Canadian Diabetes Association Clinical Practice Guidelines Vascular Protection in People with Diabetes Chapter 22 James A. Stone, David Fitchett, Steven Grover, Richard Lewanczuk, Peter Lin

Vascular Protection Checklist 2013 A • A1C – optimal glycemic control (usually ≤7%) B • BP – optimal blood pressure control (<130/80) C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat D • Drugs to protect the heart (regardless of baseline BP or LDL) A – ACEi or ARB │ S – Statin │ A – ASA if indicated E • Exercise / Eating healthily – regular physical activity, achieve and maintain healthy body weight S • Smoking cessation

Absolute Risk of MI is Higher in Patients with DM Diabetes n = 379,003 No Diabetes n = 9,018,082 Database 1994-2000 3.0 Diabetes Men Women 2.5 2.0 No diabetes Men Women No. events per 100 person- years 1.5 1.0 The ICES study was a population-based retrospective cohort study using provincial health claims. It identified all adults with (n=379 003) and without (n=9 018 082) diabetes mellitus living in Ontario, Canada, on April 1, 1994. Individuals were followed up to record CVD events until March 31, 2000. In both populations, the rate of AMI rose with age. Diabetes was associated with earlier CVD; diabetic men and women were about 15 years younger than those without diabetes in the same risk category. Reference: Booth GL, et al. Lancet 2006;368:29-36. 0.5 Age group MI = myocardial infarction All lines fitted according to a polynomial equation; R2= 0.99–1.00 for each Booth GL, et al. Lancet 2006;368:29-36.

MRFIT: Impact of Diabetes on Cardiovascular Mortality 140 120 100 80 60 40 20 Nondiabetes (n = 342,815) Diabetes (n = 5,163) 31 59 91 125 Mortality per 10,000 47 A total of 347,978 men screened for the Multiple Risk Factor Intervention Trial (MRFIT) were studied to assess predictors of CVD mortality among men with and without diabetes, and to assess the effect of diabetes on CVD death. Participants were aged 35 to 57 years. The outcome measure was CVD mortality. To evaluate the effects of three CV risk factors (serum cholesterol, systolic blood pressure [SBP], and reported number of cigarettes smoked per day), participants were grouped into eight strata for comparison: level of serum cholesterol < 200 or  200 mg/dL; SBP < 120 or  120 mmHg, and also < 140 or  140 mmHg; and cigarette use or no cigarette use. CVD death rates for those with and without diabetes were compared according to the presence of one, two, or three of these risk factors. The relative risk for CVD death in participants with none of the risk factors was 5.10 for diabetics compared to nondiabetics. With all three risk factors, the relative risk for CVD death was 2.64 for diabetics compared to nondiabetics. Reference: Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16(2):434-44. 22 12 6 None One only Two only All three Number of risk factors* *Risk factors analyzed: smoking, hypercholesterolemia and hypertension. Stamler J, et al. Diabetes Care 1993; 16(2):434-44

T2DM for > 15 Years Duration Confers a Similar Risk of Fatal CHD as Prior CHD and No Diabetes 20 year follow-up of 121,046 women aged 30 to 55 years in Nurses’ Health Study Hu F, et al. Arch Intern Med. 2001;161:1717-1723.

Multifaceted Management is Essential for T2DM Intensive multifaceted management in patients with Type 2 diabetes lowers overall mortality Multifaceted treatment strategy includes: Glucose, lipid, BP control Health behavior optimization Use of vascular protective medications

STENO-2

Multifaceted Approach for CVD Prevention Among Patients with T2DM Intensive Arm Therapies to achieve targets in glycemia, lipids, BP and microalbuminuria Multidisciplinary care q3mo ASA and ACE inhibitors (independent of BP) Type 2 Diabetes + Microalbuminuria n = 160 The STENO 2 study, published in the New England Journal of Medicine in 2003, tested the hypothesis that patients receiving intensive multifaceted diabetes care delivered in a diabetes clinic would have better clinical outcomes than patients receiving conventional diabetes care. In the Intensive group, aggressive control targets were set for major diabetes parameters (glycaemia, lipids, blood pressure), and a stepwise approach was used to try to bring as many patients to target as possible using lifestyle and pharmacologic interventions. All patients were given an ACE inhibitor, regardless of BP. An ARB was used if the patient was ACE inhibitor intolerant. In the conventional care group, diabetes care was primarily delivered by the family doctor, with specialist involvement at their discretion. Treatment was guided by the Danish Medical Association’s national guidelines, set in 1998. Patients were followed for 8 years and they examined a composite outcome of CV death, MI, CABG, PCI, Stroke, Amputation, or PVD surgery TTT: Slide illustrates the design of STENO-2 trial. Conventional Arm MD follows clinical practice guidelines 8-year follow-up composite outcome: CV death, MI, CABG, PCI, Stroke, Amputation, or PVD surgery Gaede et al. NEJM. 2003: 348;383-393

