ABSTRACT

Heart failure (HF) is an underappreciated complication of diabetes. HF occurs in individuals with diabetes at higher rates, even in the absence of other HF risk factors such as coronary artery disease and hypertension. Comorbid ischemic heart disease and cardiovascular risk factors significantly contribute to the etiology of cardiomyopathy and HF in patients with diabetes. In addition, long-standing diabetes can independently cause subclinical alteration in cardiac structure and function, eventually leading to the development and progression of HF. A complex interplay between numerous mechanisms underlies the pathophysiologic links between diabetes and HF. Patients with concurrent diabetes and HF have impaired quality of life and a poor prognosis with a high risk of hospitalization and mortality. Despite the solid epidemiologic link between poor glycemic control and HF risk, the effects of intensified glycemic control in preventing HF remain controversial. Large-scale cardiovascular outcome trials published since 2015 have confirmed the efficacy and safety of sodium-glucose co-transporter-2 inhibitors (SGLT2) inhibitors in preventing HF among patients with type 2 diabetes mellitus. In addition, several dedicated major clinical trials confirmed the cardiovascular benefits of SGLT2 inhibitors in patients with established HF, regardless of left ventricular ejection fraction or diabetes status. Furthermore, high-quality data from these clinical trials transformed SGLT2 inhibitors from glucose-lowering agents to HF drugs. This chapter outlines the complex relationship between HF and diabetes, focusing on the epidemiology, pathophysiology, and prognostic implications. Additionally, we review the current knowledge on identifying subclinical cardiac remodeling, predicting HF risk, and preventing HF in diabetes. We also summarize the recent evidence and guideline recommendations for the pharmacological treatment of patients with coexisting HF and diabetes. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Diabetes is a risk factor for cardiomyopathy and heart failure (HF) independent of traditional cardiovascular (CV) disease (CVD) risk factors such as hypertension and coronary artery disease (CAD) (1–4). The universal definition of HF recognizes patients with diabetes as “at risk for HF” (Stage A). Asymptomatic individuals with at least one of the following: 1) evidence of structural heart disease, 2) abnormal cardiac function, or 3) elevated cardiac natriuretic peptide or troponins are considered to have “pre-HF” (stage B). According to this classification, HF (stage C) is defined as a clinical syndrome with signs or symptoms of HF caused by an abnormality in cardiac structure and function and corroborated by elevated natriuretic peptide or objective evidence of cardiogenic congestion (pulmonary or systemic) (3,5).

The prevalence of diabetes is approximately 10.2% in the U.S. population, and HF affects 9 to 22% of patients with diabetes (6–10). In clinical trials of antidiabetic agents, HF was present in 4 to 30% of participants with diabetes (11). On the other hand, the prevalence of pre-diabetes or diabetes was 30 to 40% among individuals enrolled in HF trials (12,13).

Longstanding diabetes alters cardiac structure and function, resulting from the direct effects of abnormal myocardial metabolism and insulin resistance (IR) even without atherosclerotic CAD (14). The pathophysiologic link between diabetes and HF is complex and multifactorial, involving various abnormal biochemical pathways including but not limited to abnormal calcium signaling, deranged glucose/fatty acid metabolism, and inflammatory pathways contributing to myocardial fibrosis, stiffness, and hypertrophy (7,15,16). A complex interaction of these mechanisms can cause asymptomatic diastolic and systolic dysfunction, eventually leading to the clinical syndrome of HF. Conversely, HF is also associated with a higher prevalence of diabetes and is considered a predictor of future risk of type 2 diabetes mellitus (T2DM) (17).

