1. The UK
Prospective
Diabetes
Study
ukpds

2. • 20-year multicenter RCT -Interventional Trial
from 1977 to 1997
• Intensive diabetes control and reduction in
complications
 5,102 patients with newly-diagnosed type 2 diabetes
recruited between 1977 and 1991
 FPG between 6.1 to 15 mmol
 Randomized to conventional therapy vs. intensive
therapy
 Median follow-up 10.0 years, range 6 to 20 years
ukpds

3. Glucose Interventional Trial
Dietary
Run-in
Randomisation
1977-1991
Trial end
1997
744
Diet failure
2,729
Intensive
Intensive
FPG >15 mmol/l
with sulfonylurea(glibenclamide
or chlorpropramide)/insulin
P
5,102
Newly-diagnosed
type 2 diabetes
4209
1,138 (411 overweight)
Conventional
Conventional
with diet
P
149
Diet satisfactory
342 (all overweight)
Intensive
FPG <6 mmol/l
with metformin
Mean age 54 years
(IQR 48–60)
Intensive
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4. • Aim
• Conventional group- best achievable FPG
• Intensive group FPG <6mmol
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5. Any Diabetes Related Endpoint
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

6. Diabetes Related Deaths
Any of:
• fatal myocardial infarction or sudden death
• fatal stroke
• death from peripheral vascular disease
• death from renal disease
• death from hyper/hypoglycaemia
ukpds

7. HbA1c (7 vs 7.9%)
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

8. 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
0.84 0.052
Stroke
1.11 0.52
Microvascular
0.75 0.0099
Favours Favours
intensive conventional
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9. 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

10. Microalbuminuria
Urine albumin >50 mg/L
RR
p
Baseline
0.89
0.83
0.043
Six years
Nine years
Twelve years
0.88
0.76
0.67
0.13
0.00062
0.000054
Fifteen years
0.70
0.033
2
0.24
Three years
0.5
Relative Risk
& 99% CI
1
<
Favours Favours
intensive conventional
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11. Progression of Retinopathy
Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale
RR
p
0 - 3 years
0.83 0.017
0 - 9 years
0 - 12 years
2
1.03 0.78
0 - 6 years
0.5
Relative Risk
& 99% CI
1
0.83 0.012
0.79 0.015
Favours Favours
intensive conventional
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12. 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

13. • Major hypoglycemic episode
•
•
Conventional 0.7%
Intensive Chlorpropramide 1%, glibenclamide 1.4%, insulin 1.8%
• Wt Gain
•
insulin 4 kg, glibenclamide 1.7kg chlorpropramide 2.6 kg
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14. Sulphonylurea or insulin
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
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15. UKPDS Summary
• There is a direct relationship between the risk of
complications of diabetes and glycaemia over time
• The lower the glycaemia the lower the risk for
complications
• The rate of increase of risk for microvascular disease
with hyperglycaemia is greater than that for macro
vascular disease
ukpds

16. Conclusion
The UKPDS has shown that intensive blood
glucose control reduces the risk of diabetic
complications, the greatest effect being on
microvascular complications
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17. 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

18. UK Prospective Diabetes Study
Does metformin in
overweight diabetic patients
have any advantages or
disadvantages?
ukpds

19. overweight
patients
Proportion of patients with events
Diabetes related deaths
0.4
Conventional (411)
Intensive (951)
Metformin (342)
0.3
0.2
Mv C
p=0.017
0.1
MvI
p=0.11
0.0
0
3
6
9
12
Years from randomisation
15
ukpds

20. 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

21. 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

22. Metformin Comparisons
overweight patients
Any d b e ts re l a d e n d i n t
ia
e
te
po
M e tor m
f in
RR
p
0.2
RR (95% CI)
1
0.6 0.0 3
8
02
Diab e t s re l a d d e ahs
e
te
t
M e tor m
f in
0.5
8
0.0
17
All ca use m o a ty
rt li
M e tor m
f in
0.6
4
0.0
11
Myo c a l in f a to n
rdia
rc i
M e tor m
f in
0.6
1
0.0
1
favours
metformin
favours
conventional
ukpds
5

