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The Burden of Cardiovascular Disease in Patients with Diabetes
Brooke Hudspeth, PharmD, CDE
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Carrie McAdam-Marx, MSCI, PhD, RPh
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The Burden of Cardiovascular Disease in Patients with Diabetes

Brooke Hudspeth, PharmD, CDE
Adults with type 2 diabetes (T2D) have a 2-to-4–fold higher risk for cardiovascular morbidity and mortality than adults without diabetes, according to the American Heart Association (AHA). Furthermore, the AHA deems diabetes to be “1 of the 7 major controllable risk factors for cardiovascular disease (CVD).” Lack of glycemic control may lead to nerve and cardiac conduction impairments and CVD. However, glycemic control is not the only risk factor. Additional risk factors for CVD in T2D include hypertension, dyslipidemia, obesity, lack of physical activity, and smoking. Patients with T2D are also more likely to have risk factors that increase atherosclerotic cardiovascular disease (ASCVD) risk, including hypertension, dyslipidemia, and obesity. Control of these risk factors, as well as understanding the link between hyperglycemia and cardiovascular risk, is essential for the optimal management of T2D.
Am J Manag Care. 2018;24:-S0
Diabetes is a heterogenous group of metabolic disorders characterized by hyperglycemia resulting from insufficient insulin production, insulin resistance, or both.1 According to the Centers for Disease Control and Prevention (CDC), approximately 30.3 million Americans (9.4% of the population) have diabetes, with 7.2 million of them undiagnosed.2 In 2014, 14.2 million emergency department visits and 7.2 million hospital discharges involved diabetes and, in 2015, diabetes was the seventh leading cause of death in the United States.2 The vast majority (90%-95%) of individuals with diabetes have type 2 diabetes (T2D); common comorbidities include obesity (87.5% of individuals with T2D), hypertension (73.6%), dyslipidemia (58.2%-66.9%), chronic kidney disease (CKD) (36.5%), and retinopathy (28.5%).2,3

The Incidence of Cardiovascular Disease With Diabetes and Economic Consequences

According to a recent global systematic review by Acs et al, 43.1% of patients with type 2 diabetes in North America and the Caribbean have cardiovascular disease (CVD).4 Additional cardiovascular complications include heart failure (HF) (50.1%), coronary artery disease (CAD) (37.4%), myocardial infarction (MI) (18.2%), angina (17.3%), and stroke (10.5%).4 The high prevalence of these cardiovascular comorbidities contributes to the already substantial morbidity and mortality of T2D.

Atherosclerotic cardiovascular disease (ASCVD) is defined as coronary heart disease, cerebrovascular disease, or peripheral arterial disease of atherosclerotic origin.5 ASCVD is the leading cause of morbidity and mortality in T2D and is the largest contributor to both direct and indirect diabetes costs.5 The risk for ASCVD is increased in the presence of uncontrolled risk factors such as hyperglycemia, hypertension, and dyslipidemia.5 According to the National Health and Nutrition Examination Survey, more than 45% of patients with T2D are not at their glycemic goals, blood pressure goals, or lipid goals, and up to 75% of patients with T2D have not achieved their goals for all 3 risk factors, further increasing the risk for ASCVD.6

CVD Risk Factors in T2D

Traditional Risk Factors

Traditional risk factors for CVD in T2D include hypertension, dyslipidemia, obesity, lack of physical activity, poor glycemic control, and smoking.5,7 Studies have demonstrated the value of controlling modifiable risk factors in T2D. A pooled analysis of the Atherosclerosis Risk in Communities Study, Multi-Ethnic Study of Atherosclerosis, and Jackson Heart Study demonstrated that patients with T2D who had optimal blood pressure, low-density lipoprotein cholesterol (LDL-C), and target glycated hemoglobin (A1C) levels had a substantially lower risk of coronary heart disease and CVD.8 In the STENO-2 study, intensive multifactorial intervention targeting glucose, lipid, and blood pressure control had beneficial effects on vascular complications and cardiovascular death in at-risk patients with T2D.9

Multiple studies have also shown that patients with T2D are at the same risk for cardiovascular events as patients with a history of prior cardiovascular events and without diabetes.10-13 Many of these risk factors are common for both T2D and CVD, suggesting that both disorders stem from a common source.14,15

Patients with T2D have higher prevalence of lipid abnormalities.5 This is considered a triad of poor lipid count and often occurs in patients who have premature coronary heart disease. Atherogenic dyslipidemia/diabetic dyslipidemia is a lipid disorder that is associated with insulin resistance.7 The 2018 American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) consensus statement for the treatment of T2D also identifies hypertension and dyslipidemia to be the 2 most important risk factors for ASCVD.16

