Margaret M. McCarthy, PhD, RN, FNP-BC,1 and Deborah A. Chyun, PhD, RN, FAHA, FAAN2
1McCarthy is an Assistant Professor, Rory Meyers College of Nursing, New York University. 2Chyun is executive associate dean and professor, Rory Meyers College of Nursing, New York University.
PATHOPHYSIOLOGY
Cardiovascular disease (CVD), which includes stroke, peripheral vascular disease, hypertension, angina, myocardial infarction (MI), heart failure, and sudden cardiac death, is the leading cause of death in patients with type 1 diabetes (T1D) or type 2 diabetes (T2D). Adults with diabetes have death rates from heart disease that are about two to four times higher than adults without diabetes.1 Hypertension, which is present in ~40–60% of patients with T2D, plays a major role in the development of stroke, MI, and heart failure.
The pathophysiology of CVD in individuals with diabetes is complex, and the development of atherosclerotic coronary artery disease (CAD) involves the interaction of many factors, including hypertension, dyslipidemia, impaired endothelial function, inflammation, central adiposity, and hemostatic abnormalities involving platelet function, thrombosis, and fibrinolysis. Although the direct role of hyperglycemia remains controversial, hyperglycemia plays an important role in the development of microvascular complications that contribute to adverse outcomes, as well as to lipid and coagulation abnormalities that directly influence the development and progression of CAD. In patients with diabetes, CAD is generally more widespread, with stenosis in a greater number of vessels, along with more obstructive lesions within each vessel. Diffuse disease involving long segments or the distal aspects of the artery may be present, thereby limiting the usefulness of either percutaneous or surgical revascularization. Therefore, multiple risk factors must be controlled for successful prevention and management of CAD.
Although T1D represents a small percentage of patients with diabetes, there are potential differences in the pathophysiology of atherosclerosis.2 Unfortunately most of the data regarding the risk for CVD come from cohorts of patients with T2D, or from a mixed sample of patients with T1D and T2D. Data from studies of T1D, however, show an earlier onset of CVD as compared with populations without diabetes, and the age-adjusted relative risk of CVD is about 10 times that of the general population. Coronary heart disease is the predominant form of CVD, with most studies reporting cumulative incidences of approximately 15% over ~15 years of follow-up.2
CLINICAL PRESENTATION
In the early stages of CAD, minor atherosclerosis may lead to plaque buildup. Plaque rupture subsequently may lead to acute coronary syndromes (ACS), such as unstable angina and acute MI. More advanced atherosclerosis significantly narrows the vessel lumen and restricts blood flow, leading to myocardial ischemia during exercise or emotional stress. Myocardial ischemia sometimes results in angina or dyspnea, but some patients with diabetes may be asymptomatic. The first manifestation of CVD in these individuals may be acute MI, heart failure, or sudden cardiac death. Although as many as one in five individuals with T2D may have completely asymptomatic or silent ischemia,3CVD also occurs in patients who have symptomatic ischemia with angina. The mechanisms responsible for asymptomatic CAD in patients with diabetes may include cardiac autonomic neuropathy,4,5 and abnormalities in cardiac autonomic function also may serve as a risk marker in individuals with underlying asymptomatic myocardial ischemia.3 The clinical presentation of CVD is outlined in Table 10.1.
Table 10.1—Clinical Presentation of CVD
Stable angina
• Transient symptoms usually brought on by activity and relieved by rest or nitroglycerin: pressure, squeezing, fullness, or pain in center of chest lasting more than a few minutes; pain or discomfort in one or both arms, back, neck, jaw, or stomach; feeling out of breath with or before the chest discomfort
• In absence of anginal symptoms, “anginal equivalents”: excessive fatigue, dyspnea, breaking out into a cold sweat, nausea, or lightheadedness
• Diagnostic: transient ST-segment depression on exercise electrocardiogram, regional contractile abnormalities on exercise echocardiogram, or stress-induced myocardial perfusion imaging
Acute coronary syndromes
• Symptoms: as with stable angina, but change in pattern with increased frequency, severity, and duration, lasting more than a few minutes and not relieved by rest or nitroglycerin
• Signs: cool, clammy skin; increased or irregular heart rate; decreased blood pressure; restlessness; altered mental status
• Diagnostic: ST-segment elevation or depression, significant Q-waves, deep T-wave inversions, left bundle branch block, ventricular arrhythmias or heart block on electrocardiogram; elevation of serum cardiac markers; echocardiogram, myocardial perfusion imaging, and angiogram may be ordered
Heart failure
• Symptoms: swelling in feet, ankles, and legs (edema); difficulty breathing, shortness of breath, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea; weight gain; weakness or dizziness
• Signs: elevated heart rate and blood pressure; S3, S4, cardiac murmurs; crackles on lung examination; jugular venous distention and abdominojugular reflux
• Diagnostic: chest X-ray consistent with heart failure or pulmonary edema; echocardiogram, myocardial perfusion imaging, and angiogram may be ordered
Stroke
• Symptoms: sudden numbness or weakness in face, arm, hand, or leg, especially on one side of body; sudden inability to see out of one eye or to one side; sudden confusion, trouble understanding or speaking; sudden trouble walking, dizziness, or loss of balance or coordination; sudden, severe headache without known cause
• Signs: depends on site involved but may include restlessness, lethargy, altered mental status, hemiplegia, or hemiparesis
• Diagnostic: computed tomographic scans, magnetic resonance imaging, carotid or transcranial ultrasound, cerebral angiography, lumbar puncture
PREVENTION
As the understanding of the pathophysiological mechanisms responsible for CVD in individuals with diabetes continues to evolve, it has become apparent that T2D and CVD share many common antecedents. The most effective way to prevent CVD in patients is to prevent diabetes in the first place. Although it is critical that the primary prevention of CVD in all patients with diabetes become a top priority, because CVD already may be established when the person is diagnosed with diabetes, identification of underlying CVD and limiting its progression are additional goals. There is some discrepancy in treatment goals among published clinical practice guidelines, particularly for blood pressure and lipids, as well as for levels at which medications should be started. Yet, no matter how lenient the goal, it is clear that the goals for cardiac risk factors or for blood glucose are not being achieved in most patients with diabetes. Goals and strategies for multifactorial risk reduction are presented in Table 10.2.6–14
Table 10.2—Goals and Strategies for Prevention of CVD in Patients with Diabetes
Blood pressure <140/90 mmHg
• Measure at each visit.
