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Advances in Diabetes

Advances in Diabetes. Martin Kenneth Rutter MD FRCP Senior Lecturer and Honorary Consultant Physician Manchester Royal Infirmary 29 March 2011. Overview. T2DM (CVD focus) Aspirin Blood pressure, lipids, glucose Revascularisation GLP-1 agents and DPP4 inhibitors Global approach

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Advances in Diabetes

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  1. Advances in Diabetes Martin Kenneth Rutter MD FRCP Senior Lecturer and Honorary Consultant Physician Manchester Royal Infirmary 29 March 2011

  2. Overview • T2DM (CVD focus) • Aspirin • Blood pressure, lipids, glucose • Revascularisation • GLP-1 agents and DPP4 inhibitors • Global approach • Final thoughts …

  3. Complications of Type 2 Diabetes Affect Every Part of the Body Microvascular Complications Macrovascular Complications Diabetic Retinopathy Leading cause of blindness in working-age adults Stroke 2- to 4-fold increase in cardiovascular mortality and stroke Diabetic NephropathyLeading cause of end-stage renal disease Heart Disease Diabetic NeuropathyLeading cause of nontraumatic lower extremity amputations Peripheral Vascular Disease Harris MI. Clin Invest Med. 1995;18:231-239. Nelson RG, et al. Adv Nephrol Necker Hosp. 1995;24:145-156. World Health Organization. Diabetes Mellitus Fact Sheet138. 2002. ADA. National diabetes fact sheet. Available at: http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp.

  4. P < 0.001 P < 0.001 Type 2 Diabetes and CHD Seven Year Incidence of Fatal/Nonfatal MI No-Diabetes Diabetes 45.0% 7-Year Incidence of MI 20.2% 18.8% 3.5% n = 69 n = 890 n = 169 n = 1304 DM - diabetesMI - myocardial infarction NEJM 339: 229-234, 1998

  5. Survival After 1st MI and Diabetes n = 3445 n = 620 87%1 YearSurvivalPostHospital 74%1 YearSurvivalPostHospital 28 Day - 1 YearMortality 28 DayMortality Out of HospitalSCD 9% 17% 4% 9% 24%n = 145 Out of hospital 19%n = 685 Out of hospital Miettinen H. et al, Diabetes Care 1998; 21: 69-75

  6. JBS 2: Heart. 2005;91:suppl V

  7. Keeping it simpleA, B, C … of Prevention in Diabetes – what is NEW?

  8. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  9. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  10. Aspirin– what’s NEW?

  11. six studies involving 10 117 participants De Berardis G, BMJ 2009;339:b4531

  12. Aspirin meta-analysis • When aspirin was compared with placebo there was no statistically significant reduction in • major CVD • RRR 0.90, 95% CI: 0.81 to 1.00 • CVD mortality • RRR 0.94, 95% CI: 0.72 to 1.23 • All cause mortality • RRR 0.93, 95% CI: 0.82 to 1.05 De Berardis G, BMJ 2009;339:b4531

  13. Aspirin meta-analysis • When aspirin was compared with placebo there was no statistically significant reduction in • major CVD • RRR 0.90, 95% CI: 0.81 to 1.00 • CVD mortality • RRR 0.94, 95% CI: 0.72 to 1.23 • All cause mortality • RRR 0.93, 95% CI: 0.82 to 1.05 De Berardis G, BMJ 2009;339:b4531

  14. Aspirin meta-analysis • When aspirin was compared with placebo there was no statistically significant reduction in • major CVD • RRR 0.90, 95% CI: 0.81 to 1.00 • CVD mortality • RRR 0.94, 95% CI: 0.72 to 1.23 • All cause mortality • RRR 0.93, 95% CI: 0.82 to 1.05 Underpowered to rule out clinically important effect De Berardis G, BMJ 2009;339:b4531

  15. Take home message for aspirin primary prevention of CVD in T2DM • Risk of bleeding vs CVD risk reduction is uncertain • Await results of clinical trials • Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) • ASCEND Collaborative Group

  16. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  17. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  18. UKPDS: Risk Reduction withTight Blood Pressure Control P=0.0046 D P=0.019 P=0.013 P=0.0092 P=0.0038 P=0.0036 P=0.0043 * Compared with less tight control. Captopril and atenolol were equally effective in reducing risk and were equally safe in diabetes UKPDS Group. BMJ. 1998;317:703-713

  19. Blood pressure– what’s NEW?

  20. ACCORD BP trial Achieved sBP 135 mm Hg Achieved sBP 120 mm Hg Cushman et al. NEJM. 2010 March

  21. ACCORD BP trial Negative overall Cushman et al. NEJM. 2010 March

  22. ACCORD BP trial Negative overall Stroke benefit Cushman et al. NEJM. 2010 March

  23. ACCORD BP trial Negative overall Stroke benefit NNT, 5 years, one stoke: 89 Should we target elderly, African Americans, prior CVD? Probably more trials are needed Cushman et al. NEJM. 2010 March

  24. Take home message for BP in T2DM • ‘…. probably reasonable to forget all about the 130-mm-Hg BP goal in diabetes, with the evidence suggesting that 140 mm Hg is an appropriate target…’ Dr William C Cushman, March 2010, lead author for ACCORD BP

