The UK Prospective Diabetes Study - PowerPoint PPT Presentation

Loading...

PPT – The UK Prospective Diabetes Study PowerPoint presentation | free to download - id: 4098e0-MjJlM



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

The UK Prospective Diabetes Study

Description:

Prospective Diabetes Study UK Prospective Diabetes Study multi-centre randomised controlled trial of different therapies of Type 2 diabetes UKPDS : need for a long ... – PowerPoint PPT presentation

Number of Views:26
Avg rating:3.0/5.0
Slides: 101
Provided by: Caro292
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: The UK Prospective Diabetes Study


1
The UKProspectiveDiabetesStudy
2
UK Prospective Diabetes Study
  • multi-centre
  • randomised controlled trial
  • of different therapies
  • of Type 2 diabetes

3
UKPDS need for a long-term study
  • complications of Type 2 diabetes develop over
    decades
  • Protocol written 1976
  • Recruitment 1977-1991
  • End of study Sept. 1997
  • Clinical Centres 23
  • Type 2 diabetic patients 5102
  • Person years follow-up 53,000
  • Funding 23 million

4
UK Prospective Diabetes Study Centres
  • Aberdeen Lilian Murchison Manchester Andrew
    Boulton
  • Belfast City Randal Hayes Northampton Charles
    Fox
  • Belfast Royal David Hadden Norwich Richard
    Greenwood
  • Birmingham David Wright Oxford Robert Turner
  • Carshalton Steve Hyer Rury Holman
  • Memo Spathis Peterborough Jonathan Roland
  • Derby Ian Peacock Salford Tim Dornan
  • Dundee Ray Newton Scarborough Phil Brown
  • Roland Jung St Georges 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

5
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

6
Acknowledgements
  • patients
  • physicians
  • nurses
  • dietitians
  • retinal photographers
  • Retinopathy Grading Hammersmith Hospital
  • Biochemistry Diabetes Research Laboratories
  • ECG Grading Guys Hospital

7
Major Funding Bodies
  • UK Medical Research Council
  • British Diabetic Association
  • UK Department of Health USA National Institutes
    of Health (NEI, NIDDK)
  • British Heart Foundation Wellcome Trust
  • Novo Nordisk Bayer Lilly
  • Bristol Myers Squibb Lipha Hoechst
  • Farmitalia Carlo Erba

8
Glucose Control Study
UK Prospective Diabetes Study
9
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

10
Patient Characteristics
  • 5102 newly diagnosed Type 2 diabetic patients
  • age 25 - 65 years mean 53 y
  • gender male female 59 41
  • ethnic group Caucasian 82 Asian 10
  • Afro-caribbean 8
  • Body Mass Index mean 28 kg/m2
  • fasting plasma glucose (fpg) median 11.5 mmol/L
  • HbA1c median 9.1
  • hypertensive 39

11
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

12
Randomisation
fpg fasting plasma glucose (mmol/L)
13
UK Prospective Diabetes Study
Does an intensive glucose control policy reduce
the risk of complications of diabetes?
14
Randomisation of Treatment Policies
15
Treatment Policies in 3867 patients
  • Conventional Policy
  • n 1138
  • initially with diet alone
  • aim for near normal weight best fasting
    plasma glucose lt 15 mmol/L asymptomatic
  • when marked hyperglycaemia developsallocate to
    non-intensive pharmacological therapy

16
Treatment Policies in 3867 patients
  • Intensive Policy with sulphonylurea or insulin
  • n 2729
  • aim for fasting plasma glucose lt 6
    mmol/L asymptomatic
  • when marked hyperglycaemia developson
    sulphonylurea add metformin move to insulin
    therapyon insulin, transfer to complex regimens

17
Actual Therapy
18
HbA1c
cross-sectional, median values
19
Change in Body Weight
cross-sectional, mean values
20
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

21
Hypoglycaemic episodes per annum
Actual Therapy analysis
22
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

23
Any Diabetes Related Endpoint (cumulative )
1401 of 3867 patients (36)
24
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

25
Diabetes Related Deaths (cumulative)
414 of 3867 patients (11)
26
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or
photocoagulation 346 of 3867 patients (9)
27
Myocardial Infarction (cumulative)
fatal or non fatal myocardial infarction, sudden
death 573 of 3867 patients (15)
28
Aggregate Clinical Endpoints
29
Progression of Retinopathy
Two step change in Early Treatment Diabetic
Retinopathy Study (ETDRS) scale
30
Microalbuminuria
Urine albumin gt50 mg/L
31
Glucose Control Study Summary
The intensive glucose control policy maintained a
lower HbA1c by mean 0.9 over a median follow
up of 10 years from diagnosis of type 2 diabetes
with reduction in risk of 12 for any diabetes
related endpoint p0.029 25 for microvascular
endpoints p0.0099 16 for myocardial
infarction p0.052 24 for cataract
extraction p0.046 21 for retinopathy at twelve
years p0.015 33 for albuminuria at twelve
years p0.000054
32
Conclusion
The UKPDS has shown that intensive blood glucose
control reduces the risk of diabetic
complications, the greatest effect being on
microvascular complications
33
Does insulin or sulphonylurea therapy have
specific advantages or disadvantages?
UK Prospective Diabetes Study
34
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

35
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

36
Randomisation
comparison between three intensive therapies
compare each with conventional policy
37
HbA1c
cohort, median data
38
change in weight
cohort, mean data
39
Hypoglycaemic episodes per annum
Actual Therapy analysis
40
Blood Pressure
cohort, mean data
41
Any diabetes-related endpoints
C v G v Ip 0.36
42
Myocardial Infarction
C v G v Ip 0.66
43
Progression of Retinopathy 2 step change
favours intensive
favours conventional
44
Sulphonylurea 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