Left ventricular (LV) dysfunction in patients with diabetes may present with three different HF phenotypes, such as HF with preserved LV ejection fraction (LVEF ≥ 50%; HFpEF), HF with mildly-reduced LVEF (HFmrEF; LVEF 40-49%), and HF with reduced LVEF (HFrEF; LVEF ≤40%) (3). Diagnosing HFpEF and HFmrEF is often challenging since the symptomatology of HF may overlap with other comorbidities such as obesity, lung disease, and chronic kidney disease (CKD). Therefore, the guidelines usually recommend incorporating additional objective diagnostic criteria such as elevated natriuretic peptides or imaging evidence of either structural heart disease or diastolic dysfunction (18).

The coexistence of diabetes and HF is a poor prognostic factor, posing a greater risk of HF hospitalization, all-cause mortality, and CVD mortality. For instance, epidemiologic studies indicated a 50-90% higher risk of CVD mortality in patients with HF and diabetes, regardless of HF phenotype (12,19). HF patients without DM are at increased risk of developing glycemic abnormalities. In addition, newly diagnosed pre-diabetes was associated with a significantly higher risk of all-cause and CV mortality in HF patients. These findings underscore the importance of screening for pre-diabetes or diabetes among patients with HF (17,20,21). Moreover, early assessment with echocardiography can be helpful for the detection of subclinical structural abnormalities and myocardial dysfunction in asymptomatic patients with diabetes.

The pathophysiology of diabetes-related HF is complex, and despite significant advances over the past decades, many areas are still poorly understood. Since 2015, several landmark clinical trials on sodium-glucose co-transporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have revolutionized our understanding of CVD risk reduction in patients with T2DM and have led to a paradigm shift in the clinical practice recommendations for the management of T2DM (22). Incredible evidence from the CVD outcome trials (CVOTs) has confirmed the significant improvement in HF outcomes with SGLT2 inhibitors in patients with or without diabetes. These findings increased medical communities' awareness and interest in the links between diabetes and HF.

The American Diabetes Association (ADA) now recommends using SGLT2 inhibitors as first-line agents in T2DM patients with a high risk of or established HF (23). In addition, several dedicated major randomized clinical trials (RCTs) confirmed the CVD benefits of SGLT2 inhibitors in patients with established HF, regardless of LVEF or diabetes status. Moreover, these RCTs transformed SGLT2 inhibitors from glucose-lowering agents to HF drugs. The 2022 American College of Cardiology (ACC) Foundation / American Heart Association (AHA) / Heart Failure Society of America (HFSA) guideline for the management of HF recommended the use of SGLT2 inhibitors for the treatment of HF, regardless of LVEF (3).

This chapter outlines the complex relationship between HF and diabetes, focusing on the epidemiology, pathophysiology, and prognostic implications. Additionally, we review the current knowledge on identifying subclinical cardiac remodeling, predicting HF risk, and preventing HF in diabetes. We also summarize the recent evidence and guideline recommendations for the pharmacological treatment of patients with coexisting HF and diabetes.

EPIDEMIOLOGY OF DIABETES AND HF

There is a bidirectional link between diabetes and HF (24). Diabetes, either type 1 or type 2, is a strong risk factor for developing HF (25–27). In addition, HF may contribute to the pathogenesis of IR and T2DM (28). The shared underlying risk factors and the overlap of the pathophysiological mechanisms play a critical role in the frequent coexistence of T2DM and HF.

Based on the data from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2018, the prevalence of HF is 2.3% in the US general adult population (29). The prevalence of HF in individuals with diabetes ranges between 9% and 22%, depending on the characteristics of the population studied (6,8,9). Diabetes is also highly prevalent among patients with HF. In major contemporary drug trials of HF, 32% to 43% of patients with chronic HF had coexisting diabetes (12,30,31). A report from a nationwide US registry (NHANES 2005-2016) demonstrated that, among patients with HF, the prevalence rates of diagnosed and undiagnosed T2DM were 34.7% and 12.8%, respectively (32).

HF is a common but often neglected complication of diabetes (33). HF and cardiomyopathy have a heterogeneous etiology in patients with diabetes (Figure 1 and Figure 2). The strong link between diabetes and CAD, hypertension, and renal disease plays a significant role in the development of cardiomyopathy and HF in patients with diabetes (34). Moreover, HF occurs in individuals with diabetes at higher rates, even in the absence of other HF risk factors (16,35).

