São paulo  2009 Simposium SMNE – ALAD Avances en la prevención y el tratamiento de la diabetes   tipo 2  Re du cción de la...
DM 2 =  Molestia  Vascular ! ? Etiologia Fisiopatologia Complica ciones
Obstru ción  Coron á ria en el DM 2   Cálcio Coronariano Angiografia
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 ...
 
Trials relating to glucose lowering and Doctors’ enthusiasm Enthusiasm Time UGDP UKPDS PROactive PROactive (Nissen) ADOPT ...
Diabetes  19, Suppl 2, 785-830, 1970
University Group Diabetes Program 12 centros nos EUA 1027 pacientes incluídos entre Febrero de 1961 hasta 1966 Insulina Va...
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...
 
<ul><li>O   que ya se sabia antes deste estudio e que fue confirmado </li></ul><ul><ul><li>Estatinas son efectivas en la C...
 
<ul><li>O   que no se sabia antes deste estudio  </li></ul><ul><ul><li>Estatinas   la sobrevida y    riesgo CVD e AVC en...
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...
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=....
Molestia Cardiovascular en el DCCT/EDIC Pacientes con por lo menos 1 evento cardiovascular en 17 anos de seguimiento * Red...
Molestia Cardiovascular en el DCCT/EDIC N ú mero total de eventos cardiovasculares en 17 anos de seguimiento IAM fatal e n...
Conclusion from UKPDS:  Blood glucose and vascular risk in diabetes UKPDS Each 1% reduction in HbA1c  would reduce - 21% a...
The UKPDS legacy
The UKPDS legacy
UKPDS legacy – Any Diabetes End Point
UKPDS legacy - Microvascular
UKPDS legacy - MI
UKPDS legacy - Death
<ul><li>“ Metabolic Memory ”:  </li></ul><ul><li>… efe c tos de l control glucemico excelente son  “ recordados ”  por los...
“ Metabolic memory”  The UKPDS legacy <ul><li>Similar mechanism underlies DCCT/EDIC and UKPDS ? </li></ul><ul><li>Hypothes...
ADVANCE - Renal events New microalbuminuria 23.7% 25.7% Total renal events 26.9% 30.0% Percent of patients with event Inte...
Any cause mortality – ADVANCE Relative Risk Reduction  7% p=0.28 Follow-up (months) Cumulative incidence (%) 25 20 10 5 0 ...
ACCORD
ACCORD
Byron J Hoogwerf, MD Department of Endocrinology, Diabetes and Metabolism, Cleveland Clinic Principal Investigator of ACCO...
VADT   -  V eterans  A ffairs  D iabetes  T rial <ul><li>The VADT researchers suggested that  intensive  blood glucose con...
 
What do we change in clinical practice? <ul><li>Evidence is strongly in favour of intensive treatment for glycaemia early ...
Death Rate ADVANCE  – glucose lowering arm Cardiovascular death 253 289 12% (-4 to 26) All deaths 498 533 7% (-6 to 17) No...
Standard Intensive Placebo Per-Ind 0.7 0.9 1.1 1.3 Cardiovascular death - ADVANCE Annual event rate %   Hazard ratios P fo...
 
Clinical Implications of Glucose control arm – ADVANCE Trial <ul><li>These results provide the evidence </li></ul><ul><li>...
Conclusions ADVANCE (Joint effects) <ul><ul><li>The separate effects of BP lowering (perindopril-indapamide) and glucose c...
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...
Eventos  cardiovascular es -  STENO-2  N em risco Intensivo  80  72   65  61  56  50  47  31 Convencional 80  70   60  46 ...
Besides  her 0AD treatment ,  would you reinforce her medical treatment ? <ul><ul><li>Metabolic syndrome that requests a s...
STENO-2 Facts and Conclusions <ul><li>Steno 2 intervention and the observational follow up, demonstrates in type 2 diabete...
MONOTHERAPY Metabolic safety Schernthaner G et al.  Eur J Clin Invest . 2004;34:535-542. COMBINATION THERAPY  + METFORMIN ...
Protection of isolated human islets from apoptosis  induced by intermittent high glucose.  The   role of oxidative stress....
Regenera ción  Intra-Ductal  es possible <ul><li>GLP-1 </li></ul><ul><li>TZDs </li></ul><ul><li>Gliclazida </li></ul><ul><...
O’Brien RC.  J Diabetes Complications.  2000. Sulfonilureas and LDL-resistance to oxidation  Ex vivo studies of LDL from t...
Katakami N et al.  Diabetologia . 2004. Reduction in the progression of intima media thickness (IMT) Antiatherogenic effec...
Pragmatic therapy <ul><li>•  Negotiate a plan   with the patient </li></ul><ul><li>•  Initiate appropriate therapy </li></...
Treatment of Diabetes in XXI Century <ul><li>Diabetes is a condition to be treated with </li></ul><ul><ul><li>expertise </...
U niversidade of Campinas UNICAMP 2009  LIMED - Laboratório de Investigacão  em Metabolismo e Diabetes Bruno Geloneze J os...
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Simposio ALAD Avances en la prevención y el tratamiento de la diabetes tipo 2 "Documentos de posición ALAD - Reducción de la mortalidad y prevención de las complicaciones vasculares en el paciente diabético

