Cardiovascular Health in Patients with Type 2 Diabetes Nursing CE Course for RNs and LPNs

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Cardiovascular Health and Prescribing for Patients with Type 2 Diabetes for RNs and LPNs

Disclosure Statement

This course explores cardiovascular disease (CVD) pathophysiology in patients with type 2 diabetes mellitus (T2DM). In addition, it reviews the national guidelines for optimum cardiovascular (CV) health in diabetes and describes the American Diabetes Association's (ADA) evidence-based prescribing recommendations.

Upon completion of this module, learners will be able to:

• describe the pathophysiology of cardiovascular disease in type 2 diabetes mellitus
• discuss national guideline recommendations for optimal cardiovascular health in diabetes mellitus
• review evidence-based recommendations for diabetic patients with cardiovascular disease, including an overview of recommended medications, dosing, and side effects

Cardiovascular disease (CVD) is the leading cause of death among men and women of most racial and ethnic groups in the US, with approximately 697,000 deaths each year or one death every 34 seconds (The Centers for Disease Control and Prevention [CDC], 2022a). CVD costs $229 billion annually due to healthcare services, medications, and lost productivity. More specifically, 20.1 million adults age 20 and older have coronary artery disease (CAD). In addition, 805,000 people in the US experience a myocardial infarction (MI) annually. According to the National Diabetes Statistics Report, 37.3 million (11.3%) people in the US have diabetes; of those, 28.7 million have been diagnosed, and 8.5 million (23%) remain undiagnosed (CDC, 2022b). In addition, approximately 96 million (38%) people 18 years and older have prediabetes. Patients with type 2 diabetes mellitus (T2DM) are disproportionately affected by CVD compared to those without T2DM, as CVD is the leading cause of morbidity and mortality in these patients. According to the American Heart Association (AHA, 2021), adults with T2DM are 2 to 4 times as likely to die from CVD than those without diabetes. Diabetes is considered one of the seven primary modifiable risk factors for CVD. Nearly 70% of patients with T2DM who are 65 years or older die from some form of CVD. Even with the therapeutic effects of antihypertensive and lipid-lowering medications, most patients with T2DM will die from CV events (Goyal & Jialal, 2022; Rodriguez et al., 2017). Einarson and colleagues (2018) conducted a systematic review of scientific evidence regarding the prevalence of CVD in T2DM across ten years (2007 to 2017). The researchers concluded that worldwide, CVD affects more than 30% percent of individuals diagnosed with T2DM, accounts for nearly 50% of all deaths in patients with T2DM, and CAD, stroke, and MI are cited as the chief offenders (Einarson et al., 2018). Registered nurses (RNs) must understand the basis for the underlying pathophysiological processes, strategies for and challenges associated with managing CVD risk in T2DM, and the evidence-based prescribing guidelines for lowering cardiovascular (CV) risk to provide optimal care to this high-risk patient population (Nestro, 2023).

Pathophysiology of Cardiovascular Disease in Type 2 Diabetes

T2DM is a complex, chronic metabolic condition that impacts how the body metabolizes glucose. The condition is characterized by the body's inability to maintain balanced glucose due to an inadequate supply of insulin or insulin resistance mechanisms, where the body cannot effectively utilize the insulin it produces (Brutsaert, 2022; Hudspeth, 2018). This process is demonstrated in Figure 1.

Figure 1

Insulin Resistance Model

CVD, or heart disease, refers to a cluster of conditions affecting the heart and blood vessels, most commonly induced by atherosclerosis, which is the buildup of atheroma (or fatty plaque) within the arteries. As shown in Figure 2, as atherosclerosis progresses, plaque growth within the arteries accumulates, causing damage, narrowing, or blockage of the arteries, which can result in serious consequences (Brutsaert, 2022; Hudspeth, 2018).

Figure 2

Coronary Artery Disease

(National Heart, Lung and Blood Institute [NHLBI], 2022)

Atherosclerotic cardiovascular disease (ASCVD) is the largest contributor to T2DM-associated mortality. The risk of developing ASCVD increases in those with specified CV risk factors, as listed in Table 1. Some of these risk factors (i.e., hyperglycemia, insulin resistance) place patients with T2DM at increased risk for cardiac events (Hudspeth, 2018).

Table 1

Modifiable CV Risk Factors

(CDC, 2023; Lopez et al., 2022; Nesto, 2023)

Atherosclerotic lesions are formed through complex interactions of various factors, and T2DM accelerates all of these interactions (Katakami, 2018). CV damage occurs over time and is the byproduct of metabolic changes within the large blood vessels (macrovascular) and small blood vessels (microvascular) of tissues and organs. These changes begin to occur during the prediabetes stage, which elucidates why more than half of patients already have evidence of CVD at the time of T2DM diagnosis (Ignatavicius et al., 2021). As defined in Table 2, the International Diabetes Federation (IDF) cites the three most common forms of CVD as direct consequences of macrovascular tissue damage: CAD, stroke, and peripheral arterial disease (PAD). The American Diabetes Association (ADA) Professional Practice Committee released the 2022a clinical practice recommendations regarding CVD and risk management, defining ASCVD as "coronary heart disease (CHD), cerebrovascular disease, or PAD presumed to be of atherosclerotic origin" (ADA Professional Practice Committee, 2022a, p. S144). Further, the ADA cites heart failure (HF) as another significant cause of morbidity and mortality from CVD, with a twofold higher risk in T2DM patients, as hypertension often serves as the precursor to this condition. Patients with T2DM are at increased risk for all of these conditions, the onset is typically at earlier ages than those without T2DM, and they affect women more commonly than men (ADA Professional Practice Committee, 2022a).

