Summary

Heart disease remains a major cause of morbidity and mortality among individuals with type 2 diabetes. Meta-analyses have demonstrated a pooled relative risk for incident coronary heart disease (CHD) that is approximately twofold higher overall in adults with diabetes compared to those without diabetes. In studies that further stratify results by sex, the relative risk of CHD is higher in women than men in the presence of diabetes. Nonetheless, the age-standardized prevalence for all categories of heart disease remains higher in men with diabetes than women with diabetes in the United States. Although the rates of diabetes are higher in Hispanic and non-White individuals compared to non-Hispanic White adults, it should be noted that non-Hispanic White adults with diabetes generally report heart disease rates up to twice as high as Hispanic persons with diabetes, with an intermediate prevalence of any heart condition in non-Hispanic Black individuals. Despite a more than twofold increase in type 2 diabetes prevalence from the 1970s to the 2020s, the prevalence of heart disease has increased modestly in both men with diabetes and women with diabetes, while in contrast, it has remained stable or decreased for men and women without diabetes.

Classic heart disease risk markers have been clearly demonstrated to be important determinants of heart disease in diabetes, including elevated low-density lipoprotein cholesterol, elevated blood pressure, smoking, and elevated triglycerides and low high-density lipoprotein cholesterol. Obesity is an important risk factor for type 2 diabetes but has not consistently been shown to have an independent association with heart disease, possibly because obesity is in the causal pathway between these risk factors and heart disease development. However, several studies indicate that the excess prevalence of heart disease in diabetes is not fully accounted for by measured classic cardiovascular disease risk factors. In addition, novel biomarkers have been found to either add no or only modest incremental significance in the prediction of heart disease. The association between fasting glucose and heart disease displays a J-shaped curve in several studies. Glycosylated hemoglobin also has 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. Other important risk factors include lifestyle factors, such as physical activity, smoking, diet, and social determinants of health, such as food insecurity, access to health care, or poverty.

Clinical trials involving modification of cardiovascular risk factors in diabetes have helped to clarify their roles in heart disease development. Clinical trials focusing on weight reduction through an intensive lifestyle intervention specifically in people with diabetes have not demonstrated benefit in cardiovascular events despite improvement in risk factors. Whether improvement of glycemic control reduces heart disease has long been a central question, since older trials had not consistently demonstrated benefit. By contrast, lipid-lowering clinical trials have shown that statin treatment, in both secondary as well as primary prevention trials, significantly reduces atherosclerotic heart disease with a similar risk reduction to that seen in people without diabetes. Large randomized trials have demonstrated that highly purified eicosapentaenoic acid ethyl ester significantly reduces risk of ischemic events. Trials of more intensive compared to standard blood pressure control in people with diabetes did not generally find that achieving a lower goal leads to a reduction in cardiovascular events overall. The benefits of aspirin in reducing serious vascular events have been demonstrated in trials of people with diabetes, but these benefits are largely counterbalanced by an increase in major bleeding events.

Post-marketing cardiovascular outcome trials have been required by the U.S. Food and Drug Administration to demonstrate safety for all antihyperglycemic agents newly approved since 2008. All agents in the glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor classes have demonstrated safety, while some agents within these classes of medication have further demonstrated superiority in reducing major adverse cardiovascular events, hospitalization for heart failure, and kidney failure in specific populations.

In conclusion, despite intensive management of cardiovascular risk factors, the high risk for heart disease among people with diabetes remains a major health concern. Importantly, over the past few years, an increasing number of therapies have become available to reduce cardiovascular risk in people with type 2 diabetes.

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 (CDC) (4), the proportion of diabetes in the United States that is type 1 is 5%–10%, while type 2 diabetes accounts for 90%–95%. The epidemiology and etiology of type 1 (insulin-dependent) diabetes are described elsewhere (5). Aside from the Diabetes Control and Complications Trial (DCCT), there is a relative paucity of trials with cardiovascular outcomes in people with type 1 diabetes. Although longstanding type 1 diabetes carries a cardiovascular disease (CVD) mortality risk similar to type 2 diabetes (6), type 2 diabetes is the primary focus of the analyses herein, based on papers reporting diabetes defined by elevated fasting plasma glucose (FPG) values or diabetes by history.

The literature on diabetes and CVD, particularly from studies reporting the results from cardiovascular outcome trials (CVOTs) of newer glucose-lowering agents, has increased exponentially since Diabetes in America, 3rd edition, was published in 2018 (7,8). Here, each section usually starts with a review of the evidence 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 that were included in these meta-analyses.

Diabetes is clearly an established risk factor for CHD (9,10), but how much its effect varies by age, sex, country, or levels of conventional risk factors for CHD remains unresolved (11). Key characteristics of diabetes are discussed, specifically: demographic and lifestyle factors; social determinants of health, such as food insecurity or access to health care; and metabolic risk factors, including hyperglycemia and insulin (hyperinsulinemia), dyslipidemia (elevated triglycerides, high low-density lipoprotein cholesterol [LDL-C], and low high-density lipoprotein cholesterol [HDL-C]), hypertension, obesity and components of the metabolic syndrome, and novel risk markers, such as high-sensitivity C-reactive protein (hsCRP). Hypertension is a common risk factor for CHD in adults with diabetes and is an independent risk factor for heart disease, heart failure (HF), and stroke. The extent to which diabetes is associated with fatal versus nonfatal myocardial infarction (MI) is also unknown (12). 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 (13). FPG has been 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); however, available data regarding this association remain inconclusive (14,15,16).

