- Open Access
Empagliflozin improves cardiac function in heart failure with reduced ejection fraction independent of loading conditions
Cardiovascular Diabetology volume 19, Article number: 29 (2020)
The study regarding load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction is very interesting. But there are a few things we need to pay attention to.
The present Commentary refers to the recently published article by Connelly et al.  describing that empagliflozin contributes to improving cardiac function in experimental heart failure with reduced ejection fraction (HFrEF). EMPA-REG OUTCOME demonstrated that patients with type 2 diabetes at high risk for cardiovascular events who received empagliflozin, as compared with placebo, had a lower rate of the primary composite cardiovascular outcome and of death from any cause when the study drug was added to standard care . The underlying mechanisms are also being explored. It has been shown that empagliflozin improves hemodynamics in a hypertensive heart failure rat model, associated with renal protection, attenuated cardiac fibrosis, and normalization of HF genes . Glycaemic control with empagliflozin significantly ameliorated myocardial oxidative stress injury and cardiac fibrosis in diabetic mice . The drug also improves primary hemodynamic parameters and attenuates the progression of atherosclerosis by reducing hyperlipidemia and hyperglycemia  and reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats . Moreover, empagliflozin improves coronary microvascular function and contractile performance in prediabetic ob/ob−/− mice  and attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway . We believe that it is important and necessary to analyze and report the potential underlying mechanism of empagliflozin for the benefit of heart failure, especially HFrEF, both load-dependent and load-independent effects. This study identified experimental HFrEF model through ligation of the left anterior descending coronary artery to induce myocardial infarction of the left ventricle to suggest that empagliflozin had major beneficial effects on the principal load-independent measures of systolic function, preload recruitable stroke work relationship and end systolic pressure volume relationship, indicating its salutary effects were, at least in part, due to actions beyond a direct effect of reduced preload and afterload . But there are a few things we need to pay attention to. Firstly, this study established an experimental HFrEF model after myocardial infarction. Although this post myocardial infarction model develops structural hallmarks of HFrEF , there are many causes of HFrEF, a more ideal model of heart failure is warranted. In addition, following confirmation of infarct size with echocardiography 1-week post myocardial infarction, animals were then further randomized to receive the vehicle, or the sodium-glucose linked cotransporter-2 inhibitor, empagliflozin (20 mg/kg/day by gavage), for 6 weeks . Prior to randomized administration, the authors applied echocardiography only to determine the infarct size but did not confirm the structure of the heart, ejection fraction value, and other typical features and phenotypes of HFrEF. Thirdly, 20 mg/kg/day of empagliflozin was administrated, this is really too much. Remember, the dose of empagliflozin is only 10 mg or 25 mg once daily in clinical trials [2, 10], translating less than 3 mg/kg/day for rats. Finally, this is an experimental study, that is to say, a report from nonhuman study. We need evidence from clinical trials to further confirm this.
Availability of data and materials
Heart failure with reduced ejection fraction
Connelly KA, Zhang Y, Desjardins J-F, Nghiem L, Visram A, Batchu SN, Yerra VG, Kabir G, Thai K, Advani A, et al. Load-independent effects of empagliflozin contribute to improved cardiac function in experimental heart failure with reduced ejection fraction. Cardiovasc Diabetol. 2020;19(1):13.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Lee H-C, Shiou Y-L, Jhuo S-J, Chang C-Y, Liu P-L, Jhuang W-J, Dai Z-K, Chen W-Y, Chen Y-F, Lee A-S. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18(1):45.
Li C, Zhang J, Xue M, Li X, Han F, Liu X, Xu L, Lu Y, Cheng Y, Li T, et al. SGLT2 inhibition with empagliflozin attenuates myocardial oxidative stress and fibrosis in diabetic mice heart. Cardiovasc Diabetol. 2019;18(1):15.
Dimitriadis GK, Nasiri-Ansari N, Agrogiannis G, Kostakis ID, Randeva MS, Nikiteas N, Patel VH, Kaltsas G, Papavassiliou AG, Randeva HS, et al. Empagliflozin improves primary haemodynamic parameters and attenuates the development of atherosclerosis in high fat diet fed APOE knockout mice. Mol Cell Endocrinol. 2019;494:110487.
Aragón-Herrera A, Feijóo-Bandín S, Otero Santiago M, Barral L, Campos-Toimil M, Gil-Longo J, Costa Pereira TM, García-Caballero T, Rodríguez-Segade S, Rodríguez J, et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol. 2019;170:113677.
Adingupu DD, Göpel SO, Grönros J, Behrendt M, Sotak M, Miliotis T, Dahlqvist U, Gan L-M, Jönsson-Rylander A-C. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob mice. Cardiovasc Diabetol. 2019;18(1):16.
Lu Q, Liu J, Li X, Sun X, Zhang J, Ren D, Tong N, Li J. Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway. Mol Cell Endocrinol. 2020;501:110642.
van Heerebeek L, Borbély A, Niessen HWM, Bronzwaer JGF, van der Velden J, Stienen GJM, Linke WA, Laarman GJ, Paulus WJ. Myocardial structure and function differ in systolic and diastolic heart failure. Circulation. 2006;113(16):1966–73.
Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2):356–63.
We thank all scientists and participants involved in HFrEF. We would like to extend our highest thanks and respect to public health professionals and medical professionals combating COVID-19!
This work was funded by National Natural Science Foundation of China (81774229), Jiangsu Leading Talent Project of Traditional Chinese Medicine (Jiangsu TCM 2018 No. 4), Jiangsu Science and Technology Department Project (BK20161115), Major Project of Nanjing Medical Science and Technology Development during 13th Five-year Plan (ZDX16013), and Jiangsu Universities Nursing Advantage Discipline Project (2019YSHL095).
Ethics approval and consent to participate
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Liang, B., Zhao, YX. & Gu, N. Empagliflozin improves cardiac function in heart failure with reduced ejection fraction independent of loading conditions. Cardiovasc Diabetol 19, 29 (2020). https://doi.org/10.1186/s12933-020-01004-9
- Heart failure with reduced ejection fraction
- Sodium-glucose linked cotransporter-2 inhibitor