Apoptosis is a type of programmed cell death that serves a key role in embryonic development and tissue homeostasis (64). Apoptosis is mediated by death receptors, also known as extrinsic apoptotic pathways and mitochondria, also called intrinsic apoptotic pathways, both of which can activate cysteine-dependent proteases (caspases) (65). Apoptosis serves a crucial role in the development of the heart and is associated with the occurrence and development of numerous cardiovascular diseases. Studies have reported that apoptosis is a pathological feature of MI and heart failure, and that the inhibition of apoptosis can prevent and treat post-MI remodeling and heart failure (66).

Further studies have reported that SGLT2is reduces cardiac remodeling and improves cardiac function by inhibiting the apoptosis pathways. EMPA inhibits cardiomyocyte apoptosis and improves cardiac remodeling in early MI in non-diabetic mice (67).

In mice with autoimmune myocarditis induced by α-myosin-heavy chain peptides, CANA markedly reduces the Bax/Bcl-2 ratio and the level of cleaved caspase-3 protein, followed by inhibition of apoptosis, which was reported to improve myocarditis (68). In cardiac I/R rats, DAPA-induced pre-ischemia upregulated the levels of anti-apoptotic protein Bcl-2 to protect cardiomyocytes from apoptosis, thereby alleviating cardiac mitochondrial dysfunction by reducing reactive oxygen species (ROS) production (43). DAPA mediates the cardioprotective effect in diabetic rats by activating the phosphorylation of Akt, JAK2 and MAPK signaling cascades, increasing the erythropoietin levels and reducing apoptosis (69). DAPA also normalizes mitochondrial fission and reduces cardiomyocyte apoptosis by activating the phosphoglycerate mutase member 5 (PGAM5)/dynamin-related protein 1 (Drp1) signaling pathway, thereby improving cardiac remodeling after acute MI (70). However, this study did not use an agonist for the PGAM5/Drp1 pathway, so the relationship between DAPA and the PGAM5/Drp1 signaling pathway could not be assessed.

A recent study reported that in Doxorubicin-induced cardiac dysfunction, DAPA decreased the cardiac expression of Bax and cleaved caspase-3, but increased the expression of Bcl-2, as well as signal transducer and activator of transcription 3 (STAT3) that was subsequently inhibited by Doxorubicin (71). These findings indicate that DAPA activates the expression of sirtuin1 (SIRT1), which inhibits the protein kinase RNA-like endoplasmic reticulum (ER) kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α)-C/EBP homologous protein signaling pathway of the ER stress response in angiotensin II (Ang II)-treated cardiomyocytes to reduce cardiomyocyte apoptosis and improve TAC-induced cardiac remodeling in mice (72). Therefore, it may be suggested that SGLT2is improves damaged cardiac function by continual myocardial cell apoptosis.

Many of the mechanisms are effectuated through the mitochondrial pathway. However, only a small number of studies have assessed the role of SGLT2is in myocardial cell apoptosis induced by the death receptor pathway. Hence, this mechanism should be evaluated to understand the anti-apoptotic mechanism of SGLT2is.

Autophagy is a process that degrades and recirculates damaged organelles, misfolded proteins and other macromolecules through lysosomal-dependent pathways to maintain cell homeostasis and function (73). Previous studies have shown a crucial role of basal autophagy in cardiac development and in the maintenance of normal cardiac function (74–77). However, insufficient or excessive autophagy can affect the development of pathological cardiac remodeling (78–80). Furthermore, the activation of autophagy leads to the death of cardiomyocytes in MI and I/R injury and has been shown to have a dual effect in numerous research models, which may be related to the Beclin 1 (BECN1) or AMPK-mammalian target of rapamycin (mTOR) pathways (81–83). Several studies have demonstrated that SGLT2is exerts cardioprotective effects through the activation or inhibition of autophagy.

In mouse models of coronary artery ligation-induced diabetic and non-diabetic MI, EMPA-treated mice demonstrated a significant decrease in cardiomyocyte death due to excessive autophagy, which reduced autophagic flux by targeting the Na⁺/H⁺ exchanger 1 (NHE1) on cardiomyocytes (63). EMPA exerts myocardial protective effects through mitochondrial autophagy and the novel BECN1-Toll-like receptor (TLR)9-SIRT3 axis (84). Furthermore, EMPA exerts cardioprotective effects in non-diabetic mice with MI with acute hyperglycemia by suppressing beclin 1 (BCN1)-dependent autophagy rather than targeting NHE1 in cardiomyocytes (85). Previous studies have demonstrated that BCN1 promotes the crosstalk between apoptosis and autophagy (86). In another study, EMPA was reported to inhibit ER stress-induced autophagy by inhibiting the PERK/activating transcription factor 4/BCN1 signaling pathway, thereby alleviating myocardial I/R injury and cardiomyocyte apoptosis (87). Furthermore, overexpression of p62 and light chain 3II/I activates autophagy when EMPA is administered. It reduces cardiac lipid toxicity in Zucker diabetic fatty (ZDF) rats (88).