Table 2

Three Major Types of CVD and Associated Conditions

(IDF, 2016)

The pathogenesis of CVD in T2DM is a complex process mediated by several underlying cellular, molecular, and genetic processes. Cell-signaling defects in metabolic and inflammatory pathways affect the endothelium, liver, skeletal muscle, and beta cells of the pancreas. These defects are likely to have genetic components but are also largely influenced by environmental factors such as obesity, sedentary lifestyles, tobacco use, and certain medications. Patients with T2DM often have traditional risk factors for CVD, such as obesity, hypertension, dyslipidemia, and sedentary lifestyles, which creates a clear pathway for ASCVD development and its consequences (Brutsaert, 2022). The following three theories explain the mechanism of vascular complications in patients with T2DM:

• chronic hyperglycemia leads to permanent basement membrane thickening, tissue damage, and organ destruction and is a chief cause of premature development of macrovascular complications
• glucose toxicity directly or indirectly impairs the functional cell integrity
• chronic ischemia in small blood vessels causes tissue hypoxia (Brutsaert, 2022; Ignatavicius et al., 2021)

Endothelial cells are essential to maintaining homeostasis within the vasculature. These cells are tasked with generating and releasing various biochemical substances within the body to control and maintain the function and integrity of the vessels (Brutsaert, 2022; Katakami, 2018). Through the release of dilator and constrictor substances, endothelial cells serve critical roles in sustaining the balance between a series of mechanisms:

• oxidation and antioxidation
• inflammation and anti-inflammation within the vascular walls
• proliferation and antiproliferation of vascular smooth muscle cells
• dilatation and contraction of vessels
• coagulation and fibrinolysis of blood (Katakami, 2018)

The principal complication in T2DM is endothelial dysfunction, an independent risk marker for atherosclerosis and CV events. Various mechanisms can disrupt normal functioning and provoke adverse metabolic events within the endothelial cell of patients with T2DM, such as hyperglycemia, excess free fatty acid release, insulin resistance, increased levels of low-density lipoprotein (LDL) cholesterol, oxidative stress, and tobacco use. Endothelial dysfunction promotes leukocyte and platelet adhesion, thrombosis, and inflammation. Activation of these systems impairs normal functioning, increases vasoconstriction, and promotes inflammation and thrombosis, thereby rendering arteries susceptible to atherosclerosis (Brutsaert, 2022; Katakami, 2018).

Chronic hyperglycemia and insulin resistance serve essential roles in the initiation of vascular complications of DM through several mechanisms, such as: (1) increased formation of advanced glycation end products (AGEs) and activation of the receptor for advanced glycation end products (RAGE) AGE-RAGE axis, (2) oxidative stress, and (3) inflammation (Fishman et al., 2018). Insulin serves an essential dual-action role in maintaining homeostasis of the vasculature, as it stimulates endothelial cell production of nitric oxide (NO), a vasodilator that exerts antiaggregatory effects on smooth muscle. Insulin also mediates the release of endothelin (ET-1), a potent vasoconstrictor. Under normal physiological conditions, insulin activity is mediated by a vasoprotective signaling pathway called phosphoinositide 3-kinase (PI3K)/Akt. However, when insulin resistance develops, insulin responds to a pathological alternative, the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway. The MAPK/ERK pathway causes inflammation, vasoconstriction, and vascular smooth muscle cell proliferation, thereby contributing to the consequential CV byproducts of insulin resistance (Janus et al., 2016). Patients with insulin resistance have higher rates of hyperglycemia, which accelerates plaque formation and accumulation. Acute hyperglycemia does not reduce the bioavailability and endothelial-dependent vasodilation, whereas chronic hyperglycemia promotes atherogenesis and accelerates the progression of atherosclerosis (Katakami, 2018). The relationship between hyperglycemia, increased insulin secretion, and the resulting consequences are multifaceted. Several factors prompt the beta cells within the pancreas to secrete insulin, such as increased plasma glucose or amino acid levels, increased glucose-dependent insulinotropic polypeptide (GIP) secretion, decreased epinephrine secretion, decreased sympathetic activity, or increased parasympathetic activity. Once the beta cells secrete insulin, review Table 3 for the various effects of insulin on the body's tissues

Table 3

Insulin Actions

(Walsh & Sved, 2019)