23. Metformin Comparisons
overweight patients
M v Int
RR
p
0.2
RR (95% CI)
1
Any d b e ts re l a d e n d i n tp=0 . 0 0 3 4
ia
e
te
po
M e tor m
f in
0.6 0.0 3
8
02
I n t nsiv e
e
0.9
3
0.4
6
Diab e t s re l a d d e ahs
e
te
t
p=0 . 1 1
M e tor m
f in
0.5 0.0
8
17
I n t nsiv e
e
0.8
0
0.1
9
All ca use m o a ty
rt li
p=0 . 0 2 1
M e tor m
f in
0.6 0.0
4
11
I n t nsiv e
e
0.9
2
0.4
9
Myo c a l in f a to n
rdia
rc i
p=0 . 1 2
M e tor m
f in
0.6
1
0.0
1
I n t nsiv e
e
0.7
9
0.1
1
favours
metformin or
intensive
favours
conventional
ukpds
5

24. 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
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25. 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
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26. 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
Myocardial infarction
1.09 0.73
Stroke
1.21 0.61
Microvascular
0.84 0.62
1.60 0.041
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

27. 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

28. 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

29. UK Prospective Diabetes Study
Blood Pressure
Control Study
ukpds

30. 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

31. 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

32. Patient Characteristics
1148 Type 2 diabetic patients
age
gender
ethnic groups
Body Mass Index
HbA1c
56 years
55% / 45%
87%
6%
7%
29 kg/m2
6.8 %
systolic / diastolic blood pressure
urine albumin > 50 mg/l
160 / 94 mmHg
18%
male / female
Caucasian
Asian
Afro-caribbean
ukpds

33. 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

34. 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

35. 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

36. Therapy requirement
number of antihypertensive agents
None
one
two
LessTight Control Policy
% of patients
100
> two
Tight Control Policy
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

37. 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

38. 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

39. 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

40. 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

41. Microvascular endpoints
% patients with event
25%
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

42. Heart Failure
% patients with event
25%
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

43. Progression of Retinopathy : 2 step change
60
p=0.38
37
% patients
23
0
p=0.004
51
40
20
p=0.019
34
28
20
243 461
207 411
152 300
3 years
6 years
9 years
Years from randomisation
numbers above bars are % affected
ukpds

44. 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

45. 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

46. 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
ukpds
p=0.0036

47. UK Prospective Diabetes Study
Do ACE inhibitors or
Beta Blockers
have any specific advantages
or disadvantages?
ukpds

48. 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

49. Reasons for non-compliance
Captopri l
(n=400 )
Atenolo l
(n=358 )
p
non- compl iant
88 ( 2%)
2
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

50. 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

51. 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

52. 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

53. Aggregate Clinical Endpoints
RR
p
0.5
Relative Risk
& 95% CI
1
2
Any diabetes related endpoint
1.10 0.43
Diabetes related deaths
1.27 0.28
All cause mortality
1.14 0.44
Myocardial infarction
1.20 0.35
Stroke
1.12 0.74
>
Microvascular
1.29 0.30
>
Favours Favours
ACE inhibitor Beta blocker
ukpds

54. Surrogate endpoints
RR
Reti nopathy 2 step progress ion
median 1.5 y
ears
median 4.5 y
ears
median 7.5 y
ears
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
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
Relative Risk & 99% CI
0.44
0.43
0.090
0.1
1
10
favours ACE favours Beta
inhibitor blocker
ukpds

55. 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

56. UK Prospective Diabetes Study
Potential implications
for clinical care of
diabetic patients
ukpds

57. 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

58. 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

59. 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

60. 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

61. 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

62. 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