clinmedКлиническая медицинаClinical Medicine (Russian Journal)0023-21492412-1339ООО «Медицинское информационное агентство»10.30629/0023-2149-2021-99-3-172-176clinmed-210Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESВозможности кардио- и нефропротективного действия препаратов группы ингибиторов SGLT2Possibilities of cardio- and nephroprotective eff ects of drugs of the SGLT2 inhibitor grouphttps://orcid.org/0000-0002-3730-5831КурашинВ. К.KurashinV. K.

Курашин Владимир Константинович - врач-ординатор, аспирант

603005, Нижний Новгород

Vladimir K. Kurashin

603005, Nizhny Novgorod

kurashin-vk@yandex.ruhttps://orcid.org/0000-0001-7581-4138БоровковаН. Ю.BorovkovaN. Yu.

603005, Нижний Новгород

603005, Nizhny Novgorod

https://orcid.org/0000-0003-2609-3703КурашинаВ. А.KurashinaV. A.

603005, Нижний Новгород

603005, Nizhny Novgorod

https://orcid.org/0000-0002-6997-1759БаккаТ. Е.BakkaT. E.

603126, Нижний Новгород

603126, Nizhny Novgorod

ФГБОУ ВО «Приволжский исследовательский медицинский университет» Минздрава РоссииРоссияPrivolzhsky Research Medical University of the Ministry of Health of RussiaRussian FederationГБУЗ НО «Нижегородская областная клиническая больница им. Н.А. Семашко»РоссияNizhny Novgorod Regional Clinical Hospital named after Semashko N.A.Russian Federation202115092021993172176Copyright © Курашин В.К., Боровкова Н.Ю., Курашина В.А., Бакка Т.Е., 20212021Курашин В.К., Боровкова Н.Ю., Курашина В.А., Бакка Т.Е.Kurashin V.K., Borovkova N.Y., Kurashina V.A., Bakka T.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.clinmedjournal.com/jour/article/view/210

В настоящей работе предпринята попытка проанализировать данные о механизмах кардио- и нефропротекции препаратов из группы ингибиторов SGLT2 (Sodium/glucose cotransporter 2 — натрий-глюкозный котранспортер 2-го типа). Показаны данные исследований последних лет, которые свидетельствуют о влиянии препаратов данной группы на показатели центральной гемодинамики, в основном на объем циркулирующей плазмы, что может снижать риск прогрессирования и декомпенсации хронической сердечной недостаточности (ХСН). Продемонстрирована способность эмпаглифлозина уменьшать пульсовое давление, которое является маркером увеличения жесткости сосудистой стенки. Также ингибиторы SGLT2 улучшают энергообеспечение миокарда и почечной ткани путем увеличения концентрации кетоновых тел в крови, которые являются более эффективным энергетическим субстратом, нежели глюкоза и жирные кислоты. Не исключается также благоприятное действие на миокард, улучшение диастолической дисфункции миокарда. Известно, что ингибиторы SGLT2 уменьшают корковую гипоксию, снижают внутриклубочковую гипертензию и увеличивают скорость клубочковой фильтрации, уменьшая вероятность появления нефропатии, ее тяжесть и скорость прогрессирования. В некоторых исследованиях выявлены антиоксидантные, противовоспалительные, антифибротические свойства ингибиторов натрий-глюкозного котранспортера 2-го типа. Применение данной группы препаратов также приводит к снижению массы тела, больше этот эффект выражен в комбинации с другими лекарственными средствами, предназначенными для лечения ожирения. Все это делает ингибиторы SGLT2 перспективной группой лекарственных средств, имеющих большое количество патогенетических точек приложения на развитие кардиоренального синдрома.

