UKPDS overview

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UKPDS overview

  1. 1. The UK Prospective Diabetes Study ukpds
  2. 2. • 20-year multicenter RCT -Interventional Trial from 1977 to 1997 • Intensive diabetes control and reduction in complications  5,102 patients with newly-diagnosed type 2 diabetes recruited between 1977 and 1991  FPG between 6.1 to 15 mmol  Randomized to conventional therapy vs. intensive therapy  Median follow-up 10.0 years, range 6 to 20 years ukpds
  3. 3. Glucose Interventional Trial Dietary Run-in Randomisation 1977-1991 Trial end 1997 744 Diet failure 2,729 Intensive Intensive FPG >15 mmol/l with sulfonylurea(glibenclamide or chlorpropramide)/insulin P 5,102 Newly-diagnosed type 2 diabetes 4209 1,138 (411 overweight) Conventional Conventional with diet P 149 Diet satisfactory 342 (all overweight) Intensive FPG <6 mmol/l with metformin Mean age 54 years (IQR 48–60) Intensive ukpds
  4. 4. • Aim • Conventional group- best achievable FPG • Intensive group FPG <6mmol ukpds
  5. 5. Any Diabetes Related Endpoint 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 ukpds
  6. 6. Diabetes Related Deaths Any of: • fatal myocardial infarction or sudden death • fatal stroke • death from peripheral vascular disease • death from renal disease • death from hyper/hypoglycaemia ukpds
  7. 7. HbA1c (7 vs 7.9%) cross-sectional, median values 9 HbA1c (%) Conventional 8 Intensive 7 6.2% upper limit of normal range 6 0 0 3 6 9 12 Years from randomisation 15 ukpds
  8. 8. Aggregate Clinical Endpoints RR p 0.5 Relative Risk & 95% CI 1 2 Any diabetes related endpoint 0.88 0.029 Diabetes related deaths 0.90 0.34 All cause mortality 0.94 0.44 Myocardial infarction 0.84 0.052 Stroke 1.11 0.52 Microvascular 0.75 0.0099 Favours Favours intensive conventional ukpds
  9. 9. Microvascular Endpoints (cumulative) % of patients with an event 30% renal failure or death, vitreous haemorrhage or photocoagulation 346 of 3867 patients (9%) Conventional Intensive p=0.0099 20% 10% Risk reduction 25% (95% CI: 7% to 40%) 0% 0 3 6 9 12 Years from randomisation 15 ukpds
  10. 10. Microalbuminuria Urine albumin >50 mg/L RR p Baseline 0.89 0.83 0.043 Six years Nine years Twelve years 0.88 0.76 0.67 0.13 0.00062 0.000054 Fifteen years 0.70 0.033 2 0.24 Three years 0.5 Relative Risk & 99% CI 1 < Favours Favours intensive conventional ukpds
  11. 11. Progression of Retinopathy Two step change in Early Treatment Diabetic Retinopathy Study (ETDRS) scale RR p 0 - 3 years 0.83 0.017 0 - 9 years 0 - 12 years 2 1.03 0.78 0 - 6 years 0.5 Relative Risk & 99% CI 1 0.83 0.012 0.79 0.015 Favours Favours intensive conventional ukpds
  12. 12. 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% 25% for any diabetes related endpoint for microvascular endpoints p=0.029 p=0.0099 16% 24% for myocardial infarction for cataract extraction p=0.052 p=0.046 21% 33% for retinopathy at twelve years for albuminuria at twelve years p=0.015 p=0.000054 ukpds
  13. 13. • Major hypoglycemic episode • • Conventional 0.7% Intensive Chlorpropramide 1%, glibenclamide 1.4%, insulin 1.8% • Wt Gain • insulin 4 kg, glibenclamide 1.7kg chlorpropramide 2.6 kg ukpds
  14. 14. Sulphonylurea or insulin 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 ukpds
  15. 15. UKPDS Summary • There is a direct relationship between the risk of complications of diabetes and glycaemia over time • The lower the glycaemia the lower the risk for complications • The rate of increase of risk for microvascular disease with hyperglycaemia is greater than that for macro vascular disease ukpds
