Diabetes and the Cardiovascular System

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Scope of the Problem

Diabetes Mellitus

Diabetes mellitus (DM) involves insufficient production of insulin and/or failure to respond appropriately to insulin, resulting in hyperglycemia. Table 31.1 summarizes the current diagnostic criteria. Type 2 DM is characterized by insulin resistance and relative insulin deficiency (>90% of all DM cases), whereas type 1 is defined by absolute insulin deficiency. This chapter focuses on type 2 DM, except when specifically indicated otherwise.

TABLE 31.1

American Diabetes Association Diagnostic Criteria for Diabetes Mellitus ∗

Modified from American Diabetes Association. Classification and Diagnosis of Diabetes: Standards of Medical Care in Diabetes. Diabetes Care . 2020;43(suppl 1):S14–S31.

1.
Fasting plasma glucose (FPG) ≥126 mg/dL (7.0 mmol/L). Fasting is defined as no caloric intake for at least 8 hr.

2.
Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test (OGTT). The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

3.
Glycated hemoglobin (A _1c ) ≥6.5% (48 mmol/mol). The test should be performed in a laboratory using a method that is National Glycohemoglobin Standardization Program (NGSP) certified and standardized to the Diabetes Control and Complications Trial (DCCT) assay.

4.
In a patient with classic symptoms of hyperglycemia or hyperglycemic crisis, a random plasma glucose ≥200 mg/dL (11.1 mmol/L).

∗ Criteria 1 to 3 require confirmatory testing; criterion 4 does not.

Diabetes, one of the most common chronic diseases in the world, affects an estimated 463 million adults in 2019 ( Fig. 31.1 ). The mounting incidence and prevalence of type 2 DM, driven by increasing population age, obesity, and physical inactivity, compound with its high global burden (see Chapter 2, Chapter 25, Chapter 30 ), as does the increasing longevity of patients with the disease. DM will affect more than an estimated 700 million persons, 10.9% of the global adult population, by 2045.

FIGURE 31.1, Diabetes mellitus prevalence by age and sex in 2019.

Cardiovascular disease (CVD) remains the principal comorbid condition and primary contributor to mortality in patients with DM, usually in the form of coronary heart disease (CHD), but also in the incremental risk associated with DM for cerebrovascular disease, peripheral vascular disease, heart failure (HF), and atrial fibrillation (AF). For these reasons, continuing effort toward mitigating the risk of CVD in DM remains a global public health imperative.

Atherosclerotic Vascular Disease

Patients with DM have a two- to fourfold increased risk for CHD, CV mortality, all-cause mortality, and CV hospitalization compared with those without DM ( Fig. 31.2 ). ^, However, the CV risk and mortality in patients with DM remain substantially increased over those without DM, underscoring the unmet clinical need. ^,

FIGURE 31.2, Major cardiovascular outcomes in patients with type 1 DM and matched controls. Controls were matched for age, sex, and country. I bars represent 95% confidence intervals.

Diabetes entails an increased risk for myocardial infarction (MI). Across the spectrum of acute coronary syndrome (ACS) events, in which DM may affect more than one in three patients, those with DM have worse CVD outcomes (see Chapter 36, Chapter 37, Chapter 38, Chapter 39 ). Despite overall improvements in outcomes during the past several decades for ACS patients with and without DM, the gradient of risk associated with DM persists ( Fig. 31.3 ), although incremental in-hospital mortality risk associated with DM after ACS has declined ( Fig. 31.4 ). Furthermore, the graded association of increased risk in the setting of ACS extends to glucose values well below the DM threshold ( Fig. 31.5 ).

FIGURE 31.3, Adverse clinical outcomes after acute coronary syndromes during more than 1 year of follow-up, according to DM status, among patients participating in the TRITON–TIMI 38 randomized trial. CVA , Cerebrovascular accident; CVD , cardiovascular death; D , death; DM , diabetes mellitus; MI, myocardial infarction.

FIGURE 31.4, Unadjusted hospital mortality after myocardial infarction (MI) by year of study enrollment according to diabetes mellitus status (in-hospital deaths as percentage of total number of patients enrolled during each year of the study) among 1,734,431 patients with acute MI registered in the National Registry of Myocardial Infarction (NRMI) 1994 to 2006.

FIGURE 31.5, Postadmission glucose levels and mortality in a cohort of patients admitted for acute myocardial infarction (MI) with hyperglycemia on arrival, after multivariable adjustment (to convert glucose values to mmol/L multiply by 0.0555).

