Diabetes and Cardiovascular Disease

Two cardiologists review the effects of diabetes on the cardiovascular system, the influence of these effects on morbidityand mortality risks, and how to incorporate these special considerations into the management of patients in primary care.

By Mohan S. Reddy, MD, and Satyendra C. Gupta, MD

Dr. Reddy is a cardiology fellow at Good Samaritan/Veterans Affairs Medical Center and Wright State University School of Medicine, Dayton, Ohio. Dr. Gupta is chief of cardiology at the Veterans Affairs Medical Center and professor of medicine at Wright State University School of Medicine.

Diabetes mellitus, a metabolic disorder that also involves the vascular system, affects approximately 16 million Americans, half of whom are undiagnosed. It is the most potent risk factor for coronary artery disease (CAD). Patients with diabetes are two to four times more likely to have cardiovascular disease. This increased risk is seen in both type I and type II diabetes; it is more pronounced in women than men. Patients with diabetes but no CAD have the same incidence of myocardial infarction (MI) as patients with CAD but no diabetes. Other risk factors such as hypertension, smoking, and hyperlipidemia carry a worse prognosis in patients with diabetes than in those who do not have diabetes. Moreover, there is an increased prevalence of these risk factors in patients with diabetes.

In this article, we will review the underlying pathophysiology that links diabetes and heart disease. We will also discuss diabetic cardiomyopathy, clinical outcomes associated with diabetes and heart disease, and secondary prevention of heart disease in patients with diabetes.

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Link Between Diabetes and CAD

Diabetes causes CAD by inducing various metabolic abnormalities such as hyperinsulinemia, dyslipidemia, hyperglycemia, and disorders of the coagulation system (see chart below). Hyperinsulinemia leads to diabetic dyslipidemia, which is characterized by increased levels of very-low-density lipoproteins (VLDL), decreased levels of high-density lipoproteins (HDL), and the presence of small, dense, low-density lipoproteins (LDL). Hyperglycemia increases the production of oxygen-free radicals by different cells, which causes oxidation of small, dense, LDL particles and the vascular endothelium. Endothelial dysfunction is associated with impaired production of nitric oxide, which decreases vasodilation.

Glucose toxicity can also increase blood flow to retinal and renal arteries, leading to end-organ damage. In addition, postprandial hyperglycemia may induce a state of prolonged insulin resistance, which increases the risk of MI and CAD.

In diabetes, coagulation abnormalities are caused by platelet and coagulation cascade dysfunction. Platelets are in a relatively active state, which increases production of thromboxane A2. This results in increased vasoreactivity and platelet aggregation. Platelet lifespan is also decreased by 50%, impairing responsiveness to antiplatelet therapy.

The metabolic abnormalities present in diabetes create an imbalance between coagulation and the fibrinolytic system that promotes clot formation and stability. The coagulation cascade is in a relative prothrombotic state due to increased levels of von Willebrand factor, fibrinogen, d-dimer, thrombin, plasminogen activator inhibitor, and factor VII. These factors may decrease responsiveness to antithrombotics, heparin, and glycoprotein IIb-IIIa receptor blockers.

Other abnormalities such as neuropathy lead to unopposed sympathetic tone, causing an increased incidence of plaque instability that can trigger acute coronary syndromes. Sensory neuropathy causes atypical and delayed onset of symptoms, which may prevent timely diagnosis and appropriate therapy. Also, insulin resistance leads to impaired free fatty acid metabolism during myocardial ischemia. This may decrease contractility and increase infarct size and arrhythmogenicity.

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Diabetic Cardiomyopathy

In men and women between ages 35 and 64, diabetes mellitus increases the risk of congestive heart failure by four and eight times, respectively. This increased risk is not completely explained by the presence of ischemic heart disease. Over the years it has become clear that diabetes affects the heart muscle independently of the involvement of the coronary arteries.

Patients with diabetes have increased interstitial fibrosis, insoluble collagen content similar to that induced by the aging process, and myocellular hypertrophy. At the cellular level, diabetes causes impaired calcium removal from the cytoplasm, structural changes in troponin T, and increased activation of pyruvate kinase. These changes lead to decreased compliance, causing impaired contraction and relaxation of the myocardium and increased end-diastolic pressures.

Diabetic cardiomyopathy commonly presents as restrictive cardiomyopathy with predominant diastolic dysfunction. Concomitant hypertension and ischemia increase the severity of this condition. Diabetic cardiomyopathy should be treated with aggressive glycemic control, appropriate antihypertensive therapy, and early detection and treatment of ischemic heart disease, as needed.

