1. São paulo 2009 Simposium SMNE – ALAD Avances en la prevención y el tratamiento de la diabetes tipo 2 Re du cción de la mortalidad y prevención de las complicaciones vasculares en el paciente diabético Bruno Geloneze – Universidad de Campinas - Brasil

2. DM 2 = Molestia Vascular ! ? Etiologia Fisiopatologia Complica ciones

3. Obstru ción Coron á ria en el DM 2 Cálcio Coronariano Angiografia

4. Atherosclerotic Plaque Instability in T2DM 0 2 4 6 8 10 No-DM DM ateroma rico em lipídio (% da área total da placa) 0 5 10 15 20 25 30 No-DM DM Área de macrófagos (% da área total da placa) 0 10 20 30 40 50 60 70 No-DM DM incidência de trombo Moreno et al, Circulation 2000;102:2180-2184 * * p<0,05 * *

6. Trials relating to glucose lowering and Doctors’ enthusiasm Enthusiasm Time UGDP UKPDS PROactive PROactive (Nissen) ADOPT RECORD ACCORD ADVANCE

7. Diabetes 19, Suppl 2, 785-830, 1970

8. University Group Diabetes Program 12 centros nos EUA 1027 pacientes incluídos entre Febrero de 1961 hasta 1966 Insulina Variable Insulina Fija Tolbutamida Fenformina Placebo Pacientes diabéticos rec ien diagnosticados Diabetes 19, Suppl 2, 785-830, 1970

9. 0 1 2 3 4 5 6 7 8 Anos % Todas l as Causas Ta j a de Mortalidad Cumulativa por 100 Pacientes 0 1 2 3 4 5 6 7 8 tolbutamida Placebo I ns var iable I ns fija Cardiovasculares Diabetes 19, Suppl 2, 785-830, 1970

14. HbA1C: estudios con DM1 DCCT - EDIC JAMA 2003; 290:2159-67 EDIC anos p<.001 p<.001 p<.001 p=.002 p=.04 p=.08 p=.04 p=.58 p=.83

15. Preval e ncia de Hipertens ion : DCCT - EDIC JAMA 2003; 290:2159-67 EDIC anos p=.81 p=.75 p=.62 p=.002 p=.02 p=.004 p=.01 p<.001 p<.001 *

16. Molestia Cardiovascular en el DCCT/EDIC Pacientes con por lo menos 1 evento cardiovascular en 17 anos de seguimiento * Redu cion del RR en 42 % p = 0.02 N Eng J Med dec 2005; 353:2643

17. Molestia Cardiovascular en el DCCT/EDIC N ú mero total de eventos cardiovasculares en 17 anos de seguimiento IAM fatal e n o -fatal, AVC y muerte CV * Redu cion del RR en 57 % p = 0.02 N Eng J Med dec 2005; 353:2643 “ Intensive diabetes therapy has long-term beneficial effects on the risk of cardiovascular disease in patients with type 1 diabetes.”

18. Conclusion from UKPDS: Blood glucose and vascular risk in diabetes UKPDS Each 1% reduction in HbA1c would reduce - 21% any diabetes related end point - 14% myocardial infarction - 37% the risk of microvascular complications

19. The UKPDS legacy

20. The UKPDS legacy

21. UKPDS legacy – Any Diabetes End Point

22. UKPDS legacy - Microvascular

23. UKPDS legacy - MI

24. UKPDS legacy - Death

27. ADVANCE - Renal events New microalbuminuria 23.7% 25.7% Total renal events 26.9% 30.0% Percent of patients with event Intensive Standard (n=5,571) (n=5,569) Relative risk reduction (95% CI) Favours Intensive Favours Standard Hazard ratio 0.5 1.0 2.0 † P=<0.001 ‡ P=0.02 *** P=0.006 9% (2 to 15)‡ 11% (5 to 17) † New macroalbuminuria 2.9% 4.1% 30% (15 to 43) † New or worsening nephropathy 4.1% 5.2% 21% (7 to 34) ***

28. Any cause mortality – ADVANCE Relative Risk Reduction 7% p=0.28 Follow-up (months) Cumulative incidence (%) 25 20 10 5 0 Standard Intensive 0 6 12 18 24 30 36 42 48 54 60 66 15

