Summary

Heart disease remains a major cause of morbidity and mortality in type 2 diabetes and is estimated to account for 10%–11% of all vascular deaths. Surveys of the U.S. population have demonstrated an age-standardized differential for heart disease in adults with mostly type 2 diabetes that varies from 1.9 to 2.5. The age-standardized prevalence is about 50% higher in men than women overall and for most categories of heart disease, except congestive heart failure. Although rates of diabetes are higher in nonwhites than in non-Hispanic whites, it should be noted that non-Hispanic whites with diabetes generally report heart disease rates about 50% higher than Hispanic subjects with diabetes, with an intermediate prevalence in non-Hispanic blacks. Despite an approximate doubling in type 2 diabetes prevalence from the 1980s to the 2010s, the prevalence of heart disease in diabetes has remained stable.

Classic heart disease risk factors, such as elevated low-density lipoprotein (LDL) cholesterol, blood pressure, reduced high-density lipoprotein (HDL) cholesterol, and smoking, have been clearly demonstrated to be important determinants of heart disease in diabetes. However, several studies, including a very large, multinational meta-analysis, indicate that the excess prevalence of heart disease in diabetes is not accounted for by measured classic cardiovascular disease (CVD) risk factors, including levels of triglyceride, HDL cholesterol, non-HDL cholesterol, C-reactive protein, fibrinogen, and renal function. In addition, novel biomarkers have not been found to add significance in prediction of heart disease. The association between fasting glucose and heart disease displays a J-shaped curve in several studies, indicating that the risk for heart disease in subjects with fasting plasma glucose 100–125 mg/dL is only modestly elevated compared to the twofold higher risk in those with values ≥126 mg/dL, the current cut point for diagnosis of type 2 diabetes. Glycosylated hemoglobin (A1c) has also been shown to have a graded association with heart disease. The association between insulin resistance and heart disease is inconsistent, at least in part because of methodologic differences among studies. Furthermore, these studies may be complicated by cross-reactivity with proinsulin, which is a marker for beta cell failure and may be more strongly associated with heart disease than insulin levels. Obesity is the most important risk factor for type 2 diabetes but has not been shown to have an independent association with heart disease. Although similar associations with heart disease have been found for body mass index and waist measurements in a large meta-analysis of general population cohort studies, these were lost after adjustment for other risk factors, possibly because obesity is in the causal pathway between these risk factors and heart disease development. Similarly, conflicting data have been reported as to whether the presence of the metabolic syndrome in subjects with diabetes is independently associated with heart disease. In contrast to body weight, physical inactivity in those with diabetes appears to have an independent association with heart disease.

Clinical trials involving risk factor modification in diabetes have helped to clarify their roles in heart disease development, as well as the benefits and limitations of modern treatment modalities for diabetes and its complications, and have led to significant modification in treatment guidelines. Whether improvement of glycemic control reduces heart disease has long been a central question, since older trials had not demonstrated benefit. However, extended follow-up of earlier studies of improved glycemic control in both type 1 and type 2 diabetes have demonstrated a long-term so-called “legacy” benefit for heart disease, not immediately evident after completion of the active intervention phase. Intervention trials testing intensive versus standard glycemic control, however, have found no evidence of benefit of improved glycemic control on cardiovascular outcomes. In one of these trials, cardiovascular and all-cause mortality increased in the intensive control group, while a meta-analysis of 13 trials of intensive glycemic control found no significant impact on all-cause mortality. Severe hypoglycemia, longstanding diabetes, and preexisting heart disease appeared to contribute to the increased mortality and the lack of benefit for intensive glycemic control, and post hoc analyses suggested that this intervention may be most effective in more recently diagnosed subjects. With respect to lipid-lowering clinical trials, by contrast, studies have shown unequivocally that statin treatment, in both secondary as well as primary prevention trials, significantly reduces heart disease with a similar risk reduction to that seen in nondiabetic subjects. However, fenofibrate given as monotherapy or as add-on therapy to simvastatin does not confer heart disease benefit in diabetes, except possibly in the subgroup with high triglyceride and low HDL cholesterol levels. While older trials of blood pressure lowering demonstrated benefit, a more recent large trial of intensive blood pressure control did not find that achieving a lower goal leads to a reduction in cardiovascular events overall, although ischemic stroke incidence was decreased. Several trials were unable to demonstrate a significant benefit for low-dose aspirin as primary preventive therapy in diabetes. Finally, although there have been few studies of comprehensive risk factor management, one small, long-term trial was highly successful in reducing cardiovascular events by intensive glycemic blood pressure and LDL cholesterol control. In addition, a meta-analysis of physical activity trials in patients with diabetes showed a reduction in myocardial infarction and all-cause mortality. However, a large 10-year clinical trial focusing on weight reduction in people with diabetes through an intensive lifestyle change program showed no cardiovascular benefit despite improvement in risk factors.

