The UK
Prospective
Diabetes
Study
ukpds
UK Prospective Diabetes Study
multi-centre
randomised controlled trial
of different therapies
of Type 2 diabetes
ukpds
UKPDS : need for a long-term study
complications of Type 2 diabetes develop
over decades
Protocol written
Recruitment
End of study
1976
1977-1991
Sept. 1997
Clinical Centres
Type 2 diabetic patients
Person years follow-up
23
5102
53,000
Funding
£23 million
ukpds
UK Prospective Diabetes Study Centres
Aberdeen
Lilian Murchison
Belfast City
Randal Hayes
Belfast Royal
David Hadden
Birmingham
David Wright
Carshalton
Steve Hyer
Memo Spathis
Derby
Ian Peacock
Dundee
Ray Newton
Roland Jung
Exeter
Kenneth McLeod
John Tooke Stoke on Trent
Hammersmith Anne Dornhorst
Eva Kohner Torbay
Ipswich
John Day
Leicester
Felix Burden
Manchester
Northampton
Norwich
Oxford
Peterborough
Salford
Scarborough
St George’s
Stevenage
John Scarpello
Andrew Boulton
Charles Fox
Richard Greenwood
Robert Turner
Rury Holman
Jonathan Roland
Tim Dornan
Phil Brown
Nigel Oakley
Les Borthwick
Lionel Alexander
Richard Paisey
Whittington
John Yudkin
ukpds
Co-ordinating Staff
Chief Investigators :
Robert Turner, Rury Holman
Statisticians :
Irene Stratton, Carole Cull
Ziyah Mehta, Heather McElroy
Modeller :
Richard Stevens
Epidemiologists :
Andrew Neil, Amanda Adler
Diabetologists :
David Matthews, Valeria Frighi
Biochemists :
Susan Manley, Iain Ross
Administrators :
Philip Bassett, Suzy Oakes
Retinopathy Grading Centre :
Eva Kohner, Steve Aldington
Health Economics :
Alastair Gray, Maria Raikou
Grant Applications :
Ivy Samuel, Caroline Wood
Computing Support :
Ian Kennedy, John Veness
And many others
ukpds
Acknowledgements
•
•
•
•
•
patients
physicians
nurses
dietitians
retinal photographers
• Retinopathy Grading : Hammersmith Hospital
• Biochemistry : Diabetes Research Laboratories
• ECG Grading : Guy’s Hospital
ukpds
Major Funding Bodies
UK Medical Research Council
British Diabetic Association
UK Department of Health
British Heart Foundation
Novo Nordisk
Bristol Myers Squibb
Farmitalia Carlo Erba
USA National Institutes
of Health (NEI, NIDDK)
Wellcome Trust
Bayer
Lipha
Lilly
Hoechst
ukpds
UK Prospective Diabetes Study
Glucose Control Study
ukpds
Blood Glucose Control Study : Aims
to determine whether
• improved glucose control of Type 2 diabetes
will prevent clinical complications
• therapy with
sulphonylurea - first or second generation
insulin
metformin
has any specific advantage or disadvantage
ukpds
Patient Characteristics
5102 newly diagnosed Type 2 diabetic patients
age 25 - 65 years
mean
53 y
gender
male : female
59 : 41%
ethnic group
Asian
Afro-caribbean
Body Mass Index
fasting plasma glucose (fpg)
HbA1c
hypertensive
Caucasian
82%
10%
8%
mean
median
median
28 kg/m2
11.5 mmol/L
9.1 %
39%
ukpds
UK Prospective Diabetes Study
• follow-up of patients to major fatal and
non-fatal clinical endpoints
• recording of surrogate endpoints :
clinical and biochemical markers
e.g. urine albumin
retinal photographs
visual acuity
• intention to treat analysis
ukpds
Randomisation
5102 newly diagnosed Type 2 diabetic patients
Diet therapy
fpg < 6
asymptomatic
17%
fpg 6.1 - 15.0
asymptomatic
68%
fpg > 15
or symptomatic
15%
Main Randomisation
82%
Diet Failure
15%
14%
Diet Alone
3%
fpg : fasting plasma glucose (mmol/L)
ukpds
UK Prospective Diabetes Study
Does an intensive glucose
control policy reduce the risk
of complications of diabetes?
