Management of Stable Coronary Artery Disease in Patients with Diabetes Mellitus

Introduction

Within the last 2 decades, the number of patients with diabetes quadrupled from 108 million to 422 million in 2014.1 It is estimated that the burden of diabetes will continue to grow owing to the increase in the prevalence of obesity, high caloric diet, and physical inactivity worldwide. The link between diabetes and cardiovascular disease is strong as diabetes increases the risk for coronary artery disease (CAD) by two to four fold.2 It is estimated that around 80% of those with diabetes die from cardiovascular causes, mostly from ischemic events. Therefore, the challenge of detecting and managing CAD in patients with diabetes is both significant and common.  Despite the effort to reduce cardiovascular risk in diabetes patients, cardiovascular events remain high.

In 2012, the ACCF/AHA/ACP/AATS/PCNA/SCAI/STS published their guideline for the diagnosis and management of stable CAD with a few specific recommendations for CAD patients with diabetes. Since then, several advancements in the diagnosis and management of CAD and diabetes have occurred. To summarize the current evidence, the American Heart Association (AHA) recently released a scientific statement on the clinical management of stable CAD in patients with type 2 diabetes mellitus.3 This useful scientific statement provides a comprehensive overview of therapeutic options aimed at reducing cardiovascular risk in CAD patients with diabetes and improving angina symptoms when present. The scientific statement includes emphasis on the new role of sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1) agonists for cardiovascular risk reduction and the use of coronary computed tomography angiography (CCTA) for the workup of stable angina.

In this analysis, we will review and summarize the AHA scientific statement and add some relevant data from recent studies which became available after the publication of the AHA statement.

Mechanisms Linking Diabetes to CAD

The mechanisms of how diabetes is linked to CAD have been a subject of increasing attention. The complex association between diabetes and CAD may explain why it is still difficult to optimize cardiovascular risk in patients with diabetes. Insulin resistance is the hallmark of type 2 diabetes and is closely associated with adiposity, hypertension, and dyslipidemia as part of the metabolic syndrome.4 Diabetic patients are twice as likely to have HDL-cholesterol levels below the 10th percentile of the population and 50% more likely to have hypertriglyceridemia compared to non-diabetic subjects.5 Through obesity and the production of advanced glycation end-products, diabetic patients also have higher levels of subclinical inflammation and develop endothelial dysfunction. The combination of hypercholesterolemia, inflammation, and endothelial dysfunction are the key mechanisms involved in the initiation and progression of atherosclerotic coronary artery disease.6

Management of Stable CAD

Lifestyle modifications

The management of stable CAD in diabetic patients starts with adopting a heart healthy lifestyle.7 This includes a balanced low-glycemic index diet high in fibers, and vegetables and low in saturated fat. A sedentary lifestyle should be heavily discouraged. Exercise in the form of at least 150 minutes per week of moderate intensity or 75 minutes of high intensity are recommended by both the AHA/American College of Cardiology (ACC) and the American Diabetes Association (ADA).8,9 Supervised exercise is favored because it results in greater weight reduction and better HbA1c control. Weight management is very important since excessive adiposity fuels insulin resistance. Studies of weight loss show that a weight reduction of 5 to <10% significantly reduces blood pressure, HbA1c, triglyceride levels and increases HDL-cholesterol. In case of morbid obesity, a meta-analysis of 14 outcome trials of bariatric surgery with and without diabetes showed a significant 52% lower mortality, and 46% lower cardiovascular adverse events with bariatric surgery compared to a non-surgical weight loss group.10 In patients with diabetes, another meta-analysis showed that likelihood of diabetes remission with bariatric surgery was 22 times higher than with non-surgical weight loss. Moreover, the diabetic patients had a significant 26 kg weight loss, 62 mg/dL lower triglycerides, and 8 mg/dL higher HDL-C compared to non-surgical controls.11 As a result, in diabetic patients with a body mass index of ≥35 kg/m2, bariatric surgery including Roux-en-Y gastric bypass and sleeve gastrectomy are recommended.12 Smoking is the most important modifiable cardiovascular disease (CVD) risk factor in diabetic patients with multiple studies supporting a causal link between smoking and CVD and poor health outcomes. Smoking cessation is highly recommended. Regular smoking cessation counseling, nicotine replacement therapy and a referral to a tobacco treatment specialist are highly successful in achieving and maintaining smoking cessation.8

