VASCULAR PROTECTION - DIABETES - 2006 Evidence Guidelines CDA 2003 ADA 2006 CHEP 2006 André Roussin MD, FRCP Vascular laboratory Notre-Dame Hospital (CHUM) Associate professor University of Montreal

Disclosures André Roussin MD Speaker and/or Advisory board member AstraZeneca Bristol-Myers Squibb Merck Frost Schering Pfizer Canada Inc. sanofi aventis

Vascular Protection Attendee Objectives TO BE ABLE TO: Define vascular protection and interventions Understand the evidence Apply CDA, ADA, CHEP and Lipid guidelines

Vascular Protection Definition Prevent the “triple end-point” Stroke (mainly ischemic) MI Vascular death Prevent the broader vascular end-point Same as above + hospitalisation for ischemic events Also All CAD, PAD, ASO renal disease

Vascular Protection Main Intervention targets For almost all: ACE inhibitors and antiplatelet therapy Blood pressure control Glycemic control Lipid control LDL and CT/HDL HDL, TG, ApoA/ApoB, Lp(a) Smoking cessation Lifestyle modification Weight reduction Sedentarity-activity

Vascular Protection CHD and Risk factors in perspective: 1999 Type II Diabetes & Coronary Heart Disease 7 Year Incidence of Fatal/Nonfatal MI from the East West Study Non-diabetic n=1373 Diabetic n=1059 P<0.001 7-year incidence rate of myocardial infarction p<0.001 DM- diabetes mellitus MI- myocardial infarction Haffner, et al. N Engl J Med 1998;339:229-234

Vascular Protection CHD and Risk factors in perspective: 2006 10 yr Figure 1ﾑThe 10-year cumulative incidence of CHD in men and women by diabetes status andprevious CHD. Data are 10-year cumulative incidences. Corresponding data for incidence rates(per 1,000 person-years) for men for total CHD were 16.9 (1.0 reference group) and 33.9 (HR 2.0[95% CI 1.6 ﾐ2.5]) in nondiabetic (ND) and diabetic (DM) men without previous (Prev) CHD and104.8 (HR 4.7 [3.0 ﾐ7.3]) and 138.3 (6.4 [4.5ﾐ9.2]) in nondiabetic and diabetic men with previousCHD. For women, the totalCHDrates/1,000 person-years were 6.8 (1.0 reference group) and 24.6(HR 3.5 [2.8 ﾐ 4.5]) in nondiabetic and diabetic women without previous CHD and 98.0(12.8[5.1ﾐ32.0]) and 116.3 (14.5 [8.7ﾐ24.0]) in nondiabetic and diabetic women with previousCHD. The rates per 1,000 person-years for fatal CHD in men were 5.2 (1.0 reference group) and15.0 (HR 1.6 [1.2ﾐ2.1]), 39.3 (2.2 [1.1ﾐ 4.5]), and 45.0 (1.6 [1.0 ﾐ2.6]) and 1.4 (1.0 referencegroup), 10.3 (HR 2.1 [1.3ﾐ3.4]), 39.2 (2.7 [0.6 ﾐ12.7]), and 64.0 (4.1 [1.9ﾐ8.9]) in women. Howard BV et al. Diabetes Care 2006, 29:391-397

Vascular Protection CHD and Risk factors in perspective: 2006 10 yr Figure2ﾑThe 10-year cumulative incidenceof CHD by numbers of risk factors(men and women combined).Baseline risk factors include sex, LDLcholesterol 100 mg/dl, albuminuria( 300 mg/g creatinine), hypertension,HDL 40 mg/dl, triglycerides 150mg/dl, current smoking, 4th quartile offibrinogen ( 352 mg/dl), and diabetesduration 20 years. DM, diabetes;ND, no diabetes; Prev, previous. Howard BV et al. Diabetes Care 2006, 29:391-397

Prévention primaire Avantages et risques de AAS selon le risque coronarien à 5 ans .* Estimates based on 1000 patients receiving aspirin for 5 years and a relative riskreduction of 28% for coronary heart disease (CHD) events in those who receivedaspirin. CHD events nonfatal acute myocardial infarction, fatal CHD. Valuesin parentheses are 95% CIs. The following caveats apply to these estimates.1) Reduction in CHD risk may be smaller in women, but data are limited. 2) Forelderly persons, absolute risk for hemorrhagic stroke and major gastrointestinalbleeding may be two to three times higher in patients receiving aspirin; however,aspirin may provide benefit in elderly persons by reducing ischemic stroke, theincidence of which increases with age. Aspirin does not appear to improve incidenceof ischemic stroke in middle-aged patients. 3) Risk for hemorrhagic strokemay be greater with larger doses of aspirin. 4) Aspirin may not prevent myocardialinfarction in patients with uncontrolled hypertension (systolic blood pressure 150 mm Hg). 5) Long-term outcomes ( 5–7 years) are unknown. 6) Patients athigh risk ( 10% 5-year risk) may derive greater benefit from aspirin, including a15% to 20% reduction in ischemic stroke and all-cause mortality, because theirrisk is similar to that of patients with known CHD. Hayden M et al. U.S. Preventive ServicesTask Force. Ann Intern Med. 2002;136:161-172

Diabète en “prévention primaire” Antiplaquettaires La proportion de patients diabétiques est petite dans la plupart des études en prévention primaire PPP: 17% HOT: 8% PHS: 2% BMD: 2% TPT: 2% < 20 % Patients with Diabetes MellitusThe proportion of patients with diabetes mellituswas small in each trial (PPP, 17%; HOT, 8%; PHS,2%; BMD, 2%; TPT, 2%). In PHS, patients with diabetesderived greater benefit from aspirin than thosewithout diabetes (relative risk, 0.39 vs. 0.60). Pooleddata from aspirin trials in secondary prevention settings(23) and a single trial in diabetic patients with and withoutcoronary heart disease (12) also suggested that diabeticpatients benefit as much or more from aspirin asnondiabetic patients. Hayden M et al. U.S. Preventive ServicesTask Force. Ann Intern Med. 2002;136:161-172

Risk of MI over 5 years of follow-up2: Reduced by ASA from 10 % to 4% Diabète en “prévention primaire” : Antiplaquettaires Physicians Health Study In PHS, patients with diabetes derived greater benefit from aspirin than those without diabetes 1 Relative risk: 0.39 vs. 0.60 Risk of MI over 5 years of follow-up2: Reduced by ASA from 10 % to 4% Diabetes mellitus is associated with a risk of fatalcoronary heart disease that is as high as the risk associatedwith a history of myocardial infarction in patientswithout diabetes.30Whether prophylactic aspirintherapy reduces the risk of coronary events in patientswith diabetes has not been systematically studied. Inthe Physiciansﾕ Health Study, aspirin use reduced therisk of myocardial infarction in patients with diabetesfrom 10 percent to 4 percent during five years of follow-up, and no interactions with treatments for diabeteswere noted. N Engl J Med, Vol. 346, No. 19㈱ May 9, 2002 1. Hayden M et al. U.S. Preventive ServicesTask Force. Ann Intern Med. 2002;136:161-172 2. PHS. N Engl J Med 1989; 321:129-35.

Diabète en “prévention primaire” : Antiplaquettaires Antithrombotic Trialists' Collaboration 2002 % odds reduction Much of the new information comes from the early treatment diabetic retinopathy study, in which 3711 people with diabetes (and, generally, no history of myocardial infarction or stroke) were allocated to receive 650 mg aspirin dailyor placebo. BMJ 2002, vol 24: 71-86

Diabète en “prévention secondaire” Antiplaquettaires Pooled data from aspirin trials in secondary prevention settings1 and a single trial in diabetic patients with and without coronary heart disease2 suggest that diabetic patients benefit as much or more from aspirin as non diabetic patients. ETDRS Investigators.Similarly, although antiplatelet therapy was associﾁｩated with only a nonﾁｩsignificant 7% (8%) proportionalreduction in serious vascular events among patientswith diabetes mellitus (but, predominantly, no historyof myocardial infarction or stroke), these results do notprovide reliable evidence of a lack of worthwhilebenefit in such patients. Indeed, taken as a whole theyindicate the converse, although direct evidence fromfurther randomised trials of antiplatelet therapyamong diabetic patients would still be helpful.However, our previous finding that antiplatelet therapyis similarly effective among patients with preﾁｩexistingsymptomatic vascular disease who do and do not havediabetes1 suggests that aspirin is likely to be effective forthe primary prevention of vascular events amongdiabetic patients. Furthermore, there is now goodevidence that antiplatelet therapy is not associated withany special risks (such as bleeding in the eye) inpatients with diabetes.29 Hence, it may be appropriateto consider antiplatelet therapy in diabetic patientswho are at substantial risk of a first vascular event (suchas those with proteinuria)45 and nonﾁｩdiabetic patientsat high risk because of preﾁｩexisting vascular disease,even if there is no direct evidence of benefit (as forpatients undergoing coronary artery surgery or thosewith heart failure46), provided that there are no specialrisks of bleeding that might outweigh the benefit. Thus,these findings can reasonably be extrapolated to a farwider range of high risk patients than those studied,but the further the extrapolation goes, the more desirﾁｩable it is to have direct evidenceﾑfor example, forpatients with renal disease, who are at high risk ofmyocardial infarction and ischaem 1. Antiplatelet Trialists Collaboration. BMJ. 1994; 308:81-106 2. ETDRS Investigators. JAMA. 1992; 268:1292-300 Hayden M et al. U.S. Preventive ServicesTask Force. Ann Intern Med. 2002;136:161-172

Diabète type I en prévention PRIMAIRE ADA 2006 Utiliser AAS (75-162 mg/jr) comme stratégie de prévention primaire chez les diabétiques type 1: Avec risque cardio-vasculaire augmenté Incluant ceux de plus de 40 ans Ou ceux avec des facteurs de risque additionnels: Antécédents familiaux de maladie CV Hypertension Tabagisme Dyslipidémie Albuminurie Niveau d’évidence : C Recommendations! Use aspirin therapy (75ﾐ162 mg/day)as a secondary prevention strategy inthose with diabetes with a history ofmyocardial infarction, vascular bypassprocedure, stroke or transient ischemicattack, peripheral vascular disease,claudication, and/or angina. (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 2 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 1 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (C)! People with aspirin allergy, bleedingtendency, receiving anticoagulant therapy,recent gastrointestinal bleeding,and clinically active hepatic disease arenot candidates for aspirin therapy.Other anti-platelet agents may be a reasonablealternative for patients withhigh risk. (E)! Aspirin therapy should not be recommendedfor patients under the age of 21years because of the increased risk ofReyeﾕs syndrome associated with aspirinuse in this population. People underthe age of 30 years have not been studied.(E) AAS non étudiée < 30 ans AAS à éviter < 21 ans (S. Reye)