In addition to CHD, DM increases the risks of stroke (twofold increase, see Chapter 45 ), cerebrovascular disease, and peripheral arterial disease. Hyperglycemia affects approximately one in three patients with acute stroke and is associated to a two- to sixfold increased risk for adverse clinical outcomes.

Heart Failure

In the ambulatory setting, DM associates independently with a twofold to fivefold increased risk for HF over that in persons without DM, and patients with DM have worse outcomes once HF has developed. HF in DM is a key driver of CV morbidity and mortality, leading to the inclusion of HF as a major endpoint in contemporary clinical trials.

Atrial Fibrillation

It remains uncertain as to what degree DM independently augments AF risk, largely because of the difficulty in adjusting for risk factors common to both diseases. In patients with AF, DM increases stroke rate by 2% to 3.5% (see Chapter 66 ). The CHA ₂ DS ₂ –VASc score includes DM and guidelines recommend anticoagulation for all DM patients who have AF. ^,

Risk Stratification

The high CV risk of patients with DM blurs the concept of primary versus secondary prevention. Recent guidelines classify patients with DM according to CV risk. Very high risk patients are those with DM and established CVD, as well as those with target organ damage such as left ventricular hypertrophy or chronic kidney disease (CKD). Patients with DM and three or more major risk factors are also considered to be at very high risk, as multiple risk factors in DM increase risk including CV death. The high-risk category includes those with DM duration ≥10 years without target organ damage plus any other additional risk factors. Finally, younger patients (type 2 DM aged <50) with a DM duration less than 10 years and without other risk factors are considered at moderate risk.

Coronary Heart Disease in the Patient With Diabetes

Mechanistic Considerations Linking Diabetes and Atherosclerosis

Traditional CHD risk factors such as hypertension, dyslipidemia, and adiposity cluster in patients with DM (see Chapter 25, Chapter 26, Chapter 27, Chapter 28, Chapter 29, Chapter 30 ). However, this clustering does not completely account for the increased CHD risk observed among patients with DM ( Table 31.2 ).

TABLE 31.2

Examples of Mechanisms Implicated in Diabetic Vascular Disease

Modified from Orasanu G, Plutzky J. The pathologic continuum of diabetic vascular disease. J Am Coll Cardiol . 2009;53:S35.

Endothelium	↑ NF-κB activation ↓ Nitric oxide production ↓ Prostacyclin bioavailability ↑ Endothelin 1 activity ↑ Angiotensin II activity ↑ Cyclooxygenase type 2 (COX-2) activity ↑ Thromboxane A ₂ activity ↑ Reactive oxygen species ↑ Lipid peroxidation products ↓ Endothelium-dependent relaxation ↑ RAGE expression
Vascular smooth muscle cells and vascular matrix	↑ Proliferation and migration into intima ↑ Increased matrix degradation Altered matrix components
Inflammation	↑ IL-1β, IL-6, CD36, MCP-1 ↑ ICAMs, VCAMs, and selectins ↑ Activity of protein kinase C ↑ AGEs and AGE-RAGE interactions

AGEs, Advanced glycation end products; ICAMs, intracellular adhesion molecules; IL, interleukin; MCP, monocyte chemoattractant protein; NF, nuclear factor; RAGE, receptor for advanced glycation end products; VCAMs, vascular cell adhesion molecules.

The mechanisms of increased atherosclerotic risk remain poorly understood. The principal vascular perturbations linked to hyperglycemia include endothelial vasomotor dysfunction, vascular effects of advanced glycation end products (AGEs), adverse effects of circulating free fatty acids (FFAs), increased systemic inflammation, and a prothrombotic state. The myriad mechanisms contributing to endothelial dysfunction include abnormal nitric oxide biology, increased circulating endothelin and angiotensin II, and reduced prostacyclin (i.e., prostaglandin I ₂ ) activity, all of which contribute to perturbations in the regulation of blood flow. Abnormalities in lipid metabolism also contribute to the increased atherosclerotic risk associated with DM (see Chapter 25, Chapter 27 ). High triglyceride (TG) levels, low levels of high-density lipoprotein cholesterol (HDL-C), and increased small, dense low-density lipoprotein (LDL) particles characterize diabetic dyslipidemia, and contribute to aggravated atherosclerosis.

Perturbations in the coagulation and fibrinolytic pathways and in platelet biology add to the prothrombotic risk in DM. ^, These abnormalities include increased circulating tissue factor, factor VII, von Willebrand factor, and plasminogen activator inhibitor-1, and decreased levels of antithrombin III and protein C. Increased systemic inflammation accompanies DM and associates with increased oxidative stress and the accumulation of AGEs.

