Baisser le LDL Le cas du diabétique

Transcription

1 Baisser le LDL Le cas du diabétique DIEVART François Clinique Villette, Dunkerque

2 Conflits d intérêts Honoraires pour conférences ou conseils pour : Abbott, Astra Zeneca, BMS, Boehringer Ingelheim, IPSEN, Menarini, MSD, Novartis, Pfizer, Roche diagnostics, sanofi aventis france, Servier, Takeda

3 Des fondamentaux à l actualité

4 1. le modèle et ses limites 2. le cas du diabétique

5 Un peu d histoire

6 Avant 1994

7 Avant 1994 Prévention secondaire Étude CDP Œstrogènes, hormones thyroïdiennes Baisse du cholestérol Augmentation significative de la mortalité totale

8 Avant 1994 Prévention primaire Étude OMS (WHO 78 92) clofibrate patients suivis > 5 ans Augmentation significative de mortalité totale de 31 %

9 Avant 1994 : controverse il est possible de diminuer le cholestérol le risque d infarctus diminue mais la mortalité totale augmente

10 Avant 1994 : controverse La baisse du cholestérol ou le traitement?

11 Avant 1994 : controverse La baisse du cholestérol ou l effet des traitements utilisés?

12 1994 Si baisser le cholestérol diminue le risque d IDM mortel Si la réduction du cholestérol n est pas néfaste Diminuer le risque d IDM mortel chez des patients à haut risque doit diminuer la mortalité totale

13 All Cause Mortality Cause of death Placebo (n=2223) Simvastatin (n=2221) Risk Reduction Coronary % Non-CV Cancer Suicide 4 5 -Trauma 3 1 -Other 7 7 All Deaths % The Lancet, Vol 344, November 19, 1994

14 All Cause Mortality Cause of death Placebo (n=2223) Simvastatin (n=2221) Risk Reduction Coronary % Non-CV Cancer Suicide 4 5 -Trauma 3 1 -Other 7 7 All Deaths % The Lancet, Vol 344, November 19, 1994

15 4S Total Mortality: primary endpoint 1.00 Proportion alive simvastatin placebo 30% risk reduction Log rank p= Years since randomisation 6 4S Group. Lancet 1994;344:

16 Après 1994

17 Long and widing road WOSCOPS, AFCaps/TexCaps, PROSPER, HPS, CARDS, ASCOT, MIRACL, TNT Framingham HHS WHO CDP S

18 Construction du modèle

19 2005

20 Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366:

21 Toute baisse du LDL avec une statine = bénéfice CV

22 Quelles que soient données démographiques données lipidiques données cliniques

23 French guidelines LDL > 1,6 g/l or 1 RF => diet (3 months) After 3 months, if LDL not at goal => use drugs AFSSAPS. Mars 2005

24 Limites du modèle

25 AURORA Screening Treatment Month: Visit: 14 days monthly 6 Final Patients (n~2750) Inclusion criteria ESRD, on hemodialysis for 3 months years Exclusion criteria Statin within 6 months Kidney transplant likely within 1 year Creatine kinase >3xULN ALT >3xULN TSH >1.5xULN Rosuvastatin 10 mg daily (n~1350) Randomization 1:1 Matching placebo (n~1350) Study medication was administered until 620 patients had experienced a major CV event Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9

26 AURORA: Changes in lipids and hs CRP LDL C: 43% reduction TG: 16.2% reduction LDL C (mg/dl) p< TG (mg/dl) p< Rosuvastatin Placebo HDL C (mg/dl) Year HDL C: 2.9% increase p=0.045 Hs CRP (mg/l) Year Hs CRP: 11.5% decrease P< Baseline 3 months 1 year Year Values are means (95% CI) for LDL C, TG and HDL C and medians (95% CI) for Hs CRP; % change from baseline at 3 months is quoted and p values are for change at 3 months versus placebo Rosuvastatin Placebo

27 AURORA: primary endpoint Kaplan Meier estimate of time to first major CV event Placebo Cumulative incidence of primary endpoint (%) Rosuvastatin HR=0.96 (95% CI ) P= No. at risk: Years from randomization Rosuvastatin Placebo

28 Limites du modèle Insuffisance rénale dialysée (AURORA, 4D) Insuffisance cardiaque (CORONA, GISSI HF) Hémorragie cérébrale (SPARCL)