As displayed in Table 3, T2DM and dyslipidemia commonly occur together. Lipid abnormalities affect up to 70% of patients with T2DM. Atherosclerosis is also prompted by local inflammation in the vascular wall induced by hyperlipidemia, specifically high levels of LDL. Patients with T2DM have a higher prevalence of lipid abnormalities in the peripheral venous circulation, increased atherosclerotic plaque accumulation, and smaller coronary artery lumen diameter than those without T2DM. Hyperlipidemia and atherosclerotic plaques result in the recruitment and migration of monocytes and other immune and inflammatory cells into the vascular subendothelial layer. Recruited monocytes differentiate into macrophages or dendritic cells. Activated macrophages express scavenger receptors to facilitate the engulfment of native and oxidized LDL cholesterol and, along with other inflammatory cells, increase the production of chemokines and cytokines. These mechanisms promote atherosclerotic lesion progression within the inflammatory cycle (ADA Professional Practice Committee, 2022a; Janus et al., 2016; Low Wang et al., 2016).

National Guidelines for Optimal Cardiovascular Health in Type 2 Diabetes

Research has demonstrated that preventing or slowing the progression of CVD in patients with T2DM is based on controlling individual CV risk factors. Studies have consistently demonstrated that lowering the glycated hemoglobin, or hemoglobin A1C (HbA1C) level, in patients with T2DM minimally reduces CV risks when performed in isolation. Simultaneously correcting and controlling multiple CV risk factors markedly reduces CVD mortality in patients with T2DM (Nestro, 2023). Over the last decade, research has demonstrated a decline in CVD-associated morbidity and mortality when aggressive risk factor modifications are concurrently implemented. The ADA Professional Practice Committee's Standards of Care in Diabetes (2022a), a national resource for the optimal management of diabetes, includes annual updates on the evidence-based prevention and management of diabetes and diabetes-related complications. Embedded within these standards are specific guidelines on CVD and risk management in patients with T2DM, strongly emphasizing the concurrent control of hyperglycemia, hypertension, and hyperlipidemia as the central targets (ADA Professional Practice Committee, 2022a).

Evidence-Based Recommendations

Unless specified otherwise, the recommendations in this section are adapted from the ADA Professional Practice Committee (2022d), which utilizes the following ABCE evidence-grading system to demonstrate the level of evidence of each recommendation:

• A - clear evidence from well-conducted and generalizable randomized controlled trials that are adequately powered
• B – supportive evidence from well-conducted cohort studies
• C - supportive evidence from poorly controlled or uncontrolled studies
• E - expert consensus or clinical experience (ADA Professional Practice Committee, 2022d)

CVD Risk Assessment 

To improve patient outcomes and effectively manage CV risk in the context of T2DM, the American College of Cardiology (ACC, n.d.-c) and ADA Professional Practice Committee (2022a) both cite the following as essential components:

• Expand the narrow focus of glucose control to include a systematic assessment of all CV risk factors (Table 1) at least annually and perform aggressive risk reduction, emphasizing closely monitoring and controlling the ABCs of CV risk (Table 4).
• Encourage and implement an individualized, patient-centered, and collaborative approach to reducing CV risk through shared-decision making and open communication between clinicians and patients.
• Employ the ACC/AHA ASCVD risk calculator to stratify better the ASCVD risk and help guide therapy. This risk calculator, the Risk Estimator Plus, is an online tool that estimates the 10-year risk of a first ASCVD event, accounting for a diagnosis of T2DM as a risk factor.
• Routine screening for CAD is not recommended for asymptomatic patients since it does not improve as long as ASCVD risk factors are treated.
• CAD investigation should be considered for the following atypical cardiac symptoms (i.e., chest discomfort, unexplained dyspnea), associated vascular disease (i.e., transient ischemic attack [TIA], stroke, PAD, carotid bruits, claudication), or electrocardiogram [ECG] abnormalities.

Table 4

The ABCs of CVD Risk in Diabetics and Targets

(ADA Professional Practice Committee, 2022a, 2022c)

In addition to the above, the following CV risks should also be assessed at least annually (ADA Professional Practice Committee, 2022a):

• Smoking: affects microcirculation and accelerates CV complications; smoking cessation is strongly advised.
• Family history of premature CAD: is a non-modifiable risk factor for T2DM and CVD.
• Chronic kidney disease (CKD): BP control should be maintained to reduce the risk of kidney disease; CKD is a common complication of uncontrolled hypertension and diabetes.
• Presence of albuminuria (protein in the urine): is a biomarker for CVD and coronary events.

Treatment/Management

The ACC cites six steps for optimizing CV risk reduction among patients with T2DM when developing each patient's individualized treatment plan (ACC, n.d.-a; Das et al., 2020):

1. Educate patients with T2DM about CV risks (beyond poor glucose control) that might contribute to and accelerate CV damage (Table 1).
2. Empower patients to take action by setting personal goals for lowering CV risk.
3. Create an individualized plan to assess and manage CV risk on an ongoing basis and revisit this plan to reevaluate, update, and make necessary changes to promote compliance.
4. Ensure adequate glycemic control is obtained by developing a realistic plan for lifestyle changes and adhering to prescribed glucose-lowering medications.
5. Consider prescribing novel antihyperglycemic agents when appropriate (discussed in the next section).
6. Assess adherence and identify hurdles, such as cost of treatment, side effects, personal preferences, or treatment complexity.

