Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats

Abstract

The study aimed to investigate the effects of the sodium-glucose co-transporter 2 (SGLT2) inhibitor empagliflozin on chronic heart failure (HF) in normoglycemic rats. The effects of empagliflozin were compared with the standard medications for HF, e.g., angiotensin-converting enzyme (ACE) inhibitor fosinopril, beta-blocker bisoprolol, and aldosterone antagonist spironolactone. Myocardial infarction (MI) was induced in male Wistar rats via permanent ligation of the left descending coronary artery. One-month post MI, 50 animals were randomized into 5 groups (n = 10): vehicle-treated, empagliflozin (1.0 mg/kg), fosinopril (10 mg/kg), bisoprolol (10 mg/kg), and spironolactone (20 mg/kg). All medications except empagliflozin were titrated within a month and administered per os daily for 3 months. Echocardiography, 24-hour urine volume test, and treadmill exercise tests were performed at the beginning and at the end of the study. Treatment with empagliflozin slowed the progression of left ventricular dysfunction: LV sizes and ejection fraction were not changed and the minute volume was significantly increased (from 52.0 ± 15.5 to 61.2 ± 21.2 ml/min) as compared with baseline. No deaths occurred in empagliflozin group. The 24-hour urine volume tends to be higher in empagliflozin and spironolactone groups than in vehicle and fosinopril group. Moreover, empagliflozin exhibited maximal physical exercise tolerance in comparison with all investigated groups (289 ± 27 s versus 183 ± 61 s in fosinopril group, 197 ± 95 s in bisoprolol group, and 47 ± 46 s in spironolactone group, p = 0.0035 for multiple comparisons). Sodium-glucose co-transporter 2 inhibitor empagliflozin reduced progression of left ventricular dysfunction and improved tolerance of physical exercise in normoglycemic rats with HF. Empagliflozin treatment was superior with respect to physical tolerance compared with fosinopril, bisoprolol, and spironolactone.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Abbreviations

ACE:

Angiotensin-converting enzyme

CV:

Cardiovascular

EF:

Ejection fraction

FS:

Left ventricular fraction shortening

HF:

Heart failure

HR:

Heart rate

IVST:

Interventricular septum thickness

LA_ap:

Left atrial antero-posterior dimension

LA_l:

Left atrial long axis dimension

LA_s:

Left atrial short axis dimension

LV:

Left ventricular

LV EDV:

Left ventricular end-diastolic

LV EDD:

Left ventricle end-diastolic diameter

LV ESD:

Left ventricle end-systolic diameters

LV ESV:

Left ventricular end-systolic volumes

LVM:

Left ventricular myocardium mass

MAPSE:

Mitral annular plane systolic excursion

MI:

Myocardial infarction

MV:

Left ventricular minute volume

PWT:

Left ventricular posterior wall thickness in diastole

RA_l:

Long axis dimensions

RA_s:

Right atrium short axis

RAAS:

Angiotensin aldosterone system

RV:

Right ventricle antero-posterior dimension

RWT:

Left ventricular relative wall thickness

SGLT2:

Sodium-glucose co-transporter 2

SV:

Stroke volume

T2D:

Type 2 diabetes

TAPSE:

Tricuspid annular plane systolic excursion

References

  1. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, Poole-Wilson PA, Coats AJ (1997) Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation 96(2):526–534

    CAS  PubMed  Article  Google Scholar 

  2. Baartscheer A, Schumacher CA, Wüst RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ (2017) Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60(3):568–573

    CAS  PubMed  Article  Google Scholar 

  3. Beresneva ON, Kulikov AN, Parastaeva MM, Okovityi SV, Ivkin DY, Zaraiskii M (2017) The influence of empagliflozin on microRNA-21 urinary expression in Wistar rats with left coronary ligation. Nephrol Dial Transplant 32(Suppl 3):iii613–iii614. https://doi.org/10.1093/ndt/gfx174.MP504

    Article  Google Scholar 

  4. Cavaiola TS, Pettus J (2018) Cardiovascular effects of sodium glucose cotransporter 2 inhibitors. Diabetes Metab Syndr Obes 11:133–148

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. Boehringer Ingelheim Pharmaceuticals Inc. (2013) Pharmacology/toxicology NDA review and evaluation. NDA 204629

  6. Cezar MD, Damatto RL, Pagan LU, Lima AR, Martinez PF, Bonomo C, Rosa CM, Campos DH, Cicogna AC, Gomes MJ, Oliveira SA Jr, Blotta DA, Okoshi MP, Okoshi K (2015) Early spironolactone treatment attenuates heart failure development by improving myocardial function and reducing fibrosis in spontaneously hypertensive rats. Cell Physiol Biochem 36(4):1453–1466