• Goal <140/<90 mmHg or lower if no treatment burden
Lipids
• Tested at time of diagnosis (if not taking statin), and every 5 years thereafter. Obtain lipid profile at initiation of statin therapy and periodically to monitor response to therapy.
• Weight loss, reduction of saturated fat, trans fat and cholesterol intake; increase dietary omega 3 fatty acids, viscous fiber and plant stanols/sterols
Regular physical activity
• At least 3 days per week for a total of 150 min of moderate intensity or greater
• Routinely assess physical activity and exercise status.
• Encourage increase in daily activities and moderate-to-vigorous aerobic regimen, such as brisk walking.
• Individualization of exercise prescription and caution with peripheral or cardiac autonomic neuropathy or proliferative retinopathy
• Patient education regarding symptoms of angina and MI
Complete smoking cessation12,14
• Assess smoking status.
• Provide counseling, problem solving, or coping skills training, and pharmacotherapy.
Aspirin therapy6,14
• Use aspirin therapy 75–162 mg/day, as secondary prevention in those with DM and CVD. For patients with CVD and documented aspirin allergy, clopidogrel (75 mg/day) should be used. Consider ASA therapy as primary prevention in those with T1D or T2D at increased risk of CVD—includes most men and women ≥50years of age who have at least 1 additional major risk factor (family history of premature atherosclerotic CVD, hypertension, dyslipidemia, smoking, or albuminuria) and are not at increased risk for bleeding.
A1C <7%7
• Test at least two times a year in patients who are meeting treatment goals (and who have stable glycemic control).
• Medical nutrition therapy.
• Weight control.
• Regular physical activity.
• Self-monitoring of blood glucose.
• Education in self-management and problem solving.
CVD, cardiovascular disease; MI, myocardial infarction.
Recent clinical trials of intensive therapy with the goal of normalizing glycemic control to an A1C of <6.5%, in patients with established diabetes have not shown a benefit in lowering the risk of CVD outcomes.15,16Importantly, the risk for severe hypoglycemia was increased in these trials. Although some individuals, such as those with newly diagnosed diabetes, may benefit from more intensive glucose lowering, current recommendations advise an individualized approach based on risks associated with hypoglycemia, diabetes duration, life expectancy, the presence of other comorbidities and vascular complications, and available patient resources and supports.7 The American Diabetes Association (the Association), American Heart Association (AHA), and American College of Cardiology (ACC) have coauthored a statement affirming that the control of risk factors remains paramount, specifically, controlling blood pressure, reducing lipid levels with statin drugs, prescribing aspirin, and reemphasizing lifestyle modifications.17 Although glucose control is more strongly linked with microvascular complications of diabetes than with macrovascular disease, optimal glucose control is important to the control of lipid levels and may have an impact on cardiac events. To reduce microvascular and neuropathic sequelae in patients with both T1D and T2D, an A1C of <7% is the goal.17 To affect macrovascular sequelae in those with early T1D or T2D, an A1C of <7% is also a reasonable goal.17
The effects of intensive diabetes treatment as compared to conventional treatment for patients with T1D was evaluated in the Diabetes Control and Complications Trial (DCCT) with long-term follow-up in the Epidemiology of Diabetes Interventions and Complications (EDIC) trial.18 In this sample (n = 1,441) with over 17 years of follow-up, intensive control (three or more daily injections of insulin or treatment with external insulin pump, with goal A1C <6.05%) showed long-term benefits on the risk of cardiovascular disease as compared to conventional treatment (one or two daily insulin injections, with no glucose goal except to prevent symptoms of hypoglycemia or hyperglycemia). Intensive treatment reduced the risk of any cardiovascular disease event by 42% and the risk of nonfatal MI, stroke, or death from cardiovascular disease by 57%. This study demonstrated the importance of glucose lowering at the onset of diabetes, a goal often not achievable in regard to T2D.
There is emerging yet limited evidence that specific antihyperglycemic agents for T2D may be cardioprotective, such as metformin, some SGLT2 inhibitors, and GLP agonists. This issue will continue to receive attention.
The importance of blood pressure control in people with T2D was demonstrated in the U.K. Prospective Diabetes Study,19 while more recent evidence suggests that lowering systolic blood pressure to <130 mmHg has no added benefit.20 The Association’s goals call for a reduction of systolic blood pressure to <140 mmHg, but lower targets such as <130 mmHg may be appropriate for some individuals, such as younger patients, as long as this can be achieved without undue treatment burden, with a diastolic blood pressure of <90 mmHg.
Patients with confirmed office-based blood pressure >140/90 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of pharmacologic therapy to achieve blood pressure goals.
Patients with confirmed office-based blood pressure >160/100 mmHg should, in addition to lifestyle therapy, have prompt initiation and timely titration of two drugs or a single pill combination of drugs demonstrated to reduce cardiovascular events in patients with diabetes.
Treatment for hypertension should include drug classes demonstrated to reduce cardiovascular events in patients with diabetes (ACE inhibitors, angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blockers). Multiple-drug therapy is generally required to achieve blood pressure targets (but not a combination of ACE inhibitors and angiotensin receptor blockers, thiazide-like diuretics, or dihydropyridine calcium channel blocker).