In conclusion, despite intensive management of risk factors, the high risk for heart disease among people with diabetes remains a major health concern.

Introduction

Although coronary heart disease (CHD) is the major cause of morbidity and mortality in patients with type 2 diabetes, historically the diabetes-CHD association received little systematic study, even after the publication of Kelly West’s monumental book Epidemiology of Diabetes Mellitus and Its Vascular Lesions (1) and the development of standard World Health Organization (WHO) (2) and National Diabetes Data Group (3) criteria for the definition of diabetes in the 1980s.

According to the Centers for Disease Control and Prevention (4), the proportion of diabetes in the United States that is type 1 is 5%, and type 2 diabetes accounts for 90%–95%. The epidemiology and etiology of type 1 (insulin-dependent) diabetes has been reviewed (5) and is described in detail in Chapter 2 Prevalence and Incidence of Type 1 Diabetes Among Children and Adults in the United States and Comparison With Non-U.S. Countries. Although type 1 diabetes carries a cardiovascular disease (CVD) mortality risk similar to type 2 diabetes (6), this chapter mainly addresses type 2 diabetes, citing papers reporting fasting plasma glucose (FPG) or diabetes by history.

The literature on the association between diabetes and CVD has increased exponentially since Diabetes in America, 2nd edition, was published in 1995 (7). In this chapter, each section usually starts with a review and, whenever possible, concludes showing a large systematic review or meta-analysis that addresses each topic. In order to improve generalizability and statistical power, no attempt was made to exclude prospective studies done outside the United States, which were included in these meta-analyses. Point estimates are provided from each cohort study. Unless otherwise noted, individuals in most cohort studies were of European or Scandinavian ancestry and about one-third of cohorts were from the United States.

Diabetes is clearly an established risk factor for CHD (8,9), but how much its effect varies by age, sex, or levels of conventional risk factors is uncertain (10,11). Key risk factors characteristic of diabetes are discussed, specifically hyperglycemia; dyslipidemia (elevated triglycerides and low high-density lipoprotein [HDL] cholesterol); hypertension; components of the metabolic syndrome; central obesity; insulin (hyperinsulinemia); biomarkers, such as C-reactive protein; lack of physical activity; and smoking. Hypertension, or high blood pressure, is usually included in discussions of the metabolic syndrome but does not cluster with metabolic syndrome components in factor analysis. Nevertheless, hypertension is the most common risk factor in adults with diabetes and is clearly a risk factor for heart disease and stroke. The extent to which diabetes is associated with fatal versus nonfatal myocardial infarction is also unknown (12,13). Further, how much of the effect of diabetes on vascular risk can be accounted for by conventional vascular risk factors (dyslipidemia, hypertension, obesity, smoking) is unresolved (14). Different uncertainties apply regarding the best measures of dysglycemia in people without diabetes. FPG has been reported to be log-linearly and importantly associated with risk of vascular disease at all concentrations, including below the classic fasting threshold for diabetes of 126 mg/dL (6.99 mmol/L). Available data on this topic are inconclusive (15,16). In 2009, the U.S. Preventive Services Task Force stated that prospective data for FPG concentration and CHD were inconsistent and had serious limitations (17).

Figure 18.1 shows study-specific hazard ratios (HR) for CHD in people with diabetes at baseline compared with people without diabetes (18). The overall summary risk estimates from the Forest plot indicate that the overall effect is an approximate doubling of risk of CHD among those with diabetes compared to those without diabetes. Regression analyses were stratified, where appropriate, by sex and trial group and adjusted for age, smoking status, body mass index (BMI), and systolic blood pressure. Studies are ordered (top to bottom) by increasing number of CHD cases. Sizes of data markers are proportional to the inverse of the variance of the hazard ratios. The data sources shown in this Forest plot reveal the heterogeneity of associations by cohort.

Obesity is increasing steadily worldwide, especially in industrializing countries (19). In the United States, the prevalence of obesity defined by a BMI ≥30 kg/m² is 30%–35% in both middle-aged (40–59 years) and older adults (≥60 years) (20).

FIGURE 18.1

Study-Specific Hazard Ratios for Coronary Heart Disease in People With Diabetes at Baseline Compared to People Without Diabetes. Regression analyses were stratified, where appropriate, by sex and trial group, and adjusted for age, smoking status, body (more...)

Losing weight is difficult, and interventions that work in younger adults cannot be assumed to successfully translate into an older population, where low muscle mass, physical frailty, osteoporosis, comorbid disease, and cultural differences may increase risk. Sustained weight loss may be required to produce meaningful changes in health outcomes, particularly for CVD.

