The UK Prospective Diabetes Study

ukpds

UK Prospective Diabetes Study

multi-centre randomised controlled trial of different therapies of Type 2 diabetes

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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

Funding

23 5102 53,000
23 million
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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 Georges Stevenage John Scarpello Richard Paisey Whittington Andrew Boulton Charles Fox Richard Greenwood Robert Turner Rury Holman Jonathan Roland Tim Dornan Phil Brown Nigel Oakley Les Borthwick Lionel Alexander John Yudkin

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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

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Acknowledgements
patients physicians nurses dietitians retinal photographers

Retinopathy Grading : Hammersmith Hospital Biochemistry : Diabetes Research Laboratories ECG Grading : Guys Hospital
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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

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UK Prospective Diabetes Study

Glucose Control Study

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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
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Patient Characteristics
5102 newly diagnosed Type 2 diabetic patients
age 25 - 65 years gender ethnic group 53 y male : female 59 : 41%
mean

Caucasian
10%

82% Asian
8% 28 kg/m2 11.5 mmol/L 9.1 % ukpds 39%

Afro-caribbean Body Mass Index fasting plasma glucose (fpg) HbA1c hypertensive

mean
median median

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

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Randomisation
5102 newly diagnosed Type 2 diabetic patients Diet therapy

fpg < 6 asymptomatic 17%

14%

fpg 6.1 - 15.0 asymptomatic 68%

fpg > 15 or symptomatic 15%

Diet Alone 3%

Main Randomisation 82%

Diet Failure 15%

fpg : fasting plasma glucose (mmol/L)

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UK Prospective Diabetes Study

Does an intensive glucose control policy reduce the risk of complications of diabetes?
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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

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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
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Actual Therapy
Conventional Policy accept < 15 mmol/L
100 diet alone additional non-intensive pharmacological therapy

Intensive Policy aim for < 6 mmol/L

proportion of patients

80 60 40 20 0 1 2 3 4

intensive pharmacological therapy diet alone

10 11 12

10 11 12

Years from randomisation

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HbA1c
cross-sectional, median values

9 Conventional

HbA1c (%)

8 Intensive 7

6.2% upper limit of normal range

6 0

6 9 12 Years from randomisation

15

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Change in Body Weight

cross-sectional, mean values

7.5 Intensive 5.0

kg

2.5 Conventional 0.0

-2.5

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

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Hypoglycaemic episodes per annum

Actual Therapy analysis
Proportion of patients (%)
50 40 30 20 10 0 0 3 6 9 12 15

any episode

5 4 3 2 1 0 0

major episodes

12

15

Years from randomisation

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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
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Any Diabetes Related Endpoint (cumulative )

1401 of 3867 patients (36%)

60%

% of patients with an event

Conventional (1138) Intensive (2729) p=0.029

40%

20% Risk reduction 12% (95% CI: 1% to 21%) 0 3 6 9 12 Years from randomisation 15

0%

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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

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Diabetes Related Deaths (cumulative)

414 of 3867 patients (11%)

30%

% of patients with an event

Conventional (1138) Intensive (2729) p=0.34

20%

10%

0% 0 3 6 9 12 Years from randomisation 15

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Microvascular Endpoints (cumulative)

30%
% of patients with an event
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 3 6 9 12 Years from randomisation 15

0%

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Myocardial Infarction (cumulative)

30%
fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%)

% of patients with an event

Conventional Intensive p=0.052

20%

10% Risk reduction 16% (95% CI: 0% to 29%) 0 3 6 9 12 Years from randomisation 15

0%

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Aggregate Clinical Endpoints

RR Any diabetes related endpoint Diabetes related deaths All cause mortality Myocardial infarction Stroke Microvascular p 0.5 Relative Risk & 95% CI 1 2

0.88 0.029 0.90 0.34 0.94 0.44 0.84 0.052 1.11 0.52 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

RR 0 - 3 years 0 - 6 years 0 - 9 years 0 - 12 years 1.03 0.83 0.83 0.79

p 0.78 0.017 0.012 0.015

0.5

Relative Risk & 99% CI 1

Favours Favours intensive conventional

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Microalbuminuria
Urine albumin >50 mg/L

RR Baseline Three years Six years Nine years Twelve years Fifteen years 0.89 0.83 0.88 0.76 0.67 0.70 0.24

p 0.043 0.13 0.00062 0.000054 0.033

0.5

Relative Risk & 99% CI 1

<
Favours Favours intensive conventional

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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% 16% 24% for any diabetes related endpoint for microvascular endpoints for myocardial infarction for cataract extraction p=0.029 p=0.0099 p=0.052 p=0.046

21% 33%

for retinopathy at twelve years for albuminuria at twelve years

p=0.015 p=0.000054
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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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UK Prospective Diabetes Study

Does insulin or sulphonylurea therapy have specific advantages or disadvantages?