Figure 1 shows study-specific hazard ratios (HR) for CHD in people with diabetes at baseline compared with people without diabetes (17). The summary risk estimates from the forest plot indicate that the overall effect is an approximate doubling of risk for 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.

FIGURE 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...)

Obesity is increasing steadily worldwide, including in industrializing countries. In the United States, obesity prevalence in adults increased from 30.5% in 1999–2000 to 42.4% in 2017–2018 (18), yet the prevalence of obesity in persons with type 2 diabetes is even higher. According to the CDC and based on National Health and Nutrition Examination Survey (NHANES) data between 2015 and 2018, approximately 62% of adults with diabetes are obese and an additional 27.7% are overweight (19). While large research studies have demonstrated the effectiveness of lifestyle changes (dietary changes and increased physical activity) in reducing the incidence of diabetes, losing weight is difficult in real-world settings. Sustained weight loss, such as after bariatric surgery, may be required to produce meaningful changes in health outcomes, particularly for CVD.

In this article, 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. In particular, the results from CVOTs of newer glucose-lowering agents and implications for clinical care of people with diabetes are discussed.

Sources and Limitations of National Data on Heart Disease and Diabetes

Information on heart disease and diabetes is available from several surveys conducted in the United States that use national probability samples, including the National Health Interview Survey (NHIS), the NHANES, and the Behavioral Risk Factor Surveillance System (BRFSS). The NHIS is a cross-sectional household interview survey that uses a complex sampling design and has been conducted continuously since 1957. In the NHIS 2019–2020 survey cycles, participants were asked detailed questions about diabetes and heart disease. Diabetes was determined if participants answered “yes” to the following question: “(If female, other than during pregnancy) Have you ever been told by a doctor or health professional that you have diabetes or sugar diabetes?” Questions about heart disease included any history of congestive heart failure, coronary heart disease, angina, or heart attack. Although the heart disease questions in NHIS are comprehensive, a limitation is that the data are self-reported.

The NHANES is a cross-sectional, national probability sample that has been conducted periodically since 1971 and continuously since 1999. NHANES data collected from individuals for the period 2017–2020 Q1 are reported to assess current estimates in heart disease among adults with diabetes before the start of the coronavirus disease of 2019 (COVID-19) pandemic. In addition, data from survey periods between 1976–1980 and 2017–2020 Q1 are utilized to assess trends in heart disease. Participants self-reported diagnosed diabetes status, based on the question of “Other than during pregnancy, have you ever been told by a doctor or health professional that you have diabetes or sugar diabetes?” An advantage of the NHANES is that the survey includes a health exam in a mobile examination center where laboratory measures are collected. Thus, the NHANES has laboratory information on glycosylated hemoglobin (A1c) and FPG to determine undiagnosed diabetes. Participants self-reported any history of congestive heart failure, coronary heart disease, angina, or heart attack.

The BRFSS is a large, state-based, telephone-based survey conducted annually to collect data on respondents’ health-related behaviors, chronic health conditions, and use of preventive services. Data from 2019 are utilized to describe self-reported information on diagnosed diabetes, coronary heart disease or angina, and heart attack or MI.

The Healthcare Cost & Utilization Project (HCUP), National (Nationwide) Inpatient Sample (NIS) is the largest publicly available all-payer inpatient healthcare database designed to produce U.S. national estimates of in-patient utilization, access, cost, quality, and outcomes. The HCUP-NIS estimates around 35 million hospitalizations nationally. Data from the HCUP-NIS 2018 are utilized to estimate heart disease by diabetes status using ICD-10 (International Classification of Diseases, Tenth Revision) codes.

Prevalence of Heart Disease in People With Versus Without Diabetes in the United States: Nationally Representative Survey Estimates

National 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 1, 2, 3, and 4; Appendices A1, A2, A3, and A4). In adults, the prevalence of heart disease increases with age regardless of diabetes status (Figure 2). The age-standardized relative risk (RR; the ratio in persons with diabetes to those without) for any heart condition, including CHD, angina, and heart attack (plus HF in the NHANES), varies from 2.2 to 2.5, reflecting the different heart disease conditions included in the national surveys. Prevalence estimates for any heart condition are 20.6% versus 9.3% for the NHIS (Table 1) and 24.2% versus 10.3% for the NHANES (Table 2) for persons with versus without diabetes, respectively. In the BRFSS, prevalence of CHD or angina is 12.7% versus 5.2%, and for heart attack or MI, the prevalence is 13.5% versus 5.5% for those with and without diabetes, respectively (Table 3). The BRFSS is a cross-sectional, self-reported survey, which may limit interpretation. National data based on hospital discharges demonstrate similar trends between adults with and without diabetes (Table 4, Appendix A4).

TABLE 1.

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race/Ethnicity, NHIS, U.S., 2019–2020

TABLE 2.

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥20 Years, by Diabetes Status, Sex, and Race/Ethnicity, NHANES, U.S., 2017–2020 Q1

TABLE 3.

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, Race/Ethnicity, and Other Characteristics, BRFSS, U.S., 2019

TABLE 4.

