Ukpds The UK Prospective Diabetes Study. ukpds UK Prospective Diabetes Study multi-centre randomised...

ukpds

The UKThe UKProspectiveProspective

DiabetesDiabetesStudyStudy

ukpds

UK Prospective Diabetes StudyUK Prospective Diabetes Study

multi-centre

randomised controlled trial

of different therapies

of Type 2 diabetes

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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 : need for a long-term studyUKPDS : need for a long-term study

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UK Prospective Diabetes Study CentresUK 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

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Co-ordinating StaffCo-ordinating Staff

Chief Investigators : Robert Turner, Rury HolmanStatisticians : Irene Stratton, Carole Cull

Ziyah Mehta, Heather McElroyModeller : Richard StevensEpidemiologists : Andrew Neil, Amanda AdlerDiabetologists : David Matthews, Valeria FrighiBiochemists : Susan Manley, Iain RossAdministrators : Philip Bassett, Suzy OakesRetinopathy Grading Centre : Eva Kohner, Steve AldingtonHealth Economics : Alastair Gray, Maria RaikouGrant Applications : Ivy Samuel, Caroline WoodComputing Support : Ian Kennedy, John Veness

And many others

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Acknowledgements Acknowledgements

• patients • physicians• nurses• dietitians• retinal photographers

• Retinopathy Grading : Hammersmith Hospital• Biochemistry : Diabetes Research Laboratories• ECG Grading : Guy’s Hospital

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Major Funding BodiesMajor 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

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Glucose Control StudyGlucose Control Study


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Blood Glucose Control Study : AimsBlood 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 CharacteristicsPatient 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%

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• follow-up of patients to major fatal and non-fatal clinical endpoints

• recording of surrogate endpoints : clinical and biochemical markers

e.g. urine albuminretinal photographsvisual acuity

• intention to treat analysis

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RandomisationRandomisation

fpg : fasting plasma glucose (mmol/L)

5102 newly diagnosed Type 2 diabetic patients

Diet Alone3%

fpg < 6asymptomatic

17%

Main Randomisation82%

fpg 6.1 - 15.0asymptomatic

68%

Diet Failure15%

fpg > 15or symptomatic

15%

Diet therapy

14%

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


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Randomisation of Treatment PoliciesRandomisation of Treatment Policies

342 allocated to metformin

Conventional Policy30% (n=1138)

Intensive Policy70% (n=2729)

Sulphonylurean=1573

Insulinn=1156

Main Randomisationn=4209 (82%)

3867

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Treatment Policies in 3867 patientsTreatment Policies in 3867 patients

Conventional Policy

n = 1138• initially with diet alone• aim for

near normal weightbest fasting plasma glucose < 15 mmol/Lasymptomatic

• when marked hyperglycaemia developsallocate to non-intensive pharmacological therapy

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Treatment Policies in 3867 patientsTreatment Policies in 3867 patients

Intensive Policy with sulphonylurea or insulin

n = 2729 • aim for

fasting plasma glucose < 6 mmol/Lasymptomatic

• when marked hyperglycaemia developson sulphonylurea

add metforminmove to insulin therapy

on insulin, transfer to complex regimens

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Actual TherapyActual Therapy

Years from randomisation

1 2 3 4 5 6 7 8 9 10 11 120

20

40

60

80

100

pro

po

rtio

n o

f p

ati

en

ts

diet alone

1 2 3 4 5 6 7 8 9 10 11 12

intensivepharmacologicaltherapy

diet aloneadditional non-intensivepharmacological therapy

Intensive Policyaim for < 6 mmol/L

Conventional Policyaccept < 15 mmol/L

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HbAHbA1c1c cross-sectional, median values

06

7

8

9

0 3 6 9 12 15

HbA 1

c (%

)


Conventional

Intensive

6.2% upper limit of normal range

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Change in Body WeightChange in Body Weightcross-sectional, mean values

-2.5

0.0

2.5

5.0

7.5

0 3 6 9 12 15

kg


Conventional

Intensive

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Hypoglycaemic EpisodesHypoglycaemic 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 annumHypoglycaemic episodes per annum

Actual Therapy analysis

0

10

20

30

40

50

0 3 6 9 12 15

Pro

port

ion

of

pati

en

ts (

%)


0

1

2

3

4

5

0 3 6 9 12 15

any episode major episodes

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Any Diabetes Related EndpointAny 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 )Any Diabetes Related Endpoint (cumulative )

0%

20%

40%

60%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive (2729)

Conventional (1138)

Risk reduction 12%(95% CI: 1% to 21%)

p=0.029

1401 of 3867 patients (36%)

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Diabetes Related DeathsDiabetes 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)Diabetes Related Deaths (cumulative)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive (2729)

Conventional (1138)

p=0.34

414 of 3867 patients (11%)

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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


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

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Myocardial Infarction (cumulative)Myocardial Infarction (cumulative)

0%

10%

20%

30%

0 3 6 9 12 15

% o

f pa

tient

s w

ith a

n ev

ent


Intensive

Conventional

p=0.052


fatal or non fatal myocardial infarction, sudden death573 of 3867 patients (15%)

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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

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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

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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

<

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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

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ConclusionConclusion

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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Does insulin or Does insulin or sulphonylurea therapy have sulphonylurea therapy have

specific advantages or specific advantages or disadvantages?disadvantages?

