 8.4 years, are
Table 3 Mean and SD costs per patient during the trial follow-up period and mean (95% CI) cost differences for conventional vs intensive
blood glucose control with metformin in overweight patients, by cost category (£s 2004)
Conventional Intensive Mean cost
difference (95% CI)
per patient
a
Mean SD Mean SD
Antidiabetic treatment 640 997 776 639 136 (18, 254)
Anti-hypertensive treatment 626 796 612 814 −15 (−131, 101)
Cost of implementation 674 193 2,295 748 1,621 (1,539, 1,702)
Total cost of treatment 1,941 1,486 3,682 1,598 1,742 (1,521, 1,963)
Within-trial hospital inpatient costs 7,283 23,498 4,233 8,151 −3,050 (−5,666, −433)
Within-trial non-hospital and outpatient costs 2,834 1,077 2,834 1,044 0 (−153, 152)
Projected hospital inpatient costs 13,515 38,531 13,591 35,580 76 (−8,118, 8,270)
Projected non-hospital and outpatient costs 3,717 3,941 3,927 3,829 209 (−373, 792)
Total cost of complications 27,350 46,842 24,585 39,609 −2,765 (−11,695, 6,166)
Total costs, undiscounted 29,290 47,056 28,267 39,764 −1,023 (−9,972, 7,926)
Total costs, 3.5% discount rate 16,941 23,193 15,920 13,678 −1,021 (−4,291, 2,249)
Total costs, 6% discount rate 12,798 18,836 11,792 8,557 −1,006 (−3,251, 1,239)
a
Negative cost differences indicate cost-savings associated with more intensive therapies. Sub-totals may not sum exactly due to rounding
Table 4 Mean and SD costs per patient during the trial follow-up period and mean (95% CI) cost differences for tight vs less tight blood
pressure control, by cost category (£s 2004)
Less tight Tight Mean cost
difference (95% CI)
per patient
a
Mean SD Mean SD
Antidiabetic treatment 1,027 1,028 1,119 1,163 92 (−40, 224)
Anti-hypertensive treatment 554 628 1,102 720 549 (468, 630)
Cost of implementation 1,332 777 1,782 858 450 (351, 548)
Total cost of treatment 2,913 1,605 4,003 1,931 1,090 (867, 1,314)
Within-trial hospital inpatient costs 4,414 9,549 3,555 9,229 −860 (−2,002, 282)
Within-trial non-hospital and outpatient costs 2,116 788 2,144 799 −28 (−125, 70)
Projected hospital inpatient costs 13,702 36,117 13,657 38,715 −46 (−6,115, 6,024)
Projected non-hospital and outpatient costs 3,505 3,755 3,634 3,808 129 (−425, 684)
Total cost of complications 23,738 40,415 22,989 42,561 −749 (−7,371, 5,873)
Total costs, undiscounted 26,651 40,577 26,993 42,713 342 (−6,295, 6,978)
Total costs, 3.5% discount rate 15,786 16,378 15,895 16,025 108 (−2,347, 2,563)
Total costs, 6% discount rate 11,984 11,082 12,042 10,671 58 (−1,490, 1,606)
a
Negative cost differences indicate cost-savings associated with more intensive therapies. Sub-totals may not sum exactly due to rounding
872
reported in Table 4. Overall the difference in the cost of the
antihypertensive therapies between policies of tight and less
tight control was £549 (468, 630). More intensive blood
pressure control reduced the cost of complications by £749
(7,371, 5,873), and so the overall cost-effect of more inten-
sive blood pressure control was a net increase in cost of
£342 (−6,295, 6,978), or £108 (−2,347, 2,563) when dis-
counted to present value.
Outcomes The main measure of effectiveness in this anal-
ysis is expected QALYs gained per patient. Table 5 shows
mean quality-adjusted life expectancy from date of random-
isation, by allocation, for the within-trial period and pro-
jected over their remaining lifetime. Patients allocated to an
intensive blood glucose control policy with insulin and
sulphonylureas were estimated to live 16.62 QALYs com-
pared with 16.35 QALYs for patients on conventional ther-
apy. This was a non-significant trend of 0.27 (−0.48, 1.03),
or 0.15 (−0.20, 0.49) when discounted.