Age-Standardized Prevalence of History of Heart Disease Among Adults Age ≥18 Years, by Diabetes Status, Sex, and Race, HCUP-NIS, U.S., 2018

FIGURE 2.

Prevalence of Coronary Heart Disease, by Diabetes Status, Age, and Sex, U.S., 2019–2020. Coronary heart disease and diabetes status are self-reported.

Examination of these national survey results demonstrates that the age-standardized prevalence of heart disease is consistently higher among men than women, regardless of diabetes status (Tables 1, 2, 3, and 4; Appendices A1, A2, A3, and A4). There is substantial variation in the age-standardized prevalence of heart disease based on race and ethnicity. Asian and American Indian/Alaska Native individuals with diabetes reported the highest rates of CHD or angina, and American Indian/Alaska Native persons with diabetes reported the highest rates of heart attack or MI in the BRFSS 2019 (Table 3). For the NHIS 2019–2020 and NHANES 2017–2020 Q1 (which did not have sufficient numbers of American Indian/Alaska Native respondents to report separately), non-Hispanic White individuals generally reported the highest rates of heart disease (Tables 1 and 2). However, non-Hispanic Black individuals in the NHANES reported more HF than individuals from other race/ethnicity groups (Table 2).

Importantly, sex differences exist for the relative risk of CHD in the presence of diabetes. In healthy young and middle-aged U.S. adults between ages 35 and 60 years, with different underlying risks of heart disease, a study across three diverse cohorts found that women with diabetes were significantly more likely to develop CHD than those without diabetes (pooled HR 3.61, 95% CI [confidence interval] 1.97–6.61), but similar relationships were not found in men (pooled HR 1.17, 95% CI 0.71–1.94), after adjustment for age, race, education, smoking, BMI, hypertension, and dyslipidemia (20). In a large meta-analysis of 22 prospective cohorts, an excess risk of fatal CHD was found in women (RR 3.12, 95% CI 2.34–4.17) and men (RR 1.99, 95% CI 1.69–2.35) with diabetes compared to those without diabetes; however, the ratio of relative risks was 1.46 (95% CI 1.14–1.88) comparing women to men. These results suggest that the relative risk of fatal CHD associated with diabetes is about 50% higher in women than men (11).

Interestingly, large secular trends have been noted from the 1970s to 2020. Figures 3 and 4 present the prevalence of diabetes and heart disease (self-reported heart attack or HF) for women and men, respectively, across six NHANES time periods covering 1976–2020. Over the same period, the prevalence of self-reported diabetes increased from 4% to 9% in women and from 3% to 12% in men. However, the prevalence of heart disease remained stable or decreased for men and women without diabetes but increased modestly in both men and women with diabetes. Although overall heart disease prevalence has been stable, population attributable risk (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 population attributable risk has declined.

FIGURE 3.

Trends in the Age-Standardized Prevalence of Diabetes and Heart Disease Among Adult Women Age ≥20 Years, U.S., 1976–2020 Q1. Diabetes is defined as self-reported or self-report and/or A1c (≥6.5%) and/or FPG (≥126 mg/dL); (more...)

FIGURE 4.

Trends in the Age-Standardized Prevalence of Diabetes and Heart Disease Among Adult Men Age ≥20 Years, U.S., 1976–2020 Q1. Diabetes is defined as self-reported or self-report and/or A1c (≥6.5%) and/or FPG (≥126 mg/dL); (more...)

One limitation of many national survey data is the reliance on self-reported diabetes and heart disease. However, as seen in Figures 3 and 4, the prevalence of diabetes based on self-report, FPG, and A1c levels has demonstrated the same trends as self-reported data alone over the last five survey time periods. Therefore, the reported variations by age, sex, and race/ethnicity are likely real.

Risk Factors for the Development of Heart Disease in People With Diabetes

Treatment: Control of Glycemia or Other CVD Risk Factors and CVD Outcomes

Trials of Intensive Glycemic Control

Extensive epidemiologic evidence showing an association between diabetes and CVD (17) led to the hypothesis that treating diabetes to reduce blood glucose levels would lower CVD risk as a primary or secondary outcome (Table 5). The first study to test this hypothesis was the DCCT, which enrolled 1,441 people age 13–39 years with recent-onset type 1 diabetes and randomized them to either intensive (≥3 insulin injections per day—or via insulin pump—dose-adjusted to achieve a fasting glucose 70–120 mg/dL [3.89–6.66 mmol/L] and postprandial glucose <180 mg/dL [<10.00 mmol/L]) or conventional (one or two insulin injections per day dose-adjusted to avoid ketonuria or symptoms of hyperglycemia or glycosuria) insulin therapy for a mean follow-up of 6.5 years. Findings from this trial were the first to conclusively show clear benefit from intensive versus conventional glycemic control in reducing the development of retinopathy by 76%, microalbuminuria by 39%, and clinical neuropathy by 60% (159). While 41% fewer CVD events occurred in the intensively treated group, this number was not statistically significant, possibly because of the young age of the participants or small number of events.

TABLE 5.

