Several observational studies have shown that diabetes increases the risk for the development of HF by approximately two- to fourfold. In the first 20 years of follow-up in the Framingham Heart Study, diabetes was associated with an almost twofold increased risk of HF in males and a fourfold increased risk in females independent of other risk factors (such as age, systolic blood pressure, tobacco use, cholesterol, and left ventricular [LV] hypertrophy). Multivariable analyses revealed that diabetes had a high population attributable risk for HF in the Framingham Heart Study, accounting for 6% of cases in males and 12% in females. In more recent studies, including a registry of over 3 million people living in Scotland and a meta-analyses of 74 observational studies, the relative risk of incident HF remained approximately twofold higher in people with diabetes compared to those without diabetes. The diabetes-associated increased HF risk manifests across different patients populations, including the general population, older people, those with established coronary artery disease, and individuals with kidney disease. The relative risk of HF associated with diabetes may be even in higher in younger adults and in females.

Diabetes is a risk factor for both HFPEF and HFREF, and studies have shown that the magnitude of risk associated between diabetes and heart failure appears similar for both HF subtype. In the Multi-Ethnic Study of Atherosclerosis (MESA), diabetes conferred similar risks for HFPEF (HR, 1.85; 95% CI, 1.57–2.68) and HFREF (HR, 2.02; 95% CI, 1.38–2.97) compared to those without diabetes. Similarly, a meta-analysis of seven studies demonstrated that the risk magnitude associated with diabetes and incident was increased by approximately twofold and was similar for both incident HFPEF or HFREF.

In addition to overt diabetes, epidemiologic studies have demonstrated that milder abnormalities of glucose regulation (below the diagnostic threshold for diabetes) are associated with increased rates of HF. In participants without diabetes or HF at baseline in the Atherosclerosis Risk in Communities (ARIC) study, incident HF rates increased in a stepwise manner with increasing hemoglobin A1c (HbA1c) when compared with the reference group (HbA1c 5.0%–5.4%) ( Fig. 9.1 ). The presence of prediabetes has also been associated with subclinical alterations in cardiac structure and function and greater rates of symptomatic heart failure compared to those with normal glycemia. The HF risk observed in individuals with prediabetes is particularly elevated in those with other cardiovascular disease risk factors, such as elevated blood pressure, elevated cholesterol levels, elevated C-reactive protein, or current or former smoking.

Incident rates of heart failure ( HF ) according to hemoglobin A1c ( HbA1c ). The graph shows incidence-rate (per 1000 person-years) and 95% CI ( shaded area ) of HF with spline terms of A1c (knots at 5.0%, 5.5%, and 6.0%). The histograms represent the frequency distribution of A1C (4.5–6.5%) in the study sample.

From Matsushita K, Blecker S, Pazin-Filho A, et al. The association of hemoglobin a1c with incident heart failure among people without diabetes: the atherosclerosis risk in communities study. Diabetes . 2010;59(8):2020–2026.

Risk factors for incident HF in patients with diabetes are similar to those in individuals without diabetes. Studies of individuals with diabetes have shown that risk factors for the development of HF include older age, the presence of ischemic heart disease and CAD, peripheral vascular disease, nephropathy and renal insufficiency, metabolic complications of diabetes, retinopathy, obesity, hypertension, atrial fibrillation, and increased cardiac biomarkers such as high-sensitivity troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP). Longer duration of diabetes is associated with echocardiographic abnormalities of left ventricular systolic and diastolic function, and longer duration of diabetes is an important risk factor for HF development. In the ARIC study, each 5-year increase in diabetes duration was associated with a 17% relative increase risk of HF, and the incidence HF rate among individuals with a diabetes duration greater than 15 years was at least fourfold higher than those without diabetes ( Fig. 9.2 ). The magnitude of the associations between diabetes duration and incident HF was similar with both HFPEF and HFREF.

The association of prediabetes, diabetes, and diabetes duration with heart failure ( HF ). The graph shows the hazard ratio and frequency of heart failure among individuals with prediabetes and by diabetes duration. Restricted cubic splines are shown to demonstrate the association of diabetes duration with heart failure. There is a roughly linear relation between diabetes duration and HF risk among individuals with diabetes.

From Echouffo-Tcheugui JB, Zhang S, Florido R, et al. Duration of diabetes and incident heart failure: the ARIC (Atherosclerosis Risk in Communities) Study. JACC Heart Fail . 2021;9(8):594–603.

