The UK Prospective Diabetes Study: Ukpds

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 1976
Recruitment 1977-1991
End of study Sept. 1997
Clinical Centres 23
Type 2 diabetic patients 5102
Person years follow-up 53,000
Funding £23 million

ukpds
UK Prospective Diabetes Study Centres
Aberdeen Lilian Murchison Manchester Andrew Boulton
Belfast City Randal Hayes Northampton Charles Fox
Belfast Royal David Hadden Norwich Richard Greenwood
Birmingham David Wright Oxford Robert Turner
Carshalton Steve Hyer Rury Holman
Memo Spathis Peterborough Jonathan Roland
Derby Ian Peacock Salford Tim Dornan
Dundee Ray Newton Scarborough Phil Brown
Roland Jung St George’s Nigel Oakley
Exeter Kenneth McLeod Stevenage Les Borthwick
John Tooke Stoke on Trent John Scarpello
Hammersmith Anne Dornhorst Lionel Alexander
Eva Kohner Torbay Richard Paisey
Ipswich John Day Whittington John Yudkin
Leicester Felix Burden
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 USA National Institutes
of Health (NEI, NIDDK)
British Heart Foundation Wellcome Trust
Novo Nordisk Bayer Lilly

Bristol Myers Squibb Lipha Hoechst
Farmitalia Carlo Erba
ukpds
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 Caucasian 82%
Asian 10%
Afro-caribbean 8%
Body Mass Index mean 28 kg/m2
fasting plasma glucose (fpg) median 11.5 mmol/L
HbA1c median 9.1 %
hypertensive 39%
ukpds
• 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 fpg 6.1 - 15.0 fpg > 15

asymptomatic asymptomatic or symptomatic
17% 68% 15%
14%
Diet Alone Main Randomisation Diet Failure

3% 82% 15%
fpg : fasting plasma glucose (mmol/L) ukpds

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 Intensive Policy

30% (n=1138) 70% (n=2729)
Sulphonylurea Insulin
n=1573 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
accept < 15 mmol/L aim for < 6 mmol/L
100
diet alone
additional non-intensive
proportion of patients
80 pharmacological therapy
60
intensive
40 pharmacological
therapy
20 diet alone
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
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HbA1c
cross-sectional, median values
9
Conventional
8
HbA1c (%)
Intensive
7
6.2% upper limit of normal range

6
0
0 3 6 9 12 15
Years from randomisation ukpds
Change in Body Weight
cross-sectional, mean values
7.5
Intensive
5.0
kg
2.5
Conventional
0.0
-2.5
0 3 6 9 12 15
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
Actual Therapy analysis
any episode major episodes

Proportion of patients (%)
50 5
40 4
30 3
20 2
10 1
0 0
0 3 6 9 12 15 0 3 6 9 12 15
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%)
60%
Conventional (1138)
% of patients with an event
Intensive (2729)
p=0.029
40%
20%
Risk reduction 12%

0% (95% CI: 1% to 21%)
0 3 6 9 12 15
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%)
30%
Conventional (1138)
Intensive (2729)
p=0.34
20%
10%
0%
0 3 6 9 12 15
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or photocoagulation
346 of 3867 patients (9%)
30%
Conventional
Intensive
p=0.0099
20%
10%
Risk reduction 25%

0% (95% CI: 7% to 40%)
0 3 6 9 12 15
Myocardial Infarction (cumulative)
fatal or non fatal myocardial infarction, sudden death
573 of 3867 patients (15%)
30%
Conventional
Intensive
p=0.052
20%
10%
Risk reduction 16%

0% (95% CI: 0% to 29%)
0 3 6 9 12 15
Aggregate Clinical Endpoints
Relative Risk
& 95% CI
RR p 0.5 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 0.84 0.052

Stroke 1.11 0.52
Microvascular 0.75 0.0099
Favours Favours
intensive conventional
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Progression of Retinopathy
Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale
Relative Risk
& 99% CI
RR p 0.5 1 2
0 - 3 years 1.03 0.78
0 - 6 years 0.83 0.017
0 - 9 years 0.83 0.012
0 - 12 years 0.79 0.015
Favours Favours
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Microalbuminuria
Urine albumin >50 mg/L
Relative Risk
& 99% CI
RR p 0.5 1 2
Baseline 0.89 0.24
Three years 0.83 0.043
Six years 0.88 0.13
Nine years 0.76 0.00062
Twelve years 0.67 0.000054
Fifteen years 0.70 0.033 <
Favours Favours
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% for any diabetes related endpoint p=0.029
25% for microvascular endpoints p=0.0099
16% for myocardial infarction p=0.052
24% for cataract extraction p=0.046
21% for retinopathy at twelve years p=0.015
33% for albuminuria at twelve years 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
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
Diet alone Chlorpropamide Glibenclamide Insulin

