UKPDS overview

ukpds

The UKThe UKProspectiveProspective

DiabetesDiabetesStudyStudy

ukpds

• 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

Glucose Interventional TrialGlucose Interventional Trial

Intensive

Conventional

Intensive

2,729 Intensive

with sulfonylurea(glibenclamide or

chlorpropramide)/insulin

1,138 (411 overweight) Conventional

with diet

342 (all overweight) Intensive

with metformin

P

Trial end1997

P

5,102Newly-diagnosed

type 2 diabetes

744Diet failure

FPG >15 mmol/l

149Diet satisfactory FPG <6 mmol/l

DietaryRun-in

4209

Randomisation1977-1991

Mean age 54 years(IQR 48–60)

ukpds

• Aim• Conventional group- best achievable FPG• Intensive group FPG <6mmol

ukpds

Any Diabetes Related EndpointAny 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

Diabetes Related DeathsDiabetes 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

HbAHbA1c1c (7 vs 7.9%) (7 vs 7.9%)cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

HbA 1

c (%

)

Years from randomisation

Conventional

Intensive

6.2% upper limit of normal range

ukpds

Aggregate Clinical EndpointsAggregate Clinical Endpoints

Favoursconventional

0.5 1 2

0.88

0.90

0.94

0.84

1.11

0.75

0.029

0.34

0.44

0.052

0.52

0.0099

Any diabetes related endpoint

Diabetes related deaths

All cause mortality

Myocardial infarction

Stroke

Microvascular

RR p

Favoursintensive

Relative Risk& 95% CI

ukpds

Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)

p=0.0099

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive

Conventional

Risk reduction 25%(95% CI: 7% to 40%)

renal failure or death, vitreous haemorrhage or photocoagulation346 of 3867 patients (9%)

ukpds

MicroalbuminuriaMicroalbuminuriaUrine albumin >50 mg/L

0.89

0.83

0.88

0.76

0.67

0.70

0.24

0.043

0.13

0.00062

0.000054

0.033

Baseline

Three years

Six years

Nine years

Twelve years

Fifteen years

RR p 0.5 1 2


Favoursconventional

Favoursintensive

<

ukpds

Progression of RetinopathyProgression of RetinopathyTwo step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale

1.03

0.83

0.83

0.79

0.78

0.017

0.012

0.015

0 - 3 years

0 - 6 years

0 - 9 years

0 - 12 years

RR p 0.5 1 2


Favoursconventional

Favoursintensive

ukpds

Glucose Control Study SummaryGlucose 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=0.02925% for microvascular endpoints p=0.0099

16% for myocardial infarction p=0.05224% for cataract extraction p=0.046

21% for retinopathy at twelve years p=0.01533% for albuminuria at twelve yearsp=0.000054

ukpds

• 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

ukpds

Sulphonylurea or insulinSulphonylurea 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

ukpds

UKPDS SummaryUKPDS 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

ConclusionConclusion

The UKPDS has shown that intensive blood

glucose control reduces the risk of diabetic

complications, the greatest effect being on

microvascular complications

ukpds

Sulphonylurea or Insulin : Summary 1Sulphonylurea or Insulin : Summary 1

• all three therapies were similarly effective in reducing HbA1c

• all three therapies had equivalent risk reductionfor 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

Does metformin in Does metformin in overweight diabetic patients overweight diabetic patients

have any advantages or have any advantages or disadvantages?disadvantages?

UK Prospective Diabetes StudyUK Prospective Diabetes Study

ukpds

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

Diabetes related deathsDiabetes related deaths

M v Ip=0.11

overweight patients

M v C p=0.017

ukpds

Myocardial InfarctionMyocardial Infarction

M v Ip=0.12

overweight patients

0.0

0.1

0.2

0.3

0.4

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

M v Cp=0.010

ukpds

0.0

0.1

0.2

0.3

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

Microvascular endpointsMicrovascular endpoints

M v Ip=0.39

overweight patients

M v Cp=0.19

ukpds

Metformin ComparisonsMetformin Comparisons

favours metformin

favours conventional

overweight patientsRR p

Any dia b e t es re l ate d e n dpo i n tM e t for min 0 . 68 0 . 002 3

Diab e t es re l ate d d e a thsM e t for min 0 . 58 0 . 017

All ca use m ort ali tyM e t for min 0 . 64 0 . 011

Myo c ardia l in f arc tio nM e t for min 0 . 61 0 . 01

RR (95% CI)

