Proximate CVD Risk vs. Lifetime CVD Risk
Persons with both type 1 and type 2 diabetes mellitus are at significantly increased risk of atherosclerotic cardiovascular disease (CVD) presenting as coronary heart disease, stroke and peripheral vascular disease (1–3) . For the vast majority of older persons with diabetes (age >40 years), both the proximate 10-year and lifetime CVD event risk becomes sufficiently high (>20%) to justify both health behaviour modification and pharmacological interventions. However, for many younger individuals with diabetes, their proximate 10-year CVD event risk may be low (4) , yet both proximate and lifetime event rates are many times higher than for individuals of the same age without diabetes (1,5) . For these persons, their vascular age far exceeds their chronological age, significantly increasing their relative risk of CVD events. The term “vascular age” refers to models of CVD event risk that predict an individual’s CVD event risk and compare the event risk to age-adjusted CVD event risk (6) . The greater the risk factor burden, the greater the vascular age and relative CVD event risk. Such a high relative risk indicates that early intervention before the arbitrary high-risk 10-year 20% event rate is reached may be beneficial (6–10) . Thus, the use of pharmacotherapy for CVD risk factor reduction in younger persons with diabetes, who are not at a high proximate risk and yet, as a consequence of diabetes, have a steep CVD event risk trajectory, can be justified by the potentially substantial long-term benefits of earlier interventions and lifelong therapy (8–11) .
Traditional CVD event risk models predict an individual’s proximate (5- to 10-year) CVD event risk based on risk factors, such as diabetes, dyslipidemia, hypertension and smoking. These models discriminate poorly between high- and low-risk individuals (12) . Furthermore, they underestimate risk in younger individuals and have a low specificity; consequently, they cannot reliably exclude individuals with diabetes who are unlikely to benefit from long-term pharmacological vascular protection strategies before their proximate risk is high. Consequently, as most individuals with diabetes have a very high lifetime risk for a CVD event, a strategy that includes early vascular protection is justified (8–15) .
Both type 1 and type 2 diabetes are associated with increased CVD risk. In young adults (aged 20 to 39 years), type 1 diabetes is an independent risk factor for premature CVD and mortality (16) . The presence of CVD in people with type 1 diabetes is related to age, duration of diabetes, presence of retinopathy, higher glycated hemoglobin (A1C) levels and higher albumin excretion rates, as well as traditional CVD risk factors, such as elevated total cholesterol and low-density lipoprotein-cholesterol (LDL-C), smoking and excess body weight (17) . For all age groups, the majority of people with type 1 diabetes have at least 1 CV risk factor (18) . Even if an individual with type 1 diabetes has a low proximate risk of a CV event (i.e. younger and shorter duration of diabetes), his or her long-term risk is very high.
Vascular Protection in the Patient with Diabetes
Vascular protective measures in patients with diabetes include health behaviour interventions (diet, weight modification, increased physical activity, smoking cessation) and pharmacological therapies (anti-platelet agents, statins, angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs], glycemic and blood pressure [BP] control). A systematic approach to all vascular protective measures has been proven to reduce the risk of CVD events. The STENO-2 trial showed the long-term benefits of an intensive multifactorial management strategy in patients with type 2 diabetes and microalbuminuria (8,9) . Patients were randomized to receive either usual care or intensive multifactorial therapy, where the goal was to optimize health behaviour and control BP, cholesterol and blood glucose to the treatment targets recommended by clinical practice guidelines. In the intensively managed group, behaviour interventions were more frequently achieved, and BP, lipid and glycemic levels were lower than in the subjects receiving usual care, although treatment targets were usually not achieved. After 8 years of follow-up, there was a 53% relative risk reduction in major CVD events (hazard ratio [HR] 0.47, 95% confidence interval [CI] 0.24–0.73) compared to usual care with a 20% absolute risk reduction. This meant that only 5 patients with type 2 diabetes and microalbuminuria needed to be treated with the intensive multifactorial approach for 8 years to prevent 1 cardiovascular event. Microvascular complications were also substantially reduced. After 13 years, the originally intensively managed group had a significantly lower mortality rate (30% vs. 50%, p=0.02). The number needed to treat (NNT) for mortality after 13 years was 5. The STENO-2 trial shows that a process-driven, multifactorial management strategy optimizing behaviour and pharmacological interventions had a major impact on a wide range of CVD outcomes, including a 46% lower mortality. Thus, all patients with diabetes should participate in a multifactorial strategy to reduce CVD risk.