29. ACCORD

30. ACCORD

31. Byron J Hoogwerf, MD Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Principal Investigator of ACCORD “ For now, any strategy that lowers glucose and is associated with a low risk of hypoglycemia and does not cause excessive weight gain should be considered appropriate in patients with type 2 diabetes” Cleve Clin J Med 75: 729-37, 2008

35. Death Rate ADVANCE – glucose lowering arm Cardiovascular death 253 289 12% (-4 to 26) All deaths 498 533 7% (-6 to 17) Non-cardiovascular death 245 244 0% (-20 to 16) Number of patients Intensive Standard (n=5,571) (n=5,569) Relative risk reduction (95%CI) Favours Intensive Favours Standard Hazard ratio 0.5 1.0 2.0

36. Standard Intensive Placebo Per-Ind 0.7 0.9 1.1 1.3 Cardiovascular death - ADVANCE Annual event rate % Hazard ratios P for interaction=0.62 BP arm All participants 18% (2 to 32) Standard 22% (0 to 40) Intensive 14% (-11 to 34) Hazard ratio 0.5 1.0 2.0 Relative risk reduction (95% CI) Favours Per-Ind Favours Placebo RRR 24%, P=0.04 BP Glucose 1.14 1.02 0.89 0.87 All participants 7% (-11 to 23) Placebo 11% (-14 to 30) Per-Ind 2% (-28 to 25) Relative risk reduction (95% CI) Favours Intensive Favours Standard Hazard ratio 0.5 1.0 2.0 Glucose arm 1.14 1.02 0.89 0.87

40. Varia cion de la A1c en el estudio STENO 2 Gaede P, et al. N Engl J Med 2008;358:580–91. 0 4 5 6 7 8 9 10 11 Tratam i ento convencional Tratam i ento intensivo Hemoglobina glicada (%) Anos de seguimiento clinico 0 1 2 3 4 5 6 8 7 9 10 11 12 13

41. Eventos cardiovascular es - STENO-2 N em risco Intensivo 80 72 65 61 56 50 47 31 Convencional 80 70 60 46 38 29 25 14 Gaede P, et al. N Engl J Med 2008;358:580–91. Death 46% RRR CV events 59% RRR P. GAEDE et al. NEJM 2008; 358:580-91 . Anos de acompanhamento 1 2 3 4 5 6 8 7 9 10 11 12 13 0 0 10 20 30 40 50 60 70 80 Tratam i ento convencional p < 0,001 Incidência cumulativa de qualquer evento cardiovascular (%) Tratam i ento intensivo

45. Protection of isolated human islets from apoptosis induced by intermittent high glucose. The role of oxidative stress. Del Guerra et al. Diabetes Metab Res Rev . 2007 Isolated human islets, cultured for 5 days in normal or intermittent high glucose levels, with or without glibenclamide or Gliclazide MR

47. O’Brien RC. J Diabetes Complications. 2000. Sulfonilureas and LDL-resistance to oxidation Ex vivo studies of LDL from type 2 diabetic subjects and controls. Measurement of the lag time between exposure of LDL to pro-oxidant copper and the start of oxidation. Gliclazide MR

48. Katakami N et al. Diabetologia . 2004. Reduction in the progression of intima media thickness (IMT) Antiatherogenic effect Gliclazide versus Glibenclamide Ultrasonographic assessment of the carotid artery intima-media thickness (IMT) in 89 type 2 diabetic patients pretreated with glibenclamide or gliclazide; 3-year observation period

51. U niversidade of Campinas UNICAMP 2009 LIMED - Laboratório de Investigacão em Metabolismo e Diabetes Bruno Geloneze J osé Carlos Pareja Marcos Tambascia Ana Carolina Vasques Ana Claudia Felici Antonio Calixto Aurea O Silva Carla Fiori Christiane Stabe Daniela Schiavo Fernanda Filgueira Gisele Lambert Maria Luiza Fernandes Mariana Ermetice Marcelo M Lima Sabrina Nagassaki Sylka Geloneze Metabolic Surgery Elinton Chaim J osé C Pareja Cardio Metabol J Roberto Souza Otavio R Coelho Wilson Nadruz Molecular Biology Mario A Saad Mirian Ueno Cellular Biology Eliana Araujo Licio Velloso Proteomics Rodrigo Catharino GRACIAS ALAD!! Gracias Mexico!!