Diabète type II en prévention PRIMAIRE ADA 2006 Utiliser AAS (75-162 mg/jr) comme stratégie de prévention primaire chez les diabétiques type 2: Avec risque cardio-vasculaire augmenté Incluant ceux de plus de 40 ans Ou ceux avec des facteurs de risque additionnels: Antécédents familiaux de maladie CV Hypertension Tabagisme Dyslipidémie Albuminurie Niveau d’évidence : A Recommendations! Use aspirin therapy (75ﾐ162 mg/day)as a secondary prevention strategy inthose with diabetes with a history ofmyocardial infarction, vascular bypassprocedure, stroke or transient ischemicattack, peripheral vascular disease,claudication, and/or angina. (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 2 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 1 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (C)! People with aspirin allergy, bleedingtendency, receiving anticoagulant therapy,recent gastrointestinal bleeding,and clinically active hepatic disease arenot candidates for aspirin therapy.Other anti-platelet agents may be a reasonablealternative for patients withhigh risk. (E)! Aspirin therapy should not be recommendedfor patients under the age of 21years because of the increased risk ofReyeﾕs syndrome associated with aspirinuse in this population. People underthe age of 30 years have not been studied.(E)

Diabète en prévention SECONDAIRE ADA 2006 Utiliser AAS (75-162 mg/jr) comme stratégie de prévention secondaire chez les diabétiques avec: Infarctus du myocarde Procédure de revascularisation AVC ou ICT Maladie artérielle périphérique Claudication Angine Niveau d’évidence: A Recommendations! Use aspirin therapy (75ﾐ162 mg/day)as a secondary prevention strategy inthose with diabetes with a history ofmyocardial infarction, vascular bypassprocedure, stroke or transient ischemicattack, peripheral vascular disease,claudication, and/or angina. (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 2 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (A)! Use aspirin therapy (75ﾐ162 mg/day)as a primary prevention strategy inthose with type 1 diabetes at increasedcardiovascular risk, including thosewho are $40 years of age or who haveadditional risk factors (family history ofCVD, hypertension, smoking, dyslipidemia,or albuminuria). (C)! People with aspirin allergy, bleedingtendency, receiving anticoagulant therapy,recent gastrointestinal bleeding,and clinically active hepatic disease arenot candidates for aspirin therapy.Other anti-platelet agents may be a reasonablealternative for patients withhigh risk. (E)! Aspirin therapy should not be recommendedfor patients under the age of 21years because of the increased risk ofReyeﾕs syndrome associated with aspirinuse in this population. People underthe age of 30 years have not been studied.(E)

Diabète et alternatives antiplaquettaires ADA 2006 People with: Aspirin allergy Bleeding tendency Receiving anticoagulant therapy Recent gastrointestinal bleeding Clinically active hepatic disease Are not candidates for aspirin therapy. Other anti-platelet agents may be a reasonable alternative for patients with high risk. Level of evidence : E

Clopidogrel: amplified benefit over ASA In CAPRIE patients with a history of diabetes Le traitement des patients à haut risque ASA Clopidogrel Events prevented / 1000 pts/yr over aspirin p = 0.032 5 10 15 20 25 Annual event rate (%) 38 21 21,5 % 9 17,7 % 17,7 % 15,6 % 12,7 % 11,8 % Diapositive 19 L’étude CAPRIE comptait 3 866 patients atteints de diabète sucré. En prenant soin de pas compter deux fois les mêmes événements, Bhatt et al. ont compilé les taux d’événements chez les patients diabétiques appartenant aux deux branches de traitement. Chez les 1 952 patients diabétiques qui avaient été assignés de façon aléatoire au groupe recevant l’AAS, le taux d’événements annuel s’élevait à 17,7 %, contre 15,6 % chez les 1 914 patients assignés au groupe recevant le clopidogrel (p = 0,042). Les chercheurs ont trouvé que la réduction du risque absolu obtenue avec le clopidogrel était supérieure chez les patients diabétiques recevant de l’insuline : le taux d’événements a été de 21,5 % avec l’AAS, contre 17,7 % avec le clopidogrel (p = 0,106). Dans un modèle multifactoriel incorporant les caractéristiques cliniques de départ, le traitement avec le clopidogrel a été associé de façon indépendante à une réduction du nombre de cas de mort vasculaire, d’IM, d’AVC et de réhospitalisation (pour saignements ou ischémie) chez des patients diabétiques (p = 0,032). Ceci équivaut à la prévention de quelque 38 accidents ischémiques importants de plus par 1 000 années-patients si le clopidogrel est utilisé au lieu de l’AAS. Référence Bhatt et al. J Am Coll Cardiol, 2000, 35(Suppl. A), p. 409. Bhatt DL, Marso SP, Hirsch AT, et al. Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol (United States), Sep 15 2002, 90(6) p625-8 Following an ischemic event, diabetic patients have a higher rate of recurrence than patients without diabetes mellitus. 1–6 Patients with diabetes but without prior myocardial infarction (MI) have a risk of MI during follow-up that is similar to that of nondiabetic patients who have already had a prior MI. 7 The mechanisms for the heightened risk are multifactorial. 8 However, a greater thrombotic predisposition exists with diabetes, which is largely mediated by platelets. 9–13 Aspirin has been shown to have a modest benefit over placebo in reducing vascular events in patients with diabetes mellitus. 14 The intravenous antiplatelet agent abciximab has been found to be particularly efficacious in patients with diabetes who are undergoing percutaneous revascularization. 15,16 Platelet glycoprotein IIb/IIIa inhibitors, when used for acute coronary syndromes, appear to have their greatest benefit in diabetic patients. 17 The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) study randomized 19,185 patients with recent ischemic stroke, recent MI, or established peripheral arterial disease to the adenosine diphosphate (ADP) receptor antagonist clopidogrel or to aspirin. 18 An 8.7% relative risk reduction was seen in vascular death, MI, or ischemic stroke with use of clopidogrel. A subsequent analysis of CAPRIE found an additional 8.7% reduction in rehospitalization for ischemia or bleeding. 19 non-diabetic All diabetics With insulin Events : MI, IS, VD, hospitalization for ischemic event / bleeding. Bhatt et al. AJC 2002 Sep 15;90(6):625-8

Multiple vascular bed disease: the CAPRIE experience Clopidogrel over ASA to prevent IS, MI, VD and Hosp for IE or bleeding / year High-risk Population ASA Clopidogrel Event rate % RRR (%) ARR (%) NNT Total CAPRIE population 13.67 8.1 1.1 90 Patients with PAD NA Patients with mutivascular territory involvment Patients with a history of more than one ischemic event 36.5 / 3yr 10.7 3.9 26 Patients with diabetes 17.7 11.8 2.1 48 Patients with previous CABG 22.3 28.7 6.4 16 Patients taking lipid-lowering agents 14.6 18.5 2.7 37

Diabète et combinaison antiplaquettaires ADA 2006 Combination therapy using other antiplatelet agents such as clopidrogel in addition to aspirin should be used in patients with severe and progressive CVD Level of evidence : C

Primary efficacy end point in perspective CHARISMA vs CAPRIE MI Stroke CV death 28 months ASA ASA + Clop. RRR P value 12 months ARR Per year Events saved/ 1000pts/yr NNT Per yr If p < 0.05 CH: ALL 7.3% 6.8% 7% 0.22 3.12% 2.91% 0.21% 2.1 476 AT 7.9% 6.9% 13% 0.046 3.39% 2.96% 0.43% 4.3 233 RF 5.5% 6.6% -20% 0.2 2.36% 2.83% -0.88% -4.8 CP: ALL 5.83% 200 7.7% MI/PAD 4.8% All prev MI 6.25% PAD/Str. Prev. MI 10.7% 42 Background Dual antiplatelet therapy with clopidogrel plus low-dose aspirin has not been studiedin a broad population of patients at high risk for atherothrombotic events. Methods We randomly assigned 15,603 patients with either clinically evident cardiovasculardisease or multiple risk factors to receive clopidogrel (75 mg per day) plus low-doseaspirin (75 to 162 mg per day) or placebo plus low-dose aspirin and followed themfor a median of 28 months. The primary efficacy end point was a composite ofmyocardial infarction, stroke, or death from cardiovascular causes. Results The rate of the primary efficacy end point was 6.8 percent with clopidogrel plus aspirinand 7.3 percent with placebo plus aspirin (relative risk, 0.93; 95 percent confidenceinterval, 0.83 to 1.05; P = 0.22). The respective rate of the principal secondary efficacyend point, which included hospitalizations for ischemic events, was 16.7 percent and17.9 percent (relative risk, 0.92; 95 percent confidence interval, 0.86 to 0.995; P = 0.04),and the rate of severe bleeding was 1.7 percent and 1.3 percent (relative risk, 1.25; 95percent confidence interval, 0.97 tο 1.61 percent; P = 0.09). The rate of the primaryend point among patients with multiple risk factors was 6.6 percent with clopidogreland 5.5 percent with placebo (relative risk, 1.2; 95 percent confidence interval, 0.91 to1.59; P = 0.20) and the rate of death from cardiovascular causes also was higher withclopidogrel (3.9 percent vs. 2.2 percent, P = 0.01). In the subgroup with clinically evidentatherothrombosis, the rate was 6.9 percent with clopidogrel and 7.9 percent withplacebo (relative risk, 0.88; 95 percent confidence interval, 0.77 to 0.998; P = 0.046). Conclusions In this trial, there was a suggestion of benefit with clopidogrel treatment in patientswith symptomatic atherothrombosis and a suggestion of harm in patients with multiplerisk factors. Overall, clopidogrel plus aspirin was not significantly more effectivethan aspirin alone in reducing the rate of myocardial infarction, stroke, or death fromcardiovascular causes.

