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Canadian Pharmacists Association
Canadian Pharmacists Association
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Chapter 22: Vascular Protection in People with Diabetes

Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada

Immediate CVD Risk vs. Lifetime CVD Risk
  • Persons with both type 1 and type 2 diabetes are at significantly increased risk of atherosclerotic cardiovascular disease (CVD) presenting as coronary heart disease, stroke and peripheral vascular disease.
  • 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. 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.
    • For the vast majority of older persons with diabetes (age >40 years), both the immediate 10-year and lifetime CVD event risk becomes sufficiently high (>20%) to justify both health behaviour modification and pharmacological interventions.
    • The immediate 10-year CVD event risk may be low for younger individuals with diabetes, but is still higher compared to individuals of the same age without diabetes. For these persons, their vascular age far exceeds their chronological age, significantly increasing their relative risk of CVD events.
    • The use of pharmacotherapy to reduce CVD risk factors in younger patients with diabetes can provide potentially substantial long-term benefits of earlier interventions and lifelong therapy.
  • 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.
  • For all age groups, the majority of people with type 1 diabetes have at least 1 CV risk factor. Even if an individual with type 1 diabetes has a low immediate 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 involve both behavioural interventions as well as pharmacological therapies
  • 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 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, for those with type 2 diabetes age >40 years with microalbuminuria].
  • 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.
    • 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.
Strategies for Vascular Protection

Health behaviour interventions for all patients with diabetes

Smoking cessation

  • 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.

Exercise and physical activity

  • Regular exercise and physical activity have been shown to significantly reduce morbidity and mortality in persons with diabetes.

Nutrition therapy

Weight modification

Pharmacological interventions

Glycemic control

BP control

Antiplatelet therapy

  • Platelets play a pivotal role in the development of atherothrombosis. Patients with diabetes have increased in vitro platelet reactivity and aggregation, but 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.

ASA in primary prevention

  • The Antithrombotic Trialists meta-analysis included 95 randomized trials of antiplatelet therapy, of which 9 trials with 5000 people had diabetes. Subjects with diabetes showed no significant benefit in CVD risk reduction (7% ± 8% risk reduction). Primary CVD prevention trials conducted specifically in people with diabetes also have shown very little benefit.
  • 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.
  • ASA increases GI bleeding 50% to 70%. The risk is likely 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.
  • ASA should not be routinely used for the primary prevention of cardiovascular disease in people with diabetes [Grade A, Level 2]. ASA may be used in the presence of additional cardiovascular risk factors [Grade D, Consensus].

ASA in secondary prevention

  • ASA has been shown to reduce CVD events in patients with established CVD disease.
  • 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].
Renin-angiotensin-aldosterone system inhibition
  • 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:
    1. Clinical macrovascular disease [Grade A, Level 1]
    2. Age ≥55 years [Grade A, Level  1, for those with an additional risk factor or end organ damage; Grade D, Consensus, for all others]
    3. Age <55 years and microvascular complications [Grade D, Consensus]
  • The benefit of ACE inhibition for vascular protection with ramipril 10 mg daily was demonstrated by the Heart Outcomes Prevention Evaluation (HOPE) trial, as well as the micro-HOPE subgroup analysis involving patients with diabetes.
  • 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 (but sample size was too small to show a statistically significant benefit).
  • 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.

Note: Among women with childbearing potential, ACE inhibitors, ARBs or statins should only be used if there is reliable contraception.

Lipid-modifying therapies
  • 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 immediate 10-year CVD risk.
    • The Heart Protection Study (HPS) found that CV events were reduced by 22% in the patients with diabetes receiving simvastatin 40 mg daily over 5 years. The same relative benefit was observed in patients with or without evidence of CVD.
    • The Collaborative Atorvastatin Diabetes Study (CARDS) found that CV events were reduced by 37% by atorvastatin 10 mg daily 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.
    • Statin therapy should be used to reduce cardiovascular risk in adults with type 1 or type 2 diabetes with any of the following features:
    1. Clinical macrovascular disease [Grade A, Level 1]
    2. Age ≥40 years [Grade A Level 1, for type 2 diabetes; Grade D, Consensus for type 1 diabetes]
    3. 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 [Grade D, Consensus].
    • 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. Furthermore, the number of years of life saved is greater the earlier treatment is initiated.
  • 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.
Health care provider tools (from CDA)

Reducing Vascular Risk – Does your patient require vascular protective medication?
Vascular Protective Medication – Quick reference guide.
ABCDEs – Quick reference guide for all patients with diabetes.

For definitions of the levels of evidence cited in this chapter, please refer to the Guideline Recommendations: Levels of Evidence.

If you would like more details on this topic, please visit the Canadian Diabetes Association Clinical Practice Guidelines: Chapter 22.