Increased Incidence of Coronary Atherosclerosis in Type 2 Diabetes Mellitus: Mechanisms and Management

Type 2 diabetes mellitus is a vascular disease. More than 3 out of 4 diabetic patients die of causes related to atherosclerosis, in most cases (75%) because of coronary artery disease (1). Yet, 70% of diabetic persons do not believe they are at serious risk for cardiovascular disease (2). An increasing number of patients have diabetes and its attendant complications, and this trend is predicted to continue. In the United States, the number of diabetic patients is expected to increase from 15 million to 22 million by 2025 (1). This increase correlates strongly with increasing obesity (3) and is reflected in the development of diabetes at an earlier age (4). The younger age at onset portends an increased future prevalence of premature coronary artery disease and resource utilization that will exceed the current $100 billion annual expenditure in the United States (5). Type 2 diabetes increases the risk for coronary artery disease by 2 to 4 times in the overall population. Haffner and colleagues (6) found that diabetic patients with no history of coronary artery disease have the same risk for future myocardial infarction as do nondiabetic patients with known disease (Figure). The National Cholesterol Education Program considers diabetes to be a coronary disease equivalent in their lipid guidelines (7). The risk is even greater in women. Diabetes eliminates the usual female advantage in risk for death from coronary artery disease; these patients have a 5-fold to 8-fold higher death rate than do nondiabetic women (8). Although advances in cardiovascular care and revascularization techniques have decreased event rates and mortality in the population overall, these rates are increasing among diabetic patients (9). Figure. KaplanMeier estimates of the probability of death from coronary heart disease in 1059 patients with type 2 diabetes and 1378 nondiabetic patients with and without previous myocardial infarction ( MI ). The purpose of this article is to define the mechanisms for the propensity for atherosclerosis, emphasize the benefits of prevention, and review the optimal management of coronary atherosclerosis in patients with type 2 diabetes. For details of our literature search strategy, see the Appendix. The Metabolic Syndrome The metabolic syndrome, also known as the insulin-resistance syndrome or syndrome X (Table 1), affects 50 to 75 million Americans (10) and often precedes diabetes. Twenty percent of middle-aged persons and 40% of older persons are affected (10). These patients are not frankly diabetic but still have substantial risk for atherosclerosis, with rates of total and cardiovascular mortality that are double those in the general population (11). Table 1. The National Cholesterol Education Program Guidelines for Diagnosis of the Metabolic Syndrome The same therapies that decrease coronary risk may also be of benefit in preventing the onset of diabetes and its complications. The Diabetes Prevention Program (12) study randomly assigned 3234 patients with elevated fasting and postload plasma glucose levels to receive placebo or metformin or follow a lifestyle modification program. Lifestyle modifications (diet, exercise, and weight loss) decreased the incidence of newly diagnosed diabetes by 58%, and metformin therapy produced a significant decrease of 31% (12). The clinical benefits of treatment with angiotensin-converting enzyme inhibitors (13) and statins (14, 15) in the prevention of cardiac events are well established. These drugs may also delay or prevent onset of diabetes (16, 17). The Diabetes Reduction Assessment with Ramipril and Rosiglitizone Medication study will evaluate whether therapy with an angiotensin-converting enzyme inhibitor, possibly by improving insulin sensitivity, can decrease the incidence of diabetes in persons who have impaired glucose tolerance. Aggressive management of coexisting cardiac risk factors is paramount in the metabolic syndrome. The National Cholesterol Education Program expert panel (7) recommends weight loss, exercise, and treatment of hypertension (particularly with angiotensin-converting enzyme inhibitors that improve insulin sensitivity) and dyslipidemia. These patients may experience a benefit from statin therapy even greater than that in patients with isolated increased concentrations of low-density lipoprotein cholesterol (LDL) (18). Mechanisms of Vascular Disease The mechanism for the disposition to atherosclerosis in patients with type 2 diabetes is becoming better defined. Traditional risk factors are more common in these patients than in healthy persons, but coronary artery disease events still exceed the expected rate by 50% (1). Table 2 shows the proposed pathophysiologic mechanisms that explain the independent risk factor status for coronary artery disease in diabetes. Table 2. Mechanisms of Increased Atherosclerosis in Diabetic Patients Endothelial Dysfunction Endothelial dysfunction is a