STENO-2: Intensive Group Achieved Targets Patients in the intensive arm significantly achieved targets for glycemia (A1c<6.5%), cholesterol < 175 mg/dL, SBP < 130 and DBP < 80 compared to the conventional arm in the study. Gaede et al. NEJM. 2003: 348;383-393

Intensive Group had Improved CV Outcomes 60 P = 0.007 50 53 % RRR Any CV event NNT = 5 Conventional therapy 40 Intensive therapy 30 20 Intensive Therapy Resulted in Improved Combined CV OutcomesSignificantly fewer primary endpoints (a composite of CV death, non-fatal stroke or MI, revascularization, or amputation) occurred in the Intensive treatment group. 10 12 24 36 48 60 72 84 96 Months of Follow-up RRR= relative risk reduction Gaede et al. NEJM. 2003: 348;383-393

STENO 2 – Microvascular Disease Gaede et al. NEJM. 2003: 348;383-393

Use a Multifaceted Vascular Protection Strategy BP <130/80 Healthy Lifestyle/weight Smoking Cessation Physical Activity A1C ≤7% Pictorial demonstration that combination of emphasis of healthy lifestyle (stop smoking, PA, weight, diet) in addition to Rx to maintain BP/lipid/glycemic targets is essential in the care of the patient with diabetes Rx: Statins ACEi/ARB

Vascular protective medications Statins ACE-inhibitors or Angiotensin receptor blockers (ARB) ASA selective use