  16. 16. Conclusion The UKPDS has shown that intensive blood glucose control reduces the risk of diabetic complications, the greatest effect being on microvascular complications ukpds
  17. 17. Sulphonylurea or Insulin : Summary 1 • all three therapies were similarly effective in reducing HbA1c • all three therapies had equivalent risk reduction for 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 ukpds
  18. 18. UK Prospective Diabetes Study Does metformin in overweight diabetic patients have any advantages or disadvantages? ukpds
  19. 19. overweight patients Proportion of patients with events Diabetes related deaths 0.4 Conventional (411) Intensive (951) Metformin (342) 0.3 0.2 Mv C p=0.017 0.1 MvI p=0.11 0.0 0 3 6 9 12 Years from randomisation 15 ukpds
  20. 20. overweight patients Proportion of patients with events Myocardial Infarction 0.4 Conventional (411) Intensive (951) Metformin (342) 0.3 MvC p=0.010 0.2 0.1 MvI p=0.12 0.0 0 3 6 9 12 Years from randomisation 15 ukpds
  21. 21. overweight patients Proportion of patients with events Microvascular endpoints 0.3 Conventional (411) Intensive (951) Metformin (342) 0.2 M v C p=0.19 0.1 MvI p=0.39 0.0 0 3 6 9 12 Years from randomisation 15 ukpds
  22. 22. Metformin Comparisons overweight patients Any d b e ts re l a d e n d i n t ia e te po M e tor m f in RR p 0.2 RR (95% CI) 1 0.6 0.0 3 8 02 Diab e t s re l a d d e ahs e te t M e tor m f in 0.5 8 0.0 17 All ca use m o a ty rt li M e tor m f in 0.6 4 0.0 11 Myo c a l in f a to n rdia rc i M e tor m f in 0.6 1 0.0 1 favours metformin favours conventional ukpds 5
  23. 23. Metformin Comparisons overweight patients M v Int RR p 0.2 RR (95% CI) 1 Any d b e ts re l a d e n d i n tp=0 . 0 0 3 4 ia e te po M e tor m f in 0.6 0.0 3 8 02 I n t nsiv e e 0.9 3 0.4 6 Diab e t s re l a d d e ahs e te t p=0 . 1 1 M e tor m f in 0.5 0.0 8 17 I n t nsiv e e 0.8 0 0.1 9 All ca use m o a ty rt li p=0 . 0 2 1 M e tor m f in 0.6 0.0 4 11 I n t nsiv e e 0.9 2 0.4 9 Myo c a l in f a to n rdia rc i p=0 . 1 2 M e tor m f in 0.6 1 0.0 1 I n t nsiv e e 0.7 9 0.1 1 favours metformin or intensive favours conventional ukpds 5
  24. 24. Sulphonylurea 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 ukpds
  25. 25. 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 ukpds
  26. 26. Aggregate Endpoints Median follow up 6.6 years RR p Relative Risk & 95% CI 0.1 1 10 Any diabetes related endpoint 1.04 0.78 Diabetes related deaths * All cause mortality 1.96 0.039 Myocardial infarction 1.09 0.73 Stroke 1.21 0.61 Microvascular 0.84 0.62 1.60 0.041 Favours Favours added sulphonylurea metformin alone * interpret with caution in view of small numbers : 26 deaths on sulphonylurea plus metformin versus 14 deaths on sulphonylurea alone ukpds
  27. 27. Metformin in Overweight Patients • compared with conventional policy 32% risk reduction in any diabetes-related endpoints 42% risk reduction in diabetes-related deaths 36% risk reduction in all cause mortality 39% risk reduction in myocardial infarction p=0.0023 p=0.017 p=0.011 p=0.01 ukpds
  28. 28. 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 ukpds
  29. 29. UK Prospective Diabetes Study Blood Pressure Control Study ukpds
  30. 30. 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 ukpds
  31. 31. Inclusion 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 ukpds
