Type 1 Diabetes and Associated Cardiovascular Risk and Disease

Epidemiology of Type 1 Diabetes

Numerous multicenter epidemiologic studies such as the SEARCH for Diabetes in Youth study, ^, the EURODIAB study, ^, and the DIAMOND Project (World Health Organization Multinational Project for Childhood Diabetes) ^, report increases in T1D of 2% to 5% annually worldwide. The prevalence of T1D in youth younger than 20 years of age in the United States was estimated in the SEARCH study to be 2.28/1000 or over 150,000 youth with diabetes in the United States in 2001, the majority with T1D. Worldwide rates of T1D vary as expected because of variation in autoimmune system genetics, exposure to environmental triggers, and differences in survival from diagnosis of T1D and lifespan postdiagnosis as a result of differences in health care systems. These rapid and sustained increases suggest a cause that is environmental or related to a gene-environment interaction instead of genetic shifts. Multiple ongoing studies are investigating the cause of T1D to identify targets for prevention. ^, Such studies are likely long-term projects, barring dramatic scientific breakthroughs, highlighting the need to improve cardiovascular health for people with T1D. (See also Chapter 3 .)

Despite progress in clinical care and outcomes for patients with T1D, improvements in outcomes are urgently needed. ^, EURODIAB followed 28,887 children in 12 European countries and found a standardized mortality rate of 2.0. CVD was emphasized as the predominant cause for premature mortality in people with T1D in a report from the United Kingdom with a hazard ratio of 3.7 for annual mortality for people with T1D compared with the general population (8.0 versus 2.4/100,000 person-years). These data highlight the need for improved CVD health in patients with T1D; however, there is reason to believe that health outcomes for people more recently diagnosed with T1D will be superior, given that these data are based on historic outcomes before the widespread adoption of many of the current methods of care for T1D. For example, the Pittsburgh Epidemiology of Diabetes Complications (EDC) study findings reported that life expectancy for people with T1D diagnosed from 1965 to 1980 was 15 years longer than for those diagnosed from 1950 to 1964. The life expectancy of patients with T1D continues to improve ^, ; however, the average life expectancy remains reduced by approximately 20 years relative to the general population.

Rates of Cardiovascular Disease in Type 1 Diabetes

Increased rates of coronary heart disease (CHD) and death from CHD in T1D were reported in the 1970s. ^, The Pittsburgh Insulin-Dependent Diabetes Mellitus (IDDM) Morbidity and Mortality study reported a 10-fold higher rate of CHD mortality associated with type 1 diabetes mellitus (T1DM) as compared with individuals without diabetes in the United States, similar to a study from the Joslin Diabetes Clinic that reported a six-times higher rate of CHD by 55 years of age in people with T1D as compared with controls with use of Framingham study data. Among people diagnosed with diabetes who were younger than 30 years of age, the Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) reported a standardized mortality rate of 9.1 for men and 13.5 for women. More recent data from 23,751 people with insulin-treated diabetes diagnosed before 30 years of age continue to show increased standardized mortality rates for ischemic heart disease, with a markedly increased rate in women, who had rates of death from heart disease that were similar to those in men younger than 40 years with diabetes. The Pittsburgh EDC study has followed people with T1D (diagnosed from 1950 to 1980) for incidence of coronary artery disease (CAD) and has not detected decreases in CAD over time (stratified for T1D durations of 20, 25, and 30 years) despite decreases in mortality, neuropathy, and renal failure. Data from the large (N = 21,789) population-based Scottish Registry Linkage Study reported that the age-adjusted incidence rate ratio for CVD and mortality in patients with T1D compared with those without diabetes was 3.0 (95% confidence interval [CI] 2.4-3.8) for women and 2.3 (95% CI 2.0-2.7) for men. Moreover, the incidence rate ratio for all-cause mortality was elevated similarly for both women 2.7 (95% CI 2.2-3.4) and men 2.6 (95% CI 2.2-3.0). The authors concluded that despite improvement in risks for CVD and mortality for people with T1D, these rates continue to be higher than in the nondiabetic population and that CVD risk factor management needs to be improved, especially methods to achieve better glucose control.