Likewise, DAPA represses cardiac remodeling and hypoxia-induced apoptosis in heart failure through the activation of autophagy via the AMPK/mTOR pathway (89). It also protects against myocardial I/R injury by limiting NLR family pyrin domain containing 3 (NLRP3) inflammatory vesicle activation and regulating autophagy (90). The dose of DAPA administered in this study was 40 mg/kg/day, which is 20X higher compared with the allometric-adapted dose used in human clinical trials. It cannot be ruled out that the final result is related to high doses. SGLT2is exert cardioprotective effects through the activation and inhibition of autophagy via the interference of varied pathological conditions and detection time. SGLT2is regulate autophagy through the AMPK pathway, ER stress and inflammasomes. These pathways also regulate the processes of cell apoptosis, inflammation and angiogenesis. However, the association between these pathological processes and autophagy or the precise mechanisms of SGLT2is are yet to be elucidated.

Ferroptosis is a form of programmed cell death different from cell apoptosis, cell necrosis and cell autophagy. It is mediated by iron-dependent lipid peroxides and characterized by reduced intracellular glutathione (GSH) expression, reduced GSH peroxidase 4 (GPX4) activity and the accumulation of ROS and lipid peroxides (91–93). Several studies have shown the role of ferroptosis in numerous cardiovascular diseases, such as cardiomyopathy, MI, myocardial I/R injury, atherosclerosis and heart failure (94–98). Furthermore, SGLT2is exert cardioprotective effects through the ferroptosis pathway. In model rats, CANA can treat heart failure with preserved ejection fraction (HFpEF) by reducing iron intake and iron overload, reducing lipid peroxidation, increasing GSH production and inhibiting oxidative stress to regulate ferroptosis (99).

Furthermore, advanced glycation end-products inhibit the expression of solute carrier family 7 member 11 and ferritin in diabetic cardiomyopathy and reduce GSH levels. This elevates lipid peroxidation levels and ferroptosis, which in turn triggers cardiac inflammation and cardiac remodeling, including cardiomyocyte hypertrophy, pro-fibrotic response, fibrosis and ultimately cardiac dysfunction (100). Another study reported that CANA may reduce ferroptosis and improve myocardial oxidative stress in diabetic cardiomyopathy mice by regulating iron metabolism and the systemic cystine-glutamate antiporter (Xc⁻)/GSH/GPX4 axis (101). However, the relationship and specific mechanism of CANA in regulating iron metabolism and the Xc⁻/GSH/GPX4 axis require further evaluation. In addition, CANA has been reported to inhibit inflammation and ferroptosis through the activation of the AMPK pathway, thereby reducing lipotoxicity in cardiomyocytes (102).

Furthermore, EMPA prevents DNA oxidation and ferroptosis in trastuzumab-induced C57BL/6J mice, which attenuates cardiotoxicity (103). Likewise, DAPA suppresses the MAPK signaling pathway in a model of myocardial I/R injury, reducing ferroptosis and exerting protective benefits on the heart (104).

Inflammation is a leading factor affecting cardiac remodeling and the progression of heart failure (105,106). Toll-like receptors (TLRs), a family of transmembrane receptors, are recognized by danger-associated molecular patterns (DAMPs) in MI and activate nuclear factor-B (NF-κB), which in turn activates a cascade of inflammatory mediators, including cell adhesion molecules, chemokines, and inflammatory cytokines (107,108). Furthermore, the inflammasome, which are polymeric protein structures, form molecular platforms that are activated when cells are infected or stressed, stimulates the inflammatory response by activating several inflammatory cytokines, such as IL-1 and IL-18 (109). Thus, targeting specific cytokines, growth factors or inflammatory pathways could alleviate adverse cardiac remodeling.