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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

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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
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Randomisation
3041 patients
in 15 centres

Conventional Policy Diet alone n = 896 Chlorpropamide n = 619

Intensive Policy Glibenclamide n = 615 Insulin n = 911

comparison between three intensive therapies compare each with conventional policy ukpds

HbA1c
9

cohort, median data

Conventional Insulin Chlorpropamide Glibenclamide

%
7 6 0 0

4 6 8 Years from randomisation

10

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change in weight
cohort, mean data 10.0 Conventional Insulin Chlorpropamide Glibenclamide
7.5 5.0

kg
2.5 0.0 -2.5

4 6 8 Years from randomisation

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Hypoglycaemic episodes per annum

Actual Therapy analysis
Proportion of patients (%)
50 40 30 20 10 0 0 3 6 9 12 15

any episode

10 8 6 4 2 0 0

major episodes

12

15

Years from randomisation

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Blood Pressure
cohort, mean data
150 145 140 Conventional Insulin Chlorpropamide Glibenclamide

mmHg

135 85 80 75 70 0 2 4 6 8 Years from randomisation 10

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Any diabetes-related endpoints

Proportion of patients with events
0.6 0.5 0.4 0.3 0.2 0.1 0.0 0
Conventional (896) Chlorpropamide (619) Glibenclamide (615) Insulin (911)

CvGvI p = 0.36
3 6 9 12 Years from randomisation 15

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Myocardial Infarction
Proportion of patients with event
0.4
Conventional (896) Chlorpropamide (619) Glibenclamide (615) Insulin (911)

0.3

0.2

0.1

0.0 0

CvGvI p = 0.66
3 6 9 12 Years from randomisation 15

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Progression of Retinopathy : 2 step change

RR 0-3 rs y e a Chlorpro p mid a e Glib e lamid n c e I n lin s u 0-6 rs y e a Chlorpro p mid a e Glib e lamid n c e I n lin s u 0-9 rs y e a Chlorpro p mid a e Glib e lamid n c e I n lin s u 0-1 2 rs y e a Chlorpro p mid a e Glib e lamid n c e I n lin s 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 0 2 . 9 2 . 0 0 4 . 8 1 . 0 0 1 . 9 2 . 9 0 2 . 4 7 . 9 0 4 . 5 9 . 8 0 4 . 0 9 6 . 9 0 1 . . 8 0 3 . . 8 0 3 . 5 9 . 0 0 0 . . 6 0 8 . . 7 0 2 . 3 3 0 6 8 0 4 8 9 9 0 0 4 4 0 0 4 1

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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
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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

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UK Prospective Diabetes Study

Does metformin in overweight diabetic patients have any advantages or disadvantages?

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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

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Randomisation
Main Randomisation 4209
Overweight 1704 Conventional Policy 411 Non overweight 2505

Intensive Policy 1293 Metformin 342

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Insulin or Sulphonylurea 951

Patient Characteristics
overweight patients > 120% ideal body weight after three months diet therapy
age gender ethnic groups 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

Body Mass Index fasting plasma glucose HbA1c

HbA1c
overweight patients 9 Conventional
cohort, median values
Insulin Chlorpropamide Glibenclamide Metformin

HbA1c (%)

6 0

4 6 8 Years from randomisation

10

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Change in Weight
overweight patients 10 Conventional
weight change (kg)
cohort, mean values
Insulin Chlorpropamide Glibenclamide Metformin

-5

4 6 8 Years from randomisation

10

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Hypoglycaemic episodes per annum

overweight patients Actual Therapy analysis

any episode
Proportion of patients (%)
50 40 30 4 20 10 0 0 2 4 6 8 10 2 8

major episodes

0 0 2 4 6 8 10

Years from randomisation

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Any diabetes related endpoint

