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Korean Circ. J., Dec 2019, 49 (12) | https://doi.org/10.4070/kcj.2019.0180 Cardioprotective Potential of an SGLT2 Inhibitor Against Doxorubicin-Induced Heart Failure

Chang Myung Oh ^{1 †}, Sungsoo Cho ^{2 †}, Ji Yong Jang ³, Hyeongseok Kim ⁴, Sukyung Chun ¹, Minkyung Choi ¹, Sangkyu Park ^{5 *}, Young Guk Ko ^{6 *}

¹Division of Endocrinology and Metabolism, CHA Bundang Medical Center, School of Medicine CHA University, Seongnam, Korea.
²Division of Cardiovascular medicine, Department of Internal medicine, Dankook University Hospital, Dankook University School of Medicine, Cheonan, Korea.
³Division of Cardiology, National Health Insurance Service Ilsan Hospital, Goyang, Korea.
⁴Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea.
⁵Department of Biochemistry, College of Medicine, Catholic Kwandong University, Gangneung, Korea.
⁶Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University College of Medicine, Seoul, Korea.

^†These authors contributed equally

^*Corresponding authors: correspondence to Sangkyu Park or Young Guk Ko

Abstract

Background and Objectives
Recent 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.

Methods
Cardiomyopathy 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.

Results
Mice 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.

Conclusions
SGLT2 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.

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