The activation of multiple pro-inflammatory cytokines, such as TNF-α, IL-1 and IL-6, mediates cardiac remodeling through their effects on cardiomyocytes, fibroblasts and immune cells (110). These cytokines can induce cardiomyocyte hypertrophy and apoptosis (111–113). Pro-inflammatory cytokines enhance the activity of matrix metalloproteinases and decrease the production of extracellular matrix (ECM) components in fibroblasts, which causes the ECM to degrade (114–116). Thus, pro-inflammatory cytokines serve a role in pathological cardiac remodeling. Furthermore, the pleiotropic anti-inflammatory factor IL-10 decreases the expression of TNF-α, IL-1 and IL-6 to reduce cardiac inflammation (117,118).

Furthermore, SGLT2is downregulates pro-inflammatory cytokines and improves cardiac function in cardiovascular diseases. DAPA decreased the levels of inflammatory cytokines IL-6 and TNF-α in HFpEF pigs administered deoxycorticosterone acetate and Ang II to construct an ejection fraction-preserving heart failure model (41). Likewise, EMPA decreased TNF-α and IL-6 levels in patients with HfpEF and ZDF obese rats, reduced inflammation and enhanced myocardial function (119). Furthermore, EMPA markedly decreased the level of TNF-α and reduced myocardial fibrosis in hypertensive heart failure rats (42). DAPA decreased the levels of the pro-inflammatory cytokines IL-1, IL-6 and TNF-α in viral myocarditis mice infected with Coxsackievirus B3. DAPA facilitated macrophage polarization through STAT3-related pathways to reduce myocarditis (120). Furthermore, DAPA improves cardiac hypertrophy in streptozocin-induced type 2 diabetic rats by inhibiting the nuclear translocation of NF-κB and reducing the expression of calpain-1 in cardiomyocytes, decreasing IL-6 and TNF-α levels and upregulating IL-10 levels (58). In addition, DAPA regulates malondialdehyde, TNF-α and ROS levels by blocking the C-X3-C motif chemokine ligand 1/receptor 1 axis and NF-κB activity, thereby reducing lipopolysaccharide-induced inflammation and oxidative stress (121). However, this study was performed in vitro using H9C2 cells and requires validation in patients.

The NLRP3 inflammasome accelerates the process of fibrosis by stimulating the production of proinflammatory cytokines IL-1β and IL-18 (122). Several factors, including MI, stress, obesity, diabetes and metabolic syndrome, activate the NLRP3 inflammasome and promote inflammation (123–125). DAPA exerts anti-inflammatory effects on the development of diabetic cardiomyopathy in type 2 diabetic mice by decreasing the expression of NLRP3 inflammasome, IL-1β, IL-6 and TNF-α (126,127). Likewise, EMPA inhibits cardiac fibrosis and inflammation in non-diabetic mice treated with Doxorubicin via the NLRP3 and MyD88 signaling pathways and inhibition of NLRP3 and NF-κB inhibits the pro-inflammatory cytokine storms in Doxorubicin-treated cardiomyocytes (128). Furthermore, DAPA decreases p38-dependent TLR4 expression to prevent NLRP3 activation, which then enhances cardiac function in Doxorubicin-induced dilated cardiomyopathy (129). Finally, CANA reduces type 17 T-helper cell infiltration and protects cardiomyocytes from apoptosis by inhibiting the NLRP3 inflammasome pathway, which reduces myocarditis-induced cardiac inflammation (68).

Macrophages also serve a role in the inflammatory response during cardiac remodeling (130). SGLT2is reduce cardiac fibrosis by regulating macrophage M2 polarization in infarcted rat hearts via the STAT3 signaling pathway (131). Inflammatory and NF-κB signaling pathways are triggered in patients with arrhythmogenic cardiomyopathy (ACM) (132). DAPA reduces cardiac fibrosis and inflammation in ACM mice by reversing hypoxia-inducible factor (HIF)-2α signaling, inhibiting the NF-κB signaling pathway (133). Accumulating evidence indicates that the role of SGLT2is in controlling inflammation is associated with fat reduction, which is efficacious in epicardial adipose tissue (134). Although the aforementioned studies have reported that SGLT2is serve a myocardial-protective role through anti-inflammatory mechanisms, another study on EMPA reported conflicting results; EMPA did not show any effect on the NLRP3 inflammasome pathway or interleukin-1β levels (135). The present review concluded that the effectiveness of SGLT2is in inhibiting inflammation is indeterminate, and more comprehensive information is essential to draw further conclusions.