The clinical trial evidence is reviewed for interventions designed to produce healthy changes in heart disease risk factors and reduce heart disease comparing adults with or without diabetes.

Prevalence of Heart Disease in U.S. Diabetic Versus Nondiabetic Persons: U.S. Survey Estimates

In new analyses conducted for Diabetes in America, 3rd edition, nationally based surveys of the U.S. population consistently demonstrate that the prevalence of heart disease (no matter how defined) is higher among adults with diabetes than adults without diabetes (Tables 18.1–18.4, Appendices 18.1–18.4). In both adults with and without diabetes, the prevalence of heart disease increases with age (Figure 18.2). The age-standardized differential for overall heart disease (ratio in persons with diabetes to those without) varies from 1.9 to 2.5, reflecting the different heart disease conditions included in each survey: 29.7% versus 16.4% for the National Health Interview Survey (NHIS), 22.4% versus 9.4% for the National Health and Nutrition Examination Survey (NHANES), and 15.3% versus 6.2% for the Behavioral Risk Factor Surveillance System (BRFSS), for those with and without diabetes, respectively. National data based on hospital discharges demonstrate similar trends, but with a lower differential between adults with and without diabetes (Table 18.4, Appendix 18.4).

Examination of these national surveys demonstrates that the age-standardized prevalence of heart disease is consistently higher among men than women, both among those with and without diabetes (Tables 18.1–18.4, Appendices 18.1–18.4). The only exception was congestive heart failure in the NHANES 2007–2010 where prevalences were similar in men and women. These tables also demonstrate substantial variation in the age-standardized prevalence of heart disease among race/ethnicity groups. American Indians/Alaska Natives reported the highest rates of CHD or angina and heart attack or myocardial infarction in the BRFSS 2010. For the NHIS and NHANES (which did not have sufficient numbers of American Indian/Alaska Native respondents to report separately), non-Hispanic whites generally reported the highest rates. However, non-Hispanic blacks in the NHANES reported more heart failure than other race/ethnicity groups.

FIGURE 18.2

Prevalence of Coronary Heart Disease, by Diabetes Status, Age, and Sex, U.S., 2009–2010. Coronary heart disease and diabetes status are self-reported.

FIGURE 18.3

Trends in the Age-Standardized Prevalence of Obesity, Diabetes, and Heart Disease Among Adult Women Age 20–74 Years, U.S., 1976–2010. Obesity is defined as body mass index ≥30 kg/m². Diabetes is defined as self-report and/or A1c (more...)

FIGURE 18.4

Trends in the Age-Standardized Prevalence of Obesity, Diabetes, and Heart Disease Among Adult Men Age 20–74 Years, U.S., 1976–2010. Obesity is defined as body mass index ≥30 kg/m². Diabetes is defined as self-report and/or A1c (more...)

TABLE 18.1

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race/Ethnicity, NHIS, U.S., 2009–2010.

TABLE 18.2

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥20 Years, by Diabetes Status, Sex, and Race/Ethnicity, NHANES, U.S., 2007–2010.

TABLE 18.3

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race/Ethnicity, BRFSS, U.S., 2010.

TABLE 18.4

Age-Standardized Percent of Hospitalizations Listing Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race, NHDS, U.S., 2010.

While the above variations in the prevalence of heart disease are consistent with those described in Diabetes in America, 2nd edition (7), large secular trends have been noted from the 1970s to the 2010s. Figures 18.3 and 18.4 present prevalences of obesity, diabetes, and heart disease for women and men, respectively, from four different NHANES time periods covering 1976–2010. Over this time, the prevalence of obesity increased dramatically, from 17% to 37% in women and 12% to 34% in men. Over this same period, the prevalence of self-reported diabetes also increased from 4% to 7% in women and 3% to 8% in men, a similar percent increase as for obesity. However, the prevalence of heart disease remained stable or declined for both sexes. This finding was also true when men and women with and without diabetes were examined separately; however, estimates in men or women with diabetes were unstable due to smaller sample sizes (data not shown). Although heart disease prevalence has been stable, population attributable risk (PAR, here defined as the number of cases of heart disease that would not occur if diabetes could be eliminated) may not have been. In other words, the prevalence of heart disease has remained stable, even though the prevalence of diabetes has increased—that is, the association between diabetes and heart disease has decreased, and the PAR has declined.

One limitation of much national survey data is the reliance on self-reported diabetes and heart disease. However, as seen in Figures 18.3 and 18.4, the prevalence of diabetes based on FPG and glycosylated hemoglobin (A1c) levels has demonstrated the same trends as self-reported data over the last three survey time periods. Therefore, the reported variations by age, sex, and race/ethnicity are likely real.