n = 896 n = 619 n = 615 n = 911
comparison between three intensive therapies

compare each with conventional policy
ukpds
HbA1c
cohort, median data
9
Conventional InsulinChlorpropamide Glibenclamide
8
%
6
0
0 2 4 6 8 10
change in weight
cohort, mean data
10.0
Conventional Insulin Chlorpropamide Glibenclamide
7.5
5.0
kg
2.5
0.0
-2.5
0 2 4 6 8 10
Actual Therapy analysis

50 10
40 8
30 6
20 4
10 2
0 0
0 3 6 9 12 15 0 3 6 9 12 15
ukpds
Blood Pressure
cohort, mean data
150
Conventional Insulin Chlorpropamide Glibenclamide
145
140
mmHg
135
85
80
75
70
0 2 4 6 8 10
Any diabetes-related endpoints
0.6
Proportion of patients with events

Conventional (896)
0.5 Chlorpropamide (619)

Glibenclamide (615)
0.4 Insulin (911)
0.3
0.2
0.1
CvGvI
0.0 p = 0.36
0 3 6 9 12 15
Myocardial Infarction
0.4
Conventional (896)
Proportion of patients with event

Chlorpropamide (619)
Glibenclamide (615)
0.3
Insulin (911)
0.2
0.1
CvGvI
0.0 p = 0.66
0 3 6 9 12 15
Progression of Retinopathy : 2 step change
favours favours
RR p 0.2 intensive 1 conventional 5
0-3 rs
y e a p=0 . 9 9
Chlorpro pmida e 1 . 0 02 . 9 2
Glib e lamid
n c e 1 . 0 04 . 8 1
I n lins u 1 . 0 01 . 9 2
0-6 rs
y e a p=0 . 5 8
Glib e lamid
n c e 0 . 9 04 . 5 9
I n lins u 0 . 8 04 . 0 9 6
0-9 rs
y e a p=0 . 6 5
Glib e lamid
n c e 0 . 8 03 . 0 6 8
I n lins u 0 . 8 03 . 0 4 8
0-1 2 rs y e a p=0 . 0 0 5 9
Glib e lamid
n c e 0 . 6 08 . 0 0 4 4
I n lins u 0 . 7 02 . 0 0 4 1
ukpds
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
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
Non overweight
2505
Overweight
1704

411 1293
Insulin or Sulphonylurea Metformin

951 342
ukpds
overweight patients > 120% ideal body weight
after three months’ diet therapy
age mean 53 years

gender male / female 46% / 54%
ethnic groups Caucasian 86%
Asian 6%
Afro-caribbean 8%
Body Mass Index mean 31 kg/m2
fasting plasma glucose median 8.1 mmol/L
HbA1c mean 7.2 %
ukpds
HbA1c
overweight patients cohort, median values
9 Conventional Insulin Chlorpropamide Glibenclamide Metformin
8
HbA 1c (%)
6
0 0
2 4 6 8 10
Change in Weight
overweight patients cohort, mean values
10 Conventional Insulin Chlorpropamide Glibenclamide Metformin
weight change (kg)
-5 0
2 4 6 8 10
ukpds
overweight patients Actual Therapy analysis
50 8
40
6
30
4
20
2
10
0 0
0 2 4 6 8 10 0 2 4 6 8 10
ukpds
Any diabetes related endpoint
overweight
patients 0.6 Conventional (411)
Proportion of patients with events 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 15 ukpds
Diabetes related deaths
overweight
0.4
patients Conventional (411)
Proportion of patients with events Intensive (951)
0.3 Metformin (342)
Mv C
p=0.017
0.2
0.1
MvI
0.0 p=0.11
0 3 6 9 12 15
ukpds
overweight 0.4 Conventional (411)
patients
Intensive (951)
0.3 Metformin (342)
MvC
p=0.010
0.2
0.1
MvI
p=0.12
0.0
0 3 6 9 12 15
Microvascular endpoints
overweight 0.3 Conventional (411)
patients
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 15
Metformin Comparisons
overweight patients RR (95% CI)
RR p 0.2 1 5
Any dia b e tse re l ate d e n dpo i n t
M e tor f min 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 favours
metformin conventional
ukpds
Metformin Comparisons
overweight patients RR (95% CI)
M v Int RR p 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 tnesiv e 0 . 93 0 . 46
Diab e t se re l ate d d e ahst p=0 . 1 1
M e tor f min 0 . 58 0 . 017
I n tnesiv 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 tnesiv 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 tnesiv e 0 . 79 0 . 11
favours favours
metformin or conventional
intensive
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
Relative Risk
& 95% CI
Median follow up 6.6 years RR p 0.1 1 10
Diabetes related deaths * 1.96 0.039