Oxidative stress is a redox imbalance caused by the excessive production of ROS and/or an impaired antioxidant response (136). The primary ROS sources in the heart are mitochondria, NADPH oxidase (NOX), xanthine oxidase (XO) and uncoupled nitric oxide synthase (NOS) (137). A large number of heart cells can be affected by NOX via redox signal transduction. NOX regulates redox-sensitive target proteins to limit the production of ROS (138). Under physiological circumstances, normal ROS signaling controls the growth and maturation of cardiomyocytes, the processing of cardiac calcium, excitatory systolic coupling and vascular tone (139). However, oxidative stress effectuated by a sharp rise in ROS causes cardiac hypertrophy, fibrosis, apoptosis and contractile failure under pathological circumstances (140). Furthermore, oxidative stress is considered a key factor in the development of pathological cardiac remodeling and heart failure, as this disrupts mitochondrial activity by inducing oxidative damage to mitochondrial DNA, RNA, lipids and proteins. Oxidative stress also impairs myocardial cell systolic function by inducing mitochondria-associated oxidative modifications of excitation-contraction-coupled core proteins (141). Several studies have shown that the cardiac benefits of SGLT2is are reduced oxidative stress in vivo and ameliorated mitochondrial dysfunction through multiple signaling pathways.

EMPA improves mitochondrial function by inhibiting mitochondrial fission in type 2 diabetic hearts, as demonstrated by an increase in the expression of mitochondrial fusion-related proteins mitofusin-1 and optic atrophy 1 and the inhibition of DRP1 expression in type 2 diabetic db/db mice and H9C2 cardiomyocytes. In the present study, oxidative stress was reduced by increasing the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream genetic targets (59).

DAPA protects cardiomyocytes from hyperglycemia-induced damage by inhibiting NOX-mediated oxidative stress (142), whereas treatment with EMPA reduces LV hypertrophy and fibrosis after TAC and MI in non-diabetic mouse models and Sprague Dawley (SD) rats with coronary artery ligation-induced oxidative stress. Hypertrophy and fibrosis were improved by upregulating mitochondrial biogenesis, enhancing mitochondrial oxidative phosphorylation, reducing ROS production, attenuating apoptosis and increasing autophagy (39,143). EMPA treatment in diet-induced obese mice reduced cardiac fat accumulation and mitochondrial injury, improved myocardial hypertrophy and cardiac fibrosis and reduced cardiac dysfunction. This effect may be reduced by Sestrin2-mediated AMPK-mTOR signaling and Nrf2/heme oxygenase 1-mediated oxidative stress responses (144). In addition, EMPA inhibited high-fructose diet-induced cardiac dysfunction in type 2 diabetic SD rats by attenuating mitochondria-driven oxidative stress (145). DAPA reduces oxidative stress, mitochondrial dysfunction, fibrosis, hypertrophy and inflammation in Doxorubicin-stimulated rats via inhibition of PI3K/AKT/Nrf2 signaling (61). This study used only male and no female animals, while females may be more sensitive to Doxorubicin and mimic the clinical state.

Modifications in myocardial energy metabolism contribute to the development of pathological cardiac remodeling (146). It is often manifested by a switch of the heart back to the fetal genetic program and a shift in preference of metabolic substrate from fatty acids to glucose (147,148). Cardiac remodeling is associated with reduced lipid oxidation capacity and increased glucose dependence (149). Although the conversion of myocardial metabolic substrates from fatty acids to glucose lowers oxygen consumption, it can be detrimental to cardiac performance and aggravate heart failure because of insufficient energy production (150,151). Furthermore, preserving fatty acid oxidation during stress overload prevents the effects of glucose on cardiac remodeling (152,153). Thus, promoting the use of fatty acids and other metabolic substrates to regulate energy metabolism may be a promising therapeutic strategy for heart failure and to improve cardiac remodeling (154).

EMPA reduces excessive glycolysis in TAC-induced cardiac overload mice by binding to glucose transporter (GLUT) proteins, such as GLUT1 and GLUT4, which increases the expression of CD36, restores fatty acid uptake and improves mitochondrial oxidative phosphorylation. The reduced glucose uptake may also lead to an impaired pentose phosphate pathway, which in turn activates AMP-activated protein kinases and blocks mTOR complex 1 (mTORC1) to reduce cardiac hypertrophy (57).