Antithrombotic therapy

Patients with diabetes have altered platelet function and coagulation leading to a prothrombotic state.13 As a result, antithrombotic agents have been studied in patients with diabetes to reduce CVD risk. The use of aspirin for secondary prevention of CVD in patients with diabetes is heavily supported.14 Compared to other antiplatelet agents, aspirin carries the lowest risk of bleeding. However, due to the reduced response to antiplatelets in diabetic patients, other antiplatelet agents or a combination of agents have been tested. Clopidogrel was studied in the CAPRIE trial and showed a significant reduction in CVD events without a meaningful increase in bleeding events compared to aspirin alone.15 The combination of aspirin and adjuvant antiplatelet agents, either clopidogrel or ticagrelor, was shown to reduce CVD events but significantly increased bleeding. Therefore, dual antiplatelet therapy may be used with caution in patients with elevated CVD risk but low bleeding risk. Lastly, to target aberrant anticoagulation in patients with diabetes, the effect of aspirin and low-dose rivaroxaban was reported in a subset of patients enrolled in the COMPASS trial and showed a 23% reduction in the risk for composite of cardiovascular death, stroke, or myocardial infarction.16 In the TWILIGHT trial, the incidence of Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding was 4.5% and 6.7% among patients with diabetes randomized to ticagrelor monotherapy versus ticagrelor plus aspirin (hazard ratio, 0.65; 95% CI, 0.47 to 0.91, P = 0.012). Ticagrelor monotherapy was not associated with an increase in ischemic events compared with ticagrelor plus aspirin (4.6% vs. 5.9%; hazard ratio, 0.77; 95% CI, 0.55 to 1.09; P = 0.014).17

Blood pressure control

In diabetic patients, elevated blood pressure is associated with increased risk for micro- and macrovascular complications.18 Diabetic patients with elevated blood pressure are more likely to develop chronic kidney disease (CKD), suffer stroke, and die of CVD.19 While lowering blood pressure in diabetic patients with hypertension has well established benefits, the optimal target blood pressure has been debated partly since trials favoring aggressive blood pressure lowering such as the SPRINT trial have excluded diabetic patients.20 The European Society of Cardiology (ESC)/ European Society of Hypertension (ESH) and ADA currently recommend a target of <140/90 mmHg. In a selected high-risk subgroup of diabetic patients, a goal of <130/80 mmHg may be reasonable.8,21 In ACC/AHA 2017 guidelines for high blood pressure in adults, antihypertensive drug treatment should be initiated in adults with diabetes at a blood pressure of 130/80 mmHg with an on-treatment goal of less than 130/80 mmHg.22 The choice of antihypertensive agents depends on concomitant comorbidities. ACE-i/ARB are first line agents especially in the presence of albuminuria or CKD. In the presence of contra-indications to ACE-i/ARB, thiazide-like diuretics or dihydropyridine calcium channel blocker may be considered. It is important to note that thiazide diuretics can worsen glycemic control. Because β-blockers reduce myocardial oxygen demand and improve anginal symptoms in patients with stable CAD, patients with diabetes may benefit from beta-blockers for blood pressure when angina is also present. Due to the concerns that beta-blockers may mask symptoms of hypoglycemia, β-blockers should be used with caution (see details below). It is worth mentioning that beta-blockers have not been shown to reduce mortality or the risk of future myocardial infarction in stable CAD patients.

Management of dyslipidemia

Patients with diabetes have an atherogenic lipid profile with higher triglycerides, and lower HDL-cholesterol levels compared to non-diabetic subjects.5 In the absence of stable CAD, the 2018 AHA/ACC cholesterol guidelines recommend moderate-intensity statins for diabetic patients regardless of estimated 10-year ASCVD risk.23 When individuals with diabetes also have high ASCVD risk (10-year estimated ASCVD risk of >20%) or multiple ASCVD risk factors, intensifying lipid lowering using high-intensity statins is reasonable. When diabetes and CAD occur simultaneously, high-intensity or maximal statin therapy is strongly recommended. If LDL-cholesterol remains ≥70 mg/dL despite maximally tolerated statin, adding ezetimibe is reasonable. However, if LDL-cholesterol remains ≥70 mg/dL despite maximal statin plus ezetimibe or when patients are statin intolerant and ezetimibe alone is not enough, a PCSK-9 inhibitor is warranted. PCSK-9 inhibition is equally efficacious in those with and without diabetes, with a 27% relative risk reduction of cardiovascular death, myocardial infarction, stroke and hospitalization for unstable angina or revascularization in patients with established cardiovascular disease.24