Epidemiologic Evidence

Evidence from large-scale epidemiologic studies has confirmed the strong link between diabetes and HF. For instance, reports from the prospective Framingham Heart Study in the 1970s indicated that individuals with diabetes had 2-fold (in men) to 5-fold (in women) higher risk of developing HF than individuals without diabetes after adjustment for other risk factors (2,39). Similarly, contemporary cohort studies suggested that diabetes is independently associated with a 1.7 to 2.5-fold greater risk of HF (6,40).

A recent nationwide cohort study from Sweden including >679.000 patients with T2DM and >2 million matched control subjects demonstrated that a diagnosis of T2DM was associated with HF risk even if CVD risk factors, such as glycated hemoglobin, systolic blood pressure (BP), estimated glomerular filtration rate, and lipids were within a target range (41). The study also demonstrated that CVD complications have significantly declined over the past 20 years in individuals with and without T2DM. However, the decline in the rate of HF in patients with T2DM has plateaued over recent years. One potential explanation for this finding is the obesity epidemic, as adiposity plays a major role in the development of HF in patients with diabetes. For instance, a recent analysis of 2 US cohort studies demonstrated that overall obesity, abdominal obesity, and fat mass were strongly associated with a greater risk of HF in participants with diabetes. Interestingly, a similar independent association was absent in those without T2DM (42).

Ischemic heart disease is more frequently seen in HF patients with coexistent T2DM than those without T2DM (63% vs. 47%). Moreover, ~90% of the patients with T2DM and HF of non-ischemic etiology have at least one comorbidity that can contribute to HF development, such as hypertension, atrial fibrillation, valvular disease, or pulmonary disease (43).

Figure 1.

Heart failure with reduced ejection fraction due to ischemic cardiomyopathy in a patient with uncontrolled type 2 diabetes. 57-year-old female patient with a history of uncontrolled type 2 diabetes (HbA1c = 12.0) and active tobacco abuse presented with a 2-day history of intermittent midsternal chest pain. (A) Her ECG on presentation demonstrated findings of acute/recent anteroseptal myocardial infarct and old/age indeterminate inferior myocardial infarct, and her serum troponin I was markedly elevated. (B and C) Her echocardiography revealed a dilated left ventricle with severely reduced systolic function, an ejection fraction of 20-25%, and akinetic anterior and inferior wall segments. Her coronary angiography, which was performed emergently, demonstrated subacute occlusion of the proximal segment of the anterior descending artery (arrow in image D) and chronic total occlusion of the middle segment of the right coronary artery (arrow in image E).

Figure 2.

Heart failure with reduced ejection fraction due to non-ischemic cardiomyopathy in a patient with uncontrolled type 2 diabetes. 59-year-old male patient with a history of hypertension (medically managed), class I obesity, hyperlipidemia, moderate alcohol consumption, and undiagnosed type 2 diabetes (HbA1c = 13.5) presented with dyspnea on exertion, orthopnea, and leg edema and he was admitted with the diagnoses of acute decompensated heart failure. (A) His ECG on presentation demonstrated left ventricular hypertrophy with repolarization abnormalities. (B and C) His echocardiography revealed a dilated left ventricle with severely reduced systolic function and diffuse hypokinesis, an ejection fraction of 25-30%, and eccentric left ventricular hypertrophy. (D and E) His coronary angiography, performed for ischemic evaluation, demonstrated no evidence of significant epicardial coronary artery disease. The patient’s non-ischemic cardiomyopathy was attributed to a mixed presentation of alcoholic and diabetic cardiomyopathy and hypertensive heart disease.

