Dynamics of chronic heart failure with a low ejection fraction when dapagliflozin is included in standard therapy

Objective. The aim of the current research is the dapagliflozin influence on the key parameters that shows the severity of heart failure among patients with chronic heart failure with low ejection fraction.

Materials and methods. The research involves 30 mail patients average aged 61,6 ± 11,1. The basis of involving the patients is the following: heart failure with low ejection fraction of any origin and common therapy of chronic heart failure including inhibitors of angiotension converting enzyme/ antagonist of angiotension II receptors, β-blockers, antagonist of mineralocorticoid receptors. The NTproBNP level in blood was defined and there were the transthoracal echocardioscopy with Doppler mapping along with ejection fraction determination according to Simpson, the 6-minute walking test, the questionnaire on health EQ-5D, the Montreal assessment scale of cognitive functions among the heart failure with low ejection fraction patients of the inception cohort and in 6-month period affected by the therapy with SGLT2 inhibitors.

Results. The therapy with dapagliflozin has caused the decrease in the NTproBNT level up to 1914,0 ± 500,7 pg/ml, p = 0,001 that 36% less then baseline indexes. There was the increase in ejection fraction of left ventricle by 15,01% comparing with the baseline (35,2 ± 8,6% – baseline, 40,5 ± 10,8% after the SGLT2 inhibitor therapy, p = 0,07). While having 6-minute walking test the significant walking distance increase was found out. It enables us to make the conclusion about the changes of the heart failure functional class according to NYHA from III to II. Analyzing the health status level (according to the questionnaire on health EQ-5D) there was the increase from 56,4 ± 20,4 to 65,8 ± 10,1. According to the Montreal assessment scale there was enhancement of indexes: 24,4 ± 1,6 – baseline, 25,3 ± 1,7 – after the SGLT2 inhibitor therapy, p = 0,34.

1. Bui A. L., Horwich T. B., Fonarow G. C. Epidemiology and risk profile of heart failure Nat Rev Cardiol. 2010; 8: 30-41.

2. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010, Lancet. 2012; 380 (9859): 2163-2196. DOI: 10.1016/S0140-6736(12)61729-2.

3. Shah K. S., Xu H., Matsouaka R. A., Bhatt D. L., Heidenreich P. A., Hernandez A. F., Devore A. D., Yancy C. W., Fonarow G. C. Heart failure with preserved, borderline, and reduced ejection fraction: 5-year outcomes. J Am Coll Cardiol. 2017; 70 (20): 2476-2486. DOI: 10.1016/j.jacc.2017.08.074. Epub 2017 Nov 12. PMID: 29141781.

4. Wiviott S. D., Raz I., Bonaca M. P., Mosenzon O., Kato E. T., Cahn A., Silverman M. G., Zelniker T. A., Kuder J. F., Murphy S. A., Bhatt D. L., Leiter L. A., McGuire D. K., Wilding J. P. H., Ruff C. T., Gause-Nilsson I. A. M., Fredriksson M., Johansson P. A., Langkilde A. M., Sabatine M. S. DECLARE–TIMI 58 Investigators. dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019; 380 (4): 347-357. DOI: 10.1056/NEJMoa1812389. Epub 2018 Nov 10. PMID: 30415602.

5. Neal B., Perkovic V., Mahaffey K. W., de Zeeuw D., Fulcher G., Erondu N., Shaw W., Law G., Desai M., Matthews D. R. CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017; 377 (7): 644-657. DOI: 10.1056/NEJMoa1611925. Epub 2017 Jun 12. PMID: 28605608.

6. McMurray J. J. V., Solomon S. D., Inzucchi S. E., Køber L., Kosiborod M. N., Martinez F. A., Ponikowski P., Sabatine M. S., Anand I. S., Bělohlávek J., Böhm M., Chiang C. E.,Chopra V. K., de Boer R. A., Desai A. S., Diez M., Drozdz J., Dukát A., Ge J., Howlett J. G., Katova T., Kitakaze M., Ljungman C. E., Merkely B., Nicolau J. C., O'Meara E., Petrie M. C., Vinh P. N., Schou M., Tereshchenko S., Verma S., Held C., DeMets D. L., Docherty K. F., Jhund P. S., Bengtsson O., Sjöstrand M., Langkilde A. M. DAPA-HF Trial committees and investigators. dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med. 2019; 381 (21): 1995-2008. DOI: 10.1056/NEJMoa1911303. Epub 2019 Sep 19. PMID: 31535829.