This work is an attempt to analyze the data on the mechanisms of cardio- and nephroprotection of drugs of the SGLT2 inhibitor group (Sodium / glucose cotransporter 2). The data of recent studies are shown to indicate the eff ect of drugs of this group on the indices of central hemodynamics, on the volume of circulating plasma in particular, which can reduce the risk of progression and decompensation of chronic heart failure (CHF). The ability of empaglifl ozin to reduce pulsatility, a marker of increased vascular wall stiff ness, has been demonstrated. Also, SGLT2 inhibitors improve the energy supply of the myocardium and kidney tissue by increasing the concentration of ketone bodies in the blood, which are a more effi cient energy substrate than glucose and fatty acids. A direct pleiotropic eff ect on the myocardium, improvement of diastolic myocardial dysfunction is also not excluded. It is known that SGLT2 inhibitors also reduce cortical hypoxia, decrease intraglomerular hypertension and increase glomerular fi ltration rate, lessen incidence of nephropathy, its severity and rate of progression. Some studies have revealed antioxidant, anti-infl ammatory, antifi brotic eff ect of type 2 sodium glucose cotransporter inhibitors. The use of this group of drugs also leads to a decrease in body weight. This eff ect is more pronounced in combination with other drugs intended for the treatment of obesity. All this makes SGLT2 inhibitors a promising group of drugs that have a large number of pathogenetic points of application in relation to cardiorenal syndrome.

