Epidemiology

HF is rapidly increasing in individuals with diabetes mellitus (DM) and is associated with high mortality and morbidity rates [14]. A recent study involving 3.25 million participants highlighted that the presence of DM is associated with a twofold higher incidence of HF. Factors such as longer DM duration and poor glycemic control have been identified as indicators of increased HF risk [15]. However, HF can also develop in young individuals with newly diagnosed DM [16]. Diabetic cardiomyopathy has been shown to be more common in diabetic women than in men, which may be attributed to estrogen’s functional role in regulating insulin sensitivity [14]. Studies have particularly observed higher prevalence rates of HF in women with T2DM [17, 18]. This gender disparity is explained by factors such as distinct hormonal profiles, increased BMI, blood pressure, and the timing of diabetes diagnosis in women [18, 19].

Racial disparities in the prevalence of DM among individuals with HF have been observed. Multiple studies report that the prevalence of DM in HF patients ranges from 47% to 56% among Black, Hispanic, and Native American populations [20, 21].

Since insulin resistance or the development of DM is prevalent among individuals with HF, the relationship between these two conditions is bidirectional. In a registry of 7,488 HF patients, a DM prevalence of 29% was reported [3]. However, the prevalence of DM among HF patients varies across studies. Over 20% of HF patients exhibit pathological glucose homeostasis, with clinical studies on acute HF reporting prevalence rates as high as 47% [9]. Data from various registries show that the prevalence of DM among patients with HF ranges from approximately 25% to 40%, depending on the specific population studied [22].

Risk factors of for HF in T2DM

In T2DM, the primary factor directly and indirectly influencing HF development is hyperglycemia. Glycemic control is an independent predictor of HF in T2DM [23]. Additionally, the duration of diabetes increases the risk of HF by 17% every five years [24]. Furthermore, 70% of T2DM patients have HT [25]. Elevated blood pressure is associated with increased aortic stiffness, more severe cardiac structural and functional abnormalities, coronary microvascular dysfunction, and a higher risk of HF [26–28].

Approximately 60% of T2DM patients are obese, with central abdominal obesity and high fat mass index linked to an increased risk of HF in this population [29–31]. CKD is observed in 40% of T2DM patients and impaired kidney function along with albuminuria are strong independent predictors of HF in T2DM [31]. Dyslipidemia, characterized by elevated non-HDL cholesterol or decreased HDL levels, is also an independent risk factor for HF [32]. Other independent risk factors for HF development include poor glycemic control, hypoglycemia, and excessive variability in glycemic parameters [33, 34].

Reducing or managing these risk factors can lower the risk of HF in T2DM patients. While these risk factors are consistent for both HFrEF and HFpEF, certain characteristics differ between the two groups. Female gender, obesity, and physical inactivity are more common in the HFpEF group, whereas male gender and CAD are more frequently observed in HFrEF [35].

Pathophysiology

The relationship between DM and HF is not solely based on complications of ischemic heart disease but also involves metabolic disorders such as glucose toxicity and lipotoxicity due to insulin resistance, vascular endothelial dysfunction, microcirculation abnormalities, and capillary insufficiency. It has been suggested that cardiac dysfunction in the absence of significant CAD, HT, or valvular heart disease should be termed “diabetic cardiomyopathy” [36].

There are different types of HF associated with DM [37]. The development of HF and cardiac dysfunction in DM, along with associated risk factors, is summarized in Figure 1 [38].

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Figure 1. Mechanisms of systolic dysfunction in diabetic subjects

Advanced glycation end products, increased reactive oxygen species (ROS), and renin-angiotensin-aldosterone system (RAAS) activity

Diabetes-induced hyperglycemia and hyperinsulinemia lead to capillary damage, myocardial fibrosis, and mitochondrial dysfunction, contributing to myocardial hypertrophy [39]. Hyperglycemia results in the formation of advanced glycation end products (AGEs), which are glycosylated proteins or lipids formed after prolonged glucose exposure. AGEs cross-link with extracellular matrix proteins, increase fibrosis, and impair myocardial relaxation. Additionally, AGEs promote an increase in cytosolic reactive oxygen species (ROS), inflammation, and intracellular damage [40]. Glycosylated molecules initiate inflammatory signaling, promote apoptosis, fibrotic remodeling, and immune cell infiltration. The accumulation of AGEs is a driving factor for microvascular damage in diabetes.

Chronic activation of the renin-angiotensin-aldosterone system (RAAS) is observed in diabetic patients. Elevated angiotensin II (AT-II) levels cause vasoconstriction, increase afterload, and promote left ventricular (LV) hypertrophy. AT-II also supports collagen production and extracellular matrix protein accumulation, leading to myocardial contractile dysfunction [36]. This condition is associated with cardiomyocyte stiffness and myocardial collagen deposition [37]. Consequently, increased myocardial stiffness results in systolic/diastolic dysfunction, reduced myocardial strain, atrial enlargement, and higher atrial fibrillation prevalence in diabetic patients [41].