Prevention and Treatment of Coronary Heart Disease and Its Complications in the Patient with Diabetes

Lifestyle interventions remain the pillar of prevention of the atherosclerotic complications in DM. As recommended by the American Diabetes Association (ADA), American Heart Association (AHA), European Society of Cardiology (ESC), and European Association for the Study of Diabetes (EASD), therapeutic lifestyle targets include smoking abstinence, 150 minutes or more of aerobic activity weekly, weight control, and healthy diet habits. ^, ^, (See the Guidelines Tables 31G.1 through 31G.4 in the online chapter.)

ETABLE 31G.1

ACCF/AHA Recommendations for Primary Prevention of Cardiovascular Disease in People with Diabetes

Data from Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation . 2015;132:691–718; Ryden L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. The Task Force on Diabetes, Pre-diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J . 2013;34:3035–3087; ADA Standards of Medical Care in Diabetes—2016: abridged for primary care providers. Diabetes Care . 2016;34:3–21; Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach—update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2013;38:140–149; and Stone NJ, Robinson JG, Lichtenstein AH, et al.; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014;129(suppl 2):S1–S45.

Lifestyle Management

Weight

Structured programs that emphasize lifestyle changes such as reduced fat (<30%–35% of daily energy) and total energy intake and increased regular physical activity, along with regular participant contact, can produce long-term weight loss on the order of 5%–7% of starting weight, with improvement in blood pressure.
For persons with elevated plasma triglycerides and reduced high-density lipoprotein (HDL) cholesterol, improved glycemic control, moderate weight loss (5%–7% of starting weight), dietary saturated fat restriction, increased physical activity, and modest replacement of dietary carbohydrate (5%–7%) by either monounsaturated or polyunsaturated fats may be beneficial.

Medical Nutrition Therapy

To achieve reductions in low-density lipoprotein (LDL) cholesterol:
- Saturated fats should be less than 7% of energy intake.
- Dietary cholesterol intake should be less than 200 mg/day. Intake of trans -unsaturated fatty acids should be less than 1% of energy intake.
- Total energy intake should be adjusted to achieve body weight goals.
Total dietary fat intake should be moderated (<30%–35% of total calories) and should consist mainly of monounsaturated or polyunsaturated fat.
Ample intake of dietary fiber (≥14 g/1000 calories consumed) may be of benefit.
If individuals choose to drink alcohol, daily intake should be limited to one drink for adult women and two drinks for adult men. One drink is defined as 12 ounces (oz) of beer, 4 oz of wine, or 1.5 oz of distilled spirits. Alcohol ingestion increases caloric intake and should be minimized when weight loss is the goal.
Individuals with elevated plasma triglyceride levels should limit intake of alcohol, because it may exacerbate hypertriglyceridemia.
In both normotensive and hypertensive persons, a reduction in sodium intake may lower blood pressure. The goal should be to reduce sodium intake to 1200–2300 mg/day (50–100 mmol/day), equivalent to 3000–6000 mg/day of sodium chloride.

Physical Activity

To improve glycemic control, assist with weight loss or maintenance, and reduce risk of CVD, at least 150 min of moderate-intensity aerobic physical activity or at least 90 min of vigorous aerobic exercise per week is recommended. The physical activity should be distributed over at least 3 days per week, with no more than 2 consecutive days without physical activity.
For long-term maintenance of major weight loss, a larger amount of exercise (7 hr of moderate or vigorous aerobic physical activity per week) may be helpful.

Blood Pressure

Blood pressure (BP) should be measured at every routine DM visit. Patients found to have systolic blood pressure (SBP ≥130 mmHg or diastolic blood pressure (DBP) ≥80 mmHg should have BP confirmed on a separate day.
Patients with DM should be treated to achieve SBP at least <140 mmHg and DBP <90 mmHg, and for patients who can tolerate without adverse symptoms, can target as low as SBP <130 mmHg and DBP <80–85 mm Hg. Patients with SBP of 130–139 mmHg or DBP of 80–89 mmHg should initiate lifestyle modification alone (weight control, increased physical activity, alcohol moderation, sodium reduction, and emphasis on increased consumption of fresh fruits, vegetables, and low-fat dairy products) for a maximum of 3 months. If, after these efforts, targets are not achieved, treatment with pharmacologic agents should be initiated.
Patients with hypertension (SBP ≥140 mm Hg or DBP ≥90 mmHg) should receive drug therapy in addition to lifestyle and behavioral therapy.
All patients with DM and hypertension should be treated with a regimen that includes either an ACE inhibitor, or if intolerant to an ACE inhibitor, an ARB. If one class is not tolerated, the other should be substituted. Other drug classes demonstrated to reduce CVD events in patients with DM—dihydropyridine calcium channel blockers, thiazide diuretics (chlorthalidone and indapamide), and beta blockers—should be added, in listed order of preference, as needed to achieve BP targets.
If ACE inhibitors, ARBs, or diuretics are used, kidney function and serum potassium levels should be monitored within the first 3 months. If BP is stable, follow-up could occur every 6 months thereafter.
Multiple-drug therapy generally is required to achieve BP targets.