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  • Both in monotherpay and in combination with metformin more than 50% fewer hypoglycemic episodes with Gliclazide MR compared with glimepiride, making gliclazide MR one of the safest SU ad indeed he oe giving the lesser number of hypoglycemic episodes
  • Gliclazide MR exercises its antioxidant properties in preclinical study as shown in the first graph, by reducing oxidative stress induces by high glucose level. This directly leads to b cell protection as shown in the second graph where Diabeton MR significantly reduces human b cell apoptosis. Experts believe that this unique b cell protection explain the long-lasting glycemic control observed with Diabeton MR.
  • Diamicron MR, unlike other sulfonylureas, increases LDL-resistance to oxidation in type 2 diabetes and consequently reduces peroxidation of lipids which is one of the major causes of the atherosclerosis. This unique antioxidant properties, in addition to b cell protection and long-lasting efficacy leads to unique cardiovascular advantages…
  • Results showed that type 2 diabetic patients treated with D have a significant reduction in the progression of intima-media thickness compared with patients treated by glibenclamide . Authors conclude that D has a potent anti-atherogenic effect in type 2 diabetes compared to glibenclamide This is of interest in the current debate around rimonabant
  • Simposio ALAD Avances en la prevención y el tratamiento de la diabetes tipo 2 "Documentos de posición ALAD - Reducción de la mortalidad y prevención de las complicaciones vasculares en el paciente diabético