An ACE inhibitor or angiotensin receptor blocker, at the maximum tolerated dose indicated for blood pressure treatment, is the recommended first-line treatment for hypertension in patients with diabetes and urinary albumin-to-creatinine ratio ≥300 mg/g creatinine or >30–299 mg/g creatinine. If one class is not tolerated, the other should be substituted. For patients treated with an ACE inhibitor, angiotensin receptor blocker, or diuretic, serum creatinine/estimated glomerular filtration rate and serum potassium levels should be monitored. For patients with blood pressure >120/80 mmHg, lifestyle intervention consists of weight loss if overweight or obese; a Dietary Approaches to Stop Hypertension-style dietary pattern including reducing sodium and increasing potassium intake; moderation of alcohol intake and increased physical activity is recommended.21
The major lipid abnormalities associated with insulin resistance and T2D include reduced high-density lipoprotein (HDL) cholesterol and increased triglyceride levels. Oxidized, small, dense low-density lipoprotein (LDL) cholesterol particles are also atherogenic in patients with diabetes, even though LDL cholesterol is not specifically elevated in diabetes. The Association recommends use of statin therapy (high intensity) added to lifestyle therapy in all patients with diabetes and atherosclerotic CVD >40 years of age and, for patients with diabetes <40 years with additional atherosclerotic CVD risk factors, moderate- or high-intensity statin is recommended in addition to lifestyle therapy (Table 10.3). Specific medications and dosages are listed in Table 10.4.7
Table 10.3—Statin Risk Stratification
|
Age |
Risk factors |
Recommended statin intensity* |
|
<40 years |
None |
None |
|
ASCVD risk factor(s)** |
Moderate or high |
|
|
ASCVD |
High |
|
|
40–75 years |
None |
Moderate |
|
ASCVD risk factors |
High |
|
|
ASCVD |
High |
|
|
ACS and LDL cholesterol and LDL cholesterol ≥50 mg/dL (1.3 mmol/L) or in patients with a history of ASCVD who cannot tolerate high-dose statins |
Moderate plusezetimibe |
|
|
>75 years |
None |
Moderate |
|
ASCVD risk factors |
Moderate or high |
|
|
ASCVD |
High |
|
|
ACS and LDL cholesterol and ≥50 mg/dL (1.3 mmol/L) or in patients with a history of ASCVD who cannot tolerate high-dose statins |
Moderate plus ezetimibe |
*In addition to lifestyle therapy.
**ASCVD risk factors include LDL cholesterol ≥100 mg/dL (2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD.
Source: From American Diabetes Association, 2017.7
Table 10.4—Statin Intensity Based on Risk Assessment
|
High-intensity statin therapy (lowers LDL cholesterol by ≥50%) |
Moderate-intensity statin therapy (lowers LDL cholesterol by 30% to <50%) |
|
Atorvastatin 40–80 mg Rosuvastatin 20–40 mg |
Atorvastatin 10–20 mg Rosuvastatin 5–10 mg Simvastatin 20–40 mg Pravastatin 40–80 mg Lovastatin 40 mg Fluvastatin XL 80 mg Pitavastatin 2–4 mg |
Source: From the American Diabetes Association 2017.7
According to the Association’s 2017 Standards of Care, the addition of ezetimibe to moderate-intensity statin therapy may provide additional cardiovascular benefit compared with moderate-intensity statins alone and may be considered if the patient has had recent coronary syndrome with an LDL cholesterol >50 mg/dl or for those with a history of atherosclerotic CVD who cannot tolerate high-intensity statins.7 For patients with fasting triglycerides >500 mg/dL, it is recommended that other causes of hypertriglyceridemia be evaluated and medical therapy be initiated to reduce the risk of pancreatitis.7
Combination therapy of statins and fibrates generally is not recommended but may be considered for men if the triglyceride level is >204 mg/dL and the HDL cholesterol is <34 mg/dL. A combination of statins and niacin generally is not recommended because it has not been shown to provide additional cardiovascular benefits and may increase the risk of stroke.7
Physical inactivity and obesity play major roles in the development of T2D and CVD. Regular physical activity, structured exercise, and dietary modifications have beneficial effects on glycemic control, lipids, weight, and blood pressure. Recent evidence from the Prevención con Dieta Mediterránea trial suggests that following a Mediterranean diet reduces the risk of CVD.9 In general, however, recommendations should focus on reducing saturated fat, cholesterol, and trans fat intake and increasing plant stanols/sterols, omega 3 fatty acids, and viscous fiber (such as oats, legumes, and citrus). Glycemic control may also be beneficial in modifying plasma lipid levels, particularly in those with very high triglycerides and poor glycemic control.
The Look AHEAD (Action for Health in Diabetes) trial randomized more than 5,000 adults with T2D to either participate in an intensive lifestyle intervention (decreased caloric intake plus physical activity) or to receive diabetes support and education.22 Although no differences were detected in the primary outcome (i.e., composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for angina) between the groups, the intervention group did have greater weight loss and reductions in A1C, as well as improved fitness and improvement in most cardiovascular risk factors. The Italian Diabetes and Exercise Study demonstrated that an exercise (150 min/week in two supervised sessions of aerobic and resistance training) intervention in combination with structured counseling was effective in lowering A1C and improving cardiac risk factors.23
Individual exercise recommendations are required in patients with peripheral vascular disease or with cardiac autonomic neuropathy, severe retinopathy, or known CAD. Those with proliferative or severe proliferative retinopathy may need to avoid vigorous-intensity aerobic or resistance exercise, as those with decreased sensation or autonomic neuropathy may need additional evaluation. Although routine pre-exercise testing is not recommended, patients should be assessed for CV risk factors and be aware of the atypical presentation of CAD in people with diabetes. High-risk patients should be encouraged to start with short periods of low-intensity exercise and slowly increase intensity and duration as should sedentary individuals.24 All patients should be educated about the typical and atypical symptoms of myocardial ischemia and instructed to report these symptoms to their care provider, if they occur.
