Epidemiology of Acute Coronary Syndromes in Patients with Diabetes

Global Burden of Cardiovascular Disease and Diabetes

Cardiovascular diseases are the number one cause of death worldwide. In 2008, approximately 17.3 million people died from cardiovascular disease, accounting for approximately one third of all deaths; an estimated 7.3 million were caused by coronary heart disease and another 6.2 million by stroke. Until recently, cardiovascular diseases were more frequent in the developed countries, but during the past years low- and middle-income countries have been disproportionally affected. According to the 2010 Global Status Report of the World Health Organization on noncommunicable diseases, over 80% of cardiovascular disease deaths take place in low- and middle-income countries, with no differences between men and women, predominantly as a result of ischemic heart disease ( Fig. 19-1 ). Furthermore, the number of people who die from cardiovascular diseases will increase to reach 23.3 million by 2030; ischemic heart disease will remain the single leading cause of death in 2030 ( Fig. 19-2 ).

The most important behavioral risk factors of cardiovascular diseases are unhealthy diet, physical inactivity, and tobacco use. These may contribute to raised blood pressure, abnormal blood lipids, raised blood glucose, and overweight and obesity. The increasing frequencies of obesity and sedentary lifestyles—major risk factors for the development of type 2 diabetes, in both developed and developing countries—will further contribute to diabetes being a growing clinical and public health problem worldwide.

The International Diabetes Federation (IDF) reports that 371 million people had diabetes in 2012 (see also Chapter 1 ). The worldwide prevalence of diabetes was 8.4% in the population aged 20 to 79 years, including an estimated 50% (29.2% to 81.2%) of whom had undiagnosed diabetes; there were large differences in prevalence and proportions diagnosed among different regions and countries worldwide ( Fig. 19-3 ).

In 2012, 4.8 million people died from complications of diabetes mellitus. In the ranking of causes of death, diabetes will move from rank 11 in the year 2002 to rank 7 in 2030 ( Table 19-1 ).

INTERHEART, a large-scale standardized, case-control study involving 15,152 patients with acute myocardial infarction and 14,820 controls, examined the relationship between important cardiovascular risk factors, such as hypertension, diabetes mellitus, and lifestyle, and myocardial infarction in 52 countries worldwide. The study identified diabetes mellitus to be associated with a more than doubled adjusted odds for the development of myocardial infarction (odds ratio [OR] 2.37, 95% confidence interval [CI] 2.07-2.71) for the overall population after adjustment for all other risk factors.

In a population-based study in Denmark, all 3.3 million inhabitants at least 30 years of age and older were identified through the Danish Civil Registration System and followed for 5 years from 1997 to 2002 by individual-level linkage of nationwide registers to estimate cardiovascular risk associated with diabetes mellitus. Diabetes patients receiving glucose-lowering medications and individuals without diabetes, both with and without prior myocardial infarction, were compared. Regardless of age and sex the hazard ratios (HRs) for cardiovascular death were as high in patients with diabetes mellitus without prior myocardial infarction as in nondiabetic patients with prior myocardial infarction (HR in men 2.42 and 2.44, respectively, and P = 0.60; HR in women 2.45 and 2.62, respectively, and P < 0.001; Fig. 19-4 ). Based on these data, diabetes mellitus might be seen as a coronary artery disease risk equivalent. The incidence rates of myocardial infarction during the 5 years of follow-up in this study in men and women with diabetes and without prior myocardial infarction were 7.3% and 6.9%, respectively; for those with diabetes and prior myocardial infarction, the incidence rates were 23.7% and 25.0%, respectively ( Table 19-2 , Fig. 19-5 ).

Further population-based studies with long-term follow-up describing the prevalence of acute coronary syndromes (ACSs) in patients with diabetes are lacking. Available data on patients with diabetes are heterogeneous, because diabetic patients with a long duration of the disease have a different cardiovascular risk than patients with shorter disease duration. The type of diabetes treatment—that is, insulin versus noninsulin—also correlates with risk for ACS, most likely reflecting differences in underlying disease severity. In the ideal setting, information regarding the long-term risk of a patient with newly diagnosed diabetes mellitus for coronary artery disease and its complications would be desirable, but data on the long-term risk of cardiovascular events for patients with new onset of diabetes are scarce. This information could be obtained only if patients were prospectively followed from the time of their first diagnosis of diabetes mellitus. In theory, such an approach would be possible in countries where civil registration systems can be matched with, for example, prescription registries, allowing the identification of patients in whom glucose lowering treatment has been initiated.

Although population-based studies on the prevalence of ACSs in patients with diabetes are scarce, data from randomized controlled trials (RCTs) as well as from prospective observational studies such as surveys and registries in the ACS setting provide some further insights.

Diabetes in Randomized Controlled Trials and Registry Studies of Acute Coronary Syndromes

RCTs are considered to provide the highest level of evidence for recommendations in scientific treatment guidelines. Ideally, they should be representative of the clinical population covered by the guideline recommendation. However, by nature, RCTs often exclude elderly patients and patients with certain comorbidities such as renal impairment and therefore lack generalizability of the study results to the real-world setting. For example, Steg and colleagues compared patients with acute myocardial infarction enrolled in the Global Registry of Acute Coronary Events (GRACE) who had participated in a randomized trial, those who were trial eligible but who were not enrolled, and those who were ineligible. Patients who were enrolled in RCTs had a lower baseline risk and a lower mortality than patients who were not enrolled, even when they were trial eligible. Based on this analysis, the authors advised caution regarding extending the findings obtained in RCTs to the general population with acute myocardial infarction. In a review about the importance of translating data from randomized trials and registries into clinical information, Brown and colleagues deplored that results of observational studies are often dismissed in favor of prospective randomized trials.

Prospective observational studies provide an unprecedented opportunity to at least estimate the epidemiology of diseases and the varying use of management strategies, as well as their outcomes, in consecutive patients in clinical practice. Data are gained from a “real-world” selection of patients, many of whom would be excluded from RCTs, in a variety of clinical settings. In RCTs of ACS, the number of patients with diabetes is generally lower than in observational studies of ACS. This may be because of older age and a higher prevalence of comorbidities such as renal impairment in patients with diabetes, which may lead to exclusion from RCTs. In 11 RCTs of the Thrombolysis in Myocardial Infarction (TIMI) Study Group evaluating ACS treatment, only 17.1% of the study population had diabetes, as compared with 25% in the GRACE registry. Surveys and registries also help to verify that real-life daily practice is in keeping with what is recommended in the guidelines, thus completing the loop of performing clinical research, writing guidelines, and implementing the guidelines into clinical practice. Observational studies form the basis of an important part of the medical knowledge we have today and are complementary to RCTs. In the field of ACS, a plethora of national and international observational studies exist, such as GRACE, the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative, and the Euro Heart Survey ACS registry ; these studies describe the prevalence of diabetes and its impact on treatment patterns and outcomes in the real-world setting.