Lifestyle Management

Lifestyle management for T2DM and CVD risk reduction should begin at the initial contact with the patient and continue throughout all subsequent evaluations, including during the assessment for complications and management of comorbid conditions. Lifestyle strategies should be implemented preventatively, across the spectrum of care, and as part of the treatment plan in collaboration with any medications prescribed. The combination of lifestyle and pharmacologic interventions enhances treatment efficacy, aids in controlling CV risk factors, and more successfully reduces morbidity and mortality. Clinicians and patients should engage in shared decision-making to determine appropriate goals and targets across the spectrum of their diabetes care. Heart-healthy lifestyle interventions are advised for all patients with T2DM, focusing on weight reduction to reduce CV risk. The ADA Professional Practice Committee (2022a, 2022b, 2022e) recommends the following monitoring and lifestyle recommendations:

• Glucose monitoring is key to achieving glycemic targets for many patients with T2DM. Self-monitoring of blood glucose (SMBG) may help with self-management and medication adjustment, and diabetes self-management education (DSME) should be patient-centered and help guide clinical decisions; (A).
• Reduce excess body weight through caloric restriction, physical activity, and behavioral therapy (losing ≥5% of body weight can benefit glycemic control, lipids, and blood pressure). Additional weight loss often improves T2DM and CV risk; (B).
• Follow the DASH eating pattern to reduce sodium intake (less than 2,300 mg/day); (A).
• High-frequency counseling (i.e., ≥16 sessions in 6 months) should focus on dietary changes, behavioral strategies, and physical activity to achieve a 500 to 700 kcal/day energy deficit; (A).
• Increase dietary consumption of fruits and vegetables (eight to ten servings/day).
• Moderate alcohol intake (no more than two servings/day for men and no more than one serving/day for women); (A).
• Increase physical activity (150 minutes or more of moderate-to-vigorous intensive aerobic activity each week); (A).

Pharmacologic Therapy

While lifestyle interventions and modifications are essential, gaining control over T2DM and reducing CV risk usually requires adjunctive pharmacologic therapy. CV risk reduction in T2DM is primarily premised on four categories: (1) antiplatelet therapy, (2) antihypertensive medications, (3) lipid-lowering agents, and (4) antihyperglycemic drugs (ADA Professional Practice Committee, 2022a, 2022g).

Antiplatelet Therapy 

Antiplatelet therapy may be used to prevent blood clots, thereby reducing the risk of stroke or MI. The most common and well-studied form of antiplatelet therapy is low-dose acetylsalicylic acid (ASA) or aspirin. For patients with documented acetylsalicylic acid (ASA) allergy, P2Y12 inhibitors, such as clopidogrel (Plavix), are recommended alternatives (ADA Professional Practice Committee, 2022a).

Aspirin. Acetylsalicylic acid (ASA) has effectively reduced CV morbidity and mortality in high-risk patients who have endured a prior MI or stroke and is strongly recommended for secondary prevention. The benefits are less clear in primary prevention, and its use is more controversial among patients with no previous CV events. The risks associated with acetylsalicylic acid (ASA) therapy or second-line antiplatelet treatments, such as P2Y12 inhibitors, must be considered and balanced against the benefits. Acetylsalicylic acid (ASA) is an over-the-counter (OTC) nonsteroidal anti-inflammatory drug (NSAID) that is widely used to treat several conditions, such as fever, pain, and inflammation. Acetylsalicylic acid (ASA) reduces CV risk by blocking the enzyme that makes prostaglandins (cyclooxygenase), thereby reducing concentrations of prostaglandins and lowering pain levels, inflammation, and body temperature. Since acetylsalicylic acid (ASA) is a potent inhibitor of prostaglandin synthesis and platelet aggregation, it inhibits platelets for the entire cell lifespan of 7 to 10 days. Therefore, it decelerates the blood's clotting action by reducing the clumping of platelets. Acetylsalicylic acid (ASA) inhibits the function of platelets in a manner different from other NSAIDs, such as ibuprofen (Motrin), as its antithrombotic effects last longer, making it the ideal agent for MI and stroke reduction. There is a risk for bleeding events in patients taking acetylsalicylic acid (ASA), particularly gastrointestinal (GI) bleeding. The risk for GI bleeding is heightened in individuals aged 60 or older with a history of stomach ulcers, bleeding disorders, and those taking other types of anticoagulants (blood thinners). Further, those who consume three or more alcoholic beverages daily are at heightened risk for bleeding events. Aside from GI bleeding, the most common side effect is tinnitus (ringing in the ears). Enteric-coated formulations of acetylsalicylic acid (ASA) are considered safer regarding the risk of GI bleeding. They are designed to pass through the stomach and not disintegrate until they reach the small intestine. Acetylsalicylic acid (ASA) may cause a severe allergic reaction, causing hives, facial swelling, shock, or asthma (wheezing). Children, adolescents, and young adults under 21 who have or are recovering from chickenpox or flu-like syndromes should not take aspirin due to the risk of a rare but serious illness known as Reye's syndrome (ADA Professional Practice Committee, 2022a; American Geriatrics Society Beers Criteria Update Expert Panel, 2019; Woods, 2023).