Lignes directrices de l’ACD 2003 Protection rénale et vasculaire Chez tous les patients diabétiques: Antiplaquettaire (AAS à faible dose) Inhibiteur de l’ECA Contrôle de la TA Contrôle de la glycémie Contrôle des lipides Modification du mode de vie Arrêt du tabagisme 1. PROTECTION VASCULAIRE 2. MAÎTRISE DE LA TA 3. TRAITEMENT DE LA NÉPHROPATHIE En matière de prévention des complications du diabète, il convient d’abord et avant tout de réduire le risque cardiovasculaire au moyen d’une stratégie de protection vasculaire comportant plusieurs volets (présentés par ordre alphabétique) : AAS suivant les recommandations, arrêt du tabagisme, inhibiteur de l’ECA, maîtrise optimale de la lipidémie, maîtrise optimale de la tension artérielle et de la glycémie et modification du mode de vie. Référence : Canadian Journal of Diabetes, Canadian Diabetes Association 2003 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada, déc. 2003, p.S58-59. Can J Diabetes 2003;27:S58-S65. Can J Diabetes 2003; 27:S58-S65

HOPE Objectif et méthodologie de l’étude n=9 297 ≥ 55 ans, antécédents de maladie cardiovasculaire MCAS AVC/ICT MAP Diabète + 1 autre facteur de risque Hypertension Chol élevé HDL-Chol bas Tabagisme Micro-albuminurie 38% des pts Ramipril 10 mg HS vs placebo Suivi de 4,5 ans L’essai HOPE avait pour but d’évaluer l’effet du ramipril sur la réduction des événements cardiovasculaires chez les patients exposés à un risque élevé. Neuf mille deux cent quatre-vingt-dix-sept (9 297) patients exposés à un risque élevé (âgés de 55 ans ou plus) ayant des antécédents de maladie vasculaire (maladie coronarienne, accident vasculaire cérébral, artériopathie périphérique) ou présentant un diabète et un autre facteur de risque cardiovasculaire (hypertension, taux élevé de cholestérol total, faible taux de cholestérol HDL, tabagisme ou microalbuminurie documentée) ont reçu, au terme d’une randomisation, du ramipril (10 mg, 1 fois par jour par voie orale) ou un placebo de même apparence durant en moyenne 5 ans. Ont été exclus les patients qui présentaient une insuffisance cardiaque, une FEVG inférieure à 40 % ou une hypertension non maîtrisée. Le paramètre principal était composé des issues suivantes : infarctus du myocarde, AVC ou décès d’origine cardiovasculaire. Les paramètres secondaires étaient la mortalité toutes causes confondues, la nécessité de subir une revascularisation, l’hospitalisation pour cause d’angine instable ou d’insuffisance cardiaque, de même que les complications liées au diabète (nécessitant ou non une hospitalisation). L’aggravation de l’angine, l’arrêt cardiaque, l’insuffisance cardiaque (nécessitant ou non une hospitalisation), l’angine instable avec altérations visibles à l’ECG et l’apparition du diabète étaient d’autres issues à l’étude. Critères d’évaluation principaux: Mortalité CV + IM + AVC HOPE Investigators. N Engl J Med; 2000.

HOPE : Ramipril à 10 mg vs placebo Bienfaits CV du ramipril chez les patients atteints de maladie CV Âge moyen: 66 ± 7 ans 5 AVC (p = 0,0003) Mortalité totale (p = 0,0053) Nouveaux cas de diabète (p = 0,0001) lM, AVC, décès d’origine CV (p = 0,000002) -22,0 Décès d’origine CV (p = 0,0002) -26,0 Infarctus du myocarde (p = 0,0005) -20,0 -16,0 -32,0 -10 -5 -30 RRR (%) -25 -15 -20 -35 -34,0 -23,0 IC (p < 0,001) L’étude HOPE a démontré que, comparativement au placebo, le ramipril dosé à 10 mg réduisait significativement, soit de 22 %, la fréquence des infarctus du myocarde, des AVC et des décès d’origine cardiovasculaire. La fréquence des événements composant le paramètre principal a également été réduite de façon significative, soit de 20 % dans le cas de l’IM, de 32 % dans le cas de l’AVC et de 26 % dans le cas des décès d’origine cardiovasculaire. Parmi les autres événements dont la fréquence a été significativement réduite, mentionnons la mortalité totale, l’insuffisance cardiaque et les nouveaux cas de diabète. Référence : N Engl J Med 2000;342:145-53. HOPE Investigators. N Engl J Med; 2000.

HOPE : Ramipril à 10 mg vs placebo Bienfaits CV du ramipril chez les patients DIABETIQUES Décès CV Néphropathie sous-jacente Rami. Plac. Epidemio TA syst ↓ 1.9 ↑.55 ↓10 TA diast ↓3.3 ↓2.3 ↓5 IM AVC -10 Réduction du risque (%) -20 22 % 24 % p = 0,01 Pour ↓38% AVC et ↓16% MCAS p = 0,027 -30 33 % Les résultats et les risques relatifs qui figurent sur cette diapo se rapportent aux 3 577 diabétiques auxquels on donnait du ramipril ou un placebo. Le ramipril a eu un effet protecteur évident et constant sur les critères de jugement primaire, tout comme sur chacun des éléments du critère de jugement primaire combiné. Ce qui n’apparaît pas sur la diapo, ce sont les effets bénéfiques constants dans l’ensemble des sous-groupes cliniques (diabète de type 1 par rapport au diabète de type 2, hommes par rapport aux femmes, microalbuminurie par rapport à l’absence de microalbuminurie, antécédents de maladie cardiovasculaire par rapport à l’absence d’antécédents de maladie cardiovasculaire, insulinothérapie par rapport à l’absence d’insulinothérapie). Ce qui n’apparaît pas également, c’est que l’abaissement de la tension artérielle par le ramipril était de 1,9 mm pour la tension systolique et de 3,3 mm pour la tension diastolique comparativement à une élévation de la tension systolique, de 0,55 mm et une chute de la tension diastolique de 2,3 mm dans le groupe placebo. Cette variation de la tension artérielle est beaucoup trop faible pour expliquer les effets bénéfiques qui ont été observés. C’est que, selon des études épidémiologiques, il faut une chute de tension systolique de 10 mm et de tension diastolique de 5 mm pour obtenir une réduction de 38 % des accidents vasculaires cérébraux et de 16 % des maladies coronariennes. Dans cette étude, des réductions du risque > 20 % pour chacun de ces critères de jugement ont été observées pour des effets bien plus modestes sur la tension artérielle. p = 0,007 37 % -40 p = 0,0001 Hope Study Investigators. Lancet 2000, 355:253-259.

HOPE-TOO : Effets à long terme du ramipril Mortalité CV, IM et AVC Fin de l’étude HOPE 0,30 70% sur IECA 0,25 Placebo 0,20 Étude HOPE (paramètres d’évaluation combinés) Proportion de patients Ramipril 0,15 0,10 p = 0,0002 0,05 Étude HOPE-TOO (Heart Outcomes Prevention Evaluation – The Ongoing Outcomes) Dans le cadre de l’étude complémentaire HOPE-TOO, 4 528 patients ont fait l’objet d’un suivi (dans 174 centres). On a mis fin au traitement à l’insu et on a conseillé aux patients de prendre un inhibiteur de l’ECA. Les investigateurs se sont intéressés aux mêmes issues cardiovasculaires que celles dont on a tenu compte dans l’étude HOPE. La durée du suivi prolongé a été de 2,6 ans. Emploi d’un inhibiteur de l’ECA durant la phase complémentaire : - groupe ramipril de l’étude HOPE (n = 2317) : 72 % - groupe placebo de l’étude HOPE (n = 2211) : 68 % Plus de 90 % des participants à l’étude HOPE-TOO ont eu recours au ramipril. Durant le suivi postérieur à l’étude, les patients ayant reçu le ramipril présentaient un risque relatif d’IM 19 % moins élevé (IC de 95 %, de 0,65 à 1,01), un risque relatif de revascularisation 16 % moins élevé (IC de 95 %, de 0,70 à 0,99) et un risque relatif 34 % moins élevé de recevoir un nouveau diagnostic de diabète (IC de 95 %, de 0,46 à 0,95). Des réductions semblables du risque relatif d’événements vasculaires ont été observées durant et après la phase active de l’étude, et ce, peu importe le risque initial (risque relatif de 0,76, 0,89 et 0,83, respectivement, chez les patients exposés à un risque faible, moyen et élevé) ou les traitements auxiliaires utilisés (risque relatif de 0,90 pour l’AAS, de 0,76 pour les bêtabloquants et de 0,84 pour les hypolipidémiants). Conclusions Les bienfaits du ramipril se sont maintenus durant le suivi postérieur à l’étude en ce qui a trait aux décès d’origine cardiovasculaire, aux AVC et à l’hospitalisation pour cause d’insuffisance cardiaque. Une réduction additionnelle de la fréquence des IM, des interventions de revascularisation et des nouveaux cas de diabète a également été observée en dépit de taux semblables d’utilisation d’inhibiteurs de l’ECA dans les groupes formés au hasard. Il est probable que la réduction des issues cardiovasculaires démontrée dans l’étude HOPE ne témoigne que d’une partie des effets du traitement prolongé par le ramipril. Référence : Long-Term Effects of Ramipril on Cardiovascular Events and on Diabetes. Results of the HOPE Study Extension. Circulation; oct. 2005. 0,0 1 2 3 4 5 6 7 Temps (années) Nbre sous placebo 4652 4432 4204 3981 3647 2719 1923 1550 Nbre sous ramipril 4645 4456 4256 4079 3789 2819 2075 1731 HOPE/HOPE-TOO Study Investigators. Circulation. 2005; 112:1339-46.