Strategies for Vascular Protection
Health behaviour interventions for all patients with diabetes
Smoking, in individuals with diabetes, is an independent risk factor for all-cause mortality. It increases the risk of myocardial infarction (MI) 3-fold, stroke by 30%, progression to end stage renal disease, and is associated with poorer glycemic control. Quitting smoking reduces CV risk, reduces the risk of renal disease and improves glycemic control (19,20) .
Exercise and physical activity
Regular exercise and physical activity are key components in the vascular protection paradigm as they have been shown to significantly reduce morbidity and mortality in persons with diabetes (21) . The benefits of regular physical activity are described in the Physical Activity and Diabetes chapter, p. S40.
The benefits of a healthy diet are described in the Nutrition Therapy chapter, p. S45.
While optimal glycemic control is central to the prevention of microvascular complications of diabetes, the benefits of tight glycemic control to reduce the risk for macrovascular disease have been more difficult to show. The goals for glycemic control and the cardiovascular benefits are discussed in the Targets for Glycemic Control chapter, p. S31, and options for glycemic control are discussed in the Pharmacotherapy in Type 1 Diabetes chapter, p. S56, and the Pharmacologic Management of Type 2 Diabetes chapter, p. S61.
BP control is necessary in a high proportion of patients with diabetes. The goals of treatment and options to achieve BP targets are discussed in the Treatment of Hypertension chapter, p. S117.
Platelets play a pivotal role in the development of atherothrombosis. As patients with diabetes have increased in vitro platelet reactivity and aggregation, they might be expected to have enhanced benefit from platelet inhibition with agents such as acetylsalicylic acid (ASA). However, in vitro tests of platelet aggregation suggest that patients with diabetes have platelets that are more likely to be resistant to the inhibitory effect of ASA (22,23) . Despite the proven advantages of ASA therapy in patients with established CVD, the evidence for benefits of ASA therapy for the primary prevention of coronary artery disease (CAD) events in persons with diabetes is less robust.
ASA in primary prevention
In the general population, ASA reduces nonfatal MI in men without a history of CVD (24) . In women without a history of CVD, the Women's Health Study (WHS) indicated that ASA reduces the risk for stroke but not for MI (25) . Yet, the benefits in patients with diabetes are less apparent. The Antithrombotic Trialists meta-analysis included 95 randomized trials of antiplatelet therapy published up to 1997. Of these, only 9 trials with 5000 people had diabetes. Compared to a 22% reduction in the risk of major CV events among all 140 000 high-risk subjects on antiplatelet therapy, subjects with diabetes showed no significant benefit (7% ± 8% risk reduction) (26) .
Primary CVD prevention trials conducted specifically in people with diabetes also have shown very little benefit. The Early Treatment of Diabetic Retinopathy Study (ETDRS) and the Japanese Prevention of Atherosclerosis with ASA in Diabetes (JPAD) trial included patients with diabetes without known atherosclerotic disease (27,28) . The ETDRS trial with ASA 650 mg demonstrated a borderline significant reduction of fatal and nonfatal MI (relative risk [RR] 0.85, 95% CI 0.73–1.00) yet no reduction of stroke (RR 1.18, 95% CI 0.88–1.58) (27) . The JPAD trial used ASA 81 to 100 mg and showed no significant benefit for either MI or stroke (28) . The Prevention of Progression of Arterial Disease and Diabetes (POPADAD) trial in patients with diabetes and peripheral vascular disease showed that ASA 100 mg did not reduce CAD, death, nonfatal MI or stroke (29) . However, poor adherence to treatment, with only 50% of patients taking assigned therapy after 5 years, may have played a role in the apparently absent treatment effect in these patients with vascular disease.
Meta-analysis of the diabetes cohorts from large clinical trials, such as WHS, British Male Doctors (BMD), Hypertension Optimal Treatment (HOT), Primary Prevention Project (PPP), and Thrombosis Prevention Trial (TPT), also have suggested that ASA has little or no benefit for the primary prevention of CAD events (25,30–38) . The Baigent meta-analysis included BMD, PHS, WHS, TPT, and HOT and showed a modest 12% reduction of CVD events (RR 0.88, 95% CI 0.82–0.94) (34) . However, the other 4 meta-analyses that also included ETDRS, JPAD, and POPADAD showed no significant reduction in either CAD events or stroke for patients with diabetes (35–38) .