In elderly hypertensive patients, BP should be lowered gradually to avoid complications.
Orthostatic measurement of BP should be performed in people with DM and hypertension when clinically indicated.
Patients not achieving target BP despite multidrug therapy should be referred to a physician specializing in the care of patients with hypertension.

Lipids

In adult patients with DM, lipid levels should be measured at least annually and more often if needed to achieve goals. In adults with DM younger than 40 with low-risk lipid values (LDL-C <100 mg/dL, HDL-C >50 mg/dL, triglycerides <150 mg/dL), lipid assessments may be repeated every 2 years.
Lifestyle modification deserves primary emphasis in all individuals with DM. Patients should focus on the reduction of saturated fat and cholesterol intake, weight loss (if indicated), and increases in dietary fiber and physical activity. These lifestyle changes have been shown to improve the lipid profile in patients with DM. In persons with DM who are older than 40, without overt CVD, statin therapy should be considered for primary prevention with recommendation to use at least moderate-dose and ideally intense-dose statins, independent of baseline LDL-C levels. On maximally tolerated statin, the goal is a LDL-C level <100 mg/dL (2.6 mmol/L), and ideally <70 mg/dL (1.8 mmol/L) for those as highest CVD risk. If LDL-lowering drugs are used, a reduction of at least 50% in LDL-C levels should be obtained.
If baseline LDL-C is <100 mg/dL, statin therapy should be initiated based on risk factor assessment and clinical judgment. Major risk factors in this category include age, sex, race/ethnicity, cigarette smoking, hypertension (BP >140/90 mm Hg or use of antihypertensive medication), high total cholesterol and low HDL-C (<40 mg/dL), and family history of premature coronary heart disease (CHD in male first-degree relative ≤55 years of age; CHD in female first-degree relatives ≤65 years of age).
In people with DM who are younger than 40, without overt CVD, but who are estimated to be at increased risk for CVD either by clinical judgment or by risk calculator, at least moderate-intensity statin therapy is recommended, with LDL-C goal of <100 mg/dL.
Combination therapy with LDL-lowering drugs (e.g., statins, ezetimibe, PCSK9 inhibitors) and fibrates or niacin may be necessary to achieve lipid targets, but to date, only the addition of ezetimibe to statin therapy has proven incremental CV outcomes benefit.
Beyond the consensus of therapeutic lifestyle intervention, the ADA and AHA guidelines have evolved significantly over recent years, no longer recommending pharmacologic treatment of low HDL-C or high triglyceride levels, except for those with extremely high-fasting triglyceride levels, to consider fish oil or a fibrate to mitigate pancreatitis risk.

Tobacco

All patients with DM should be asked about tobacco use status at every visit.
Every tobacco user should be advised to quit.
The tobacco user’s willingness to quit should be assessed.
The patient can be assisted by counseling and by developing a plan to quit.
Follow-up, referral to special programs, or pharmacotherapy (including nicotine replacement and bupropion) should be incorporated as needed.

Antiplatelet Agents

The ADA and AHA recommend aspirin therapy (75–162 mg/day) for primary prevention in patients with DM at increased CV risk (e.g., estimated 10-year risk >10%), including most age 50 and older who have additional risk factors (e.g., family history of CVD, hypertension, smoking, dyslipidemia, albuminuria). In contrast, the ESC/EASD guidelines discourage aspirin for primary prevention in patients with DM, except for those estimated to be at the very highest CV risk, in whom such use may be considered.
People with aspirin allergy, bleeding tendency, existing anticoagulant therapy, recent gastrointestinal bleeding, and clinically active hepatic disease are poor candidates for aspirin, especially for primary prevention. Other antiplatelet agents may be a reasonable alternative for patients with high risk.