HOPE et TA ambulatoire Comparaison avec la TA en clinique 38 patients ±71 ans avec ASO M Inf ont eu MAPA TA 151/81 par apport à 139/79 pour HOPE TA en clinique ↓ 8/2 NS MAPA jour ↓ 6/2 NS MAPA nuit ↓ 17/8 p < 0.001 MAPA 24hr ↓ 10/4 p < 0.03 Attention! Petit sous-groupe Patients + âgés Avec TA élevée Svensson P et al. Hypertension 2001; 38: e28-e32

MI and microvascular endpoints Incidence by mean systolic BP and HbA1c concentration UKPDS 36 UKPDS 35 MI Microvascular end points MI Microvascular end points 50 80 60 40 20 40 MI MI 30 Adjusted incidence/ 1000 person-y (%) Adjusted incidence/ 1000 person-y (%) 20 10 110 120 130 140 150 160 170 5 6 7 8 9 10 11 Updated mean systolic BP (mm Hg) Updated mean HbA1c concentration (%) Adler et al. BMJ. 2000, 321: 412-419. Stratton et al. BMJ. 2000, 321: 405-412

MI and microvascular endpoints Incidence by mean systolic BP UKPDS 36 50 MI 40 30 Adjusted incidence/ 1000 person-y (%) 20 10 AbstractObjective To determine the relation between systolicblood pressure over time and the risk ofmacrovascular or microvascular complications inpatients with type 2 diabetes.Design Prospective observational study.Setting 23 hospital based clinics in England, Scotland,and Northern Ireland.Participants 4801 white, Asian Indian, andAfroﾁﾓCaribbean UKPDS patients, whetherrandomised or not to treatment, were included inanalyses of incidence; of these, 3642 were included inanalyses of relative risk.Outcome measures Primary predefined aggregateclinical outcomes: any complications or deaths relatedto diabetes and all cause mortality. Secondaryaggregate outcomes: myocardial infarction, stroke,lower extremity amputation (including death fromperipheral vascular disease), and microvasculardisease (predominantly retinal photocoagulation).Single end points: nonﾁﾓfatal heart failure and cataractextraction. Risk reduction associated with a 10 mmHg decrease in updated mean systolic blood pressureadjusted for specific confoundersResults The incidence of clinical complications wassignificantly associated with systolic blood pressure,except for cataract extraction. Each 10 mm Hgdecrease in updated mean systolic blood pressure wasassociated with reductions in risk of 12% for anycomplication related to diabetes (95% confidenceinterval 10% to 14%, P < 0.0001), 15% for deathsrelated to diabetes (12% to 18%, P < 0.0001), 11% formyocardial infarction (7% to 14%, P < 0.0001), and13% for microvascular complications (10% to 16%,P < 0.0001). No threshold of risk was observed for anyend point.Conclusions In patients with type 2 diabetes the riskof diabetic complications was strongly associated withraised blood pressure. Any reduction in bloodpressure is likely to reduce the risk of complications,with the lowest risk being in those with systolic bloodpressure less than 120 mm Hg. 110 120 130 140 150 160 170 Updated mean systolic BP (mm Hg) Adler et al. BMJ. 2000, 321: 412-419

MI and microvascular endpoints Incidence by mean systolic BP UKPDS 36 Incidence rates (95% confidence interval) of myocardial infarction and microvascular end points bycategory of updated mean systolic blood pressure, adjusted for age, sex, and ethnic group expressed for white men aged 50-54 yearsat diagnosis and mean duration of diabetes of 10 years MI AbstractObjective To determine the relation between systolicblood pressure over time and the risk ofmacrovascular or microvascular complications inpatients with type 2 diabetes.Design Prospective observational study.Setting 23 hospital based clinics in England, Scotland,and Northern Ireland.Participants 4801 white, Asian Indian, andAfroﾁﾓCaribbean UKPDS patients, whetherrandomised or not to treatment, were included inanalyses of incidence; of these, 3642 were included inanalyses of relative risk.Outcome measures Primary predefined aggregateclinical outcomes: any complications or deaths relatedto diabetes and all cause mortality. Secondaryaggregate outcomes: myocardial infarction, stroke,lower extremity amputation (including death fromperipheral vascular disease), and microvasculardisease (predominantly retinal photocoagulation).Single end points: nonﾁﾓfatal heart failure and cataractextraction. Risk reduction associated with a 10 mmHg decrease in updated mean systolic blood pressureadjusted for specific confoundersResults The incidence of clinical complications wassignificantly associated with systolic blood pressure,except for cataract extraction. Each 10 mm Hgdecrease in updated mean systolic blood pressure wasassociated with reductions in risk of 12% for anycomplication related to diabetes (95% confidenceinterval 10% to 14%, P < 0.0001), 15% for deathsrelated to diabetes (12% to 18%, P < 0.0001), 11% formyocardial infarction (7% to 14%, P < 0.0001), and13% for microvascular complications (10% to 16%,P < 0.0001). No threshold of risk was observed for anyend point.Conclusions In patients with type 2 diabetes the riskof diabetic complications was strongly associated withraised blood pressure. Any reduction in bloodpressure is likely to reduce the risk of complications,with the lowest risk being in those with systolic bloodpressure less than 120 mm Hg. Adler et al. BMJ. 2000, 321: 412-419

Blood pressure control ADA 2006 Measure BP every visit Confirm any pressure ≥ 130/80 with 2nd visit If between 130-139 or 80-89 Try non-pharm. Tx for max 3 months If not controlled, add Rx If ≥ 140/90 ⇒ non-pharm. Tx AND Rx Initial Rx to include ACEI or ARB Add CCB, DIURETIC or BB TARGET: BP < 130/80

CHEP 2006 Treatment of Systolic-Diastolic Hypertension for Diabetes WITHOUT Diabetic Nephropathy Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg Urinary albumin excretion rate less than 30 mg/day 1. ACE-Inhibitor or ARB or 2. Thiazide diuretic or Dihydropyridine CCB Combination of first line agents Diabetes without Nephropathy IF ACE-I and ARB and DHP-CCB or Thiazide are contraindicated or not tolerated, SUBSTITUTE • Cardioselective BB* or • Long-acting NON DHP-CCB Addition of one or more of: Cardioselective BB or Long-acting CCB 3. For persons with diabetes and normal urinary albumin excretion (less than 30 mg/day) and blood pressure greater than 130/80 mm Hg despite lifestyle interventions, an ACE inhibitor (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years), or an angiotensin II receptor blocker (Grade A for persons with LVH and age greater than or equal to 55 years, Grade B for persons without LVH irrespective of age) or a thiazide diuretic (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years) is recommended. If these drugs are contraindicated or cannot be tolerated, a cardioselective beta-adrenergic blocker (grade B) or long acting calcium channel blocker (grade C) can be substituted. If blood pressure targets cannot be reached despite an ACE inhibitor, angiotensin II receptor blocker, or thiazide diuretic, then these drugs in combination or addition of one or more of a cardioselective beta-blocker or long acting calcium channel blocker can be considered (Grade D). Comment: The recommendation of the use of a thiazide diuretic as first-line therapy in hypertensive patients with diabetes and normal urinary albumin excretion (along with ACE-inhibitors and ARBs) is based on interpretation of the results from ALLHAT. 4. For persons with diabetes and a serum creatinine over 150 mol/L, the choice of antihypertensive drugs is the same as above, except that a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired (grade D). Comment: Note that the implicit restriction of the use of thiazides to a “low dose” has been removed. This is based on the observation that the ALLHAT chlorthalidone regimen could not be viewed as a “low-dose” regimen. DHP: dihydropyridine More than 3 drugs may be needed to reach target values for diabetic patients * Cardioselective BB: Acebutolol, Atenolol, Bisoprolol , Metoprolol

CHEP 2006 Treatment of Systolic-Diastolic Hypertension for Diabetes WITH Diabetic Nephropathy Urinary albumin excretion rate over 30 mg/day THRESHOLD equal or over 130/80 mmHg and TARGET below 130/80 mmHg If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired DIABETES with Nephropathy ACE Inhibitor or ARB IF ACE-I and ARB are contraindicated or not tolerated, SUBSTITUTE • Long-acting CCB or • Thiazide diuretic Addition of one or more of Thiazide diuretic or Long-acting CCB 3 - 4 drugs combination may be needed Treatment of hypertension in association with diabetes mellitus 1. Persons with diabetes mellitus should be treated to attain diastolic blood pressures of 80 mmHg or less (grade A) and systolic blood pressures of 130 mmHg or less (grade C). (These target blood pressure levels are the same as the blood pressure thresholds) 2. For persons with diabetes and albuminuria (urinary albumin excretion rates over 30 mg/day) an ACE inhibitor or an angiotensin II receptor blocker is recommended as initial therapy (Grade A). If blood pressure remains greater than 130/80 mmHg despite lifestyle interventions and an ACE inhibitor or angiotensin II receptor blocker, then addition of one or more of a thiazide diuretic, long-acting calcium channel blocker, or use of ACE inhibitor and angiotensin II receptor blocker in combination can be considered (Grade D). If an ACE inhibitor and angiotensin II receptor blocker cannot be tolerated, a cardioselective beta-adrenergic blocker (Grade B), long acting calcium channel blocker (Grade C), or thiazide diuretic can be substituted (Grade B). Comment: We have recommended that this be changed, but not on the basis of ALLHAT. Sentence 2 in the version that was approved implies that use of an ACE inhibitor - ARB combination should be tried ahead of all other add-on and combination options. There is no evidence to support this position and it was not the original intent of the Diabetic subcommittee to indicate a preference for ACE inhibitor/ARB combination therapy over any other strategy. We think the modified wording more clearly indicates this.

Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg CHEP 2006 Treatment of Systolic-Diastolic Hypertension for Diabetes SUMMARY Threshold equal or over 130/80 mmHg and TARGET below 130/80 mmHg with Nephropathy ACE Inhibitor or ARB Diabetes 1. ACE-Inhibitor or ARB or 2. Thiazide diuretic or DHP-CCB Combination (Effective 2-drug combination) without Nephropathy 3. For persons with diabetes and normal urinary albumin excretion (less than 30 mg/day) and blood pressure greater than 130/80 mm Hg despite lifestyle interventions, an ACE inhibitor (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years), or an angiotensin II receptor blocker (Grade A for persons with LVH and age greater than or equal to 55 years, Grade B for persons without LVH irrespective of age) or a thiazide diuretic (Grade A for persons aged greater than or equal to 55 years, Grade B for persons aged less than 55 years) is recommended. If these drugs are contraindicated or cannot be tolerated, a cardioselective beta-adrenergic blocker (grade B) or long acting calcium channel blocker (grade C) can be substituted. If blood pressure targets cannot be reached despite an ACE inhibitor, angiotensin II receptor blocker, or thiazide diuretic, then these drugs in combination or addition of one or more of a cardioselective beta-blocker or long acting calcium channel blocker can be considered (Grade D). Comment: The recommendation of the use of a thiazide diuretic as first-line therapy in hypertensive patients with diabetes and normal urinary albumin excretion (along with ACE-inhibitors and ARBs) is based on interpretation of the results from ALLHAT. 4. For persons with diabetes and a serum creatinine over 150 mol/L, the choice of antihypertensive drugs is the same as above, except that a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired (grade D). Comment: Note that the implicit restriction of the use of thiazides to a “low dose” has been removed. This is based on the observation that the ALLHAT chlorthalidone regimen could not be viewed as a “low-dose” regimen. More than 3 drugs may be needed to reach target values for diabetic patients If Creatinine over 150 µmol/L or creatinine clearance below 30 ml/min ( 0.5 ml/sec), a loop diuretic should be substituted for a thiazide diuretic if control of volume is desired