HPS: Statin Therapy Beneficial Among Patients with Diabetes SIMVASTATIN PLACEBO Rate ratio & 95% CI (10269) (10267) STATIN better PLACEBO better Previous MI 999 (23.5%) 1250 (29.4%) Other CHD (not MI) 460 (18.9%) 591 (24.2%) No prior CHD CVD 172 (18.7%) 212 (23.6%) PVD 327 (24.7%) 420 (30.5%) Lancet. 2002 Jul 6;360(9326):7-22. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Heart Protection Study Collaborative Group. Abstract BACKGROUND: Throughout the usual LDL cholesterol range in Western populations, lower blood concentrations are associated with lower cardiovascular disease risk. In such populations, therefore, reducing LDL cholesterol may reduce the development of vascular disease, largely irrespective of initial cholesterol concentrations. METHODS: 20,536 UK adults (aged 40-80 years) with coronary disease, other occlusive arterial disease, or diabetes were randomly allocated to receive 40 mg simvastatin daily (average compliance: 85%) or matching placebo (average non-study statin use: 17%). Analyses are of the first occurrence of particular events, and compare all simvastatin-allocated versus all placebo-allocated participants. These "intention-to-treat" comparisons assess the effects of about two-thirds (85% minus 17%) taking a statin during the scheduled 5-year treatment period, which yielded an average difference in LDL cholesterol of 1.0 mmol/L (about two-thirds of the effect of actual use of 40 mg simvastatin daily). Primary outcomes were mortality (for overall analyses) and fatal or non-fatal vascular events (for subcategory analyses), with subsidiary assessments of cancer and of other major morbidity. FINDINGS: All-cause mortality was significantly reduced (1328 [12.9%] deaths among 10,269 allocated simvastatin versus 1507 [14.7%] among 10,267 allocated placebo; p=0.0003), due to a highly significant 18% (SE 5) proportional reduction in the coronary death rate (587 [5.7%] vs 707 [6.9%]; p=0.0005), a marginally significant reduction in other vascular deaths (194 [1.9%] vs 230 [2.2%]; p=0.07), and a non-significant reduction in non-vascular deaths (547 [5.3%] vs 570 [5.6%]; p=0.4). There were highly significant reductions of about one-quarter in the first event rate for non-fatal myocardial infarction or coronary death (898 [8.7%] vs 1212 [11.8%]; p<0.0001), for non-fatal or fatal stroke (444 [4.3%] vs 585 [5.7%]; p<0.0001), and for coronary or non-coronary revascularisation (939 [9.1%] vs 1205 [11.7%]; p<0.0001). For the first occurrence of any of these major vascular events, there was a definite 24% (SE 3; 95% CI 19-28) reduction in the event rate (2033 [19.8%] vs 2585 [25.2%] affected individuals; p<0.0001). During the first year the reduction in major vascular events was not significant, but subsequently it was highly significant during each separate year. The proportional reduction in the event rate was similar (and significant) in each subcategory of participant studied, including: those without diagnosed coronary disease who had cerebrovascular disease, or had peripheral artery disease, or had diabetes; men and, separately, women; those aged either under or over 70 years at entry; and--most notably--even those who presented with LDL cholesterol below 3.0 mmol/L (116 mg/dL), or total cholesterol below 5.0 mmol/L (193 mg/dL). The benefits of simvastatin were additional to those of other cardioprotective treatments. The annual excess risk of myopathy with this regimen was about 0.01%. There were no significant adverse effects on cancer incidence or on hospitalisation for any other non-vascular cause. INTERPRETATION: Adding simvastatin to existing treatments safely produces substantial additional benefits for a wide range of high-risk patients, irrespective of their initial cholesterol concentrations. Allocation to 40 mg simvastatin daily reduced the rates of myocardial infarction, of stroke, and of revascularisation by about one-quarter. After making allowance for non-compliance, actual use of this regimen would probably reduce these rates by about one-third. Hence, among the many types of high-risk individual studied, 5 years of simvastatin would prevent about 70-100 people per 1000 from suffering at least one of these major vascular events (and longer treatment should produce further benefit). The size of the 5-year benefit depends chiefly on such individuals' overall risk of major vascular events, rather than on their blood lipid concentrations alone. Diabetes 276 (13.8%) 367 (18.6%) ALL PATIENTS 2033 (19.8%) 2585 (25.2%) 24% reduction (P<0.00001) HPS: Heart protection study 0.4 0.6 0.8 1.0 1.2 1.4 HPS Lancet 2002;360:7-22

CARDS: Effect of Statin for PRIMARY Prevention in DM Age 40-75, no history of CVD T2DM plus one or more: Retinopathy Albuminuria Hypertension Smoking Intervention: Atorvastatin 10 mg vs. Placebo Outcome: ACS, revascularization, stroke Lancet. 2004 Aug 21-27;364(9435):685-96. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. Source EURODIAB, Department of Epidemiology and Public Health, Royal Free and University College Medical School, London, UK. helen.colhoun@ucd.ie Abstract BACKGROUND: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld. Colhoun HM, et al. Lancet 2004;364:685.

CARDS: Statins Reduced CVD in Patients with DM Lancet. 2004 Aug 21-27;364(9435):685-96. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V, Fuller JH; CARDS investigators. Source EURODIAB, Department of Epidemiology and Public Health, Royal Free and University College Medical School, London, UK. helen.colhoun@ucd.ie Abstract BACKGROUND: Type 2 diabetes is associated with a substantially increased risk of cardiovascular disease, but the role of lipid-lowering therapy with statins for the primary prevention of cardiovascular disease in diabetes is inadequately defined. We aimed to assess the effectiveness of atorvastatin 10 mg daily for primary prevention of major cardiovascular events in patients with type 2 diabetes without high concentrations of LDL-cholesterol. METHODS: 2838 patients aged 40-75 years in 132 centres in the UK and Ireland were randomised to placebo (n=1410) or atorvastatin 10 mg daily (n=1428). Study entrants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride amount of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking, or hypertension. The primary endpoint was time to first occurrence of the following: acute coronary heart disease events, coronary revascularisation, or stroke. Analysis was by intention to treat. FINDINGS: The trial was terminated 2 years earlier than expected because the prespecified early stopping rule for efficacy had been met. Median duration of follow-up was 3.9 years (IQR 3.0-4.7). 127 patients allocated placebo (2.46 per 100 person-years at risk) and 83 allocated atorvastatin (1.54 per 100 person-years at risk) had at least one major cardiovascular event (rate reduction 37% [95% CI -52 to -17], p=0.001). Treatment would be expected to prevent at least 37 major vascular events per 1000 such people treated for 4 years. Assessed separately, acute coronary heart disease events were reduced by 36% (-55 to -9), coronary revascularisations by 31% (-59 to 16), and rate of stroke by 48% (-69 to -11). Atorvastatin reduced the death rate by 27% (-48 to 1, p=0.059). No excess of adverse events was noted in the atorvastatin group. INTERPRETATION: Atorvastatin 10 mg daily is safe and efficacious in reducing the risk of first cardiovascular disease events, including stroke, in patients with type 2 diabetes without high LDL-cholesterol. No justification is available for having a particular threshold level of LDL-cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statins. The debate about whether all people with this disorder warrant statin treatment should now focus on whether any patients are at sufficiently low risk for this treatment to be withheld. Colhoun HM, et al. Lancet 2004;364:685.

