Diabetes is an independent risk factor for heart failure (HF). In patients with either heart failure with preserved ejection fraction (HFpEF) or heart failure with reduced ejection fraction (HFrEF), diabetes increases the risk of cardiovascular mortality.
Pathogenesis
The development of heart failure in patients with diabetes is the result of multiple contributing factors. In addition to the direct and indirect damage caused by hyperglycemia, other metabolic conditions such as obesity also exert detrimental effects on the myocardium. From a pathophysiological perspective, myocardial metabolic dysfunction, calcium regulation abnormalities, mitochondrial dysfunction, oxidative stress, impaired cardiac microcirculation, and excessive neurohormonal activation all play significant roles in the onset and progression of heart failure in diabetes.
Myocardial Metabolic Dysfunction
The primary energy sources for myocardial cells are free fatty acids and glucose. Under fasting conditions, myocardial cells preferentially utilize free fatty acids for energy, while glucose is used during postprandial, stress, or ischemic states. In diabetes, hyperglycemia and insulin resistance reduce the expression of glucose transporter (GLUT) receptors on the surface of myocardial cells, leading to decreased glucose uptake and increased metabolism of free fatty acids. This process not only consumes more oxygen but also results in lipid accumulation within myocardial cells, causing lipotoxicity and impairing both systolic and diastolic myocardial function.
Calcium Regulation Abnormalities
Metabolic dysfunction and oxidative stress in myocardial tissue in diabetes can impair the function of calcium channels and related regulatory proteins. This leads to intracellular calcium overload in myocardial cells, contributing to a decline in both systolic and diastolic function.
Mitochondrial Dysfunction and Oxidative Stress
Mitochondrial dysfunction and elevated oxidative stress levels further promote the development of heart failure. Mitochondrial damage is thought to be caused by mechanisms such as fatty acid-mediated mitochondrial uncoupling, which increases myocardial oxygen consumption, impaired mitochondrial calcium regulation, and post-translational modifications of mitochondrial proteins that disrupt their function. Mitochondrial dysfunction leads to the production of superoxide, causing oxidative stress damage and impairing myocardial cell function.
Impaired Cardiac Microcirculation
Impaired cardiac microcirculation is attributed to several factors, including the deposition of advanced glycation end products (AGEs) in small arteries, which leads to microvascular remodeling and vascular disease. Hyperglycemia-induced endothelial damage reduces nitric oxide synthesis, impairing vasodilation and further exacerbating microcirculatory dysfunction, thereby worsening myocardial damage.
Excessive Neurohormonal Activation
Both diabetes and heart failure are associated with abnormal neurohormonal activity. In diabetes, premature activation of the renin-angiotensin-aldosterone system (RAAS) leads to excessive production of angiotensin II and aldosterone. This promotes myocardial hypertrophy, collagen deposition, fibroblast proliferation, oxidative damage, and apoptosis. Additionally, angiotensin II exacerbates myocardial damage by promoting calcium overload in myocardial cells and worsening ischemic injury.
Clinical Manifestations
Patients with diabetes and heart failure may present with either HFpEF or HFrEF. Diabetic patients may experience progressive diastolic dysfunction, which can develop into HFpEF characterized primarily by impaired diastolic function. Alternatively, they may exhibit cardiac enlargement with systolic dysfunction, manifesting as HFrEF. Detailed clinical manifestations are discussed in the relevant sections on Heart Failure.
Diagnosis and Differential Diagnosis
These can be seen in the relevant sections on Heart Failure and Diabetes.
Treatment
Treatment primarily involves three aspects: blood glucose management, heart failure control, and management of comorbidities.
Blood Glucose Management
Blood Glucose Control Targets
Blood glucose targets should follow an individualized approach. For most patients, glycated hemoglobin (HbA1c) levels should be maintained at <7.0%. For those with a long disease duration, limited life expectancy, advanced age, or frailty, less stringent glucose control targets may be appropriate.
Choice of Glucose-Lowering Medications
For diabetic patients with concomitant heart failure, SGLT2 inhibitors (SGLT2i) with proven cardiovascular benefits are recommended as a priority. If blood glucose control remains inadequate, GLP-1 receptor agonists or other agents with cardiovascular protective effects, such as metformin, may be added. Thiazolidinediones (including pioglitazone and rosiglitazone) are not recommended in patients with heart failure due to their potential to increase the risk of heart failure.
Pharmacological Treatment of Heart Failure
Treatment of HFrEF
The four cornerstone therapies for HFrEF include RAAS inhibitors (preferably ARNI or replacing ACEI/ARB with ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA), and SGLT2i. These four classes of medications have robust evidence from clinical trials demonstrating their ability to reduce heart failure hospitalizations and cardiovascular mortality. Diuretics and digoxin may alleviate heart failure symptoms and reduce hospitalization rates but do not improve long-term outcomes.
Treatment of HFpEF
Currently, only SGLT2 inhibitors (such as empagliflozin or dapagliflozin) have demonstrated a clear benefit in reducing heart failure hospitalizations and cardiovascular mortality. Diuretics can be used in patients with signs or symptoms of volume overload to improve symptoms, enhance exercise tolerance, and reduce hospitalizations, although they do not improve long-term outcomes.
Patients with Chronic Kidney Disease
In patients with concomitant proteinuria and an eGFR ≥25 ml/(min·1.73 m2), finerenone may be considered to improve cardiovascular and renal outcomes.
Management of Comorbidities
The treatment of comorbidities such as hypertension, coronary artery disease, obesity, and hyperlipidemia is detailed in the respective sections.