кардиоренальный синдромингибиторы SGLT2хроническая сердечная недостаточностьхроническая болезнь почеккардиопротекциянефропротекцияcardiorenal syndromeSGLT2 inhibitorschronic heart failurechronic kidney diseasecardioprotectionnephroprotectionReferencesGBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national agesex specifi c all-cause and cause-specifi c mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171. DOI: 10.1016/S0140-6736(14)61682-2GBD 2013 Mortality and Causes of Death Collaborators. Global, regional, and national agesex specifi c all-cause and cause-specifi c mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385:117–171. DOI: 10.1016/S0140-6736(14)61682-2Бойцов С.А., Самородская И.В., Старинская М.А., Семенов В.Ю., Какорина Е.П. Анализ структуры и динамики показателей смертности от болезней системы кровообращения в России в 2006 и 2014 гг. Профилактическая медицина. 2016;19(2):11–12.Boytsov S.A., Samorodskaya I.V., Starinskaya M.A., Semenov V.Ju., Kakorina E.P. Analysis of structure and dynamics of indicators of mortality from cardiovascular diseases in Russia in 2006 and 2014. Profi lakticheskaja medicina. 2016;19(2):11–12. (in Russian)Natalia G. Vallianou, Shah Mitesh, Agathoniki Gkogkou, Eleni Geladari. Chronic Kidney Disease and Cardiovascular Disease: Is there Any Relationship? Cur. Cardiol. Rev. 2019;15:55. DOI: 10.2174/157 3403X14666180711124825Natalia G. Vallianou, Shah Mitesh, Agathoniki Gkogkou, Eleni Geladari. Chronic Kidney Disease and Cardiovascular Disease: Is there Any Relationship? Cur. Cardiol. Rev. 2019;15:55. DOI: 10.2174/157 3403X14666180711124825Kim H., Yoo T.H., Choi K.H., Oh K.H., Lee J., Kim S.W., Kim T.H., Sung S., Han S.H., KNOW-CKD Group. Baseline Cardiovascular Characteristics of Adult Patients with Chronic Kidney Disease from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). J. Korean Med. Sci. 2017;32(2):231–239. DOI: 10.3346/jkms.2017.32.2.231Kim H., Yoo T.H., Choi K.H., Oh K.H., Lee J., Kim S.W., Kim T.H., Sung S., Han S.H., KNOW-CKD Group. Baseline Cardiovascular Characteristics of Adult Patients with Chronic Kidney Disease from the KoreaN Cohort Study for Outcomes in Patients With Chronic Kidney Disease (KNOW-CKD). J. Korean Med. Sci. 2017;32(2):231–239. DOI: 10.3346/jkms.2017.32.2.231Sarnak M.J., Amann K., Bangalore S., Cavalcante J.L., Charytan D.M., Craig J.C.et al. Conference participants. Chronic kidney disease and coronary artery disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2019;74(14):1823–1838. DOI: 10.1016/j.jacc.2019.08.1017Sarnak M.J., Amann K., Bangalore S., Cavalcante J.L., Charytan D.M., Craig J.C.et al. Conference participants. Chronic kidney disease and coronary artery disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 2019;74(14):1823–1838. DOI: 10.1016/j.jacc.2019.08.1017GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–733. DOI: 10.1016/S0140-6736(20)30045-3GBD Chronic Kidney Disease Collaboration. Global, regional, and national burden of chronic kidney disease, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2020;395(10225):709–733. DOI: 10.1016/S0140-6736(20)30045-3Provenzano M., Coppolino G., Faga T., Garofalo C., Serra R., Andreucci M. Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer. Rev. Cardiovasc. Med. 2019;20(4):209–220. DOI: 10.31083/j.rcm.2019.04.548Provenzano M., Coppolino G., Faga T., Garofalo C., Serra R., Andreucci M. Epidemiology of cardiovascular risk in chronic kidney disease patients: the real silent killer. Rev. Cardiovasc. Med. 2019;20(4):209–220. DOI: 10.31083/j.rcm.2019.04.548McGuire D.K., Shih W.J., Cosentino F., Charbonnel B., Cherney D.Z.I., Dagogo-Jack S.et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021;6(2):148–158. DOI: 10.1001/jamacardio.2020.4511McGuire D.K., Shih W.J., Cosentino F., Charbonnel B., Cherney D.Z.I., Dagogo-Jack S.et al. Association of SGLT2 Inhibitors With Cardiovascular and Kidney Outcomes in Patients With Type 2 Diabetes: A Meta-analysis. JAMA Cardiol. 