P2Y12 Inhibitors. P2Y12 inhibitors are a group of antiplatelet drugs that may be used instead of acetylsalicylic acid (ASA) for patients with an allergy or other contraindication. Clopidogrel (Plavix) is the most widely used and studied P2Y12 inhibitor for reducing CV risk. Still, other medications in this class may also be considered, such as ticlopidine (Ticlid), ticagrelor (Brilinta), and prasugrel (Effient). Clopidogrel (Plavix) binds to the P2Y12 receptor on platelets, preventing adenosine diphosphate (ADP) from activating platelets. The tolerability and side effects of clopidogrel (Plavix) are similar to that of acetylsalicylic acid (ASA), as it also poses a risk for bleeding events, particularly GI bleeding and ulcers. Ticlopidine (Ticlid) carries an added risk of neutropenia (a decline in the white blood cell count), which heightens the risk of acquiring an infection, and thrombotic thrombocytopenic purpura (TTP), an immune disorder that destroys platelets and occurs in about 1 out of every 250,000 people. Ticagrelor (Brilinta) may worsen kidney function and induce shortness of breath and therefore is not advised in patients with T2DM who have underlying renal dysfunction (ADA Professional Practice Committee, 2022a; Hennekens, 2021; Woods, 2023).

Antihypertensive Medications

Treatment of hypertension reduces CV events and microvascular complications in patients with T2DM. Several studies have demonstrated that antihypertensive therapy reduces ASCVD events, HF, and microvascular complications in patients with T2DM. Treatment should focus on controlling BP to achieve individualized targets utilizing drug classes demonstrated to reduce CV events, specifically in patients with T2DM. These agents include angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), thiazide-like diuretics, or dihydropyridine calcium channel blockers (CCBs), as outlined in Table 5. ACEIs and ARBs are considered first-line antihypertensive agents in patients with T2DM, as they lower blood pressure and reduce the risk of kidney dysfunction from microvascular complications. The ADA cautions that BP targets more aggressive than < 140/90 mmHg are not likely to improve CV outcomes among most patients with T2DM and are more likely to contribute to adverse effects and costs. Therefore, a balance between the potential benefits and risks must be considered before prescribing more intensive antihypertensive therapy (ADA Professional Practice Committee, 2022a).

Table 5

Antihypertensive Medication Therapy in Type 2 Diabetes

*Preferred agents in patients with T2DM

 (ADA Professional Practice Committee, 2022a; Bloch & Basile, 2022; Heidenreich et al., 2022; Scheen, 2018)

For patients with resistant hypertension (defined as a BP ≥140/90 mmHg despite a therapeutic strategy that includes lifestyle modifications and three classes of antihypertensive medications, including a thiazide-like diuretic), adding a mineralocorticoid receptor antagonist (MRA) may be considered in addition to existing treatment with an ACEI or ARB, thiazide-like diuretic, and CCB. However, before diagnosing resistant hypertension, the clinician should confirm the absence of any barriers that may impair adherence to the existing antihypertensive medication regimen and the potential for secondary hypertension (ADA Professional Practice Committee, 2022a).

Numerous studies have demonstrated that primary aldosteronism and hyperaldosteronism are common in patients with resistant hypertension. MRAs, also referred to as aldosterone antagonists, have well-established benefits regarding their efficacy in managing resistant hypertension. MRAs effectively act on the renin-angiotensin-aldosterone pathway, providing CV and renal protection. Spironolactone (Aldactone) and eplerenone (Inspra) are the most extensively studied MRAs in managing resistant hypertension. MRAs are classified as potassium-sparing diuretics, as they prevent the body from absorbing too much salt and avert potassium excretion. These drugs bind to the androgen receptors to prevent their interaction with testosterone. Therefore, typical side effects include gynecomastia, breast pain, erectile dysfunction, and menstrual irregularities, occurring in up to 9% of patients and reversible upon drug discontinuation (Yugar-Toledo et al., 2017).

These side effects are most common with spironolactone (Aldactone), the prototype of MRAs, which has been the subject of numerous studies over time with demonstrated efficacy. Spironolactone (Aldactone) is much more potent than eplerenone (Inspra), a second-generation selective MRA. Eplerenone (Inspra) carries a higher affinity for the mineralocorticoid receptor and a lower affinity for androgen receptors than spironolactone (Aldactone). While it poses a lower risk of adverse effects, it is more expensive. MRAs can also reduce albuminuria and have additional CV risk reduction benefits. The most common adverse effect among all MRAs is hyperkalemia, so monitoring serum creatinine and potassium levels is strongly advised. Additional side effects include drowsiness, lightheadedness, blurred vision, nausea, vomiting, diarrhea, headache, increased thirst, and orthostatic hypotension. Newer data have suggested that MRAs may provide preferential benefits in treating obesity-related hypertension, particularly in individuals with high dietary sodium intake (ADA Professional Practice Committee, 2022a; Dudenbostel & Calhoun, 2017; Leopold & Ingelfinger, 2023; Yugar-Toledo et al., 2017).