ukpds
Randomisation of Treatment Policies
Main Randomisation
n=4209 (82%)
342 allocated to
metformin
3867
Conventional Policy
30% (n=1138)
Intensive Policy
70% (n=2729)
Sulphonylurea
n=1573
Insulin
n=1156
ukpds
Treatment Policies in 3867 patients
Conventional Policy
n = 1138
• initially with diet alone
• aim for
near normal weight
best fasting plasma glucose < 15 mmol/L
asymptomatic
• when marked hyperglycaemia develops
allocate to non-intensive pharmacological therapy
ukpds
Treatment Policies in 3867 patients
Intensive Policy with sulphonylurea or insulin
n = 2729
• aim for
fasting plasma glucose < 6 mmol/L
asymptomatic
• when marked hyperglycaemia develops
on sulphonylurea
add metformin
move to insulin therapy
on insulin, transfer to complex regimens
ukpds
Actual Therapy
Intensive Policy
aim for < 6 mmol/L
Conventional Policy
accept < 15 mmol/L
100
proportion of patients
diet alone
additional non-intensive
pharmacological therapy
80
60
intensive
pharmacological
therapy
40
diet alone
20
0
1
2
3
4
5
6
7
8
9
10 11 12
1
2
3
4
5
6
7
8
9
10 11 12
Years from randomisation
ukpds
HbA1c
cross-sectional, median values
9
HbA1c (%)
Conventional
8
Intensive
7
6.2% upper limit of normal range
6
0
0
3
6
9
12
Years from randomisation
15
ukpds
Change in Body Weight
cross-sectional, mean values
7.5
Intensive
kg
5.0
2.5
Conventional
0.0
-2.5
0
3
6
9
12
Years from randomisation
15
ukpds
Hypoglycaemic Episodes
• self-reported at each clinic visit
• assessed by clinician to determine severity
• graded as
minor : treated by patient alone
major : requiring third party assistance
• grade of most severe episode recorded
• all major episodes audited from clinical records
ukpds
Hypoglycaemic episodes per annum
Proportion of patients (%)
Actual Therapy analysis
any episode
50
5
40
4
30
3
20
2
10
1
0
0
0
3
6
9
12
major episodes
15
0
3
6
9
12
15
Years from randomisation
ukpds
Any Diabetes Related Endpoint
1401 of 3867 patients (36%)
First occurrence of any one of:
• diabetes related death
• non fatal myocardial infarction, heart failure or angina
• non fatal stroke
• amputation
• renal failure
• retinal photocoagulation or vitreous haemorrhage
• cataract extraction or blind in one eye
ukpds
Any Diabetes Related Endpoint (cumulative )
1401 of 3867 patients (36%)
% of patients with an event
60%
Conventional (1138)
Intensive (2729)
p=0.029
40%
20%
Risk reduction 12%
(95% CI: 1% to 21%)
0%
0
3
6
9
12
Years from randomisation
15
ukpds
Diabetes Related Deaths
414 of 3867 patients (11%)
Any of:
• fatal myocardial infarction or sudden death
• fatal stroke
• death from peripheral vascular disease
• death from renal disease
• death from hyper/hypoglycaemia
ukpds
Diabetes Related Deaths (cumulative)
414 of 3867 patients (11%)
% of patients with an event
30%
Conventional (1138)
Intensive (2729)
p=0.34
20%
10%
0%
0
3
6
9
12
Years from randomisation
15
ukpds
Microvascular Endpoints (cumulative)
% of patients with an event
30%
renal failure or death, vitreous haemorrhage or photocoagulation
346 of 3867 patients (9%)
Conventional
Intensive
p=0.0099
20%
10%
Risk reduction 25%
(95% CI: 7% to 40%)
0%
0
3
6
9
12
Years from randomisation
15
ukpds
Myocardial Infarction (cumulative)
fatal or non fatal myocardial infarction, sudden death