Proportion of patients with events

overweight patients

0.6

Conventional (411) Intensive (951) Metformin (342)

0.4 M v C p=0.0023

0.2

0.0 0 3 6 9 12 Years from randomisation

MvI p=0.0034
15

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Diabetes related deaths

Proportion of patients with events

overweight patients

0.4

Conventional (411) Intensive (951) Metformin (342) 0.3 Mv C p=0.017 0.2

0.1

0.0 0 3 6 9 12 Years from randomisation

MvI p=0.11
15

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Myocardial Infarction
Proportion of patients with events

overweight patients

0.4

Conventional (411) Intensive (951) Metformin (342)

0.3

MvC p=0.010
0.2

0.1

0.0 0 3 6 9 12 Years from randomisation

MvI p=0.12
15

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Microvascular endpoints
Proportion of patients with events

overweight patients

0.3

Conventional (411) Intensive (951) Metformin (342)

0.2 M v C p=0.19

0.1

0.0 0

MvI p=0.39
3 6 9 12 Years from randomisation 15

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Metformin Comparisons
overweight patients
Any d ia b e ts e re l a te d e n d po i n t M e tor f m in Diab e t s e re l a te d d e ahs t M e tor f m in All ca use m o rt a li ty M e tor f m in Myo c a rdia l in f a rc t io n M e tor f m in RR p
0.2

RR (95% CI)
1

0.6 8 0.0 02 3

0.5 8

0.0 17

0.6 4

0.0 11

0.6 1

0.0 1
favours metformin favours conventional

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Metformin Comparisons
overweight patients
M v Int RR p

RR (95% CI)
0.2 1 5

Any d ia b e ts e re l a te d e n d po i n tp=0 . 0 0 3 4 M e tor f m in 0.6 8 0.0 02 3 I n tn esiv e 0.9 3 0.4 6 Diab e t s e re l a te d d e ahs t p=0 . 1 1 M e tor f m in 0.5 8 0.0 17 I n tn esiv e 0.8 0 0.1 9 All ca use m o rt a li ty p=0 . 0 2 1 M e tor f m in 0.6 4 0.0 11 I n tn esiv e 0.9 2 0.4 9 Myo c a rdia l in f a rc t io n p=0 . 1 2 M e tor f m in 0.6 1 0.0 1 I n tn esiv e 0.7 9 0.1 1
favours metformin or intensive favours conventional

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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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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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Aggregate Endpoints
Median follow up 6.6 years Any diabetes related endpoint Diabetes related deaths * All cause mortality Myocardial infarction Stroke Microvascular RR p Relative Risk & 95% CI 0.1 1 10

1.04 0.78 1.96 0.039 1.60 0.041 1.09 0.73 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

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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

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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

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UK Prospective Diabetes Study

Blood Pressure Control Study

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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

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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
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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 hy pertensiv e patients on antihy pertensiv e therapy n = 421 not on antihy pertensiv e therapy n = 727

randomisation less tight blood pressure control aim : BP < 180/105 mmHg av oid 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%

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Blood Pressure : Tight vs Less Tight Control

cohort, median values
180 Less tight control Tight control 160

mmHg

140 100 80 60 0 2 4 6 Years from randomisation 8

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Mean Blood Pressure

mmHg Less tight control baseline 160 / 94 mean over 9 years 154 / 87

Tight control difference p ACE inhibitor Beta blocker difference p

161 / 94 1/0 n.s. 159 / 94 159 / 93 0/0 n.s.