  32. 32. Patient Characteristics 1148 Type 2 diabetic patients age gender ethnic groups Body Mass Index HbA1c 56 years 55% / 45% 87% 6% 7% 29 kg/m2 6.8 % systolic / diastolic blood pressure urine albumin > 50 mg/l 160 / 94 mmHg 18% male / female Caucasian Asian Afro-caribbean ukpds
  33. 33. Randomisation 1148 hypertensive patients on antihypertensive therapy n = 421 not on antihypertensive therapy n = 727 randomisation less tight blood pressure control aim : BP < 180/105 mmHg avoid ACE inhibitor : Beta blocker n = 390 34% tight blood pressure control aim : BP < 150 / 85 mmHg ACE inhibitor n = 400 35% Beta blocker n = 358 31% ukpds
  34. 34. Blood Pressure : Tight vs Less Tight Control cohort, median values 180 Less tight control Tight control mmHg 160 140 100 80 60 0 2 4 6 Years from randomisation 8 ukpds
  35. 35. 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. <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 ukpds
  36. 36. Therapy requirement number of antihypertensive agents None one two LessTight Control Policy % of patients 100 > two Tight Control Policy 80 60 40 20 0 1 2 3 4 5 6 7 8 1 2 3 4 5 6 7 8 Years from randomisation ukpds
  37. 37. Any diabetes-related endpoints % of patients with events 50% Less tight blood pressure control (390) Tight blood pressure control (758) 40% 30% 20% 10% risk reduction 24% p=0.0046 0% 0 3 6 Years from randomisation 9 ukpds
  38. 38. Diabetes-related deaths 20% Less tight blood pressure control (390) % of patients with events Tight blood pressure control (758) 15% 10% 5% risk reduction 32% p=0.019 0% 0 3 6 Years from randomisation 9 ukpds
  39. 39. Myocardial Infarction 25% Less Tight Blood Pressure Control (390) % of patients with event Tight Blood Pressure Control (758) 20% 15% 10% 5% risk reduction 21% p=0.13 0% 0 3 6 Years from randomisation 9 ukpds
  40. 40. Stroke 25% Less Tight Blood Pressure Control (390) % patients with event Tight Blood Pressure Control (758) 20% 15% 10% 5% risk reduction 44% p=0.013 0% 0 3 6 Years from randomisation 9 ukpds
  41. 41. Microvascular endpoints % patients with event 25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758) 20% 15% 10% 5% risk reduction 37% p=0.0092 0% 0 3 6 Years from randomisation 9 ukpds
  42. 42. Heart Failure % patients with event 25% Less Tight Blood Pressure Control (390) Tight Blood Pressure Control (758) 20% 15% risk reduction 56% p=0.0043 10% 5% 0% 0 3 6 Years from randomisation 9 ukpds
  43. 43. Progression of Retinopathy : 2 step change 60 p=0.38 37 % patients 23 0 p=0.004 51 40 20 p=0.019 34 28 20 243 461 207 411 152 300 3 years 6 years 9 years Years from randomisation numbers above bars are % affected ukpds
  44. 44. Deterioration of Vision : 3 lines on ETDRS chart % patients 30 p=0.40 p=0.47 19 20 10 0 p=0.004 7 9 5 293 575 3 years 10 8 257 523 6 years 180 332 9 years Years from randomisation numbers above bars are % affected ukpds
  45. 45. Urine Albumin >50 mg/L 40 p=0.052 p=0.008 p=0.33 % patients 33 29 29 30 24 20 18 20 10 0 317 618 3 years 274 543 6 years 166 299 9 years Years from randomisation numbers above bars are % affected ukpds
  46. 46. 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 diabetes-related deaths stroke microvascular disease 24% 32% 44% 37% p=0.0046 p=0.019 p=0.013 p=0.0092 heart failure retinopathy progression deterioration of vision 56% 34% 47% p=0.0043 p=0.0038 ukpds p=0.0036
  47. 47. UK Prospective Diabetes Study Do ACE inhibitors or Beta Blockers have any specific advantages or disadvantages? ukpds