Statins or Other Lipid-Lowering Therapy

The most prevalent pattern of dyslipidemia in patients with T2DM includes low levels of HDL cholesterol combined with elevated LDL and triglyceride levels. Significant evidence supports the critical importance of reducing LDL levels as one of the most effective ways to reduce ASCVD. Statins are the preferred first-line pharmacologic therapy for most patients with T2DM due to their well-established benefits in lowering LDL cholesterol and cardioprotective factors. They work by inhibiting hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, which is the enzyme in the cholesterol biosynthesis pathway. While statins are highly effective at lowering LDL, they can be associated with toxicity. The most common adverse effect and reason for discontinuation of statin therapy are statin-associated muscle symptoms (SAMSs); up to 72% of all statin adverse events are muscle related. SAMSs can present as myalgia, myopathy, myositis with elevated creatinine kinase, or rhabdomyolysis in its most severe form. Other side effects include joint and abdominal pain, neurological and neurocognitive effects, hepatotoxicity, and renal toxicity (ADA Professional Practice Committee, 2022a; Ward et al., 2019).

High-intensity statin therapy is cited for achieving greater than 50% reduction in LDL cholesterol; moderate-intensity statin regimens typically achieve 30% to 49% reductions in LDL cholesterol. Low-dose statin therapy is generally not recommended in patients with T2DM, but at times may be the maximal dose of statin that a patient can tolerate. For patients who do not tolerate the intended intensity of statin, the maximally tolerated statin dose should be used (ADA Professional Practice Committee, 2022a).

While other lipid-lowering agents are available, the evidence for using drugs that target these lipid fractions is not nearly as rigorous or extensive as the literature surrounding statin therapy, particularly regarding efficacy in patients with T2DM. In patients that are not achieving individualized lipid profile targets on statin therapy or those with intolerance to an increased dosage of statin, the ADA Professional Practice Committee recommends combination therapy with ezetimibe (Zetia) or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor such as evolocumab (Repatha) or alirocumab (Praluent; ADA Professional Practice Committee, 2022a).

Ezetimibe (Zetia). Ezetimibe (Zetia) belongs to a class of drugs called cholesterol absorption inhibitors. They work by inhibiting the absorption of dietary cholesterol in the intestines and lowering LDL levels in the blood. In a randomized controlled trial, ezetimibe (Zetia) 10 mg was added to moderate-intensity simvastatin (Zocor) 40 mg and compared with simvastatin (Zocor) 40 mg alone. Among patients with T2DM, this combination demonstrated a significant reduction in major CV events with an absolute risk reduction of 5% and a relative risk reduction of 14% over single-agent simvastatin (Zocor; Giugliano et al., 2018). Ezetimibe (Zetia) may be taken at the same time as statins. A commonly cited benefit is that it can help reduce the statin dose and, consequently, the associated risk for muscle injury and SAMSs. It is tolerable across clinical trials; the most common side effects reported include drowsiness, diarrhea, sinus congestion, and joint pain. Ezetimibe (Zetia) should be avoided in patients with moderate to severe liver dysfunction due to the rare risk of liver failure. Other rare adverse effects include allergic reactions, rhabdomyolysis, pancreatitis, and a severe skin rash characterized by red, blistering, and peeling skin (Rosenson, 2023).

PCSK9 inhibitors. PCSK9 inhibitors are approved for patients with inadequately treated levels of LDL while on other agents. PCSK9 is an enzyme that is predominantly produced in the liver. PCSK9 binds to the LDL receptor on the surface of hepatocytes (liver cells), destroying LDL receptors and increasing plasma LDL levels. PCSK9 inhibitors, such as evolocumab (Repatha) and alirocumab (Praluent), are humanized monoclonal antibodies that bind to free plasma PCSK9, promoting the destruction of this enzyme. This leaves less free PCSK9 to attach to the LDL receptors, thereby lowering LDL levels. These medications can lower LDL levels by as much as 60% in patients concurrently on statin therapy and reduce the rates of stroke and MI. They are approved for patients with ASCVD or familial hypercholesterolemia who receive maximally tolerated doses of statin therapy but require additional lowering of LDL levels. These medications can only be administered by subcutaneous injection and are unavailable in oral preparations. The most commonly reported side effects are injection site reactions, usually mild and limited to erythema, pain, and bruising. There are no reports of these medications inducing muscle breakdown or liver impairment; however, hypersensitivity reactions have been reported, including rash, pruritus, and urticaria. There is concern that PCSK9 inhibitors can potentially influence hepatitis C infectivity, but this is not yet confirmed, and more studies are needed to establish this as a definitive risk factor (ADA Professional Practice Committee, 2022a; Stroes et al., 2023).