Multiple risk factors for CVD in T1D exist, with glucose control considered to be the most likely factor accounting for increased risk as compared with nondiabetic controls. Despite a relatively small number of events compared with studies in patients with T2D, the DCCT and EDIC trials reported a 57% reduction in CVD in the intensively managed as compared with the conventional arm after 17 years of follow-up. Similarly, the Coronary Artery Calcification in Type 1 Diabetes (CACTI) study, a longitudinal study of atherosclerosis in 1416 young adults with and without T1D, reported an association of HbA1c with progression of coronary artery calcification (CAC), an intermediate marker of coronary atherosclerosis. However, data from epidemiologic studies on glucose control in T1D and CVD are inconclusive and have been the subject of review. The ADA recommends an ABC approach to CVD: In addition to glucose control (HbA1c or A), blood pressure (B) and cholesterol (C) are emphasized. Other modifiable CVD risk factors for people with T1D include kidney disease, obesity, insulin resistance, inflammation, and lifestyle factors such as smoking, diet, and exercise. Nonmodifiable CVD risk factors include genetics and family history and T1D duration. These are reviewed later in the chapter.

Specific Considerations for Cardiovascular Disease in Type 1 Diabetes: Age and Comparison with Type 2 Diabetes

T1D is frequently diagnosed in childhood, which includes the challenges associated with the physiologic changes of puberty. It has been well established by studies such as the Bogalusa Heart Study, the Muscatine study, the Pathobiological Determinants of Atherosclerosis in Youth (PDAY) study, and the Young Finns Study that atherosclerosis begins in youth and that the extent of atherosclerosis is associated with the presence and extent of CVD risk factors. These studies also demonstrate tracking of CVD risk factors from childhood into adulthood and argue for earlier attention to CVD risk. Therefore, primary prevention of CVD and attention to CVD risk factors has gained increased attention in the past decade. For example, the ADA, the AHA, the American Academy of Pediatrics (AAP), and the International Society for Pediatric and Adolescent Diabetes (ISPAD) have all published guidelines for CVD health in youth with T1D; Figure 11-1 shows the AHA guidelines for risk stratification and treatment. One such example of these includes thresholds for pharmacologic treatment of dyslipidemia and goals for lipids, although these are not based on randomized trials assessing CVD outcomes. Age- and gender-specific normal and abnormal values linked to the National Cholesterol Education Program—Adult Treatment Panel III (NCEP-ATP III) lipoprotein thresholds have also been calculated using National Health and Nutrition Examination Survey (NHANES) data that recognize physiologic variations seen with pubertal development. Additional considerations for CVD risk factors in the pediatric diabetes population that have raised concerns about treatment include costs, lack of outcome data, potential life-long treatment, and adverse effects. Arguments for treatment include the tracking of CVD risk factors levels from childhood into adulthood, extensive data in adults on the benefits of lowering CVD risk factors to prevent CVD in adults with T1D, and the association of CVD risk factors with intermediate markers of atherosclerosis ( Table 11-1 ).

In adults, recommendations for CVD risk modification in T1D continue to evolve. For adults, NCEP-ATP III considers diabetes to be a CHD risk equivalent and therefore uses goals for low-density lipoprotein cholesterol (LDL-C) and non–high-density lipoprotein cholesterol (HDL-C) of below 100 mg/dL (optional < 70) and below 130 mg/dL (optional < 100), respectively. The most recent joint position statement from the ADA and AHA does not distinguish CVD risk between T1D and T2D, citing a lack of evidence to do so. As additional data accumulate, specific recommendations for adults with T1D will evolve. The recent ADA-AHA Scientific Statement on CVD in T1D summarizes the relative association of specific CVD risk factors and CVD events in T1D versus T2D ( Table 11-2 ), including that women with T1D are equally affected as men with T1D, unlike in T2D, in which men have increased rates of CVD.

Cardiovascular Disease Pathophysiology in Type 1 Diabetes

The recent ADA-AHA Scientific Statement calls for additional research into the differences in the atherosclerotic process between T1D and T2D, although a summary of available data follows. A small study found similar CAC scores in T1D and T2D patients, but more obstructive lesions, more noncalcified lesions, and more lesions in general in T2D compared with T1D patients. An earlier small study reported less atherosclerosis in T1D versus T2D patients. Angiographic studies suggest more severe stenoses and more extensive involvement in people with T1D compared with those without diabetes, and another reported more severe distal disease with an approximately four times higher burden of atherosclerosis. An autopsy study in T1D reported plaques were soft and fibrous with a more concentric location. These studies were generally small and may not be representative of the T1D population. The nature of plaque in T1D is less well studied than in T2D, but the plaque may be more calcified and fibrotic and contain less lipid. More studies using techniques such as intravascular ultrasound and postmortem studies are needed.