Edwin gale.cost effective diabetes treatment

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Edwin gale.cost effective diabetes treatment

  1. 1. Effective and Cost-Effective Treatment for Diabetes Edwin Gale Edwin Gale University of Bristol, UK
  2. 2. I have no financial conflicts of interest
  3. 3. Effective and Cost-Effective Treatment The scope of the problem What are we trying to achieve? Choosing the right treatment
  4. 4. Most of the medicaltextbooks are based uponexperience gainedin Western populations.The culture, phenotype andgenotype of diabetes differsbetween major populationgroupsEgyptian people shouldrewrite the textbooks foruse in Egypt!
  5. 5. A Century of Economic GrowthHigh employment, increasing disposable income, cheap food and energy (and everything that goes with these things) are changing the phenotype of the human species The changing phenotype of the human species (affluent variety) Diabetologia 2004;47:1339-1342
  6. 6. Health Correlates of Economic Growth: A Changing Human Phenotype Increasing height: 1 cm/decade Changing body proportions Increasing weight-to-height ratio Increasing longevity: 3-4 months for every calendar year
  7. 7. Estimated Numbers with Diabetes (in millions) in 2000 and 2030Western Countries Growing economies
  8. 8. Diabetes Prevalence as % Population in Denmark Courtesy of Bendix Carstensen
  9. 9. Diabetes Prevalence as % Population in Denmark Courtesy of Bendix Carstensen
  10. 10. The Affluent Phenotype BP LipidsAtheroma Glucose Cancer
  11. 11. Excess calorie intake is a major driver of the affluent phenotype … … and reduced calorie intake reverses most Edwin Gale of its features
  12. 12. Incidence of diabetes in Oslo, 1925-54 Westlund 1966
  13. 13. Diabetes Mortality in the UK, 1938-58 World War IIDeaths/100k Trowell, 1962
  14. 14. Calorie restriction is the only form of therapy that strikes at the root cause of diabetes Pharmacotherapy largely represents the attempt to compensate for a failure of Edwin Gale calorie restriction
  15. 15. Summary: The Human PhenotypeAffluent humans are developing a new and distinctive phenotypeDiseases of relative overnutrition have emerged as the leading causes of deathIncreasing longevity is a major factor in the diabetes epidemic
  16. 16. Effective and Cost-Effective Treatment The scope of the problem What are we trying to achieve? Choosing the right treatment
  17. 17. What are we trying to achieve? 1. Near-normal glucose control? 2. Near-normal life expectancy? 3. Near-normal life quality?
  18. 18. Near-normal glucose control Offers strong protection against microvascular complications - but the benefit diminishes with increasing age But weak protection against cardiovascular outcomes Has not been shown to improve life expectancy in type 2 diabetes Intensified glucose control can reduce
  19. 19. Lifetime Risk of Blindness by Age at Diagnosis and HbA1cn/1000 Age at diagnosis Ann Int Med 1997;127:788
  20. 20. Lifetime Risk of ESRF by Age at Diagnosis and HbA1cn/1000 Age at diagnosis Ann Int Med 1997;127:788
  21. 21. Microvascular DiseaseRisk diminishes with age and/or limited life expectancy.The full benefits seen in young patients with type 1 diabetes are not achieved in older people with type 2 diabetes
  22. 22. Near-normal glucose control Offers strong protection against microvascular complications But weak protection against cardiovascular outcomes Has not been shown to improve life expectancy in type 2 diabetes Intensified glucose control can reduce quality of life
  23. 23. HRs for CV outcomes, DM vs non-diabetesEmerging Risk Factors Collaboration (EFRC), Lancet 2010;375:2215-22
  24. 24. Emerging Risk Factors Collaboration (EFRC), NEJM 2011;364:829-41
  25. 25. A 50-year-old man with diabetes loses 6 years of life expectancy 60% of the excess mortality is due to vascular deathsEmerging Risk Factors Collaboration (EFRC), NEJM 2011;364:829-41
  26. 26. Numbers Needed to Treat [To prevent 1 CVD event]Glucose (HbA1c 0.9%) : 119Cholesterol trials (1mM) 44Blood Pressure trials (10/6mmHg) 34 Yudkin et al, Diabetologia 2010
  27. 27. Near-normal glucose control Offers strong protection against microvascular complications But weak protection against cardiovascular outcomes Has not been shown to improve life expectancy in type 2 diabetes Intensified glucose control can reduce quality of life
  28. 28. Mortality – intensive versus standard Meta-Analysis: 13 studies, 34533 patients All cause mortality OR: 1.04 (0.91 – 1.19)Cardiovascular deathOR: 1.11 (0.96 – 1.43)Boussageon R et al. BMJ 2011
  29. 29. Relationship Between Glycated Haemoglobin and Mortality in 47,970 Patients Oral therapy Insulin UK General Practice Research Database, Currie et al, Lancet 2010
  30. 30. Near-normal glucose control Offers strong protection against microvascular complications But weak protection against cardiovascular outcomes Has not been shown to improve life expectancy in type 2 diabetes Intensified glucose control can reduce quality of life
  31. 31. Patient perceptions of intensive glucose lowering701 pts with T2DM asked re QOL utilities; a score of 1.0 = perfect health, 0 = deathIntensive glucose control scored 0.67, or 1/3 of a year‟s quality of life Huang et al, Diabetes Care (2007) 30:2478
  32. 32. Check Point Intensified glucose lowering therapy ALONE offers limited benefits in type 2 diabetesBUT Combined attention to all cardiovascular risk factors can make a dramatic difference to outcomes
  33. 33. STENO-2Randomized 160 NEJM 2008;358:580 80 80Trial Ends 67 63 Mean 7.8 yr 55 38Study Ends Mean 5.5 yrDied 24 (9 CVD) 40 (19 CVD) Intensified Conventional (1 dropped out) (2 dropped out)
  34. 34. Effective and Cost-Effective Treatment The scope of the problem What are we trying to achieve? Choosing the right treatment
  35. 35. When?Why? Who? How?