Who Should Receive Statins? (regardless of baseline LDL-C) 2013 ≥40 yrs old or Macrovascular disease or Microvascular disease or DM >15 yrs duration and age >30 years or Warrants therapy based on the 2012 Canadian Cardiovascular Society lipid guidelines Among women with childbearing potential, statins should only be used in the presence of proper preconception counseling & reliable contraception. Stop statins prior to conception.

What if baseline LDL-C ≤2.0 mmol/L? Within CARDS and HPS, the subgroups that started with lower baseline LDL-C still benefited to the same degree as the whole population If the patient qualifies for statin therapy based on the algorithm, use the statin regardless of the baseline LDL-C and then target an LDL reduction of ≥50% HPS Lancet 2002;360:7-22 Colhoun HM, et al. Lancet 2004;364:685.

Vascular protective medications Statins ACE-inhibitors or Angiotensin receptor blockers (ARB) ASA selective use

Association of SBP and CV Mortality in Men With T2DM 250 No diabetes Diabetes 200 Per 10,000 person-years CV mortality rate 150 100 The presence of diabetes further increases the already elevated risk associated with hypertension for CV mortality. The higher the systolic blood pressure (SBP), the greater the absolute excess risk for cardiovascular (CV) mortality among diabetic patients. In the large cohort of men screened for MRFIT (the Multiple Risk Factor Intervention Trial), the relationship of SBP and other CV risk factors to CV mortality was compared in men with diabetes (n=5163) and in men without diabetes (n=342,815). The absolute risk of CV death was 3 times higher for men with diabetes than for men without diabetes after adjusting for age, race, income, serum cholesterol, SBP, and cigarette smoking (P<0.0001). SBP had a positive relationship with the risk of CV death, with a significant trend in subjects with or without diabetes (P<0.001). At every SBP level, CV death was much greater for men with diabetes than for men without diabetes. With higher SBP levels, the CV mortality rate increased more steeply in men with diabetes than in men without diabetes. The combination of diabetes and hypertension thus dramatically increases CV risk. References Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care. 1993;16:434-444. 50 <120 120-139 140-159 160-179 180-199 ≥200 SBP (mmHg) Stamler J, et al. Diabetes Care. 1993;16:434-444.

Hypertension in Diabetes UKPDS 50 40 30 20 10 Less tight control (mean BP 154/87 mmHg) Tight control (mean BP 144/82 mmHg) Patients with events (%) Tight BP control: 24% reduction of events (95% CI 8-38) In the UKPDS study, tight BP control aimed to reduce BP to less than 140/80 mmHg. The achieved BP was 144/82 mmHg. In the usual-care control, the achieved BP was 154/87 mmHg. Cardiovascular events were reduced 24% by enhanced BP control. In addition, death due to diabetes, and the incidence of heart failure, stroke, and microvascular disease were significantly reduced. Reference: UKPDS Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998; 317:703-13. 1 2 3 4 5 6 7 8 9 Years from randomization UKPDS Study Group. BMJ 1998; 317:703-13.