Contrastingly, EMPA has been shown to improve diabetic cardiac remodeling in diabetic cardiomyopathic rats by reducing fatty acid and increasing glucose metabolism (155), although this may be related to increased fatty acids in diabetic heart disease, which leads to lipid toxicity and insulin resistance (146,156), hence the contrasting results reported. EMPA significantly elevated cardiac metabolism and cardiac ATP production in coronary artery-ligated non-diabetic male SD rats by increasing ketone body bioavailability and myocardial oxidation of glucose and fatty acids (39). However, this study did not provide direct evidence that EMPA-treated hearts were associated with increased ketone body oxidation, nor did it quantify the relationship between ketone body oxidation and increased myocardial ATP levels.

Similarly, EMPA altered the myocardial fuel metabolic substrates from glucose to ketone bodies, free fatty acids and branched-chain amino acids in non-diabetic pigs induced by 2 h of proximal balloon occlusion of the left anterior descending branch. This improved myocardial energy, enhanced LV systolic function and improved unfavorable LV remodeling (38).

Angiogenesis is the physiological and pathological process of forming new microvessels from pre-existing capillaries in response to hypoxia. Angiogenesis involves endothelial cell proliferation, migration, differentiation, tube formation and regulation of angiogenic factors (157–159). The development of cardiac remodeling is significantly influenced by microvascular density (157,160). Several studies have demonstrated that promoting angiogenesis increases the density of microvessels and arteriolar, thus reducing cardiac remodeling (161–165).

Previous studies have shown that EMPA promotes myocardial microcirculatory perfusion and cardiac function by reducing AMPK-mediated mitochondrial fission and oxidative stress and stabilizing F-actin (166). Studies in a mouse model of diabetes-related hindlimb ischemia found that DAPA promotes vascular endothelial cell proliferation and migration through the prolyl hydroxylase domain protein 2/HIF-1α axis, the secretion of multiple angiogenic factors, the formation of neovascularization and increases in blood perfusion (167). EMPA improves systolic dysfunction during LV pressure overload in mice by activating the AKT/endothelial NOS (eNOS)/NO pathway to prevent endothelial apoptosis and maintain capillarization (168). In the event of myocardial I/R injury in non-diabetic mice, EMPA inhibits the DNA-dependent protein kinase catalytic subunit/fission 1 protein/mitochondrial fission pathway, protecting the microvascular system (169). However, the microvascular function in vivo is difficult to evaluate. In this study, only electron microscopy was used to observe the structural changes of microvessels in mice treated with EMPA, which is insufficient. However, coronary blood flow reserve can also be used. Another study demonstrated that DAPA reduces cardiac endothelial dysfunction and microvascular injury by inhibition of the XO/sarco(endo) plasmic reticulum calcium ATPase 2/calmodulin-dependent kinase II/coffilin pathway in I/R injury mice (170). EMPA also improves endothelial cell dysfunction induced by a mutant aldehyde dehydrogenase 2 unable to metabolize acetaldehyde by inhibiting NHE1 and activating the AKT kinase and eNOS pathways (171). EMPA attenuates cardiac microvascular I/R injury through the activation of the AMP-activated protein kinase α1 (AMPKα1)/UNC-52-like kinase 1/FUN14 domain containing 1/mitophagy pathway (172).

The development of cardiac fibrosis is regulated by members of the TGF-β family, particularly TGF-β1, which activates Smad-dependent or non-Smad-mediated signaling pathways (173). TGF-β1 is a key cytokine mediating the conversion of cardiac fibroblasts into myofibroblasts that is regulated by numerous substances (174). Previous studies have shown that EMPA significantly decreases TGF-β1/Smad2 levels and upregulates the expression of the negative feedback regulator Smad7 to alleviate cardiac oxidative stress and fibrosis in diabetic mice (175). Furthermore, the antifibrotic activity of Smad7 on TGF-β and epidermal growth factor receptor 2 reduces myofibroblast activation and the production of structural and matrix proteins (176). Early administration of EMPA during MI reduces myocardial fibrosis and inhibits the TGF-1/Smad3 fibrotic pathway (177). This study explored the effects of EMPA on early cardiac physiology and fibrosis after myocardial infarction. Only samples taken after 4 weeks of administration were examined, and earlier samples were not evaluated, so the results may differ. DAPA reduces TGF-β1 levels and increases the expression of the negative feedback regulator Smad7 in Ang II-induced cardiac remodeling (178).

Reportedly, the activation of AMPKα inhibits the TGF-β/Smad pathway (179,180). DAPA protects against diabetic cardiomyopathy and myocardial fibrosis by inhibiting endothelial-interstitial transformation and fibroblast activation in the AMPKα/TGF-β/Smad signaling pathway (181). Furthermore, DAPA reduces myocardial fibrosis by inhibiting TGF-β1/Smad signaling pathways in normoglycemic chronic heart failure rabbits (182).