  36. 36. When? Why?Life Quality CV RiskOther risksLongevity
  37. 37. When? Does intensified Why? therapy benefit?Life Quality CV RiskOther risksLongevity Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  38. 38. When? Does intensified Why? therapy benefit?Life Quality No CV RiskOther risksLongevity Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  39. 39. When? Does intensified Why? therapy benefit?Life Quality No CV Risk MarginalOther risksLongevity Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  40. 40. When? Does intensified Why? therapy benefit?Life Quality No CV Risk MarginalOther risks MinorLongevity Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  41. 41. When? Does intensified Why? therapy benefit?Life Quality No CV Risk MarginalOther risks MinorLongevity No Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  42. 42. When? Does intensified Why? therapy benefit?Life Quality No CV Risk Marginal But early interventionOther risks Minor is beneficial!Longevity No Hemmingsen B et al: Cochrane Database Syst Rev. 2011 Jun 15;6:CD008143 Yudkin et al, Diabetologia 2010;53:2079-85
  43. 43. VADT - HR for Primary Outcome in Intensive Arm 1.4 1.2Hazard Ratio 1 0.8 0.6 0.4 0.2 0 0 3 6 9 12 15 18 21 24 Duration of Diabetes (yrs)
  44. 44. When?Why? How?
  45. 45. Comorbidity and Glucose Control, New onset patients aged 60-64 yrs Comorb. Life Exp Days addedCase 1 0 14.6 yrs +106Case 2 3 9.7 yrs + 44Case 3 7 4.8 yrs + 8 Huang et al, Ann Int Med (2008) 149:11-19
  46. 46. When? Why? Who?Life Quality Life Quality CV Risk CV RiskOther risks Other risksLongevity Longevity
  47. 47. When? Why? Who?Life Quality Life Quality Prognosis, patient choice CV Risk CV RiskOther risks Other risksLongevity Longevity
  48. 48. When? Why? Who?Life Quality Life Quality Prognosis, patient choice CV Risk CV RiskOther risks Other risks Established vascular disease?Longevity Longevity
  49. 49. When?Why? Who? How?
  50. 50. When? Why? Who? How?Life Quality Life Quality Life Quality CV Risk CV Risk CV RiskOther risks Other risks Other risksLongevity Longevity Longevity
  51. 51. When? Why? Who? How? Life QualityDiabetes therapies previouslyconsidered solely in terms of CV RiskHbA1c reduction ... Other risks Longevity
  52. 52. Spot Quiz• Treatment A lowers HbA1c from 10.5% to 9%• Treatment B lowers HbA1c from 7.6% to 7%• Which treatment is more potent?
  53. 53. HbA1c: Baseline vs. change Diabetes Care 2006;29:2137
  54. 54. When? Why? Who? How?Diabetes therapies previously Life Qualityconsidered solely in terms of CV RiskHbA1c reduction ... Other risksBut global profile nowseen as more important Longevity
  55. 55. Check PointMost patients have been exposed to multipletreatmentsRCT evidence does not (with some exceptions)allow us to assess the global impact of specifictherapies upon cardiovascular risk
  56. 56. Glucose-lowering AgentsCore therapies: Biguanides Sulfonylureas Human InsulinNewer therapies: Thiazolidinediones DPP-4 inhibitors GLP-1 agonistsOther: Acarbose Meglitinides SGLT-2 inhibitors
  57. 57. ADA / EASD Guidelines Revised Treatment Algorithm At diagnosis:STEP 1 Lifestyle + metformin Tier 1* Tier 2† HbA1C >7.0%STEP 2 Add basal Add Add GLP-1 Add pioglitazone insulin sulfonylurea agonist ± SUSTEP 3 Intensive insulin Nathan et al. Diabetes Care 2008
  58. 58. Core Therapies LifestyleMetformin Human insulin SUs
  59. 59. Lifestyle …Is the starting point for any treatmentNo treatment for diabetes can work effectivelywithout adjustment of lifestyleDiabetes conferences are 90% aboutpharmacology and 10% about human behaviourReal world therapy is the other way round
  60. 60. Reduces CV disease! ? METFOR MIN Fights cancer!