Blood pressure response in the INSIGHT study Diabetic vs non-diabetic patients Figure 1. Comparison of BP response to treatment titration indiabetics and nondiabetics. SBP (left axis) and DBP (right axis)were measured after initial randomization and optional treatmenttitration over 18 weeks in 1139 diabetics (M, f) and 4530 nondiabetics(L, l). 5669 pts Brown M J et al. Hypertension 2000; 35: 1038-1042

Blood pressure response in the INSIGHT study Diabetic vs non-diabetic patients 5669 pts AbstractﾑThe aim of our investigation was to determine whether the presence of additional risk factors or type ofhypertension (diastolic or isolated systolic) influences blood pressure (BP) response to treatment. The InternationalNifedipine GITS Study: Intervention as a Goal in Hypertension Treatment (INSIGHT) study is a double-blindedoutcome comparison of calcium channel blockade with diuretics in high-risk patients aged 55 to 80 years. Dynamicrandomization between nifedipine once daily and hydrochlorothiazide/amiloride was performed to ensure thatapproximately equal numbers of patients in the 2 groups had each of the major cardiovascular risk factors. Patients withisolated systolic hypertension were also separately randomized. Atenolol or enalapril was the mandatory second-linedrug. In 5669 patients who completed the 18-week titration, BP fell from 172615/9969 mm Hg (mean6SD) whilereceiving placebo to 139612/8267 mm Hg. Twenty-six percent of patients required 2 drugs, and 4% required 3 drugs.Patients with diabetes were the most resistant to treatment, requiring second and third drugs 40% and 100% morefrequently than patients without diabetes and achieving marginally the highest final BP, for any risk group, of141613/8268 mm Hg. Age, smoking, gender, hypercholesterolemia, left ventricular hypertrophy, and existingatherosclerosis had little (,1 mm Hg) or no influence on BP at the end of titration, but all except smoking slightlyreduced the initial response of either systolic or diastolic BP. Patients with isolated systolic hypertension were slightlymore responsive than average to treatment. Our findings suggest that in patients at high absolute risk of cardiovascularcomplications from hypertension, the risk factors themselves do not prevent the recommended BP targets frombeing achieved. (Hypertension. 2000;35:1038-1042.) Brown M J et al. Hypertension 2000; 35: 1038-1042

MI and microvascular endpoints Incidence by HbA1c concentration UKPDS 35 80 60 40 20 MI Adjusted incidence/ 1000 person-y (%) AbstractObjective To determine the relation betweenexposure to glycaemia over time and the risk ofmacrovascular or microvascular complications inpatients with type 2 diabetes.Design Prospective observational study.Setting 23 hospital based clinics in England, Scotland,and Northern Ireland.Participants 4585 white, Asian Indian, andAfroﾁﾓCaribbean UKPDS patients, whetherrandomised or not to treatment, were included inanalyses of incidence; of these, 3642 were included inanalyses of relative risk.Outcome measures Primary predefined aggregateclinical outcomes: any end point or deaths related todiabetes and all cause mortality. Secondary aggregateoutcomes:myocardial infarction, stroke, amputation(including death from peripheral vascular disease), andmicrovascular disease (predominantly retinal photoﾁﾓcoagulation). Single end points: nonﾁﾓfatal heart failureand cataract extraction. Risk reduction associated with a1% reduction in updated mean HbA1c adjusted forpossible confounders at diagnosis of diabetes.Results The incidence of clinical complications wassignificantly associated with glycaemia. Each 1%reduction in updated mean HbA1c was associated withreductions in risk of 21% for any end point related todiabetes (95% confidence interval 17% to 24%,P < 0.0001), 21% for deaths related to diabetes (15%to 27%, P < 0.0001), 14% for myocardial infarction(8% to 21%, P < 0.0001), and 37% for microvascularcomplications (33% to 41%, P < 0.0001). No thresholdof risk was observed for any end point.Conclusions In patients with type 2 diabetes the riskof diabetic complications was strongly associated withprevious hyperglycaemia. Any reduction in HbA1c islikely to reduce the risk of complications, with thelowest risk being in those with HbA1c values in thenormal range ( < 6.0%). 5 6 7 8 9 10 11 Updated mean HbA1c concentration (%) Stratton et al. BMJ. 2000, 321: 405-412

MI and microvascular endpoints Incidence by HbA1c concentration UKPDS 35 Incidence rates and 95% confidence intervals for myocardial infarction and microvascular complications by category of updated mean haemoglobin A1c concentration, adjusted for age, sex, and ethnic group, expressed for white men aged 50-54 years at diagnosis and with mean duration of diabetes of 10 years AbstractObjective To determine the relation betweenexposure to glycaemia over time and the risk ofmacrovascular or microvascular complications inpatients with type 2 diabetes.Design Prospective observational study.Setting 23 hospital based clinics in England, Scotland,and Northern Ireland.Participants 4585 white, Asian Indian, andAfroﾁﾓCaribbean UKPDS patients, whetherrandomised or not to treatment, were included inanalyses of incidence; of these, 3642 were included inanalyses of relative risk.Outcome measures Primary predefined aggregateclinical outcomes: any end point or deaths related todiabetes and all cause mortality. Secondary aggregateoutcomes:myocardial infarction, stroke, amputation(including death from peripheral vascular disease), andmicrovascular disease (predominantly retinal photoﾁﾓcoagulation). Single end points: nonﾁﾓfatal heart failureand cataract extraction. Risk reduction associated with a1% reduction in updated mean HbA1c adjusted forpossible confounders at diagnosis of diabetes.Results The incidence of clinical complications wassignificantly associated with glycaemia. Each 1%reduction in updated mean HbA1c was associated withreductions in risk of 21% for any end point related todiabetes (95% confidence interval 17% to 24%,P < 0.0001), 21% for deaths related to diabetes (15%to 27%, P < 0.0001), 14% for myocardial infarction(8% to 21%, P < 0.0001), and 37% for microvascularcomplications (33% to 41%, P < 0.0001). No thresholdof risk was observed for any end point.Conclusions In patients with type 2 diabetes the riskof diabetic complications was strongly associated withprevious hyperglycaemia. Any reduction in HbA1c islikely to reduce the risk of complications, with thelowest risk being in those with HbA1c values in thenormal range ( < 6.0%). Stratton et al. BMJ. 2000, 321: 405-412

Maîtrise glycémique pour la protection vasculaire : Une fois tous les patients sous IECA, AAS et maîtrise des lipides (statine) 5 Infarctus du myocarde mortel ou non : ACD 2003 : CIBLES GLYCÉMIQUES A1c  7 % chez la plupart des patients A1c  6 % quand cela est possible en toute sécurité Diminution de 14 % pour chaque % de réduction de l’A1C p < 0,0001 Rapport de risque 1 0,5 L’étude UKPDS a fait ressortir une relation linéaire directe entre les valeurs de l’A1c moyenne et la fréquence des infarctus du myocarde : chaque pourcentage de réduction (absolue) de l’A1c moyenne était associé à une diminution de 14 % de la fréquence des IM. L’étude UKPDS, une recherche observationnelle prospective, a été réalisée dans 23 cliniques d’hôpitaux d’Angleterre, d’Écosse et d’Irlande du Nord. En tout, 4 585 participants, affectés ou non à un traitement au terme d’une randomisation, ont été inclus dans les analyses de la fréquence; de ce nombre, 3 642 ont été inclus dans les analyses du risque relatif. PARAMÈTRES D’ÉVALUATION : Paramètre principal composé d’issues cliniques prédéfinies : toute issue ou mortalité liée au diabète et mortalité toutes causes confondues. Paramètre secondaire composé des événements suivants : infarctus du myocarde, AVC, amputation (incluant la mortalité attribuable à une artériopathie périphérique) et maladie microvasculaire (principalement photocoagulation de la rétine). Paramètres simples : insuffisance cardiaque non mortelle et extraction de cataracte. La diminution du risque associée à chaque pourcentage de réduction de l’A1c moyenne mise à jour a été rectifiée en fonction des facteurs confusionnels ayant pu être présents au moment du diagnostic de diabète. RÉSULTATS : La fréquence des complications cliniques était associée de manière significative à la glycémie. Chaque pourcentage de réduction de l’A1c moyenne mise à jour était associé à une diminution de 21 % du risque que survienne n’importe laquelle des issues ayant trait au diabète (intervalle de confiance à 95 %, de 17 à 24 %, p < 0,0001), de 21 % pour la mortalité associée au diabète (de 15 à 27 %, p < 0,0001), de 14 % pour les infarctus du myocarde (de 8 à 21 %, p < 0,0001) et de 37 % pour les complications microvasculaires (de 33 à 41 %, p < 0,0001). Aucun seuil de risque n’a été observé, quelle que soit l’issue. CONCLUSIONS : Chez les patients atteints de diabète de type 2, le risque de complications diabétiques était étroitement associé à une hyperglycémie antérieure. Toute diminution de la valeur de l’A1c est susceptible de réduire le risque de complications, le plus faible risque étant associé aux valeurs de l’A1c se situant dans la plage normale (< 6,0 %). Référence : Stratton et al. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 12 août 2000;321(7258):405-12. 5 6 7 8 9 10 11 A moyenne mise à jour 1c UKPDS 35. BMJ 2000; 321: 405-12.