ASA increases gastrointestinal bleeding 50% to 70% (39) , but the absolute rates of bleeding are low, with a risk of approximately 3 per 10 000 in the overall population. It is likely the risk is higher in patients with diabetes, with an estimate of 1 to 2 per 1000 in middle-aged individuals and as high as >5 per 1000 in people >70 years old (39) .
In summary, pooled estimates suggest that for primary prevention of CVD events in people with diabetes, ASA results in no reduction of CAD events and stroke but an important increase in gastrointestinal hemorrhage. Thus, despite a plethora of data, there remains sufficient uncertainty about the use of ASA in the primary prevention of CAD events in persons with diabetes, and its routine use in primary CVD event prevention is not recommended.
ASA in secondary prevention
ASA has been shown to reduce CVD events in patients with established CVD disease (40) . The clinical trial evidence, as reflected in the 2011 Canadian Cardiovascular Society Guidelines on the Use of Antiplatelet Therapy in the Outpatient Setting, supports the use of ASA 75 to 162 mg daily for the secondary prevention of CAD events in those with diabetes (41) .
Renin-angiotensin-aldosterone system inhibition
The benefit of ACE inhibition for vascular protection with ramipril 10 mg daily was demonstrated by the Heart Outcomes Prevention Evaluation (HOPE) trial (42) . It was also shown in the Micro-HOPE subset analysis of patients with diabetes, which enrolled individuals with diabetes, aged ≥55 years, with 1 other CV risk factor (total cholesterol >5.2 mmol/L, high-density lipoprotein <0.9 mmol/L, hypertension, microalbuminuria or smoking) or established CVD (43) . In subjects with diabetes enrolled in the European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) study, the benefits from perindopril 8 mg daily were similar to those observed in the overall group; however, in this subgroup, the sample size was too small to show a statistically significant benefit (44) . More recently, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) indicated similar vascular protective effect from the ARB telmisartan 80 mg daily as the ACE inhibitor ramipril 10 mg daily in a subset of patients with diabetes (45) .
Whether the benefits of ACE inhibition result from a reduction of BP remains controversial. The benefits of ACE inhibition in both the HOPE and EUROPA trials were observed in individuals with or without a history of hypertension, and in those with higher and lower BP readings (42,46) . Furthermore, recent analyses of BP trials have indicated a benefit of ACE inhibition beyond that of BP lowering (47) .
A recent meta-analysis indicates that ACE inhibitors and ARBs reduce CVD events in normotensive individuals with and without diabetes (48) . Accordingly, the use of ACE inhibitors or ARBs for vascular protection with persons with diabetes ≥55 years or with any evidence of organ damage is recommended, even in the absence of hypertension. Furthermore, for patients with diabetes and hypertension, an ACE inhibitor or ARB should be considered as a first-line agent for BP control.
The role of lipid-modifying therapies in the protection against CAD events in persons with diabetes is presented in the Dyslipidemia chapter, p. S110. In 2008, the Canadian Diabetes Association recommended that all men with diabetes ≥45 years of age and women with diabetes ≥50 years of age be treated with a statin to reduce LDL-C to ≤2.0 mmol/L (49) . The 2008 guidelines also recommended that, below these ages, patients with diabetes and higher CVD risk (e.g. those with established macrovascular disease, microvascular disease, diabetes of >15 years’ duration and age >30 years, and individuals with a very elevated single risk factor) should receive statin therapy.