  61. 61. Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death)Intensive (metformin) vs. Conventional glucose control HR (95%CI) UKPDS 80
  62. 62. Metformin in Patients with Established Atherosclerosis Method:Comparison of 2 year mortality in 19,691patients with diabetes and known vasculardisease, treated with or without metformin,in the REACH registry. Roussel et al, Arch Int Med 2010;170:1892-99
  63. 63. Metformin in Patients with Established Atherosclerosis +Metformin -Metformin% Mortality 6.3 (5.2-7.4) 9.8 (8.4-11.2%)Hazard Ratio 0.76 (0.65-0.89) (adjusted) Roussel et al, Arch Int Med 2010;170:1892-99
  64. 64. Benefits of Metformin (Hazard Ratios)Age 65-80 0.77 (0.62-0.95)Heart failure 0.69 (0.54-0.90)GFR 30-60 0.64 (0.48-0.86)MF + INS 0.64 (0.46-0.89) Roussel et al, Arch Int Med 2010;170:1892-99
  65. 65. Metformin: SummaryMechanism of cardiovascular protection unclear – related to mechanism of cancer protection? Observational studies to date show consistent reductions in overall and cardiovascular mortality
  66. 66. SulfonylureasGloyn et al, New Engl J Med 2004;350:1838-1849
  67. 67. Closure of the K+ channel leads to membrane depolarization
  68. 68. KATP channelsTransducers between intracellular energy metabolismand electrical excitabilityFound in many tissues including heart and brainMostly closed in tissues outside the beta cell; open inresponse to ischaemia, hormones or neurotransmittersIn cardiac muscle and neurones the reduction inelectrical activity protects against damage Frances Ashcroft, J Clin Invest 2005;115;2047-58
  69. 69. Variant forms of the channelKir 6.2 SUR1 beta cellsKir 6.2 SUR2A cardiomyocytesKir 6.2 SUR2B arterial smooth muscle All sulfonylureas show some cross-reactivity
  70. 70. Potential cardiovascular consequences of failure to open KATP channelsThe default setting for cardiovascular KATPchannels is closure. Opening results in -• Limitation of myocardial damage during ischaemia• Loss of preconditioning• Masking of ST segment elevation• Loss of smooth muscle relaxation in coronaryarteries Bell, CMAJ 2006;174:185-6
  71. 71. Myocardial Infarction Hazard Ratio (fatal or non-fatal myocardial infarction or sudden death)Intensive (SU/Ins) vs. Conventional glucose control HR (95%CI) UKPDS 80
  72. 72. Sulfonylureas: Summary No clear evidence that theoretical risk translates into actual risk No clear evidence that prognosis worse after myocardial infarction Best avoided in interventional cardiologyGliclazide probably safer than glibenclamide
  73. 73. Disadvantages of Newer Therapies Benefits overstated Unsupported claims “Newer” may not mean „better” Evidence base not yet established Long term safety unknown Much more expensive!
  74. 74. A Situation of Diminishing Returns Analogs DPP4s SUs TZDs Metformin Insulin 1920 1960 2010
  75. 75. And Escalating Costs 1500 Rosiglitazone Pioglitazone Sitagliptin 1000 Euros/yr Analog + LantusMetformin 500Gliclazide Human Pork UK Formulary, 2006
  76. 76. Costs as % total Costs of glucose- lowering medication in England Currie et al, Diabet Med 2010;27:744-52
  77. 77. Costs as % total Total Costs (£m) Adjusted to 2008 Currie et al, Diabet Med 2010;27:744-52
  78. 78. Costs as % total Total Costs (£m) Adjusted to 2008 Costs (in England) 2000 = £289.9 million 2008 = £590.4 million Currie et al, Diabet Med 2010;27:744-52
  79. 79. Prescriptions by Cost and Volume (2008) Currie et al, Diabet Med 2010;27:744-52
  80. 80. Insulin costs (£) per 1000 units BNF (accessed Oct 2011)
  81. 81. Insulin costs (£) per 1000 units Cumulative excess cost of analogues to the NHS is ~£650 million Currie et al, BMJ in press
  82. 82. Overall Summary Metformin emerges as “best buy” The disadvantages of the sulfonylureas have been over-statedAnalogue insulins have marginal benefits only in type 2 diabetes Newer therapies should be reserved for second line use
  83. 83. Where Next?Future clinical trials will need to evaluate global risks and benefits of individualtherapies (and combinations) rather than focusing on glucose-lowering efficacy
  84. 84. The Physician’s PrayerFrom inability to let well alone,From too much zeal for the new and contempt forwhat is old,From putting knowledge before wisdom,Science before art and cleverness before common sense,From treating patients as casesAnd from making the cure of the disease more grievousthan the endurance of the same, Good Lord deliver us. Sir Robert Hutchison (1871-1960)
  85. 85. Thank youfor listening

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