Commentary on “Cardioprotective Effects of Dapagliflozin against Isoproterenol-induced Myocardial Injury in Rats: Biochemical and Histopathological Evidence”

Sodium-glucose cotransporter-2 inhibitors (SGLT2 inhibitors), a class of drugs initially approved for the treatment of diabetes mellitus, have rapidly revolutionized the therapeutic landscape. Besides diabetes mellitus, the SGLT2 inhibitors dapagliflozin (DAPA) and Empagliflozin are now approved for treatment of heart failure with reduced ejection fraction and for treatment of heart failure with preserved ejection failure. These drugs are also approved for the management of chronic kidney disease.1 In this issue of the journal Bayomy2 provide further preclinical evidence supporting the cardioprotective effects of DAPA in Isoproterenol (ISO) induced myocardial injury in rats. The study adds to the growing evidence confirming the ability of DAPA to cause significant reductions in cardiac injury biomarkers, cardiac troponin-I, creatine kinase-MB, and lactate dehydrogenase. DAPA attenuates lipid peroxidation and restores antioxidant defense mechanisms by upregulating superoxide dismutase and reduced glutathione (GSH). Pretreatment with DAPA also leads to a reduction of anti-inflammatory markers, tumor necrosis factor-alpha, and interleukin-6 (IL-6). The research demonstrates that DAPA regulates cardiomyocyte apoptosis by normalizing pro-apoptotic genes (BAX) while increasing expression of anti-apoptotic genes (Bcl2). Histopathological evidence shows preservation of structural integrity of cardiomyocytes, as evidenced by electron microscopy. This further adds to the mechanisms of DAPA’s useful effects in attenuating cardiac ischemia, a novel finding of this research. Many recent studies have explored various mechanisms of SGLT2 inhibitors, especially DAPA and empagliflozin, in preclinical models of myocardial injury causing acute ischemia. It was demonstrated that DAPA decreases ISO-induced cardiomyocyte hypertrophy by reducing cell size and improving cellular structure. DAPA reduces cardiac cytosolic Na+ and Ca2+ concentrations through inhibition of Na+/H+ exchanger (NHE1) and Glucose transporter 1 (GLUT1) expression in cardiomyocytes, which are thought to provide cardioprotective effects. Decreased reactive oxygen species production and inflammation by activating the AKT pathway, which influences downstream markers of fibrosis, hypertrophy, and inflammation, also play a critical role in its useful effects.3 It is known that mitochondria are present in abundance in the cardiac cells, where they are the source of energy in the form of Adenosine Triphosphate (ATP), and mitochondrial fission activity is one of the crucial events that affect cell function. A study found that DAPA mitigated ISO-induced cardiac hypertrophy by suppressing dynamin-associated protein 1-mediated mitochondrial fission. Furthermore, DAPA has been shown to prevent ISO-induced mitochondrial swelling and cristae breakage, hence preserving mitochondrial integrity against ischemic injury.4 Research has proven that SGLT2 inhibitors improve myocardial energetics by improving utilization of ketone bodies (KB) and free fatty acids.5 The epigenetic effects of KB Beta hydroxy butyrate have been proposed as these inhibit class 1 histone deacetylases and modify genes related to oxidative stress, as well as decreasing inflammation through the NLRP3 inflammasome pathway. Preclinical in vivo and in vitro studies in myocardial ischemic models have also proposed that DAPA inhibits iron overload and ferroptosis through the Mitogen-activated protein kinase signaling pathway. Ferroptosis is cell death involving a non–apoptotic mechanisms, mainly mediated through iron overload, depletion of GSH reductase, and accumulation of hydroperoxides.6 A recent study has shown that DAPA mitigates post-myocardial infarction cardiac fibrosis. It has proposed a dual-pathway by which DAPA attenuates cardiac remodeling in both in vivo and in vitro models by directly suppressing profibrotic activation in cardiac fibroblasts through reduced secretion of Collagen I and III and downregulation of α-smooth muscle actin expression.7 The plethora of mechanistic studies leading to the mounting preclinical evidence for the use of DAPA in ischemic injury calls for its clinical corroboration. There is a need for carefully designed clinical studies which could help reveal the usefulness of these drugs in the context of myocardial ischemic injury. Looking into the diverse cardiorenal-metabolic and pleotropic effects of DAPA and SGLT2 inhibitors as a group, one wonders whether we have stumbled on the most versatile drugs which could be labeled as the wonder drugs of the 21st century. However, as is always true in medicine, we need to tread cautiously while remaining optimistic. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.