HOT: BP Control Reduces CV Events Diabetes Subgroup 30 P<0.005 24.4 Goal of therapy: target diastolic BP 25 20 18.8  90 mm Hg (n=501) MI, stroke, CV mortality/1000 pt-y  85 mm Hg (n=501) 15  80 mm Hg (n=499) Lancet. 1998 Jun 13;351(9118):1755-62. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Hansson L, Zanchetti A, Carruthers SG, Dahlöf B, Elmfeldt D, Julius S, Ménard J, Rahn KH, Wedel H, Westerling S. Source University of Uppsala, Department of Public Health and Social Sciences, Clinical Hypertension Research, Sweden. Abstract BACKGROUND: Despite treatment, there is often a higher incidence of cardiovascular complications in patients with hypertension than in normotensive individuals. Inadequate reduction of their blood pressure is a likely cause, but the optimum target blood pressure is not known. The impact of acetylsalicylic acid (aspirin) has never been investigated in patients with hypertension. We aimed to assess the optimum target diastolic blood pressure and the potential benefit of a low dose of acetylsalicylic acid in the treatment of hypertension. METHODS: 18790 patients, from 26 countries, aged 50-80 years (mean 61.5 years) with hypertension and diastolic blood pressure between 100 mm Hg and 115 mm Hg (mean 105 mm Hg) were randomly assigned a target diastolic blood pressure. 6264 patients were allocated to the target pressure < or =90 mm Hg, 6264 to < or =85 mm Hg, and 6262 to < or =80 mm Hg. Felodipine was given as baseline therapy with the addition of other agents, according to a five-step regimen. In addition, 9399 patients were randomly assigned 75 mg/day acetylsalicylic acid (Bamycor, Astra) and 9391 patients were assigned placebo. FINDINGS: Diastolic blood pressure was reduced by 20.3 mm Hg, 22.3 mm Hg, and 24.3 mm Hg, in the < or =90 mm Hg, < or =85 mm Hg, and < or =80 mm Hg target groups, respectively. The lowest incidence of major cardiovascular events occurred at a mean achieved diastolic blood pressure of 82.6 mm Hg; the lowest risk of cardiovascular mortality occurred at 86.5 mm Hg. Further reduction below these blood pressures was safe. In patients with diabetes mellitus there was a 51% reduction in major cardiovascular events in target group < or =80 mm Hg compared with target group < or =90 mm Hg (p for trend=0.005). Acetylsalicylic acid reduced major cardiovascular events by 15% (p=0.03) and all myocardial infarction by 36% (p=0.002), with no effect on stroke. There were seven fatal bleeds in the acetylsalicylic acid group and eight in the placebo group, and 129 versus 70 non-fatal major bleeds in the two groups, respectively (p<0.001). INTERPRETATION: Intensive lowering of blood pressure in patients with hypertension was associated with a low rate of cardiovascular events. The HOT Study shows the benefits of lowering the diastolic blood pressure down to 82.6 mm Hg. Acetylsalicylic acid significantly reduced major cardiovascular events with the greatest benefit seen in all myocardial infarction. There was no effect on the incidence of stroke or fatal bleeds, but non-fatal major bleeds were twice as common. 11.9 10 5 Hansson et al. Lancet. 1998;351:1755. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet. 1998;351:1755-1762.

Micro-HOPE (ACEi): CV Benefits Primary Outcome (NNT 22) 0.16 All Mortality (NNT 31) 0.2 Placebo Ramipril 10 mg 0.08 0.1 RR = 0.75 (0.64-0.88) p = 0.0004 RR = 0.76 (0.63-0.92) p = 0.004 Kaplan-Meier rates 400 800 1200 400 800 1200 1600 1600 0.12 0.16 0.08 Stroke (NNT 53) CV Death (NNT 29) MI (NNT 37) The illustrated results and relative risks are for the 3577 people with diabetes who were allocated to ramipril or placebo. Ramipril had a clear and consistent protective effect on the primary outcome as well as on each component of the composite primary outcome. Not shown is the fact that the benefit was consistent across every clinical subgroup (type 1 vs. type 2 diabetes, men vs. women, microalbuminuria vs. no microalbuminuria, previous CV disease vs. no previous CV disease, and insulin therapy vs. no insulin. Also not shown is the fact that the BP reduction with ramipril was 1.9 mm systolic and 3.3 mm diastolic, vs. a rise in the placebo group of 0.55 mm systolic and a fall of 2.3 mm diastolic. This change in blood pressure is much too small to account for the CV benefits that were observed. That is, from epidemiologic studies a BP fall of 10 mm systolic and 5 mm diastolic is needed to effect a 38% reduction in stroke and a 16% reduction in CHD. In this study, risk reductions of > 20% for both these outcomes were noted for much more modest blood pressure effects. 0.08 0.04 0.06 RR = 0.78 (0.64-0.94) p = 0.01 RR = 0.67 (0.5-0.9) p = 0.0074 RR = 0.63 (0.49-0.79) p = 0.001 1000 2000 1000 2000 1000 2000 Duration of follow-up (days) HOPE study investigators. Lancet. 2000;355:253-59.

