Heart failure (HF) is a leading cause of mortality and morbidity worldwide [1]. HF is associated with several risk factors, the most prominent of which is T2DM, which has a high risk of mortality and short survival span. In addition, individuals with T2DM have a greater risk of HF independent of coronary heart disease, and some studies support HF prevention therapies ^[2][3][4][2,3,4]. These two abnormalities may be addressed effectively on their own, but establishing a treatment for HF associated with T2DM remains a challenge.

Sodium–glucose cotransporter-2 (SGLT-2) inhibitors are a class of hypoglycemic drug that was recently discovered to have potential cardiovascular-protective effects in adults ^[5][6][5,6]. SGLT-2 inhibitors modulate the sodium-glucose cotransporter in the proximal convoluted tubule of the kidney, preventing glucose reabsorption and lowering blood glucose by increasing urine glucose excretion [5]. SGLT-2 inhibitors have also been reported in recent studies to lower blood pressure and body weight, which may have cardiovascular implications ^{[6][7][8][9][10][11]}[6,7,8,9,10,11]. One of the SGLT-2 inhibitors is dapagliflozin, which is commonly used in HF clinics. Several well-designed randomized controlled trials (RCTs) of dapagliflozin have shown remarkable cardiovascular benefits ^[7][8][7,8].

Exercise capacity is defined as the ability of the cardiovascular system to supply sufficient oxygen to the musculoskeletal system during exercise and extract the supplied oxygen from the blood by the exercising muscles [9]. Exercise capacity is usually reduced in patients with HF and is characterized by an inability to sustain physical effort [9]. Dapagliflozin has demonstrated cardiovascular safety and efficacy in reducing cardiovascular events and related hospitalizations associated with HF regardless of the incidence of T2DM ^[10][11][12][10,11,12]. However, there is a controversial effect on exercise capacity. Therefore, the objective of this narrative resviearchw is to highlight the effect of dapagliflozin on exercise capacity and cardiovascular risk in individuals with HF reported in clinical studies.

2. Dapagliflozin as a Drug

Dapagliflozin is a selective SGLT-2 inhibitor that reduces renal glucose absorption by inhibiting the SGLT-2 receptors present in the S1 region of the proximal kidney tubules [12]. Dapagliflozin was recently approved in the United States for lowering the risk of HF hospitalizations in patients with T2DM and cardiovascular disease risk markers based on these promising results [10]. Dapagliflozin works by altering visceral fat and blood glucose levels, which are both elements of metabolic syndrome and linked to the severity of cardiovascular disease. The physiological mechanisms by which dapagliflozin produces its cardioprotective benefits are uncertain, and more research is anticipated. Dapagliflozin is used as a monotherapy in patients with T2DM who are resistant to metformin or for whom it is not recommended. In terms of lowering the levels of hemoglobin A1c (HbA1c), dapagliflozin is comparable to metformin as monotherapy [13]. Furthermore, in patients with suboptimal glycemic control, dapagliflozin could be used to supplement existing antihyperglycemic drugs. Dapagliflozin has a half-life of 12.9 h and is excreted mostly in the urine as its 3-O-glucuronide metabolite [10]. There is greater systemic circulation of dapagliflozin in patients with renal and hepatic dysfunction [14]. Dapagliflozin protects the heart and circulatory system through a complex mechanism. Improvements in the circumstances of ventricular preload, cardiac metabolism and bioenergetics, Na+/H+ exchange, sugar and lipid metabolism, circulatory load, cardiovascular system, and other factors could all be part of the mechanistic strategy (Figure 1) [15]. However, the underlying mechanisms of the prevention of HF are thought to be a relief of ventricular loading conditions and reduction of preload through diuretic and natriuretic actions. Dapagliflozin has an effect on the functionality of cardiac cells and a putative effect on modulating the cardiac physiology in HF ^[16][17][16,17]. A number of cardioprotective sequelae of dapagliflozin contribute to altering HF pathophysiology, including diuresis/natriuresis, blood pressure reduction, erythropoiesis, enhanced cardiac energy metabolism, inflammatory minimization, suppression of the sympathetic nervous system, and prevention of adverse cardiac remodeling [18]. In vitro, dapagliflozin causes adenosine 5′-monophosphate activated protein kinase (AMPK) phosphorylation, resulting in down-regulation of protein kinase (PKC) phosphorylation in cardiac myoblast H9c2 cells after hypoxia/reoxygenation (H/R) treatment. The AMPK/PKC nicotinamide adenine dinucleotide phosphate hydrogen (NADPH) oxidase pathway has shown that dapagliflozin therapy reduces H/R-induced oxidative stress. Through AMPK/PKC/NADPH oxidase signaling, dapagliflozin also corrects H/R-induced abnormalities in PGC-1 expression, mitochondrial membrane potential, and mitochondrial DNA copy number. Dapagliflozin appears to have the ability to reduce ischemia/reperfusion (I/R) induced oxidative stress and, subsequently, cardiac apoptosis by modulating AMPK, minimizing the cardiac dysfunction mediated by I/R injury [19]. In Sprague Dawley rats, dapagliflozin has been shown to alleviate angiotensin II-induced cardiac remodeling by modulating transforming growth factor (TGF)-1/Smad signaling in a non-glucose-lowering-dependent mechanism [11]. Another study suggested that dapagliflozin significantly reduces the high glucose-induced endothelial–mesenchymal transition (EndMT) in human umbilical vein endothelial cells (HUVECs) and fibroblast collagen secretion. Similarly, dapagliflozin abolishes upregulation of TGF/Smad signaling and inhibition of AMPK activity. The anti-EndMT actions of dapagliflozin were then reversed in HUVECs using AMPK siRNA and compound C. In addition, dapagliflozin can protect against dilated cardiomyopathy and myocardial fibrosis by decreasing fibroblast activation and EndMT through suppression of AMPK-mediated TGF/Smad signaling [20]. In a mouse model with transverse aortic constriction, dapagliflozin treatment improved cardiac systolic performance and prevented myocardial fibrosis and cardiomyocyte death, suggesting that it could be used as a novel therapeutic to combat pathological cardiac remodeling in non-diabetics [21].