Glycemic Control

The HbA _1c goal for most patients with DM in general is less than 7% in the absence of CVD, with higher targets such as 8% (or higher) endorsed for patients with moderate to severe CVD or other serious comorbidities.

Type 1 Diabetes Mellitus

At present, all the recommendations listed above for patients with type 2 DM appear to be appropriate for those with type 1 DM as well.

ADA , American Diabetes Association; AHA , American Diabetes Association; CHD , coronary heart disease; DM , Diabetes mellitus; HDL , high-density lipoprotein; LDL , low-density lipoprotein.

ETABLE 31G.2

ACCF/AHA Recommendations for Secondary Prevention of Cardiovascular Disease Specific to Patients with Diabetes

Data from Fox CS, Golden SH, Anderson C, et al. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation . 2015;132:691–718; Authors/Task Force Members; Rydén L, Grant PJ, Anker SD, et al. ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. The Task Force on Diabetes, Pre-diabetes, and Cardiovascular Diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J . 2013;34:3035–3087; American Diabetes Association. Standards of Medical Care in Diabetes—2016: abridged for primary care providers. Diabetes Care . 2016;34:3–21; Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach—update to a position statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care . 2015;38:140–149; and Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation . 2014;129(suppl 2):S1–S45.

Class	Indication	Level of Evidence
I	Care for DM should be coordinated with the patient’s primary care physician and/or endocrinologist.	C
	Lifestyle modifications including daily physical activity, weight management, blood pressure control, and LDL cholesterol management are recommended for all patients with DM.	B
	ACE inhibitors (or ARBs for those with ACE inhibitor intolerance) should be started and continued indefinitely in patients with DM, unless contraindicated.	A
	Use of aldosterone blockade in post-MI patients without significant kidney dysfunction or hyperkalemia is recommended in patients who are already receiving therapeutic doses of an ACE inhibitor and beta blocker, who have a left ventricular ejection fraction ≤40% and DM.	A
IIa	Metformin is an effective first-line pharmacotherapy and can be useful if not contraindicated.	A
IIa	Individualizing the intensity of blood glucose–lowering interventions based on the individual patient’s risk of hypoglycemia during treatment is reasonable.	C
IIb	Initiation of pharmacotherapy interventions to achieve target HbA _1c may be reasonable.	A
	A target HbA _1c of 7% or lower may be considered, whereas the ADA/EASD endorse a target of 8% or higher for those with moderate to severe CVD.	C
	Less stringent HbA _1c goals may be considered for other patients with a history of severe hypoglycemia, limited life expectancy, advanced microvascular complications, or extensive comorbidity, or those in whom the goal is difficult to attain despite intensive therapeutic interventions.	C

ACE, Angiotensin-converting enzyme; ADA, American Diabetes Association; CVD , cardiovascular disease; DM, Diabetes mellitus; EASD, European Association for the Study of Diabetes; LDL , low-density lipoprotein; MI, myocardial infarction; PCI , percutaneous coronary intervention.

ETABLE 31G.3

ACCF/AHA Recommendations for Management of Unstable Angina/Non–ST-Segment Elevation Myocardial Infarction (UA/NSTEMI) and ST-Segment Elevation Myocardial Infarction (STEMI) in Patients with Diabetes

Data from Jneid H, Anderson JL, Wright RS, et al. 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; Roffi M, Patrono C, Collet JP, et al. 2015 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J . 2016;37:267–315; O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation . 2013;127:e362–e425; and ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J . 2012;33:2569–2619.

Class	Indication	Level Of Evidence
I	ACE inhibitors should be given and continued indefinitely for patients recovering from MI with diabetes unless contraindicated.	A
I	Long-term aldosterone receptor blockade should be prescribed for patients with MI without significant renal dysfunction (estimated creatinine clearance should be >30 mL/min) or hyperkalemia (potassium should be <5 mEq/L) who are already receiving therapeutic doses of an ACE inhibitor, have an ejection fraction less than 40%, and have DM, with or without clinical heart failure.	A
IIa	Use of an insulin-based regimen to achieve and maintain glucose levels less than 180 mg/dL while avoiding hypoglycemia for hospitalized patients with acute coronary syndromes, with either a complicated or uncomplicated course, is reasonable.	B
	For patients with UA/NSTEMI and multivessel disease, CABG using the internal mammary arteries can be beneficial over PCI in patients with medically treated DM.	B
	PCI is reasonable for UA/NSTEMI patients with DM with single-vessel disease and inducible ischemia.	B
IIb	The use of upstream GP IIb/IIIa inhibitors may be considered in UA/NSTEMI patients with DM already receiving aspirin and a P2Y ₁₂ receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) who are selected for an invasive strategy and are not otherwise at high risk for bleeding.	B

DM, Diabetes mellitus; MI, myocardial infarction; PCI , percutaneous coronary intervention.