573 of 3867 patients (15%)
% of patients with an event
30%
Conventional
Intensive
p=0.052
20%
10%
Risk reduction 16%
(95% CI: 0% to 29%)
0%
0
3
6
9
12
Years from randomisation
15
ukpds
Aggregate Clinical Endpoints
RR
p
0.5
Relative Risk
& 95% CI
1
2
Any diabetes related endpoint 0.88 0.029
Diabetes related deaths
0.90 0.34
All cause mortality
0.94 0.44
Myocardial infarction
Stroke
Microvascular
0.84 0.052
1.11 0.52
0.75 0.0099
Favours Favours
intensive conventional
ukpds
Progression of Retinopathy
Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale
0 - 3 years
0 - 6 years
0 - 9 years
0 - 12 years
RR
p
1.03
0.83
0.83
0.79
0.78
0.017
0.012
0.015
0.5
Relative Risk
& 99% CI
1
2
Favours Favours
intensive conventional
ukpds
Microalbuminuria
Urine albumin >50 mg/L
Baseline
Three years
Six years
Nine years
Twelve years
Fifteen years
RR
p
0.5
0.89
0.83
0.88
0.76
0.67
0.70
0.24
0.043
0.13
0.00062
0.000054
0.033
<
Relative Risk
& 99% CI
1
2
Favours Favours
intensive conventional
ukpds
Glucose Control Study Summary
The intensive glucose control policy maintained a lower
HbA1c by mean 0.9 % over a median follow up of 10 years
from diagnosis of type 2 diabetes with reduction in risk of:
12%
25%
for any diabetes related endpoint
for microvascular endpoints
p=0.029
p=0.0099
16%
24%
for myocardial infarction
for cataract extraction
p=0.052
p=0.046
21%
33%
for retinopathy at twelve years
for albuminuria at twelve years
p=0.015
p=0.000054
ukpds
Conclusion
The UKPDS has shown that intensive blood
glucose control reduces the risk of diabetic
complications, the greatest effect being on
microvascular complications
ukpds
UK Prospective Diabetes Study
Does insulin or
sulphonylurea therapy have
specific advantages or
disadvantages?
ukpds
Sulphonylurea Therapy
advantages
• known to improve glycaemic control
• stimulates endogenous insulin production
disadvantages
• in the heart sulphonylurea mimics ATP
and may prevent vasodilation in ischaemia
• 1st generation agents may increase arrhythmia
ukpds
Insulin Therapy
advantages
• well-used therapy to improve glycaemic control
• may be essential for many patients
disadvantages
• need for injections
• risk of weight gain and hypoglycaemia
• raised insulin levels may promote atherosclerosis
ukpds
Randomisation
3041 patients
in 15 centres
Conventional Policy
Diet alone
n = 896
Intensive Policy
Chlorpropamide
n = 619
Glibenclamide
n = 615
Insulin
n = 911
comparison between three intensive therapies
compare each with conventional policy
ukpds
HbA1c
9
cohort, median data
Conventional InsulinChlorpropamide Glibenclamide
%
8
7
6
0
0
2
8
6
4
Years from randomisation
10
ukpds
change in weight
cohort, mean data
10.0
Conventional Insulin Chlorpropamide Glibenclamide
7.5
kg
5.0
2.5
0.0
-2.5
0
2
4
6
8
Years from randomisation
10
ukpds
Hypoglycaemic episodes per annum
Proportion of patients (%)
Actual Therapy analysis
any episode
50
10
40
8
30
6
20
4
10
2
0
0
0
3
6
9
12
major episodes
15
0
3
6
9
12
15
Years from randomisation
ukpds
Blood Pressure
cohort, mean data
150
Conventional Insulin Chlorpropamide Glibenclamide
145
mmHg
140
135
85
80
75
70
0
2
4
6
8
Years from randomisation
10
ukpds
Proportion of patients with events
Any diabetes-related endpoints
0.6
Conventional (896)