Clinical Trials of Intensive Glucose Control on Cardiovascular Disease Risk

Examination of whether intensive glycemia control could prevent complications, including CVD, in people with type 2 diabetes then became a topic of inquiry in the UKPDS, which enrolled 3,867 adults with newly diagnosed type 2 diabetes and randomized them to either sulfonylurea or insulin versus diet alone for a mean follow-up of 10 years (160). Mean A1c levels of 7.0% and 7.9% (63 mmol/mol) were achieved in the drug versus diet-treated groups, respectively, and microvascular events were reduced 21%–34% by drug treatment. Although a metformin-treated subgroup (n=342) had 42% less diabetes-related death and 36% less all-cause mortality compared to the diet-treated subgroup (n=411) (161), the main trial failed to show a significant impact of intensive control on their composite CVD outcome (16% reduction, p=0.052) (161).

The near miss of the UKPDS to show CVD benefit led to widespread speculation that larger studies of people with type 2 diabetes at higher cardiovascular risk may benefit with greater intensification of their A1c than had been attempted in the UKPDS. Three large trials ensued—Action in Diabetes and Vascular Disease: Preterax and Diamicron Evaluation (ADVANCE) (162), Action to Control Cardiovascular Risk in Diabetes (ACCORD) (163), and the Veterans Affairs Diabetes Study (VADT) (164)—and were published in rapid succession. ADVANCE enrolled 11,140 adults age ≥55 years with type 2 diabetes with an additional cardiovascular risk factor and randomized them to glucose-lowering medications to achieve an A1c <6.5% versus standard care for a median follow-up of 5 years (162). Again, microvascular events were reduced by 14% (in this case, driven by less microalbuminuria) with no reduction in macrovascular events.

More concerning than the lack of cardiovascular benefit observed was the increase in all-cause mortality reported in ACCORD. ACCORD enrolled 10,251 people with type 2 diabetes with an average age of 62 years and randomized them to intensive glucose-lowering medications to achieve an A1c <6.0% versus A1c 7.0%–7.9% for a mean follow-up of 3.5 years (163). The trial was stopped early due to an observed 22% increased rate of all-cause mortality. Lastly, the VADT enrolled 1,791 military veterans with type 2 diabetes, 40% of whom had already had a cardiovascular event, and randomized them to glucose-lowering medications to achieve an A1c reduction of 1.5% greater than the control group for a mean follow-up of 5.6 years (164). Although benefit for several renal parameters was reported, no benefit was seen for the composite cardiovascular endpoint or any of the individual cardiovascular measures.

The concept that glucose lowering reduced cardiovascular events in people with diabetes was virtually abandoned. Fortunately, several of these trials entered long-term observational phases that have provided valuable lessons. The DCCT morphed into the Epidemiology of Diabetes Interventions and Complications (EDIC). During the 30-year follow-up of participants in EDIC, intensive treatment (~25 years post-intervention end) rendered a 32% reduction in cardiovascular events, lending credence to the notion of “metabolic memory” (165). Ten-year follow-up of the UKPDS boasted a persistent 24% reduction in microvascular disease and, finally, a significant 15% lower rate of MI and 15% less all-cause mortality (166). Unfortunately, after 15 years, the VADT did not demonstrate benefits in observational follow-up, as the A1c values had long since converged between groups (167).

A large meta-analysis combined 13 trials all aimed at showing the benefit of tight glycemic control (i.e., A1c <7%) for CVD prevention in people with type 2 diabetes, including the landmark trials described above (168). When combined and including 34,533 participants with varying durations of diabetes, intensive glycemic control was associated with a 15% reduction in nonfatal MI, with no benefit for all-cause or cardiovascular mortality compared to the standard glucose-lowering group (as defined in each trial), confirming its modest importance for cardiovascular protection over the short term in an out-patient setting.

Concurrently, a number of studies examined the benefit of glycemic control in the inpatient setting. Trials examining the benefit of insulin therapy post-MI yielded equivocal results (Diabetes Intensive Glucose After Myocardial Infarction [DIGAMI] 1 & 2 (169,170)), and the benefit of insulin therapy in a surgical intensive care unit (171) could not be reproduced in a medical intensive care unit (172). To reconcile the disagreements, the larger Normoglycemia in Intensive Care Evaluation – Survival Using Glucose Algorithm Regulation (NICE SUGAR) study randomized 6,104 critically ill patients requiring 3 or more days of hospitalization in an intensive care unit to intensive versus conventional glucose control (blood glucose 81–108 mg/dL [4.50–5.99 mmol/L] vs. <180 mg/dL) (173). Major findings from this trial showed no benefit (in median number of days in the hospital, intensive care unit, or requiring mechanical ventilation, or the need for renal replacement therapy), yet clear detriment (more severe hypoglycemia and higher 90-day mortality), in the intensively treated patients.