  48. 48. Blood Pressure : ACE inhibitor vs Beta blocker cohort, median values 180 Less tight control ACE inhibitor Beta blocker mm Hg 160 140 100 80 60 0 2 4 6 Years from randomisation 8 ukpds
  49. 49. Reasons for non-compliance Captopri l (n=400 ) Atenolo l (n=358 ) p non- compl iant 88 ( 2%) 2 125 (35%) <0.0001 cough 16 ( %) 4 0 <0.0001 inc rea sed creatini ne 5 (1%) 0 0.064 c laudi cation, col d finger s or toes 0 15 4%) ( <0.0001 bron cho spas m 0 22 6%) ( <0.0001 1 (0%) 6 (2%) 0.057 impotenc e ukpds
  50. 50. Any Diabetes Related Endpoint (cumulative) 429 of 1148 patients (37%) % of patients with an event 50% Less tight BP control (n=390) Beta blocker (n=358) ACE inhibitor (n=400) Less tight vs Tight p=0.0046 40% 30% 20% 10% 0% 0 ACE vs Beta blocker p=0.43 3 6 9 Years from randomisation ukpds
  51. 51. Diabetes Related Deaths (cumulative) 144 of 1148 patients (13%) % of patients with an event 20% Less tight BP control (n=390) Beta blocker (n=358) ACE inhibitor (n=400) Less tight vs Tight p=0.019 15% 10% 5% 0% 0 ACE vs Beta blocker p=0.28 3 6 9 Years from randomisation ukpds
  52. 52. Microvascular Endpoints (cumulative) renal failure or death, vitreous haemorrhage or photocoagulation 122 of 1148 patients (11%) % of patients with an event 20% Less tight BP control Beta blocker ACE inhibitor Less tight vs Tight p=0.0092 15% 10% 5% 0% 0 ACE vs Beta blocker p=0.30 3 6 9 Years from randomisation ukpds
  53. 53. Aggregate Clinical Endpoints RR p 0.5 Relative Risk & 95% CI 1 2 Any diabetes related endpoint 1.10 0.43 Diabetes related deaths 1.27 0.28 All cause mortality 1.14 0.44 Myocardial infarction 1.20 0.35 Stroke 1.12 0.74 > Microvascular 1.29 0.30 > Favours Favours ACE inhibitor Beta blocker ukpds
  54. 54. Surrogate endpoints RR Reti nopathy 2 step progress ion median 1.5 y ears median 4.5 y ears median 7.5 y ears Ur ine albumi n > 50 mg/L 3 year s 6 year s 9 year s Ur ine albumi n > 300 mg/L 3 year s 6 year s 9 year s p 0.99 0.99 0.91 0.75 0.82 0.28 1.11 0.93 1.20 0.55 0.65 0.31 1.41 0.75 0.48 Relative Risk & 99% CI 0.44 0.43 0.090 0.1 1 10 favours ACE favours Beta inhibitor blocker ukpds
  55. 55. 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 ukpds
  56. 56. UK Prospective Diabetes Study Potential implications for clinical care of diabetic patients ukpds
  57. 57. UK Prospective Diabetes Study An intensive glucose control policy HbA1c 7.0 % vs 7.9 % reduces risk of any diabetes-related endpoints microvascular endpoints myocardial infarction 12% 25% 16% p=0.030 p=0.010 p=0.052 A tight blood pressure control policy 144 / 82 vs 154 / 87 mmHg reduces risk of any diabetes-related endpoint microvascular endpoint stroke 24% 37% 44% p=0.005 p=0.009 p=0.013 ukpds
  58. 58. 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 ukpds
  59. 59. 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 guidelines but is difficult to accomplish in some patients • epidemiological analysis suggests that any reduction of hyperglycaemia would be advantageous ukpds
  60. 60. Which goals of therapy? • current guidelines suggest blood pressure <140 / 85 mmHg or <130 / 85 mmHg • the risk of diabetic complications was reduced in the UKPDS blood pressure control trial which 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 ukpds
  61. 61. 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 ukpds
  62. 62. 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 ukpds

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