Diabetes is an independent predictor of progression from preclinical HF (stage A and stage B) to clinic HF (stage C) (44). A population-based analysis on the National Scottish Register found that HF hospitalization risk was ~2-fold higher among patients with diabetes than those without diabetes (45). A prospective cohort study, including individuals from the southeastern U.S., demonstrated that hypertension and diabetes were associated with the highest HF risk in white and black participants (46). The population-attributable risk of HF was highest for hypertension (31.8%), followed by diabetes (17%). A population-based case-control study also observed an attributable risk of HF at ~17% for diabetes, without any significant difference between HFpEF and HFrEF (47).

Epidemiologic studies have demonstrated a higher incidence of HF in men than in women with diabetes (27,40). This finding is consistent with the strong association between HF risk and male sex in the general population. However, interestingly, diabetes contributes to the future risk of HF more in women than in men, as supported by multiple epidemiologic studies (27,39). In a meta-analysis of 47 cohort studies including >12 million individuals, type 1 diabetes mellitus (T1DM) and T2DM were associated with a 47% and 9% greater excess risk of HF in women than men, respectively (48). The basis for the sex-specific disparity in HF risk attributable to diabetes remains unclear.

IMPACT OF DIABETES ON CARDIAC STRUCTURE AND FUNCTION

The frequent coexistence of diabetes with other comorbidities, such as hypertension and obesity, makes it difficult to understand the relative contribution of each disease entity in cardiac remodeling and dysfunction in clinical practice (65). However, growing evidence has supported an independent association between diabetes and various alterations in cardiac structure and function. These asymptomatic subclinical alterations at earlier stages can be detrimental and increase the risk of developing HF and CVD morbidity and mortality in general (44). Recognizing these subclinical alterations is critical for the early identification of high-risk patients and preventing overt HF and diabetic cardiomyopathy.

Left Ventricular Hypertrophy

LV hypertrophy (LVH) is characterized by increased LV mass due to myocardial remodeling. LVH is usually caused by a complex interaction between several factors, including hypertension, diabetes, metabolic syndrome, obesity, gender, ethnicity, and genetic and neurohumoral factors (66). There are three distinct LV geometric abnormality patterns: concentric remodeling (normal LV mass with increased relative wall thickness), concentric LVH (increased LV mass and increased relative wall thickness), and eccentric LVH (increased LV mass and normal relative wall thickness) (Figure 3).

Figure 3.

Based on linear measurements, relative wall thickness and left ventricular mass index determine left ventricular geometric patterns. LVH, left ventricular hypertrophy.

LVH has long been recognized as a target organ response and a strong independent risk factor for HF, CAD, stroke, and CVD mortality (66,67). LVH leads to LV diastolic dysfunction by reduced LV compliance, impaired diastolic filling, prolonged isovolumetric relaxation, and increased LV and left atrial filling pressures (16). The universal definition of HF recognizes asymptomatic LVH, LV systolic dysfunction, and LV diastolic dysfunction as “pre-HF” to emphasize the progressive nature of HF and the importance of HF prevention (5).

LVH is common among adults with diabetes, with an estimated prevalence as high as 70% (68). A pooled analysis of 3 epidemiological cohort studies, including 2900 individuals with T2DM and no known CVD, demonstrated that 67% of the participants had at least one of the following echocardiographic abnormalities: LVH, left atrial enlargement, or diastolic dysfunction (44). Coexistent hypertension appears to be the main contributor to LVH in patients with diabetes (69). However, several studies have also demonstrated an independent association between diabetes and LVH. In the Framingham Heart Study, serum glucose, insulin levels, and IR were significantly linked to concentric LV remodeling, a finding that was more striking in women than in men (70,71). Results from a prospective cohort study with a 25-year follow-up period indicated that long-standing glycemic abnormalities have a cumulative effect on LV remodeling, and patients with early-onset diabetes tend to have a worse degree of LVH (72).

