Empagliflozin Protects Cardiac Mitochondrial Fatty Acid Metabolism in a Mouse Model of Diet-Induced Lipid Overload



Sodium-glucose cotransporter 2 (SGLT2) inhibitors prevent heart failure and decrease cardiovascular mortality in patients with type 2 diabetes. Heart failure is associated with detrimental changes in energy metabolism, and the preservation of cardiac mitochondrial function is crucial for the failing heart. However, to date, there are no data to support the hypothesis that treatment with a SGLT2 inhibitor might alter mitochondrial bioenergetics in diabetic failing hearts. Thus, the aim of this study was to investigate the protective effects of empagliflozin on mitochondrial fatty acid metabolism.


Mitochondrial dysfunction was induced by 18 weeks of high-fat diet (HFD)-induced lipid overload. Empagliflozin was administered at a dose of 10 mg/kg in a chow for 18 weeks. Palmitate metabolism in vivo, cardiac mitochondrial functionality and biochemical parameters were measured.


In HFD-fed mice, palmitate uptake was 1.7, 2.3, and 1.9 times lower in the heart, liver, and kidneys, respectively, compared with that of the normal chow control group. Treatment with empagliflozin increased palmitate uptake and decreased the accumulation of metabolites of incomplete fatty acid oxidation in cardiac tissues, but not other tissues, compared with those of the HFD control group. Moreover, empagliflozin treatment resulted in fully restored fatty acid oxidation pathway-dependent respiration in permeabilized cardiac fibers. Treatment with empagliflozin did not affect the biochemical parameters related to hyperglycemia or hyperlipidemia.


Empagliflozin treatment preserves mitochondrial fatty acid oxidation in the heart under conditions of chronic lipid overload.

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Fig. 1
Fig. 2



Carbonyl cyanide m-chlorophenyl hydrazine


Electron transfer system


Fatty acid oxidation-dependent pathway


High-fat diet


NADH-dependent pathway


Sodium hydrogen exchanger


Oxidative phosphorylation


Residual oxygen consumption


Sodium-glucose cotransporter 2




  1. 1.

    Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28. https://doi.org/10.1056/NEJMoa1504720.

    CAS  Article  PubMed  Google Scholar 

  2. 2.

    Filippatos TD, Liontos A, Papakitsou I, Elisaf MS. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131(2):82–8. https://doi.org/10.1080/00325481.2019.1581971.

    Article  PubMed  Google Scholar 

  3. 3.

    Maejima Y. SGLT2 inhibitors play a salutary role in heart failure via modulation of the mitochondrial function. Front Cardiovasc Med. 2019;6:186. https://doi.org/10.3389/fcvm.2019.00186.

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl Sci. 2018;3(5):575–87. https://doi.org/10.1016/j.jacbts.2018.07.006.

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Yurista SR, Sillje HHW, Oberdorf-Maass SU, Schouten EM, Pavez Giani MG, Hillebrands JL, et al. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail. 2019;21:862–73. https://doi.org/10.1002/ejhf.1473.

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Mizuno M, Kuno A, Yano T, Miki T, Oshima H, Sato T, et al. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. Physiol Rep. 2018;6(12):e13741. https://doi.org/10.14814/phy2.13741.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Andreadou I, Efentakis P, Balafas E, Togliatto G, Davos CH, Varela A, et al. Empagliflozin limits myocardial infarction in vivo and cell death in vitro: role of STAT3, mitochondria, and redox aspects. Front Physiol. 2017;8:1077. https://doi.org/10.3389/fphys.2017.01077.

    Article  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, et al. Empagliflozin decreases myocardial cytoplasmic Na(+) through inhibition of the cardiac Na(+)/H(+) exchanger in rats and rabbits. Diabetologia. 2017;60(3):568–73. https://doi.org/10.1007/s00125-016-4134-x.

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Durak A, Olgar Y, Degirmenci S, Akkus E, Tuncay E, Turan B. A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol. 2018;17(1):144. https://doi.org/10.1186/s12933-018-0790-0.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2018;15:335–46. https://doi.org/10.1016/j.redox.2017.12.019.

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Makrecka-Kuka M, Liepinsh E, Murray AJ, Lemieux H, Dambrova M, Tepp K, et al. Altered mitochondrial metabolism in the insulin-resistant heart. Acta Physiol (Oxf). 2020;228(3):e13430. https://doi.org/10.1111/apha.13430.

    CAS  Article  Google Scholar 

  12. 12.