The estimated number of QALYs in overweight patients
allocated to an intensive blood glucose control policy with
metformin showed a non-significant increase of 0.88 (−0.54,
2.29), compared with overweight patients on the conven-
tional glucose control policy (Table 5). Patients allocated to
a tight blood pressure control policy were estimated to
obtain 14.16 QALYs, compared with 13.71 amongst those
allocated to a less tight blood pressure control policy. The
overall lower number of QALYs in this randomisation com-
pared with the glucose control analyses reflects the older age
at which these hypertensive patients were randomised into
this embedded study (56.4 vs 53.3 years).
Cost-effectiveness One way of representing the combina-
tions of cost and effect differences reported above for each
intervention is to plot the changes on a cost-effectiveness
plane, which simultaneously represents the difference in
the mean costs (on the y-axis) and life expectancy (on the
x-axis) [20]. Figure 1a–c shows cost-effectiveness planes
for the intensive blood glucose, metformin and tight blood
pressure control analyses, respectively. The vertical I-bars
show the 95% CI for the cost-difference (from Table 2) and
the horizontal I-bars show the 95% CI for the difference in
QALYs (from Table 5). The two I-bars cross at the point
estimates of cost and effect and the slope of the line join-
ing that point to the origin of the plane represents the
point estimate of cost per QALY. The discounted cost of
an intensive blood glucose control policy with insulin or
sulphonylureas was on average £884 more per patient and
the discounted benefits gained were 0.15 QALYs, giving a
cost to utility ratio of £6,028 per QALY gained. The dis-
counted cost of intensive blood glucose control policy with
metformin in overweight patients was on average £1,021
(−4,291, 2,249) less than the conventional policy and had a
longer discounted life expectancy of 0.55 QALYs, making
this treatment strategy both cost-saving and more effective.
In these circumstances, calculation of a cost to effectiveness
ratio is not appropriate, as such a ratio would fail to dif-
ferentiate between an intervention that was cost-saving and
outcome-enhancing, and an intervention that increased costs
with poorer outcomes [21]. Finally, the discounted cost of
tight blood pressure control policy was on average £108
more per patient, and discounted life expectancy was 0.29
QALYs longer, giving a cost to utility ratio of £369 per
QALY gained.
The joint uncertainty in costs and QALYs is shown by the
elliptical contours in Fig. 1a–c, which cover 95% of the
integrated joint density (assuming joint normality). In all
three cases the 95% confidence surface extends beyond a
single quadrant of the cost-effectiveness pane and in these
situations the calculation of 95% CIs for cost-effectiveness
can be problematic due to the inherent instability of ratio
statistics. An alternative presentation is given in Fig. 2,
which shows, for different values of the maximum will-
ingness to pay for a QALY, the probability that the inter-
vention under evaluation is cost-effective. These curves are
known as cost-effectiveness acceptability curves and have
become an accepted way of presenting uncertainty in cost-
effectiveness information that can simultaneously summarise
Table 5 Within-trial and lifetime modelled quality-adjusted life
expectancy of conventional vs intensive blood glucose control with
insulin or sulphonylureas; conventional vs intensive blood glucose
control with metformin in overweight patients; and tight vs less tight
blood pressure control, at varying discount rates
Item Mean (SD) undiscounted
QALYs per patient
Mean difference (95% CI) in
QALYs per patient
Conventional Intensive Discount rate per year
0% 3.5% 6%
Within-trial
Intensive blood glucose control 7.62 (2.71) 7.72 (2.69) 0.10 (−0.09, 0.29) 0.08 (−0.07, 0.22) 0.06 (−0.05, 0.17)
Metformin therapy 8.09 (2.50) 8.37 (2.33) 0.28 (−0.09, 0.63) 0.22 (−0.04, 0.48) 0.18 (−0.02, 0.39)
Tight blood pressure control 7.63 (2.36) 7.77 (2.18) 0.12 (−0.10, 0.34) 0.10 (−0.08, 0.28) 0.08 (−0.06, 0.24)
Total
Intensive blood glucose control 16.35 (8.36) 16.62 (8.35) 0.27 (−0.48, 1.03) 0.15 (−0.20, 0.49) 0.10 (−0.12, 0.31)
Metformin therapy 16.44 (8.49) 17.32 (7.94) 0.88 (−0.54, 2.29) 0.55 (−0.10, 1.20) 0.40 (−0.01, 0.80)
Tight blood pressure control 13.71 (8.00) 14.16 (7.81) 0.45 (−0.70, 1.60) 0.29 (−0.26, 0.85) 0.22 (−0.14, 0.59)
QALY quality-adjusted life year
873
uncertainty due to sampling variation, but also uncertainty
concerning the appropriate threshold for cost-effective de-
cision-making [20]. The point at which the curves cross the
vertical axis shows the probability that treatment is cost-
saving.
