Empagliflozin, an SGLT2 Inhibitor, Reduced the Mortality Rate after Acute Myocardial Infarction with Modification of Cardiac Metabolomes and Antioxidants in Diabetic Rats

Abstract

The mechanism by which SGLT2 inhibitors reduce cardiac events in diabetic patients remains unclear. Here, we examined the effects of an SGLT2 inhibitor on the acute survival rate after myocardial infarction (MI) in an animal model of type 2 diabetes mellitus (DM) and the possible involvement of modification of cardiac metabolomes and antioxidative proteins. MI was induced in DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats and Long-Evans Tokushima Otsuka (LETO) control rats. Treatment with empagliflozin (10 mg/kg per day, 14 days) before MI reduced blood glucose and increased blood and myocardial b-hydroxybutyrate (bOHB) levels in OLETF. Survival rate at 48 hours after MI was significantly lower in OLETF rats than in LETO rats (40% vs. 84%), and empagliflozin significantly improved the survival rate in OLETF rats to 70%, although the sizes of MI were comparable. Patterns of metabolomes and gene expression in the noninfarcted myocardium of OLETF rats were consistent with increased fatty acid oxidation and decreased glucose oxidation. The patterns were modified by empagliflozin, suggesting both increased glucose oxidation and ketone utilization in OLETF rats. Empagliflozin prevented reduction of ATP level in the noninfarcted myocardium after MI and significantly increased myocardial levels of Sirt3 and superoxide dismutase 2 in OLETF rats. Administration of bOHB partially mimicked the effects of empagliflozin in OLETF rats. The results suggest that empagliflozin prevents DM-induced increase in post-MI mortality, possibly by protective modification of cardiac energy metabolism and antioxidant proteins.

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

“…Furthermore, it has been found that the utilization rate of ketone bodies is reduced during the course of myocardial ischemia [33]. Studies have suggested that increasing the use of ketone bodies, fatty acid, and branched-chain amino acids inhibited adenosine triphosphate (ATP) reduction, increasing ATP content in the myocardium in the empagliflozin group [34]. In the present study, the serum ketone bodies were also increased in the empagliflozin group, which may have resulted in the decreased myocardial oxygen consumption and decreased cardiac sympathetic nerve activity in patients with AMI being administered empagliflozin.…”

Predictive value of random blood glucose versus fasting blood glucose on in-hospital adverse events in patients with ST-segment elevation acute myocardial infarction

“…Specifically, acute hyperglycemia exaggerates inflammation by the oxidative mechanism [27]. Animal experiments show that SGLT2 inhibitors can reduce the mortality of myocardial infarction in diabetic mice through cardiac energy metabolism and protective modification of antioxidant proteins, suggesting that hyperglycemia is associated with energy metabolism disorder and oxidative stress in myocardial infarction [28]. Risso reported that intermittent high glucose enhanced apoptosis of human endothelial cells [29].…”

Effect of hyperglycaemia and diabetes on acute myocardial ischaemia–reperfusion injury and cardioprotection by ischaemic conditioning protocols

“…Furthermore, anti-diabetic drugs can either confer cardioprotection or interfere with endogenous cardioprotection & Penna, 2011;Skyschally et al, 2009). IPost has been reported to confer cardioprotection via the production of several different autacoids (such as bradykinin, adenosine and opioids), which recruit known cardioprotective signalling pathways (such as the SAFE, NO/PKG and RISK cascades) and which converge on the mitochondrial permeability transition pore (Bell et al, 2016;Boengler, Heusch, & Schulz, 2011;Cohen & Downey, 2011;Lacerda, Opie, & Lecour, 2012;Oosterlinck et al, 2013;Pagliaro et al, 2011;Penna et al, 2015).…”