Clinical pharmacy

Medications representing a new class of drugs – inhibitors of sodium-glucose transport protein type 2 (SGLT2 inhibitors, gliflozins) have appeared in the clinical practice relatively recently. Now they are a new hope for the treatment of chronic heart failure (HF) in patients with/without type 2 diabetes mellitus (DM2). The article briefly discusses the main mechanisms of action of gliflozins, which allowed their active use in clinical practice, in particular, the ability of gliflosins to affect the size and the functional activity of epicardial adipose tissue, as well as the state of the sympathetic nervous system, thereby preventing the development of HF. The main results of the large-scale randomized clinical trials, such as CANVAS, CREDENCE, EMPA, EMPAREG OUTCOME, DECLARE-TIMI 58 are presented. They analyze the effects of canagliflozin, empagliflozin, dapagliflozin on various cardiovascular outcomes: cardiovascular death, myocardial infarction, nonfatal stroke, HF, frequency of hospitalizations caused by HF. Modern concepts of the probable mechanisms of the cardioprotective action of gliflozins are given. The results of meta-analyses revealing the possibility of including gliflozins in the treatment of HF, DM2, as well as those who studied the cardiovascular safety of this drugs have been analyzed. The results of a recently published international trial DAPAHF studied the cardioprotective properties of dapagliflozin in HF, have been considered. The unique pleotropic cardiovascular properties of SGLT2 inhibitors (dapagliflozin) and their ability to prevent the progression of HF and reduce cardiovascular mortality allow us to hope that these drugs have a specific cardioprotective activity with respect to the treatment of HF with the reduced and preserved ejection fraction. Glyflosins, particularly dapagliflozine, are believed to be the fifth class of drugs recommended for the treatment of CH withthe reduced left volume ejection fraction, regardless of the presence or absence of DM2.

Giugliano, D., & Esposito, K. (2019). Class effect for SGLT-2 inhibitors: a tale of 9 drugs. Cardiovascular Diabetology, 18(1). https://doi.org/10.1186/s12933-019-0899-9

Åkerblom, A., Oldgren, J., Latva-Rasku, A., Johansson, L., Lisovskaja, V., Karlsson, C., … Nuutila, P. (2019). Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients—a description of the DAPACARD study. Upsala Journal of Medical Sciences, 124(1), 59–64. https://doi.org/10.1080/03009734.2018.1515281

Patel, D. K., & Strong, J. (2019). The Pleiotropic Effects of Sodium–Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit. Diabetes Therapy, 10(5), 1771–1792. https://doi.org/10.1007/s13300-019-00686-z

McMurray, J. J. V., DeMets, D. L., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Langkilde, A. M., … Sabatine, M. S. (2019). A trial to evaluate the effect of the sodium–glucose co‐transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA‐HF). European Journal of Heart Failure, 21(5), 665–675. https://doi.org/10.1002/ejhf.1432

Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., … Sabatine, M. S. (2019). Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. New England Journal of Medicine, 380(4), 347–357. https://doi.org/10.1056/nejmoa1812389

Wiviott, S. D., Raz, I., Bonaca, M. P., Mosenzon, O., Kato, E. T., Cahn, A., … Sabatine, M. S. (2018). The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 Trial. American Heart Journal, 200, 83–89. https://doi.org/10.1016/j.ahj.2018.01.012

Olgar, Y., & Turan, B. (2019). A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn2+-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress. Canadian Journal of Physiology and Pharmacology, 97(6), 528–535. https://doi.org/10.1139/cjpp-2018-0466

Mancini, S. J., Boyd, D., Katwan, O. J., Strembitska, A., Almabrouk, T. A., Kennedy, S., … Salt, I. P. (2018). Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-23420-4

Meng, L., Uzui, H., Guo, H., & Tada, H. (2018). Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts. Molecular Medicine Reports, 17, 6887–6892. https://doi.org/10.3892/mmr.2018.8688

Basu, D., Huggins, L.-A., Scerbo, D., Obunike, J., Mullick, A. E., Rothenberg, P. L., … Goldberg, I. J. (2018). Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition. Arteriosclerosis, Thrombosis, and Vascular Biology, 38(9), 2207–2216. https://doi.org/10.1161/atvbaha.118.311339