With costs and effects discounted at a 3.5% rate, in-
tensive blood glucose control has a 10% chance of being
cost-saving. At a ceiling ratio of £20,000 per QALY there is
a 74% chance that it is cost-effective. There is a 77% prob-
ability that metformin would prove to be cost-saving
compared with a conventional policy, and due to the po-
sition of the point estimate of cost-effectiveness in the dom-
inant quadrant of the cost-effectiveness plane, the chance
that metformin is cost-effective at a ratio of £20,000 per
QALY is 98%. Tight blood pressure control has a 47%
chance of being cost-saving and an 86% chance of being
cost-effective compared with less tight control.
Sensitivity analysis Sensitivity analyses performed to ex-
amine whether the results in the main analysis are robust to
different assumptions are displayed in Fig. 3. The effect of
a 50% higher standard practice cost than in the baseline
estimates, after discounting, was an increase in the average
cost per QALY for intensive blood glucose control with
insulin or sulphonylurea from £6,028 to £10,051, while a
50% reduction in standard practice costs reduced the cost
per QALY to £2,251. Lowering the costs of complications
had the effect of increasing the cost per QALY, as the value
of averted events was lessened and so net cost rose, and the
same effect was found with the tight blood pressure control
policy. The sensitivity analyses of intensive blood glucose
control with metformin are not shown in Fig. 3 as this was
an intervention dominated by the comparator (lower costs
and better outcomes); neither a 50% increase in antidia-
beti c therapy costs or standard practice costs, nor a 50%
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
£0 £5000 £10 000 £15 000 £20 000 £25 000 £30 000
Value of ceilin
g
ratio (lambda)
Probability cost-effective
Fig. 2 Cost-effectiveness ac-
ceptability curves: probability
that the cost per quality-adjusted
life year gained is cost-effective
as a function of the decision-
maker’s ceiling cost to effec-
tiveness ratio. Top curve
metformin, middle curve tight
blood pressure control, lower
curve intensive blood glucose
control
–£6000
–£5000
–£4000
–£3000
–£2000
–£1000
£0
£1000
£2000
£3000
£4000
–1 –0.5 0 0.5 1 1.5
Additional QALYs
Incremental costs
–£6000
–£5000
–£4000
–£3000
–£2000
–£1000
£0
£1000
£2000
£3000
£4000
–1 –0.5 0 0.5 1 1.5
Additional QALYs
Incremental costs
–£6000
–£5000
–£4000
–£3000
–£2000
–£1000
£0
£1000
£2000
£3000
£4000
–1 –0.5 0 0.5 1 1.5
Additional QALYs
Incremental costs
abc
Fig. 1 Cost-effectiveness planes showing mean difference in cost
and effect and 95% CI and 95% confidence ellipses for cost-
effectiveness for a intensive vs conventional blood glucose control
with insulin or sulphonylureas, b intensive vs conventional blood
glucose control with metformin in overweight patients and c tight vs
less tight blood pressure control in type 2 diabetes. QALY Quality-
adjusted life year
874
reduction in com plication costs, altered the status of inten-
sive blood gl ucose control with metformin as a cost-
reducing intervention.
We also show the impact of different assumptions re-
garding continuing health effects beyond the trial and utility
weights used to estimate QALYs. In regard to health effects,
we have estimated the cost : effectiveness ratios: (1) using
only the benefits attained within the trial; and (2) assuming
that the average difference in HbA
1
c (or blood pressure)
between policies continues beyond the trial as a way of
capturing continuing treatment effects. In regard to inten-
sive blood glucose control, disregarding benefits beyond
the trial increased the average cost per QALY to £11,050,
while assuming a continuing treatment effect reduced the
average cost to effectiveness ratio to £4,209. To examine the
impact of adopting a higher utility weight for people with-
out complications when calculating QALYs, we re-ran the
simulation adopting the assumption that the mean utility for
people without complications is 1.0 (i.e. they are in full
health), rather than 0.79 as used in the main analysis. After a
discounting, the differences in conventional vs intensive
blood glucose control with insulin or sulphonylureas, con-
ventional vs intensive blood glucose control with metfor-
min and tight vs less tight blood pressure control were 0.19
(−0.17, 0.55), 0.69 (−0.02, 1.41) and 0.36 (−0.29, 1.00),
respectively. As the figure shows for intensive blood glu-
cose control with insulin or sulphonylureas and for tight
blood pressure control, these changes did not have a major
impact on the estimated cost-effectiveness.