Chlorpropamide (619)
0.5
Glibenclamide (615)
0.4
Insulin (911)
0.3
0.2
0.1
CvGvI
p = 0.36
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
Proportion of patients with event
Myocardial Infarction
0.4
Conventional (896)
Chlorpropamide (619)
Glibenclamide (615)
0.3
Insulin (911)
0.2
0.1
CvGvI
p = 0.66
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
Progression of Retinopathy : 2 step change
RR
0-3
rs
y e a
Chlorpro pmid
a e
Glib e lamid
n c e
I n lins u
0-6
rs
y e a
Chlorpro pmid
a e
Glib e lamid
n c e
I n lins u
0-9
rs
y e a
Chlorpro pmid
a e
Glib e lamid
n c e
I n lins u
0-1 2 rs y e a
Chlorpro pmid
a e
Glib e lamid
n c e
I n lins u
p=0 . 9 9
1
1
1
p=0 . 5 8
0
0
0
p=0 . 6 5
0
0
0
p=0 . 0 0
1
0
0
p 0.2
favours
intensive
favours
1 conventional
. 0 02 . 9 2
. 0 04 . 8 1
. 0 01 . 9 2
. 9 02 . 4 7
. 9 04 . 5 9
. 8 04 . 0 9 6
. 9 01 .
. 8 03 .
. 8 03 .
5 9
. 0 00 .
. 6 08 .
. 7 02 .
3 3
0 6 8
0 4 8
9 9
0 0 4 4
0 0 4 1
ukpds
5
Sulphonylurea or Insulin : Summary 1
• all three therapies were similarly effective in
reducing HbA1c
• all three therapies had equivalent risk reduction
for major clinical outcomes
compared with conventional policy
• in those allocated to chlorpropamide there was
equivalent reduction of risk of microalbuminuria but
no reduction of risk of progression of retinopathy
ukpds
Sulphonylurea or insulin : Summary 2
Sulphonylurea therapy
• no evidence of deleterious effect on myocardial
infarction, sudden death or diabetes related deaths
Insulin therapy
• no evidence for more atheroma-related disease
ukpds
UK Prospective Diabetes Study
Does metformin in
overweight diabetic patients
have any advantages or
disadvantages?
ukpds
Introduction
• the UKPDS has shown that an intensive glucose
control policy using sulphonylurea or insulin
therapy is effective in reducing the risk of
complications in both overweight and normal
weight patients
• overweight (>120% Ideal Body Weight) UKPDS
patients could be randomised to an intensive
glucose control policy with metformin instead of
diet, sulphonylurea or insulin
ukpds
Randomisation
Main Randomisation
4209
Overweight
1704
Conventional Policy
411
Non overweight
2505
Intensive Policy
1293
Insulin or Sulphonylurea
951
Metformin
342
ukpds
Patient Characteristics
overweight patients > 120% ideal body weight
after three months’ diet therapy
age
gender
ethnic groups
Body Mass Index
fasting plasma glucose
HbA1c
mean
male / female
Caucasian
Asian
Afro-caribbean
mean
median
mean
53 years
46% / 54%
86%
6%
8%
31 kg/m2
8.1 mmol/L
7.2 %
ukpds
HbA1c
HbA 1c (%)
overweight patients
9 Conventional
cohort, median values
Insulin Chlorpropamide
Glibenclamide
Metformin
8
7
6
0
0
2
4
6
8
Years from randomisation
10
ukpds
Change in Weight
weight change (kg)
overweight patients
10 Conventional
cohort, mean values
Insulin Chlorpropamide
Glibenclamide
Metformin
5
0
-5
0
2
4
6
8
Years from randomisation
10
ukpds
Hypoglycaemic episodes per annum
overweight patients
Actual Therapy analysis
Proportion of patients (%)
any episode
major episodes
50
8
40
6
30
4
20
2
10
0
0
0
2
4
6
8
10
0
2
4
6
8
10
Years from randomisation
ukpds
overweight
patients
Proportion of patients with events
Any diabetes related endpoint
0.6
Conventional (411)
Intensive (951)
Metformin (342)
0.4 M v C
