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. 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 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