DIABETES AND CARDIOVASCULAR EVENTS
Type 2 diabetes (T2DM) is common in adults and is characterized by insulin resistance that results in hyperglycemia. Diabetes increases the risk of microvascular and macrovascular events. As a result, patients with diabetes have a higher risk of dying from cardiovascular disease and are at a higher risk for developing heart failure. The duration of diabetes and degree of glycemic control with diabetes is a significant predictor of future events. Thus, identification of patients at risk for diabetes, prediabetes, and new-onset diabetes allows for intensified therapy that may reduce the chances of developing diabetes and mitigate the risk of complications from diabetes. Patients are considered to have diabetes if they have a fasting plasma glucose of ≥126 mg/dL, oral glucose tolerance test with a 2-hour postprandial glucose ≥200 mg/dL, glycosylated hemoglobin of ≥6.5%, or random plasma glucose ≥200 mg/dL. Exercise, weight loss, and metformin improve insulin sensitivity and are effective strategies to reduce the risk of developing diabetes in patients with prediabetes. Drugs from two different classes have been shown to be effective in reducing cardiovascular events specifically in patients with diabetes. The sodium/glucose cotransport-2 inhibitors, liraglutide, and semaglutide have been shown to reduce cardiovascular events in patients with diabetes. Because of the high degree of cardiovascular disease in patients with diabetes, efforts to use drugs with proven cardiovascular benefit, together with intensive cardiovascular risk factor modification, offer the ability to reduce the incidence of cardiovascular events in this high-risk population of patients.
Diabetes mellitus is the resultant state of insulin deficiency that causes elevated blood glucose. The etiologies of this insulin deficiency can broadly be classified as either type 1 or type 2 diabetes. Type 1 diabetes is characterized by an autoimmune process that results in β-cell dysfunction and inadequate insulin production. This form of diabetes frequently presents during childhood or adolescence, and requires insulin supplementation due to the inadequate production of insulin by the pancreas.
Type 2 diabetes (T2DM) is more common in adults and is characterized by insulin resistance. Because most adult patients have T2DM, it is this group that will be the focus of this chapter. All of the mechanisms that underlie the development of insulin resistance have not been fully elucidated. It is likely that the disease is caused by the interaction of multiple different factors, including genetic, environmental, and lifestyle factors, all of which contribute to the development of the disease. It is clear that obesity plays a central role and decreases the body’s responsiveness to insulin. This decrease in the response to insulin is known as insulin resistance, and patients with insulin resistance are considered to have prediabetes. In patients with prediabetes, higher levels of insulin are required to maintain glucose homeostasis. These increased demands on the pancreas place the insulin-producing β cells under stress. Ultimately, the pancreas is no longer able to produce enough insulin to maintain euglycemia, and thus, hyperglycemia results. These patients are considered to have progressed from prediabetes to T2DM. In patients with longstanding and poorly controlled T2DM, insulin production can fall, exacerbating the insulin deficiency and excess hepatic glucose production, which results in physiology that can resemble T1DM. The presence of T2DM increases the risk of multiple adverse health events, including death. Broadly speaking, diabetes complications can be divided into those that are microvascular or macrovascular in origin (Fig. 17.1). Microvascular disorders include retinopathy (diabetes remains a leading of blindness), nephropathy (which can lead to end-stage renal disease), and neuropathy. Macrovascular complications from diabetes refer to those events that are predominately seen in larger caliber vessels and include myocardial infarction, stroke, and peripheral arterial disease. Patients with diabetes are at considerably higher risk of atherosclerosis and ischemic events.
Multiple biological mechanisms link diabetes and atherosclerosis. The higher burden of atherosclerosis seen in patients with diabetes is related partially to the direct effects of hyperglycemia. Hyperglycemia increases the proliferation of vascular smooth muscle cells that causes vascular beds to have diffusely diseased vessels and decreased capacity for delivery of blood (Fig. 17.2). Hyperglycemia also results in oxidative stress and the formation of reactive oxygen species, which, in turn, promote lipid oxidation, endothelial damage, inflammation, and progression of lipid-rich plaques. Finally, alterations in lipid metabolism and the association of hypertension and obesity that occur frequently in patients with diabetes also contribute to the development of atherosclerosis and the increased risk of cardiovascular events seen in this population.