    1. 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. 2. DM 2 = Molestia Vascular ! ? Etiologia Fisiopatologia Complica ciones
    3. 3. Obstru ción Coron á ria en el DM 2 Cálcio Coronariano Angiografia
    4. 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 * *
    5. 6. Trials relating to glucose lowering and Doctors’ enthusiasm Enthusiasm Time UGDP UKPDS PROactive PROactive (Nissen) ADOPT RECORD ACCORD ADVANCE
    6. 7. Diabetes 19, Suppl 2, 785-830, 1970
    7. 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
    8. 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
    9. 11. <ul><li>O que ya se sabia antes deste estudio e que fue confirmado </li></ul><ul><ul><li>Estatinas son efectivas en la CVD estabelecida (prevencion secund.) </li></ul></ul><ul><ul><li>Estatinas en la prevencion primária = benefícios inconclusivos </li></ul></ul><ul><ul><li>Datos ambíguos : estatinas en personas con BAJO riesgo </li></ul></ul><ul><ul><li>Eficácia : más de 65 anos = em debate </li></ul></ul><ul><ul><li>Efecto más intenso en los Diabéticos = no totalmente definido </li></ul></ul>
    10. 13. <ul><li>O que no se sabia antes deste estudio </li></ul><ul><ul><li>Estatinas  la sobrevida y  riesgo CVD e AVC en personas sin CVD </li></ul></ul><ul><ul><li>Efecto semejante en: > 65 anos, mujeres, DM 2. </li></ul></ul><ul><ul><li>Personas de ALTO riesgo devem utilizar estatinas en largo plazo </li></ul></ul>
    11. 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
    12. 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 *
    13. 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
    14. 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.”
    15. 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
    16. 19. The UKPDS legacy
    17. 20. The UKPDS legacy
    18. 21. UKPDS legacy – Any Diabetes End Point
    19. 22. UKPDS legacy - Microvascular
    20. 23. UKPDS legacy - MI
    21. 24. UKPDS legacy - Death
    22. 25. <ul><li>“ Metabolic Memory ”: </li></ul><ul><li>… efe c tos de l control glucemico excelente son “ recordados ” por los organos-blanco a largo plazo , en respecto a cambios induzidos por la terapia… </li></ul>
    23. 26. “ Metabolic memory” The UKPDS legacy <ul><li>Similar mechanism underlies DCCT/EDIC and UKPDS ? </li></ul><ul><li>Hypothesis ! </li></ul><ul><ul><li>reduction on Advanced Glycation End Products </li></ul></ul><ul><ul><li>less AGEs from better glycemic control </li></ul></ul><ul><ul><li>fewer AGEs = long-term protection </li></ul></ul><ul><ul><li>reduction in the progression of renal disease </li></ul></ul><ul><ul><li>less renal disease = long-term protection ! </li></ul></ul>
    24. 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) ***
    25. 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
    26. 29. ACCORD
    27. 30. ACCORD
    28. 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
    29. 32. VADT - V eterans A ffairs D iabetes T rial <ul><li>The VADT researchers suggested that intensive blood glucose control early on - closer to the diagnosis of diabetes - may be more helpful in preventing cardiovascular problems than intensifying control later. </li></ul>The Take-Home Message of VADT trial <ul><li>Reducing the risk of severe hypoglycemia is important, since they strongly predicted cardiovascular events in the study. </li></ul>Presented by Carlos Abraira, M.D at the ADA, 68th Scientific Sessions, San Francisco, CA, June 2008.
    30. 34. What do we change in clinical practice? <ul><li>Evidence is strongly in favour of intensive treatment for glycaemia early in T2DM </li></ul><ul><li>Evidence shows that in those with established CVD that a rapid lowering of glycaemia to aggressive targets may cause excess mortality. </li></ul><ul><li>Gliclazide MR, among few OADs, may be appropriate for preventing microvascular disease (nephropathy) and lowers glucose at an appropriate rate </li></ul>
    31. 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
    32. 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
    33. 38. Clinical Implications of Glucose control arm – ADVANCE Trial <ul><li>These results provide the evidence </li></ul><ul><li>To support the current guideline recommendations to lower HbA1c to ≤ 6.5% or ≤7% </li></ul><ul><li>That a pragmatic and progressive glucose control regimen as used in ADVANCE can achieve an HbA1c of ≤ 6.5%, & reduce serious complications, primarily renal, with safety </li></ul><ul><li>That this regimen will provide these benefits with acceptable rates of hypoglycaemia and no weight gain </li></ul>
    34. 39. Conclusions ADVANCE (Joint effects) <ul><ul><li>The separate effects of BP lowering (perindopril-indapamide) and glucose control (gliclazide MR-based) are independent for all outcomes, (no interaction) </li></ul></ul><ul><ul><li>The joint effects of these two treatments provide very substantial benefits </li></ul></ul><ul><ul><ul><li>Around one third reduction in nephropathy and renal events </li></ul></ul></ul><ul><ul><ul><li>One quarter reduction in cardiovascular death </li></ul></ul></ul><ul><ul><ul><li>Close to one fifth reduction in all-cause mortality </li></ul></ul></ul>Multifactorial treatments including routine blood pressure lowering and intensive glucose control are indicated for all patients with type 2 diabetes
    35. 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
    36. 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
    37. 42. Besides her 0AD treatment , would you reinforce her medical treatment ? <ul><ul><li>Metabolic syndrome that requests a strict control of vascular risk factors (VRF) : </li></ul></ul><ul><ul><ul><li>BP </li></ul></ul></ul><ul><ul><ul><li>Lipids </li></ul></ul></ul><ul><ul><ul><li>Smoking …. </li></ul></ul></ul>STENO Attitude !
    38. 43. STENO-2 Facts and Conclusions <ul><li>Steno 2 intervention and the observational follow up, demonstrates in type 2 diabetes: </li></ul><ul><li>The interest to intensify the treatment, including glucose-lowering, to reduce vascular complications </li></ul><ul><li>The sooner we treat intensively, the better the long term outcomes  benefits amplified in the long run </li></ul><ul><li>Gliclazide MR was the SU of choice in the intensive arm </li></ul>
    39. 44. MONOTHERAPY Metabolic safety Schernthaner G et al. Eur J Clin Invest . 2004;34:535-542. COMBINATION THERAPY + METFORMIN 0 6 12 18 24 Number of patients 2.6% 8.6% GLICLAZIDE MR GLIMEPIRIDE n = 229 n = 255 <ul><li>50% fewer hypoglycemic episodes with Gliclazide MR versus Glimepiride </li></ul>0 6 12 18 24 Number of patients 5.3% 9.6% GLICLAZIDE MR GLIMEPIRIDE n = 133 n = 156
    40. 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
    41. 46. Regenera ción Intra-Ductal es possible <ul><li>GLP-1 </li></ul><ul><li>TZDs </li></ul><ul><li>Gliclazida </li></ul><ul><li>Exenatida </li></ul>Euglicemia + Eulipemia son más importantes!
    42. 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
    43. 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
    44. 49. Pragmatic therapy <ul><li>• Negotiate a plan with the patient </li></ul><ul><li>• Initiate appropriate therapy </li></ul><ul><li>• Negotiate reasonable personalised targets, </li></ul><ul><li>which should change with time </li></ul><ul><li>• Aim to shift surrogates by appropriate amounts </li></ul><ul><li>( ↓ 10mmHg BP, ↓ 1% HbA1c, ↓ 25% cholesterol) </li></ul><ul><li>• Consider non-surrogate treatment (e.g. exercise) </li></ul>
    45. 50. Treatment of Diabetes in XXI Century <ul><li>Diabetes is a condition to be treated with </li></ul><ul><ul><li>expertise </li></ul></ul><ul><ul><li>dedication </li></ul></ul><ul><ul><li>commitment </li></ul></ul><ul><li>To treat diabetes is going to be easier and easier, but….. </li></ul><ul><li>To treat diabetic patient remains a great challenge </li></ul><ul><li>Any option - easy to use, with high efficiency and low rates of side effects must be considered as a first line therapy </li></ul><ul><li>Strong evidences and personal experiences are always welcome </li></ul>Bruno Geloneze – Brasil – 2009
    46. 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!!

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