    Liepinsh E, Makrecka-Kuka M, Makarova E, Volska K, Svalbe B, Sevostjanovs E, et al. Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance. Pharmacol Res. 2016;113(Pt B):788–95. https://doi.org/10.1016/j.phrs.2015.11.014.

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Patorno E, Pawar A, Franklin JM, Najafzadeh M, Deruaz-Luyet A, Brodovicz KG, et al. Empagliflozin and the risk of heart failure hospitalization in routine clinical care. Circulation. 2019;139(25):2822–30. https://doi.org/10.1161/CIRCULATIONAHA.118.039177.

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME Trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–14. https://doi.org/10.2337/dc16-0330.

    Article  PubMed  Google Scholar 

  15. 15.

    Young ME, Guthrie PH, Razeghi P, Leighton B, Abbasi S, Patil S, et al. Impaired long-chain fatty acid oxidation and contractile dysfunction in the obese Zucker rat heart. Diabetes. 2002;51(8):2587–95. https://doi.org/10.2337/diabetes.51.8.2587.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Hawley SA, Ford RJ, Smith BK, Gowans GJ, Mancini SJ, Pitt RD, et al. The Na+/glucose cotransporter inhibitor canagliflozin activates AMPK by inhibiting mitochondrial function and increasing cellular AMP levels. Diabetes. 2016;65(9):2784–94. https://doi.org/10.2337/db16-0058.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, et al. SGLT2 inhibition by empagliflozin promotes fat utilization and browning and attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49. https://doi.org/10.1016/j.ebiom.2017.05.028.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Ye Y, Jia X, Bajaj M, Birnbaum Y. Dapagliflozin attenuates Na(+)/H(+) exchanger-1 in cardiofibroblasts via AMPK activation. Cardiovasc Drugs Ther. 2018;32(6):553–8. https://doi.org/10.1007/s10557-018-6837-3.

    CAS  Article  PubMed  Google Scholar 

  19. 19.

    Nambu H, Takada S, Fukushima A, Matsumoto J, Kakutani N, Maekawa S, et al. Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure. Eur J Pharmacol. 2020;866:172810. https://doi.org/10.1016/j.ejphar.2019.172810.

    CAS  Article  PubMed  Google Scholar 

  20. 20.

    Uthman L, Baartscheer A, Bleijlevens B, Schumacher CA, Fiolet JWT, Koeman A, et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia. 2018;61(3):722–6. https://doi.org/10.1007/s00125-017-4509-7.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Tomar D, Jana F, Dong Z, Quinn WJ 3rd, Jadiya P, Breves SL, et al. Blockade of MCU-mediated Ca(2+) uptake perturbs lipid metabolism via PP4-dependent AMPK dephosphorylation. Cell Rep. 2019;26(13):3709–25 e7. https://doi.org/10.1016/j.celrep.2019.02.107.

    CAS  Article  Google Scholar 

  22. 22.

    Fillmore N, Levasseur JL, Fukushima A, Wagg CS, Wang W, Dyck JRB, et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol Med. 2018;24(1):3. https://doi.org/10.1186/s10020-018-0005-x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  23. 23.

    How OJ, Aasum E, Kunnathu S, Severson DL, Myhre ES, Larsen TS. Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts. Am J Physiol Heart Circ Physiol. 2005;288(6):H2979–85. https://doi.org/10.1152/ajpheart.00084.2005.

    CAS  Article  PubMed  Google Scholar 

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Availability of Data and Materials

The data sets used and/or analyzed during the current study are available from the corresponding author on reasonable request.


Authors were supported by the European Union’s Horizon 2020 research and innovation program under grant agreement No. 857394.

Author information




M.M-K., M.D., and E.L. designed the research. M.M-K., S.K., M.V., K.V., H.C., and J.K. conducted experiments. M.M-K., M.D., and E.L. analyzed and interpreted the data. M.M.-K. wrote the manuscript. The study was supervised by M.M.-K., M.D., and E.L. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Marina Makrecka-Kuka.

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The experimental procedures involving animals were performed in accordance with the guidelines of the European Community and local laws and policies, and all of the procedures were approved by the Food and Veterinary Service, Riga, Latvia.

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Makrecka-Kuka, M., Korzh, S., Videja, M. et al. Empagliflozin Protects Cardiac Mitochondrial Fatty Acid Metabolism in a Mouse Model of Diet-Induced Lipid Overload. Cardiovasc Drugs Ther 34, 791–797 (2020). https://doi.org/10.1007/s10557-020-06989-9

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  • Empagliflozin
  • Fatty acid oxidation
  • Mitochondria
  • Heart