CCS position statement 2006 Treatment of dyslipidemia and prevention of CVD Niveau de risque Risque MCAS en 10 ans Recommendations But du traitement Objectif accessoire LDL-C mmol/L CT/HDL Baisse de LDL-C Apo B Élevé ≥ 20 % ou ASO ou Diabète Cible primaire < 2.0 Cible secondaire < 4.0 > 50% < 0.85 Modéré 10 - 19% Traiter si ≥ 3.5 ≥ 5.0 > 40% < 1.05 Bas < 10% ≥ 6.0 < 1.2 Adapté de: Can J Cardiol 2006; 22 (11): 913-927

Étude HPS Notion de patient à risque plutôt que de lipides anormaux Hypertension n=8,455 (41%) CVD n=3,280 (16%) PVD n=6,748 (33%) Diabetes n=5,963 (29%) CHD n=13,379 (65%) with CHD 1,458 (7%) no CHD 1,822 (9%) 4,042 (20%) no CHD 2,706 (13%) 1,978 (10%) 3,985 (19%) 2,860 (14%) 5,595 (27%) with MI 8,510 (41%) no MI 4,869 (24%) 20,536 patients Lancet 2002; 360: 7-22

Étude HPS Évènements selon le critère d’entrée Baseline feature Statin (n=10,269) Placebo (n=10,267) Risk ratio and 95% CI Previous MI 1,007 1,255 Other CHD (not MI) 452 597 No prior CHD CVD 182 215 PVD 332 427 Diabetes 279 369 At entry to the study, there were 8,510 patients with prior MI, 4,876 with other coronary disease and 7,150 with no history of coronary disease. Most of the patients with a history of previous MI were elderly, female or had "low" cholesterol levels, and were not considered by their own doctors to have a clear indication for a statin at the time of study entry. Among the patients with no prior CHD, 1,820 had cerebrovascular disease, 2,701 had peripheral vascular disease, and 3,982 had diabetes (with some overlap between these three groups). ALL PATIENTS 2,042 2,606 24% SE 2.6 reduction (19.9%) (25.4%) (2P<0.00001) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Statin worse Lancet 2002; 360: 7-22

CARDS Collaborative Atorvastatin Diabetes Study Objective and Design Test the effectiveness and safety of lipid lowering for “primary” prevention in diabetic patients with low levels of LDL-C Atorvastatin 10mg Placebo 2838 patients Placebo 6 week pre-randomisation placebo run in phase then visits at month 1, 3, 6 and 6 monthly Colhoun H M. Lancet 2004: 364: 685-696

CARDS Eligibility Criteria Type 2 male or female diabetes 40-75 years of age No clinical history of CAD, CVD or severe PAD LDL-C 4.14 mmol/L TG 6.78 mmol/L One of : Hypertension defined as receiving antihypertensive treatment or SBP 140 mm Hg or DBP 90 mm Hg Retinopathy Microalbuminuria or macroalbuminuria Current smoking Colhoun H M. Lancet 2004: 364: 685-696

CARDS Endpoints Primary Efficacy Parameters Acute CHD death Non-fatal MI including silent MI Hospitalised unstable angina Resuscitated cardiac arrest Coronary revascularisation Stroke Secondary Efficacy Parameters Total mortality Any cardiovascular endpoint Lipid and lipoproteins Major coronary events Colhoun H M. Lancet 2004: 364: 685-696

CARDS Diabetes Related Characteristics 214 (15.0%) 228 (16.2%) Diet only 932 (65.3%) 916 (65.0%) Oral hypoglycaemic only 210 (14.7%) 207 (14.7%) Insulin only 72 (5.0%) 59 (4.2%) Insulin+oral hypoglycaemic 10.0 (3.3) 9.8 (3.2) Plasma glucose mmol/L 7.9 (1.4) 7.8 (1.4) HbA1c % Diabetes treatment 7.9 (6.4) 7.8 (6.3) Diabetes duration (years) Atorvastatin Mean (SD) or N (%) Placebo Mean (SD) or N (%) Colhoun H M. Lancet 2004: 364: 685-696

CARDS Lipid Levels by Treatment Total cholesterol (mmol/L) LDL cholesterol (mmol/L) Average difference 26% 1.4 mmol/L (54mg/dL) p<0.0001 Average difference 40% 1.2 mmol/L (46mg/dL) p<0.0001 6 4 3 4 2 2 1 1 2 3 4 4.5 1 2 3 4 4.5 Years of Study Years of Study Placebo Atorvastatin Colhoun H M. Lancet 2004: 364: 685-696

CARDS Cumulative Hazard for Primary Endpoint Relative Risk Reduction 37% (95% CI: 17-52) p=0.001 5 10 15 1 2 3 4 4.75 Placebo 127 events Cumulative Hazard (%) Atorvastatin 83 events Years Placebo 1410 1351 1306 1022 651 305 Atorva 1428 1392 1361 1074 694 328 Colhoun H M. Lancet 2004: 364: 685-696

CARDS Cumulative Hazard for Any CVD Endpoint Relative Risk Reduction= 32% (95% CI 15-45) p=0.001 5 10 15 20 1 2 3 4 4.75 Placebo 189 events Atorvastatin 134 events Cumulative Hazard (%) Years Placebo 1410 1334 1275 992 621 287 Atorva 1428 1372 1337 1040 663 306 Colhoun H M. Lancet 2004: 364: 685-696

CARDS Cumulative Hazard for All Cause Mortality Relative Risk Reduction 27% (95%CI: -1-48) p=0.059 1 2 3 4 4.75 6 8 10 Placebo 82 deaths Cumulative Hazard (%) Atorvastatin 61 deaths Years Placebo 1410 1395 1370 1094 709 332 Atorva 1428 1418 1401 1110 730 351 Colhoun H M. Lancet 2004: 364: 685-696

CARDS Treatment Effect on the Primary Endpoint by Subgroup Placebo** Atorva** Hazard Ratio Risk Reduction (CI) LDL-C ≥ 3.06 66 (9.5) 44 (6.1) 38% (9-58) LDL-C < 3.06 61 (8.5) 39 (5.6) 37% (6-58) p=0.96 HDL-C ≥ 1.35 62 (8.4) 36 (5.2) 41% (11-61) HDL-C < 1.35 65 (9.6) 47 (6.4) 35% (5-55) p=0.71 Trig. ≥ 1.7 67 (9.6) 40 (5.5) 44% (18-62) Trig. < 1.7 60 (8.4) 43 (6.1) 29% (-5-52) p=0.40 .2 .4 .6 .8 1 1.2 * units in mmol/L (mg/dL) ** N (% of randomised) Favours Atorvastatin Favours Placebo Colhoun H M. Lancet 2004: 364: 685-696

ASPEN Atorvastatin Study for Prevention of CAD Endpoints in Non-insulin-dependent DM Objective and Design assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. 2410 pts double blind 4 year study Composite primary endpoint: CV death, MI, Stroke, PTCA, CABG, Resc. card. Arrest , ACS requiring hosp. Knopp RH et al. Diabetes Care 2006; 29(7):1478-85

ASPEN Results for 2410 patients for 4 years LDL-Chol and End points Atorvastatine 10 mg Placebo Reduction LDL-Chol 29% vs Placebo P < 0.0001 - Composite Primary end-point (CPEP) All patients 13.7% HR 0.9 ns 15.0% CPEP without MI-PTCA-CABG 1905 pts 10.4% HR 0.97 ns 10.8% CPEP with MI-PTCA-CABG 505 pts 26.2% HR 0.82 ns 30.8% MI, fatal or not 27% RRR P = 0.10 OBJECTIVE: Cardiovascular disease (CVD) risk is increased in type 2 diabetes. The purpose of this study was to assess the effect of 10 mg of atorvastatin versus placebo on CVD prevention in subjects with type 2 diabetes and LDL cholesterol levels below contemporary guideline targets. RESEARCH DESIGN AND METHODS: Subjects were randomly assigned to receive 10 mg of atorvastatin or placebo in a 4-year, double-blind, parallel-group study. The composite primary end point comprised cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, recanalization, coronary artery bypass surgery, resuscitated cardiac arrest, and worsening or unstable angina requiring hospitalization. RESULTS: A total of 2,410 subjects with type 2 diabetes were randomized. Mean LDL cholesterol reduction in the atorvastatin group over 4 years was 29% versus placebo (P < 0.0001). When we compared atorvastatin versus placebo, composite primary end point rates were 13.7 and 15.0%, respectively (hazard ratio 0.90 [95% CI 0.73-1.12]). In the subset of 1,905 subjects without prior myocardial infarction or interventional procedure, 10.4% of atorvastatin- and 10.8% of placebo-treated subjects experienced a primary end point (0.97 [0.74-1.28]). In the 505 subjects with prior myocardial infarction or interventional procedure, 26.2% of atorvastatin- and 30.8% of placebo-treated subjects experienced a primary end point (0.82 [0.59-1.15]). Relative risk reductions in fatal and nonfatal myocardial infarction were 27% overall (P = 0.10) and 19% (P = 0.41) and 36% (P = 0.11) for subjects without and with prior myocardial infarction or interventional procedure, respectively. CONCLUSIONS: Composite end point reductions were not statistically significant. This result may relate to the overall study design, the types of subjects recruited, the nature of the primary end point, and the protocol changes required because of changing treatment guidelines. For these reasons, the results of the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) did not confirm the benefit of therapy but do not detract from the imperative that the majority of diabetic patients are at risk of coronary heart disease and deserve LDL cholesterol lowering to the currently recommended targets. Knopp RH et al. Diabetes Care 2006; 29(7):1478-85

TNT diabetes analysis Baseline and final LDL cholesterol levels Atorvastatin 10 mg (n=753) Atorvastatin 80 mg (n=748) Mean baseline LDL cholesterol levels (mmol/L) after 8-week open-label treatment 2.5 Final LDL cholesterol levels (mmol/L) after randomization 2.6 2.0 Shepherd J. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA.

TNT diabetes analysis Efficacy outcomes Atorvastatin 10 mg (n=753) Atorvastatin 80 mg (n=748) Hazard ratio (95% CI) p Total major cardiovascular events 17.9 % 13.8 % 0.75 (0.58-0.97) 0.026 Total major cerebrovascular events 10.0 % 7.0 % 0.69 (0.48-0.98) 0.037 Shepherd J. American Diabetes Association 2005 Scientific Sessions; June 10-14, 2005; San Diego, CA.