p=0.0023
0.2
MvI
p=0.0034
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
overweight
patients
Proportion of patients with events
Diabetes related deaths
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
Mv C
p=0.017
0.2
0.1
MvI
p=0.11
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
overweight
patients
Proportion of patients with events
Myocardial Infarction
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
MvC
p=0.010
0.2
0.1
MvI
p=0.12
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
overweight
patients
Proportion of patients with events
Microvascular endpoints
0.3
Conventional (411)
Intensive (951)
Metformin (342)
0.2 M v C
p=0.19
0.1
MvI
p=0.39
0.0
0
3
6
9
12
Years from randomisation
15
ukpds
Metformin Comparisons
overweight patients
Any dia b e tse re l ate d e n dpo i n t
M e tor
f min
RR
p
0.2
RR (95% CI)
1
0 . 68 0 . 002 3
Diab e t se re l ate d d e ahs
t
M e tor
f min
0 . 58
0 . 017
All ca use m ort ali ty
M e tor
f min
0 . 64
0 . 011
Myo c ardia l in f arc tio n
M e tor
f min
0 . 61
0 . 01
favours
metformin
favours
conventional
ukpds
5
Metformin Comparisons
overweight patients
M v Int
RR
p
RR (95% CI)
0.2
1
5
Any dia b e tse re l ate d e n dpo i n tp=0 . 0 0 3 4
M e tor
f min
0 . 68 0 . 002 3
I n tn
esiv e
0 . 93
0 . 46
Diab e t se re l ate d d e ahs
t
p=0 . 1 1
M e tor
f min
0 . 58 0 . 017
I n tn
esiv e
0 . 80
0 . 19
All ca use m ort ali ty
p=0 . 0 2 1
M e tor
f min
0 . 64 0 . 011
I n tn
esiv e
0 . 92
0 . 49
Myo c ardia l in f arc tio n
p=0 . 1 2
M e tor
f min
0 . 61
0 . 01
I n tn
esiv e
0 . 79
0 . 11
favours
metformin or
intensive
favours
conventional
ukpds
Sulphonylurea plus Metformin
• patients primarily randomised to intensive therapy with
sulphonylurea were not given additional metformin until
their fpg was >15 mmol/L or they developed
hyperglycaemic symptoms
• in view of the progressive hyperglycaemia in these
patients, a protocol modification was made to secondarily
randomise the subset of patients who were on maximum
sulphonylurea therapy and had fpg >6 mmol/L to earlier
addition of metformin
ukpds
Aim
• the aim of this secondary randomisation was to assess
the degree to which glycaemic control might be
improved by early combination therapy with metformin
• in view of the interesting results in the primary
metformin study a secondary analysis was undertaken
to examine any endpoints that had occurred
ukpds
Aggregate Endpoints
Median follow up 6.6 years
RR
p
Relative Risk
& 95% CI
0.1
1
10
Any diabetes related endpoint 1.04 0.78
Diabetes related deaths *
All cause mortality
1.96 0.039
1.60 0.041
Myocardial infarction
1.09 0.73
Stroke
Microvascular
1.21 0.61
0.84 0.62
Favours Favours
added sulphonylurea
metformin alone
* interpret with caution in view of small numbers : 26 deaths on
sulphonylurea plus metformin versus 14 deaths on sulphonylurea alone
ukpds
Metformin in Overweight Patients
• compared with conventional policy
32% risk reduction in any diabetes-related endpoints
42% risk reduction in diabetes-related deaths
36% risk reduction in all cause mortality
39% risk reduction in myocardial infarction
p=0.0023
p=0.017
p=0.011
p=0.01
ukpds
Metformin : Summary
• the addition of metformin in patients already treated
with sulphonylurea requires further study
