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The UK Prospective Diabetes Study. UK Prospective Diabetes Study. multi-centre randomised controlled trial of different therapies of Type 2 diabetes. UKPDS : need for a long-term study. complications of Type 2 diabetes develop over decades Protocol written 1976 Recruitment 1977-1991

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The UK Prospective Diabetes Study

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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. 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 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. UK Prospective Diabetes Study 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 HbA1cmedian 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. 14% 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. Main Randomisationn=4209 (82%) 342 allocated to metformin 3867 Conventional Policy30% (n=1138) Intensive Policy70% (n=2729) Insulinn=1156 Sulphonylurean=1573 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 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 >50 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 p=0.029 • 25% for microvascular endpoints p=0.0099 • 16% for myocardial infarction p=0.052 • 24% for cataract extraction p=0.046 • 21% for retinopathy at twelve years p=0.015 • 33% for albuminuria at twelve years p=0.000054

    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. UK Prospective Diabetes Study 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 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. UK Prospective Diabetes Study 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

    48. Randomisation Main Randomisation4209 Non overweight2505 Overweight1704 Conventional Policy411 Intensive Policy1293 Insulin or Sulphonylurea951 Metformin342

    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 HbA1cmean 7.2 %

    50. HbA1c overweight patients cohort, median values