Multiple studies have identified that worsened glycemic control is associated with greater risk for the development of HF in individuals with diabetes. For each 1% increase in HbA1c in individuals with diabetes, the risk of incident HF increases by 8% to 36%. The relationship between HbA1c and incident HF in a community-based study of diabetic individuals with and without baseline coronary heart disease is shown in Fig. 9.3 .

Crude incidence rates (95% CI) of heart failure ( HF ) in participantes with diabetes in the Atherosclerosis Risk in Communities ( ARIC ) study by baseline hemoglobin A1c ( HbA1c ) categories and coronary heart disease ( CHD ) status at baseline ( A , without CHD; B , with CHD).

From Pazin-Filho A, Kottgen A, Bertoni AG, et al. HbA1c as a risk factor for heart failure in persons with diabetes: the Atherosclerosis Risk in Communities (ARIC) study. Diabetologia . 2008;51:2197–2204.

Specific glucose-lowering therapies have also been associated with incident HF. Observational studies have demonstrated that insulin use at baseline is associated with increased rates of HF in individuals with diabetes, but it remains unclear whether insulin use is a marker of diabetes duration and severity or whether it directly contributes to increased heart failure events. Long-term follow-up of randomized, controlled clinical trials that have prospectively studied insulin use have not confirmed greater rates of HF associated with insulin, suggesting that insulin is more likely a marker for diabetes duration and severity rather than a contributor to greater rates of HF. Thiazolidinediones (TZDs) have been associated with fluid retention and increased rates of HF in randomized controlled trials. Although the exact mechanisms of the increased HF events with TZDs are not known, the predominant proposed mechanism relates to TZD-associated volume expansion caused by increased renal sodium reabsorption rather than a direct effect on myocardial structure and function. While dipeptidyl peptidase 4 inhibitors have generally neither reduced nor increased major adverse cardiovascular events, saxagliptin has been associated with increased hospitalization for HF compared to a placebo. Sodium glucose cotransporter type-2 (SGLT-2) inhibitors have consistently been shown to be associated with reductions in HF events in patients with diabetes and established cardiovascular disease or high-cardiovascular risk.

Elevated circulating biomarkers of cardiovascular disease, including high-sensitivity troponin T (hsTnT), high-sensitivity C-reactive protein, and N-terminal pro-B-type natriuretic peptide (NT-proBNP), are also associated with increased risk of incident HF in individuals with diabetes. In one study, males and females with a hsTnT level >15 and >10 pg/mL, respectively, had a nearly fourfold increased risk of future HF hospitalization. The adjusted hazard for HF hospitalization in those with elevated levels on NT-proBNP was also nearly fourfold increased.

As expected, rates of incident HF in patients with diabetes vary depending on the duration of diabetes and concomitant HF risk factors present. Several risk scores incorporating multiple factors have been proposed to help identify those with diabetes who have greatest risk for HF. These scores have based on clinical risk factors and cardiac biomarkers. Examples of HF risk scores are demonstrated in Table 9.1 . For instance, the WATCH-DM risk score is a weighted integer scoring system that includes 10 clinical, laboratory, and ECG measures, including weight (BMI), age, hypertension, creatinine, high-density lipoproteiin (HDL) cholesterol, diabetes control (fasting plasma glucose), QRS duration, prior myocardial infarction, and prior coronary artery bypass graft surgery. As demonstrated in Fig. 9.4 , those in the highest quintile of WATCH-DM score (score ≥14 points) had a 5-year incidence of HF of 17.4% compared to the lowest quintile score (score ≤7 points) who had a 5-year HF incidence of 1.1%.

The WATCH-DM scoring variables and 5-year heart failure ( HF ) incidence based on approximate quintiles of WATCH-DM score (very low ≤7, low 8–9, average 10, high 11–13, and very high ≥14). CABG , Coronary artery bypass grafting; CR , creatinine; DBP , diastolic blood pressure; FPG , fasting plasma glucose; HDL-C , high-density lipoprotein cholesterol; MI , myocardial infarction; SBP , systolic blood pressure; yrs , years.

From Segar MW, et al. Machine learning to predict the risk of incident heart failure hospitalization among patients with diabetes: the WATCH-DM risk score. Diabetes Care . 2019;42(12):2298–2306.