45
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

46
Does metformin in overweight diabetic patients
have any advantages or disadvantages?
UK Prospective Diabetes Study
47
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 (gt120 Ideal Body Weight) UKPDS
    patients could be randomised to an intensive
    glucose control policy with metformin instead of
    diet, sulphonylurea or insulin

48
Randomisation
Main Randomisation4209
Non overweight2505
Overweight1704
Conventional Policy411
Intensive Policy1293
Metformin342
Insulin or Sulphonylurea951
49
Patient Characteristics
  • overweight patients gt 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

50
HbA1c
overweight patients
cohort, median values
51
Change in Weight
overweight patients
cohort, mean values
52
Hypoglycaemic episodes per annum
overweight patients
Actual Therapy analysis
53
Any diabetes related endpoint
overweight patients
M v C p0.0023
M v Ip0.0034
54
Diabetes related deaths
overweight patients
M v C p0.017
M v Ip0.11
55
Myocardial Infarction
overweight patients
M v Cp0.010
M v Ip0.12
56
Microvascular endpoints
overweight patients
M v Cp0.19
M v Ip0.39
57
Metformin Comparisons
overweight patients
RR (95 CI)
favours metformin
favours conventional
58
Metformin Comparisons
overweight patients
RR (95 CI)
favours metformin or intensive
favours conventional
59
Sulphonylurea plus Metformin
  • patients primarily randomised to intensive
    therapy with sulphonylurea were not given
    additional metformin until their fpg was gt15
    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 gt6 mmol/L to earlier addition of metformin

60
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

61
Aggregate Endpoints

interpret with caution in view of small numbers
26 deaths on sulphonylurea plus metformin
versus 14 deaths on sulphonylurea alone
62
Metformin in Overweight Patients
  • compared with conventional policy 32 risk
    reduction in any diabetes-related endpoints
    p0.002342 risk reduction in diabetes-related
    deaths p0.01736 risk reduction in all cause
    mortality p0.01139 risk reduction in
    myocardial infarction p0.01

63
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

64
Blood Pressure Control Study
UK Prospective Diabetes Study
65
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

66
Inclusion criteria
patients NOT on anti-hypertensive
therapy systolic gt160 and/or diastolic gt 90
mmHg patients already ON anti-hypertensive
therapy systolic gt150 and/or diastolic gt 85
mmHg excluded if required strict blood
pressure control severe illness
contraindication to study medication or declined
informed consent
67
Patient 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 gt 50 mg/l 18

68
Randomisation
69
Blood Pressure Tight vs Less Tight Control
cohort, median values
Less tight control Tight control
70
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. lt0.0001 ACE inhibitor 159 / 94 144 /
83 Beta blocker 159 / 93 143 / 81 difference 0 /
0 1 / 1 p n.s. n.s. / p0.02
71
Therapy requirement
72
Any diabetes-related endpoints
73
Diabetes-related deaths
74
Myocardial Infarction
75
Stroke
76
Microvascular endpoints
77
Heart Failure
risk reduction 56 p0.0043
78
Progression of Retinopathy 2 step change
Years from randomisation
numbers above bars are affected
79
Deterioration of Vision 3 lines on ETDRS chart


patients
Years from randomisation
numbers above bars are affected
80
Urine Albumin gt50 mg/L


patients
Years from randomisation
numbers above bars are affected
81
Blood Pressure Control Study
  • in 1148 Type 2 diabetic patients a tight blood
    pressure control policy which achieved blood
    pressure of 144 / 82 mmHg gave reduced risk for
  • any diabetes-related endpoint 24 p0.0046
  • diabetes-related deaths 32 p0.019
  • stroke 44 p0.013
  • microvascular disease 37 p0.0092
  • heart failure 56 p0.0043
  • retinopathy progression 34 p0.0038
  • deterioration of vision 47 p0.0036

82
UK Prospective Diabetes Study
Do ACE inhibitors or Beta Blockers have any
specific advantages or disadvantages?
83
Blood Pressure ACE inhibitor vs Beta blocker
cohort, median values
Less tight control ACE inhibitor Beta blocker
84
Reasons for non-compliance
85
Any Diabetes Related Endpoint (cumulative)
429 of 1148 patients (37)
86
Diabetes Related Deaths (cumulative)
144 of 1148 patients (13)
87
Microvascular Endpoints (cumulative)
renal failure or death, vitreous haemorrhage or
photocoagulation 122 of 1148 patients (11)
88
Aggregate Clinical Endpoints
89
Surrogate endpoints
Relative Risk 99 CI
favours Beta blocker
favours ACE inhibitor
90
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

91
Potential implications for clinical care of
diabetic patients
UK Prospective Diabetes Study
92
UK Prospective Diabetes Study
  • An intensive glucose control policy HbA1c 7.0
    vs 7.9
  • reduces risk of
  • any diabetes-related endpoints 12 p0.030
  • microvascular endpoints 25 p0.010
  • myocardial infarction 16 p0.052
  • A tight blood pressure control policy 144 / 82 vs
    154 / 87 mmHg reduces risk of
  • any diabetes-related endpoint 24 p0.005
  • microvascular endpoint 37 p0.009
  • stroke 44 p0.013

93
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

94
Which goals of therapy?
  • current guidelines suggest HbA1c lt7
  • the risk of diabetic complications was reduced in
    the UKPDS trial which achieved a median HbA1c
    7.0in 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

95
Which goals of therapy?
  • current guidelines suggest blood pressurelt140 /
    85 mmHg or lt130 / 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

96
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

97
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

98
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

99
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
100
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
About PowerShow.com