Risk Factors for the Development of Coronary Heart Disease in Persons With Diabetes

The Metabolic Syndrome

The classic metabolic syndrome includes five CVD risk factors that are more common in individuals with diabetes than in those without. Five key factors were described in 1992 by Bierman (46), who recognized that almost all potentially modifiable CVD risk factors (except cigarette smoking and total cholesterol) were associated with diabetes. The initial choice of the components—hypertension, high triglycerides, low HDL cholesterol levels, waist girth or waist-to-hip ratio, and in some definitions, high insulin levels or diabetes—was logical, but the cut points defining normality were arbitrary.

There are important differences in recommended diagnostic criteria for the metabolic syndrome (Table 18.5). The National Cholesterol Education Program (Adult Treatment Panel III) (NCEP) defined the metabolic syndrome as the presence of three or more of five components (47). In 2005, the International Diabetes Federation (IDF) considered that central obesity was a requirement for the diagnosis of the metabolic syndrome along with any two other features (48). In contrast, the WHO criteria stated that glucose intolerance or type 2 diabetes together with two other features is a sine qua non for a metabolic syndrome diagnosis (49). The NCEP, IDF, and WHO definitions have all been shown to predict incident type 2 diabetes and CVD. However, limited data are available to assess which of these definitions best predicts diabetes or heart disease (50,51). Although laboratory features, such as increased C-reactive protein, raised alanine aminotransferase, hyperuricemia, and microalbuminuria, are common in the presence of the metabolic syndrome, they are not included in metabolic syndrome diagnostic criteria.

Controversy over the scientific basis for the definition of this cluster of risk factors stems from the arbitrariness of the included (and excluded) variables and their cut points, the loss of risk prediction when continuous risk factors are categorized, and the unproven assumption that there is a single underlying biology (52,53). Nevertheless, the metabolic syndrome is a commonly used phenotype for clinicians, drawing attention to the importance of previously neglected risk factors, such as central obesity and elevated triglycerides, and to the potential importance of interventions when modest elevations in risk factors occur together (54).

Cohort studies from Italy (55), Finland and Sweden (56), and the United States (57) have shown that adults with a combination of at least three metabolic syndrome risk factors have more than a threefold increased risk of CVD.

In the Kuopio Ischemic Heart Study, the increased CVD risk associated with the metabolic syndrome occurred in the absence of diabetes (58). In contrast, the NHANES II Mortality Study, a cohort study of a representative sample of adults in the United States, did not find that the metabolic syndrome significantly increased the risk of heart disease when participants with diabetes were excluded (59). In the NHANES, the metabolic syndrome was inferior to established risk factor models like the Framingham CVD risk score for either type 2 diabetes or CVD (60).

TABLE 18.5

Metabolic Syndrome Definitions.

Clinical Trials: Control of Glycemia or Other CVD Risk Factors and CVD Risk

Summaries of major trials involving glycemic, lipid, blood pressure, anti-platelet, and lifestyle management are shown in Tables 18.6–18.10. The following text highlights the results and interpretation of these trials. This section also provides systematic reviews of published clinical trials where available.

Extensive epidemiologic evidence documents the direct relation of diabetes with CHD and CVD (Tables 18.1–18.4, Appendices 18.1–18.4). In a meta-analysis comprising 9,123 persons with diabetes from 13 observational studies, Selvin et al. (103) showed a pooled relative risk of CVD in those with type 1 diabetes of 1.15 (95% CI 0.92–1.43) and type 2 diabetes of 1.18 (95% CI 1.10–1.26) for each 1% increase in A1c. Using NHANES III data from 19,025 adults, Saydah et al. (104) reported A1c ≥8% (≥64 mmol/mol) versus <6% (<42 mmol/mol) was associated with a hazard ratio of 3.38 (95% CI 1.98–5.77) for CVD mortality.

These observational epidemiologic studies suggested a direct relation of extent of glycemic control with risk of CHD and CVD events and promoted interest in examining whether intensive glycemic control in a randomized clinical trial setting is associated with reductions in future CHD or CVD events. The potential roles of intensive blood pressure control, lipid modification, antiplatelet therapy, multiple risk factor control, and lifestyle management in reducing CVD event risk have been the subject of a number of clinical trials in the prediction or prevention of diabetes.