Novel Antihyperglycemic Medications and Cardiovascular Risk Reduction

Glucose control is the cornerstone of T2DM management regarding reducing target organ damage and limiting complications. It is well-established that metformin (Glucophage) is the first-line antihyperglycemic treatment for T2DM and also helps lower the risk of CVD as a byproduct. The ADA Professional Practice Committee states that metformin (Glucophage) should be continued for glucose-lowering as long as the eGFR remains above 30 mL/min/1.73 m2; however, it should be avoided in unstable or hospitalized patients with HF. In 2008, the US Food & Drug Administration (FDA) issued guidance for CV outcome trials to be performed for all new medications for patients with T2DM due to concerns for increased CV risk. Over the last decade, several large randomized controlled trials have reported statistically significant reductions in CV events using the novel antihyperglycemic medications listed below. Both classes reduced the risk of major adverse CV events to a comparable degree in patients with T2DM and established ASCVD across large meta-analyses (ADA Professional Practice Committee, 2022a).

Sodium-glucose cotransporter-2 (SGLT2) inhibitors. SGLT2 inhibitors are FDA-approved for use with other diabetic medications to lower blood sugar in adults with T2DM and include empagliflozin (Jardiance), canagliflozin (Invokana) and dapagliflozin (Farxiga). These agents work by causing the kidneys to excrete excess sugar through the urine and, over time, have an impact on reducing A1C levels. SGLT2 inhibitors have demonstrated a reduction in the progression of kidney disease across numerous clinical trials but have limited efficacy in patients with eGFR under 45 mL/ min/1.73 m2. They carry secondary benefits of weight loss, reductions in systolic BP, and circulating fluid levels (edema), all of which reduce the stress on the CV and renal systems. Since these agents cause increased diuresis, the most common side effects include dehydration, hypotension, syncope, and falls. They carry the rare but serious side effect of necrotizing fasciitis of the perineum, which is a severe infection of the genitals and surrounding area. These agents are also associated with an increased risk of yeast infection and urinary tract infection in females. There are ongoing investigations into case reports of SGLT2 inhibitor-associated diabetic ketoacidosis (DKA; Blonde et al., 2022). There are a few variances in efficacy and side effect profiles between the three agents, as follows:

• Empagliflozin (Jardiance) is the most well-established regarding CV risk reduction across clinical trials; it significantly reduces the risk of death from MI and stroke in adults with T2DM and CVD. The EMPA-REG OUTCOME trial was associated with significantly lower rates of all-cause and CV death and a lower risk of hospitalization for HF (Zinman et al., 2015). Therefore, the FDA added an indication for empagliflozin (Jardiance) to reduce the risk of CV mortality in adults with T2DM and CVD (Blonde et al., 2022).
• Canagliflozin (Invokana) carries an increased risk of leg and foot amputation. The Canagliflozin Cardiovascular Assessment Study (CANVAS) trial demonstrated that over a year, the risk of amputation for patients in the trial was equivalent to 5.9 out of every 1,000 patients versus 2.8 out of every 1,000 patients treated with a placebo. The CANVAS study did find that canagliflozin (Invokana) significantly reduced CV mortality, MI, and stroke compared to the placebo (Neal et al., 2017). For this reason, it should not be prescribed to patients with PAD or a history of prior amputation, peripheral vascular disease, neuropathy, and diabetic foot ulcers. In addition, canagliflozin (Invokana) is associated with an increased risk of bone fractures associated with decreased bone mineral density (FDA, 2018). The Canagliflozin and Renal Events in Diabetes with Established Neuropathy Clinical Evaluation (CREDENCE) trial found that canagliflozin (Invokana) reduced end-stage renal disease (ESRD) by 32% and lowered the risk of CV mortality, MI, and stroke. In addition, canagliflozin (Invokana) had no significant increase in lower-limb amputations (Perkovic et al., 2019).
• In the Dapagliflozin Effect on Cardiovascular Events - Thrombosis in Myocardial Infarction (DECLARE-TIMI) trial, Dapagliflozin (Farxiga) reduced CV death and HF hospitalizations; however, it did not significantly lower the combined risk of CV death and nonfatal MI or stroke (Wiviott et al., 2019). The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial found a lowered risk of ESRD, CV mortality, and hospitalization for HR in the dapagliflozin (Farxiga) group compared to the placebo (Heerspink et al., 2020).