29 Limites du modèle Hypertriglycéridémie isolée: effet clinique non connu quelles valeurs? Intolérance aux statines

30 JUPITER Trial Design No Prior CVD or DM Men >50, Women >60 LDL <130 mg/dl hscrp >2 mg/l 4-week run-in Rosuvastatin 20 mg (N=8901) Placebo (N=8901) MI Stroke Unstable Angina CVD Death CABG/PTCA Ridker et al, Circulation 2003;108:

31 JUPITER Baseline Blood Levels (median, interquartile range) Rosuvastatin Placebo (N = 8901) (n = 8901) hscrp, mg/l 4.2 ( ) 4.3 ( ) LDL, mg/dl 108 (94 119) 108 (94 119) HDL, mg/dl 49 (40 60) 49 (40 60) Triglycerides, mg/l 118 (85 169) 118 (86 169) Total Cholesterol, mg/dl 186 ( ) 185 ( ) [ Mean LDL = 104 mg/dl ] Ridker et al NEJM 2008

32 Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Ridker et al NEJM 2008 Cumulative Incidence HR 0.56, 95% CI P < Placebo 251 / % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1, ,901 8,621 8,353 6,508 3,872 1,963 1,

33 JUPITER AURORA Predicted Benefit Based on LDL Reduction vs Observed Benefit 55 Proportional reduction in vascular event rate (95% CI) A to Z TNT IDEAL CTT PROVE IT JUPITER OBSERVED hscrp? JUPITER PREDICTED AURORA PREDICTED AURORA CV risk: 9,5 % per year 0 0 0,5 1 Mean LDL cholesterol difference between treatment groups (mmol/l) D après Ridker et al NEJM 2008

34 Limites du modèle Le plus tôt serait il le mieux?

35 Jusqu où faut il baisser le cholestérol? Le plus bas est il le mieux?

36 Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366:

37 Relation entre cholestérol obtenu et réduction du risque d AVC 0.8 Relative Risk Reduction of Stroke MIRACL SCAT CARE VA-HIT PCABGT LIPID PLAC II MAAS REGRESS POSCH 4S KAPS BIP LA WOSCOPS Stockholm CDP Niac CDP Clo WHO LRC Helsinki Hjermann et al Final Cholesterol (mg/dl) Corvol JC, et al. Arch Intern Med. 2003;163: With permission.

38

39

40 Essais d intervention ayant démontré le bénéfice clinique d un abaissement du LDL en dessous d 1 g/l MIRACL PROVE IT TNT IDEAL SPARCL LDL, baseline 1,24 g/l 1,06 g/l 0,98 g/l 1,22 g/l 1,33 g/l LDL, in control group 1,35 g/l 0,95 g/l 1,01 g/l 1,04 g/l 1,29 g/l LDL, in pts treated with atorvastatin 80 mg/d 0,72 g/l 0,62 g/l 0,77 g/l 0,81 g/l 0,73 g/l LDL difference 0,63 g/l 0,33 g/l 0,24 g/l 0,23 g/l 0,56 g/l Study Follow Up (mean) 4 mois 2 ans 4,9 ans 4,8 ans 4,9 ans Relative risk, coronary events 0,84 0,84 0,80 0,89 0,65 Relativerisk, total mortality 0,94 0,72 1,01 0,98 1,00

41 Efficacy and safety of more intensive lowering of LDL cholesterol: a meta analysis of data from 170,000 participants in 26 randomised trials Lancet 2010; 376: DOI: /S (10)

42 Second CTT cycle: more vs less intensive statin therapy Study Treatment comparison N Target population Entry lipid criteria PROVE-IT A 80 vs. P ACS TC 240 mg/dl A to Z S 40 then S 80 vs. placebo then S ACS TC 250 mg/dl TNT A 80 vs. A 10 10,001 Prior CHD LDL-C mg/dl TG 600 mg/dl IDEAL A 80 vs. S Prior CHD TG 600 mg/dl SEARCH S 80 vs. S 20 12,064 Prior CHD TC 4.5 mmol/l or 3.5 if on statins