Discussion
Summary of main findings This paper presents the results of
a set of cost-effectiveness studies based on the primary
results from the UKPDS with model-derived extrapolation
to 100% mortality of the trial cohort. These indicate that
intensive blood glucose control with insulin or sulphony-
lureas, intensive blood glucose control with metformin and
tight blood pressure control in hypertensive patients with
type 2 diabetes each has a cost per QALY gained that is
lower than other accepted uses of healthcare resources. In
the UK, interventions appear to have a high chance of ac-
ceptance by the National Institute for Clinical Excellence if
their cost-effectiveness is more favourable than approxi-
mately £30,000 per QALY [22]. As the results are based
primarily on clinical trial information, the effectiveness and
resource use data used are less likely to be affected by the
sources of bias, confounding and uncertainty that often
impair non-randomised study designs.
These results mark an important advance on our previous
estimates of the cost-effectiveness of diabetes treatment
policies, in that t he outcome measures used here capture
the improved quality of life associated with lower rates of
complications in patients randomised to policies of more
intensive blood glucose or tighter blood pressure control as
well as the survival benefit from a reduced number of fatal
events. The estimated gains in quality-adjusted life expec-
tancy range from 0.17 QALYs for intensified blood glucose
control with insulin or sulphonylureas to 0.88 QALYs for
metformin therapy in overweight patients. The cost esti-
mates also include many changes in the unit cost of drugs in
the UK, for example the total cost of antihypertensive drugs
in the tight blood pressure control group of patients are
estimated to be £1,102 per patient, which is approximately
15% lower than those reported in a previous study due to
reductions in the cost of captopril following the expiration
of its patent in the UK [4].
A previous modelling study which reported the cost-
utility of an intensive blood glucose policy with insulin or
sulphonylureas and tighter blood pressure control [23] pro-
duced similar outcome estimates, but the cost of imple-
menting these policies appeared to be much higher in a US
healthcare setting, resulting in somewhat less favourable
cost to effectiveness ratios. For example, the incremental
cost of treatment with a policy of intensive blood glucose
control was estimated to be $12,213 (equivalent to £6,600 at
2004 exchange rates), over three times the estimated UK
£0
£2000
£4000
£6000
£8000
£10 000
£12 000
ABCDE ABCDE
Cost per QALY
Intensive blood glucose control Tight blood pressure control
A = Anti-diabetic therapy costs 50% higher/lower; B = Standard practice costs 50% higher/lower; C = Cost o
f
complications 50% lower/higher; D = Utility of 1 when free of complications; E = Treatment benefit beyond
trial: none/continuin
g
Fig. 3 Sensitivity of cost-
effectiveness of intensive blood
glucose control with insulin or
sulphonylureas and tight blood
pressure control to changes in
assumptions concerning antidi-
abetic treatment costs, standard
practice costs, costs of compli-
cations, quality of life and
treatment benefit beyond trial
875
incremental cost. These differences suggest the need to un-
dertake country-specific cost-effectiveness analyses when
costs differ markedly between healthcare systems. This may
be due to differences in the cost of diabetes therapies, or the
cost of treating complications that may influence the scope
for savings. While our sensitivity analyses also highlight
the impact of c hanges in the cost of therapy/implementa-
tion and the cost of complications, our results su ggest that
all three policies are likely to remain cost-effective under a
wide range of assumptions.
Implications of results The objective of undertaking eco-
nomic evaluation is to improve the allocation of health
resources by stimulating the adoption of cost-effective in-
terventions and curtailing those that offer poor value for
money. Our results would indicate that there is potential for
the cost of therapies to be partly offset by reductions in the
costs of treating complications of diabetes. However, these
costs and benefits may well be incurred by different parties
or funding streams, depending on the configuration of the
healthcare system. Mechanisms may therefore have to be
devised to ensure that the correct incentives are in place to
improve diabetes care. It should also be noted that any sav-
ing from reduced complications may not be realised as fi-
nancial savings, but a reduction in hospitalisations may free
up resources that may be reallocated elsewhere.