Trials of Blood Pressure Control

Reducing blood pressure, usually with pharmacologic therapy, is one of the cornerstones of CVD prevention. A few trials of patients with type 2 diabetes specifically sought to address the question of whether a blood pressure target of <130/80 mmHg, or lower, was better than the standard target of <140/90 mmHg. The trials and their results are outlined in Table 6. The Hypertension Optimal Treatment (HOT) trial, published nearly 25 years ago, included 1,501 patients with type 2 diabetes out of a total sample of 18,790 and randomized patients to a goal diastolic blood pressure of ≤80 mmHg, ≤85 mmHg, or ≤90 mmHg (199). For all patients randomized to ≤80 mmHg compared to those randomized to ≤90 mmHg, regardless of diabetes status, no significant reduction was seen in the risk of nonfatal MI, nonfatal stroke, or cardiovascular death (3-point MACE; RR 0.93, 95% CI 0.78–1.12). However, in the subset of 1,501 patients with type 2 diabetes, a significant reduction in 3-point MACE was seen (RR 0.49, 95% CI 0.29–0.81). The ADVANCE BP trial enrolled 11,140 patients with type 2 diabetes and randomly allocated them in a 1:1 ratio to fixed-dose perindopril/indapamide or placebo (200). The achieved mean blood pressure was 136/73 mmHg in the active treatment group and 142/75 mmHg in the placebo group. Significant reduction was observed in the trial primary endpoint of cardiovascular death, MI, stroke, or microvascular (new or worsening renal or diabetic eye disease) events (HR 0.91, 95% CI 0.83–1.00, p=0.04). The 3-point MACE outcome showed a similar direction and magnitude of effect but was not statistically significant (HR 0.92, 95% CI 0.81–1.04). The ACCORD BP trial randomized 4,733 patients with type 2 diabetes in a 1:1 ratio to a target systolic blood pressure of <120 mmHg (intensively managed group) compared to <140 mmHg (201). There was no significant difference in the primary composite endpoint of time to a first nonfatal MI, nonfatal stroke, or cardiovascular death, with an event rate of 1.9% in the intensive target arm and 2.1% in the standard target arm (HR 0.88, 95% CI 0.73–1.06) (202).

TABLE 6.

Randomized Controlled Trials of Intensive Blood Pressure Control That Included Patients With Type 2 Diabetes

However, evidence from the Systolic Blood Pressure Intervention Trial (SPRINT) trial has reenergized this debate, even though SPRINT specifically excluded patients with diabetes. To what extent SPRINT trial findings can be extended to patients with type 2 diabetes is not clear. Eligible patients randomized to a goal systolic blood pressure of <120 mmHg compared to <140 mmHg had a 25% relative reduction in the risk of the primary composite outcome of nonfatal MI, ACS, stroke, HF, or cardiovascular death (HR 0.75, 95% CI 0.64–0.89) (203). Data from a trial conducted in China, in which patients age 60–80 years were randomly allocated to an intensive blood pressure control arm (goal systolic blood pressure 110–<130 mmHg) or a standard control arm (goal systolic blood pressure 130–<150 mmHg), found a substantial reduction in the primary composite outcome of stroke, ACS (acute MI and hospitalization for unstable angina), acute decompensated HF, coronary revascularization, atrial fibrillation, or death from cardiovascular causes (HR 0.74, 95% CI 0.60–0.92) (204). Approximately 19% of the 8,511 patients randomized had type 2 diabetes at baseline, and no evidence of heterogeneity of the benefits of intensive therapy was found when the trial was stratified by the presence or absence of diabetes at baseline (204).

Trials of Comprehensive Risk Factor and Lifestyle Management

Few trials that include interventions targeted at multiple risk factors for CVD among persons with diabetes have been published (Table 7). The Steno-2 trial was conducted among 160 patients with type 2 diabetes who were randomized to intensive therapy designed to lower glucose, LDL-C, and blood pressure; after a 7.8-year follow-up, those in the intensive therapy arm had a significantly lower risk of CVD events (HR 0.47, 95% CI 0.24–0.73) (216). A further 5.5-year follow-up of this study cohort showed a subsequent 46% lower total mortality, 57% lower CVD death rate, and 59% lower risk of subsequent CVD events (217).

TABLE 7.

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

A meta-analysis of clinical trials of at least 12 weeks duration in patients with type 2 diabetes evaluated the ability of structured exercise training or physical activity advice to lower A1c levels compared with a control group; 47 randomized clinical trials (n=8,538 subjects) were included (218). Structured aerobic exercise, structured resistance training, and both combined were each associated with declines in A1c levels compared with control participants.

The intensive lifestyle approach employed in the Diabetes Prevention Program (DPP) (219)—a trial in people with prediabetes, rather than diabetes—involved a targeted weight loss of 7% and 150 minutes per week of physical activity. The mean age of the 3,234 participants was 51 years; mean BMI was 34.0 kg/m²; 68% were women; 45% were members of minority groups. The lifestyle intervention compared to placebo resulted in a 58% reduction in the onset of new type 2 diabetes when the trial was stopped early based on observed benefits in preventing diabetes, with an average follow-up of 2.8 years. A study based on extended follow-up from the DPPOS (220) examined whether regression from prediabetes (defined as consistently having FPG 5.6–6.9 mmol/L [100.9–124.3 mg/dL] and/or 2-hour plasma glucose levels of 7.8–11.0 mmol/L [140.5–198.2 mg/dL] on annual OGTT during the DPP period and never having met the criteria for the diagnosis of diabetes) to normal glucose regulation has a carry-over effect in reducing long-term diabetes risk. This study in DPPOS showed a 56% reduced risk of developing diabetes over 10 years in those who returned to normal glucose during the intervention phase. However, while the intensive lifestyle intervention achieved similar benefits on blood pressure and dyslipidemia compared to metformin and placebo treatment arms in the DPPOS (221), no effect of lifestyle intervention was found on the prevention of subclinical atherosclerosis as measured by CAC compared to placebo, although there was a protective effect of metformin (222).

