Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

Abstract

Background and ObjectivesRecent studies have shown that sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce the risk of heart failure (HF)-associated hospitalization and mortality in patients with diabetes. However, it is not clear whether SGLT2 inhibitors have a cardiovascular benefit in patients without diabetes. We aimed to determine whether empagliflozin (EMPA), an SGLT2 inhibitor, has a protective role in HF without diabetes.MethodsCardiomyopathy was induced in C57BL/6J mice using intraperitoneal injection of doxorubicin (Dox). Mice with HF were fed a normal chow diet (NCD) or an NCD containing 0.03% EMPA. Then we analyzed their phenotypes and performed in vitro experiments to reveal underlying mechanisms of the EMPA's effects.ResultsMice fed NCD with EMPA showed improved heart function and reduced fibrosis. In vitro studies showed similar results. Phloridzin, a non-specific SGLT inhibitor, did not show any protective effect against Dox toxicity in H9C2 cells. SGLT2 inhibitor can cause increase in blood ketone levels. Beta hydroxybutyrate (βOHB), which is well known ketone body associated with SGLT2 inhibitor, showed a protective effect against Dox in H9C2 cells and in Dox-treated mice. These results suggest elevating βOHB might be a convincing mechanism for the protective effects of SGLT2 inhibitor.ConclusionsSGLT2 inhibitors have a protective effect in Dox-induced HF in mice. This implied that SGLT2 inhibitor therapy could be a good treatment strategy even in HF patients without diabetes.

Sodium–glucose cotransporter 2 inhibitor Dapagliflozin attenuates diabetic cardiomyopathy

“…The significant reductions of cardiovascular events with SGLT2I's could not be attributed solely to their glucose lowering effects. SGLT2 inhibitor (EMPA) had a protective effect in Dox-induced HF in mice as manifested by improved heart function and reduced fibrosis [21]. In the Fig.…”

The Role of AMPK Activation for Cardioprotection in Doxorubicin-Induced Cardiotoxicity

“…Different SGLT2 inhibitors have moreover been shown to activate AMPK in cardiofibroblasts [168] and adipocytes [169]. Two recent studies furthermore showed that SGLT2 inhibitors preserve heart function in mice [170] and rats [171] treated with DOX. Another antidiabetic drug, liraglutide, a glucagon-like peptide-1 (GLP1) analogue, protected rats from DOX-induced inflammation and necrosis by activating AMPK and the Akt signalling pathway [90].…”

Redox Imbalances in Ageing and Metabolic Alterations: Implications in Cancer and Cardiac Diseases. An Overview from the Working Group of Cardiotoxicity and Cardioprotection of the Italian Society of Cardiology (SIC)

“…In addition, more recently, sodium-glucose co-transporter 2 (SGLT2) inhibitors, a new class of antidiabetic agents that improve glycaemic control, were shown to reduce the risk of heart failure-associated hospitalization and mortality in patients with diabetes. Interestingly, it was demonstrated that SGLT2 inhibitors attenuated DOXO-induced cardiotoxicity in mice [154]. This protective effect was mediated by elevated beta-hydroxybutyrate levels, which reduced ROS production and improved mitochondrial dysfunction in cardiomyocytes.…”