ETABLE 31G.4

ACCF/AHA Recommendations for the Diagnosis and Management of Heart Failure in Patients with Diabetes

Class	Indication	Level Of Evidence
I	For patients with DM (all of whom are at high risk for developing HF), blood sugar should be controlled in accordance with contemporary guidelines.	C
I	Physicians should control systolic and diastolic hypertension and diabetes mellitus in patients with HF in accordance with recommended guidelines.	C
IIa	Empagliflozin should be considered in patients with type 2 DM to prevent or delay the onset of HF and to prolong life.	B
IIa	Treating dysglycemia should be considered to prevent or delay the onset of HF.	C
IIb	ACE inhibitors can be useful to prevent HF in patients with DM.	A
IIb	ARBs can be useful to prevent HF in patients with DM.	C

ACE , Angiotensin-converting enzyme; ARBs , angiotensin II receptor blockers; DM , diabetes mellitus; HF , heart failure.

Beyond lifestyle modifications, pharmacologic strategies effectively reduce CVD risk in DM. ^, ^, Such interventions include assiduous blood pressure (BP) and LDL cholesterol (LDL-C) management for all patients, and for patients at highest risk and angiotensin-converting enzyme (ACE) inhibitors independent of BP. Daily aspirin therapy is no longer recommended for patients with DM without established atherosclerotic cardiovascular disease (ASCVD), except in those with a very high ASCVD risk. ^, ^, The benefits of glucose control on macrovascular CVD risk mitigation remain far less robust. ^,

Lipid Management

Type 2 DM is associated with a characteristic pattern of dyslipidemia, reviewed in detail in Chapter 27 . Each component of the diabetic dyslipidemia profile associates independently with CVD risk, including increased small, dense LDL particles, increased apolipoprotein B concentration, increased TG levels, and decreased HDL-C. Despite extensive research in modifying TG and HDL-C levels, the reduction of LDL-cholesterol remains the cornerstone of therapeutic lipid intervention in patients with DM. ^,

Statins

Contemporary guidelines for the management of diabetic dyslipidemia focus on the use of statins, ^, ^, ^, with estimates of numbers needed to treat (NNT) to prevent one major adverse CVD complication over 5 years in the setting of DM: 39 for patients without CVD and 19 among patients with prevalent CVD (see Chapter 25, Chapter 27 ). These guidelines do not require an increased LDL-C to initiate statin therapy for patients with DM, and recommend treatment of all DM patients. The 2018 Guideline on the Management of Blood Cholesterol endorsed by multiple groups recommends moderate-intensity statin therapy in adults aged 40 to 75 years with DM regardless of estimated 10-year ASCVD risk. Adults with DM who have multiple ASCVD risk factors or prevalent ASCVD should receive a high-intensity statin with the aim to reduce LDL-C by 50%.

Statin therapy can hasten the onset of DM in patients at risk of developing DM. Nevertheless, the benefits in terms of CV event reduction greatly exceed the risks of statin-induced DM. The ESC guidelines endorse a treat-to-target approach. Diabetic patients with very high CVD risk should achieve an LDL-C target of less than 55 mg/dL or achieve a decrease in LDL-C of at least 50%. Most other patients with DM are categorized as “high risk,” with an LDL-C target of at least less than 70 mg/dL.

Ezetimibe

Ezetimibe inhibits the intestinal cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1). The Improved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) assessed the effect of more intensive LDL-C targets with simvastatin/ezetimibe versus standard target control using simvastatin in 18,144 patients following ACS events. After a mean follow-up of 5.7 years, ezetimibe/simvastatin yielded a significant 6.7% relative risk reduction (RRR) for the primary composite endpoint. In the subgroup of patients with DM, the beneficial effect on outcome was stronger than in patients without DM with a hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.78 to 0.94. The results in this subgroup were mainly due to a lower incidence of MI and ischemic stroke.