The largest trial to address the value of behavioral intervention for CVD prevention in adults with known diabetes is the Look AHEAD study of 5,145 U.S. adults with BMI ≥25 kg/m² and type 2 diabetes (223). This study compared an intensive lifestyle group, consisting of weekly group and individual counseling in the first 6 months followed by three sessions for the next 6 months and refresher sessions afterwards, to diabetes support and education alone, involving three group sessions annually in the first 4 years and decreasing to one thereafter. Look AHEAD showed that those in the intensive group lost significantly more weight (6.2% vs. 0.9% of starting weight), had greater improvement in fitness, blood pressure, HDL-C, and triglycerides, and were significantly more likely to experience remission in their diabetes (223). In October 2012, the National Institutes of Health announced early termination of this trial after ≤11 years due to absent differences in CVD events and lack of a reasonable likelihood of showing a CVD difference if the study were continued for the planned 13 years (224). However, in post hoc analysis, those who lost at least 10% of their bodyweight compared to individuals with stable weight or weight gain in the first year of the Look AHEAD study had a 21% lower risk (adjusted HR 0.79, 95% CI 0.64–0.98, p=0.034) of the primary cardiovascular composite outcome, which included cardiovascular death, nonfatal acute MI, nonfatal stroke, or admission to hospital for angina (93). Other analyses from Look AHEAD (93) reported that the initial differences in benefit in risk factors and physical activity between groups diminished substantially during later years of the trial, and at the end of the 9.6-year median follow-up, the primary outcome of cardiovascular death, nonfatal MI, stroke, or hospitalization due to angina did not differ when comparing the intervention and control groups (HR 0.95, p=0.51).

Cardiovascular Outcome Trials of Glucose-Lowering Medications

Before 2008, new diabetes medications could be approved by the FDA for marketing in the United States if they lowered the surrogate endpoint A1c. These trials were often small, of short duration, and excluded patients with established CVD. However, the combination of a lack of adverse cardiovascular event reduction in trials testing glucose-lowering strategies (ACCORD, ADVANCE, VADT) and an increased mortality risk observed in ACCORD, as well as suggestion of cardiovascular harm from the rosiglitazone development program, prompted the FDA to require evidence of cardiovascular safety in new diabetes drugs (225,226). The result of this decision was that pharmaceutical companies that wanted to bring a novel antihyperglycemic medication to market in the United States were required to conduct large CVOTs in patients with established or at high risk for CVD.

Since that FDA guidance, a large number of rigorously conducted cardiovascular and kidney safety and efficacy trials have been conducted. Many more are planned or underway (227). The investment in this area of endocrine, cardiovascular, and renal medicine speaks to the clinical importance of the area, as well as to the unprecedented cardiovascular event reduction seen with two novel classes of medications originally designed and marketed as glucose reduction agents: the sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the glucagon-like peptide-1 receptor agonists (GLP-1 RA). While this section focuses on SGLT2i and GLP-1 RAs, large outcome trials have been conducted for dipeptidyl peptidase-4 inhibitors (DPP4i), long-acting insulin (insulin glargine and insulin degludec), a thiazolidinedione, and alpha-glucosidase inhibitors (227). Furthermore, trials testing dual SGLT2 and SGLT1 inhibitors have been published (228,229), and the dual GLP-1 RA and glucose-dependent insulinotropic polypeptide (GIP) agonist, tirzepatide, approved in 2022 by the FDA for treatment of type 2 diabetes, is being studied in ongoing CVOTs (230).

Sodium-Glucose Cotransporter-2 Inhibitors

SGLT2i reduce glucose reabsorption in the proximal tubule of the kidney, thereby leading to reductions in A1c through glucosuria. The SGLT2i that have demonstrated benefit in reducing MACE among people with diabetes are empagliflozin, canagliflozin, and dapagliflozin. The SGLT1/2i sotagliflozin also has demonstrated cardiovascular benefit in people with diabetes. The trials in which SGLT2i medications were tested and their outcomes are listed in Table 8 (228,229,231,232,233,234). A meta-analysis reported an 11% reduction in the risk of 3-point MACE, a 23% reduction in the risk of hospitalization for HF or cardiovascular mortality, and a 16% reduction in all-cause mortality with SGLTi (235). The mechanism of the effects of SGLT2i on ASCVD, HF, and cardiovascular death outcomes are not well established but do appear to be largely independent of their effects on blood glucose. Indeed, in trials in patients with HF who were not required to have type 2 diabetes for eligibility, dapagliflozin and empagliflozin showed substantial benefit in patients with HF with reduced ejection fraction (236,237) and in patients with HF with preserved ejection fraction (238,239). SGLT2i also have important benefits for patients with chronic kidney disease (CKD) with or without diabetes, as discussed further in the SGLT2 Inhibitors in Chronic Kidney Disease section; a meta-analysis of published trials estimated a 45% reduction in the risk of worsening estimated glomerular filtration rate (eGFR), end-stage kidney disease, or kidney death (HR 0.55, 95% CI 0.48–0.64) in those randomized to active SGLT2i therapy (235).

TABLE 8.