Current recommendations for the use of aspirin are listed in table 10.2. Aspirin has been shown to be effective in secondary prevention of reducing cardiovascular mortality and morbidity in high-risk patients but is less clear as a primary prevention in those with no previous CV events.
All individuals with diabetes should have a yearly assessment of cardiac risk factor status.7 Although control of blood glucose is important in preventing microvascular complications, simultaneous control of lipid levels and blood pressure, avoidance of obesity and smoking, and engagement in regular physical activity are mandatory in the prevention of CVD. Evidence supports a multifactorial approach to CVD risk reduction. In the STENO-2 trial, 160 patients with T2D and persistent microalbuminuria received either intensive therapy or conventional therapy for a mean of 7.8 years, followed by observation for a mean of 5.5 years. The intensive intervention with multiple drug combinations and behavior modification appeared to have a sustained benefit in reducing vascular complications and death from any cause and from cardiovascular causes.25 Many individuals with diabetes continue to smoke, and complete smoking cessation should be the goal.7,8,12
Although these recommendations pertain to adults, the increasing incidence of both T1D and T2D in youth has been addressed in a recent Scientific Statement from the AHA.26 Recommendations for screening, treatment, and differences between approaches in T1D and T2D are addressed. Given the longer exposure to CAD risk factors in individuals who develop diabetes at a young age, risk factor modification is crucial to prevent CAD later in life.
Smoking Cessation Assistance
Smoking cessation assistance is available online at the American Cancer Society’s website. For more information, visit www.cancer.org/healthy/stayawayfromtobacco/index.
TREATMENT
Nonsurgical Intervention
Once the diagnosis of CAD is made, aggressive treatment of dyslipidemia and hypertension, prevention of thrombosis with aspirin, and treatment with medications to reduce myocardial ischemia become even more essential, following the same principles outlined in Table 10.2. Specific medications for CVD management in patients with diabetes, along with precautions to observe in this population, are outlined in Table 10.5.
Table 10.5—Cardiac Medications in Patients with Diabetes
Angiotensin-Converting Enzyme (ACE) Inhibitors/Angiotensin Receptor Blockers (ARBs)
• Contraindications: angioedema, severe cough, bilateral renal artery stenosis, anuric renal failure, significant hyperkalemia, hypotension, shock
• Monitor renal function and potassium levels.
β-Blockers
• Caution: assess for worsening of glycemic and lipid control.
• Contraindications: bradycardia, second- or third-degree arteriovenous block, hypotension, moderate or severe heart failure, active wheezing
• Assess risk of masking hypoglycemia in patients requiring insulin.
• If used in the presence of bronchospastic disease, active heart failure, and conduction system disease, assess for deterioration.
• Initiate slowly and avoid abrupt withdrawal.
Calcium Channel Blockers
• Diltiazem and verapamil are contraindicated in patients who have heart failure with systolic dysfunction; amlodipine and felodipine may be used to treat angina in patients with heart failure.
• Caution: heart failure, left ventricular dysfunction, arteriovenous block, sinus node dysfunction.
Digoxin
• Contraindications: sinus node dysfunction or arteriovenous block
• Potential interactions with many medications
• Monitor renal function and electrolytes (hypokalemia and hypomagnesia).
Diuretics
•Aldosterone antagonist; spironolactone useful, particularly in patients with heart failure, but caution in patients with renal insufficiency because of possible hyperkalemia
Lipid-Lowering Agents
• HMG-CoA (3-hydroxy-3-methyl-glutaryl-coenzyme A ) reductase inhibitors (statins) contraindicated with acute liver disease, heavy alcohol intake, or significant elevations in liver function tests (LFTs); monitor LFTs and closely monitor patients with hepatic dysfunction; assess for myalgias and potential myopathy with creatine phosphokinase (CPK) measurement, especially when used in combination with fibrates.
Nitrates
• Use with caution in patients with autonomic neuropathy.
• Avoid nitrate tolerance by dosing with 8- to 12-h nitrate-free period.
• Caution in setting of acute myocardial infarction (MI) with presence of hypotension or right ventricular infarction
Platelet Inhibitors and Anticoagulants
• Monitor for bleeding with anticoagulants.
• Maintain partial thromboplastin time (aPTT) (heparin) and prothrombin time.
• Follow international normalized ratio (PT/INR) (warfarin).
• Provide patient education regarding possible medication and dietary interactions with warfarin.
• In patients allergic to or unable to take aspirin, use clopidrel. Prasugrel should not be given to patients with a history of stroke or transient ischemic attack; effectiveness questioned in those ≥74 years or weighing <60 kg.
Heart failure is prevalent in the population with diabetes and its diagnosis presents additional challenges. Treatment of heart failure in patients with diabetes should focus not only on the management of heart failure but also on coexistent hypertension, CAD, and renal disease as well as glucose control. Guidelines for the overall management of heart failure, based on class I evidence27 and the four stages of heart failure, are shown in Table 10.6.28Stage A includes individuals at high risk of developing heart failure; stage B includes individuals with left ventricular dysfunction but without symptoms; and stage C includes individuals with left ventricular dysfunction with either current or prior symptoms. Refractory, end-stage heart failure is considered stage D.
Table 10.6—Recommendations for Treating Heart Failure
• Achieve adequate blood pressure and lipid control following current guidelines.
• Counsel avoidance of smoking, alcohol, and illicit drugs.
• Obesity, diabetes, and known cardiotoxic agents should be controlled or avoided.
• Angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blockers (ARB), angiotensin receptor-neprilysin inhibitor ( ARNI) along with a beta blocker and an aldosterone antagonist is the recommended therapy for patients with chronic symptomatic heart failure with reduced ejection fraction.