2021;6(2):148–158. DOI: 10.1001/jamacardio.2020.4511Zou C.Y., Liu X.K., Sang Y.Q., Wang B., Liang J. Eff ects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: A meta-analysis. Medicine (Baltimore). 2019;98(49):e18245. DOI: 10.1097/MD.0000000000018245Zou C.Y., Liu X.K., Sang Y.Q., Wang B., Liang J. Eff ects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: A meta-analysis. Medicine (Baltimore). 2019;98(49):e18245. DOI: 10.1097/MD.0000000000018245Williams D.M., Nawaz A., Evans M. Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors: Are They All the Same? A Narrative Review of Cardiovascular Outcome Trials. Diabetes Ther. 2021;12(1):55–70. DOI: 10.1007/s13300-020-00951-6Williams D.M., Nawaz A., Evans M. Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors: Are They All the Same? A Narrative Review of Cardiovascular Outcome Trials. Diabetes Ther. 2021;12(1):55–70. DOI: 10.1007/s13300-020-00951-6Nakagawa Y., Kuwahara K. Sodium-Glucose Cotransporter-2 inhibitors are potential therapeutic agents for treatment of non-diabetic heart failure patients. J. Cardiol. 2020;76(2):123–131. DOI: 10.1016/j.jjcc.2020.03.009Nakagawa Y., Kuwahara K. Sodium-Glucose Cotransporter-2 inhibitors are potential therapeutic agents for treatment of non-diabetic heart failure patients. J. Cardiol. 2020;76(2):123–131. DOI: 10.1016/j.jjcc.2020.03.009Giorgino F., Vora J., Fenici P., Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc. Diabetol. 2020;19(1):196. DOI: 10.1186/s12933-020-01163-9Giorgino F., Vora J., Fenici P., Solini A. Renoprotection with SGLT2 inhibitors in type 2 diabetes over a spectrum of cardiovascular and renal risk. Cardiovasc. Diabetol. 2020;19(1):196. DOI: 10.1186/s12933-020-01163-9Vasquez-Rios G., Nadkarni G. SGLT2 Inhibitors: Emerging Roles in the Protection Against Cardiovascular and Kidney Disease Among Diabetic Patients. Int. J. Nephrol. Renovasc. Dis. 2020;13:281–296. DOI: 10.2147/IJNRD.S268811Vasquez-Rios G., Nadkarni G. SGLT2 Inhibitors: Emerging Roles in the Protection Against Cardiovascular and Kidney Disease Among Diabetic Patients. Int. J. Nephrol. Renovasc. Dis. 2020;13:281–296. DOI: 10.2147/IJNRD.S268811Petrie M.C., Verma S., Docherty K.F., Inzucchi S.E., Anand I., Belohlávek J.et al. Eff ect of Dapaglifl ozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes. JAMA. 2020;323(14):1353–1368. DOI: 10.1001/jama.2020.1906Petrie M.C., Verma S., Docherty K.F., Inzucchi S.E., Anand I., Belohlávek J.et al. Eff ect of Dapaglifl ozin on Worsening Heart Failure and Cardiovascular Death in Patients With Heart Failure With and Without Diabetes. JAMA. 2020;323(14):1353–1368. DOI: 10.1001/jama.2020.1906Böhm M., Slawik J., Brueckmann M., Mattheus M., George J.T., Ofstad A.P.et al. Effi cacy of empaglifl ozin on heart failure and renal outcomes in patients with atrial fi brillation: data from the EMPA-REG OUTCOME trial. Eur. J. Heart Fail. 2020;22(1):126–135. DOI: 10.1002/ejhf.1663Böhm M., Slawik J., Brueckmann M., Mattheus M., George J.T., Ofstad A.P.et al. Effi cacy of empaglifl ozin on heart failure and renal outcomes in patients with atrial fi brillation: data from the EMPA-REG OUTCOME trial. Eur. J. Heart Fail. 2020;22(1):126–135. DOI: 10.1002/ejhf.1663Patorno E., Pawar A., Franklin J.M., Najafzadeh M., Déruaz- Luyet A., Brodovicz K.G., Sambevski S., Bessette L.G., Santiago Ortiz A.J., Kulldorff M., Schneeweiss S. Empaglifl ozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care. Circulation. 2019;139(25):2822–2830. DOI: 10.1161/CIRCULATIONAHA.118.039177Patorno E., Pawar A., Franklin J.M., Najafzadeh M., Déruaz- Luyet A., Brodovicz K.G., Sambevski S., Bessette L.G., Santiago Ortiz A.J., Kulldorff M., Schneeweiss S. Empaglifl ozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care. Circulation. 