PCSK9 Inhibitors

Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) with antibodies such as alirocumab or evolocumab reduce LDL-C by 40% to 60% over statins, with similar effects in patients with or without DM. ^, The FOURIER trial showed a significant 15% RRR for the primary composite endpoint of CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization with evolocumab versus placebo in 27,564 patients with clinically evident CVD. At study baseline, 11,031 patients (40%) had DM. Evolocumab significantly and consistently reduced cardiovascular outcomes in patients with and without DM at baseline. Evolocumab did not increase the risk of new-onset DM in patients without DM at baseline (HR, 1.05, 0.94 to 1.17), including patients with prediabetes (HR, 1.00, 0.89 to 1.13).

In the ODYSSEY OUTCOMES trial, alirocumab significantly reduced the risk of the primary composite endpoint (CV death, MI, stroke, or hospital admission for unstable angina) compared with placebo, with an HR of 0.85 (95% CI 0.78, 0.93). In a subgroup analysis of patients with DM, alirocumab resulted in similar relative reductions in the incidence of the primary endpoint in each glycemic category, but a greater absolute risk reduction in the incidence of the primary outcome in patients with DM (2.3%, 95% CI 0.4 to 4.2) than in those with prediabetes (1.2%, 0.0 to 2.4) or normoglycemia (1.2%, −0.3 to 2.7; absolute risk reduction p _interaction =0·0019). Alirocumab did not increase the incidence of DM.

Fibric acid derivatives (fibrates)

Fibrates are agonists of the nuclear transcriptional regulator peroxisome proliferator–activated receptor alpha (PPAR-α) that lower TGs and modestly increase HDL-C. Although fibrates favorably affect two of the fundamental abnormalities of diabetic dyslipidemia beyond LDL-C lowering by raising HDL-C and lowering TGs, the net CVD effects of this drug class remain uncertain, with no significant benefit observed in two CV outcomes trials of patients with type 2 DM, many of whom were treated with statins. Sub-analyses of these trials suggest that the subset of patients with high baseline TGs concomitant with low HDL-C may derive incremental CVD risk reduction with fibrates added to background therapy—a hypothesis pending confirmation in a dedicated randomized trial.

Omega-3 fatty acids

Omega-3 fatty acids (fish oil) can reduce circulating TGs up to 40% (see Chapter 25, Chapter 27, Chapter 29 ), and hold promise in the treatment of diabetic dyslipidemia. With no interactions with statins, prescription-grade n-3 fatty acids in high dose is attractive as an add-on therapy to statins for incremental TG reduction. The Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial randomized 12,536 patients with impaired fasting glucose, impaired glucose tolerance, or DM who randomly received either a 1-g capsule containing at least 900 mg (≥90%) of ethyl esters of n-3 fatty acids or a capsule containing 1 g of olive oil daily. The primary outcome was CV mortality. Over a median follow-up of 6.2 years with 1155 CV deaths to analyze, there was no effect on the primary outcome with fish oil versus control (9.1% vs. 9.3%, respectively; P = 0.72). However, the REDUCE-IT trial examined a higher dose of highly purified eicosapentaenoic acid (icosapent ethyl, 2 g twice daily) in patients with established CVD or with DM and other risk factors, who had been receiving statin therapy and who had a fasting TG level of 135 to 499 mg/dL (1.52 to 5.63 mmol/L) and a LDL-C level of 41 to 100 mg/dL (1.06 to 2.59 mmol/L). Compared with placebo, icosapent ethyl significantly reduced the combined endpoint of CV death, non-fatal MI, or non-fatal stroke with a HR of 0.75; (95% CI, 0.68 to 0.83) in the overall population, with a similar benefit in the subgroup of patients with DM.

Inclisiran

The subcutaneous injection of inclisiran, a small interfering RNA that targets PCSK9 mRNA offers a novel strategy to reduce LDL-C. In a phase 2, multicenter, double-blind, placebo-controlled, trial in patients at high risk for CVD, inclisiran dose-dependently reduced PCSK9 and LDL-C levels. At day 180, the least-squares mean reductions in LDL-C levels were 27.9% to 41.9% after a single dose of inclisiran and 35.5% to 52.6% after two doses ( P < 0.001 for all comparisons vs. placebo). In the ORION-1 trial inclisiran associated with marked declines in LDL-C in both patients without and with DM.