43 MORE VS LESS STATIN Proportional effects on MAJOR VASCULAR EVENTS (unweighted for 1 year LDL C differences) No. of events (% pa) More statin Less statin Relative risk (CI) Nonfatal MI CHD death Any major coronary event 1175 (1.3%) 645 (0.7%) 1725 (1.9%) 1380 (1.5%) 694 (0.7%) 1973 (2.2%) 0.85 ( ) 0.93 ( ) 0.87 ( ) CABG PTCA Unspecified 637 (0.7%) 1166 (1.3%) 447 (0.5%) 731 (0.9%) 1508 (1.8%) 502 (0.6%) 0.86 ( ) 0.76 ( ) 0.87 ( ) Any coronary revascularisation 2250 (2.6%) 2741 (3.2%) 0.81 ( ) Ischaemic stroke Haemorrhagic stroke 440 (0.5%) 69 (0.1%) 526 (0.6%) 57 (0.1%) 0.84 ( ) 1.21 ( ) Unknown stroke Any stroke 63 (0.1%) 572 (0.6%) 80 (0.1%) 663 (0.7%) 0.79 ( ) 0.86 ( ) Any major vascular event 3837 (4.5%) 4416 (5.3%) 0.85 ( ) 99% or 95% CI More statin better Less statin better 43

44 Le plus bas est il le mieux? OUI

45 Le plus bas est il le mieux? Chez qui?

46 Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL C reduction, by baseline prognostic factors No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Previous coronary disease: CHD Non-CHD vascular None 8395 (4.5%) 674 (3.1%) 1904 (1.4%) (5.6%) 802 (3.7%) 2425 (1.8%) 0.79 ( ) 0.81 ( ) 0.75 ( ) Diabetes: Type 1 diabetes Type 2 diabetes No diabetes 145 (4.5%) 2494 (4.2%) 8272 (3.2%) 192 (6.0%) 2920 (5.1%) (4.0%) 0.77 ( ) 0.80 ( ) 0.78 ( ) Sex: Male Female 8712 (3.5%) 2261 (2.5%) (4.4%) 2625 (2.9%) 0.77 ( ) 0.83 ( ) Age (years) 65 >65, 75 > (2.9%) 4032 (3.7%) 885 (4.8%) 7455 (3.6%) 4908 (4.6%) 987 (5.4%) 0.78 ( ) 0.78 ( ) 0.84 ( ) Body mass index (kg/m 2 ): <25 25,< (3.0%) 5033 (3.3%) 2732 (3.3%) 3688 (3.7%) 6125 (4.1%) 3331 (4.1%) 0.79 ( ) 0.78 ( ) 0.78 ( ) Smoking status: Current smokers Non-smokers 2268 (3.6%) 8703 (3.1%) 2896 (4.7%) (3.9%) 0.78 ( ) 0.78 ( ) Total (13.0%) (15.8%) 0.78 ( ) 99% or 95% CI Statin/more better Control/less better 46

47 Proportional effects on MAJOR VASCULAR EVENTS per mmol/l LDL C reduction, by baseline prognostic factors No. of patients (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Treated hypertension: Yes No 6176 (3.7%) 4543 (2.7%) 7350 (4.5%) 5707 (3.5%) 0.80 ( ) 0.76 ( ) Systolic blood pressure (mm Hg): < ,< (3.2%) 3145 (3.0%) 2067 (3.6%) 6500 (3.8%) 4049 (3.9%) 2473 (4.5%) 0.80 ( ) 0.75 ( ) 0.79 ( ) Diastolic blood pressure (mm Hg): <80 80,< (3.5%) 3670 (3.0%) 2452 (3.0%) 5306 (4.2%) 4587 (3.8%) 3128 (3.9%) 0.81 ( ) 0.77 ( ) 0.77 ( ) Estimated GFR (ml/min/1.73m 2 ): < 60 60, < (4.1%) 6161 (3.2%) 1315 (2.5%) 3354 (5.1%) 7540 (4.0%) 1571 (3.0%) 0.77 ( ) 0.78 ( ) 0.77 ( ) HDL-C (mmol/l): 1.0 >1.0, 1.3 > (4.0%) 3656 (3.1%) 2199 (2.4%) 6165 (5.0%) 4452 (3.9%) 2633 (2.9%) 0.78 ( ) 0.77 ( ) 0.80 ( ) Total (13.0%) (15.8%) 0.78 ( ) 99% or 95% CI Statin/more better Control/less better 47