2019;139(25):2822–2830. DOI: 10.1161/CIRCULATIONAHA.118.039177Grempler R., Thomas L., Eckhardt M., Himmelsbach F., Sauer A., Sharp D.E., Bakker R.A., Mark M., Klein T., Eickelmann P. Empaglifl ozin a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 2012;14(1):83–90. DOI: 10.1111/j.1463-1326.2011.01517.xGrempler R., Thomas L., Eckhardt M., Himmelsbach F., Sauer A., Sharp D.E., Bakker R.A., Mark M., Klein T., Eickelmann P. Empaglifl ozin a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes. Metab. 2012;14(1):83–90. DOI: 10.1111/j.1463-1326.2011.01517.xHeise T., Seewaldt-Becker E., Macha S., Hantel S., Pinnetti S., Seman L., Woerle H.J. Safety tolerability pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empaglifl ozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 2013;15(7):613–21. DOI: 10.1111/dom.12073Heise T., Seewaldt-Becker E., Macha S., Hantel S., Pinnetti S., Seman L., Woerle H.J. Safety tolerability pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empaglifl ozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab. 2013;15(7):613–21. DOI: 10.1111/dom.12073Heise T., Jordan J., Wanner C., Heer M., Macha S., Mattheus M.et al. Pharmacodynamic Eff ects of single and multiple doses of empaglifl ozin in patients with type 2 Diabetes. Clin. Ther. 2016;38(10):2265–2276. DOI: 10.1016/j.clinthera.2016.09.001Heise T., Jordan J., Wanner C., Heer M., Macha S., Mattheus M.et al. Pharmacodynamic Eff ects of single and multiple doses of empaglifl ozin in patients with type 2 Diabetes. Clin. Ther. 2016;38(10):2265–2276. DOI: 10.1016/j.clinthera.2016.09.001Rajasekeran H., Lytvyn Y., Cherney D.Z. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6. DOI: 10.1016/j.kint.2015.12.038Rajasekeran H., Lytvyn Y., Cherney D.Z. Sodium-glucose cotransporter 2 inhibition and cardiovascular risk reduction in patients with type 2 diabetes: the emerging role of natriuresis. Kidney Int. 2016;89(3):524–6. DOI: 10.1016/j.kint.2015.12.038Kario K., Ferdinand KC.., O’Keefe J.H. Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Prog. Cardiovasc. Dis. 2020;63(3):249–262. DOI: 10.1016/j.pcad.2020.04.003Kario K., Ferdinand KC.., O’Keefe J.H. Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Prog. Cardiovasc. Dis. 2020;63(3):249–262. DOI: 10.1016/j.pcad.2020.04.003Tąpolska M., Spałek M., Szybowicz U., Domin R., Owsik K., Sochacka K.et al. . Arterial stiff ness parameters correlate with estimated cardiovascular risk in humans: a clinical study. Int. J. Environ. Res. Public Health. 2019;16(14):2547. DOI: 10.3390/ijerph16142547Tąpolska M., Spałek M., Szybowicz U., Domin R., Owsik K., Sochacka K.et al. . Arterial stiff ness parameters correlate with estimated cardiovascular risk in humans: a clinical study. Int. J. Environ. Res. Public Health. 2019;16(14):2547. DOI: 10.3390/ijerph16142547Chirinos J.A., Segers P., Hughes T., Townsend R. Large-Artery Stiff ness in Health and Disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 20193;74(9):1237–1263. DOI: 10.1016/j.jacc.2019.07.012Chirinos J.A., Segers P., Hughes T., Townsend R. Large-Artery Stiff ness in Health and Disease: JACC State-of-the-Art Review. J. Am. Coll. Cardiol. 20193;74(9):1237–1263. DOI: 10.1016/j.jacc.2019.07.012Vasan R.S., Short M.I., Niiranen T.J., Xanthakis V., DeCarli C., Cheng S., Seshadri S., Mitchell G.F. Interrelations between arterial stiff ness, target organ damage, and cardiovascular disease outcomes. J. Am. Heart Assoc. 2019;8(14):e012141. DOI: 10.1161/JAHA.119.012141Vasan R.S., Short M.I., Niiranen T.J., Xanthakis V., DeCarli C., Cheng S., Seshadri S., Mitchell G.F. Interrelations between arterial stiff ness, target organ damage, and cardiovascular disease outcomes. J. Am. Heart Assoc. 2019;8(14):e012141. DOI: 10.1161/JAHA.119.012141Chilton R., Tikkanen I., Cannon C.P., Crowe S., Woerle H.J., Broedl U.C., Johansen O.E. Eff ects of empaglifl ozin on blood pressure and markers of arterial stiff ness and vascular resistance in patients with type 2 diabetes. Diabetes Obes. Metab. 2015;17(12):1180–93. DOI: 10.1111/dom.12572. Epub 2015 Oct 9. PMID: 26343814; PMCID: PMC5057299Chilton R., Tikkanen I., Cannon C.P., Crowe S., Woerle H.J., Broedl U.C., Johansen O.E. Eff ects of empaglifl ozin on blood pressure and markers of arterial stiff ness and vascular resistance in patients with type 2 diabetes. Diabetes Obes. Metab. 