Hypertension Management

Hypertension affects approximately 70% of patients with DM, with a steep-graded association between increasing BP and adverse CV outcomes ( Fig. 31.6 ) (see Chapter 26 ). Numerous classes of antihypertensive medications have reduced CVD risk in patients with DM. BP targets for patients with DM have historically been more aggressive than for the overall population, with a goal of less than 130/80 mmHg in patients with DM, and a target of less than 140/80 mmHg in those not tolerating the lower goal. ^, ^, ^,

FIGURE 31.6, Hazard ratios (95% confidence intervals as floating absolute risks) as estimate of association between category of updated mean systolic blood pressure and myocardial infarction (MI), stroke, and heart failure (HF), with log linear scales. Reference category (hazard ratio of 1.0) is systolic pressure less than 120 mm Hg for MI and less than 130 mm Hg for stroke and HF; P values reflect contribution of systolic pressure to multivariable model. Data adjusted for age at diagnosis of diabetes mellitus (DM), ethnic group, smoking status, presence of albuminuria, hemoglobin A 1c (HbA 1c ), high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglyceride.

Renin-Angiotensin-Aldosterone System Antagonists

ACE inhibitors and angiotensin II receptor blockers (ARBs) are cornerstones of therapy for hypertension in DM because of their favorable effects on diabetic nephropathy and CVD outcomes. ^, ^, ^,

Angiotensin-converting enzyme inhibitors

Data from randomized trials of patients with and without hypertension underpin the recommendation for ACE inhibitors as first-line agents for treatment of hypertension in the patient with DM. For example, the Heart Outcomes Prevention Evaluation (HOPE) trial compared ramipril (10 mg daily) with placebo in patients at increased risk for CVD and found that ramipril was superior to placebo in the DM subset of 3577 patients for the primary outcome of CV death, MI, and stroke (RRR, 25%; P = 0.004) and for overt nephropathy (RRR, 24%; P = 0.027). The DM sub-analysis of the EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) trial, which tested perindopril versus placebo; showed an RRR of 19% among the 1502 participants with DM. These results and those from meta-analyses support the consideration of ACE inhibitors for all patients with DM who have prevalent CVD, a clustering of CVD risk factors, or nephropathy with or without albuminuria. ^, ^,

Angiotensin Ii receptor blockers

Data on CV outcomes with ARBs are much less robust than those on ACE inhibitors, particularly in patients with DM. The Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with Cardiovascular Disease (TRANSCEND) trial enrolled 5926 patients with intolerance to ACE inhibitors, randomly assigned to receive telmisartan (80 mg daily) or placebo, 2118 of which had DM. The overall trial failed to achieve statistical superiority for telmisartan versus placebo on the primary composite of CVD death, MI, stroke, and HF hospitalization (HR, 0.92; 95% CI 0.81 to 1.05), with a completely neutral point estimate in the subset with DM. Various guidelines have endorsed ARBs and ACE inhibitors in DM, ^, ^, acknowledging the weaker evidence for ARBs. ACE inhibitors should remain first-line agents, with ARBs reserved for patients with intolerance to ACE inhibitors, and the two classes of medications should not be combined. ^,

Calcium Channel Blockers

Dihydropyridine calcium channel blockers (e.g., amlodipine, felodipine, nitrendipine, nisoldipine) are generally well tolerated and effectively lower BP. Analyses of data on DM subsets in randomized clinical trials suggest a magnitude of CVD clinical benefit similar to or greater than that observed in cohorts without DM.

Thiazide Diuretics

Concern about the adverse glycemic and triglyceridemic effects of the thiazide diuretic types of medications, including hydrochlorothiazide, chlorthalidone, indapamide, and bendroflumethiazide, has led to some hesitancy regarding their use in patients with DM. However, randomized trials of chlorthalidone and indapamide that included substantial numbers of patients with DM have consistently demonstrated CVD benefits. In a sub-analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the CVD effects of chlorthalidone compared with both lisinopril and amlodipine were similar in patients with DM or impaired fasting glucose, despite modest but statistically significant increases in incident DM associated with chlorthalidone use. Also, indapamide combined with perindopril in the Action in Diabetes and Vascular Disease: Preterax and Diamicron-MR Controlled Evaluation (ADVANCE) trial of 11,140 patients with DM showed superior CV outcomes. A meta-analysis of randomized trials further supports the benefits of chlorthalidone and indapamide in the treatment of patients with DM. ^,

Beta Blockers

Beta blockers are rarely used as routine antihypertensive therapies in patients with DM. ^, Beta blockers offer no benefit over other evidence-based classes of medications, with some concern for increased risk for a composite of CV disease, stroke, and HF based on recent meta-analysis. Therefore, use of beta blockers should be primarily limited to patients with HF with reduced ejection fraction (HFrEF) (carvedilol, metoprolol succinate, or bisoprolol) and after MI. Beta blockers have a place in therapy of angina and for rate control of AF.

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