• on balance, metformin treatment would appear to
be advantageous as primary pharmacological
therapy in diet-treated overweight patients
ukpds
UK Prospective Diabetes Study
Blood Pressure
Control Study
ukpds
Blood Pressure Control Study : Aims
to determine whether
• tight blood pressure control policy can reduce
morbidity and mortality in Type 2 diabetic patients
• ACE inhibitor (captopril) or Beta blocker (atenolol)
is advantageous in reducing the risk of
development of clinical complications
ukpds
Inclusion criteria
patients NOT on anti-hypertensive therapy
systolic >160 and/or diastolic > 90 mmHg
patients already ON anti-hypertensive therapy
systolic >150 and/or diastolic > 85 mmHg
excluded if:
required strict blood pressure control; severe illness;
contraindication to study medication or declined
informed consent
ukpds
Patient Characteristics
1148 Type 2 diabetic patients
age
gender
male / female
ethnic groups
Caucasian
Asian
6%
Afro-caribbean
7%
Body Mass Index
HbA1c
systolic / diastolic blood pressure
urine albumin > 50 mg/l
56 years
55% / 45%
87%
29 kg/m2
6.8 %
160 / 94 mmHg
18%
ukpds
Randomisation
1148 hypertensive patients
on antihypertensive therapy
n = 421
not on antihypertensive therapy
n = 727
randomisation
less tight blood pressure control
aim : BP < 180/105 mmHg
avoid ACE inhibitor : Beta blocker
n = 390
34%
tight blood pressure control
aim : BP < 150 / 85 mmHg
ACE inhibitor
n = 400
35%
Beta blocker
n = 358
31%
ukpds
Blood Pressure : Tight vs Less Tight Control
cohort, median values
180 Less tight control Tight control
mmHg
160
140
100
80
60
0
2
4
6
Years from randomisation
8
ukpds
Mean Blood Pressure
mmHg
baseline
mean over 9 years
Less tight control
160 / 94
154 / 87
Tight control
difference
p
ACE inhibitor
161 / 94
1/0
n.s.
159 / 94
144 / 82
10 / 5
<0.0001
144 / 83
Beta blocker
difference
159 / 93
0/0
143 / 81
1/1
p
n.s.
n.s. / p=0.02
ukpds
Therapy requirement
number of antihypertensive agents
None
one
two
LessTight Control Policy
> two
Tight Control Policy
% of patients
100
80
60
40
20
0
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
Years from randomisation
ukpds
Any diabetes-related endpoints
% of patients with events
50%
Less tight blood pressure control (390)
Tight blood pressure control (758)
40%
30%
20%
10%
risk reduction
24% p=0.0046
0%
0
3
6
Years from randomisation
9
ukpds
Diabetes-related deaths
20%
Less tight blood pressure control (390)
% of patients with events
Tight blood pressure control (758)
15%
10%
5%
risk reduction
32% p=0.019
0%
0
3
6
Years from randomisation
9
ukpds
Myocardial Infarction
25%
Less Tight Blood Pressure Control (390)
% of patients with event
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
21% p=0.13
0%
0
3
6
Years from randomisation
9
ukpds
Stroke
25%
Less Tight Blood Pressure Control (390)
% patients with event
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
44% p=0.013
0%
0
3
6
Years from randomisation
9
ukpds
Microvascular endpoints
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
10%
5%
risk reduction
37% p=0.0092
0%
0
3
6
Years from randomisation
9
ukpds
Heart Failure
25%
% patients with event
Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
20%
15%
risk reduction
56% p=0.0043
10%
5%
0%
0