Cardiovascular Outcome Trials of SGLT2 Inhibitors in Patients With Type 2 Diabetes

Glucagon-Like Peptide-1 Receptor Agonists

GLP-1 RAs mimic the action of endogenous GLP-1 by mimicking glucose-dependent insulin secretion and inhibiting glucagon secretion from the pancreas. The effects of GLP-1 RAs on cardiovascular outcomes are heterogeneous, with some agents (liraglutide, semaglutide SQ, dulaglutide, albiglutide, and efpeglenatide) demonstrating clinically important reduction in MACE (Table 9) (240,241,242,243,244,245,246,247). Other agents, including lixisenatide and exenatide, have demonstrated cardiovascular safety but no evidence of cardiovascular benefit (240,243). The oral formulation of semaglutide has shown evidence of cardiovascular safety, but the published trial (PIONEER-6) was not powered to demonstrate cardiovascular benefit (246). A larger CVOT with oral semaglutide is ongoing (the SOUL trial, NCT03914326). A meta-analysis of randomized trials of GLP-1 RAs reported a 12% reduction in MACE, 12% reduction in cardiovascular mortality, 16% reduction in the risk of fatal and nonfatal stroke, and 9% reduction in the risk of fatal and nonfatal MI (248). The authors also noted a 12% reduction in all-cause mortality and 9% reduction in hospitalization for HF; all reductions were statistically significant. The mechanisms by which GLP-1 RAs exert their cardiovascular benefit are unknown but are at best only partially explained by their effects on blood glucose (A1c reduction). GLP-1 RAs may exert their cardiovascular benefit through beneficial changes in cardiovascular risk factors, including blood pressure, lipids, weight, or subclinical inflammation (249).

TABLE 9.

Cardiovascular Outcome Trials of GLP-1 RA in Patients With Type 2 Diabetes

Unanswered Questions for Patients and Providers

As described, ample evidence is available from placebo-controlled CVOTs that both SGLT2i and GLP-1 RAs reduce MACE, hospitalization for HF, and other clinically important outcomes for patients with type 2 diabetes. However, a number of key clinical questions have yet to be answered, including whether the medications are as effective at preventing MACE in lower-risk (i.e., without established CVD) patients; whether one class of therapy is better than the other for the prevention of cardiovascular outcomes and, if so, for which outcomes in which patients; and whether combination therapy with SGLT2i and GLP-1 RAs will offer benefits that are additive, more than additive, or sub-additive.

Some of these questions have begun to be addressed with the inclusion of lower-risk patients in randomized trials. In those analyses, summarized in a meta-analysis, SGLT2i do not appear to reduce atherosclerotic cardiovascular events like MI or stroke in patients without established CVD. However, these drugs have substantial beneficial effects on HF hospitalization and progression of kidney disease in patients with and without ASCVD at baseline (250). In a meta-analysis of randomized trials of GLP-1 RAs, the effect on cardiovascular outcomes appeared similar across the presence or absence of CVD at baseline (249). Observational pharmacoepidemiologic studies have compared SGLT2i to GLP-1 RAs and raised the possibility that SGLT2i may be superior to GLP-1 RAs among patients with established CVD in hospitalization for HF (251). Large comparative effectiveness interventional trials have been planned and are underway to address which therapy is better for which outcomes in which patients and to compare combination SGLT2i and GLP-1 RA therapy to monotherapy with either agent (252).

Evidence-Based Recommendations for Diabetes Management From Professional Societies

Many professional societies have recommendations for pharmacologic therapy for cardiovascular risk factor and CVD prevention in people with type 2 diabetes (75,268,269,270) in conjunction with lifestyle modifications, which include ≥5% weight loss through individualized medical nutrition (diet), physical activity, and/or behavioral therapy. These recommendations are summarized in Table 10 and detailed below.

TABLE 10.

Evidence-Based Clinical Recommendations From Professional Societies for the Pharmacological Prevention of Cardiovascular Disease in Patients with Diabetes, 2023

Conclusion

Among people with diabetes in the United States, the prevalence of CVD remains overall about twofold greater than in people without diabetes, although sex differences also exist. These disparities represent a major health care challenge.

The relevance of dysglycemia to risk of CVD remains uncertain in people with prediabetes or diabetes, which raises questions about the role of hyperglycemia per se. Intensive versus standard glucose-lowering strategies and mortality have not necessarily demonstrated CVD benefit, and instead, some clinical trial data suggest that intensive management of moderate hyperglycemia may cause harm in high-risk subjects. Also, despite the increase in diabetes prevalence, little evidence exists 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 in diabetes.

Pharmacological options for the primary and secondary prevention of CVD include the use of statin therapy, which is widely recommended for most people with diabetes age ≥40 years. Additionally, ezetimibe and PCSK9i have cardiovascular benefit among high-risk individuals with residual LDL-C elevation on maximally tolerated statin treatment, while bempedoic acid was demonstrated to have cardiovascular benefit in patients who are intolerant to statin therapy. However, despite the importance of elevated triglycerides and low HDL-C as risk factors, the cardiovascular outcome benefit of targeting lipid fractions beyond LDL-C is unproven. IPE has CVD benefit among individuals with elevated triglyceride levels despite the use of statins, although the mechanism is independent of triglyceride-lowering. To date, no trials have conclusively demonstrated a benefit of fibrate therapy when added to statin therapy among persons with diabetes. A large trial in people with diabetes has demonstrated benefit of aspirin in reducing vascular events, but this benefit was counterbalanced by an increased risk of major bleeding.

The use of newer glucose-lowering agents to reduce risk of major cardiovascular events and cardiovascular deaths has been demonstrated over recent years among those with a history of established CVD and also for those at high risk, such as those with CKD. In addition, SGLT2i have demonstrated benefit in reducing hospitalization for HF and reducing CKD progression.