Diabetic cardiomyopathy may present with distinct LVH features (34). Thickened and stiff LV walls with normal LV volume usually characterize diabetic cardiomyopathy with HFpEF phenotype. Furthermore, at the cellular level, cardiomyocytes appear hypertrophied with normal sarcomere structure and increased collagen deposition in the interstitial space. Contrarily, diabetic cardiomyopathy with HFrEF phenotype usually manifests with eccentric LVH with dilated LV volume. At the cellular level, cardiomyocytes appear to have damage with loss of sarcomeres and replacement of some cardiomyocytes with interstitial fibrosis (38).

LV Systolic Dysfunction

Traditionally, impaired LVEF is the primary marker of cardiomyopathy and systolic dysfunction. LVEF is a simple measure commonly used in the CV risk evaluation and management of CVD. However, LVEF does not capture the full spectrum of myocardial function (77). Global longitudinal strain (GLS) evaluated by speckle-tracking echocardiography is a robust technique that measures tissue deformation in a longitudinal direction (Figure 4). Reduced GLS is a marker of reduced contractility (75). GLS is more sensitive than conventional LVEF as a measure of systolic function and has an additional prognostic value (77,78). Therefore, it is now commonly used to detect subclinical LV systolic dysfunction.

Figure 4.

Global longitudinal strain by speckle tracking echocardiography. Assessment of global longitudinal strain (GLS) in a healthy, asymptomatic individual with a GLS of -25%. The top row displays a regional strain map superimposed on the grayscale two-dimensional echocardiographic images in apical four-chamber (A4C), apical two-chamber (A2C), and apical three-chamber (A3C) views. The bottom left bullseye displays regional longitudinal strain for each segment of a 16-segment left ventricle model. Bright red denotes the most negative normal values of GLS. The bottom right bullseye shows the time (ms) between aortic valve opening and peak longitudinal strain, a measure of desynchrony, for each segment.

Impaired GLS is highly prevalent in asymptomatic, normotensive patients with diabetes and normal LVEF (67,79,80). Diabetes is associated with reduced GLS, even in adolescents and young adults with T1DM or T2DM (81,82). Moreover, an inverse correlation exists between HbA1C and GLS regardless of diabetes status, race, and sex (83). Not surprisingly, impaired GLS is a robust independent predictor of new-onset HF and mortality in patients with diabetes (67).

Diabetes can lead to clinical HF syndrome in individuals with asymptomatic LV systolic dysfunction. An RCT that included adults with asymptomatic LV systolic dysfunction demonstrated that diabetes increased the risk of HF development by 53% and doubled the risk of HF hospitalization over a median follow-up of 3 years (84).

Better glycemic control in patients with diabetes can lead to improvements in LV systolic and diastolic function indices. In a prospective cohort study of subjects with uncontrolled T2DM, lowering of average HbA1c from 10.3% to 8.3% over 12 months was associated with a 21% increase in GLS and a 24% increase in septal e’ velocity, a marker of myocardial relaxation (85).

PATHOPHYSIOLOGIC LINKS BETWEEN DIABETES AND HF

A complex interplay between numerous mechanisms underlies the pathophysiologic links between diabetes and HF. These pathophysiologic mechanisms include but are not limited to impaired cardiac insulin signaling, glucotoxicity, lipotoxicity, mitochondrial dysfunction, myocardial fibrosis, oxidative stress, impaired myocardial calcium handling, CV autonomic dysfunction, endocardial dysfunction, overactivation of the renin-angiotensin-aldosterone system (7) (Figure 5). The relative contribution of each pathophysiologic mechanism and their relationship with the phenotype of diabetic cardiomyopathy are still poorly understood. The pathophysiology of cardiomyopathy and HF vary depending on the type of diabetes (T1DM vs. T2DM) and type of HF (HFrEF vs. HFpEF) (86).

Figure 5.

Pathophysiological mechanisms, subclinical abnormalities, and clinical manifestations of diabetic cardiomyopathy. AGEs, advanced glycation end-products; CMP, cardiomyopathy; EF, ejection fraction; HF, heart failure; LV, left ventricular; RAAS, renin-angiotensin-aldosterone system. *In patients with type-1 diabetes mellitus.

