diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM8216diaendo-8216Research ArticleДиагностика, контроль, лечениеDiagnosis, control, treatmentЭмпаглифлозин как новая стратегия управления исходами у пациентов с сахарным диабетом 2 типа и высоким кардиоваскулярным рискомEmpagliflozin as a new management strategy on outcomes in patients with type 2 diabetes mellitushttps://orcid.org/0000-0003-1851-0941СалуховВладимир ВладимировичSalukhovVladimir V.

доктор медицинских наук, начальник 1 кафедры  и клиники (терапии усовершенствования врачей)

vlasaluk@yandex.ruДемидоваТатьяна ЮльевнаDemidovaTatiana Y.t.y.demidova@gmail.comФГБВОУ ВО Военно-медицинская академия им. С.М. Кирова МО РФРоссияS.M. Kirov Military Medical AcademyRussian FederationГБОУ ДПО РМАПО Минздрава РоссииРоссияRussian Medical Academy of Postgraduate EducationRussian Federation201602122016196494510Copyright © Салухов В.В., Демидова Т.Ю., 20162016Салухов В.В., Демидова Т.Ю.Salukhov V.V., Demidova T.Y.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.dia-endojournals.ru/jour/article/view/8216

У пациентов с сахарным диабетом 2 типа (СД2) наблюдается повышенный риск развития сердечно-сосудистых осложнений. Хотя гипергликемия способствует развитию и прогрессированию атеросклероза и сердечной недостаточности, существующие до настоящего времени подходы по нормализации уровня глюкозы не оказывали заметного влияния на снижение кардиоваскулярного риска. Ингибиторы натрий-глюкозного котранспортера 2 (SGLT2) типа представляют собой новый класс антигипергликемических препаратов, которые улучшают гликемический контроль благодаря инсулинонезависимому механизму действия, связанному с увеличением экскреции глюкозы с мочой. В обзоре представлен анализ результатов исследования EMPA-REG Outcome, посвященного долгосрочной оценке сердечно-сосудистой безопасности эмпаглифлозина – ингибитора SGLT2. Обсуждаются впечатляющие результаты этого исследования, которые позволяют судить о кардио- и нефропротективных свойствах эмпаглифлозина. В статье приводятся и анализируются существующие в настоящее время гипотезы механизма действия этого сахароснижающего препарата, предопределившего столь выраженное и комплексное влияние на исходы у пациентов с СД2 и высоким кардиоваскулярным риском. Рассматривается место ингибиторов SGLT2 в современных алгоритмах оказания помощи больным СД2, а также роль эмпаглифлозина в комплексном многофакторном управлении СД2.

Patients with type 2 diabetes mellitus have an increased risk of cardiovascular (CV) complications. Although hyperglycaemia contributes to the pathogenesis of atherosclerosis and heart failure in these patients, glucose-lowering strategies did not have a significant effect on reducing CV risk, particularly in patients with a long duration of type 2 diabetes mellitus and prevalent CV disease (CVD). Sodium-glucose linked transporter-2 (SGLT2) inhibitors are a new class of anti-hyperglycaemic medications that increase glycaemic control via insulin-dependent mechanism of action associated with increased urinary glucose excretion.

In this review, we present an analysis of the Empa-Reg Outcomes investigation, focussed on assessing the CV safety of empagliflozin, an inhibitor of SGLT2. We discuss the impressive results of trials that provide evidence on the cardiac and renal properties of empagliflozin. We present and analyse the current hypothesis on the mechanism of action of glucose-lowering medication, which has such a severe and complex impact on outcomes in patients with type 2 diabetes at high CV risk.