ONTARGET: ARB Therapy is as Effective as ACEi for CVD Prevention N Engl J Med. 2008 Apr 10;358(15):1547-59. doi: 10.1056/NEJMoa0801317. Epub 2008 Mar 31. Telmisartan, ramipril, or both in patients at high risk for vascular events. ONTARGET Investigators, Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. The following toggler user interface control may not be accessible. Tab to the next button to revert the control to an accessible version. Destroy user interface controlCollaborators (969) Source Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada. yusufs@mcmaster.ca Abstract BACKGROUND: In patients who have vascular disease or high-risk diabetes without heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and morbidity from cardiovascular causes, but the role of angiotensin-receptor blockers (ARBs) in such patients is unknown. We compared the ACE inhibitor ramipril, the ARB telmisartan, and the combination of the two drugs in patients with vascular disease or high-risk diabetes. METHODS: After a 3-week, single-blind run-in period, patients underwent double-blind randomization, with 8576 assigned to receive 10 mg of ramipril per day, 8542 assigned to receive 80 mg of telmisartan per day, and 8502 assigned to receive both drugs (combination therapy). The primary composite outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure. RESULTS: Mean blood pressure was lower in both the telmisartan group (a 0.9/0.6 mm Hg greater reduction) and the combination-therapy group (a 2.4/1.4 mm Hg greater reduction) than in the ramipril group. At a median follow-up of 56 months, the primary outcome had occurred in 1412 patients in the ramipril group (16.5%), as compared with 1423 patients in the telmisartan group (16.7%; relative risk, 1.01; 95% confidence interval [CI], 0.94 to 1.09). As compared with the ramipril group, the telmisartan group had lower rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema (0.1% vs. 0.3%, P=0.01) and a higher rate of hypotensive symptoms (2.6% vs. 1.7%, P<0.001); the rate of syncope was the same in the two groups (0.2%). In the combination-therapy group, the primary outcome occurred in 1386 patients (16.3%; relative risk, 0.99; 95% CI, 0.92 to 1.07); as compared with the ramipril group, there was an increased risk of hypotensive symptoms (4.8% vs. 1.7%, P<0.001), syncope (0.3% vs. 0.2%, P=0.03), and renal dysfunction (13.5% vs. 10.2%, P<0.001). CONCLUSIONS: Telmisartan was equivalent to ramipril in patients with vascular disease or high-risk diabetes and was associated with less angioedema. The combination of the two drugs was associated with more adverse events without an increase in benefit. (ClinicalTrials.gov number, NCT00153101 [ClinicalTrials.gov].). ONTARGET study investigators. NEJM. 2008:358:1547-59.

Macrovascular disease or Microvascular disease 2013 Who Should Receive ACEi or ARB Therapy? (regardless of baseline blood pressure) ≥55 years of age or Macrovascular disease or Microvascular disease At doses that have shown vascular protection [perindopril 8 mg daily (EUROPA), ramipril 10 mg daily (HOPE), telmisartan 80 mg daily (ONTARGET)] ACE inhiibitor or ARB therapy should be offered to people with diabetes age ≥55 years, or in the presence of macrovasular disease or microvascular disease. This recommendation is regardless of blood pressure. It is important that the ACEi or ARB be titrated to the doses that have been shown to provide vascular protection since low dose ACE-inhibitor or ARB may not result in any benefit (DIABHYCAR study). These vascular protection benefits have been shown to be present irrespective of baseline blood pressure. Since it is not proven that low dose ACEi or ARB confers the same vascular protection, it is recommended that the ACEi or ARB dose be increased to the vascular protective doses (peripdopril 8mg, ramipril 10 mg, telmisartan 80 mg daily). Given that not all ACEi or ARB have conducted “vascular protection” type of studies and of those that have, not all have been positive, it is justified to titrate to doses shown to have vascular protection. Among women with childbearing potential, ACEi or ARB should only be used in the presence of proper preconception counseling & reliable contraception. Stop ACEi or ARB either prior to conception or immediately upon detection of pregnancy EUROPA Investigators, Lancet 2003;362(9386):782-788. HOPE study investigators. Lancet. 2000;355:253-59. ONTARGET study investigators. NEJM. 2008:358:1547-59