Several trials addressed residual hypertriglyceridemia in statin treated patients. However, the REDUCE-IT trial of high-dose icosapent ethyl in patients with hypertriglyceridemia was the only trial showing cardiovascular benefit.25 REDUCE-IT enrolled patients with established CVD or patients without CVD but who had diabetes plus an additional CVD risk factor. After a median follow up of 4.9 years, icosapent ethyl resulted in a 25% relative risk reduction in a composite endpoint of cardiovascular death, nonfatal myocardial infarction, stroke, coronary revascularization, or unstable angina compared to placebo. The effects were consistent in those with or without diabetes. Based on these results, The Food and Drug Administration (FDA) approved icosapent ethyl for patients with either CAD or diabetes with two or more CVD risk factors who also have elevated triglycerides (>150 mg/dL) despite statin therapy. Both the ADA and the National Lipid Association (NLA) recently updated their recommendations to include the use of icosapent ethyl in those with clinical atherosclerotic cardiovascular disease (ASCVD) or diabetes with cardiac risk factors when fasting triglycerides are elevated (135 to 499 mg/dL) despite statin therapy.26,27

Glucose control

Suboptimal glucose control in diabetic patients with CAD is associated with higher rates of micro- and macrovascular events. Therefore, adequate glucose control is a major goal in treating diabetic patients with coronary artery disease.  Metformin remains the first line agent when glucose levels are not adequately controlled despite lifestyle modifications.8 Metformin has favorable glycemic and weight loss effects and low side effect profile (especially the lack of hypoglycemia).8 However, the evidence for long term cardiovascular benefit with metformin remains limited. When glucose levels remain uncontrolled while on metformin, adding other pharmacological agents should be tailored to the individual patient.

While insulin and sulfonylureas were commonly added second-line agents when metformin alone is not enough for glycemic control, the lack of cardiovascular benefit with insulin or sulfonylurea resulted in a change in the ADA recommendation when SGLT-2 inhibitors and GLP-1 agonists became available.8 In diabetic patients with established ASCVD, the ADA currently recommends either an SGLT-2 inhibitor (e.g. empagliflozin > canagliflozin) or a GLP-1 agonist (e.g. liraglutide > semaglutide > exenatide) for secondary CVD prevention. If either a GLP-1 agonist or SGLT-2 inhibitor added to metformin does not achieve adequate glycemic control, then further intensification with combining both a GLP-1 agonist plus an SGLT-2 inhibitor should be considered prior to adding other agents. Of note, the FDA recently approved dapagliflozin in adults with and without diabetes who also have New York Heart Association's functional class II-IV heart failure with reduced ejection fraction (<40%) to reduce the risk of cardiovascular death and hospitalization for heart failure.28,29 Moreover, based on recent data from the DAPA-HF trial, dapagliflozin reduced new-onset diabetes by 32%.

Management of Stable Angina Symptoms

In patients with stable angina and diabetes, symptoms of ischemia may be atypical and are often underdiagnosed. However, when present, the development of anginal symptoms is associated with decreased physical function and reduced disease-specific quality of life. In the symptomatic management of stable angina, the goal is to confirm the diagnosis of CAD and exclude high risk disease and reduce symptoms through optimal medical therapy with or without revascularization if needed.

Functional versus anatomic evaluation of CAD

Using noninvasive testing to confirm stable CAD as the cause of chest pain and excluding other causes is recommended. Noninvasive testing of CAD could either be done using anatomic imaging with CCTA or functional stress testing to demonstrate ischemia using an electrocardiogram or imaging modalities. The choice of anatomic versus functional tests has been a topic of recent debate especially in light of results from SCOT-HEART30 and the ISCHEMIA trials.31

In SCOT-HEART, patients randomized to either CCTA or functional testing for the workup of stable angina were followed up for 5 years and assessed for the development of death from CAD or nonfatal myocardial infarction.30 Those in the CCTA arm had a significant 41% relative risk reduction for the primary outcome compared to the functional arm with no heterogeneity of effect by diabetes status. These results were at least partly driven by a higher uptake of preventive therapies such as aspirin or statins in the CCTA arm. An important finding was that most cardiac events occurred in patients with non-obstructive CAD as seen on CCTA who may not have manifested with ischemia using functional testing.