3
6
Years from randomisation
9
ukpds
Progression of Retinopathy : 2 step change
60
p=0.38
p=0.019
p=0.004
51
37
% patients
40
34
28
23
20
0
20
243 461
207 411
152 300
3 years
6 years
9 years
Years from randomisation
numbers above bars are % affected
ukpds
Deterioration of Vision : 3 lines on ETDRS chart
% patients
30
p=0.40
p=0.47
19
20
10
0
p=0.004
7
9
5
293 575
3 years
10
8
257 523
6 years
180 332
9 years
Years from randomisation
numbers above bars are % affected
ukpds
Urine Albumin >50 mg/L
40
p=0.052
p=0.008
p=0.33
% patients
33
29
29
30
24
20
18
20
10
0
317
618
3 years
274
543
6 years
166
299
9 years
Years from randomisation
numbers above bars are % affected
ukpds
Blood Pressure Control Study
in 1148 Type 2 diabetic patients
a tight blood pressure control policy which achieved
blood pressure of 144 / 82 mmHg gave reduced risk
for
any diabetes-related endpoint
diabetes-related deaths
stroke
microvascular disease
24%
32%
44%
37%
p=0.0046
p=0.019
p=0.013
p=0.0092
heart failure
retinopathy progression
deterioration of vision
56%
34%
47%
p=0.0043
p=0.0038
p=0.0036
ukpds
UK Prospective Diabetes Study
Do ACE inhibitors or
Beta Blockers
have any specific advantages
or disadvantages?
ukpds
Blood Pressure : ACE inhibitor vs Beta blocker
cohort, median values
180
Less tight control ACE inhibitor Beta blocker
mm Hg
160
140
100
80
60
0
2
4
6
Years from randomisation
8
ukpds
Reasons for non-compliance
Captopri l
(n=400 )
Atenolo l
(n=358 )
p
non- compl iant
88 (22%)
125 (35%)
<0.0001
cough
16 (4%)
0
<0.0001
inc rea sed creatini ne
5 (1%)
0
0.064
c laudi cation,
col d finger s or toes
0
15 (4%)
<0.0001
bron cho spas m
0
22 (6%)
<0.0001
1 (0%)
6 (2%)
0.057
impotenc e
ukpds
Any Diabetes Related Endpoint (cumulative)
429 of 1148 patients (37%)
% of patients with an event
50%
Less tight BP control (n=390)
Beta blocker (n=358)
ACE inhibitor (n=400)
Less tight vs Tight
p=0.0046
40%
30%
20%
10%
0%
0
ACE vs Beta blocker p=0.43
3
6
9
Years from randomisation
ukpds
Diabetes Related Deaths (cumulative)
144 of 1148 patients (13%)
% of patients with an event
20%
Less tight BP control (n=390)
Beta blocker (n=358)
ACE inhibitor (n=400)
Less tight vs Tight
p=0.019
15%
10%
5%
0%
0
ACE vs Beta blocker p=0.28
3
6
9
Years from randomisation
ukpds
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or photocoagulation
122 of 1148 patients (11%)
% of patients with an event
20%
Less tight BP control
Beta blocker
ACE inhibitor
Less tight vs Tight
p=0.0092
15%
10%
5%
0%
0
ACE vs Beta blocker p=0.30
3
6
9
Years from randomisation
ukpds
Aggregate Clinical Endpoints
RR
p
0.5
Relative Risk
& 95% CI
1
2
Any diabetes related endpoint
1.10 0.43
Diabetes related deaths
All cause mortality
1.27 0.28
1.14 0.44
Myocardial infarction
Stroke
1.20 0.35
1.12 0.74
>
Microvascular
1.29 0.30
>
Favours Favours
ACE inhibitor Beta blocker
ukpds
Surrogate endpoints
Reti nopathy 2 step progress ion
median 1.5 years
median 4.5 years
median 7.5 years
Ur ine albumi n > 50 mg/L
3 year s
6 year s
9 year s
Ur ine albumi n > 300 mg/L
3 year s
6 year s
9 year s
RR
p
0.99
0.99
0.91
0.75
0.82
0.28
1.11
0.93
1.20
0.55
0.65
0.31
1.41
0.75
0.48
0.44
0.43
0.090
Relative Risk & 99% CI
0.1
1
10
favours ACE favours Beta
inhibitor blocker
ukpds
Conclusion