Effects of long-term fenofibrate therapy on CV events Background Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing todyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Loweringin Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.Methods We did a multinational, randomised controlled trial with 9795 participants aged 50ﾐ75 years, with type 2diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, werandomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterolconcentration of 3�0ﾐ6�5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4�0 or more or plasma triglyceride of1�0ﾐ5�0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcomewas coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecifiedsubgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered(number ISRCTN 64783481).Findings Vital status was confirmed on all but 22 patients. Averaged over the 5 yearsﾕ study duration, similar proportionsin each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo(17%) than fenofibrate (8%; p!0�0001) commenced other lipid treatments, predominantly statins. 5�9% (n=288) ofpatients on placebo and 5�2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazardratio [HR] 0�89, 95% CI 0�75ﾐ1�05; p=0�16). This finding corresponds to a significant 24% reduction in non-fatalmyocardial infarction (0�76, 0�62ﾐ0�94; p=0�010) and a non-significant increase in coronary heart disease mortality(1�19, 0�90ﾐ1�57; p=0�22). Total cardiovascular disease events were significantly reduced from 13�9% to 12.5% (0�89,0�80ﾐ0�99; p=0�035). This finding included a 21% reduction in coronary revascularisation (0�79, 0�68ﾐ0�93; p=0�003).Total mortality was 6�6% in the placebo group and 7�3% in the fenofibrate group (p=0�18). Fenofibrate was associatedwith less albuminuria progression (p=0�002), and less retinopathy needing laser treatment (5�2% vs 3�6%, p=0�0003).There was a slight increase in pancreatitis (0�5% vs 0�8%, p=0�031) and pulmonary embolism (0�7% vs 1�1%,p=0�022), but no other significant adverse effects.Interpretation Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reducetotal cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rateof starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit. Lancet 2005 366: 1849-61

Effects of long-term fenofibrate therapy on CV events Background Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing todyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Loweringin Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.Methods We did a multinational, randomised controlled trial with 9795 participants aged 50ﾐ75 years, with type 2diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, werandomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterolconcentration of 3�0ﾐ6�5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4�0 or more or plasma triglyceride of1�0ﾐ5�0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcomewas coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecifiedsubgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered(number ISRCTN 64783481).Findings Vital status was confirmed on all but 22 patients. Averaged over the 5 yearsﾕ study duration, similar proportionsin each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo(17%) than fenofibrate (8%; p!0�0001) commenced other lipid treatments, predominantly statins. 5�9% (n=288) ofpatients on placebo and 5�2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazardratio [HR] 0�89, 95% CI 0�75ﾐ1�05; p=0�16). This finding corresponds to a significant 24% reduction in non-fatalmyocardial infarction (0�76, 0�62ﾐ0�94; p=0�010) and a non-significant increase in coronary heart disease mortality(1�19, 0�90ﾐ1�57; p=0�22). Total cardiovascular disease events were significantly reduced from 13�9% to 12.5% (0�89,0�80ﾐ0�99; p=0�035). This finding included a 21% reduction in coronary revascularisation (0�79, 0�68ﾐ0�93; p=0�003).Total mortality was 6�6% in the placebo group and 7�3% in the fenofibrate group (p=0�18). Fenofibrate was associatedwith less albuminuria progression (p=0�002), and less retinopathy needing laser treatment (5�2% vs 3�6%, p=0�0003).There was a slight increase in pancreatitis (0�5% vs 0�8%, p=0�031) and pulmonary embolism (0�7% vs 1�1%,p=0�022), but no other significant adverse effects.Interpretation Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reducetotal cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rateof starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit. Lancet 2005. 366: 1849-61

Effects of long-term fenofibrate therapy on CV events Background Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing todyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Loweringin Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.Methods We did a multinational, randomised controlled trial with 9795 participants aged 50ﾐ75 years, with type 2diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, werandomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterolconcentration of 3�0ﾐ6�5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4�0 or more or plasma triglyceride of1�0ﾐ5�0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcomewas coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecifiedsubgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered(number ISRCTN 64783481).Findings Vital status was confirmed on all but 22 patients. Averaged over the 5 yearsﾕ study duration, similar proportionsin each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo(17%) than fenofibrate (8%; p!0�0001) commenced other lipid treatments, predominantly statins. 5�9% (n=288) ofpatients on placebo and 5�2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazardratio [HR] 0�89, 95% CI 0�75ﾐ1�05; p=0�16). This finding corresponds to a significant 24% reduction in non-fatalmyocardial infarction (0�76, 0�62ﾐ0�94; p=0�010) and a non-significant increase in coronary heart disease mortality(1�19, 0�90ﾐ1�57; p=0�22). Total cardiovascular disease events were significantly reduced from 13�9% to 12.5% (0�89,0�80ﾐ0�99; p=0�035). This finding included a 21% reduction in coronary revascularisation (0�79, 0�68ﾐ0�93; p=0�003).Total mortality was 6�6% in the placebo group and 7�3% in the fenofibrate group (p=0�18). Fenofibrate was associatedwith less albuminuria progression (p=0�002), and less retinopathy needing laser treatment (5�2% vs 3�6%, p=0�0003).There was a slight increase in pancreatitis (0�5% vs 0�8%, p=0�031) and pulmonary embolism (0�7% vs 1�1%,p=0�022), but no other significant adverse effects.Interpretation Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reducetotal cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rateof starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit. Lancet 2005. 366: 1849-61

Effects of long-term fenofibrate therapy on CV events Background Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing todyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Loweringin Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.Methods We did a multinational, randomised controlled trial with 9795 participants aged 50ﾐ75 years, with type 2diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, werandomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterolconcentration of 3�0ﾐ6�5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4�0 or more or plasma triglyceride of1�0ﾐ5�0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcomewas coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecifiedsubgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered(number ISRCTN 64783481).Findings Vital status was confirmed on all but 22 patients. Averaged over the 5 yearsﾕ study duration, similar proportionsin each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo(17%) than fenofibrate (8%; p!0�0001) commenced other lipid treatments, predominantly statins. 5�9% (n=288) ofpatients on placebo and 5�2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazardratio [HR] 0�89, 95% CI 0�75ﾐ1�05; p=0�16). This finding corresponds to a significant 24% reduction in non-fatalmyocardial infarction (0�76, 0�62ﾐ0�94; p=0�010) and a non-significant increase in coronary heart disease mortality(1�19, 0�90ﾐ1�57; p=0�22). Total cardiovascular disease events were significantly reduced from 13�9% to 12.5% (0�89,0�80ﾐ0�99; p=0�035). This finding included a 21% reduction in coronary revascularisation (0�79, 0�68ﾐ0�93; p=0�003).Total mortality was 6�6% in the placebo group and 7�3% in the fenofibrate group (p=0�18). Fenofibrate was associatedwith less albuminuria progression (p=0�002), and less retinopathy needing laser treatment (5�2% vs 3�6%, p=0�0003).There was a slight increase in pancreatitis (0�5% vs 0�8%, p=0�031) and pulmonary embolism (0�7% vs 1�1%,p=0�022), but no other significant adverse effects.Interpretation Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reducetotal cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rateof starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit. Lancet 2005. 366: 1849-61

Effects of long-term fenofibrate therapy on CV events Drop-outs and Drop-ins (mostly statins) Background Patients with type 2 diabetes mellitus are at increased risk of cardiovascular disease, partly owing todyslipidaemia, which can be amenable to fibrate therapy. We designed the Fenofibrate Intervention and Event Loweringin Diabetes (FIELD) study to assess the effect of fenofibrate on cardiovascular disease events in these patients.Methods We did a multinational, randomised controlled trial with 9795 participants aged 50ﾐ75 years, with type 2diabetes mellitus, and not taking statin therapy at study entry. After a placebo and a fenofibrate run-in phase, werandomly assigned patients (2131 with previous cardiovascular disease and 7664 without) with a total-cholesterolconcentration of 3�0ﾐ6�5 mmol/L and a total-cholesterol/HDL-cholesterol ratio of 4�0 or more or plasma triglyceride of1�0ﾐ5�0 mmol/L to micronised fenofibrate 200 mg daily (n=4895) or matching placebo (n=4900). Our primary outcomewas coronary events (coronary heart disease death or non-fatal myocardial infarction); the outcome for prespecifiedsubgroup analyses was total cardiovascular events (the composite of cardiovascular death, myocardial infarction, stroke,and coronary and carotid revascularisation). Analysis was by intention to treat. The study was prospectively registered(number ISRCTN 64783481).Findings Vital status was confirmed on all but 22 patients. Averaged over the 5 yearsﾕ study duration, similar proportionsin each group discontinued study medication (10% placebo vs 11% fenofibrate) and more patients allocated placebo(17%) than fenofibrate (8%; p!0�0001) commenced other lipid treatments, predominantly statins. 5�9% (n=288) ofpatients on placebo and 5�2% (n=256) of those on fenofibrate had a coronary event (relative reduction of 11%; hazardratio [HR] 0�89, 95% CI 0�75ﾐ1�05; p=0�16). This finding corresponds to a significant 24% reduction in non-fatalmyocardial infarction (0�76, 0�62ﾐ0�94; p=0�010) and a non-significant increase in coronary heart disease mortality(1�19, 0�90ﾐ1�57; p=0�22). Total cardiovascular disease events were significantly reduced from 13�9% to 12.5% (0�89,0�80ﾐ0�99; p=0�035). This finding included a 21% reduction in coronary revascularisation (0�79, 0�68ﾐ0�93; p=0�003).Total mortality was 6�6% in the placebo group and 7�3% in the fenofibrate group (p=0�18). Fenofibrate was associatedwith less albuminuria progression (p=0�002), and less retinopathy needing laser treatment (5�2% vs 3�6%, p=0�0003).There was a slight increase in pancreatitis (0�5% vs 0�8%, p=0�031) and pulmonary embolism (0�7% vs 1�1%,p=0�022), but no other significant adverse effects.Interpretation Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reducetotal cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations. The higher rateof starting statin therapy in patients allocated placebo might have masked a moderately larger treatment benefit. Lancet 2005. 366: 1849-61

Lipid Tx: meta-analysis BMJ 2006 Major coronary events in Primary prevention trials Mean F-up 4.5 yrs 21% RRR Objective To evaluate the clinical benefit of lipid lowering drugtreatment in patients with and without diabetes mellitus, forprimary and secondary prevention Design Systematic review and meta-analysis.Data sources Cochrane, Medline, Embase, and reference listsup to April 2004.Study selection Randomised, placebo controlled, double blindtrials with a follow-up of at least three years that evaluated lipidlowering drug treatment in patients with and without diabetesmellitus.Data extraction Two independent reviewers extracted data. Theprimary outcome was major coronary events defined ascoronary heart disease death, non-fatal myocardial infarction,or myocardial revascularisation procedures. Results Twelve studies were included. Lipid lowering drugtreatment was found to be at least as effective in diabeticpatients as in non-diabetic patients. In primary prevention, therisk reduction for major coronary events was 21% (95%confidence interval 11% to 30%; P < 0.0001) in diabetic patientsand 23% (12% to 33%; P = 0.0003) in non-diabetic patients. Insecondary prevention, the corresponding risk reductions were21% (10% to 31%; P = 0.0005) and 23% (19% to 26%;P ! 0.00001). However, the absolute risk difference was threetimes higher in secondary prevention. When results wereadjusted for baseline risk, diabetic patients benefited more inboth primary and secondary prevention. Blood lipids werereduced to a similar degree in both groups.Conclusions The evidence that lipid lowering drug treatment(especially statins) significantly reduce cardiovascular risk indiabetic and non-diabetic patients is strong and suggests thatdiabetic patients benefit more, in both primary and secondaryprevention. Future research should define the threshold fortreatment of these patients and the desired target lipidconcentrations, especially for primary prevention. Costa J et al. BMJ 2006; 332: 1115-1124