Glucagon-like peptide 1 receptor agonists (GLP-1RAs). Clinical trial data have demonstrated CV risk reduction in patients with T2DM taking liraglutide (Victoza), semaglutide (Ozempic), and dulaglutide (Trulicity). These agents work by interfering with the functioning of GLP-1, an incretin peptide hormone released from the ileum and colon after intake. GLP-1 receptor activation stimulates insulin release, inhibits glucagon secretion, slows gastrointestinal transit, and suppresses appetite (Brown & Everett, 2019). They are typically reserved for those requiring two or more antidiabetic agents to reach and maintain their target A1C level. GLP-1RAs have significant A1C-lowering properties, with an average A1C reduction of 1.5%. GLP-1RAs also pose secondary benefits, including weight loss and lowering lipids and blood pressure, which can be cardioprotective. GLP-1RAs approved for CV risk reduction in patients with T2DM were only available as injectable medications. Therefore, mild injection site reactions are routinely reported, manifested as discomfort, inflammation, redness, or bruising at the injection site. In 2019, the FDA approved semaglutide (Rybelsus), the first oral GLP-1RA. Semaglutide (Rybelsus) is not recommended as a first choice GLP-1RA for T2DM because there is a black box warning about the potential risk for thyroid c-cell tumors. Patients with a family history of medullary thyroid carcinoma (MTC), a diagnosis of MTC, or multiple endocrine neoplasia syndrome type 2 (MEN2) should not take semaglutide (Rybelsus). GLP-1RAs can delay gastric emptying, causing fullness and nausea or vomiting. They should, therefore, be used with caution in patients with gastroparesis, those with a history of gastric bypass, or severe gastroesophageal reflux disease (GERD). Patients should be educated on the importance of staying well-hydrated and consuming smaller meals to avoid fullness and vomiting (Blonde et al., 2022; Munoz, 2018). There are a few variances in efficacy and side effect profiles between the three agents, as follows (Blonde et al., 2022; Munoz, 2018):

• Dulaglutide (Trulicity) is dispensed as a single-dose pen and prefilled syringe that needs to be refrigerated and protected from sunlight. Nausea is a commonly reported side effect in up to 12.4% of patients taking the 0.75 mg dose, which increases to 21.1% in patients taking the 1.5 mg dose. The average weight loss on dulaglutide (Trulicity) is 2.5 kg. The drug also carries a low risk of sinus tachycardia in up to 6% of patients.
• Liraglutide (Victoza) and semaglutide (Ozempic) are similar agents. They are dispensed as multi-dose pens and must be refrigerated before first use but can be stored at room temperature afterward. Nausea occurs in up to 20% of patients taking these medications, and semaglutide (Ozempic) is associated with more significant weight loss than liraglutide (Victoza; 4.5 kg versus 2.5 kg). Liraglutide (Victoza) is FDA-approved to reduce the risk of CV mortality, nonfatal MI, and nonfatal stroke in adults with T2D and CVD.

Dual-targeted treatment. In May 2022, the FDA approved tirzepatide (Mounjaro) injection for use in patients with T2DM. Tirzepatide (Mounjaro) is the first approved dual-targeted therapy that activates GLP-1 and GIP receptors that help control glucose levels. It is administered by injection once weekly. Clinical trials have evaluated three different dosing options (5 mg, 10 mg, and 15 mg) as either stand-alone therapy or as an add-on to other T2DM medications. When patients received the 15 mg dose, tirzepatide (Mounjaro) effectively reduced A1C levels by 1.6% compared to the placebo in stand-alone trials and 0.5% compared to other diabetic medications. Tirzepatide (Mounjaro) also reduced weight by an average of 12 pounds compared to the placebo. Side effects can include nausea, vomiting, diarrhea, constipation, upper abdominal comfort, and decreased appetite. Tirzepatide (Mounjaro) did cause thyroid c-cell tumors in rats, but whether it causes these tumors in humans is unknown. Patients with a family history of MTC, a diagnosis of MTC, or MEN2 should not take tirzepatide (Mounjaro; FDA, 2022).

The ACC (n.d.-c) has established guidelines for when to consider adding an SGLT2-inhibitor or GLP-IRA to a patient's glucose-lowering regimen, such as a dual-diagnosis of ASCVD and T2DM, those T2DM patients notmeeting their glycemic targets, at the time of hospital discharge following a cardiovascular or T2DM-related hospitalization, or those with other risk factors present for CVD (ACC, n.d.-c). These medications are intended to be used with the ADA Professional Practice Committee's (2022a) evidence-based CV risk reduction prescribing guidelines.

Older Adults

Special consideration is required when managing CV risk in older adults with T2DM, as they are more prone to adverse effects and increased medication complications. According to the ADA Professional Practice Committee, 2022a, 2022f), overtreatment of T2DM in the older adult population is common, contributes to hypoglycemia, and should be avoided. Complex medication regimens should be de-intensified (simplified) to reduce the risk of hypoglycemia and polypharmacy and promote compliance. Further, the cost of medications must be considered to reduce the risk of cost-related nonadherence. The nurse plays an integral role in patient safety by performing medication reconciliation at each visit and reporting concerns regarding complex medication regimens to the clinician. The nurse should simultaneously clarify that the patient adequately understands the dosing instructions and confirm there are no barriers to treatment regarding side effects, cost, or the ability to physically obtain the prescribed medications (ADA Professional Practice Committee, 2022a, 2022f).

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