There is clinical trial evidence of the benefits of statin therapy for primary prevention in patients with diabetes at ages prior to achieving a high proximate 10-year CVD risk. The Heart Protection Study (HPS) enrolled 5963 individuals from age 40 years with diabetes, of whom 49% had no evidence of CVD. CV events were reduced by 22% (95% CI 13–30) in the patients with diabetes receiving simvastatin 40 mg daily for the 5-year treatment period (50) . The same relative benefit was observed in patients with or without evidence of CVD. In the 615 patients with type 1 diabetes, there was a similar (although not statistically significant) risk reduction as observed in the 5438 patients with type 2 diabetes (50) . The Collaborative Atorvastatin Diabetes Study (CARDS) included 2838 patients with diabetes, 1 CV risk factor, and age >40 years. They were treated for an average of 3.9 years with either atorvastatin 10 mg daily or placebo (51) . CV events were reduced by 37% (95% CI −52% to −17%; p=0.001) by atorvastatin compared to placebo, with a 36% reduction of acute coronary heart disease, a 31% reduction of coronary revascularization and a 48% reduction of stroke. There was a strong trend toward a 27% reduction of all-cause mortality (95% CI −48% to 1%; p=0.059). Consequently, both the HPS and CARDS studies provided evidence supporting the use of statin therapy for all patients with diabetes ≥40 years of age with or without 1 CV risk factor. The CARDS study concluded with the statement: “The debate about whether all patients with type 2 diabetes warrant statin treatment should now focus on whether any patients can reliably be identified as being at sufficiently low risk for this safe and efficacious treatment to be withheld” (52) .
As a direct reflection of this evidence, the current guidelines have taken into account the impact of diabetes on lifetime risk for CVD, increased vascular aging, premature development of CVD and shorter life expectancy for the individual with diabetes. In addition, the poor predictive value of current risk models does not allow adequate selection of individuals who are likely (or not) to benefit from statin therapy. Earlier treatment is predicted to result in enhanced cost-effective benefit (52) . Consequently, the current guideline recommendations are for use of statins for primary prevention of CVD at the earliest time (or youngest age), supported by clinical trial evidence when there is no other compelling reason to use statins. Given the wealth of experience with statin use, there is little safety concern for their long-term use. The cost effectiveness of statin use for primary prevention in patients with diabetes has been shown to be similar to or greater than the benefits seen in individuals with established CVD and no diabetes (51) . Furthermore, the number of years of life saved is greater the earlier treatment is initiated. Now, with highly effective generic statins available, cost effectiveness will likely improve further. Consequently, a reasonable position is to recommend statin therapy for primary CVD prevention for all patients with diabetes ≥40 years of age.
The current guidelines continue to support the use of statins in secondary prevention in those with evidence of end organ damage (macrovascular disease, microvascular disease, particularly microalbuminuria). In addition, there are other circumstances, not specific to diabetes, that may warrant statin therapy for a particular individual based on the 2012 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia (53) .
LDL reduction should aim to achieve targets recommended in the current guidelines, and statins should be prescribed up to the maximally tolerated and approved dose. However, the use of other lipid-lowering agents in addition to statins may be necessary in some patients to achieve LDL goals.
Note: Among women with childbearing potential, ACE inhibitors, ARBs or statins should only be used if there is reliable contraception.
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
Regular physical activity
Optimal glycemic control (usually A1C ≤7%)
Optimal blood pressure control (<130/80 mm Hg)
Additional vascular protective medications in the majority of adult patients (see recommendations below) [Grade D, Consensus, for type 1 diabetes; Grade D, Consensus, for children/adolescents; Grade A, Level 1 (8,9) , for those with type 2 diabetes age >40 years with microalbuminuria].
Statin therapy should be used to reduce cardiovascular risk in adults with type 1 or type 2 diabetes with any of the following features:
Clinical macrovascular disease [Grade A, Level 1 (50) ]
Age ≥40 years [Grade A Level 1 (50,51) , for type 2 diabetes; Grade D, Consensus for type 1 diabetes]
Age <40 years and 1 of the following:
Diabetes duration >15 years and age >30 years [Grade D, Consensus]
Microvascular complications [Grade D, Consensus]
Warrants therapy based on the presence of other risk factors according to the 2012 Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia (53) . [Grade D, Consensus]
ACE inhibitor or ARB, at doses that have demonstrated vascular protection, should be used to reduce cardiovascular risk in adults with type 1 or type 2 diabetes with any of the following:
Clinical macrovascular disease [Grade A, Level 1 (43,45) ]
Age ≥55 years [Grade A, Level 1 (43,45) , 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]
ASA should not be routinely used for the primary prevention of cardiovascular disease in people with diabetes [Grade A, Level 2 (36) ]. ASA may be used in the presence of additional cardiovascular risk factors [Grade D, Consensus].
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].
A1C, glycated hemoglobin; ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; ASA, acetylsalicylic acid.