Stroke 1.21 0.61
Microvascular 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 p=0.0023

42% risk reduction in diabetes-related deaths p=0.017
36% risk reduction in all cause mortality p=0.011
39% risk reduction in myocardial infarction 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
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
1148 Type 2 diabetic patients
age 56 years
gender male / female 55% / 45%
ethnic groups Caucasian 87%
Asian 6%
Afro-caribbean 7%
Body Mass Index 29 kg/m2
HbA1c 6.8 %
systolic / diastolic blood pressure 160 / 94 mmHg
urine albumin > 50 mg/l 18%
ukpds
Randomisation
1148 hypertensive patients
on antihypertensive therapy not on antihypertensive therapy

n = 421 n = 727
randomisation
less tight blood pressure control tight blood pressure control

aim : BP < 180/105 mmHg aim : BP < 150 / 85 mmHg
avoid ACE inhibitor : Beta blocker ACE inhibitor Beta blocker

n = 390 n = 400 n = 358
34% 35% 31%
ukpds
Blood Pressure : Tight vs Less Tight Control
cohort, median values
180 Less tight control Tight control
160
140
mmHg
100
80
60
0 2 4 6 8
ukpds
Mean Blood Pressure
mmHg baseline mean over 9 years

Less tight control 160 / 94 154 / 87
Tight control 161 / 94 144 / 82
difference 1/0 10 / 5
p n.s. <0.0001
ACE inhibitor 159 / 94 144 / 83
Beta blocker 159 / 93 143 / 81
difference 0/0 1/1
p n.s. n.s. / p=0.02
ukpds
Therapy requirement
number of antihypertensive agents
None one two > two
LessTight Control Policy Tight Control Policy

100
% of patients
80
60
40
20
0
1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8
ukpds
Any diabetes-related endpoints
50% Less tight blood pressure control (390)
% of patients with events 40%

Tight blood pressure control (758)
30%
20%
10%
risk reduction
0%
24% p=0.0046
0 3 6 9
Diabetes-related deaths
20% Less tight blood pressure control (390)
Tight blood pressure control (758)
% of patients with events
15%
10%
5%
risk reduction
0%
32% p=0.019
0 3 6 9
25% Less Tight Blood Pressure Control (390)
Tight Blood Pressure Control (758)
% of patients with event 20%
15%
10%
5%
risk reduction
0%
21% p=0.13
0 3 6 9
Stroke
25%
Less Tight Blood Pressure Control (390)
20%
% patients with event
15%
10%
5%
risk reduction
0% 44% p=0.013
0 3 6 9
Microvascular endpoints
25%

% patients with event 20%
15%
10%
5%
risk reduction
0%
37% p=0.0092
0 3 6 9
Heart Failure
25%

% patients with event 20%
15%
risk reduction
56% p=0.0043
10%
5%
0%
0 3 6 9
Progression of Retinopathy : 2 step change
p=0.38 p=0.019 p=0.004
60
51
40 37
% patients
34
28
23
20
20
0
243 461 207 411 152 300
3 years 6 years 9 years
numbers above bars are % affected
ukpds
Deterioration of Vision : 3 lines on ETDRS chart
p=0.40 p=0.47 p=0.004
30
19
% patients
20
10
10 9
7 8
5
0
293 575 257 523 180 332

ukpds
Urine Albumin >50 mg/L
p=0.052 p=0.008 p=0.33
40
33
30 29 29
% patients
24
20
20 18
10
0
317 618 274 543 166 299

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 24% p=0.0046
diabetes-related deaths 32% p=0.019
stroke 44% p=0.013
microvascular disease 37% p=0.0092
heart failure 56% p=0.0043
retinopathy progression 34% p=0.0038
deterioration of vision 47% p=0.0036
ukpds
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
160
140
mm Hg
100
80
60
0 2 4 6 8
ukpds
Reasons for non-compliance
Captopri l Atenolo l
(n=400 ) (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, 0 15 (4%) <0.0001
col d finger s or toes
bron cho spas m 0 22 (6%) <0.0001
impotenc e 1 (0%) 6 (2%) 0.057
ukpds
Any Diabetes Related Endpoint (cumulative)
429 of 1148 patients (37%)
50% Less tight BP control (n=390)