2015;17(12):1180–93. DOI: 10.1111/dom.12572. Epub 2015 Oct 9. PMID: 26343814; PMCID: PMC5057299Sugiyama S., Jinnouchi H., Kurinami N., Hieshima K., Yoshida A., Jinnouchi K.et al. The sglt2 inhibitor dapaglifl ozin signifi cantly improves the peripheral microvascular endothelial function in patients with uncontrolled type 2 diabetes mellitus. Intern. Med. 2018;57(15):2147–2156. DOI: 10.2169/internalmedicine.0701-17Sugiyama S., Jinnouchi H., Kurinami N., Hieshima K., Yoshida A., Jinnouchi K.et al. The sglt2 inhibitor dapaglifl ozin signifi cantly improves the peripheral microvascular endothelial function in patients with uncontrolled type 2 diabetes mellitus. Intern. Med. 2018;57(15):2147–2156. DOI: 10.2169/internalmedicine.0701-17Solini A., Giannini L., Seghieri M., Vitolo E., Taddei S., Ghiadoni L., Bruno R.M. Dapaglifl ozin acutely improves endothelial dysfunction., reduces aortic stiff ness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc. Diabetol. 2017;16(1):138. DOI: 10.1186/s12933-017-0621-8Solini A., Giannini L., Seghieri M., Vitolo E., Taddei S., Ghiadoni L., Bruno R.M. Dapaglifl ozin acutely improves endothelial dysfunction., reduces aortic stiff ness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc. Diabetol. 2017;16(1):138. DOI: 10.1186/s12933-017-0621-8Ferreira M.T., Leite N.C., Cardoso C.R., Salles G.F. Correlates of aortic stiff ness progression in patients with type 2 diabetes: importance of glycemic control: the Rio de Janeiro type 2 diabetes cohort study. Diabetes Care. 2015;38(5):897–904. DOI: 10.2337/dc14-2791Ferreira M.T., Leite N.C., Cardoso C.R., Salles G.F. Correlates of aortic stiff ness progression in patients with type 2 diabetes: importance of glycemic control: the Rio de Janeiro type 2 diabetes cohort study. Diabetes Care. 2015;38(5):897–904. DOI: 10.2337/dc14-2791Herat L.Y., Magno A.L., Rudnicka C., Hricova J., Carnagarin R., Ward N.C.et al. SGLT2 Inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl. Sci. 2020;5(2):169–179. DOI: 10.1016/j.jacbts.2019.11.007Herat L.Y., Magno A.L., Rudnicka C., Hricova J., Carnagarin R., Ward N.C.et al. SGLT2 Inhibitor-induced sympathoinhibition: a novel mechanism for cardiorenal protection. JACC Basic Transl. Sci. 2020;5(2):169–179. DOI: 10.1016/j.jacbts.2019.11.007Ferrannini E., Mark M., Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A «Thrifty Substrate» Hypothesis. Diabetes Care. 2016;39(7):1108–14. DOI: 10.2337/dc16-0330Ferrannini E., Mark M., Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A «Thrifty Substrate» Hypothesis. Diabetes Care. 2016;39(7):1108–14. DOI: 10.2337/dc16-0330Cahill G.F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 2006;26:1–22. DOI: 10.1146/annurev.nutr.26.061505.111258Cahill G.F. Jr. Fuel metabolism in starvation. Annu. Rev. Nutr. 2006;26:1–22. DOI: 10.1146/annurev.nutr.26.061505.111258Maejima Y. SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function. Front. Cardiovasc. Med. 2020;6:186. DOI: 10.3389/fcvm.2019.00186Maejima Y. SGLT2 Inhibitors Play a Salutary Role in Heart Failure via Modulation of the Mitochondrial Function. Front. Cardiovasc. Med. 2020;6:186. DOI: 10.3389/fcvm.2019.00186Pabel S., Wagner S., Bollenberg H., Bengel P., Kovács Á., Schach C. et al. Empaglifl ozin directly improves diastolic function in human heart failure. Eur. J. Heart Fail. 2018;20(12):1690–1700. DOI:10.1002/ejhf.1328Pabel S., Wagner S., Bollenberg H., Bengel P., Kovács Á., Schach C. et al. Empaglifl ozin directly improves diastolic function in human heart failure. Eur. J. Heart Fail. 2018;20(12):1690–1700. DOI:10.1002/ejhf.1328Hamdani N., Bishu KG., von Frieling-Salewsky M., Redfi eld MM., Linke WA. Deranged myofi lament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc. Res. 2013;97(3):464–71. DOI: 10.1093/cvr/cvs353Hamdani N., Bishu KG., von Frieling-Salewsky M., Redfi eld MM., Linke WA. Deranged myofi lament phosphorylation and function in experimental heart failure with preserved ejection fraction. Cardiovasc. Res. 2013;97(3):464–71. DOI: 10.1093/cvr/cvs353Petrykiv S., Sjöström C.D., Greasley P.J., Xu J., Persson F., Heerspink H.J.L. Diff erential eff ects of dapaglifl ozin on cardiovascular risk factors at varying degrees of renal function. Clin. J. Am. Soc. Nephrol. 