7. Cherney D. Z., Perkins B. A., Soleymanlou N., Maione M., Lai V., Lee A., Fagan N. M., Woerle H. J., Johansen O. E., Broedl U. C., von Eynatten M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014; 129 (5): 587-597. DOI: 10.1161/CIRCULATIONAHA.113.005081. Epub 2013 Dec 13. PMID: 24334175.

8. Chilton R., Tikkanen I., Cannon C. P., Crowe S., Woerle H. J., Broedl U. C., Johansen O. E. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015; 17 (12): 1180-1193. DOI: 10.1111/dom.12572. Epub 2015 Oct 9. PMID: 26343814; PMCID: PMC5057299.

9. Zhang N., Feng B., Ma X., Sun K., Xu G., Zhou Y. Dapagliflozin improves left ventricular remodeling and aorta sympathetic tone in a pig model of heart failure with preserved ejection fraction. Cardiovasc Diabetol. 2019; 18 (1): 107. DOI: 10.1186/s12933-019-0914-1. PMID: 31429767; PMCID: PMC6702744.

10. Sano M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J Cardiol. 2018; 71 (5): 471-476. DOI: 10.1016/j.jjcc.2017.12.004. Epub 2018 Feb 4. PMID: 29415819.

11. Wan N., Rahman A., Hitomi H., Nishiyama A. The effects of sodium-glucose cotransporter 2 inhibitors on sympathetic nervous activity. Front endocrinol (Lausanne). 2018; 9: 421. DOI: 10.3389/fendo.2018.00421. PMID: 30093883; PMCID: PMC6070601.

12. Chhabra K. H., Morgan D. A., Tooke B. P., Adams J. M., Rahmouni K., Low M. J. Reduced renal sympathetic nerve activity contributes to elevated glycosuria and improved glucose tolerance in hypothalamus-specific Pomc knockout mice. Mol Metab. 2017; 6 (10): 1274-1285. DOI: 10.1016/j.molmet.2017.07.005. Epub 2017 Jul 17. PMID: 29031726; PMCID: PMC5641634.

13. Fedak P. W., Verma S., Weisel R. D., Skrtic M., Li R. K. Cardiac remodeling and failure: from molecules to man (Part III). Cardiovasc Pathol. 2005; 14 (3): 109-119. DOI: 10.1016/j.carpath.2005.03.004. PMID: 15914295.

14. Lee T. M., Chang N. C., Lin S. Z. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017; 104: 298- 310. DOI: 10.1016/j.freeradbiomed.2017.01.035. Epub 2017 Jan 26. PMID: 28132924.

15. Kang S., Verma S., Hassanabad A. F., Teng G., Belke D. D., Dundas J. A., Guzzardi D. G., Svystonyuk D. A., Pattar S. S., Park D. S. J., Turnbull J. D., Duff H. J., Tibbles L. A., Cunnington R. H., Dyck J. R. B., Fedak P. W. M. Direct effects of empagliflozin on extracellular matrix remodelling in human cardiac myofibroblasts: novel translational clues to explain EMPA-REG OUTCOME Results. Can J Cardiol. 2020; 36 (4): 543-553. DOI: 10.1016/j.cjca.2019.08.033. Epub 2019 Aug 29. PMID: 31837891.

16. Tanaka H., Soga F., Tatsumi K., Mochizuki Y., Sano H., Toki H., Matsumoto K., Shite J., Takaoka H., Doi T., Hirata K.I. Positive effect of dapagliflozin on left ventricular longitudinal function for type 2 diabetic mellitus patients with chronic heart failure. Cardiovasc Diabetol. 2020; 19 (1): 6. DOI: 10.1186/s12933-019-0985-z. PMID: 31910853; PMCID: PMC6947966.

17. Benetti E., Mastrocola R., Vitarelli G., Cutrin J. C., Nigro D., Chiazza F., Mayoux E., Collino M., Fantozzi R. Empagliflozin protects against diet-induced nlrp-3 inflammasome activation and lipid accumulation. J Pharmacol Exp Ther. 2016; 359 (1): 45-53. DOI: 10.1124/jpet.116.235069. Epub 2016 Jul 20. PMID: 27440421