Hypertension, which is common in T2D, is considered a major risk factor for ASCVD, HF, and microvascular complications, and it is also associated with insulin resistance (IR).5 The prevalence of hypertension in T2D depends on the type and duration of diabetes, age, sex, race, ethnicity, body mass index, history of glycemic control, the presence of kidney disease, and other related factors.17 Patients with both hypertension and diabetes double their risk for CVD.7 Since 1990, it has been demonstrated that improvements in blood pressure control have led to decreased ASCVD mortality rates for T2D.17-21 Numerous studies have demonstrated that antihypertensive therapy reduces ASCVD events, HF, and microvascular complications in patients with diabetes.5,17,22-26 Even greater benefits are seen when multiple CVD risk factors are addressed together.27

There is a strong association between obesity and IR, leading to the increased risk of T2D and prediabetes.28 People with prediabetes also are at an increased risk for cardiovascular disease and often have the presence of other cardiovascular disease risk factors such as IR, hypertension, and dyslipidemia. Some ASCVD risk factors may be improved with intensive lifestyle intervention focusing on weight loss through increased physical activity and reduced caloric intake, as evidenced in the Look AHEAD trial.29 Weight loss can both improve CVD risk and increase insulin sensitivity.7,16 Obesity and IR are also associated with hypertension.7 Lack of physical activity is another risk factor that may lead to obesity. Increasing physical activity and weight loss are interventions that can prevent or delay the onset of T2D as well as reduce blood pressure and help reduce the risk of CVD.7 Additionally, multiple studies demonstrate that smoking increases the risk of CVD in T2D.30,31 The treatment of these traditional risk factors is very important for the reduction of CVD risk in patients with T2D.32,33 

Nontraditional Risk Factors

In addition to the traditional risk factors for CVD in T2D, there are several nontraditional risk factors. Nontraditional risk factors for CVD in T2D include IR hyperinsulinemia, postprandial hyperglycemia, glucose variability, microalbuminuria, hematologic factors, thrombogenic factors, inflammation evidenced by elevated C-reactive protein, hyperhomocysteinemia and vitamin deficiencies, erectile dysfunction, genetics, and epigenetics.14 In terms of thrombogenic factors, T2D is also associated with elevated plasminogen activator inhibitor-1 (PAI-1) levels, which contribute to a hypercoagulable state and can lead to an increased risk of cardiovascular complications.34 There is an interaction and overlap between traditional risk factors and nontraditional risk factors that further increases the risk for CVD in patients with T2D. Many traditional and nontraditional risk factors occur simultaneously, thereby compounding the risk for CVD.14 Martín-Timón et al further describe the delicate interplay between the risk factors and IR, lipids, proteins, and other factors that affect the development of CVD in patients with T2D.14

Most patients with T2D, and also many with prediabetes, are insulin resistant. IR is characterized by the presence of several ASCVD risk factors.16 IR develops in several organs and muscles, such as the skeletal muscle, liver, adipose tissue, and heart. The pancreatic beta cell increases insulin secretion (hyperinsulinemia) in response to IR to maintain normoglycemia. When the beta cell can no longer keep up with the demand, hyperglycemia ensues. Thus, IR and hyperinsulinemia are key abnormalities of T2D. Obesity plays a major role in the development of IR.14 The molecular mechanism by which IR causes T2D and increased CVD is not entirely understood; however, it has been shown that it may be linked to abnormalities in insulin signaling.35 Increased concentrations of high-sensitivity C-reactive protein as a marker of inflammation are also associated with IR, T2D, and the development of T2D.14 Inflammation has been strongly linked to endothelial dysfunction and plays a role in the development of the metabolic syndrome that leads to IR.36,37

Postprandial hyperglycemia and glucose variability have also been shown to increase the risk of CVD in patients with and without T2D.14,38-42 These glucose excursions can be linked to postprandial elevated triglyceride levels and are related to augmented oxidative stress, systemic inflammation, and endothelial dysfunctions that have been associated with atherosclerosis and cardiovascular events.14,43,44

Microalbuminuria describes a urinary albumin excretion between 30 mg and 300 mg per 24 hours. It is used to identify patients who are at an increased risk of CVD and progressive renal disease. In T2D, microalbuminuria is a sign of vascular damage to the glomerulus. Microalbuminuria has been identified as an important risk factor for diabetes and is identified by the American Diabetes Association (ADA) as a cardiovascular risk factor that should be screened annually in patients with T2D.5,14

There are several hematologic and thrombogenic factors, such as PAI-1, that are affected by T2D. These include increases in hypercoagulation that are more pronounced in the postprandial state as well as decreased fibrinolysis.14,45 The increased platelet activity contributes to the increased incidence of cardiovascular events in T2D.45 Increased plasma fibrinogen is also associated with T2D and is considered an additional CVD risk factor.46,47

The Relationship Between Elevated Glucose and CVD

 
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