Sodium–glucose cotransporter 2 inhibitors represent a paradigm shift in the prevention of heart failure in type 2 diabetes patients

Figure 1. Classification of 3 type of heart failure and clinical diagnosis of HFpEF Characteristics of patients with heart failure with preserved ejection fraction(HFpEF) were shown in this figure. BNP, brain natriuretic peptide; CMRI, cardiac magnetic resonance imaging; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LVEF, left ventricular ejection fraction; NT‐proBNP, N‐terminal prohormone of brain natriuretic peptide; TTE, transthoracic echocardiography 39 , 45 , 46 .

Figure 2. Potential mechanisms for the progression of heart failure. Patients with diabetes can be placed into two categories: those who have visceral obesity and type 2 diabetes mellitus (T2DM), with multiple coronary risk factors; and those who are lean, and have long‐standing, poorly controlled type 2 or type 1 diabetes mellitus (T1DM). The former category is characterized by the progression of coronary atherosclerosis, resulting in acute coronary syndrome and severe local perfusion defects, then progression to heart failure with reduced ejection fraction (HFrEF). In addition, insulin resistance and hyperinsulinemia induce volume overload, resulting in high cardiac preload. Furthermore, insulin resistance and visceral adiposity are associated with vascular inflammation, endothelial cell dysfunction and a reduction in capillary density, which lead to higher cardiac afterload and an impairment in left ventricular distension, resulting in the progression of heart failure with preserved ejection fraction (HFpEF). The latter category comprises patients with prolonged hyperglycemia, and hyperglycemia‐induced vascular and cardiac tissue abnormalities, which impair left ventricular distension…

Figure 3. Oxidative stress and effects of inflammatory cytokines in the cardiac tissue in obese type 2 diabetes patients and the sites of sodium–glucose cotransporter 2 (SGLT2) inhibitor action. Systemic low‐grade inflammation is a characteristic of patients with visceral obesity and insulin resistance. Plasma inflammatory cytokine concentrations are high in these patients, and activate intracellular cytokine signaling in cardiomyocytes. Impaired activation of endothelial nitric oxide synthase (eNOS) and higher nicotinamide dinucleotide phosphate (NADPH) oxidase activity in endothelial cells are also characteristics of patients with insulin resistance. Oxidative stress in cardiac tissues also induces intracellular inflammatory cytokine signaling in cardiomyocytes, which results in higher nitric oxide synthase (iNOS) expression, cell death, accumulation of extracellular matrix (ECM) proteins, and an increase in the rigidity of proteins in cardiac muscle cells. Furthermore, systemic inflammation and the activation of endothelial cells stimulates monocyte infiltration and transformation into macrophages. Activated macrophages produce transforming growth factor‐β (TGF‐β), which in turn…

Figure 4. Sodium–glucose cotransporter 2 (SGLT2) inhibitors inhibit Na+‐H+ exchanger 1 (NHE1) and increase ketone body production, which ameliorate cardiac dysfunction in type 2 diabetes. The NHE1 is directly inhibited by SGLT2 inhibitors. The activation of NHE1 increases cytosolic [Na+] and [Ca2+], and reduces mitochondrial [C2+]. These ionic derangements result in impaired efficiency of mitochondrial adenosine triphosphate (ATP) production, Ca2+ overload and cell death. Treatment with SGLT2 inhibitors ameliorates these abnormalities in intracellular ion concentrations. Plasma ketone body concentrations are high in diabetes patients because of insulin deficiency, higher counter‐regulatory hormone activity and a deficiency in dietary carbohydrate intake. Although ketone body production in diabetes is high in both the fasting and postprandial states, SGLT2 inhibitors also increase serum ketone concentrations. Red arrows: ↑ increase, ↓ decrease. β‐HB, β‐hydroxybutyrate; AcAc CoA, acetoacetyl coenzyme A; AcAc, acetoacetate; MCT, monocarboxylate transporter; NCX, Na+‐Ca2+ exchanger; VDCC, voltage‐dependent calcium channel.