• ARNIs should replace ACE inhibitors (or ARBs) when stable patients with mild-to-moderate heart failure on these therapies have an adequate blood pressure and are otherwise tolerating standard therapies well. ARNIs, however, should not be used with an ACE inhibitor and should not be used by patients with a history of angioedema.
• Control ventricular rate in atrial fibrillation.
• Treat thyroid disorders.
Treat sleep disorders
• Moderate sodium restriction, daily measurement of weight, influenza and pneumococcal vaccination27
• Encourage physical activity, exercise training, or cardiac rehabilitation.
• Implantable cardioverter-defibrillator for primary prevention of sudden cardiac death, or as secondary prevention to prolong survival, may be indicated.28
• Evaluate and treat signs and symptoms
—Periodic if stage A and regularly if in other stages
—In stage B and higher, consider valve replacement or repair for hemodynamically significant stenoses/regurgitation.
—In stage C and higher
* diuretics if evidence of fluid retention
* digitalis unless contraindicated
* withdrawal of drugs known to adversely affect clinical status
—In stage D
* meticulous treatment of fluid retention
* referral for heart failure program and cardiac transplantation
Blood pressure should be lowered to <140/90 mmHg, and in most patients, even more aggressive lowering of blood pressure is indicated to reduce afterload and reverse left ventricular hypertrophy when present,19 and if they can be achieved without undue treatment burdens.
Lower targets may be appropriate for some individuals.7 The European Society of Cardiology published guidelines for the treatment of heart failure in those with diabetes.29 Metformin may be used in type 2 diabetes in those with stable congestive heart failure, if eGFR remains >30 mL/min, but avoided in those who are hospitalized or have unstable heart failure, Thiazolidinediones (TZDs) are not recommended in patients with moderate-to-severe heart failure because of the risk of sodium and water retention and worsening of heart failure. Sulfonylureas also are associated with an increased risk of worsening heart failure and should be used with caution. Dipeptidylpeptidase-4 inhibitors (DPP4is; gliptins), which increase incretin secretion, thereby stimulating insulin release, and long-acting glucagon-like peptide 1 (GLP-1) receptor agonists, which act as incretin mimetics, improve glycemic indices but do not reduce and may increase the risk of cardiovascular events and worsening heart failure.30–32 Importantly, there are no data on the safety of gliptins and GLP-1 analogs in patients with HF. The effect of sodium-glucose co-transporter 2 inhibitors is not entirely well known at this time. Several studies have demonstrated a decrease in cardiovascular mortality with liraglutide and empagloflozin but no specific guidelines have included them at this time.
Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) improve symptoms and reduce mortality and are indicated in T2D and heart failure. In addition to an ACEI or ARB, a β -blocker should be given to all patients with left ventricular ejection fraction ≤40%. If ACEIs, ARBs, or diuretics are used, serum creatinine or estimated glomerular filtration rate (eGFR) and potassium levels should be monitored.7 Low-dose mineralocorticoid receptor antagonists are indicated in those with persistent symptoms. Diuretics are useful for the relief of dyspnea and edema in heart failure with fluid overload, irrespective of the ejection fraction. Loop diuretics are preferred over thiazides, which have been associated with hyperglycemia and insulin resistance. Nonpharmacologic treatment may include cardiac resynchronization and implantable cardioverter defibrillators.
Increasing evidence suggests that individuals with diabetes have an increased risk for heart failure that is independent of the atherosclerosis. In patients with diabetes who are unresponsive to medical therapy, consideration should be given to cardiac transplantation. Although transplant rejection is a relatively rare occurrence in the current era of immunosuppressive therapy, patients requiring insulin are at higher risk for poor outcomes at transplantation. Higher doses of insulin and other adjuvant hypoglycemic agents usually are required during the early posttransplantation phase, when high doses of corticosteroids are used.
In the setting of ACS, which includes unstable angina and acute MI, early and appropriate management is critical to limit myocardial damage and prevent complications. MI may occur without the warning of prior angina, and patients may have atypical symptoms that delay them seeking medical attention and thus gaining the benefits of timely reperfusion. Cardiac autonomic neuropathy may further complicate management of patients with diabetes because of the associated increased heart rate and a decreased awareness of ischemic symptoms. Although early coronary reperfusion, aspirin, β-blockers, ACEIs, lipid-lowering agents, and coronary revascularization have dramatically improved the survival of patients with diabetes and MI, those patients with known CVD and diabetes-related microvascular complications still have a higher risk of complications than patients without diabetes, both during and after hospitalization (Table 10.7).33-40
Table 10.7—Complications to Assess and Prevent in Patients with Diabetes and CAD
After acute myocardial infarction (MI)
• Heart failure
• Cardiogenic shock
• Postinfarction angina
• Heart block
• Atrial arrhythmias
• Renal insufficiency
• Recurrent MI and heart failure after discharge
After percutaneous interventions
• MI
• Renal failure
• Stroke
• Retroperitoneal bleeding, femoral hematoma, femoral or iliac artery dissection or occlusion, pseudoaneurysm formation
• Restenosis, MI, and need for repeat revascularization
After coronary artery bypass surgery
• MI
• Renal failure
• Stroke
• Sternal wound infection
• Recurrent angina and heart failure
Patients with diabetes presenting with ST-segment elevation, indicative of MI (STEMI), who are within 12 h of the onset of symptoms, should be considered for primary angioplasty with stent placement, particularly when evidence points to heart failure or hemodynamic instability, in which case the establishment of secure vessel patency may be critical. At times, additional surgical revascularization is necessary, particularly when significant residual CAD is present with recurrent angina or inducible ischemia.41 In centers where primary angioplasty is not available, thrombolytic therapy should be administered unless this is contraindicated because of bleeding risk. Following revascularization, hemostatic abnormalities in individuals with diabetes remain problematic. Therefore, subsequent antithrombotic treatment to prevent reocclusion, as described in the following section, is an important part of follow-up care.
