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UK Prospective Diabetes Study. multi-centrerandomised controlled trialof different therapiesof Type 2 diabetes. complications of Type 2 diabetes develop over decadesProtocol written 1976Recruitment 1977-1991End of study Sept. 1997Clinical Centres23Type 2 diabetic patients5102P
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1. The UKProspectiveDiabetesStudy
2. UK Prospective Diabetes Study
multi-centre
randomised controlled trial
of different therapies
of Type 2 diabetes
3. 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 Ł23 million UKPDS : need for a long-term study
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 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
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 : Guy’s 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
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
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 < 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 < 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
19. Change in Body Weight
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
25. Diabetes Related Deaths (cumulative)
33. Does insulin or sulphonylurea therapy have specific advantages or disadvantages?
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
37. HbA1c
38. change in weight
39. Hypoglycaemic episodes per annum
40. Blood Pressure
41. Any diabetes-related endpoints
42. Myocardial Infarction
43. Progression of Retinopathy : 2 step change
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?
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 (>120% Ideal Body Weight) UKPDS patients could be randomised to an intensive glucose control policy with metformin instead of diet, sulphonylurea or insulin
49. Patient Characteristics 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 %
50. HbA1c
51. Change in Weight
52. Hypoglycaemic episodes per annum
53. Any diabetes related endpoint
54. Diabetes related deaths
55. Myocardial Infarction
56. Microvascular endpoints
57. Metformin Comparisons
58. Metformin Comparisons
61. Aggregate Endpoints
62. Metformin 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 mortality p=0.01139% risk reduction in myocardial infarction p=0.01
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
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
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 > 50 mg/l 18%
68. Randomisation
69. Blood Pressure : Tight vs Less Tight Control
70. Mean Blood Pressure
71. Therapy requirement
72. Any diabetes-related endpoints
73. Diabetes-related deaths
74. Myocardial Infarction
75. Stroke
76. Microvascular endpoints
77. Heart Failure
81. 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 Study
83. Blood Pressure : ACE inhibitor vs Beta blocker
84. Reasons for non-compliance
86. Diabetes Related Deaths (cumulative)
89. Surrogate endpoints
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
92. UK Prospective Diabetes Study 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
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
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
100. UK Prospective Diabetes Study