UK Prospective Diabetes Study

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Sulphonylurea TherapySulphonylurea 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 TherapyInsulin 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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Diet alonen = 896

Conventional Policy

Chlorpropamiden = 619

Glibenclamiden = 615

Insulinn = 911

Intensive Policy

3041 patientsin 15 centres

comparison between three intensive therapies

compare each with conventional policy

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HbAHbA1c1c

cohort, median data

06

7

8

9

0 2 4 6 8 10

%


GlibenclamideChlorpropamideConventional Insulin

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change in weightchange in weightcohort, mean data

-2.5

0.0

2.5

5.0

7.5

10.0

0 2 4 6 8 10

kg


ChlorpropamideConventional Insulin Glibenclamide

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0

10

20

30

40

50

0 3 6 9 12 15

Pro

port

ion o

f pati

ents

(%

)


0

2

4

6

8

10

0 3 6 9 12 15


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Blood PressureBlood Pressure

70

75

80

85

135

140

145

150

0 2 4 6 8 10

mm

Hg


ChlorpropamideConventional Insulin Glibenclamide

cohort, mean data

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Any diabetes-related endpointsAny diabetes-related endpoints

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (896)

Chlorpropamide (619)

Glibenclamide (615)

Insulin (911)

C v G v Ip = 0.36

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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

nt


Conventional (896)

Chlorpropamide (619)

Glibenclamide (615)

Insulin (911)

Myocardial InfarctionMyocardial Infarction

C v G v Ip = 0.66

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

RR p

0-3 yearsChlorpropamideGlibenclamideInsulin

p=0.991.021.041.01

0.920.810.92


p=0.580.920.940.84

0.470.590.096


p=0.650.910.830.83

0.330.0680.048


p=0.00591.000.680.72

0.990.00440.0041

favours intensive

favours conventional

0.2 1 5

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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

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Sulphonylurea or insulin : Summary 2Sulphonylurea 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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Does metformin in Does metformin in overweight diabetic patients overweight diabetic patients

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


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IntroductionIntroduction

• 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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Main Randomisation4209

Overweight1704

Non overweight2505

Conventional Policy411

Intensive Policy1293

Metformin342

Insulin or Sulphonylurea951

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overweight patients > 120% ideal body weightafter 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 %

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HbAHbA1c1c

cohort, median values

06

7

8

9

0 2 4 6 8 10

HbA

1c (

%)


ChlorpropamideConventional GlibenclamideInsulin Metformin

overweight patients

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Change in WeightChange in Weight

cohort, mean values

-5

0

5

10

0 2 4 6 8 10

wei

ght

chan

ge (

kg)


ChlorpropamideConventional GlibenclamideInsulin Metformin

overweight patients

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0

10

20

30

40

50

0 2 4 6 8 10

Pro

port

ion o

f pati

ents

(%

)



0

2

4

6

8

0 2 4 6 8 10

overweight patients

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0.0

0.2

0.4

0.6

0 3 6 9 12 15

Pro

port

ion

of p

atie

nts

with

eve

nts


Conventional (411)

Intensive (951)

Metformin (342)

Any diabetes related endpointAny diabetes related endpoint

M v Ip=0.0034

overweight patients

M v C p=0.0023

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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

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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

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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

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Metformin ComparisonsMetformin Comparisons

favours metformin


overweight patientsRR p

Any diabetes related endpointMetformin 0.68 0.0023

Diabetes related deathsMetformin 0.58 0.017

All cause mortalityMetformin 0.64 0.011

Myocardial infarctionMetformin 0.61 0.01

RR (95% CI)

0.2 1 5

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Metformin ComparisonsMetformin Comparisons

favours metformin or

intensive


overweight patientsM v Int RR p

Any diabetes related endpointMetforminIntensive

p=0.00340.680.93

0.00230.46

Diabetes related deathsMetforminIntensive

p=0.110.580.80

0.0170.19

All cause mortalityMetforminIntensive

p=0.0210.640.92

0.0110.49

Myocardial infarctionMetforminIntensive

p=0.120.610.79

0.010.11

RR (95% CI)

0.2 1 5

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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

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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

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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

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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

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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

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Blood Pressure Blood Pressure Control StudyControl Study


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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

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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

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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%

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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

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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



Less tight control Tight control

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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

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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

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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

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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)


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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)


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StrokeStroke

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





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Microvascular endpointsMicrovascular endpoints

0%

5%

10%

15%

20%

25%

0 3 6 9

% p

atie

nts

with

eve

nt





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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

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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

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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

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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

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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

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

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


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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



Less tight control ACE inhibitor Beta blocker

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Reasons for non-complianceReasons for non-complianceCaptopril(n=400)

Atenolol(n=358) p

non-compliant 88 (22%) 125 (35%) <0.0001

cough 16 (4%) 0 <0.0001

increased creatinine 5 (1%) 0 0.064

claudication,cold fingers or toes

0 15 (4%) <0.0001

bronchospasm 0 22 (6%) <0.0001

impotence 1 (0%) 6 (2%) 0.057

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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

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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)



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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



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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

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Surrogate endpointsSurrogate endpoints

RR p

Retinopathy 2 step progressionmedian 1.5 years 0.99 0.75median 4.5 years 0.99 0.82median 7.5 years 0.91 0.28

Urine albumin > 50 mg/L3 years 1.11 0.556 years 0.93 0.659 years 1.20 0.31

Urine albumin >300 mg/L3 years 1.41 0.446 years 0.75 0.439 years 0.48 0.090

Relative Risk & 99% CI

favours ACE inhibitor

favours Beta blocker

0.1 1 10

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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

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Potential implications Potential implications for clinical care of for clinical care of diabetic patientsdiabetic patients


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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

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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

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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

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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

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PolypharmacyPolypharmacy

• 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 TherapiesDifferences 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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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 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

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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 UK Prospective Diabetes Study multi-centre randomised...

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