Screening for coronary artery disease in asymptomatic patients with type 2 diabetes mellitus

In China, the prevalence of type 2 diabetes mellitus is increasing rapidly due to aging of the population, increased frequency of obesity, and suboptimal nutritional habits.1-3 Currently, the number of people with diabetes was estimated to be 20 million and will be projected to double by the year 2030. The age-adjusted prevalence of diabetes among patients with acute myocardial infarction has increased significantly over the past two decades, and diabetic patients without known coronary artery disease have similar rates of subsequent myocardial infarction compared with non-diabetic counterparts with a previous myocardial infarction.4 Diabetes is a strong risk factor for cardiovascular disorders, including coronary artery disease. Atherosclerosis accounts for 65%-80% of all deaths among diabetic patients, compared with one-third of all deaths in the general population. On the other hand, the reported prevalence of diabetic patients with asymptomatic coronary artery disease varied from 4% to 75%. Myocardial ischemia in patients with diabetes is often silent and contributes to more advanced coronary artery disease on initial presentation. Once coronary artery disease becomes symptomatic in diabetics, morbidity and mortality are high and the outcome will be significantly worse than that in patients without diabetes.5 Because of the well-established association between diabetes and atherosclerosis, many physicians already performed screening tests for early detection of coronary artery disease in diabetic patients.6-8 Exercise electrocardiographic (ECG) stress testing remains an inexpensive approach that has been used to assess asymptomatic diabetic patients for suspected coronary artery disease. Given the differences in presentation of coronary artery disease within the diabetic population and particularly the higher incidence of silent myocardial ischemia, many studies have collectively support the notion that among higher-risk cohorts of asymptomatic patients with diabetes, up to nearly one third may have unrecognized coronary artery disease, and that exercise ECG testing may provide useful diagnostic information on identifying a subgroup of asymptomatic diabetic patients who have significant coronary artery disease as defined by angiography.9 Myocardial perfusion scanning with pharmacological stress is well recognized to provide greater diagnostic accuracy than exercise ECG testing in diabetic patients. The value of stress echocardiographic imaging in patients with diabetes remains unclear. Hennessy et al10 evaluated 52 patients with diabetes referred for coronary angiography using dobutamine stress echocardiography, and revealed that the sensitivity, specificity, and positive and negative predictive values of this technique for coronary artery disease detection were 82%, 54%, 84%, and 50%, respectively. Increasing data are available to support both its diagnostic accuracy and, in particular, its prognostic value in stratifying diabetic patients for further cardiac events.11 The utility of stress nuclear cardiac imaging for studying the prevalence and severity of coronary artery disease in asymptomatic diabetic patients was investigated by the DIAD (Detection of Ischemia in Asymptomatic Diabetics)study.12 The findings suggest that one in every five asymptomatic patients with type 2 diabetes, aged 50-77 years, would have silent myocardial ischemia. More importantly, 1 in 16 patients overall and 1 in 12 men would have markedly abnormal (moderate-to-large) myocardial perfusion abnormalities. The study indicates that overall asymptomatic patients with diabetes have at least an intermediate probability of coronary artery disease, a prevalence that may justify screening by noninvasive testing such as stress myocardial perfusion imaging.7,8 The extent of coronary calcification assessed by electron beam computed tomography (CT) is closely associated with total coronary artery atherosclerotic plaque burden, and coronary artery calcium scores predict incident coronary artery disease in general population.13 A recent, large observational study by Raggi et al,14 comprising 903 diabetic patients and 9474 non-diabetic low-to-intermediate risk subjects, demonstrated that diabetic patients with no detectable coronary artery calcium had an excellent 5-year survival, which was significantly different from non-diabetic counterparts, implying that coronary calcium continues to be a robust prognostic marker even in the presence of type 2 diabetes. The study also showed that all-cause mortality in asymptomatic patients with diabetes increased in proportion to their baseline coronary artery calcium scores. Consequently, a risk stratification approach using the combination of coronary artery calcium score and clinical variables was superior to each individually. Recently, numerous studies have shown that multi-slice