An improved understanding of the natural history of atherosclerosis in diabetes and its risk factors during the earlier phases of diabetes development will continue to facilitate the development of innovative and targeted therapies to prevent CVD in the future.

List of Abbreviations

A1c

glycosylated or glycated hemoglobin

ABI

ankle-brachial index

ACC

American College of Cardiology

ACCORD

Action to Control Cardiovascular Risk in Diabetes

ACEI

angiotensin-converting enzyme inhibitor

ACS

acute coronary syndrome

ADA

American Diabetes Association

ADVANCE

Action in Diabetes and Vascular Disease: Preterax and Diamicron Evaluation

AHA

American Heart Association

ARB

angiotensin receptor blocker

ARIC

Atherosclerosis Risk in Communities study

ASCVD

atherosclerotic cardiovascular disease

BMI

body mass index

BNP

B-type natriuretic peptides

BRFSS

Behavioral Risk Factor Surveillance System

CAC

coronary artery calcium

CCTA

contrast CT angiography

CDC

Centers for Disease Control and Prevention

CHD

coronary heart disease

CI

confidence interval

cIMT

carotid intimal medial thickness

CKD

chronic kidney disease

CLEAR

Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen trial

CREDENCE

Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial

CRP

C-reactive protein

CT

computed tomography

CVD

cardiovascular disease

CVOT

cardiovascular outcome trial

DAPA-CKD

Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial

DCCT

Diabetes Control and Complications Trial

DHA

docosahexaenoic acid

DPP

Diabetes Prevention Program

DPPOS

Diabetes Prevention Program Outcomes Study

EDIC

Epidemiology of Diabetes Interventions and Complications study

eGFR

estimated glomerular filtration rate

EPA

eicosapentaenoic acid

FDA

U.S. Food and Drug Administration

FIELD

Fenofibrate Intervention and Event Lowering in Diabetes trial

FOURIER

Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk trial

FPG

fasting plasma glucose

GLP-1

glucagon-like peptide-1

GLP-1 RA

glucagon-like peptide-1 receptor agonist

HDL-C

high-density lipoprotein-cholesterol

HF

heart failure

HR

hazard ratio

hsCRP

high-sensitivity C-reactive protein

hs-cTn

high-sensitivity cardiac troponin

IMPROVE IT

Improved Reduction of Outcomes: Vytorin Efficacy International Trial

IPE

icosapent ethyl

JPAD

Japanese Primary Prevention of Atherosclerosis with Aspirin for Diabetes study

LDL-C

low-density lipoprotein-cholesterol

Look AHEAD

Action for Health in Diabetes

MACE

major adverse cardiovascular event

MESA

Multi-Ethnic Study of Atherosclerosis

MI

myocardial infarction

MRA

mineralocorticoid receptor antagonist

MRFIT

Multiple Risk Factor Intervention Trial

NHANES

National Health and Nutrition Examination Survey

NHIS

National Health Interview Survey

NT-proBNP

N-terminal proB-type natriuretic peptides

OGTT

oral glucose tolerance test

OR

odds ratio

PAD

peripheral artery disease

PCE

pooled cohort equations

PCSK9i

proprotein convertase subtilisin/kexin type 9 inhibitors

REDUCE-IT

Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial

RR

relative risk

SD

standard deviation

SGLT2i

sodium-glucose cotransporter-2 inhibitor

SPRINT

Systolic Blood Pressure Intervention Trial

UKPDS

United Kingdom Prospective Diabetes Study

USPSTF

U.S. Preventive Services Task Force

VADT

Veterans Affairs Diabetes Trial

WHO

World Health Organization

Conversions

A1c: (% x 10.93) - 23.50 = mmol/mol

Glucose: mg/dL x 0.0555 = mmol/L

HDL-C or LDL-C: mg/dL x 0.0259 = mmol/L

Triglycerides: mg/dL x 0.0113 = mmol/L

Acknowledgment

This is an update of: Barrett-Connor E, Wingard D, Wong N, Goldberg R: Heart Disease and Diabetes. Chapter 18 in Diabetes in America, 3rd ed. Cowie CC, Casagrande SS, Menke A, Cissell MA, Eberhardt MS, Meigs JB, Gregg EW, Knowler WC, Barrett-Connor E, Becker DJ, Brancati FL, Boyko EJ, Herman WH, Howard BV, Narayan KMV, Rewers M, Fradkin JE, Eds. Bethesda, MD, National Institutes of Health, NIH Pub No. 17-1468, 2018, p. 18.1–18.30

Article History

Received in final form on January 5, 2023.

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Appendices

Dr. Kalyani is a standing member of the FDA Endocrinologic and Metabolic Drugs Advisory Committee. Dr. Everett has received consulting fees from Circulation (Associate Editor), Eli Lilly & Co, Gilead Sciences, Ipsen Biosciences Inc, Janssen (Johnson & Johnson), Provention Bio, and UpToDate (royalties for peer review content). Dr. Everett is a co-investigator on a grant funded by Novo Nordisk, which is paid to his institution. Dr. Perrault reported no conflicts of interest. Dr. Michos has received consulting fees from AstraZeneca, Amarin, Amgen, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Esperion Therapeutics, Medtronic, Novartis, Novo Nordisk, and Pfizer. Dr. Michos is a co-investigator on a grant funded by Merck, which is paid to her institution.