Trials of Intensive Glycemic Control

Diabetes Control and Complications Trial/Epidemiology of Diabetes and Interventions and Complications Study

The Diabetes Control and Complications Trial (DCCT) (105) examined whether intensive versus conventional control of glucose with insulin therapy (accomplishing mean A1c levels of approximately 7% [53 mmol/mol] vs. 9% [75 mmol/mol], respectively) would reduce development or progression of microvascular complications in 1,441 patients with type 1 diabetes (Table 18.6). Substantial reductions were observed in the development or progression of retinopathy, microalbuminuria, albuminuria, and clinical neuropathy within the intensive glycemic control group. While 41% fewer CVD events occurred in the intensively treated individuals, these results did not achieve statistical significance, possibly due to the small number of events in this relatively young population. DCCT participants continued to be followed in the Epidemiology of Diabetes Interventions and Complications (EDIC) study; after 11 years, when the differences in A1c between the groups had disappeared, the rate of CVD complications continued to diverge, indicating a possible “metabolic memory” from earlier glycemic control. The extended follow-up showed 46 CVD events among 31 patients in the intensive control group compared to 98 events in 52 patients in the conventional control group, with a statistically significant 42% reduction in events (p=0.02) (106).

United Kingdom Prospective Diabetes Study

The UKPDS tested the hypothesis that intensive glycemic control could reduce CVD disease in persons with type 2 diabetes. A group of 3,867 patients with newly diagnosed type 2 diabetes was randomized to treatment with sulfonylureas or insulin compared to diet alone (107). Mean A1c levels of 7.0% and 7.9% (63 mmol/mol) in the intensive versus standard glycemic control groups, respectively, were obtained, and microvascular events were reduced by 21%–34%. The combined incidence of nonfatal myocardial infarction and sudden death did not reach statistical significance (16% risk reduction, p=0.052), although the randomized substudy of overweight patients did show metformin therapy significantly reduced CVD events (108). The results of the 10-year post-trial follow-up showed loss of the A1c differences between groups, that microvascular event reduction of 24% (p=0.001) between the groups persisted, and a statistically significant reduction in myocardial infarction (15%, p=0.01) and all-cause mortality (21%, p=0.01) emerged. Even greater reductions in myocardial infarction and all-cause mortality were seen in the overweight, metformin-treated subjects (33% and 27%, respectively) (109). These results add to those of the DCCT/EDIC in type 1 diabetes patients in supporting a long-term glycemic legacy effect from the on-trial intensive glycemic control strategy, at least in those with primarily uncomplicated, shorter duration diabetes as was the case for the DCCT and UKPDS.

TABLE 18.6

Clinical Trials of Intensive Glucose Control on Cardiovascular Disease Risk.

Action to Control Cardiovascular Risk in Diabetes; Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; Veterans Affairs Diabetes Trial; and Outcome Reduction With Initial Glargine Intervention Trials

In light of the continued uncertainty of the effects of intensive glycemic control on macrovascular outcomes in patients with type 2 diabetes, these four trials more formally tested this hypothesis, employing an even more intensive glucose target of A1c <6.0% compared to 7.0%–7.9% in the conventional control groups over 3.5 years. Patients enrolled in these studies had more advanced diabetes of longer duration than the earlier studies, many with prior macrovascular disease.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) (110), 10,251 patients were enrolled with a mean baseline A1c of 8.3% (67 mmol/mol) and mean age of 62 years. The Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) (111) had slightly older patients (mean age 66 years) but with a lower mean A1c (7.5% [58 mmol/mol]), and the Veterans Affairs Diabetes Trial (VADT) cohort (112) had the youngest average age (60 years) but the highest baseline A1c (9.4% [79 mmol/mol]). All three trials failed to show benefit in cardiovascular outcomes, and while ACCORD showed a reduction in nonfatal myocardial infarction of 24% (p=0.004), both cardiovascular and all-cause mortality (HR 1.22, p=0.04) were actually increased. In the VADT, severe hypoglycemia was the strongest predictor of CVD mortality. In contrast, a subsequent analysis of ACCORD showed CVD deaths occurred in those who did not respond to the intensive therapy (113). A post hoc subgroup analysis of ACCORD and ADVANCE showed those without preexisting macrovascular disease did benefit, experiencing fewer CVD events. These observations are consistent with the hypothesis of lack of benefit of intensive glycemic control among those with prolonged, more advanced diabetes who have known macrovascular disease and support the concept that intensive glycemic control may benefit less complicated, more newly diagnosed persons with diabetes who have not had longstanding poor glycemic control and more advanced diabetes. Further, in those with more advanced diabetes, it may be difficult to realize benefit from intensive glycemic control initiated many years after initial diagnosis of diabetes.

Finally, the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial tested the effects of normalizing FPG in 12,537 individuals with CVD risk factors plus either IFG, impaired glucose tolerance, or type 2 diabetes. Subjects who were randomized to either insulin or standard care (and to n-3 fatty acids or placebo) showed no difference in cardiovascular events between the two groups (114).