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Increased Mortality in Diabetic Patients

The recent decline in mortality in patients with heart disease has been attributed to a reduction in cardiovascular risk factors and improved treatment. However, the decline in mortality in diabetic patients with heart disease, particularly women, has not kept pace with the general population. Mortality after acute MI is 1.2 to 2 times higher in this group than in patients who do not have diabetes.

It has been demonstrated that thrombolytic therapy for ST-segment elevation MI is more beneficial in diabetic patients. In an overview of almost 69,000 patients, the subgroup with diabetes showed greater survival benefit from such therapy, with 37 lives saved per 1000, compared to 11 lives saved per 1000 in the nondiabetic group.

Despite these beneficial effects, patients with diabetes are less likely to receive thrombolytic therapy than patients without diabetes. Reasons for this may be atypical presentation, delayed onset and recognition of symptoms, decreased sensitivity of a 12-lead electrocardiogram due to attenuation of ST and T wave changes by oral hypoglycemic agents, and undue concern about bleeding complications. In patients with diabetic retinopathy, the single most important reason is the misconception that thrombolytic therapy will precipitate intraocular bleeding. Data from the GUSTO-1 trial showed no incidence of this complication in this subgroup of patients. Therefore, diabetic retinopathy should not be considered an absolute contraindication for thrombolytic therapy.

Small studies have shown improved outcomes with primary angioplasty compared to thrombolytic therapy in ST-segment elevation MI. In the Primary Angioplasty in MI (PAMI) study, 400 patients were randomized to undergo primary angioplasty or receive thrombolytic therapy. In diabetic patients, in-hospital mortality was significantly reduced with angioplasty compared to thrombolytic therapy. However, larger studies are needed to further evaluate the validity of these results.

Compared to nondiabetic patients with heart disease, diabetic patients tend to be older, have a worse risk profile, and have more extensive CAD with diffuse involvement of multiple vessels and poor left ventricular function. In the Bypass Angioplasty Revascularization Investigation (BARI) trial, patients with multivessel disease were randomized to undergo coronary artery bypass graft (CABG) surgery or percutaneous coronary intervention (PCI). After five years of follow-up, diabetic patients who had undergone CABG surgery had better survival rates than the PCI group (80.6% versus 65.5%, p = 0.005).

Similar results were seen in the long-term follow-up of the Emory Angioplasty versus Surgery Trial (EAST) patients. Eight-year survival in the CABG group was 75.5% compared to 60.1% in the PCI group. Benefit in the surgical group was mainly seen in patients who received a left internal mammary artery graft. The anatomical superiority of the internal mammary artery graft over a saphenous vein graft and better revascularization compared to the PCI group probably explains the survival benefits of CABG surgery in diabetic patients. Another reason could be the altered vascular response in diabetic patients to balloon injury. The procoagulant state, decreased fibrinolytic activity, increased proliferation of the endothelium, and increased inflammation in diabetic patients may also play a role.

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Use of Beta Blockers

Aspirin has proved to be of benefit in patients with diabetes and ischemic heart disease. However, due to their prothrombotic state and increased platelet activation, this subgroup of patients may need more aggressive antiplatelet therapy.

Traditionally, diabetes has been considered a relative contraindication for the use of beta blockers. Many clinicians are concerned that beta blockers may increase triglyceride levels, impair glucose metabolism, and mask symptoms of hypoglycemia. (Beta blockers with additional alpha-receptor blocking properties such as carvedilol do not cause deleterious metabolic effects.) However, beta blockers have been shown to improve survival twofold in patients with diabetes and acute MI when compared to nondiabetic patients with acute MI.

Beta blockers also have significant survival benefit in patients with prior MI, unstable angina, or cardiomyopathy. In diabetic patients with such a medical history, the Bezafibrate Infarction Prevention (BIP) study, a prospective randomized trial, demonstrated that beta blocker therapy had greater survival benefit compared to nondiabetic patients. Moreover, the survival benefit far outweighed the adverse metabolic effects.

Therefore, in patients with diabetes and a history of MI, unstable angina, or cardiomyopathy, beta blockers should definitely be used. Close monitoring of glucose and lipid levels is advised. However, in diabetic patients with coexisting hypertension and no history of MI, unstable angina, or cardiomyopathy, beta blockers should be used sparingly.

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Pattern of Lipoprotein Anomalies

There is an increased association between diabetes and hyperlipidemia, hypertension, and obesity that leads to an increased incidence of CAD. Obesity is present in 80% of patients with diabetes, which also contributes to hyperlipidemia in diabetic patients.