Lipid Tx: meta-analysis BMJ 2006 Major coronary events in Secondary prevention trials Mean F-up 4.5 yrs 21% RRR Objective To evaluate the clinical benefit of lipid lowering drugtreatment in patients with and without diabetes mellitus, forprimary and secondary prevention Design Systematic review and meta-analysis.Data sources Cochrane, Medline, Embase, and reference listsup to April 2004.Study selection Randomised, placebo controlled, double blindtrials with a follow-up of at least three years that evaluated lipidlowering drug treatment in patients with and without diabetesmellitus.Data extraction Two independent reviewers extracted data. Theprimary outcome was major coronary events defined ascoronary heart disease death, non-fatal myocardial infarction,or myocardial revascularisation procedures. Results Twelve studies were included. Lipid lowering drugtreatment was found to be at least as effective in diabeticpatients as in non-diabetic patients. In primary prevention, therisk reduction for major coronary events was 21% (95%confidence interval 11% to 30%; P < 0.0001) in diabetic patientsand 23% (12% to 33%; P = 0.0003) in non-diabetic patients. Insecondary prevention, the corresponding risk reductions were21% (10% to 31%; P = 0.0005) and 23% (19% to 26%;P ! 0.00001). However, the absolute risk difference was threetimes higher in secondary prevention. When results wereadjusted for baseline risk, diabetic patients benefited more inboth primary and secondary prevention. Blood lipids werereduced to a similar degree in both groups.Conclusions The evidence that lipid lowering drug treatment(especially statins) significantly reduce cardiovascular risk indiabetic and non-diabetic patients is strong and suggests thatdiabetic patients benefit more, in both primary and secondaryprevention. Future research should define the threshold fortreatment of these patients and the desired target lipidconcentrations, especially for primary prevention. Costa J et al. BMJ 2006; 332: 1115-1124

Tabagisme: outils thérapeutiques Le médecin Cliniques anti-tabac Substituts tabagiques: timbres etc Bloqueurs “non-sélectifs” Bupropion Bloqueurs cannabinoides CB1 Rimonabant Bloqueurs nicotiniques Cytisine: Selective α4 β2 Nicotinic Receptor Partial Agonist Varenicline: Selective α4 β2 Nicotinic Receptor Partial Agonist

Varenicline vs Bupropion vs Placebo Carbon monoxide confirmed continuous quit rates 10 minutes of standardized, individual smoking cessation counseling from trained staff smoking cessation booklet at the baseline visit. 7 week Tx → 52 week follow-up Results From a 7-Week, Randomized, Placebo- and Bupropion-ControlledTrial With 1-Year Follow-upMitchell Nides, PhD; Cheryl Oncken, MD, MPH; David Gonzales, PhD; Stephen Rennard, MD; Eric J. Watsky, MD;Rich Anziano, MS; Karen R. Reeves, MD; for the Varenicline Study GroupBackground: Currently available smoking cessationtherapies have limited success rates. Varenicline tartrateis a novel, selective nicotinic receptor partial agonistdeveloped specifically for smoking cessation. Thisstudy evaluated the efficacy, tolerability, and safety of 3varenicline doses for smoking cessation. Bupropion hydrochloridewas included as an active control.Methods: A phase 2, multicenter, randomized, doubleblind,placebo-controlled study of healthy smokers (18-65years old). Subjects were randomized to varenicline tartrate,0.3 mg once daily (n=128), 1.0 mg once daily(n=128), or 1.0 mg twice daily (n=127), for 6 weeks plusplacebo for 1 week; to 150-mg sustained-release bupropionhydrochloride twice daily (n=128) for 7 weeks; orto placebo (n=127) for 7 weeks.Results: During the treatment phase, the continuous quitrates for any 4 weeks were significantly higher for vareniclinetartrate, 1.0 mg twice daily (48.0%; P .001) and 1.0mgonce daily (37.3%; P .001), than for placebo (17.1%).Thebupropionratewas33.3%(P=.002vsplacebo).Thecarbonmonoxideﾐconfirmedcontinuous quit ratesfromweek4toweek52were significantly higher in the varenicline tartrate,1.0mgtwice daily, group compared with the placebogroup(14.4%vs4.9%;P=.002).Thebupropionratewas6.3%(P=.60 vs placebo). Discontinuation owing to treatmentemergentadverse events was 15.9% for bupropion, 11.2%to14.3%forvarenicline,and9.8%forplacebo.Nodose-relatedincreases occurred in adverse events for varenicline.Conclusions: Varenicline tartrate demonstrated bothshort-term (1 mg twice daily and 1 mg once daily) andlong-term efficacy (1 mg twice daily) vs placebo. Vareniclinewas well tolerated and may provide a novel therapyto aid smoking cessation.Arch Intern Med. 2006;166:1561-1568 Nides M et al. Arch Intern Med. 2006;166:1561-1568

Lifestyle Modification Low Cardiorespiratory Fitness and Physical Inactivity as Predictors of Mortality in Men with Type 2 Diabetes FIT UNFIT Background: Although physical activity is recommendedas a basic treatment for patients with diabetes, its longtermassociation with mortality in these patients is unknown.Objective: To evaluate the association of low cardiorespiratoryfitness and physical inactivity with mortality in menwith type 2 diabetes.Design: Prospective cohort study.Setting: Preventive medicine clinic.Patients: 1263 men (50 ! 10 years of age) with type 2diabetes who received a thorough medical examinationbetween 1970 and 1993 and were followed for mortalityup to 31 December 1994.Measurements: Cardiorespiratory fitness measured by amaximal exercise test, self-reported physical inactivity atbaseline, and subsequent death determined by using theNational Death Index.Results: During an average follow-up of 12 years, 180patients died. After adjustment for age, baseline cardiovasculardisease, fasting plasma glucose level, high cholesterollevel, overweight, current smoking, high blood pressure,and parental history of cardiovascular disease, men inthe low-fitness group had an adjusted risk for all-causemortality of 2.1 (95% CI, 1.5 to 2.9) compared with fit men.Men who reported being physically inactive had an adjustedrisk for mortality that was 1.7-fold (CI, 1.2-fold to2.3-fold) higher than that in men who reported beingphysically active.Conclusions: Low cardiorespiratory fitness and physicalinactivity are independent predictors of all-cause mortalityin men with type 2 diabetes. Physicians should encouragepatients with type 2 diabetes to participate in regularphysical activity and improve cardiorespiratory fitness. Wein M et al. Ann Intern Med 2000; 132: 605-611

Lifestyle Modification Low Cardiorespiratory Fitness and Physical Inactivity as Predictors of Mortality in Men with Type 2 Diabetes * Compared with fit men.  Conventional risk factors were baseline cardiovascular disease, parental cardiovasculardisease, high cholesterol level, current smoking, diabetes status, glucose level, alcoholintake, high blood pressure, and overweight. Based on data from 1188 men.� Compared with active men. Background: Although physical activity is recommendedas a basic treatment for patients with diabetes, its longtermassociation with mortality in these patients is unknown.Objective: To evaluate the association of low cardiorespiratoryfitness and physical inactivity with mortality in menwith type 2 diabetes.Design: Prospective cohort study.Setting: Preventive medicine clinic.Patients: 1263 men (50 ! 10 years of age) with type 2diabetes who received a thorough medical examinationbetween 1970 and 1993 and were followed for mortalityup to 31 December 1994.Measurements: Cardiorespiratory fitness measured by amaximal exercise test, self-reported physical inactivity atbaseline, and subsequent death determined by using theNational Death Index.Results: During an average follow-up of 12 years, 180patients died. After adjustment for age, baseline cardiovasculardisease, fasting plasma glucose level, high cholesterollevel, overweight, current smoking, high blood pressure,and parental history of cardiovascular disease, men inthe low-fitness group had an adjusted risk for all-causemortality of 2.1 (95% CI, 1.5 to 2.9) compared with fit men.Men who reported being physically inactive had an adjustedrisk for mortality that was 1.7-fold (CI, 1.2-fold to2.3-fold) higher than that in men who reported beingphysically active.Conclusions: Low cardiorespiratory fitness and physicalinactivity are independent predictors of all-cause mortalityin men with type 2 diabetes. Physicians should encouragepatients with type 2 diabetes to participate in regularphysical activity and improve cardiorespiratory fitness. Wein M et al. Ann Intern Med 2000; 132: 605-611

Lifestyle modification CDA 2003

Lifestyle modification: Aerobic physical activity ADA 2006 To improve glycemic control, assist with weight maintenance, and reduce risk of CVD, at least 150 min/week of moderate-intensity aerobic physical activity (50–70% of maximum heart rate) is recommended and/or at least 90 min/week of vigorous aerobic exercise (>70% of maximum heart rate) The physical activity should be distributed over at least 3 days/week and with no more than 2 consecutive days without physical activity Level of evidence : A

Lifestyle modification: Resistance exercise ADA 2006 In the absence of contraindications, people with type 2 diabetes should be encouraged to: perform resistance exercise three times a week targeting all major muscle groups progressing to three sets of 8-10 repetitions at a weight that cannot be lifted more than 8-10 times Level of evidence : A

VASCULAR PROTECTION - DIABETES - 2006 For almost all: ACEI + ASA 80mg BP < 130/80 A1C ≤ 7% for most patients A1C ≤ 6% if can be achieved securely Statins for most pts with high CV risk Reduce LDL-Chol ≥ 50% Minimal target: LDL-Chol ≤ 2.0 mmol/L and TC/HDL ≤ 4 Smoking cessation Lifestyle modification Good eating habits and healthy weight Aerobic and resistance exercise 3 times per week Merci Thank you