MAPK is a class of highly conserved serine/threonine protein kinases regulated by a cascade of tertiary phosphorylation activation (183,184). MAPK is divided into four subgroups: Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), p38 MAPK and ERK5 (185,186). Under pathological conditions, the MAPK signaling pathway is activated by numerous extracellular stimulation signals and is essential for cell proliferation, differentiation, apoptosis and stress response (184,187). These findings suggested that the MAPK signaling pathway regulates cardiac remodeling due to multiple pathologies (188–191).

Furthermore, TAC activated ERK1/2, p38 and JNK in mice and treatment with DAPA inhibited the expression of JNK and p38 to reduce cardiac remodeling (56). Likewise, DAPA attenuated palmitic acid-induced cell hypertrophy and apoptosis and improved cardiac dysfunction and remodeling in high-fat diet-induced obese mice. This protective effect both in vivo and in vitro is mediated by the NHE1/MAPK signaling pathway (192), and whether DAPA exerts cardio-protective effects through NHE1 requires further evaluation. Furthermore, this suggests that the protective effect of EMPA on the heart may be mediated through stimulation of the ERK1/2 signaling pathway in I/R injury (69).

mTOR, a class of atypical serine/threonine protein kinases, is a member of the phosphatidylinositol 3-kinase (PI3K)-related protein kinase family. The interaction of mTOR with different proteins forms two macromolecular complexes with different structures and functions, mTORC1 and mTORC2 (193). mTOR also integrates multiple extracellular signals, such as nutrient levels, energy and growth factors, and serves a role in cell growth, proliferation, survival, protein synthesis, autophagy and metabolism (194,195). Several studies have shown its crucial role in the physiological and pathological processes of the heart (196–201). Furthermore, the Akt and AMPK pathways are regulators of mTORC1, with AMPK negatively regulating the mTOR signaling pathway (202).

Another study reported that Ertugliflozin reduces LV fibrosis in mice with cardiac hypertrophy by activating the AMPK/mTOR pathway and inhibiting its downstream targets p70S6K and 4E-BP1 (203). This target mediates translation to promote mTORC1 synthesis and causes mTORC1-induced myocardial hypertrophy (204). Likewise, EMPA modulates autophagy in cardiomyocytes to ameliorate sunitinib-induced cardiac dysfunction, an effect mediated by the activation of sunitinib-inhibited AMPK and reducing Sunitinib-activated mTOR levels (37). AMPK/mTOR is one of the main pathways regulating autophagy, which can be regulated by direct phosphorylation of UNC-51-like kinases 1 (205). Furthermore, EMPA improves obesity-related cardiac dysfunction by increasing the AMPK level and endothelial nitric oxide synthase phosphorylation, and inhibiting Akt and mTOR phosphorylation (144). Previous research has demonstrated that the heart can be protected by inhibiting the PI3K/AKT/mTOR pathway (206). CANA alleviates cardiomyocyte lipotoxicity in diabetic cardiomyopathy mouse models by blocking the mTOR/HIF-1 pathway (207). Likewise, CANA is an SGLT1i/SGLT2is and its impact on the mTOR signaling pathway should be excluded from SGLT1 interference.

Serum and glucocorticoid-induced protein kinase 1 (SGK1) are the main mediators of cardiac remodeling through the activation of epithelial sodium channel (ENaC) proteins responsible for promoting fibrosis and upregulating NHE1 activity (208,209). DAPA attenuates LVDD and myocardial fibrosis by modulating SGK1 signaling and ENaC protein (210). Due to the use of pigs in this study, the sample size was small and the results had statistical limitations. The JAK/STAT signaling pathway is a promoter of fibroblast activation and ischemic-induced cardiac dysfunction (211,212). CANA attenuates fibrosis by reducing JAK/STAT signaling, activating AMPK and through antioxidant signaling (213). Characteristics of diabetic cardiomyopathy include decreased cyclic guanosine monophosphate (cGMP) levels and altered soluble guanylate cyclase enzyme (sGC)-cGMP- dependent protein kinase (PKG) signaling, which regulate systolic and diastolic dysfunction under diabetic conditions (214,215). Furthermore, EMPA improves cardiac function by preventing oxidative stress-induced injury via the sGC/cGMP/PKG pathway (216).