Kondo, H., & Takahashi, N. (2019). Reduced hospitalization for heart failure using anti-diabetic drug dapagliflozin: implications of DECLARE–TIMI 58 for the basic science community. Cardiovascular Research, 115(6), e54–e57.. https://doi.org/10.1093/cvr/cvz073

Díaz-Rodríguez, E., Agra, R. M., Fernández, Á. L., Adrio, B., García-Caballero, T., González-Juanatey, J. R., & Eiras, S. (2017). Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability. Cardiovascular Research, 114(2), 336–346. https://doi.org/10.1093/cvr/cvx186

Sato, T., Aizawa, Y., Yuasa, S., Kishi, S., Fuse, K., Fujita, S., … Okabe, M. (2018). The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovascular Diabetology, 17(1). https://doi.org/10.1186/s12933-017-0658-8

Tang, H., Fang, Z., Wang, T., Cui, W., Zhai, S., & Song, Y. (2016). Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus. The American Journal of Cardiology, 118(11), 1774–1780. https://doi.org/10.1016/j.amjcard.2016.08.061

Monami, M., Dicembrini, I., & Mannucci, E. (2016). Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials. Acta Diabetologica, 54(1), 19–36. https://doi.org/10.1007/s00592-016-0892-7

Saad, M., Mahmoud, A. N., Elgendy, I. Y., Abuzaid, A., Barakat, A. F., Elgendy, A. Y., … Mukherjee, D. (2017). Cardiovascular outcomes with sodium–glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials. International Journal of Cardiology, 228, 352–358. https://doi.org/10.1016/j.ijcard.2016.11.181

Sonesson, C., Johansson, P. A., Johnsson, E., & Gause-Nilsson, I. (2016). Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis. Cardiovascular Diabetology, 15(1). https://doi.org/10.1186/s12933-016-0356-y

Usman, M. S., Siddiqi, T. J., Memon, M. M., Khan, M. S., Rawasia, W. F., Talha Ayub, M., … Golzar, Y. (2018). Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis. European Journal of Preventive Cardiology, 25(5), 495–502. https://doi.org/10.1177/2047487318755531

McMurray, J. J. V., Solomon, S. D., Inzucchi, S. E., Køber, L., Kosiborod, M. N., Martinez, F. A., … Langkilde, A.-M. (2019). Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. New England Journal of Medicine, 381(21), 1995–2008. https://doi.org/10.1056/nejmoa1911303

1.    Giugliano, D. Class effect for SGLT-2 inhibitors: a tale of 9 drugs / D. Giugliano, K. Esposito // Cardiovasc. Diabetol. – 2019. – № 18. – P. 94. https://doi.org/10.1186/s12933-019-0899-9 

2.    Effects of DAPAgliflozin on CARDiac substrate uptake, myocardial efficiency, and myocardial contractile work in type 2 diabetes patients – a description of the DAPACARD study / A. Akerbloma, J. Oldgren, A. Latva-Rasku et al. // Upsala J. of Med. Sci. – 2019. – № 124. – P . 59–64. https://doi.org/10.1080/03009734.2018.1515281 

3.    Patel, D. K. The Pleiotropic Effects of Sodium–Glucose Cotransporter-2 Inhibitors: Beyond the Glycemic Benefit / D. K. Patel, J. Strong // Diabetes Ther. – 2019. – № 10. – P. 1771–1792. https://doi.org/10.1007/s13300-019-00686-z 

4.    A trial to evaluate the effect of the sodium-glucose co-transporter 2 inhibitor dapagliflozin on morbidity and mortality in patients with heart failure and reduced left ventricular ejection fraction (DAPA-HF) / J. J. V. McMurray, D. L. DeMets, S. E. Inzucchi et al. // Eur. J. Heart Fail. – 2019. – № 21. – P. 665–675. https://doi.org/10.1002/ejhf.1432 

5.    Dapagliflozin and cardiovascular outcomes in type 2 diabetes / S. D. Wiviott, I. Raz, M. P. Bonaca et al. // N. Engl. J. Med. – 2019. – № 380. – P. 347–357. https://doi.org/10.1056/nejmoa1812389 

6.    The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial / S. D. Wiviott, I. Raz, M. P. Bonaca et al. // Am. Heart J. – 2018. – № 200. – P. 83–89. https://doi.org/10.1016/j.ahj.2018.01.012 