precursor to and an effect of atherosclerosis. The vascular endothelium is a multifunctional organ system that resists thrombosis and atherogenesis and regulates blood flow by producing nitric oxide, the prime mediator of vascular reactivity. Diabetes impairs endothelial function (19) through several proposed mechanisms (Table 3). The clinical implications of endothelial dysfunction are not limited to increased atherosclerosis. Endothelial cells also help form collateral circulation, which is reduced in patients with diabetes (25) and may explain the increased infarct extension and congestive heart failure after myocardial infarction in these patients. Table 3. Mechanisms for Endothelial Dysfunction in Type 2 Diabetes Mellitus Dyslipidemia Dyslipidemia is a known risk factor for coronary atherosclerosis, and lipid abnormalities are common in diabetic patients. Elevated levels of small, dense LDL particles, low levels of high-density lipoprotein (HDL) cholesterol, and high triglyceride levels make up the condition known as diabetic dyslipidemia. In 1 study, patients with diabetic dyslipidemia had a worse prognosis than did those with isolated elevated LDL levels (26). However, dyslipidemia does not fully explain the increased incidence of coronary artery disease. At any lipid level, diabetic patients have more severe coronary disease than their nondiabetic counterparts, possibly because of an increased incidence of atherogenic lipid abnormalities, such as small, dense LDL particles. The presence of these particles (subclass phenotype B) is associated with a 3-fold increase in myocardial infarction (27) and is an important part of the metabolic syndrome (28). In addition, increased oxidation of LDL in diabetic patients has been associated with increased risk for coronary artery disease, possibly by promoting endothelial dysfunction. Oxidized LDL is cytotoxic to endothelium; it impairs endothelium-dependent vasodilation by inactivating nitric oxide (20) and causes endothelial disruption (29). Thrombogenesis The propensity for clotting is increased in patients with diabetes (30). The level of plasminogen activator inhibitor, which suppresses fibrinolysis, is elevated in the serum and atherectomy specimens of diabetic patients (31), and elevated levels are associated with an increased risk for myocardial infarction (32). In addition, increased concentrations of prothrombotic substances (such as tissue factor, fibrinogen, and factor VII) are found in diabetic patients (33). Clinically, this increased thrombogenicity improves with better glucose control (34). Platelet-dependent thrombosis has also been linked to an elevated glucose level (35), and diabetic patients have more platelet aggregation in response to platelet activation (36). This state of hyperaggregability of platelets may explain the enhanced efficacy of antiplatelet agents, such as glycoprotein IIb/IIIa inhibitors (37). Oxidative Stress On the molecular level, oxidative stress (a relative increase in oxygen free radicals) appears to play a role in diabetic atherogenesis (38). Hyperglycemia leads to increased production of reactive oxygen species and to nonenzymatic glycoxidation of proteins, which alters their structure and function. Ultimately, these altered proteins (known as advanced glycation end products) accumulate in patients with a chronically elevated glucose level (38). The effects of advanced glycation end products (through receptors for advanced glycation end products) cause increases in vascular permeability, procoagulant activity, adhesion molecule expression, and monocyte influx that contribute to vascular injury. Advanced glycation end products also affect dyslipidemia by altering LDL receptormediated clearance mechanisms (39). Autonomic Neuropathy Autonomic neuropathy, which leads to an increased propensity for malignant arrhythmia, is another possible mechanism for the high morbidity and mortality from coronary artery disease in diabetic patients. Sympathovagal imbalance from parasympathetic denervation occurs in 40% to 50% of patients (40). The resulting variation in areas of denervation in the myocardium may lead to arrhythmogenesis and sudden cardiac death (41). Preventive Management Modification of Risk Factors for Coronary Artery Disease and Glycemic Control Although it is intuitive that improved glucose control will decrease the risk for macrovascular events, this effect has not been conclusively demonstrated. The United Kingdom Prospective Diabetes Study 33 compared intensive glucose control with sulfonylureas or insulin and conventional care. A total of 3867 patients with newly diagnosed type 2 diabetes (median age, 54 years) were randomly allocated to receive intensive therapy with sulfonylureas or insulin and were followed for a mean of 10 years. Tight glycemic control reduced the incidence of microvascular but not macrovascular complications (42). Therefore, despite evidence of an increase in cardiovascular events with increasing blood glucose levels (43), no strong evidenc