Changes to Glycemic Goal. The findings from these trials led in part to a 2013 revision in the ADA guidelines for glycemic control, where A1c <8% is considered acceptable for those with more complicated type 2 diabetes, such as when accompanied by macrovascular disease, with a goal of <7% still reasonable for those with shorter duration diabetes and with uncomplicated diabetes (115). Because it is possible that the early follow-up of 5 years was too short to show reduced mortality, in 2010, the ADA recommended tighter glucose control in patients with recently diagnosed diabetes, long life expectancy, and no significant CVD (116). A working group report on hypoglycemia and diabetes commissioned by the ADA and the Endocrine Society concurred that a A1c goal of <7% is appropriate for newly diagnosed or less complicated diabetes, with less stringent goals for those with more complicated diabetes (117). The report noted that while hypoglycemia was associated with an increased risk of death in ACCORD, ADVANCE, and VADT, its effects on other diabetic complications make it difficult to establish risk and benefits with respect to these complications. The importance of patient education, dietary and exercise modifications, careful glucose monitoring, medication adjustment, and careful surveillance by the clinician in preventing hypoglycemic episodes was emphasized.

In 2011, Boussageon et al. (118) published a meta-analysis of 13 randomized clinical trials to determine whether all-cause mortality and deaths from cardiovascular events were associated with intensive glucose-lowering treatment in people with type 2 diabetes. The quality of the clinical trials was assessed by the Jadad score. Of 34,533 patients, 18,315 received intensive glucose-lowering treatment, and 16,218 received standard treatment. Intensive treatment did not significantly alter all-cause mortality (risk ratio 1.04, 99% CI 0.91–1.19) or cardiovascular death (risk ratio 1.11, 95% CI 0.86–1.43). Intensive therapy was associated with reductions in the risk of nonfatal myocardial infarction (risk ratio 0.85, 95% CI 0.74–0.96, p<0.001) and microalbuminuria (risk ratio 0.90, 95% CI 0.85–0.96, p<0.001) but caused a more than twofold increase in the risk of severe hypoglycemia (risk ratio 2.33, 95% CI 1.62–3.36, p<0.001). The authors calculated that 117–150 patients would need to be treated over a period of 5 years to prevent one myocardial infarction, whereas one severe episode of hypoglycemia would occur in every 15–52 patients. In an analysis restricted to high-quality studies (Jadad score >3), intensive treatment was not associated with any significant risk reductions but resulted in a 47% increase in risk of congestive heart failure (p<0.001) (118).

Another systematic review considered the quality and agreement of 11 current English language guidelines for oral diabetes medications applied in the United States, United Kingdom, and Canada (119). Ten guidelines agreed that thiazolidinediones are associated with higher rates of edema and congestive heart failure compared with other oral diabetes medications. Seven guidelines agreed that metformin is the favored first-line oral agent.

A different question is whether glucose control improves outcomes in hospitalized diabetes patients who had an acute myocardial infarction and who were seen in an intensive care unit and required prolonged ventilator support or coronary artery bypass surgery (120,121,122,123,124). The Normoglycemia in Intensive Care Evaluation–Survival Using Glucose Algorithm Regulation (NICE SUGAR) Study, the largest in-patient glucose control study to date, was designed to confirm whether intensive control (glucose 81–108 mg/dL [4.50–5.99 mmol/L]) improves outcomes compared with usual care (glucose <180 mg/dL [<10.00 mmol/L]). In this study, the intensive glucose criterion group treated with insulin had increased incidences of severe hypoglycemia and 90-day mortality (125). These results led to modification of the then-current consensus guidelines by the ADA and the American Association of Clinical Endocrinologists, which were revised to recommend a target glucose of 140–180 mg/dL (7.77–10.00 mmol/L) for the majority of critically ill patients and pre-meal and random blood glucose targets <140 mg/dL and <180 mg/dL, respectively, in all hospitalized patients (126).