Beta blocker (n=358)

40% ACE inhibitor (n=400)
Less tight vs Tight
30% p=0.0046
20%
10%
0% ACE vs Beta blocker p=0.43

0 3 6 9
Diabetes Related Deaths (cumulative)
144 of 1148 patients (13%)
20% Less tight BP control (n=390)

Beta blocker (n=358)

15% ACE inhibitor (n=400)
Less tight vs Tight
p=0.019
10%
5%

0 3 6 9
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or photocoagulation
122 of 1148 patients (11%)
20% Less tight BP control
Beta blocker
15% ACE inhibitor
Less tight vs Tight
p=0.0092
10%
5%

0 3 6 9
Aggregate Clinical Endpoints
Relative Risk
& 95% CI
RR p 0.5 1 2
Diabetes related deaths 1.27 0.28

Stroke 1.12 0.74 >
Microvascular 1.29 0.30 >
Favours Favours
ACE inhibitor Beta blocker
ukpds
Surrogate endpoints
Relative Risk & 99% CI
RR p 0.1 1 10
Reti nopathy 2 step progress ion
median 1.5 years 0.99 0.75
Ur ine albumi n > 50 mg/L
3 year s 1.11 0.55
6 year s 0.93 0.65
9 year s 1.20 0.31
Ur ine albumi n > 300 mg/L
3 year s 1.41 0.44
6 year s 0.75 0.43
9 year s 0.48 0.090
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
Potential implications
for clinical care of
diabetic patients
ukpds
An intensive glucose control policy HbA1c 7.0 % vs 7.9 %
reduces risk of
any diabetes-related endpoints 12% p=0.030
microvascular endpoints 25% p=0.010
myocardial infarction 16% p=0.052
A tight blood pressure control policy 144 / 82 vs 154 / 87 mmHg

reduces risk of
any diabetes-related endpoint 24% p=0.005
microvascular endpoint 37% p=0.009
stroke 44% 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
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
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

The UK Prospective Diabetes Study: Ukpds

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The UK Prospective Diabetes Study: Ukpds

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The UK

complications of Type 2 diabetes develop

Funding £23 million

• Retinopathy Grading : Hammersmith Hospital

UK Medical Research Council

Novo Nordisk Bayer Lilly

Glucose Control Study

age 25 - 65 years mean 53 y

• follow-up of patients to major fatal and

• recording of surrogate endpoints :

• intention to treat analysis

fpg < 6 fpg 6.1 - 15.0 fpg > 15

Diet Alone Main Randomisation Diet Failure

fpg : fasting plasma glucose (mmol/L) ukpds

Does an intensive glucose

Conventional Policy Intensive Policy

• when marked hyperglycaemia develops

Intensive Policy with sulphonylurea or insulin

• when marked hyperglycaemia develops

Years from randomisation

6.2% upper limit of normal range

• self-reported at each clinic visit

any episode major episodes

Risk reduction 12%

Risk reduction 25%

Risk reduction 16%

Myocardial infarction 0.84 0.052

The UKPDS has shown that intensive blood

Conventional Policy Intensive Policy

Diet alone Chlorpropamide Glibenclamide Insulin

comparison between three intensive therapies

any episode major episodes

Proportion of patients with events

0.5 Chlorpropamide (619)

Proportion of patients with event

• all three therapies had equivalent risk reduction

• in those allocated to chlorpropamide there was

Conventional Policy Intensive Policy

Insulin or Sulphonylurea Metformin

age mean 53 years

Diab e t se re l ate d d e ahs

All ca use m ort ali ty

Myo c ardia l in f arc tio n

• in view of the progressive hyperglycaemia in these

• in view of the interesting results in the primary

Myocardial infarction 1.09 0.73

• compared with conventional policy

32% risk reduction in any diabetes-related endpoints p=0.0023

• the addition of metformin in patients already treated

• on balance, metformin treatment would appear to

• tight blood pressure control policy can reduce

• ACE inhibitor (captopril) or Beta blocker (atenolol)

patients already ON anti-hypertensive therapy

1148 hypertensive patients

on antihypertensive therapy not on antihypertensive therapy

less tight blood pressure control tight blood pressure control

avoid ACE inhibitor : Beta blocker ACE inhibitor Beta blocker

mmHg baseline mean over 9 years

LessTight Control Policy Tight Control Policy

% of patients with events 40%

Tight Blood Pressure Control (758)

Tight Blood Pressure Control (758)

Years from randomisation