In addition, it is becoming increasingly clear that patients with diabetes are also at increased risk of heart failure. The relationship between diabetes and heart failure has been known for some time; however, it was believed that diabetes predominately increased the risk for ischemic cardiomyopathies secondary to the higher rates of coronary artery disease seen in this population. Although coronary artery disease remains a significant risk factor for heart failure, it has been shown that the relationship between diabetes and heart failure is independent of the presence of atherosclerosis. In the REduction of Atherothrombosis for Continued Health (REACH) registry, which is a large international registry of patients with either established atherosclerosis or at high risk for atherosclerosis, patients with previous myocardial infarction or stroke had higher rates of heart failure than patients without established cardiovascular disease. However, the presence of diabetes resulted in a similar relative increase in the risk of heart failure, regardless of whether patients had a previous ischemic event or only had risk factors for heart failure. Patients with diabetes are at risk for heart failure with preserved ejection fraction, and this form of heart failure occurs independently from coronary artery disease. Although diabetes also increases the risk of other events (e.g., infections), preventing microvascular, macrovascular, and heart failure complications are the dominant goals of the current therapies for diabetes.
The prevalence of diabetes is increasing across the world. In 1980, it was estimated that 108 million people had diabetes, and that is affected approximately 4.3% of the world’s population. Over the past 25 years, the rate of diabetes has grown exponentially, such that in 2014, it was estimated that diabetes was present in 422 million people worldwide and affected approximately 9% of men and 8% of women. Although some of this increase is believed to be secondary to aging of the population, overall increases in the prevalence of obesity are thought to be a consider- able driver for the more than fourfold increase in prevalence. The incidence rate of diabetes is expected to continue to climb, and some studies have suggested that >700 million people may have diabetes by 2025.
There are multiple risk factors for the development of diabetes, including genetic predisposition, caloric intake and/or diet, and physical activity (or the lack thereof). All of these issues factor into the risk of developing diabetes. Ultimately, the rates of T2DM are closely linked with the presence of obesity. Most increases in the prevalence of diabetes are at least somewhat linked with the increasing incidence of obesity. Although diabetes and obesity are increasing in the United States, the rates of diabetes are increasing at the highest absolute rates in the developing world. This increase appears to be due, at least in part, to the increase of high caloric diets and decreases in energy use as these societies move from predominately agrarian to more industrialized ways of life. Efforts to prevent the increase in the prevalence of diabetes are focused on the developing world because these increases are con- tributing significantly to the overall increase in the incidence of diabetes.
Patients with diabetes have higher rates of death compared with patients without diabetes. When evaluating the reasons for the differential rates of death, the largest contributor to the excess in deaths in patients with diabetes are cardiovascular events. Thus, targeting cardiovascular events is likely the most effective strategy to improve out-comes in patients with diabetes. Although rates of cardiovascular complications are declining, both in the general population and in patients with diabetes, the large increases in the number of patients with obesity and diabetes may threaten the long-term decreases in the cardiovascular event rate.
The duration of diabetes and degree of glycemic control with diabetes is a significant predictor of future diabetes complications. Previous studies have shown that glycosylated hemoglobin (HbA1c), which is a marker of glucose levels over the previous 3 months, predicts cardiovascular events in patients both with and without established diabetes. The duration of diabetes is also a significant independent predictor of future diabetes complications. Thus, identification of patients at risk for diabetes, prediabetes, and new-onset diabetes allows for intensified therapy that may mitigate the risk of long-term complications from diabetes.
The American Diabetes Association (ADA) has identified some important risk factors associated with the development of diabetes: lack of physical activity; patients of African American, Latino, Native American, Asian American, Pacific Islander race or ethnicity; patients with a family history of diabetes (particularly those with first-degree relatives who have diabetes); women previously diagnosed with gestational disease; patients with hypertension; patients with low high-density lipoprotein cholesterol (<35 mg/dL) and/or high triglycerides (>250 mg/ dL); patients with evidence of insulin resistance (HbA1C ≥5.7%); patients with impaired glucose tolerance (glucose of 140–199 mg/dL on a 2-hour glucose tolerance test) or impaired fasting glucose (100–125 mg/dL); patients with severe obesity; patients with acanthosis nigricans and/or polycystic ovarian syndrome; patients with hypertension (≥140/90 mm Hg or on treatment); and patients with a known cardiovascular disease are all independent predictors of having diabetes.
Current guidelines recommend screening for diabetes in patients who are overweight and/or obese and have at least one of the previously mentioned risk factors for diabetes. The diagnosis of diabetes requires the presence of at least one of four different clinical findings: (1) fasting plasma glucose of ≥126 mg/dL; (2) oral glucose tolerance test (with equivalent of 75 g anhydrous glucose dissolved in water) with a 2-hour postprandial glucose of ≥200 mg/dL; (3) HbA1C ≥6.5%; or (4) random plasma glucose of ≥200 mg/dL.