Cardiovascular Outcomes Trials of Newer Glucose-Lowering Agents

Since 2015, results of several key cardiovascular outcomes trials of newer glucose-lowering agents have been reported. The first of these was the EMPA-REG trial (127) of patients with diabetes and prior cardiovascular disease involving the sodium glucose transporter-2 (SGLT2) inhibitor empagliflozin. The trial showed a significant 14% relative risk reduction in the composite cardiovascular endpoint, with greater reductions in death from cardiovascular causes (38%), hospitalization for heart failure (35%), and death from all causes (32%) compared to usual care and placebo. To further demonstrate whether the EMPA-REG findings were a class effect, other SGLT2 inhibitor cardiovascular trials, Canagliflozin Cardiovascular Assessment (CANVAS) trial with canagliflozin (128), Dapagliflozin Effect on Cardiovascular Events (DECLARE) trial with dapagliflozin (129), and Cardiovascular Outcomes Following Ertugliflozin Treatment in Type 2 Diabetes Mellitus Participants With Vascular Disease (VERTIS CV) trial with ertugliflozin (130), are in progress. These trials will help demonstrate the extent to which any cardiovascular benefits may be due to changes in other risk factors beyond the effects on glycemic control. The Evaluation of Lixisenatide in Acute Coronary Syndrome (ELIXA) trial (131) of subjects with diabetes and a prior myocardial infarction or unstable angina involved the glucagon-like peptide-1 receptor antagonist (GLP-1 RA) lixisenatide, a derivative of exenatide. This trial did not show benefit (HR 1.02 for a composite endpoint of major adverse cardiovascular events [cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke]) from the relatively short 25-month median follow-up. But in the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (132) involving 3.8 years median follow-up, there was a significant 13% reduction in the composite cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and stroke) and a reduction of cardiovascular mortality with the GLP-1 RA liraglutide compared to placebo. Liraglutide, unlike lixisenatide, has nearly 100% homology to human GLP-1. In the short Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes (SUSTAIN-6) (133), use of semaglutide compared to placebo was associated with a reduction in the composite cardiovascular outcome of 26%, with an even greater 39% reduction in stroke. Other GLP-1 RA cardiovascular endpoint trials, including the Exenatide Study of Cardiovascular Event Lowering Trial (EXSCEL) with exenatide LR (134) and the Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND) with dulaglutide (135) are due to report in 2018 and 2019, respectively. Importantly, these trials will help clarify the mechanisms for the cardiovascular benefits seen in SUSTAIN-6 regarding whether they are a class effect.

TABLE 18.7

Clinical Trials of Lipid Modification on Cardiovascular Disease Risk.

Lipid-Modifying Clinical Trials

Management of dyslipidemia in persons with diabetes has focused on lowering LDL cholesterol. The strongest evidence for CVD risk reduction derives from statin clinical trials (Table 18.7). A subgroup of the Heart Protection Study (HPS) enrolled 5,963 patients with type 1 or type 2 diabetes who were assigned to simvastatin 40 mg treatment or placebo. The active medication was associated with a 22% (p<0.0001) risk reduction of a first major coronary event (136). This was followed by the Collaborative Atorvastatin Diabetes Study (CARDS), in which atorvastatin 10 mg daily versus placebo resulted in a 37% (p=0.001) reduction in major cardiovascular events (137). Moreover, in a large meta-analysis of 18,686 subjects with diabetes randomized to statin therapy versus placebo, each mmol/L reduction in LDL cholesterol resulted in a 21% reduction in CVD events, similar to the risk reduction seen in nondiabetic individuals (138).

Given the predominance of low HDL cholesterol and/or high triglycerides in persons with diabetes, researchers have examined whether therapy with fibric acid derivatives could reduce CVD events. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial (139), 9,795 patients with type 2 diabetes not taking a statin at entry were randomized to fenofibrate 200 mg daily versus placebo; after an average of 5 years follow-up, there was no significant risk reduction in the primary outcome of CHD death or non-fatal myocardial infarction, although in a subgroup analysis, fenofibrate reduced total CVD events. The authors suggested that subjects beginning statin use during the course of the study (as a result of changing guidelines recommending statins in those with diabetes) may have contributed to this null effect. The ACCORD Lipid Substudy (140) randomized a subset (n=5,518) of participants all treated with simvastatin to receive either masked fenofibrate or placebo; after nearly 5 years, no reduction in CVD outcomes was seen in the combination group among the overall study sample (HR 0.92, 95% CI 0.79–1.08, p=0.32). However, among the subset of participants with high triglycerides (≥200 mg/dL [≥2.26 mmol/L]) and low HDL cholesterol (<35 mg/dL [<0.91 mmol/L]), a significant reduction (HR 0.69, p=0.03) in CVD outcomes was observed. Nevertheless, the failure to show additional benefit from fenofibrate therapy in prevention of CVD events over statin therapy in the overall cohort of adults with diabetes has contributed to continued support for the use of statin therapy alone for management of dyslipidemia in persons with diabetes, and combination therapy is not recommended due to lack of demonstrated additional benefit beyond statins (115).

TABLE 18.8

Clinical Trials of Blood Pressure Control on Cardiovascular Disease Risk.

TABLE 18.9

Clinical Trials of Antiplatelet/Aspirin Use on Cardiovascular Disease Risk.