The pattern of lipoprotein abnormalities in type I diabetes is similar to that seen in nondiabetic patients. These abnormalities can be corrected by tighter glycemic control. In type II diabetic patients, however, the pattern of lipid abnormalities differs when compared to nondiabetic patients. Type II patients frequently have hypertriglyceridemia, decreased levels of HDL, and increased levels of small, dense LDL. These abnormalities are only partly corrected by tighter control of blood glucose levels.

In the Scandinavian Simvastatin Survival Study (4S), out of 4,444 patients studied, 201 had diabetes. These patients had increased LDL and normal triglyceride levels, which do not represent typical diabetic dyslipidemia. Patients who received simvastatin had a 55% reduction in CAD-related events and a 43% decrease in all-cause mortality compared to the placebo group.

In the Cholesterol and Recurrent Events (CARE) study, out of 4,159 patients with MI, 586 patients had diabetes. The diabetic patients taking pravastatin had a 25% reduction in major cardiovascular events compared to a 23% reduction in nondiabetic patients treated with pravastatin. In the pravastatin treatment group, the reduction of events was greater in patients with triglyceride levels below 144 mg/dl than in patients with levels of 144 mg/dl or higher. In the above study, treatment with statins reduced cardiovascular events and dyslipidemia but did not normalize dyslipidemia. These results argue for a multifaceted approach to treatment of dyslipidemia in diabetic patients.

In a recent study, atorvastatin was shown to lower LDL and triglyceride levels better than other statins. In the Helsinki Heart Study, gemfibrozil therapy proved beneficial in patients with increased triglyceride and decreased HDL levels. In the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), patients with diabetic dyslipidemia had fewer coronary events and strokes with treatment with fibric acid derivatives. The statin drugs decrease LDL levels markedly but have minimal effect on triglyceride levels. Therefore, in patients with significantly elevated triglyceride levels (above 200 mg/dl) and vascular disease, combination therapy with statins and fibrates should be strongly considered. Careful monitoring is required, however, because there might be an increased incidence in side effects such as myopathy and liver abnormalities.

Appropriate treatment of dyslipidemia also improves endothelial function. Clinical studies have suggested that statins improve endothelial function and protect patients from cardiovascular events and death, particularly patients with diabetes or impaired glucose tolerance.

The table below presents the American Diabetes Association guidelines for treatment of hyperlipidemia. In the recently published Third Report of the National Cholesterol Education Program, the presence of diabetes without CAD is considered a CAD equivalent and the recommended treatment goal is an LDL level not greater than 100 mg/dl.

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Worse Prognosis with Hypertension

Hypertension is more prevalent in patients with diabetes: About 50% have it, compared with 25% of nondiabetic patients. Hypertension also carries a worse prognosis for cardiovascular disease in patients with diabetes.

Three-fourths of patients with coexisting diabetes and hypertension require a combination of two or more drugs to control their blood pressure. Because of adverse metabolic effects seen with the combination of thiazide diuretics and beta blockers, alternate agents such as angiotensin converting enzyme (ACE) inhibitors and calcium channel blockers are widely used for this purpose. In the Systolic Hypertension in Europe (Syst-Eur) trial, 10% of patients with diabetes showed significant survival benefit with use of long-acting calcium channel blockers. In the Appropriate Blood Pressure Control in Diabetes (ABCD) trial, patients treated with ACE inhibitors had a decreased incidence of cardiovascular events over a five-year follow-up period compared to patients treated with long-acting calcium channel blockers. In the Fosinopril versus Amlodipine Cardiovascular Events Trial (FACET), there was a greater decrease in cardiovascular events in the combined treatment group (ACE inhibitor plus a calcium channel blocker) than in either monotherapy group alone.

The above trial results demonstrate that ACE inhibitors are the most effective first-line antihypertensive agent for diabetic patients. If blood pressure is not adequately controlled with ACE inhibitors, the addition of a long-acting calcium channel blocker is an attractive alternative. The recommended goal is a blood pressure of less than 130/85 mm Hg.

The Heart Outcomes Prevention Evaluation (HOPE) study investigators have also demonstrated that ACE inhibitors are beneficial in diabetic patients because they reduce the incidence of cardiovascular events and other diabetes-related complications. Moreover, in this study, nondiabetic patients taking ACE inhibitors had a decreased incidence of new-onset diabetes compared to patients who were not taking ACE inhibitors.

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Unique Patient Population

Diabetic patients with cardiovascular disease form a unique patient population with a higher morbidity and mortality compared with nondiabetic patients. To manage these patients appropriately requires a thorough knowledge of the clinical outcomes associated with diabetes and heart disease and effective strategies for secondary prevention of heart disease in the presence of diabetes.

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