Patients are considered to have prediabetes if the HbA1c is between 5.7% and 6.4% (additional criteria for prediabetes include fasting plasma glucose between 100 and 124 mg/dL or glucose tolerance test with 2-hour glucose between 140 and 199 mg/dL). Patients with prediabetes are at increased risk of developing diabetes over time, and patients with tests closer to the upper range for prediabetes have a greater risk than patients with test results that are closer to the lower range. Patients with diabetes should be encouraged to begin exercise programs, work to lose weight, initiate therapies designed to modify cardiovascular risk factors, and reduce the risk of cardiovascular events. Previous studies have found that exercise and weight loss are particularly efficacious in reducing the risk of developing diabetes.
MANAGEMENT AND THERAPY
The management of patients with diabetes depends upon whether patients have prediabetes and/or insulin sensitivity or if they have developed T2DM. The goals of therapy for patients with prediabetes focus on improving risk factor control and preventing the progression from insulin resistance to diabetes. Current recommendations focus on therapies shown to improve insulin sensitivity. Exercise and weight loss improve insulin sensitivity and have been shown to be effective strategies to reduce the risk of progression to diabetes. In a trial of 3234 patients with elevated fasting and postload plasma but without diabetes, patients randomized to lifestyle modification programs with goals of ≥7% weight loss and 150 minutes of physical activity per week had lower incidence of diabetes. In this same study, patients randomized to metformin also had lower rates of diabetes compared with patients who had usual care. However, the incidence of new-onset diabetes was lowest in those patients who received lifestyle interventions. Thus, in patients with prediabetes, lifestyle modifications and metformin form the foundation of current treatment recommendations. In patients with prediabetes who have had a stroke or transient ischemic attack, treatment with pioglitazone has been shown to be effective in reducing the progression to diabetes and decreasing the risk of future stroke or myocardial infarction.
In patients with established diabetes, the goals of therapy focus on the prevention of the microvascular and macrovascular complications of diabetes. Early identification of retinopathy through diabetic eye examinations, detection of nephropathy with urine microalbumin, and diabetic foot examinations to identify neuropathy and its complications are the cornerstones for preventing microvascular complications (Fig. 17.3). Glycemic control and glucose-lowering drugs are particularly important in preventing the microvascular complications of diabetes. In the United Kingdom Prospective Diabetes Study (UKPDS), microvascular events such as diabetic nephropathy were reduced with intensive glucose control. Although this study was performed in an era in which there were limited drugs for diabetes, and cardiovascular risk factors were not as aggressively controlled, there is a continued role for glycemic control in reducing microvascular complications.
The impact of glucose control on cardiovascular and other macrovascular events remains less clear. Previous studies have shown a clear association between the degree of glycemic control and the risk for cardiovascular events; yet, there are less data on whether glycemic control can reduce the risk of cardiovascular events. In the UKPDS trial, patients randomized to intensive glucose lowering had evidence of lower rates of myocardial infarction. However, this benefit was not seen during the initial trial, and only became evident after 10 years of follow-up. Similar studies, such as the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, the Veterans Affairs Diabetes Trial (VADT), and Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation (ADVANCE) trial, which randomized a more contemporary cohort of patients either to an intensive or routine glucose-lowering strategy, also did not show lower rates of either cardiovascular death or myocardial infarction. When pooled together in a meta-analysis, these studies suggested that intensive glycemic control likely does reduce myocardial infarction.
Current treatment guidelines for the treatment of diabetes recommend metformin as a first-line therapy for lowering glucose in patients with diabetes. Metformin is effective in lowering blood glucose, and a small trial has provided some evidence, albeit with a small number of events, that it may also reduce cardiovascular events. It remains the first-line therapy based upon the long history of use that has provided observational evidence of safety and efficacy with regard to glucose control. Although there is limited evidence for reductions in cardiovascular events, metformin is widely available and affordable, making it a reasonable choice for the initial treatment of patients with diabetes.
Most patients with diabetes will either have such poorly controlled glucose when diagnosed with diabetes that they will require more than one drug or will have progression of diabetes over time, making further therapies necessary. Current treatment guidelines support the concept of individualizing diabetes therapy based on individual patient factors. In patients at risk of cardiovascular disease, using therapies that have been shown to reduce cardiovascular risk should take a precedence over those therapies that have only been found to be effective in improving glucose control.