Decision-makers will be interested not only in cost-ef-
fectiveness but also in the total cost of implementing these
interventions. We have estimated previously that improved
glycaemic and blood pressure control would cost approxi-
mately £101 m per annum for the entire population of
people with type 2 diabetes in England [11]. This represents
a small proportion (<1%) of the incremental growth in UK
healthcare spending between 2001 and 2005 and should be
similarly affordable in other healthcare systems.
Limitations Although the sensitivity analyses we undertook
suggest that our conclusions should be robust over a wide
range of assumptions made, a number of limitations should
be noted. First, we included only the costs of diabetic ther-
apy during the within-trial period and, secondly, our extra-
polation beyond the trial period does not assume continuing
treatment effects in the main analysis (e.g. patients in the
blood glucose study were assumed to have the same mean
HbA
1
c from the end of the trial). Analysts are likely to be
interested in the lifetime costs and benefits of therapies
based on various assumptions about treatment costs and
benefits continuing, but this would require further simula-
tion modelling. Thirdly, we have reported the cost-utility of
three interventions which have been considered separately.
However, in clinical practice it is likely that many patients
will be treated simultaneously for hyperglycaemia and
hypertension as well as other risk factors such as dys-
lipidaemia. Joint delivery of these interventions will lower
implementation costs and therefore should further improve
the cost to effectiveness ratios r eported here.
Since the UKPDS was first designed, the standards of
normal care for people with diabetes have risen and further
intensification of treatment has occurred following pub-
lication of the UKPDS results. One consequence is that
the incremental benefits obtained from the randomised
comparisons reported here may now be more difficult to
achieve, although the incremental costs would also be re-
duced. However, epidemiological analyses of the UKPDS
have indicated linear relationships between HbA
1
c and risk
of complications and between blood pressure and risk of
complications, but further evidence is required in order to
assess both the effectiveness and cost-effectiveness of fur-
ther intensifying treatment. Meanwhile, it should be noted
that considerable scope still exists to attain recommended
standards of diabetes care, in the UK and elsewhere [24].
Care was taken as part of the modelling exercise to prop-
agate parameter uncertainties through the model. The re-
sults of the analysis show that, while th e point estimates
of cost-effectiveness fall within the acceptable range, we
cannot be confident, at conventional error probabilities, that
the modelled interventions are cost-effective. This is due to
the non-significant differences associated with the QALY
outcomes reported in Table 5. Nevertheless, the balance of
probabilities favours greater intervention in diabetes being
cost-effective, and the non-negligible chance that these
interventions turn out not to be cost-effective if implemen-
ted must be weighed against the even greater probability
that, if these interventions are not implemented, patients
will have been denied cost-effective care. Information on
the 5-year follow-up of the UKPDS will offer the oppor-
tunity of testing the model predictions and further refining
the cost-effectiveness estimates and the precision with which
they are estimated.
Conclusion In conclusion, the analyses reported here pro-
vide further evidence that the cost-effectiveness of interven-
tions to reduce the burden of diabetes-related complications
compares favourably with that of other accepted uses of
healthcare resources. The results should be of interest and
use to other economists and health service researchers, and
in particular should be considered by decision-makers when
considering the allocation of resources to diabetes care. We
believe the results illustrate a convincing economic ratio-
nale for improving standards of care for patients with type 2
diabetes.
Conflict of interest declaration. The authors are employed
by the University of Oxford. This paper makes use of a
simulation model that we have called the UKPDS Out-
comes Model. All of the information necessary to reproduce
the UKPDS Outcomes Model is in the public domain, but it
is conceivable that a future user with a commercial interest
in the UKPDS Outcomes Model might prefer to use the
software already created by University programmers. De-
pending on the nature of the proposed use of the UKPDS
Outcomes Model, the University of Oxford might charge a
fee in this case.
876
Acknowledgements The cooperation of the patients and many NHS
and non-NHS staff at the centres is much appreciated. The major
grants for this study were from the UK Medical Research Council;
British Diabetic Association; the UK Department of Health; the
National Eye Institute and the National Institute of Digestive, Dia-
betes and Kidney Disease in the National Institutes of Health, USA;
the British Heart Foundation; Novo-Nordisk; Bayer; Bristol Myers
Squibb; Hoechst; Lilly; Lipha; and Farmitalia Carlo Erba. Other
funding companies and agencies, the supervising committees, and all
participating staff are listed in an earlier paper [1]. P. M. Clarke is
partly supported by an NHMRC grant 300565. A. Briggs is supported
by an NHS Public Health Career Scientist award. R. Stevens was
supported by Health Foundation. We are grateful to I. Stratton and A.