Myocardial lipotoxicity

Excess free fatty acids, due to DM and obesity, primarily accumulate as triglycerides in adipose tissue. Ectopic fat deposits in non-adipose organs, such as the myocardium, liver, and skeletal muscle, disrupt mitochondrial function and lead to organ dysfunction [42]. Lipotoxicity in cardiomyocytes manifests as fat accumulation and lipid droplets. Increased oxidative stress and inflammation result in cardiac fibrosis and hypertrophy [42].

In the liver and skeletal muscle, fat deposition induces chronic inflammation and insulin resistance, leading to impaired glucose tolerance, dyslipidemia, and HT. Excess fatty acids accumulate as lipid droplets and triglycerides in cells while increasing diacylglycerol and ceramide levels [36]. Diacylglycerol exacerbates insulin resistance and oxidative stress through protein kinase C activation. Ceramide induces mitochondrial dysfunction and oxidative stress, contributing to LV hypertrophy and cardiac dysfunction [43]. Glucagon-like peptide-1 receptor agonists (GLP-1RAs), such as semaglutide, have demonstrated significant benefits in managing HFpEF, particularly in patients with obesity and type 2 diabetes. The STEP-HFpEF trial, a randomized controlled study published in the New England Journal of Medicine, evaluated the effects of semaglutide in this patient population. Participants receiving semaglutide experienced notable improvements in HF symptoms, physical function, and quality of life compared to those on placebo. Additionally, semaglutide led to substantial weight loss and reductions in inflammatory markers, suggesting a multifaceted mechanism of action. These findings highlight the potential of GLP-1RAs as a therapeutic option for HFpEF, addressing both metabolic and cardiovascular aspects of the disease [44].

Mitochondrial dysfunction

In diabetes, progressive mitochondrial dysfunction in cardiomyocytes leads to lipid accumulation, increased ROS production, and exacerbation of diabetic cardiomyopathy. Mitochondrial bioenergetic impairment disrupts intracellular calcium handling, causing abnormalities in myocardial contraction and relaxation [44]. Dysfunctional mitochondria undergo mitophagy, a protective autophagic process that clears abnormal mitochondria and reduces myocardial apoptosis. However, excessive mitophagy can exacerbate myocardial damage in diabetic cardiomyopathy [36, 44].

Cardiac autonomic dysfunction

Cardiac autonomic neuropathy involves abnormalities in heart rate control, vascular hemodynamics, and cardiac structure and function. Hyperglycemia triggers oxidative stress and the accumulation of toxic glycosylation products, leading to neuronal dysfunction and death [44].

Abnormal myocardial calcium handling

In murine models of T2DM, increased intracellular resting Ca²⁺, delayed Ca²⁺ transitions, reduced sarcoplasmic reticulum Ca²⁺ pumping, and impaired Ca²⁺ reuptake result in contractile and relaxation abnormalities [45].

Vasculopathy

Prolonged hyperglycemia leads to vasculopathy, with a linear relationship between glucose levels and adverse effects. Both microvascular and macrovascular complications are major contributors to morbidity and mortality in diabetic patients. Changes in endothelial and vascular smooth muscle cells play a key role in vasculopathy. Regarding myocardial perfusion, DM induces both macrovascular and microvascular ischemia, contributing to myocardial dysfunction [44].

Diagnosis

The presence of DM indicates that patients are at risk for HF and should be considered within the Stage A HF category, as well as at high risk for progression to subsequent stages of HF. At this stage, controlling blood glucose and other risk factors can alter the clinical risk of HF. According to ACC/AHA guidelines, Stage B HF, also referred to as “pre-HF”, is associated with an increased risk of cardiovascular and all-cause mortality, as well as progression to more advanced stages of overt HF. Many individuals with diabetes can be classified as Stage B [46].

Recommended laboratory evaluations for patients with HF include natriuretic peptides, complete blood count, urinalysis, serum electrolytes, blood urea nitrogen, serum creatinine, glucose, fasting lipid profile, liver function tests, and thyroid function tests. Chest X-rays and a 12-lead electrocardiogram are also advised. Imaging studies, such as transthoracic echocardiography, provide valuable information for evaluating patients with suspected or confirmed HF [46].

Additionally, in diabetic patients with suspected CAD, stress testing, myocardial perfusion scintigraphy, CT coronary angiography, and, if necessary, invasive coronary angiography should be performed.

Treatment