    CAS  PubMed  Article  Google Scholar 

  7. Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN, Desjardins JF, Thai K, Gilbert RE (2019) Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic Transl Sci 4(1):27–37

    PubMed  PubMed Central  Article  Google Scholar 

  8. Empagliflozin outcome trial in patients with chronic heart failure with preserved ejection fraction (EMPEROR-Preserved). Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03057951?term=emperor&rank=2. Accessed 20 Feb 2017

  9. Empagliflozin outcome trial in patients with chronic heart failure with reduced ejection fraction (EMPEROR-Reduced). Clinicaltrials.gov. https://clinicaltrials.gov/ct2/show/NCT03057977?term=emperor&rank=1. Accessed 20 Feb 2017

  10. Gohlke P, Unger T (1995) Chronic low-dose treatment with perindopril improves cardiac function in stroke-prone spontaneously hypertensive rats by potentiation of endogenous bradykinin. 76(15):41E–45E

  11. Gohlke P, Linz W, Schölkens BA, Kuwer I, Bartenbach S, Schnell A, Unger T (1994) Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin. Hypertension 23(4):411–418

    CAS  PubMed  Article  Google Scholar 

  12. Grempler R, Thomas L, Eckhardt M, Himmelsbach F, Sauer A, Sharp DE, Bakker RA, Mark M, Klein T, Eickelmann P (2012) Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab 14(1):83–90

    CAS  Article  Google Scholar 

  13. Hayek T, Attias J, Coleman R, Brodsky S, Smith J, Breslow JL, Keidar S (1999) The angiotensin-converting enzyme inhibitor, fosinopril, and the angiotensin II receptor antagonist, losartan, inhibit LDL oxidation and attenuate atherosclerosis independent of lowering blood pressure in apolipoprotein E deficient mice. Cardiovasc Res 44:579–587

    CAS  PubMed  Article  Google Scholar 

  14. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ (2016) Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 134(10):752–772

    CAS  PubMed  Article  Google Scholar 

  15. Heidenreich P (2015) Heart failure prevention and team-based interventions. Heart Fail Clin 11(3):349–358

    PubMed  Article  Google Scholar 

  16. Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, Dollet L, Le May C, Toumaniantz G, Manrique A, Charpentier F, Staels B, Magré J, Cariou B, Prieur X (2017) The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes 66(4):1030–1040

    CAS  PubMed  Article  Google Scholar 

  17. Kaplan A, Abidi E, El-Yazbi A, Eid A, Booz GW, Zouein FA (2018) Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Fail Rev 23(3):419–437 https://doi.org/10.1007/s10741-017-9665-9

  18. Karpov AA, Ivkin DY, Dracheva AV, Pitukhina NN, Uspenskaya YK, Vaulina DD, Uskov IS, Eyvazova SD, Minasyan SM, Vlasov E, Buryakina AV, Galagudza MM (2014) Rat model of post-infarct heart failure by left coronary artery occlusion: technical aspects, functional and morphological assessment. Biomedicine 1:32–48

    Google Scholar 

  19. Kluger AY, Tecson KM, Lee AY, Lerma EV, Rangaswami J, Lepor NE, Cobble ME, McCullough PA (2019) Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc Diabetol 18(1):99

    PubMed  PubMed Central  Article  Google Scholar 

  20. Konstam MA, Kramer DG, Patel AR, Maron MS, Udelson JE (2011) Left ventricular remodeling in heart failure: current concepts in clinical significance and assessment. JACC Cardiovasc Imaging 4(1):98–108

    PubMed  Article  Google Scholar 

  21. Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P (2017) CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation 137(9):989–991

    Article  Google Scholar 

  22. Kulikov AN, Okovityj SV, Ivkin DY, Karpov AA, Lisitsky DS, Lyubishin MM et al (2016) Effects of empagliflozin in an experimental model of chronic heart failure in normoglycemic rats. Russ Heart Fail J 17(6):454–460

    Article  Google Scholar 

  23. Kulikov AA, Okovityi SV, Ivkin DY, Karpov AA, Lisitskyi DS, Lubishin MM, Alekseeva PA, Pitukhina NN, Smirnov AV, Kaiukov IG, Parusova EV (2017) Empagliflozin influence on the course of experimental heart failure in normoglycemic rats. Eur J Heart Fail 19–S1:165

    Google Scholar 

  24. Lee TM, Chang NC, Lin SZ (2017) Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 104:298–310

    CAS  PubMed  Article  Google Scholar 

  25. Martens P, Mathieu C, Verbrugge FH (2017) Promise of SGLT2 inhibitors in heart failure: diabetes and beyond. Curr Treat Options Cardiovasc Med 19(3):23