Farmer for comments on the manuscript.
References
1. UKPDS Group (1998) Intensive blood-glucose control with
sulphonylureas or insulin compared with conventional treat-
ment and risk of complications in patients with type 2 diabetes
(UKPDS 33). Lancet 352:837–853
2. Gray A, Raikou M, McGuire A et al (2000) Cost effectiveness
of an intensive blood glucose control policy in patients with
type 2 diabetes: economic analysis alongside randomised con-
trolled trial (UKPDS 41). BMJ 320:1373–1378
3. UKPDS Group (1998) Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 dia-
betes (UKPDS 38). BMJ 317:703–713
4. UKPDS Group (1998) Cost effectiveness analysis of improved
blood pressure control in hypertensive patients with type 2
diabetes (UKPDS 40). BMJ 317:720–726
5. UKPDS Group (1998) Effect of intensive blood-glucose control
with metformin on complications in overweight patients with
type 2 diabetes (UKPDS 34). Lancet 352:854–865
6. Clarke P, Gray A, Adler A et al (2001) Cost-effectiveness
analysis of intensive blood-glucose control with metformin in
overweight patients with type II diabetes (UKPDS No. 51).
Diabetologia 44:298–304
7. Torrance GW (1986) Measurement of health state utilities for
economic appraisal: a review. J Health Econ 5:1–30
8. NICE (2004) Guide to the methods of technology appraisal.
National Institute for Clinical Excellence, London
9. UKPDS Group (1991) UK Prospective diabetes study VIII:
study design, progress and performance. Diabetologia 34:877–
890
10. Netten A, Curtis L (2003) Unit costs of health and social care
2003. Personal Social Services Research Unit, Canterbury,
Kent (University of Kent)
11. Gray A, Clarke P, Farmer A, Holman R (2002) Implementing
intensive control of blood glucose concentration and blood
pressure in type 2 diabetes in England: cost analysis (UKPDS
63). BMJ 325:860
12. Clarke P, Gray A, Legood R, Briggs A, Holman R (2003) The
impact of diabetes-related complications on healthcare costs:
results from the United Kingdom Prospective Diabetes Study
(UKPDS 65). Diabetes Med 20:442–450
13. HM Treasury (2003) The green book: appraisal and evaluation
in central government: treasury guidance. The Stationery Office,
London
14. UKPDS Group (1999) 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 22:1125–1136
15. DCCT (1996) Lifetime benefits and costs of intensive therapy
as practiced in the diabetes control and complications trial. The
diabetes control and complications trial research group. JAMA
276:1409–1415
16. Clarke P, Gray A, Holman R (2002) Estimating utility values
for health states of type 2 diabetic patients using the EQ-5D
(UKPDS 62). Med Decis Making 22:340–349
17. Clarke P, Gray A, Briggs A et al (2004) A model to estimate the
lifetime health outcomes of patients with Type 2 diabetes: the
United Kingdom prospective diabetes study (UKPDS) out-
comes model (UKPDS 68). Diabetologia 47:1747–1759
18. Brown JB, Russell A, Chan W, Pedula K, Aickin M (2000) The
global diabetes model: user friendly version 3.0. Diabetes Res
Clin Pract 50:S15–S46
19. Hougaard P (2000) Analysis of multivariate survival data
(statistics for biology and health). Springer, Berlin Heidelberg
New York
20. Van Hout B, Al MJ, Gordon GS, Rutten FF (1994) Costs,
effects and C/E-ratios alongside a clinical trial. Health Econ
3:309–319
21. Stinnett AA, Mullahy J (1997) The negative side of cost-
effectiveness analysis. JAMA 277:1931–1932
22. Rawlins MD, Culyer AJ (2004) National Institute for Clinical
Excellence and its value judgments. BMJ 329:224
–227
23. CDC Group (2002) Cost-effectiveness of intensive glycemic
control, intensified hypertension control, and serum cholesterol
level reduction for type 2 diabetes. JAMA 287:2542–2551
24. Audit Commission (2000) Testing times: a review of diabetes
services in England and Wales. Audit Commission, London
877