7.    Olgar, Y. A sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin comparison with insulin shows important effects on Zn²⁺-transporters in cardiomyocytes from insulin-resistant metabolic syndrome rats through inhibition of oxidative stress / Y. Olgar, B. Turan // Can. J. Physiol. Pharmacol. – 2019. – № 97. – P. 528–535. https://doi.org/10.1139/cjpp-2018-0466 

8.    Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms / S. J. Mancini, D. Boyd, O. J. Katwan et al. // Sci. Rep. – 2018. – № 8. – P. 52–76. https://doi.org/10.1038/s41598-018-23420-4 

9.    Role of SGLT1 in high glucose level-induced MMP-2 expression in human cardiac fibroblasts / L. Meng, H. Uzui, H. Guo et al. // Mol. Med. Rep. – 2018. – № 17. – P. 6887–6892. https://doi.org/10.3892/mmr.2018.8688 

10.  Mechanism of Increased LDL (Low-Density Lipoprotein) and Decreased Triglycerides With SGLT2 (Sodium-Glucose Cotransporter 2) Inhibition / D. Basu, L. A. Huggins, D. Scerbo et al. // Arterioscler. Thromb. Vasc. Biol. – 2018. – № 38. – P. 2207–2216. https://doi.org/10.1161/atvbaha.118.311339 

11.  Kondo, H. Reduced hospitalization for heart failure using anti-diabetic drug dapagliflozin: implications of DECLARE–TIMI 58 for the basic science community / H. Kondo, N. Takahashi // Cardiovasc. Res. – 2019. – № 115. – P. 54–57. https://doi.org/10.1093/cvr/cvz073 

12.  Effects of dapagliflozin on human epicardial adipose tissue: modulation of insulin resistance, inflammatory chemokine production, and differentiation ability / E. Dıaz-Rodrıguez, R. M. Agra, F. Fernandez et al. // Cardiovasc. Res. – 2018. – № 114. – P. 336–346. https://doi.org/10.1093/cvr/cvx186 

13.  The effect of dapagliflozin treatment on epicardial adipose tissue volume / T. Sato, Y. Aizawa, S. Yuasa et al. // Cardiovasc. Diabetol. – 2018. – № 17. – P. 6. https://doi.org/10.1186/s12933-017-0658-8 

14.  Meta-Analysis of Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Cardiovascular Outcomes and All-Cause Mortality Among Patients With Type 2 Diabetes Mellitus / H. Tang, Z. Fang, T. Wang et al. // Am. J. Cardiol. – 2016. – № 118. – P. 1774–1780. https://doi.org/10.1016/j.amjcard.2016.08.061 

15.  Monami, M. Effects of SGLT-2 inhibitors on mortality and cardiovascular events: a comprehensive meta-analysis of randomized controlled trials / M. Monami, I. Dicembrini, E. Mannucci // Acta Diabetol. – 2017. – № 54. – P. 19–36. https://doi.org/10.1007/s00592-016-0892-7 

16.  Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus: A meta-analysis of placebo-controlled randomized trials / M. Saad, A. N. Mahmoud, I. Y. Elgendy et al. // Int. J. Cardiol. – 2017. – № 228. – P. 352–358. https://doi.org/10.1016/j.ijcard.2016.11.181 

17.  Cardiovascular effects of dapagliflozin in patients with type 2 diabetes and different risk categories: a meta-analysis / C. Sonesson, P. A. Johansson, E. Johnsson, I. Gause-Nilsson // Cardiovasc. Diabetol. – 2016. – № 15. – P. 15–37. https://doi.org/10.1186/s12933-016-0356-y 

18.  Sodium-glucose co-transporter 2 inhibitors and cardiovascular outcomes: A systematic review and meta-analysis / M. S. Usman, T. J. Siddiqi, M. M. Memon et al. // Eur. J. Prev. Cardiol. – 2018. – № 25. – P. 495–502. https://doi.org/10.1177/2047487318755531 

19.  Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction / J. J. V. McMurray, S. D. Solomon, S. E. Inzucchi et al. // N. Engl. J. Med. – 2019. – № 381. – P. 1995–2008. https://doi.org/10.1056/nejmoa1911303