48 Avec quels risques?

49 Proportional effects on SITE SPECIFIC CANCER per mmol/l LDL C reduction No. of first cancers (% pa) Statin/more Control/less Relative risk (CI) per mmol/l LDL-C reduction Gastrointestinal 1166 (0.3%) 1194 (0.3%) 0.97 ( ) Genitourinary Respiratory 1596 (0.5%) 813 (0.2%) 1645 (0.5%) 814 (0.2%) 0.97 ( ) 1.00 ( ) Female breast Haematological 267 (0.3%) 305 (0.1%) 241 (0.3%) 291 (0.1%) 1.07 ( ) 1.04 ( ) Melanoma 159 (0.0%) 142 (0.0%) 1.14 ( ) Other/unknown 754 (0.2%) 737 (0.2%) 1.04 ( ) Any 5060 (1.4%) 5064 (1.4%) 1.00 ( ) 99% or 95% CI Statin/more better Control/less better 49

50 Le bénéfice dépasse largement les risques

51 CTT Meta analysis Statins decrease mortality Cholesterol Treatment Trialists Collaboration Cause des décés Causes vasculaires: Coronaire AVC Autre vasculaire Vasculaire non coronaire Traitement (n = 45,054) Evénts (%) Controle (n = 45,002) Statine Control meilleure meilleur Toute cause vasculaire Cause non vasculaire: Cancer Respiratoire Trauma Autres Toutes non vasculaires Tous décés Risque relatif CTT Collaborators. Lancet. 2005;366:

52 Even in primary prevention (BMJ 2009)

53 Sans exclure les précautions d utilisation

54 French guidelines

55 Le bénéfice dépasse largement les risques

56 Et en dehors des statines?

57 Relation réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events Avec une statine 40% Event Reduction 30% 21% 20% 10% 0% 10% (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366:

58 Inhibiteurs de l absorption du cholestérol Fibrates

59 Ezetimibe évaluation ENHANCE (2008), eze + S vs S : no effect on carotid IMT (720 pts, 2 years) SEAS (2008), eze + S vs S: no effect on CV events in pts in primary prevention with Aortic Stenosis, slight increase in cancer incidence (1873 pts, 2 years) ARBITER 6 HALTS (2009): S + (Eze vs Niacin): carotid IMT decreased with niacin and didn t change with eze (208 pts, 14 months)

60 SEAS : Kaplan-Meier Curves for Primary and Secondary Outcomes and Death Rossebø AB et al. N Engl J Med 2008 Sep 2 [Epub ahead of print]

61 15 10 CARDS RRR = 37% Effects on major CV events PLACEBO 5 ATORVASTATINE FIBRATES FIELD RRR = 11% HPS-Diabète RRR = 24% PLACEBO HPS-Diabète RR = -24% SIMVASTATINE Années de suivi

62 15 10 CARDS RRR = 37% Effects on major CV events PLACEBO 5 ATORVASTATINE FIELD RR = 0,89; ns HPS-Diabète RRR = 24% PLACEBO HPS-Diabète RR = -24% SIMVASTATINE Années de suivi

63 French guidelines

64 Et le HDL?

65 Lipids: HDL

66 AFCaps/TexCaps: Objectif Comparer la lovastatine au placebo en prévention du 1er événement coronarien majeur Chez des hommes et des femmes en prévention CV primaire, avec un LDL peu élevé et un HDL bas. JAMA 1998;279:

67 Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina: AFCAPS/TexCAPS Cumulative incidence placebo 0.02 lovastatin >5 37% relative risk reduction p<0.001 Years of follow up Downs JR et al. JAMA 1998;279:

68 Cardiovascular Endpoints: AFCAPS/TexCAPS Subjects with No History of CHD and Average Cholesterol Number of events Outcomes placebo (n=3301) lovastatin (n=3304) RRR (%) p value Fatal or nonfatal MI + unstable angina + sudden cardiac death* <0.001 Revascularisation <0.001 Fatal and nonfatal MI Unstable angina * primary endpoint, RRR relative risk reduction Downs JR et al. JAMA 1998;279:

69 1. le modèle et ses limites 2. le cas du diabétique

70 De quoi décèdent les diabétiques? Décès (%) Maladie cardiaque ischémique Autre maladie cardiaque Diabète Cancer AVC Infection Autre Dans 75 % des cas le décès est de cause CV Adapté de GEISS LS. et al. In Diabetes in America. 2nd ed :

71 Diabète de type 2 : un risque coronarien élevé Comparaison de l incidence des IM pendant 7 ans en fonction des antécédents ou non d IM Patients sans antécédent d IM Patients ayant un antécédent d IM 3,5 % 18,8 % Patients non diabétiques 20,2 % 45 % Patients diabétiques de type 2 HAFFNER SM. et al. NEJM 1998 ; 339 :

72 Une maladie associée à un risque CV élevé Incidence à 7ans des événements CV (%) Non diabétiques : Diabétiques : -MI +MI Non coronariens ( - IM) -MI +MI -MI +MI -MI +MI -MI +MI -MI +MI Coronariens ( + IM) IDM AVC Décès CV Haffner SM et al. N Engl J Med 1998;339:

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74 Le diabète est il un équivalent coronarien? Qu est ce que cela veut dire?