CT coronary angiography has emerged as a safe, noninvasive, patient-friendly diagnostic modality to detect the presence of coronary atherosclerosis. The diagnostic potential of multi-slice CT angiography is more powerful because it allows not only the detection of significant coronary stenosis but also the presence of nonobstructive calcific and noncalcific (lipid or fibrous) plaques.15 There are claims that, after scaling up with advanced technology, CT angiography might replace invasive coronary angiography. However, as yet, there are no data to support this hypothesis. The new appropriateness criteria applied to CT angiography found that use of CT angiography/magnetic resonance imaging for structure and function and for the diagnosis in symptomatic patients at intermediate risk for coronary artery disease is appropriate, but repeat testing and general screening uses were viewed less favorable.16,17 In a multicenter study of multi-slice CT angiography, 1629 nonstented segments were evaluated, of which 427 were inevaluable and 96 false-positive. After censoring all inevaluable segments as positive, the sensitivity for detecting more than 70% luminal stenoses was 94%, specificity 67%, positive predictive value 6%, and negative predictive value 99%.18 Furthermore, the estimated radiation dose for a 16-slice CT scan is between 4 and 16.3 mSv depending on whether ECG pulsing is used and on the gender of the patient (radiation doses are higher in women). For 64-slice CT scans, the radiation dose is higher, between 4.8 and 21.4 mSv. Comparatively, for contrast angiography the radiation dose is 5.6 mSv.19 Previous studies demonstrated an association of serum glycosylated hemoglobin (HbA1c) level with the severity of coronary artery disease in type 2 diabetic patients,20 and serum glycated albumin level plateaued several weeks in diabetic patients in whom glucose levels were initially poorly controlled and then intensive insulin management was used to rapidly bring glucose levels under control, while HbA1c levels were still falling.21 Pu and colleagues22 evaluated the clinical value with determination of serum glycated albumin level in assessing the presence and severity of coronary artery disease for patients with type 2 diabetes. Their results showed that serum glycated albumin level was significantly higher in type 2 diabetic patients with than in those without coronary artery disease without an overlap of confidence intervals for serum glycated albumin levels between these two patient populations. For diabetic patients with coronary artery disease, serum glycated albumin level was significantly higher in patients with 3-vessel disease and high-risk coronary disease than in those with 1-vessel disease. In addition, it also correlated closely with the number of diseased coronary arteries and lesions. Although serum HbA1c level correlated significantly with glycated albumin values, no difference was observed in HbA1c levels between type 2 diabetic patients with and without coronary artery disease, and no association of HbA1c with the number of diseased vessels was observed either. These findings suggest that determination of serum glycated albumin level may offer more substantial information regarding coronary vasculopathy in diabetic patients, compared to conventional HbA1c measurement. Multiple Logistic regression analysis revealed that serum glycated albumin level was an independent determinant for the development of coronary artery disease in type 2 diabetic patients. After adjusting for age and sex, a serum glycated albumin level ≥20% appeared to be a significant predictor of coronary artery disease in diabetes. When serum glycated albumin level was used as a continuous variable in the same model, it remained a significant predictor, indicating that for every 1.0% increase in serum glycated albumin level there was a 10% increase in the likelihood of coronary artery disease development in diabetic patients. Determination of serum glycated albumin level can be used as a surrogate measure of vascular complications in patients with type 2 diabetes,23,24 and may warrant glycated albumin assay a simple test for identifying the presence and severity of coronary artery disease in these patients.25,26 However, this study is flawed with its retrospective nature. Therefore, further prospective studies are needed to validate the clinical significance of glycated albumin measurement for screening coronary artery disease in asymptomatic patients with type 2 diabetes. Taken together, the prevalence of coronary artery disease in patients with type 2 diabetes is high enough such that a meaningful number of afflicted individuals should be identified. Many screening tests can accurately characterize low- and high-risk patients even they remain asymptomatic. Identification of asymptomatic type 2 diabetic patients with coronary artery disease should lead to treatment that improves clinical outcomes.