Unstable angina and non-STEMI are part of the spectrum of ACS that leave the individual with diabetes at an increased risk for adverse outcomes, including death, progression to STEMI, and subsequent readmission for unstable angina. Patients with unstable angina and diabetes have more extensive CAD, involving a greater number and longer segments of vessels, sometimes including the left main coronary artery. Some of these patients may have had prior coronary artery bypass graft (CABG), and patients presenting with imminent closure of diseased saphenous vein grafts pose particular challenges.
The initial therapy of ACS includes the administration of β-blockers, aspirin, heparin, clopidrel or glycoprotein IIb/IIIa inhibitors, and nitrates.42 Those patients at significant risk for subsequent cardiac events, such as those with marked or widespread resting ST-segment depression, prior MI, decreased left ventricular function, or heart failure, may undergo early coronary angiography and revascularization. The question of treating CAD in patients with diabetes was explored in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D). The BARI 2D trial randomized 2,368 patients with T2D and CAD to either prompt revascularization or intensive medical therapy alone; and to either insulin-sensitization or insulin-provision diabetes therapy. BARI 2D showed that in patients with T2D and stable CAD with documented ischemia, mortality was not influenced by prompt revascularization or by diabetes management strategies that adopted insulin provision or sensitization. In appropriately chosen T2D patients CABG was superior to medical therapy alone in reducing CV events, particularly among patients assigned to receive insulin sensitization.43 A noninvasive approach with further risk stratification based on stress echocardiography or myocardial perfusion imaging may be preferable in low-risk patients and those with major comorbidity who are at high risk with the invasive approach.
The first Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction (DIGAMI 1) study demonstrated that intensive insulin treatment improved survival at 1 year and at 3.4-year follow-up,44,45 but a second trial, DIGAMI 2, failed to show a difference between two glucose-insulin management arms and a control group receiving routine medical management aimed at maintaining glucose levels between 7 mmol/L and 10 mmol/L (126 mg/dL and 180 mg/dL).46 In addition, aggressive versus moderate glucose control has been studied in patients undergoing CABG and current recommendations are for a blood glucose goal of <180 mg/dL during surgery and throughout the intensive care unit stay. As in the routine management of diabetes, aggressive glucose control is not advocated and hypoglycemia should be avoided.47After both STEMI and ACS, aggressive management of cardiac risk factors is warranted, including self-monitoring of blood glucose levels to target A1C concentrations <7% (Table 10.2).
Percutaneous or Surgical Revascularization
The decision to use percutaneous coronary intervention (PCI) or surgical revascularization depends on a number of factors, including the suitability of the target vessels as well as the overall risk status of the patient. PCI usually is implemented for single-vessel disease, and the use of drug-eluting intracoronary stents has improved PCI outcomes by reducing the rate of restenosis. Multivessel disease in patients with diabetes often requires CABG. Although many patients with diabetes safely undergo CABG, older age and the presence of other diabetes-related complications (particularly nephropathy) place the individual at higher risk of poorer operative outcomes. Although the benefit of CABG over PCI in individuals with diabetes has been debated, the recent Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial, which compared CABG to PCI (with drug-eluting stent) demonstrated better cardiac outcomes in patients who underwent CABG.48 These findings, along with other trials, support the superiority of CABG over PCI in patients with diabetes who have multivessel disease.38 Complications associated with both procedures, which should be assessed, are outlined in Table 10.7.
Primary PCI is recommended in patients with STEMI who have ischemic symptoms of <12 h,37 as well as in those with cardiogenic shock or acute severe heart failure, regardless of time from MI onset. Aspirin is administered before PCI and should be continued indefinitely. P2Y12 receptor inhibitors should be given either before or at the time of PCI. Although formerly clopidogrel was used widely, newer agents (prasugrel and ticagrelor) have been shown to be superior; these should be continued for 1 year in patients who receive a stent. Glycoprotein IIb/IIIa receptor antagonists, along with heparin or bivalirudin, can be used in selected patients. In the absence of available PCI within 120 min, fibrinolytic therapy should be instituted within 12 h of ischemic symptoms. In the setting of Unstable Angina/Non ST-elevation Myocardial Infarction (UA/NSTEMI) antiplatelet therapy with a P2Y12 receptor inhibitor should be initiated.42 Although shown to reduce adverse cardiac endpoints, prasugrel use has been associated with significant bleeding and should not be used in certain conditions (see Table 10.7). Differences in bleeding complications have not been observed between ticagrelor and clopidogrel, and ticagrelor has demonstrated better cardiac outcomes.41,42
Strategies for optimizing risk factor control after either PCI or surgical revascularization should be intensified in the population with T2D. As with primary prevention in individuals free of CVD and secondary prevention in those with established CVD, ongoing, intensive, multifactorial risk factor management after PCI or surgical revascularization is critical (Table 10.2).
SUMMARY
Nurses need to have an understanding of the pathophysiology of CVD in individuals with diabetes, along with the clinical presentation of the various manifestations of CVD. Nurses play a particularly important role in coaching those with diabetes regarding the prevention and treatment of CVD. Nurses need to provide education regarding the goals of treatment and conduct an ongoing assessment for goal attainment.