Sodium/Glucose Cotransport-2 Inhibitors
Currently, drugs from two different classes have been shown to be effective in reducing cardiovascular events in patients with diabetes. The sodium/glucose cotransport-2 inhibitors (SGLT-2i) have been shown to reduce cardiovascular events in patients with diabetes with either established atherosclerosis or who are at high risk for developing cardiovascular disease. These drugs work by inhibiting the SGLT-2 cotransporter, which is found in the proximal tubule of the kidney.
When functioning normally, this cotransporter serves to re-uptake glucose that has been filtered by the kidney. Inhibition of this cotransporter results in glycosuria, which causes a mild osmotic diuretic effect and reductions in blood pressure and weight.
Thus far, two large cardiovascular outcome trials found that treatment with empagliflozin (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients—Removing Excess Glucose [EMPA-REG]) and canagliflozin (Canagliflozin Cardiovascular Assessment Study [CANVAS]) reduces major cardiovascular events, as well as hospitalization for heart failure and progression of renal disease. In the Comparative Effectiveness of Cardiovascular Outcomes (CVD- REAL) study, a large observational study of 1.4 million patients with diabetes from six different countries, patients with diabetes initiated on SGLT-2i had a lower risk of death and hospitalization for heart failure, which provided further support for the role of SGLT-2i in the treatment of patients with diabetes. These drugs were the first class of drugs designed specifically to lower glucose that were found to be effective in reducing the risk of cardiovascular disease. Because of the nature of these drugs, it seems unlikely that the beneficial effects were related to reductions in glucose control. The exact mechanism by which these drugs improved cardiovascular outcomes remains unclear, but might be secondary to effects on weight, blood pressure, and progression of renal disease.
Some agonists of glucagon-like peptide–1 (GLP-1) have also been shown to improve outcomes in patients with diabetes. The physiological role of GLP-1 is to help maintain glucose homeostasis and glycogen storage. The ingestion of food results in the release of GLP-1, which lowers plasma glucose by increasing insulin secretion and glycogen storage. Agonists of GLP-1 and dipeptidyl peptidase IV (DPP-IV) inhibitors (drugs that block the breakdown of GLP-1, which results in higher levels of biologically active GLP-1), have been found to be effective in lowering plasma glucose. Two specific GLP-1 agonists, liraglutide and semaglutide, have been shown to reduce cardiovascular events in patients with diabetes. These benefits have not been seen with other GLP-1 agonists or with DPP-IV inhibitors. In the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome Results (LEADER) trial, patients treated with liraglutide had a lower risk of cardiovascular death, myocardial infarction, or stroke (13.0% vs. 14.9%; hazard ratio [HR]: 0.87; 95% confidence interval [CI]: 0.78–0.97), with consistent effects on cardiovascular death (4.7% vs. 6.0%; HR: 0.78; 95% CI: 0.66–0.93), myocardial infarction (HR: 0.86; 95% CI: 0.73–1.00; P = 0.046), and stroke (HR: 0.86; 95% CI: 0.71–1.06). Semaglutide is a longer acting GLP-1 agonist that was studied in a small randomized clinical trial that also showed reductions in cardiovascular events.
The exact mechanism by which liraglutide and semaglutide reduce major cardiovascular events has not been fully elucidated. GLP-1 receptors have been found in a variety of different cardiovascular tissues. Animal models suggest that GLP-1 agonists may activate molecular pathways that are important for myocardial survival. Human studies with intravenous GLP-1 at a pharmacological dose found improvements in left ventricular function, maximum oxygen uptake, and physical performance in subjects with congestive heart failure, as well as reductions in blood pressure in patients with hypertension. These studies raise the potential for a nonglycemic mechanism of cardiovascular benefit.
In addition to the SGLT-2i and GLP-1 agonists, patients with diabetes and established cardiovascular disease should have aggressive cardiovascular risk factor modification. Patients with blood pressures >120 mm Hg (systolic) or >80 mm Hg (diastolic) should increase exercise, lose weight, and decrease salt intake. Results from a large meta-analysis of 40 trials of antihypertensive therapy have found that the pharmacological treatment of hypertension is most beneficial in patients with diabetes who have a baseline blood pressure of >140 mm Hg. There are some studies that have suggested achieving a goal blood pressure of 130 mm Hg rather than 140 mm Hg, which could result in a small reduction in the percentage of cardiovascular events and stroke. However, current ADA guidelines recommend the initiation of antihypertensive therapy for patients with blood pressures >140 mm Hg (systolic) or >90 mm Hg (diastolic).