0.2 1 5

ukpds

Metformin ComparisonsMetformin Comparisons

favours metformin or

intensive

favours conventional

overweight patientsM v I n t RR p

Any dia b e t es re l ate d e n dpo i n tM e t for minI n t ensiv e

p=0 . 0 0 3 40 . 680 . 93

0 . 002 30 . 46

Diab e t es re l ate d d e a thsM e t for minI n t ensiv e

p=0 . 1 10 . 580 . 80

0 . 0170 . 19

All ca use m ort ali tyM e t for minI n t ensiv e

p=0 . 0 2 10 . 640 . 92

0 . 0110 . 49

Myo c ardia l in f arc tio nM e t for minI n t ensiv e

p=0 . 1 20 . 610 . 79

0 . 010 . 11

RR (95% CI)

0.2 1 5

ukpds

Sulphonylurea plus MetforminSulphonylurea 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

AimAim

• 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 EndpointsAggregate Endpoints

1.04

1.96

1.60

1.09

1.21

0.84

0.78

0.039

0.041

0.73

0.61

0.62



All cause mortality


Stroke

Microvascular

RR pMedian follow up 6.6 years 0.1 1 10

Favourssulphonylureaalone

Favoursadded

metformin


*

* interpret with caution in view of small numbers : 26 deaths on sulphonylurea plus metformin versus 14 deaths on sulphonylurea alone

ukpds

Metformin in Overweight PatientsMetformin in Overweight Patients

• compared with conventional policy

32% risk reduction in any diabetes-related endpoints p=0.002342% risk reduction in diabetes-related deaths p=0.01736% risk reduction in all cause mortalityp=0.01139% risk reduction in myocardial infarction p=0.01

ukpds

Metformin : SummaryMetformin : 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 Blood Pressure Control StudyControl Study


ukpds

Blood Pressure Control Study : AimsBlood 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 criteriaInclusion 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 CharacteristicsPatient Characteristics

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

RandomisationRandomisation

on antihypertensive therapyn = 421

not on antihypertensive therapyn = 727

avoid ACE inhibitor : Beta blockern = 390

34%

less tight blood pressure controlaim : BP < 180/105 mmHg

ACE inhibitorn = 400

35%

Beta blockern = 358

31%

tight blood pressure controlaim : BP < 150 / 85 mmHg

randomisation

1148 hypertensive patients

ukpds

Blood Pressure : Tight vs Less Tight Control Blood Pressure : Tight vs Less Tight Control

60

80

100

140

160

180

0 2 4 6 8

mm

Hg


cohort, median values

Less tight control Tight control

ukpds

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

Mean Blood PressureMean Blood Pressure

ukpds

Therapy requirementTherapy requirement

1 2 3 4 5 6 7 80

20

40

60

80

100

% o

f pa

tient

s

LessTight Control Policy

1 2 3 4 5 6 7 8


None one two > two

Tight Control Policy

number of antihypertensive agents

ukpds

Any diabetes-related endpointsAny diabetes-related endpoints

0%

10%

20%

30%

40%

50%

0 3 6 9

% o

f pa

tient

s w

ith e

vent

s


Tight blood pressure control (758)

Less tight blood pressure control (390)

risk reduction24% p=0.0046

ukpds

Diabetes-related deathsDiabetes-related deaths

0%

5%

10%

15%

20%

0 3 6 9

% o

f pa

tient

s w

ith e

vent

s


Tight blood pressure control (758)

Less tight blood pressure control (390)


ukpds

Myocardial InfarctionMyocardial Infarction

0%

5%

10%

15%

20%

25%

0 3 6 9

% o

f pa

tient

s w

ith e

vent


Tight Blood Pressure Control (758)

Less Tight Blood Pressure Control (390)


ukpds

StrokeStroke

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





ukpds

Microvascular endpointsMicrovascular endpoints

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





ukpds

Heart FailureHeart Failure

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt




risk reduction 56% p=0.0043

ukpds

Progression of Retinopathy : 2 step changeProgression of Retinopathy : 2 step change