144 / 82 10 / 5 <0.0001 144 / 83 143 / 81 1/1 n.s. / p=0.02

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Therapy requirement
number of antihypertensive agents None one two LessTight Control Policy 100 > two

Tight Control Policy

% of patients

80 60 40 20 0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Years from randomisation

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Any diabetes-related endpoints

50% Less tight blood pressure control (390) Tight blood pressure control (758) 40%

% of patients with events

30%

20%

10%

0% 0 3 6

risk reduction 24% p=0.0046

9

Years from randomisation

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Diabetes-related deaths
20% Less tight blood pressure control (390) Tight blood pressure control (758)

% of patients with events

15%

10%

5%

0% 0 3 6

risk reduction 32% p=0.019

9

Years from randomisation

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Myocardial Infarction
25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758)

% of patients with event

20%

15%

10%

5%

0% 0

risk reduction 21% p=0.13

3 6 Years from randomisation 9

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Stroke
25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758)

% patients with event

20%

15%

10%

5%

0% 0 3 6

risk reduction 44% p=0.013

9

Years from randomisation

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Microvascular endpoints
25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758)

% patients with event

20%

15%

10%

5%

0% 0 3 6

risk reduction 37% p=0.0092

9

Years from randomisation

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Heart Failure
25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758)

% patients with event

20%

15%

risk reduction 56% p=0.0043

10%

5%

0% 0 3 6 9

Years from randomisation

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Progression of Retinopathy : 2 step change

60 p=0.38 p=0.019 p=0.004 51 % patients 40 23 20 37 28

34

20

243 461

207 411

152 300

3 years

6 years

9 years ukpds

Years from randomisation

numbers above bars are % affected

Deterioration of Vision : 3 lines on ETDRS chart

30 p=0.40 p=0.47 p=0.004

% patients

20

19

10

9 5

10 8

293 575

257 523

180 332

3 years

6 years

9 years
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Years from randomisation

numbers above bars are % affected

Urine Albumin >50 mg/L

40

p=0.052

p=0.008
29

p=0.33
33
29

% patients

30
24 20 10 0
317 618

18

20

274

543

166

299

3 years

6 years

9 years

Years from randomisation

numbers above bars are % affected

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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 heart failure retinopathy progression deterioration of vision 24% 32% 44% 37% 56% 34% 47% p=0.0046 p=0.019 p=0.013 p=0.0092 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
180 160

Less tight control ACE inhibitor Beta blocker

mm Hg

140 100 80 60 0 2 4 6 Years from randomisation 8

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Reasons for non-compliance

Captopri l (n=400 ) non- compl iant 88 ( 22%) Atenolo l (n=358 ) 125 (35%) p <0.0001

cough inc rea sed creatini ne c laudi cation, col d finger s or toes bron cho spas m impotenc e

16 ( 4%) 5 (1%) 0 0 1 (0%)

0 0 15 ( 4%) 22 ( 6%) 6 (2%)

<0.0001 0.064 <0.0001 <0.0001 0.057

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Any Diabetes Related Endpoint (cumulative)

429 of 1148 patients (37%)

50%

% of patients with an event

40% 30% 20% 10% 0% 0

Less tight BP control (n=390) Beta blocker (n=358) ACE inhibitor (n=400) Less tight vs Tight p=0.0046

ACE vs Beta blocker p=0.43 3 6 9 Years from randomisation

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Diabetes Related Deaths (cumulative)

144 of 1148 patients (13%)

20%

% of patients with an event

15% 10% 5% 0% 0

Less tight BP control (n=390) Beta blocker (n=358) ACE inhibitor (n=400) Less tight vs Tight p=0.019

ACE vs Beta blocker p=0.28 3 6 9 Years from randomisation

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Microvascular Endpoints (cumulative)

20%
renal failure or death, vitreous haemorrhage or photocoagulation 122 of 1148 patients (11%)

% of patients with an event

15% 10% 5% 0% 0

Less tight BP control Beta blocker ACE inhibitor Less tight vs Tight p=0.0092

ACE vs Beta blocker p=0.30 3 6 9 Years from randomisation

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Aggregate Clinical Endpoints

RR Any diabetes related endpoint Diabetes related deaths All cause mortality Myocardial infarction Stroke Microvascular p 0.5 Relative Risk & 95% CI 1 2

1.10 0.43 1.27 0.28 1.14 0.44 1.20 0.35 1.12 0.74 1.29 0.30 > >
Favours Favours ACE inhibitor Beta blocker

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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 0.99 0.99 0.91 1.11 0.93 1.20 1.41 0.75 0.48 p 0.75 0.82 0.28 0.55 0.65 0.31 0.44 0.43 0.090
favours ACE favours Beta inhibitor blocker

Relative Risk & 99% CI

0.1 1 10

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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

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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

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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
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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
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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

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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
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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

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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
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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