  25. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  26. A, B, C … • Advice • Education, self management, concordance with treatment • Smoking, diet, physical activity, and weight • Aspirin, ACEI • BP < 130/80 mm Hg • Cholesterol • Total cholesterol <4.0 mmol/l or 25% reduction • LDL cholesterol <2.0 mmol/l or a 30% reduction in LDL

  27. CARDS • The only CVD primary prevention statin trial in diabetes • 2838 people with T2DM and one risk factor • retinopathy, albuminuria, current smoking, or hypertension • Randomised to atorvastatin 10 mg od or placebo • Acute coronary events reduced by 36% • Stroke reduced by 48% • Acute coronary events, coronary revascularisation, or stroke was reduced by 37% Colhoun HM, Lancet 2004; 364: 685–96

  28. Lipids– what’s NEW?

  29. N=5518 T2DM • RCT: simvastatin + fenofibrate or placebo • Outcome: nonfatal MI or stroke or CVD death • Follow-up: 4.7 years Ginsberg HN, N Engl J Med 2010: 29;362: 1563-74

  30. Primary outcome • 2.2% in the fenofibrate group • 2.4% in the placebo group • HR (95% CI) 0.92 (0.79 to 1.08); P = 0.32) Ginsberg HN, N Engl J Med 2010: 29;362: 1563-74

  31. benefit for men and possible harm for women • possible benefit for patients with both a high baseline triglyceride level and a low baseline level of high-density lipoprotein cholesterol Ginsberg HN, N Engl J Med 2010: 29;362: 1563-74

  32. Take home message for lipids in T2DM • No role for the routine combination use of fenofibrate and simvastatin to reduce cardiovascular risk in T2DM

  33. A, B, C… D, E, F and G

  34. … D, E, F and G • Diabetes control • A normal HbA1c, metformin if overweight, insulin if targets not reached, DIGAMI protocol • Eye care • Yearly digital photography • Feet care • Yearly examination • ‘Guardian’ drugs for CVD prevention • Aspirin 75 mg daily • Statin is appropriate in most people with diabetes in • ACE inhibitor/ARB therapy is indicated when there is microalbuminuria or proteinuria or diabetic nephropathy

  35. … D, E, F and G • Diabetes control • A normal HbA1c, metformin if overweight, insulin if targets not reached, DIGAMI protocol • Eye care • Yearly digital photography • Feet care • Yearly examination • ‘Guardian’ drugs for CVD prevention • Aspirin 75 mg daily • Statin is appropriate in most people with diabetes in • ACE inhibitor/ARB therapy is indicated when there is microalbuminuria or proteinuria or diabetic nephropathy

  36. Glucose and CVD– what is known

  37. 11,092 black or white adults no DM or CVD in ARIC followed for 15 years Selvin E, N Engl J Med 2010;362:800-11

  38. Myocardial Infarction fatal or non fatal myocardial infarction, sudden death 573 of 3867 patients (15%) UKPDS. Lancet. 1998;352:837-853

  39. Myocardial Infarction overweight patients M v Cp=0.01 M v Ip=0.12 UKPDS. Lancet. 1998;352:837-853

  40. UKPDS 10-Year data: Intensive Glucose Control and MI in T2DM SU or insulin, p=0.01 Metformin, p=0.005 Holman RR et al. N Engl J Med 2008;359:1577-89

  41. ADVANCE and ACCORD • ADVANCE - no significant effects of the type of glucose control on CVD • HR (95% CI): 0.94 (0.84 to 1.06) • ACCORD - stopped because of a higher number of deaths in patients allocated to intensive glucose lowering • HR (95% CI): 1.22 (1.01 to 1.46) Patel et al. N Engl J Med 2008;358:2560-72 Gerstein et al. N Engl J Med 2008;358:2545-59

  42. ACCORD deaths Mortality, % 20 Intensive: HbA1c target <6% 15 10 5 Standard: HbA1c 7-8% 0 2 4 0 6 Follow-up, years Gerstein et al. N Engl J Med 2008;358:2545-59

  43. ACCORD Intense – HbA1c target <6% Standard – 7-8% Gerstein et al. N Engl J Med 2008;358:2545-59

  44. ACCORD deaths – why? • Hypos • Too low, too quick? • Glucose range • Off-target effects, eg. weight gain • Drug combos, or rosiglitazone! • Chance finding Holman RR et al. N Engl J Med 2008;359:1577-89 Gerstein et al. N Engl J Med 2008;358:2545-59

  45. Higher HbA1c target OK (ADA) • a history of severe hypoglycaemia • limited life expectancy • advanced microvascular or macrovascular complications • extensive co-morbid conditions • longstanding diabetes

  46. Glucose lowering drugs - what’s NEW?

  47. Recent advances Incretin effect Incretin Exenatide ‘Gliptins’ DPPP-4 inhibitors GLP-1 GIP

  48. What are Incretins? “Gut-derived factors that increase glucose-stimulated insulin secretion” In●cre●tin IntestineSecretion Insulin Creutzfeldt. Diabetologia. 1985;28:565

  49. The Incretins GLP-1: Glucagon-Like Peptide1 A G F S S V L G A H E T T D Y E S Q A K A K F L R I V E W G G GIP: Gastric Inhibitory Polypeptide Glucose-Dependent Insulinotropic Peptide A G F S I Y M K H Y E T I D A D S I Q Q N K A F G D L K N V L D K W W Q K T I N Q H Drucker. Diabetes Care. 2003;26:2929

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