сахарный диабет 2 типахроническая сердечная недостаточностьсердечно-сосудистая смертностьгипергликемияинсулинорезистентностьфакторы рискаэмпаглифлозинtype 2 diabetes mellituschronic heart failurecardiovascular mortalityhyperglycemiainsulin resistancerisk factorsempagliflozinReferencesTancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373(18):1720-1732. doi: 10.1056/NEJMoa1504347Tancredi M, Rosengren A, Svensson AM, et al. Excess Mortality among Persons with Type 2 Diabetes. N Engl J Med. 2015;373(18):1720-1732. doi: 10.1056/NEJMoa1504347Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States. N Engl J Med. 2014;371(3):286-287. doi: 10.1056/NEJMc1406009Gregg EW, Williams DE, Geiss L. Changes in diabetes-related complications in the United States. N Engl J Med. 2014;371(3):286-287. doi: 10.1056/NEJMc1406009Emerging Risk Factors C, Di Angelantonio E, Kaptoge S, et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52-60. doi: 10.1001/jama.2015.7008Emerging Risk Factors C, Di Angelantonio E, Kaptoge S, et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52-60. doi: 10.1001/jama.2015.7008Халимов Ю.Ш., Салухов В.В., Улупова Е.О. Гипогликемии как основной фактор выбора целей гликемического контроля и тактики лечения больных сахарным диабетом типа 2. // Consilium medicum. – 2012. – Т. 14. – №12 – С.٢٥-٣٠. [Khalimov YuSh, Salukhov VV, Ulupova EO. Gipoglikemii kak osnovnoy faktor vybora tseley glikemicheskogo kontrolya i taktiki lecheniya bol'nykh sakharnym diabetom tipa 2. Consilium medicum. 2012:14(12):25-30 (in Russ)]Халимов Ю.Ш., Салухов В.В., Улупова Е.О. Гипогликемии как основной фактор выбора целей гликемического контроля и тактики лечения больных сахарным диабетом типа 2. // Consilium medicum. – 2012. – Т. 14. – №12 – С.٢٥-٣٠. [Khalimov YuSh, Salukhov VV, Ulupova EO. Gipoglikemii kak osnovnoy faktor vybora tseley glikemicheskogo kontrolya i taktiki lecheniya bol'nykh sakharnym diabetom tipa 2. Consilium medicum. 2012:14(12):25-30 (in Russ)]Defronzo R. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50(5):191-197. doi: 10.1016/s0300-2977(97)00012-0Defronzo R. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med. 1997;50(5):191-197. doi: 10.1016/s0300-2977(97)00012-0DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. doi: 10.1007/s00125-010-1684-1DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links. The Claude Bernard Lecture 2009. Diabetologia. 2010;53(7):1270-1287. doi: 10.1007/s00125-010-1684-1Obunai K, Jani S, Dangas GD. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91(6):1169-1184, x. doi: 10.1016/j.mcna.2007.06.003Obunai K, Jani S, Dangas GD. Cardiovascular morbidity and mortality of the metabolic syndrome. Med Clin North Am. 2007;91(6):1169-1184, x. doi: 10.1016/j.mcna.2007.06.003Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56(4):686-695. doi: 10.1007/s00125-012-2817-5Sattar N. Revisiting the links between glycaemia, diabetes and cardiovascular disease. Diabetologia. 2013;56(4):686-695. doi: 10.1007/s00125-012-2817-5ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328. doi: 10.1056/NEJMoa1203858ORIGIN Trial Investigators, Gerstein HC, Bosch J, et al. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328. doi: 10.1056/NEJMoa1203858Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998;352(9131):837-853. doi: 10.1016/s0140-6736(98)07019-6Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998;352(9131):837-853. doi: 10.1016/s0140-6736(98)07019-6Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. The Lancet. 2005;366(9493):1279-1289. doi: 10.1016/s0140-6736(05)67528-9Dormandy JA, Charbonnel B, Eckland DJA, et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. The Lancet. 2005;366(9493):1279-1289. doi: 10.1016/s0140-6736(05)67528-9Miyazaki Y, Mahankali A, Matsuda M, et al. Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone. Diabetes Care. 2001;24(4):710-719. doi: 10.2337/diacare.24.4.710Miyazaki Y, Mahankali A, Matsuda M, et al. Improved Glycemic Control and Enhanced Insulin Sensitivity in Type 2 Diabetic Subjects Treated With Pioglitazone. Diabetes Care. 2001;24(4):710-719. doi: 10.2337/diacare.24.4.710Шамхалова М.Ш., Ярек-Мартынова И.Р., Трубицына Н.П., и др. Особенности сахароснижающей терапии у больных сахарным диабетом и хронической болезнью почек // Сахарный диабет. – 2013. – Т. 16. – №3 – C. 97-102. [Shamkhalova MS, Yarek-Martynova IR, Trubitcyna NP, Shestakova MV. Glucose-lowering therapies in patients with diabetes mellitus and chronic kidney disease. Diabetes mellitus. 2013;16(3):97-102. (in Russ)] doi: 10.14341/2072-0351-823Шамхалова М.Ш., Ярек-Мартынова И.Р., Трубицына Н.П., и др. Особенности сахароснижающей терапии у больных сахарным диабетом и хронической болезнью почек // Сахарный диабет. – 2013. – Т. 16. – №3 – C. 97-102. [Shamkhalova MS, Yarek-Martynova IR, Trubitcyna NP, Shestakova MV. Glucose-lowering therapies in patients with diabetes mellitus and chronic kidney disease. Diabetes mellitus. 2013;16(3):97-102. (in Russ)] doi: 10.14341/2072-0351-823Шестакова М.В., Шамхалова М.Ш., Ярек-Мартынова И.Я., и др. Сахарный диабет и хроническая болезнь почек: достижения, нерешенные проблемы и перспективы лечения // Сахарный диабет. – 2011. – Т. 14. – №1 – C. 81-88. [Shestakova MV, Shamkhalova MS, Yarek-Martynova IY, et al. Diabetes mellitus and chronic kidney disease: achievements, unresolved problems, and prospects for therapy. Diabetes mellitus. 2011;14(1):81-88. (in Russ)] doi: 10.14341/2072-0351-6254Шестакова М.В., Шамхалова М.Ш., Ярек-Мартынова И.Я., и др. Сахарный диабет и хроническая болезнь почек: достижения, нерешенные проблемы и перспективы лечения // Сахарный диабет. – 2011. – Т. 14. – №1 – C. 81-88. [Shestakova MV, Shamkhalova MS, Yarek-Martynova IY, et al. Diabetes mellitus and chronic kidney disease: achievements, unresolved problems, and prospects for therapy. Diabetes mellitus. 2011;14(1):81-88. (in Russ)] doi: 10.14341/2072-0351-6254Kimura G. Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens. 2016;10(3):271-278. doi: 10.1016/j.jash.2016.01.009Kimura G. Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens. 2016;10(3):271-278. doi: 10.1016/j.jash.2016.01.009Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med. 2015;373(22):2117-2128. doi: 10.1056/NEJMoa1504720Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. doi: 10.1172/JCI72227Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499-508. doi: 10.1172/JCI72227Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study. Diabetes Care. 2016;39(5):717-725. doi: 10.2337/dc16-0041Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 Inhibitors and Cardiovascular Risk: Lessons Learned From the EMPA-REG OUTCOME Study. Diabetes Care. 2016;39(5):717-725. doi: 10.2337/dc16-0041Kalra S, Singh V, Nagrale D. Sodium-Glucose Cotransporter-2 Inhibition and the Glomerulus: A Review. Adv Ther. 2016;33(9):1502-1518. doi: 10.1007/s12325-016-0379-5Kalra S, Singh V, Nagrale D. Sodium-Glucose Cotransporter-2 Inhibition and the Glomerulus: A Review. Adv Ther. 2016;33(9):1502-1518. doi: 10.1007/s12325-016-0379-5DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55(4):845-855. doi: 10.1172/JCI107996DeFronzo RA, Cooke CR, Andres R, et al. The effect of insulin on renal handling of sodium, potassium, calcium, and phosphate in man. J Clin Invest. 1975;55(4):845-855. doi: 10.1172/JCI107996Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. The Lancet. 2016;387(10017):435-443. doi: 10.1016/s0140-6736(15)00805-3Xie X, Atkins E, Lv J, et al. Effects of intensive blood pressure lowering on cardiovascular and renal outcomes: updated systematic review and meta-analysis. The Lancet. 2016;387(10017):435-443. doi: 10.1016/s0140-6736(15)00805-3Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism. Diabetes. 2016;65(7):2032-2038. doi: 10.2337/db16-0049Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via Switching Metabolism Toward Lipid Utilization, Moderately Increases LDL Cholesterol Levels Through Reduced LDL Catabolism. Diabetes. 