2017;12(5):751–759. DOI: 10.2215/CJN.10180916Petrykiv S., Sjöström C.D., Greasley P.J., Xu J., Persson F., Heerspink H.J.L. Diff erential eff ects of dapaglifl ozin on cardiovascular risk factors at varying degrees of renal function. Clin. J. Am. Soc. Nephrol. 2017;12(5):751–759. DOI: 10.2215/CJN.10180916Nespoux J., Vallon V. SGLT2 inhibition and kidney protection. Clin Sci (Lond). 2018;132(12):1329–1339. DOI: 10.1042/CS20171298Nespoux J., Vallon V. SGLT2 inhibition and kidney protection. Clin Sci (Lond). 2018;132(12):1329–1339. DOI: 10.1042/CS20171298Yoshimoto T., Furuki T., Kobori H., Miyakawa M., Imachi H., Murao K., Nishiyama A. Eff ects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. J. Investig. Med. 2017;65(7):1057–1061. DOI: 10.1136/jim-2017-000445Yoshimoto T., Furuki T., Kobori H., Miyakawa M., Imachi H., Murao K., Nishiyama A. Eff ects of sodium-glucose cotransporter 2 inhibitors on urinary excretion of intact and total angiotensinogen in patients with type 2 diabetes. J. Investig. Med. 2017;65(7):1057–1061. DOI: 10.1136/jim-2017-000445Osorio H., Coronel I., Arellano A., Pacheco U., Bautista R., Franco M., Escalante B. Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid. Med. Cell. Longev. 2012;2012:542042. DOI: 10.1155/2012/542042Osorio H., Coronel I., Arellano A., Pacheco U., Bautista R., Franco M., Escalante B. Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid. Med. Cell. Longev. 2012;2012:542042. DOI: 10.1155/2012/542042Tang L., Wu Y., Tian M., Sjöström C.D., Johansson U., Peng X.R., Smith D.M., Huang Y. Dapaglifl ozin slows the progression of the renal and liver fi brosis associated with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2017;313(5):E563–E576. DOI: 10.1152/ajpendo.00086.2017Tang L., Wu Y., Tian M., Sjöström C.D., Johansson U., Peng X.R., Smith D.M., Huang Y. Dapaglifl ozin slows the progression of the renal and liver fi brosis associated with type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 2017;313(5):E563–E576. DOI: 10.1152/ajpendo.00086.2017Li C., Zhang J., Xue M., Li X., Han F., Liu X. et al. SGLT2 inhibition with empaglifl ozin attenuates myocardial oxidative stress and fi brosis in diabetic mice heart. Cardiovasc. Diabetol. 2019;18(1):15. DOI: 10.1186/s12933-019-0816-2Li C., Zhang J., Xue M., Li X., Han F., Liu X. et al. SGLT2 inhibition with empaglifl ozin attenuates myocardial oxidative stress and fi brosis in diabetic mice heart. Cardiovasc. Diabetol. 2019;18(1):15. DOI: 10.1186/s12933-019-0816-2Heerspink H.J.L., Perco P., Mulder S., Leierer J., Hansen M.K., Heinzel A., Mayer G. Canaglifl ozin reduces infl ammation and fi - brosis biomarkers: a potential mechanism of action for benefi cial eff ects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62(7):1154–1166. DOI: 10.1007/s00125-019-4859-4Heerspink H.J.L., Perco P., Mulder S., Leierer J., Hansen M.K., Heinzel A., Mayer G. Canaglifl ozin reduces infl ammation and fi - brosis biomarkers: a potential mechanism of action for benefi cial eff ects of SGLT2 inhibitors in diabetic kidney disease. Diabetologia. 2019;62(7):1154–1166. DOI: 10.1007/s00125-019-4859-4Dekkers C.C.J., Petrykiv S., Laverman G.D., Cherney D.Z., Gansevoort R.T., Heerspink H.J.L. Eff ects of the SGLT-2 inhibitor dapaglifl ozin on glomerular and tubular injury markers. Diabetes Obes. Metab. 2018;20(8):1988–1993. DOI: 10.1111/dom.13301Dekkers C.C.J., Petrykiv S., Laverman G.D., Cherney D.Z., Gansevoort R.T., Heerspink H.J.L. Eff ects of the SGLT-2 inhibitor dapaglifl ozin on glomerular and tubular injury markers. Diabetes Obes. Metab. 