Stage B heart failure (pre-HF) refers to a phase of asymptomatic structural and functional cardiac abnormalities and/or an asymptomatic elevation in cardiac biomarkers (NT-proBNP or high-sensitivity troponin) that is associated with increases in the risk for symptomatic HF. Asymptomatic LV dysfunction and abnormalities of cardiac structure and function are more commonly present in patients with diabetes than in those without diabetes. These abnormalities include LV systolic and diastolic dysfunction and diabetes-associated increases in LV mass, relative wall thickness, and left atrial size. In patients with diabetes in the Framingham Heart Study, the prevalence of asymptomatic LV dysfunction (defined as left ventricular ejection fraction [LVEF] < 50%) was 7%. In a more recent pooled-cohort study of adults older than 40 years (mean age 72 years) without prevalent cardiovascular disease and without LVEF <45%, the prevalence of at least one echocardiographic abnormality consistent with stage B HF (either increased LV mass, increased left atrial (LA) size, or diastolic dysfunction) was 67% (the least restrictive definition), and the prevalence of two or more echocardiographic abnormalities consistent with stage B HF was 20%. In this study, approximately 12% of adults with diabetes had both elevated natriuretic peptide levels and two or more echocardiographic abnormalities (the most restrictive definition for stage B HF) ( Fig. 9.5 ). Importantly, the presence of these imaging and biomarker abnormalities were associated with a stepwise increase in HF risk; the 5-year cumulative incidence of HF among participants with at least one echocardiographic abnormality, at least two echocardiographic abnormalities, and at least two echocardiographic abnormality plus elevated natriuretic peptide was 8.4%, 11.2%, and 12.8%, respectively.

Prevalence of cardiomyopathy in people with diabetes and without known cardiovascular disease in the Atherosclerosis Risk in Communities Study. Among adults with diabetes but without known cardiovascular disease, three separate criteria for asymptomatic cardiomyopathy were assessed. Least restrictive definition was the presence of at least one echocardiographic abnormality (either increased left ventricular mass, increased left atrial size, or diastolic dysfunction); intermediate restrictive included two or more echocardiographic abnormalities; the most restrictive definition included two or more echocardiographic abnormalities plus elevated natriuretic peptide levels.

From Segar MW, et al. Prevalence and prognostic implications of diabetes with cardiomyopathy in community-dwelling adults. J Am Coll Cardiol . 2021;78(16):1587–1598.

HF is a growing health and economic burden, in large part due to an aging population. It is estimated that 6 million US adults have HF, and the prevalence is projected to rise to over 8 million adults with HF by 2030. In clinical trials of HF, including both HFREF and HFPEF, the prevalence of diabetes ranges between 20% and 40%. The prevalence of diabetes in clinical HF trial populations varies by age, chronic kidney disease, and coexistence of other cardiovascular conditions. The prevalence of DM appears even higher in patients hospitalized with acute HF, reaching levels greater 40%. There is also significant heterogeneity among different ethnic groups in regards to HF. In patient level data from two large global cohorts, the prevalence of DM was lowest in Whites (29.3%), followed by Japanese/Koreans (34.1%), Blacks (35.9%), Chinese (42.3%), Indians (44.2%), and highest in Malays (51.9%).

Furthermore, the prevalence of diabetes in HF populations may be even greater when systematic diabetes screening occurs and individuals with previously unrecognized diabetes are identified. For example, in a cohort of outpatients with systolic HF who underwent systematic oral glucose tolerance testing, almost 20% of individuals without a prior diagnosis of diabetes were found to have newly diagnosed diabetes.

In addition to diabetes contributing to greater HF incidence, evidence suggests that HF itself may be considered an insulin-resistant state with increased risk for incident diabetes. The potential reasons for this association have not been well established but include potential increased neurohormonal activation promoting both skeletal and myocardial insulin resistance. Increased sympathetic nervous stimulation, renin-angiotensin-aldosterone (RAAS) overactivity, and reduced activity of natriuretic peptides may affect skeletal muscle blood flow, reduce skeletal muscle glucose uptake, and increase systemic and local inflammation and fibrosis. Risk factors for incident diabetes among people with HF include elevated BMI and waist circumference, smoking history, elevated HbA1c or glucose, higher systolic blood pressure, longer duration of HF, diuretic therapy, and higher New York Heart Association functional class. Given bidirectional association, it is not surprising that diabetes and HF frequently coexist.