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76 PLAN Le diabète est il un équivalent coronarien? MAIS

77

78 PLAN Le diabète est il un équivalent coronarien? MAIS Physiopathologie différente

79 Diabetic Atheromas Have a Different Pathobiology Than Nondiabetic Atheromas P=.001 Inflammation Diabetes (n=36) No diabetes (n=32) P=.0001 Neovascularization P=.005 Collagen III Diabetes Diabetes Diabetes No diabetes No diabetes No diabetes Purushothaman K R et al. J Am Coll Cardiol. 2006;47(suppl A):295A.

80 PLAN Le diabète est il un équivalent coronarien? MAIS Études non concordantes (dépend des caractéristiques des patients)

81 Major Cardiovascular Events at 6-12 Month Follow-Up % of Patients No diabetes with Vascular Disease (n=988) p<0.001 Diabetes without Vascular Disease (n=694) 11.2 Diabetes with Vascular Disease (n=587) p=0.41 p= p< p< p= Death MI Unstable Angina PCI or CABG TIA or Stroke Composite On file at Canadian Heart Research Centre.

82 PLAN Le diabète est il un équivalent coronarien? MAIS Antiagrégants plaquettaires

83 Antithrombotic Trialists Collaboration: VASCULAR EVENTS Category APT CTRL Reduction Prior MI 13.5% 17.0% 25%±4 Acute MI 10.4% 14.2% 30%±4 Prior stroke/tia 17.8% 21.4% 22%±4 Acute stroke 8.2% 9.1% 11%±3 Other high risk* CAD 6.2% 8.9% 37%±5 Embolic risk 13.5% 16.8% 26%±7 PAD 5.8% 7.1% 23%±8 Other 11.3% 12.6% 13%±7 All trials 10.7% 13.2% 22%±

84 Antithrombotic Trialists Collaboration Effects on VASCULAR EVENTS in patients with OTHER HIGH-RISK CONDITIONS Category APT CTRL Reduction Haemodialysis 2.9% 4.9% 41%±16 Diabetes 15.7% 16.7% 7%±8 Carotid disease 10.6% 12.8% 19%±22 All high-risk patients 22%±2 (P<0.0001)

85 PLAN Le diabète est il un équivalent coronarien? MAIS Lipides

86 Results: primary outcome CHD events (CHD death + nonfatal MI) Placebo Fenofibrate HR = % CI = P=0.16

87 Relation entre réduction d incidence des événements vasculaires majeurs et réduction moyenne du LDL C à 1 an 50% Major CV events 40% Event Reduction 30% 21% 20% 10% 0% 10% (0.4 g/l) LDL c reduction mmol/l Lancet 2005; 366:

88 Collaborative Atorvastatin Diabetes Study (CARDS) Patient Population Type 2 diabetes mellitus Men and women years of age Primary CHD and stroke prevention LDL C 160 mg/dl ( 4.14 mmol/l) TG 600 mg/dl ( 6.78 mmol/l) 1 additional RF HTN (or on HTN treatment) Retinopathy Albuminuria Current smoking 2838 patients Atorvastatin 10 mg (n=1428) 4-year follow-up Double-blind placebo (n=1410) Primary endpoint: time to first major CV event (CHD death, nonfatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularization, stroke Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins Colhoun HM et al. Lancet 2004;364:

89 CARDS: Patient Baseline Lipids Total cholesterol (mg/dl) (mmol/l) LDL cholesterol (mg/dl) (mmol/l) HDL cholesterol (mg/dl) (mmol/l) Triglycerides* (mg/dl) (mmol/l) Placebo (n = 1410) Mean (SD) 207 (32) 5.35 (0.82) 117 (27) 3.02 (0.70) 55 (13) 1.42 (0.34) 148 ( ) 1.67 ( ) Atorvastatin (n = 1428) Mean (SD) 207 (32) 5.36 (0.83) 118 (28) 3.04 (0.72) 54 (12) 1.39 (0.32) 150 ( ) 1.70 ( ) *Median (interquartile range) Colhoun HM et al. Lancet 2004;364: Reprinted with permission from Elsevier.