REFERENCES
1. Centers for Disease Control and Prevention. National Diabetes Fact Sheet: National Estimates and General Information on Diabetes and Prediabetes in the United States. Atlanta, GA, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, 2011
2. de Ferranti SD, de Boer IH, Fonseca V, Fox CS, Golden SH, Lavie CJ, Magge SN, Marx N, McGuire DK, Orchard TJ, Zinman B, Eckel RH. Type 1 diabetes mellitus and cardiovascular disease: a scientific statement from the American Heart Association and American Diabetes Association. Diabetes Care 2014;37:2843–2863
3. Wackers FJT, Young LH, Inzucchi SE, Chyun DA, Davey JA, et al. Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study. Diabetes Care 2004;27:1954–1961
4. Vinik AI, Mitchell BD, Maser RE, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003;26:1553–1579
5. Maser RE, Vinik AI, Mitchell BD, Freeman R. The association between cardiovascular autonomic neuropathy and mortality in individuals with diabetes. Diabetes Care 2003;26:1895–1901
6. American Diabetes Association. Nutrition therapy recommendations for management of adults with diabetes (Position Statement). Diabetes Care 2014;37(Suppl. 1):S120–S143
7. American Diabetes Association. Standards of medical care in diabetes—2017. Diabetes Care 2017;40(Suppl. 1):S1-S131
8. Pigone E, Alberts MJ, Colwell JA, Cushman M, Inzucchi SE, Mukherjee D, Rosenson RS, Willimas CD, Wilson PW, Kirkman MS. Aspirin for primary prevention of cardiovascular events in people with diabetes: a position statement of the American Diabetes Association, a scientific statement of the American Heart Association, and an expert consensus document of the American College of Cardiology Foundation. Circulation2010;121:2694–2701
9. Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, Gomez-Gracia E, Ruiz-Gutierrez V, Fiol M, Lapetra J, Lamuela-Raventos RM, Serra-Majem L, Pinto X, Basora J, Munoz MA, Martinez JA, Martinez-Gonzalez MA. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;368:1279–1290
10. National Cholesterol Education Program (NCEP). Third report of the NCEP expert panel on detection, evaluation and treatment of high blood cholesterol in adults (Adult Treatment Panel III). Bethesda, MD, National Heart, Lung, and Blood Institute, National Institutes of Health, 2001, p. 1–28
11. American Diabetes Association. Physical activity/exercise and diabetes (Position Statement). Diabetes Care 2016;27(Suppl. 1):S27–S30
12. American Diabetes Association. Smoking and diabetes (Position Statement). Diabetes Care 2016;27(Suppl. 1):S29
13. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the eighth joint national committee (JNC 8). JAMA 2014;311:507–552
14. Fox C, Golden E, Anderson C, Bray G, Deedwania P, et al. Update on prevention of cardiovascular disease in adult with type 2 diabetes mellitus in light of recent evidence. Circulation 2015;132:691–718
15. Ray KK, Seshasai SRK, Wijesuriya S, Sivakumaran R, Nethercott S, Preiss D, Erqou S, Sattar N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009;373:1765–1772
16. Boussageon R, Bejan-Angoulvant T, Saadatian-Elahi M, Lafont S, Bergonneau C, Kassai B, Erpeldinger S, Gueyffier F, Cornu C. Effect of intensive glucose lowering on all-cause mortality, cardiovascular death, and microvascular events in type 2 diabetes; meta-analysis of randomised controlled trials. BMJ 2011:343:d4169
17. Skyler JS, Bergenstal R, Bonow RO, Buse J, Deedwania P, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care 2009;32:187–192
18. Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM, Orchard TJ, Raskin P, Zinman B; Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–2653
19. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ 1998;317:703–713
20. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and Bayesian random-effects meta-analyses of randomized trials. Circulation 2011;123:2799–2810
21. American Diabetes Association. Standards of medical care in diabetes—2017. Cardiovascular disease and risk management. Sec 9. Diabetes Care 2017;40(Suppl. 1):S75–S87
22. Look AHEAD Research Group, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Reboussin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Wadden TA, Wagenknecht LE, West DS, Williamson DF, Yanovski SZ. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N Engl J Med 2013;369:145–154
23. Balducci S, Zanuso S, Nicolucci A, De FP, Cavallo S, Cardelli P, Fallucca S, Alessi E, Fallucca F, Pugliese G. Effect of an intensive exercise intervention strategy on modifiable cardiovascular risk factors in subjects with type 2 diabetes mellitus: a randomized controlled trial: the Italian Diabetes and exercise Study (IDES). Arch Intern Med 2010;170:1794–1803
24. ADA. Lifestyle management. Standards of medical care in diabetes—2017. Diabetes Care 2017;40(Suppl. 1):S33–S43
25. Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial intervention on mortality in type 2 diabetes. N Engl J Med 2008;358:580–591
26. Maahas DM, Daniels SR, de Ferranti SD, Dichek HL, Flynn J, Goldstein BI, Kelly AS, Nadeau KJ, Martyn-Nemeth P, Osganian SK, Quinn L, Shah AS, Urbina E, on behalf of the American Heart Association Atherosclerosis, Hypertension and Obesity in Youth Committee of the Council on Cardiovascular Disease in the Young, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council for High Blood Pressure Research, and Council on Lifestyle and Cardiometabolic Health. Cardiovascular disease risk factors in youth with diabetes mellitus: a scientific statement from the American Heart Association. Circulation2014;130:1532–1558
27. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos G, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C. 2016 ACC/AHA/HFSA focused update on new pharmacological therapy for heart failure: an update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation. 2016;134.