PROGNOSTIC IMPLICATIONS OF DIABETES IN HF

Data from epidemiologic studies and clinical trials have consistently demonstrated that individuals with concurrent diabetes and HF have impaired quality of life, are at high risk of hospitalization and mortality, and have an overall poor prognosis (33,117). In addition, coexistent prediabetes also appears to increase the risk of morbidity and mortality in patients with HF as well (118).

A large meta-analysis including >380,000 subjects with acute and chronic HF from 43 registries and clinical trials revealed that diabetes was associated with a 28% increased risk of all-cause mortality and ~35% increased risk of both CV death and hospitalization (mostly from HF) over a three year follow up (119). Interestingly, the adverse impact of diabetes on the risk of hospitalization and mortality did not differ according to the LVEF group (≤35% vs. >35%) but was higher in patients with chronic HF than those with acute HF. Observational studies have suggested a U-shaped relationship between HbA1c and mortality in patients with coexisting HF and diabetes. Aguliar et al. reported that HbA1c of 7.1% to ≤7.8% was associated with the lowest risk of mortality when compared with the other quantiles of HbA1c in a cohort of ambulatory patients with HF who were receiving medical therapy for diabetes in the early 2000s (120).

Several potential mechanisms have been proposed to explain the prognostic impacts of diabetes in HF. Diabetes is linked to multimorbidity, which significantly alters HF outcomes. Moreover, diabetes induces myocardial fibrosis, inflammation, and endothelial dysfunction, leading to higher LV pressures, poor functional status, and impaired exercise capacity in patients with HF (121–125). Diabetes predisposes neurohumoral overactivation and alterations of renal sodium handling, which may lead to congestion, cardiorenal syndrome, and impaired diuretic responsiveness (121). Also, hyperglycemia in patients with diabetes upregulates SGLT2, which leads to increased renal sodium absorption and volume expansion (121). Moreover, the increased burden of ischemic heart disease and other diabetes-related comorbidities, such as CKD, contribute to the detrimental effects of HF (126).

Data from the Swedish Heart Failure Registry demonstrated that the diabetes-associated mortality risk is more pronounced in individuals with HF of ischemic etiology than those with nonischemic etiology (43). The 2-year survival rate was less than 50% among those with HF, T2DM, and ischemic heart disease.

The presence of preexisting microvascular disease is an independent risk factor for the risk of future HF events in patients with T2DM (44). In addition, microvascular disease portends an increased risk of mortality and morbidity in patients with HF. A post hoc analysis of a large RCT demonstrated a significant association between a history of microvascular complications and future risk of adverse events among study subjects with diabetes and HFpEF (127).

PREVENTION OF HF IN PATIENTS WITH DIABETES

The critical importance of HF prevention is underscored by HF staging, where risk factors such as hypertension and diabetes are classified as stage A (at risk for HF) (3). Because of the detrimental prognostic impact of clinical HF, the prevention of asymptomatic cardiac remodeling and dysfunction (pre-HF, stage B) and symptomatic HF (stage C) are among the primary goals of the management of patients with diabetes (128).

TREATMENT OF HF IN PATIENTS WITH DIABETES

The primary objectives in managing HF are to reduce mortality, prevent HF hospitalization, and improve patients’ clinical status, quality of life, and functional capacity (18). The major components of managing HF are lifestyle changes, education and support for HF self-management, monitoring, control of the underlying causes and associated comorbidities, pharmacologic therapy, cardiac rehabilitation, device therapies, mechanical circulatory support, and cardiac transplantation (171). The major society guidelines for the management of patients with HF include the ACC/AHA/HFSA guidelines published in 2022 (3) and the European Society of Cardiology (ESC) guidelines published in 2021 (18).