ACE inhibitors and Beta blockers were equally
effective in lowering mean blood pressure in
hypertensive patients with type 2 diabetes and in
reducing the risk of:
•
•
•
any diabetes related endpoint
diabetes related deaths
microvascular endpoints
ukpds
UK Prospective Diabetes Study
Potential implications
for clinical care of
diabetic patients
ukpds
UK Prospective Diabetes Study
An intensive glucose control policy HbA1c 7.0 % vs 7.9 %
reduces risk of
any diabetes-related endpoints
microvascular endpoints
myocardial infarction
12%
25%
16%
p=0.030
p=0.010
p=0.052
A tight blood pressure control policy 144 / 82 vs 154 / 87 mmHg
reduces risk of
any diabetes-related endpoint
microvascular endpoint
stroke
24%
37%
44%
p=0.005
p=0.009
p=0.013
ukpds
Choice of Therapies
diabetes :
• each of the available therapies studied can be used
• in overweight, diet-treated patients, metformin may
be advantageous
hypertension :
• Beta blockers and ACE inhibitors each provide
protection
ukpds
Which goals of therapy?
• current guidelines suggest HbA1c <7%
• the risk of diabetic complications was reduced in the
UKPDS trial which achieved a median HbA1c 7.0%
in the intensive glucose control group
• this HbA1c level is in accord with current guidelines
but is difficult to accomplish in some patients
• epidemiological analysis suggests that any reduction
of hyperglycaemia would be advantageous
ukpds
Which goals of therapy?
• current guidelines suggest blood pressure
<140 / 85 mmHg or <130 / 85 mmHg
• the risk of diabetic complications was reduced
in the UKPDS blood pressure control trial
which achieved a mean blood pressure 144 / 82 mmHg
in the tight control group
• this result is in accord with current guidelines,
which are also supported by the epidemiological analysis
ukpds
Polypharmacy
• glycaemia
combinations of agents with different actions
will be needed
more patients will require insulin
• blood pressure
many patients will need 3 or more different
types of agents
ukpds
Differences between Therapies
• sulphonylurea, insulin and metformin are each
effective in reducing the risk of any diabetes related
endpoints and microvascular endpoints
• no evidence of increased risk of complications for
any single therapy
• ACE inhibitors and Beta blockers are each effective
in reducing the risk of macrovascular and
microvascular endpoints
• no evidence that either is specifically advantageous
ukpds
UK Prospective Diabetes Study
The UKPDS has shown conclusively that :
• intensive therapy to reduce glycaemia is worthwhile
as it reduces risk of complications
• tight blood pressure control is worthwhile as it
reduces risk of complications
• there are no major differences between the
therapies tested
• reduction in risk of complications of diabetes
is a realisable goal
ukpds
Beneficial Effects of Intensive Therapy
The UKPDS has shown that
more intensive monitoring
more intensive use of existing therapies
which improves
blood glucose control
blood pressure control
can reduce the risk of diabetic complications
ukpds
UK Prospective Diabetes Study
papers presenting major results of the study
UKPDS 33: Lancet (1998) 352, 837-853
UKPDS 34: Lancet (1998) 352, 854-865
UKPDS 38: BMJ (1998) 317, 703-713
UKPDS 39: BMJ (1998) 317, 713-720
ukpds