2018;20(8):1988–1993. DOI: 10.1111/dom.13301Leng W., Ouyang X., Lei X., Wu M., Chen L., Wu Q., Deng W., Liang Z. The SGLT-2 Inhibitor Dapaglifl ozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE-/Mice. Mediators Infl amm. 2016;2016:6305735. DOI: 10.1155/2016/6305735Leng W., Ouyang X., Lei X., Wu M., Chen L., Wu Q., Deng W., Liang Z. The SGLT-2 Inhibitor Dapaglifl ozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE-/Mice. Mediators Infl amm. 2016;2016:6305735. DOI: 10.1155/2016/6305735Panchapakesan U., Pegg K., Gross S., Komala M.G., Mudaliar H., Forbes J., Pollock C., Mather A. Eff ects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS One. 2013;8(2):e54442. DOI: 10.1371/journal.pone.0054442Panchapakesan U., Pegg K., Gross S., Komala M.G., Mudaliar H., Forbes J., Pollock C., Mather A. Eff ects of SGLT2 inhibition in human kidney proximal tubular cells–renoprotection in diabetic nephropathy? PLoS One. 2013;8(2):e54442. DOI: 10.1371/journal.pone.0054442Zhang Y., Nakano D., Guan Y., Hitomi H., Uemura A., Masaki T., Kobara H., Sugaya T., Nishiyama A. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fi brosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018;94(3):524–535. DOI: 10.1016/j.kint.2018.05.002Zhang Y., Nakano D., Guan Y., Hitomi H., Uemura A., Masaki T., Kobara H., Sugaya T., Nishiyama A. A sodium-glucose cotransporter 2 inhibitor attenuates renal capillary injury and fi brosis by a vascular endothelial growth factor-dependent pathway after renal injury in mice. Kidney Int. 2018;94(3):524–535. DOI: 10.1016/j.kint.2018.05.002Garvey W.T., Van Gaal L., Leiter L.A., Vijapurkar U., List J., Cuddihy R., Ren J., Davies M.J. Eff ects of canaglifl ozin versus glimepiride on adipokines and infl ammatory biomarkers in type 2 diabetes. Metabolism. 2018;85:32–37. DOI: 10.1016/j.metabol.2018.02.002Garvey W.T., Van Gaal L., Leiter L.A., Vijapurkar U., List J., Cuddihy R., Ren J., Davies M.J. Eff ects of canaglifl ozin versus glimepiride on adipokines and infl ammatory biomarkers in type 2 diabetes. Metabolism. 2018;85:32–37. DOI: 10.1016/j.metabol.2018.02.002Khan S.S., Ning H., Wilkins J.T., Allen N., Carnethon M., Berry J.D., Sweis R.N., Lloyd-Jones D.M. Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018;3(4):280–287. DOI: 10.1001/jamacardio.2018.0022Khan S.S., Ning H., Wilkins J.T., Allen N., Carnethon M., Berry J.D., Sweis R.N., Lloyd-Jones D.M. Association of Body Mass Index With Lifetime Risk of Cardiovascular Disease and Compression of Morbidity. JAMA Cardiol. 2018;3(4):280–287. DOI: 10.1001/jamacardio.2018.0022Iliodromiti S., Celis-Morales C.A., Lyall D.M., Anderson J., Gray S.R., Mackay D.F. et al. The impact of confounding on the associations of diff erent adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent. Eur. Heart. J. 2018;39(17):1514–1520. DOI: 10.1093/eurheartj/ehy057Iliodromiti S., Celis-Morales C.A., Lyall D.M., Anderson J., Gray S.R., Mackay D.F. et al. The impact of confounding on the associations of diff erent adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent. Eur. Heart. J. 2018;39(17):1514–1520. DOI: 10.1093/eurheartj/ehy057Ferrannini G., Hach T., Crowe S., Sanghvi A., Hall K.D., Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730–5. DOI: 10.2337/dc15-0355Ferrannini G., Hach T., Crowe S., Sanghvi A., Hall K.D., Ferrannini E. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730–5. DOI: 10.2337/dc15-0355Frías J.P., Guja C., Hardy E., Ahmed A., Dong F., Öhman P., Jabbour S.A. Exenatide once weekly plus dapaglifl ozin once daily versus exenatide or dapaglifl ozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–1016. DOI: 10.1016/S2213-8587(16)30267-4Frías J.P., Guja C., Hardy E., Ahmed A., Dong F., Öhman P., Jabbour S.A. Exenatide once weekly plus dapaglifl ozin once daily versus exenatide or dapaglifl ozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2016;4(12):1004–1016. DOI: 10.1016/S2213-8587(16)30267-4

The authors declare that there are no conflicts of interest present.