The main components of lifestyle changes recommended for patients with HF are physical exercise, smoking cessation, restriction of or abstinence from alcohol consumption, dietary modifications, and avoidance of obesity (18). ACC/AHA/HFSA and ESC guidelines strongly recommend regular aerobic exercise and exercise training to improve functional capacity and symptoms in patients with HF who can participate. The ACC/AHA/HFSA guideline indicated that avoiding excessive dietary sodium intake is reasonable (class IIa) for patients with symptomatic HF to reduce congestive symptoms (3). However, because of a lack of affirmative evidence from clinical trials, the guidelines did not provide precise recommendations about the limit of daily sodium intake and whether it should vary depending on the type, stage, or severity of HF or comorbidities.

PHARMACOLOGIC THERAPY OF T2DM IN PATIENTS WITH HF

Lifestyle therapy is essential to managing patients with diabetes and established or high risk for HF. We point the readers to documents from ADA and ACC/AHA for detailed review and recommendations on lifestyle therapy in this patient population (3,4,157).

In this chapter, we provide a focused review of the effects of glucose-lowering agents from a HF perspective. Glycemic control is essential in patients with diabetes who have additional CV risk factors or established CVD. The ADA Standards of Medical Care in Diabetes recommend a holistic, multifactorial, and patient-centered approach when choosing antidiabetic medications. As per the guidelines, antidiabetic therapy should be selected according to patient-specific goals such as cardiorenal protection or achieving and maintaining glycemic and weight management goals. Moreover, considering comorbidities, such as HF and CKD, is essential when determining management goals (23,141).

CONCLUSIONS

HF and cardiomyopathy have a heterogeneous etiology in patients with diabetes. Diabetes-related comorbidities, such as CAD and hypertension, contribute to the pathogenesis of HF in patients with diabetes. The pathophysiologic link between diabetes and HF is multifactorial, involving various abnormal biochemical pathways. A complex interaction of these mechanisms contributes to the development of asymptomatic diastolic and systolic dysfunction, eventually leading to the clinical syndrome of HF.

The coexistence of diabetes and HF is a poor prognostic factor, and it poses a higher risk of HF hospitalization, all-cause mortality, and CVD mortality. Therefore, the prevention of asymptomatic cardiac remodeling and progression into symptomatic HF are among the primary goals of the clinical management of patients with diabetes. BP lowering has substantial benefits in preventing HF among individuals with diabetes. Despite the well-established favorable effects of weight loss, the role of lifestyle changes and weight loss in preventing HF among diabetic patients remains uncertain. Observational data demonstrated a significant reduction in HF outcomes in response to metabolic surgeries among patients with diabetes and morbid obesity.

Guideline-directed medical therapy for HF has robust morbidity and mortality benefits in individuals with or without diabetes. Subgroup analysis or meta-analysis of major HF RCTs demonstrated that the effectiveness of HF therapies such as beta-blockers, RAAS inhibitors, ARNI, and MRAs do not vary based on patients’ diabetes status, and these therapies lead to similar reductions in morbidity and mortality among HF patients with or without diabetes.

Since 2015, several landmark clinical trials of SGLT2 inhibitors and GLP1-RA have revolutionized our understanding of CVD risk reduction in patients with T2DM and have led to a paradigm shift in the clinical practice recommendations for managing T2DM. SGLT-2 inhibitors are the preferred agents in the glucose-lowering regimen independent of baseline HbA1c in T2DM patients with known or at risk for HF.

Several dedicated major clinical trials confirmed the CVD benefits of SGLT2 inhibitors in patients with established HF, regardless of LVEF or diabetes status. High-quality data from these clinical trials transformed SGLT2 inhibitors from a glucose-lowering agent to a HF drug. Moreover, SGLT2 inhibitors are the only medication class with U.S. FDA approval and strong guideline indication (class I or IIa) for all HF patients across different LVEF groups.

ACKNOWLEDGMENT

We thank Halis Kaan Akturk for his contribution to the previous version of this chapter.

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