    PubMed  Article  Google Scholar 

  26. McMurray JJV, DeMets DL, Inzucchi SE, Køber L, Kosiborod MN, Langkilde AM, Martinez FA, Bengtsson O, Ponikowski P, Sabatine MS, Sjöstrand M (2019) Solomon SD; DAPA-HF Committees and Investigators. The dapagliflozin and prevention of adverse-outcomes in heart failure (DAPA-HF) trial: baseline characteristics. Eur J Heart Fail 21(11):1402–1411

    CAS  PubMed  Article  Google Scholar 

  27. Natali A, Nesti L, Fabiani I, Calogero E, Di Bello V (2017) Impact of empagliflozin on subclinical left ventricular dysfunctions and on the mechanisms involved in myocardial disease progression in type 2 diabetes: rationale and design of the EMPA-HEART trial. Cardiovasc Diabetol 16(1):130

    PubMed  PubMed Central  Article  Google Scholar 

  28. Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657

    CAS  Article  Google Scholar 

  29. Nilsson KR, Duscha BD, Hranitzky PM, Kraus WE (2008) Chronic heart failure and exercise intolerance: the hemodynamic paradox. Curr Cardiol Rev 4(2):92–100

    PubMed  PubMed Central  Article  Google Scholar 

  30. Okovityi SV, Beresneva ON, Parastaeva MM, Ivanova GT, Ivkin DY, Ivkina AS, Sipovsky VG, Zaraysky MI, Karpov AA, Kucher AG, Bogdanova EO, Sipovskaya EB, Kulikov AN, Kayukov IG (2018) Empagliflozin renal safety in normoglycemic rats failure. Nephrology (Saint-Petersburg) 22(1):83–90

    Article  Google Scholar 

  31. Roger VL (2013) Epidemiology of heart failure. Circ Res 113(6):646–659

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  32. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ (2019) Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol 73(15):1931–1944

    CAS  PubMed  Article  Google Scholar 

  33. Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radović N, Jadrijević S, Aleksic I, Walles T, Sauvant C, Sabolić I, Koepsell H (2015) Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch 467(9):1881–1898

    CAS  PubMed  Article  Google Scholar 

  34. Watanabe K, Ohta Y, Inoue M, Ma M, Wahed MI, Nakazawa M, Hasegawa G, Naito M, Fuse K, Ito M, Kato K, Hanawa H, Kodama M, Aizawa Y (2001) Bisoprolol improves survival in rats with heart failure. J Cardiovasc Pharmacol 38(Suppl 1):S55–S58

    CAS  PubMed  Article  Google Scholar 

  35. Xia A, Xue Z, Li Y, Wang W, Xia J, Wei T, Cao J, Zhou W (2014) Cardioprotective effect of betulinic acid on myocardial ischemia reperfusion injury in rats. Evid Based Complement Alternat Med 573745

  36. Yurista SR, Sillje HHW, Oberdorf-Maass SU, Schouten EM, Pavez Giani MG, Hillebrands JL, van Goor H, van Veldhuisen DJ, de Boer RA, Westenbrink BD (2019) 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 21(7):862–873 https://doi.org/10.1002/ejhf.1473

  37. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Silvio E (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128

    CAS  Article  Google Scholar 

Download references

Acknowledgments

We thank Kaiukov I.G., Beresneva O.N., and Galkina O.V. for their excellent technical assistance.

Funding

This work was supported by the St. Petersburg Chemical and Pharmaceutical University, Saint Petersburg, Russia.

Author information

Affiliations

Authors

Contributions

M. Krasnova: provision of study material, collection and assembly of data, data analysis and interpretation, and manuscript writing; A. Kulikov: conception and design, collection and assembly of data, data analysis and interpretation, and manuscript writing; S. Okovityi: conception and design, administrative support, data analysis, and interpretation; D. Ivkin: collection and assembly of data and data analysis; A. Smirnov: collection and assembly of data; A. Karpov: statistical data analysis and interpretation; E. Kaschina: data analysis and interpretation, manuscript writing advising, and final approval of manuscript. All authors read and approved the manuscript.

Corresponding author

Correspondence to Marina Krasnova.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Krasnova, M., Kulikov, A., Okovityi, S. et al. Comparative efficacy of empagliflozin and drugs of baseline therapy in post-infarct heart failure in normoglycemic rats. Naunyn-Schmiedeberg's Arch Pharmacol 393, 1649–1658 (2020). https://doi.org/10.1007/s00210-020-01873-7

Download citation

Keywords

  • Chronic heart failure
  • Left ventricular dysfunction
  • Empagliflozin
  • Physical exercise
  • Normoglycemic rats