Vascular protective medications Statins ACE-inhibitors or Angiotensin receptor blockers (ARB) ASA selective use

What About ASA for 1⁰ Prevention of CVD? Included: Six studies, n = 10,117 participants De Berardis G et al. BMJ 2009;339:b4531

No. of events/No. in group ASA Control/placebo RR (95% CI) RR (95% CI) Major CV events ASA for 1⁰ Prevention in Diabetes Meta analysis of 6 studies (n = 10,117) JPAD POPADAD WHS PPP ETDRS Total 68/1262 105/638 58/514 20/519 350/1856 601/4789 86/1277 108/638 62/513 22/512 379/1855 657/4795 0.80 (0.59-1.09) 0.97 (0.76-1.24) 0.90 (0.63-1.29) 0.90 (0.50-1.62) 0.90 (0.78-1.04) 0.90 (0.81-1.00) Myocardial infarction JPAD POPADAD WHS PPP ETDRS PHS Total 28/1262 90/638 36/514 5/519 241/1856 11/275 395/5064 14/1277 82/638 24/513 10/512 283/1855 26/258 439/5053 0.87 (0.40-1.87) 1.10 (0.83-1.45) 1.48 (0.88-2.49) 0.49 (0.17-1.43) 0.82 (0.69-0.98) 0.40 (0.20-0.79) 0.86 (0.61-1.21) No overall benefit for: Major CV events MI Stroke CV mortality All-cause mortality Stroke JPAD POPADAD WHS PPP ETDRS Total 12/1262 37/638 15/514 9/519 92/1856 181/4789 32/1277 50/638 31/513 10/512 78/1855 201/4795 0.89 (0.54-1.46) 0.74 (0.49-1.12) 0.46 (0.25-0.85) 0.89 (0.36-2.17) 1.17 (0.87-1.58) 0.83 (0.60-1.14) Death from CV causes This meta-analysis examined whether ASA is beneficial for patients with diabetes who have no clinical evidence of CVD. Of 6 eligible studies included in the meta-analysis of over 10,000 participants, there is no statistically significant reduction in the risk of Major CV events, MI, stroke, CV mortality or all-cause mortality when ASA was compared with placebo for primary prevention among patients with diabetes. Of 157 studies in the literature searches, six were eligible (10,117 participants). When ASA was compared with placebo, there was no statistically significant reduction in the risk of major CV events (five studies, 9,584 participants; RR 0.90; 95% CI 0.81-1.00), CV mortality (four studies, 8,557 participants; RR 0.94; 95% CI 0.72-1.23), or all-cause mortality (four studies, 8,557 participants; RR 0.93; 95% CI 0.82-1.05). Significant heterogeneity was found in the analyses for MI (I2 = 62.2%; p = 0.02) and stroke (I2 = 52.5%; p = 0.08). ASA significantly reduced the risk of MI in men (RR 0.57; 95% CI 0.34-0.94) but not in women (RR 1.08; 95% CI 0.71-1.65; p for interaction = 0.056). Evidence relating to harms was inconsistent. These authors concluded that a clear benefit of ASA in the primary prevention of major CV events in people with diabetes remains unproved, that sex may be an important effect modifier, and that toxicity is to be explored further. The analysis shows ASA has benefit for men in prevention of MI but not for stroke prevention, but no benefit in women for either MI or stroke prevention Reference: De Berardis G, Sacco M, Strippoli GF, et al. Aspirin for primary prevention of cardiovascular events in people with diabetes: meta-analysis of randomised controlled trials. BMJ 2009; 339:b4531. JPAD POPADAD PPP ETDRS Total 1/1262 43/638 10/519 244/1856 298/4275 10/1277 35/638 8/512 275/1855 328/4282 0.10 (0.01-0.79) 1.23 (0.80-1.89) 1.23 (0.49-3.10) 0.87 (0.73-1.04) 0.94 (0.72-1.23) JPAD = Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes POPADAD = Prevention of Progression of Arterial Disease and Diabetes PPP = Primary Prevention Project ETDRS = Early Treatment Diabetic Retinopathy Study PHS = Physicians’ Health Study WHS = Women’s Health Study De Beradis G, et al. BMJ 2009; 339:b4531. All-cause mortality JPAD POPADAD PPP ETDRS Total 34/1262 94/638 25/519 340/1856 493/4275 38/1277 101/638 20/512 366/1855 525/4282 0.90 (0.57-1.14) 0.93 (0.72-1.21) 1.23 (0.69-2.19) 0.91 (0.78-1.06) 0.93 (0.82-1.05) 2 0.03 0.125 0.5 1 8 Favors ASA Favors control/placebo