Medical treatment of angina

Optimal medical therapy is effective and remains the foundation for reducing symptoms of stable angina in patients with diabetes.8 Common agents used for anginal relief aim at either reducing myocardial oxygen demand or increasing myocardial oxygen supply. β-blockers or calcium channel blockers are usually first line. Vasodilating β-blockers (e.g. carvedilol, labetalol) are preferred over non-dilating β-blockers (metoprolol, atenolol) due to their neutral effect on glucose metabolism and blood lipid profile. As mentioned above, beta-blockers should be used with caution in those at high risk of hypoglycemia. Calcium channel blockers are effective but nondihydropyridines should be avoided in those with impaired left ventricular systolic function. Ranolazine reduces myocardial ischemia through direct effect on cellular metabolism and is the only antianginal therapy which improves glycemic control. Often, two or more antianginal medications are required for optimal symptom control when anginal episodes are moderate in frequency.

Revascularization

Diabetic patients with stable angina often have diffuse and extensive CAD that is less amenable to revascularization.32 The treatment paradigm for patients with stable CAD and ischemia is changing in light of recent trials such as COURAGE33 and ISCHEMIA.34 The ISCHEMIA trial randomized patients with moderate to severe ischemia by functional testing to either an early invasive approach with or without revascularization if indicated versus a conservative approach. CCTA was performed prior to randomization to exclude left main disease unless coronary anatomy was previously defined, or the estimated glomerular filtration rate was 30 to <60 mL/min. Over a median of 3.2 years, there was no significant difference between the two treatment arms in the incidence of the composite primary outcome of death from cardiovascular causes, myocardial infarction, or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. These results were consistent by diabetes status. Of note, there was a benefit in the invasive arm in lowering spontaneous myocardial infarction that was offset by an increase in procedural myocardial infarction. Whether revascularization with PCI or CABG was more likely to account for these differences in myocardial infarction is still unclear. With regards to anginal relief, 35% of those enrolled in ISCHEMIA had no anginal symptoms, and in those who had symptoms, the majority had infrequent angina.  Patients assigned to an invasive approach had significant and durable angina control and improvement in quality of life if they had daily/weekly or monthly angina.35 Therefore, starting with a conservative approach using intensive medical management is safe and effective in stable CAD patients with diabetes and moderate to severe ischemia. An invasive strategy should be reserved to those with intractable angina despite medical therapy.

In summary, stable angina and CAD are common in patients with diabetes associated with significant morbidity and mortality. The recently released AHA scientific statement on the clinical management of stable CAD in patients with type 2 diabetes mellitus is a valuable document for clinicians taking care of this high-risk population. As outlined in the statement and summarized above, the management of stable angina in diabetic patients lays on a foundation of adopting a healthy lifestyle and optimizing medical management with disease modifying agents such as lipid-lowering therapy and antiplatelets and the use of SGLT-2 inhibitors or GLP-1 agonists among others (Figure 1). While revascularization is effective in those with intractable symptoms despite medical therapy, routine revascularization added to medical therapy has not been shown to reduce future cardiac events. To date, only medical therapy has been shown to reduce the risk of future death and other adverse cardiac events in this high-risk population.

Figure 1

Figure 1

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Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Stable Ischemic Heart Disease, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Nonstatins, Chronic Angina

Keywords: Diabetes Mellitus, Metabolic Syndrome X, Dyslipidemias, Platelet Aggregation Inhibitors, Antihypertensive Agents, Fibrinolytic Agents, Cholesterol, HDL, Cholesterol, LDL, Metoprolol, Atenolol, Risk Factors, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Labetalol, Sedentary Lifestyle, Weight Loss, Obesity, Morbid, Cardiovascular Diseases, Sodium Chloride Symporter Inhibitors, Smoking Cessation, Coronary Artery Disease, Gastric Bypass, Tobacco, Coronary Artery Disease, Angina, Stable, Blood Glucose, Primary Prevention, Secondary Prevention


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