Years from randomisationnumbers above bars are % affected

243 461 207 411 152 3000

20

40

60

% p

atie

nts

23 20

37

28

51

34

3 years 6 years 9 years

p=0.38 p=0.019 p=0.004

ukpds

Deterioration of Vision : 3 lines on ETDRS chartDeterioration of Vision : 3 lines on ETDRS chart


% p

atie

nts

293 575 257 523 180 3320

10

20

30

7 59

8

19

10


p=0.40 p=0.47 p=0.004

ukpds

Urine Albumin >50 mg/LUrine Albumin >50 mg/L


% p

atie

nts

317 618 274 543 166 2990

10

20

30

40

24

18

29

20

33

29


p=0.008p=0.052 p=0.33

ukpds

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

Blood Pressure Control StudyBlood Pressure Control Study

ukpds

Do ACE inhibitors or Do ACE inhibitors or Beta Blockers Beta Blockers

have any specific advantages have any specific advantages or disadvantages?or disadvantages?


ukpds

Blood Pressure : ACE inhibitor vs Beta blockerBlood Pressure : ACE inhibitor vs Beta blocker

60

80

100

140

160

180

0 2 4 6 8

mm

Hg


cohort, median values

Less tight control ACE inhibitor Beta blocker

ukpds

Reasons for non-complianceReasons for non-complianceCaptopri 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

impotenc e 1 (0%) 6 (2%) 0.057

ukpds

Any Diabetes Related Endpoint (cumulative)Any Diabetes Related Endpoint (cumulative)429 of 1148 patients (37%)

0%

10%

20%

30%

40%

50%

0 3 6 9

% o

f pa

tient

s w

ith a

n ev

ent


ACE inhibitor (n=400)

Beta blocker (n=358)

Less tight BP control (n=390)

ACE vs Beta blocker p=0.43

Less tight vs Tightp=0.0046

ukpds

Diabetes Related Deaths (cumulative)Diabetes Related Deaths (cumulative)144 of 1148 patients (13%)

0%

5%

10%

15%

20%

0 3 6 9

% o

f pa

tient

s w

ith a

n ev

ent


ACE inhibitor (n=400)

Beta blocker (n=358)

Less tight BP control (n=390)



ukpds

Microvascular Endpoints (cumulative)Microvascular Endpoints (cumulative)renal failure or death, vitreous haemorrhage or photocoagulation

122 of 1148 patients (11%)

0%

5%

10%

15%

20%

0 3 6 9

% o

f pa

tient

s w

ith a

n ev

ent


ACE inhibitor

Beta blocker

Less tight BP control



ukpds

Aggregate Clinical EndpointsAggregate Clinical Endpoints

1.10

1.27

1.14

1.20

1.12

1.29

0.43

0.28

0.44

0.35

0.74

0.30



All cause mortality


Stroke

Microvascular

RR p 0.5 1 2


>

>

FavoursBeta blocker

FavoursACE inhibitor

ukpds

Surrogate endpointsSurrogate endpoints

RR p

Reti nopathy 2 step progress ionmedian 1.5 years 0.99 0.75median 4.5 years 0.99 0.82median 7.5 years 0.91 0.28

Ur ine albumi n > 50 mg/L3 year s 1.11 0.556 year s 0.93 0.659 year s 1.20 0.31

Ur ine albumi n > 300 mg/L3 year s 1.41 0.446 year s 0.75 0.439 year s 0.48 0.090

Relative Risk & 99% CI

favours ACE inhibitor

favours Beta blocker

0.1 1 10

ukpds

ConclusionConclusion

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 Potential implications for clinical care of for clinical care of diabetic patientsdiabetic 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 TherapiesChoice 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?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 guidelinesbut is difficult to accomplish in some patients

• epidemiological analysis suggests that any reduction of hyperglycaemia would be advantageous

ukpds

Which goals of therapy?Which goals of therapy?

• current guidelines suggest blood pressure<140 / 85 mmHg or <130 / 85 mmHg

• the risk of diabetic complications was reducedin the UKPDS blood pressure control trialwhich 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


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 TherapyBeneficial 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

Date post:	02-Jun-2015
Category:	Health & Medicine
Upload:	peninsulaendocrine
View:	2,252 times
Download:	5 times

UKPDS overview

Health & Medicine