Lipid-lowering therapy is an important aspect in the prevention of cardiovascular disease in patients with diabetes. In patients with diabetes and established cardiovascular disease, lowering low-density lipoprotein cholesterol (LDL-C) to extremely low levels reduces the risk of cardiovascular events. In the Improved Reduction of Out-comes: Vytorin Efficacy International Trial (IMPROVE-IT), patients with an acute coronary syndrome were randomized to either simvastatin 40 mg/ezetimibe 10 mg or simvastatin 40 mg. Patients with diabetes who were treated with ezetimibe had lower rates of cardiovascular death, myocardial infarction, unstable angina that required hospitalization, coronary revascularization, or stroke at 7 years (45.5% vs. 40.0%; HR: 0.86; 95% CI: 0.78–0.94). The effects of ezetimibe in patients with diabetes was greater than in patients without diabetes (P value [interaction] = .02). Further reductions in cardiovascular events have also been shown with proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which have been studied for use, in addition to statins. In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial, patients treated with evolocumab, a PCSK9 inhibitor, had a mean LDL-C of 30 mg/dL and significantly lower rates of cardiovascular events. Although there are no specific trials in patients with diabetes, in the FOURIER trial, a large proportion of patients had diabetes (37%). Taken together, these studies suggest that patients with diabetes benefit from aggressive lowering of LDL-C.
Current guidelines recommend that intensive statin therapy should be used for all patients with diabetes and known cardiovascular disease or those with risk factors for cardiovascular disease who are younger than 75 years old. Moderate intensity statins should be used in patients 40 to 75 years old without risk factors for cardiovascular disease. Because of the data on ezetimibe and PCSK9 inhibitors when used in addition to statin medications, it is highly likely that future guidelines may move toward recommendations that support a low goal LDL-C in patients with diabetes.
Antiplatelet therapy reduces the risk of future cardiovascular events in patients at high risk of cardiovascular disease without established atherosclerosis and in patients with established atherosclerosis. Aspirin is recommended for long-term use in patients with diabetes who have had either a previous ischemic event or known atherosclerosis. The benefit of aspirin in patients with diabetes who have no evidence of atherosclerosis is less clear. As such, current recommendations support the use of aspirin in patients with a 10% risk of cardiovascular disease during the next 10 years of follow-up. Traditionally, patients with diabetes who are 50 years or older are considered to be at increased risk if they have at least one other cardiovascular risk factor (family history of early atherosclerosis, hypertension, smoking, dyslipidemia, or albuminuria). In those patients with diabetes who are younger than 50 years old and have lar risk factors, aspirin therapy is not recommended.
Following a myocardial infarction, lifelong aspirin and additional antiplatelet therapy with a P2Y12 inhibitor for at least 1 year is indicated. Because of the high rate of recurrent cardiovascular events in patients with diabetes, this population has particular benefit from more intensive antiplatelet therapy with ticagrelor and prasugrel. Although patients in clinical practice are often treated with only 12 months of dual antiplatelet therapy, patients with diabetes should be considered for long-term therapy. Patients with diabetes in the Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial, which evaluated the usefulness of long-term ticagrelor in patients 1 to 3 years after an acute myocardial infarction, had lower rates of cardiovascular events, including cardiovascular death. This supports longer duration or more intensive antiplatelet therapy in patients with diabetes and a previous myocardial infarction.
There have been significant advances in the care of patients with diabetes that have resulted in an overall decline in the rates of cardiovascular events. However, these improvements are threatened by the prevalence of diabetes with an increasing overall number of cardiovascular events. Future efforts to improve outcomes in patients with established T2DM will focus on methods to more accurately prevent diabetes. Current prevention strategies focus mostly on risk stratification by identifying events that have already occurred (e.g., previous myocardial infarction). Moving forward, using cardiovascular biomarkers such as high-sensitivity troponin or B-type natriuretic peptide may allow more accurate prediction of which patients are at highest risk of future cardiovascular events and who could benefit from more intensive therapies.
New pharmacotherapies such GLP-1 agonists and SGLT-2i have been shown to reduce cardiovascular risk in patients with diabetes and established cardiovascular disease. Further work is needed to understand whether these same cardiovascular benefits can be seen in patients without established cardiovascular disease and possibly even in patients with only prediabetes. In addition, it will important to better understand the mechanism of action in these drugs to explore additional targets that could provide further benefit, and so that clinicians can better understand how to most effectively use these therapies.