Insufficient evidence to support use of ASA for primary prevention ASA Not Routinely Recommended for 1⁰ Prevention for CVD Among Patients with DM Insufficient evidence to support use of ASA for primary prevention Risk of bleeding CVD protection 2013 There is insufficient evidence at this time to support routine use of ASA in primary prevention Need to balance the risk of bleeding vs CVD protection from ASA therapy Will need to await until results of clinical trials such as Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) and ASCEND Collaborative Group to shed light on the role of ASA for primary prevention

Don`t Forget To………….. Do your part Protect their heart Multifaceted approach + Individualize therapy

Vascular Protection Checklist 2013 A • A1C – optimal glycemic control (usually ≤7%) B • BP – optimal blood pressure control (<130/80) C • Cholesterol – LDL ≤2.0 mmol/L if decided to treat D • Drugs to protect the heart (regardless of baseline BP or LDL) A – ACEi or ARB │ S – Statin │ A – ASA if indicated E • Exercise / Eating healthily – regular physical activity, achieve and maintain healthy body weight S • Smoking cessation

Recommendation 1 All individuals with diabetes (type 1 or type 2) should follow a comprehensive, multifaceted approach to reduce cardiovascular risk including: Achievement and maintenance of healthy body weight Healthy diet Regular physical activity Smoking cessation Optimal glycemic control (usually A1C <7%) Optimal blood pressure control (<130/80 mmHg) Additional vascular protective medications in the majority of adult patients [Grade D, consensus for T1DM, children/adolescents; Grade A, Level 1 for T2DM]

Recommendation 2 2013 Statin therapy should be used to reduce CV risk in adults with type 1 or type 2 diabetes with any of the following features: Clinical macrovascular disease [Grade A, Level 1] Age ≥40 years [Grade A, Level 1 T2DM; Grade D Consensus T1DM] Age <40 and one of the following: Diabetes duration > 15 years and age >30 yrs Microvascular complication Warrants therapy for other reasons based on the 2012 CCS guidelines for the management of dyslipidemia [Grade D, consensus]

Recommendation 3 2013 ACE inhibitor or ARB, at doses that have demonstrated vascular protection, should be used to reduce CV risk in adults with type 1 or type 2 diabetes with any of the following: Clinical macrovascular disease [Grade A, Level 1] Age ≥55 years [Grade A, Level 1 for those with an additional risk factor or end organ damage; Grade D, consensus for all others] Age <55 years and microvascular complications [Grade D, consensus]

Among women with childbearing potential, ACE inhibitor, ARB, or statin should only be used if there is reliable contraception.

Recommendation 4 2013 ASA should not be routinely used for the primary prevention of cardiovascular disease in people with diabetes [Grade B, Level 2] ASA may be used in the presence of additional cardiovascular risk factors [Grade D, Consensus]

Recommendation 5 and 6 Low-dose ASA therapy (81–325 mg) may be used for secondary prevention in people with established cardiovascular disease [Grade D, Consensus] Clopidogrel (75 mg) may be used in people unable to tolerate ASA [Grade D, Consensus]

CDA Clinical Practice Guidelines www.guidelines.diabetes.ca – for professionals 1-800-BANTING (226-8464) www.diabetes.ca – for patients