2016;65(7):2032-2038. doi: 10.2337/db16-0049Ferrannini G, Hach T, Crowe S, et al. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730-1735. doi: 10.2337/dc15-0355Ferrannini G, Hach T, Crowe S, et al. Energy Balance After Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care. 2015;38(9):1730-1735. doi: 10.2337/dc15-0355Amato MC, Giordano C, Galia M, et al. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(4):920-922. doi: 10.2337/dc09-1825Amato MC, Giordano C, Galia M, et al. Visceral Adiposity Index: a reliable indicator of visceral fat function associated with cardiometabolic risk. Diabetes Care. 2010;33(4):920-922. doi: 10.2337/dc09-1825Ridderstråle M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691-700. doi: 10.1016/s2213-8587(14)70120-2Ridderstråle M, Andersen KR, Zeller C, et al. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691-700. doi: 10.1016/s2213-8587(14)70120-2Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020-1031. doi: 10.1210/jc.2011-2260Bolinder J, Ljunggren O, Kullberg J, et al. Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab. 2012;97(3):1020-1031. doi: 10.1210/jc.2011-2260Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262-274. doi: 10.7326/0003-4819-159-4-201308200-00007Vasilakou D, Karagiannis T, Athanasiadou E, et al. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann Intern Med. 2013;159(4):262-274. doi: 10.7326/0003-4819-159-4-201308200-00007Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Rajasekeran H, Lytvyn Y, Cherney DZ. 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):524-526. doi: 10.1016/j.kint.2015.12.038Rajasekeran H, Lytvyn Y, Cherney DZ. 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):524-526. doi: 10.1016/j.kint.2015.12.038Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi: 10.2337/dc14-1096Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420-428. doi: 10.2337/dc14-1096Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016;37(42):3192-3200. doi: 10.1093/eurheartj/ehw110Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016;37(42):3192-3200. doi: 10.1093/eurheartj/ehw110Odden MC, Amadu AR, Smit E, et al. Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002. Am J Kidney Dis. 2014;64(4):550-557. doi: 10.1053/j.ajkd.2014.04.024Odden MC, Amadu AR, Smit E, et al. Uric acid levels, kidney function, and cardiovascular mortality in US adults: National Health and Nutrition Examination Survey (NHANES) 1988-1994 and 1999-2002. Am J Kidney Dis. 2014;64(4):550-557. doi: 10.1053/j.ajkd.2014.04.024Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811-1821. doi: 10.1056/NEJMra0800885Feig DI, Kang DH, Johnson RJ. Uric acid and cardiovascular risk. N Engl J Med. 2008;359(17):1811-1821. doi: 10.1056/NEJMra0800885Lytvyn Y, Skrtic M, Yang GK, et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015;308(2):F77-83. doi: 10.1152/ajprenal.00555.2014Lytvyn Y, Skrtic M, Yang GK, et al. Glycosuria-mediated urinary uric acid excretion in patients with uncomplicated type 1 diabetes mellitus. Am J Physiol Renal Physiol. 2015;308(2):F77-83. doi: 10.1152/ajprenal.00555.2014Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148. doi: 10.1186/s12933-014-0148-1Taegtmeyer H. Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts. Circulation. 2002;105(14):1727-1733. doi: 10.1161/01.cir.0000012466.50373.e8Taegtmeyer H. Adaptation and Maladaptation of the Heart in Diabetes: Part I: General Concepts. Circulation. 2002;105(14):1727-1733. doi: 10.1161/01.cir.0000012466.50373.e8Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and Progression of Kidney Disease in Type 2 Diabetes. N Engl J Med. 2016;375(4):323-334. doi: 10.1056/NEJMoa1515920Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306(2):F194-204. doi: 10.1152/ajprenal.00520.2013Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol. 2014;306(2):F194-204. doi: 10.1152/ajprenal.00520.2013Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307(3):F317-325. doi: 10.1152/ajprenal.00145.2014Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob/ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol. 2014;307(3):F317-325. doi: 10.1152/ajprenal.00145.2014Gerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-142. doi: 10.1111/j.1464-5491.2009.02894.xGerich JE. Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med. 2010;27(2):136-142. doi: 10.1111/j.1464-5491.2009.02894.xMalatiali S, Francis I, Barac-Nieto M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp Diabetes Res. 2008;2008:305403. doi: 10.1155/2008/305403Malatiali S, Francis I, Barac-Nieto M. Phlorizin prevents glomerular hyperfiltration but not hypertrophy in diabetic rats. Exp Diabetes Res. 2008;2008:305403. doi: 10.1155/2008/305403Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-971. doi: 10.1038/ki.2013.356Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int. 2014;85(4):962-971. doi: 10.1038/ki.2013.356Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-473. doi: 10.1111/dom.12090Yale JF, Bakris G, Cariou B, et al. Efficacy and safety of canagliflozin in subjects with type 2 diabetes and chronic kidney disease. Diabetes Obes Metab. 2013;15(5):463-473. doi: 10.1111/dom.12090Климонтов В.В., Мякина Н.Е. Хроническая болезнь почек при сахарном диабете. – Новосибирск: Издательство НГУ; 2014. [Klimontov VV, Myakina NE. Khronicheskaya bolezn' pochek pri sakharnom diabete. Novosibirsk: Izdatel'stvo NGU; 2014. (in Russ)]Климонтов В.В., Мякина Н.Е. Хроническая болезнь почек при сахарном диабете. – Новосибирск: Издательство НГУ; 2014. [Klimontov VV, Myakina NE. Khronicheskaya bolezn' pochek pri sakharnom diabete. Novosibirsk: Izdatel'stvo NGU; 2014. (in Russ)]Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59(9):1860-1870. doi: 10.1007/s00125-016-4008-2Cherney D, Lund SS, Perkins BA, et al. The effect of sodium glucose cotransporter 2 inhibition with empagliflozin on microalbuminuria and macroalbuminuria in patients with type 2 diabetes. Diabetologia. 2016;59(9):1860-1870. doi: 10.1007/s00125-016-4008-2Pollock CA, Lawrence JR, Field MJ. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am J Physiol. 1991;260(6):F946-F952.Pollock CA, Lawrence JR, Field MJ. Tubular sodium handling and tubuloglomerular feedback in experimental diabetes mellitus. Am J Physiol. 1991;260(6):F946-F952.Bank N, Aynedjian HS. Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest. 1990;86(1):309-316. doi: 10.1172/jci114700Bank N, Aynedjian HS. Progressive increases in luminal glucose stimulate proximal sodium absorption in normal and diabetic rats. J Clin Invest. 1990;86(1):309-316. doi: 10.1172/jci114700Vallon V, RICHTER K, BLANTZ RC, et al. Glomerular hyperfiltration in experimental diabetes mellitus potential role of tubular reabsorption. J Am SocNephrol. 1999;10(12):2569-2576.Vallon V, RICHTER K, BLANTZ RC, et al. Glomerular hyperfiltration in experimental diabetes mellitus potential role of tubular reabsorption. J Am SocNephrol. 1999;10(12):2569-2576.Scheen AJ. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. Clin Pharmacokinet. 2015;54(7):691-708. doi: 10.1007/s40262-015-0264-4Scheen AJ. Pharmacokinetics, Pharmacodynamics and Clinical Use of SGLT2 Inhibitors in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease. Clin Pharmacokinet. 2015;54(7):691-708. doi: 10.1007/s40262-015-0264-4Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28. doi: 10.1186/1475-2840-13-28Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28. doi: 10.1186/1475-2840-13-28Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Cherney DZ, Perkins BA, Soleymanlou N, et al. 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.113.005081Shimizu M, Furuichi K, Toyama T, et al. Long-term outcomes of Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy. Diabetes Care. 2013;36(11):3655-3662. doi: 10.2337/dc13-0298Shimizu M, Furuichi K, Toyama T, et al. Long-term outcomes of Japanese type 2 diabetic patients with biopsy-proven diabetic nephropathy. Diabetes Care. 2013;36(11):3655-3662. doi: 10.2337/dc13-0298Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217-2224. doi: 10.2337/dc10-0612Ferrannini E, Ramos SJ, Salsali A, et al. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care. 2010;33(10):2217-2224. doi: 10.2337/dc10-0612Rahmoune H, Thompson PW, Ward JM, et al. Glucose Transporters in Human Renal Proximal Tubular Cells Isolated From the Urine of Patients With Non-Insulin-Dependent Diabetes. Diabetes. 2005;54(12):3427-3434. doi: 10.2337/diabetes.54.12.3427Rahmoune H, Thompson PW, Ward JM, et al. Glucose Transporters in Human Renal Proximal Tubular Cells Isolated From the Urine of Patients With Non-Insulin-Dependent Diabetes. Diabetes. 2005;54(12):3427-3434. doi: 10.2337/diabetes.54.12.3427Ortola FV, Ballermann BJ, Anderson S, et al. Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. J Clin Invest. 1987;80(3):670-674. doi: 10.1172/JCI113120Ortola FV, Ballermann BJ, Anderson S, et al. Elevated plasma atrial natriuretic peptide levels in diabetic rats. Potential mediator of hyperfiltration. J Clin Invest. 1987;80(3):670-674. doi: 10.1172/JCI113120Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752-772. doi: 10.1161/CIRCULATIONAHA.116.021887Heerspink HJ, Perkins BA, Fitchett DH, et al. Sodium Glucose Cotransporter 2 Inhibitors in the Treatment of Diabetes Mellitus: Cardiovascular and Kidney Effects, Potential Mechanisms, and Clinical Applications. Circulation. 2016;134(10):752-772. doi: 10.1161/CIRCULATIONAHA.116.021887Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-862. doi: 10.1111/dom.12127Lambers Heerspink HJ, de Zeeuw D, Wie L, et al. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853-862. doi: 10.1111/dom.12127Liu T, Takimoto E, Dimaano VL, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115(1):44-54. doi: 10.1161/CIRCRESAHA.115.303062Liu T, Takimoto E, Dimaano VL, et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ Res. 2014;115(1):44-54. doi: 10.1161/CIRCRESAHA.115.303062Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics. Diabetes Metab. 2016;42(4):224-233. doi: 10.1016/j.diabet.2016.05.006Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: Comparison with classic diuretics. Diabetes Metab. 2016;42(4):224-233. doi: 10.1016/j.diabet.2016.05.006Franse LV, Pahor M, Di Bari M, et al. Hypokalemia Associated With Diuretic Use and Cardiovascular Events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000;35(5):1025-1030. doi: 10.1161/01.hyp.35.5.1025Franse LV, Pahor M, Di Bari M, et al. Hypokalemia Associated With Diuretic Use and Cardiovascular Events in the Systolic Hypertension in the Elderly Program. Hypertension. 2000;35(5):1025-1030. doi: 10.1161/01.hyp.35.5.1025Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-1225. doi: 10.1161/CIRCULATIONAHA.105.595496Williams B, Lacy PS, Thom SM, et al. Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation. 2006;113(9):1213-1225. doi: 10.1161/CIRCULATIONAHA.105.595496Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72-81. doi: 10.1111/dom.12585Salem V, Izzi-Engbeaya C, Coello C, et al. Glucagon increases energy expenditure independently of brown adipose tissue activation in humans. Diabetes Obes Metab. 2016;18(1):72-81. doi: 10.1111/dom.12585Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: A "Thrifty Substrate" Hypothesis. Diabetes Care. 2016;39(7):1108-1114. 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):1108-1114. doi: 10.2337/dc16-0330Neel JV. Diabetes Mellitus: A “Thrifty” Genotype Rendered Detrimental by “Progress”? Am Journal HumGenet. 1962;14(4):353-362.Neel JV. Diabetes Mellitus: A “Thrifty” Genotype Rendered Detrimental by “Progress”? Am Journal HumGenet. 1962;14(4):353-362.Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;37(27):2129-2200. doi: 10.1093/eurheartj/ehw128

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