28. Ruilope M, Authors/Task Force Members, Ruschitzka F, Rutten FH, Van der Meer P, Document Reviewers, Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, FonarowGC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: a report of theAmerican College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239
29. Ponikowski P, Authors/Task Force Members, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González- Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Filippatos F, McMurray JJ, Aboyans V, Achenbach S, Agewall S, Al-Attar N, Atherton JJ, Bauersachs J, Camm AJ, Carerj S, Ceconi C, Coca C, Elliott P, Erol C, Ezekowitz J, Fernández-Golfín C, Fitzsimons D, Guazzi M, Guenoun M, Hasenfuss G, Hindricks G, Hoes AW, Iung B, Jaarsma T, Kirchhof P, Knuuti J, Kolh P, Konstantinides S, Lainscak M, Lancellotti P, Lip GYH, Maisano F, Mueller C, Petrie MC, Piepoli MF, Priori SG, Torbicki A, Tsutsui H, van Veldhuisen DJ, Windecker S, Yancy C, Zamorano JL, ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers, Zamorano JL, Aboyans V, Achenbach S, Agewall S, Badimon L, Barón-Esquivias G, Baumgartner H, Bax JJ, Bueno H, Carerj S, Dean V, Erol C, FitzsimonsD , Gaemperli O, Kirchhof P, Kolh P, Lancellotti P, Lip GYH, Nihoyannopoulos P, Piepoli MF, Ponikowski P, Roffi M, Torbicki A, Vaz Carneiro A, Windecker S, Sisakian HS, Isayev E, Kurlianskaya A, Mullens W, Tokmakova M, Agathangelou P, Melenovsky V, Wiggers H, Hassanein M, Uuetoa T, Lommi J, Kostovska ES, Juillière Y, Aladashvili A, Luchner A, Chrysohoou C, Nyolczas N, Thorgeirsson G, Weinstein JM, Di Lenarda A, Aidargaliyeva N, Bajraktari G, Beishenkulov M, Kamzola G, Abdel-Massih T, Čelutkienė J, Noppe S, Cassar A, Vataman E, Abir-Khalil S, van Pol P, Mo R, Straburzyńska-Migaj E, Fonseca C, Chioncel O, Shlyakhto E, Otasevic P, Goncalvesová E, Lainscak M, Molina BD, Schaufelberger M, Suter T, Yılmaz MB, Voronkov L, Davies C; 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016;37(27):2129-2200.
30. Marso SP, Daniels GH, Brown-Frandserk, Kristensen P, Mann JF, Nauck MA, et al. Liraglutice and cardiovasvcular outcomes in type 2 diabetes. N Engl J Med 2016;375:311–322. DOI: 10.1056/NEJMoa1603827
31. Zinman B, Wanner C, Lachin JM, et al.; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117–2128
32. Abdul-Ghani M, DelPrato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG outcomes study. Diabetes Care 2016;39:717–725
33. Nesto RW, LeWinter M, Bell D, Bonow RO, Semenkovich CF, et al. Thiazolidinedione use, fluid retention, and congestive heart failure. Diabetes Care 2004;27:256–623
34. Brener SJ, Mehran R, Dressler O, Cristea E, Stone GW. Diabetes mellitus, myocardial reperfusion and outcome in patients with ST-elevation myocardial infarction treated with primary angioplasty (from HORIZONS AMI). Am J Cardiol 2012;109:1111–1116
35. Donahoe SM, Stewart GC, McCabe CH, et al. Diabetes and mortality following acute coronary syndromes. JAMA 2007;298:765–775
36. Wallentin L, Lagerqvist B, Husted S, Kotny F, Stahle, Swahn E. Outcomes at 1 year after invasive compared with a non-invasive strategy in unstable coronary artery disease: the FRISC II invasive randomized trial. Lancet2000;356:9–16
37. Cannon CP, Weintrab WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med2001;344:1879–1887
38. Choi SS, Mehran R. Revascularization strategies in patients with type 2 diabetes mellitus. Expert Rev Cardiovasc Ther 2013;11:1337–1347
39. Wright RS, Anderson JL, Adams CD, et al. ACCF/AHA focused update of the guidelines for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011;123:2022–2060
40. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology, Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes. Eur Heart J 2007;28:1598–1660
41. American College of Emergency Physicians; Society for Cardiovascular Angiography and Interventions; O’Gara PT, Kushner FG, Ascheim DD, Casey DE Jr, Chung MK, de Lemos JA, Ettinger SM, Fang JC, Fesmire FM, Franklin BA, Granger CB, Krumholz HM, Lingerbaum JA, Morrow DA, Newby LK, Ornato JP, Ou N, Radford MJ, Tamis-Holland JE, Tommaso CL, Tracy CM, Woo YJ, Zhao DX, Anderson JL, Jacobes AK, Halperin JL, Albert NM, Brindis RG, Creager MA, DeMets D, Guyton RA, Hochman JS, Kovacs RJ, Kusher FG, Ohman EM, Stevenson WG, Yancy CW. ACCF/AHA guideline for the management of ST-elevation myocardial infarction. JACC2013;61:e78–140
42. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction. (Updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2012;126:875–910
43. Rutter MK, Nesto RW. The BARI 2D study: a randomized trial of therapies for type 2 diabetes and coronary artery disease. Diab & Vasc Dis Res 2010;7:69–72
44. Malmberg K. Prospective randomised study on intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus: DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group. BMJ 1997;314:1512–1515
45. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al. Randomized trial of insulin-glucose infusion followed by subcutaneous insulin treatment in diabetic patients with acute myocardial infarction (DIGAMI Study): effects on mortality at 1 year. J Am Coll Cardiol 1995;26:57–65
46. Malmberg K, Ryden L, Wedel H, Birkeland K, Bootsma A, Dickstein K, Efendic S, Fisher M, Hamsten A, Herlitz J, Hildebrandt P, MacLeod K, Laakso M, Torp-Pedersen C, Waldenstron A; for the DIGAMI 2 Investigators. Intense metabolic control by means of insulin in patients with diabetes mellitus and acute myocardial infarction (DIGAMI 2): effects on mortality and morbidity. Eur Heart J 2005;25:650–661
47. Lazar HL, McDonnell MM, Chipkin S, Fitzgerald C, Bliss C, Cabral H. Effects of aggressive versus moderate glycemic control on clinical outcomes in diabetes coronary artery bypass graft patients. Ann Surg2011;254:458–464
48. Farkouh ME, Domanski M, Sleeper LA, et al. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med 2012;367:2375–2384