Trials of Antiplatelet/Aspirin Management

Compared to the role of aspirin in secondary prevention, data among adults with diabetes are limited (Table 18.9). In the Antithrombotic Trialists meta-analysis of antiplatelet therapy (144), there was a 22% benefit in CVD risk in the overall cohort that was attenuated to only a 7% (nonsignificant) benefit in a subset of almost 5,000 patients with diabetes. Among hypertensive subjects enrolled in the HOT study, including 1,501 participants with diabetes, aspirin was associated with a 36% reduction in risk for myocardial infarction and 15% reduction in risk for major CVD events (141). Three other randomized clinical trials examining the role of aspirin in primary prevention of CVD that included subjects with diabetes have been reported. The Primary Prevention Project (PPP) showed 100 mg per day aspirin versus placebo to result in only a nonsignificant 10% reduction in death, myocardial infarction, or stroke among the 1,031 patients with type 2 diabetes compared to a 41% risk reduction in those without diabetes (145). Further, the Prevention of Progression of Arterial Disease and Diabetes (POPADAD) showed no significant reduction in risk of CVD events in the 1,276 patients with type 1 or type 2 diabetes who were randomized to 100 mg aspirin daily versus placebo (146). The Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) study also showed only a nonsignificant 20% reduction in risk of CVD events associated with aspirin 81 or 100 mg per day versus placebo in 2,539 patients with type 2 diabetes (147).

TABLE 18.10

Clinical Trials of Comprehensive Risk Factor Control and Lifestyle Management on Cardiovascular Risk.

Conclusion

Among people with diabetes in the United States, the prevalence of CVD remains about twofold greater than in people without diabetes. This disparity represents a major health care challenge. Understanding the determinants of the excess risk for CVD in patients with diabetes remains far from complete. The relevance of dysglycemia is unclear in both nondiabetic and prediabetic subjects, which raises questions about the role of hyperglycemia per se. Some clinical trial data suggest that intensive management of moderate hyperglycemia may cause harm in high-risk subjects. Also, despite the worrying increase in obesity and diabetes prevalence, there is little evidence that measures of obesity are related to CVD independent of other risk factors or that weight reduction through change in lifestyle yields benefit for CVD prevention. Traditional risk factors, such as dyslipidemia, hypertension, and smoking, clearly are important, although some studies call into question the importance of mild elevations in blood pressure. Furthermore, despite the importance of low HDL cholesterol as a risk factor, benefit beyond LDL cholesterol-targeted statin therapy for lipoprotein medications is unproven. An improved understanding of the natural history of atherosclerosis in diabetes and its risk factors during the earlier phases of diabetes development may open the door to earlier and perhaps more innovative cardioprevention therapies.

List of Abbreviations

A1c

glycosylated hemoglobin

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation

Apo

apolipoprotein

BMI

body mass index

BRFSS

Behavioral Risk Factor Surveillance System

CAC

coronary artery calcium

CHD

coronary heart disease

CI

confidence interval

CIMT

carotid intimal-medial thickness

CVD

cardiovascular disease

DCCT

Diabetes Control and Complications Trial

DECODE

Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe

DPP

Diabetes Prevention Program

DPPOS

Diabetes Prevention Program Outcomes Study

EDIC

Epidemiology of Diabetes Interventions and Complications study

EPIC

European Prospective Investigations into Cancer

FPG

fasting plasma glucose

GLP-1

glucagon-like peptide-1

GLP-1 RA

GLP-1 receptor antagonist

HDL

high-density lipoprotein

HOMA-IR

homeostasis model assessment of insulin resistance

HOT

Hypertension Optimal Treatment trial

HR

hazard ratio

IDF

International Diabetes Foundation

IFG

impaired fasting glucose

LDL

low-density lipoprotein

Look AHEAD

Action for Health in Diabetes

MESA

Multi-Ethnic Study of Atherosclerosis

MRFIT

The Multiple Risk Factor Intervention Trial

NCEP

National Cholesterol Education Program (Adult Treatment Panel III)

NHANES

National Health and Nutrition Examination Survey

NHIS

National Health Interview Survey

OGTT

oral glucose tolerance test

PAR

population attributable risk

RR

relative risk

SD

standard deviation

SGLT2

sodium glucose transporter-2

SUSTAIN-6

Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

UKPDS

United Kingdom Prospective Diabetes Study

VADT

Veterans Affairs Diabetes Trial

WHO

World Health Organization

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Appendices

APPENDIX 18.1. Crude and Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race/Ethnicity, U.S., 2009–2010

APPENDIX 18.2. Crude and Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥20 Years, by Diabetes Status, Sex, and Race/Ethnicity, U.S., 2007–2010

APPENDIX 18.3. Crude and Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race/Ethnicity, U.S., 2010

APPENDIX 18.4. Crude and Age-Standardized Percent of Hospitalizations Listing Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race, U.S., 2010

CONVERSIONS

Conversions for A1c, cholesterol, glucose, insulin, and triglyceride values are provided in Diabetes in America Appendix 1 Conversions.

DUALITY OF INTEREST

Drs. Barrett-Connor, Wingard, Wong, and Goldberg reported no conflicts of interest, with the following potential exceptions. Dr. Barrett-Connor served as an advisory panel member and contracted advisor for Eli Lilly. Dr. Wong received research support through the University of California, Irvine, from Bristol Myers-Squibb.