90 CARDS: Lipid Levels by Treatment Total Cholesterol (mg/dl) Average difference 26%, 54 mg/dl; P< LDL Cholesterol (mg/dl) Average difference 40%, 46 mg/dl; P< Median TC (mg/dl)* 240 Placebo 160 Atorvastatin Years of Study Median LDL-C (mg/dl)* 160 Placebo Atorvastatin Years of Study Colhoun HM et al. Lancet 2004;364: Reprinted with permission from Elsevier.

91 CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Cumulative Hazard, (%) Placebo Atorvastatin Relative Risk Reduction 37% (95% CI, 17 52) P = Years Colhoun HM et al. Lancet 2004;364: Reprinted with permission from Elsevier Placebo 127 events Atorvastatin 83 events

92 Messages Le diabète est associé à une augmentation du risque CV Le diabétique partage certains caractères physiopathologiques avec le coronarien L effet du traitement des coronariens n est pas identique chez le diabétique: antiagrégant Si le risque est supérieur, corriger le surrisque avec les moyens validés (statines pour tous, PA en dessous de 140/90 mm Hg)

93 Merci de votre attention B

94 Back up B

95 CHARISMA Trial Design Patients age 45 years at high risk of Low dose ASA mg/day atherothrombotic events (n=15603) R Double-blind treatment up to 1040 primary efficacy events* Clopidogrel 75 mg/day (n=7802) 1-month visit Low dose ASA mg/day 3-month visit Visits every 6 months Final visit (Fixed study end date) Placebo 1 tablet/day (n=7801) * MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148:

96 Overall Population: Prior Medical History Clopidogrel + ASA (%) Placebo + ASA (%) Characteristic (n=7802) (n=7801) Hypertension Hypercholesterolemia Congestive heart failure Prior MI Atrial fibrillation Prior stroke TIA Diabetes PAD PCI CABG Carotid endarterectomy Peripheral angioplasty or bypass Diabetic nephropathy Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

97 Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death) Cumulative event rate (%) Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] P= Months since randomization First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA mg/day The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

98 Results for Primary Endpoint by Prior Medical History p value Characteristic N HR (95% CI) interaction Diabetes Yes (0.84, 1.17) 0.28 No (0.74, 1.03) Hypertension Yes (0.83, 1.08) 0.57 No (0.68, 1.12) Hypercholesterolemia Yes (0.83, 1.10) 0.46 No (0.70, 1.07) History of CABG Yes (0.82, 1.34) 0.28 No (0.79, 1.03) History of PCI Yes (0.69, 1.17) 0.77 No (0.82, 1.07) History of MI Yes (0.69, 1.00) 0.13 No (0.86, 1.17) History of Stroke Yes (0.69, 1.04) 0.29 No (0.84, 1.12) Multiple Risk Factors (0.91, 1.59) Manifest CV Disease (0.77, 0.998) Clopidogrel Better Placebo Better Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

99 Statin Therapy Reduces CVD Events in DM Approximately to Un Rx d Risk in Non Diabetics CTT Meta Analysis of 14 Statin Trials a Major Vascular Event Rate b, % 40 Control CVD Risk Higher Than Patients 34,9 With No Diabetes on Placebo Treatment c ,6 Residual Risk 24,8 19,4 Residual Risk 0 Diabetes a 4.3 year mean follow up of patients with diabetes; n = patients with no diabetes b Nonfatal MI, CHD death, stroke, or coronary revascularization c Event rate per 1 mmol/l (39 mg/dl) reduction in LDL C No Diabetes CTT Collaborators. Lancet. 2008;371:

100 Flow of patients 9795 randomised 6051 Australia, 2351 New Zealand, 1393 Finland 4900 Placebo 4895 Fenofibrate 200 mg 5 withdrew consent 10 lost to follow-up 4 withdrew consent 12 lost to follow-up 4856 (99%) primary outcome confirmed 4852 (99%) primary outcome confirmed

101

102 Proportional effects on cause-specific mortality per mmol/l reduction in LDL cholesterol in participants presenting with or without diabetes Cholesterol Treatment Trialists' (CTT) Collaborators Lancet 2008;371:117-25