diaendoСахарный диабетDiabetes mellitus2072-03512072-0378Endocrinology research centre10.14341/DM13085diaendo-13085Research ArticleОбзорыReviewНейропротекторный потенциал глифлозиновNeuroprotective potential of gliflozinshttps://orcid.org/0000-0002-9093-7985КокинА. С.KokinA. S.

Кокин Артем Сергеевич, ординатор 

г. Тюмень

Artem S. Kokin, clinical resident

Tyumen

kokin.artem45@gmail.comhttps://orcid.org/0000-0001-9253-8075СуплотоваЛ. А.SuplotovaL. A.

Суплотова Людмила Александровна, д.м.н., профессор

625023 г. Тюмень, ул. Одесская, д. 54

Lyudmila A. Suplotova, MD, PhD, Professor 

54 Odesskaya str, 625023 Tyumen

suplotovala@mail.ruТюменский государственный медицинский университетРоссияTyumen State Medical UniversityRussian Federation202316112023266596602Copyright © Кокин А.С., Суплотова Л.А., 20232023Кокин А.С., Суплотова Л.А.Kokin A.S., Suplotova L.A.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/13085

Глифлозины – сравнительно новый класс пероральных сахароснижающих препаратов, все более широко входящий в рутинную практику при лечении пациентов с сахарным диабетом 2 типа (СД2). Гипогликемический эффект глифлозинов связан со стимуляцией глюкозурии, однако, помимо выраженного сахароснижающего эффекта и высокой безопасности эти препараты так же обладают множеством плейотропных свойств, ввиду наличия как прямых, так и опосредованных точек приложения. Целью настоящей работы является обзорное представление наиболее изученных на данный момент нейропротекторных эффектов этого класса препаратов. В качестве материалов в ходе работы использовались исследования зарубежных коллег, в том числе фундаментальные работы in vitro, а также клинические испытания. Анализ работ показал, что нейропротективное действие глифлозинов связано со множеством различных механизмов - так, глифлозины реализуют противовоспалительный эффект путем активации М2-субпопуляции макрофагов, снижением провоспалительных нейромедиаторов (относящихся, в первую очередь к инфламмасоме). Кроме того, в следствии снижения активности сигнального пути mTOR препараты уменьшают количество бета-амилоида и улучшают процессы нейротрансмиссии. Группой работ было также показано и антиацетилхолинэстеразное действие глифлозинов, не говоря уже о снижении интенсивности неферментативного гликирования протеинов и инсулинорезистентности. Все вышеперечисленные механизмы обеспечивают противовоспалительный, антиатерогенный эффект, улучшение когнитивных способностей у пациентов, снижение частоты геморрагических ОНМК, а также потенциально могут улучшать прогнозы у пациентов с болезнью Альцгеймера (БА). Описанные выше эффекты были получены в ходе доклинических испытаний и множества экспериментальных работ, а некоторые эффекты уже продемонстрировали свою состоятельность и в ходе проспективных клинических испытаний. Однако, полученных данных пока недостаточно для формирования четких показаний для этого класса препаратов в неврологии, поэтому тема требует дальнейшего изучения и клинических испытаний.

Gliflozins are a relatively new class of oral antihyperglycemic drugs that are increasingly being introduced into routine practice in the treatment of patients with type 2 diabetes mellitus (DM2). The hypoglycemic effect of gliflozins is associated with the stimulation of glucosuria, however, in addition to a pronounced hypoglycemic effect and high safety, these drugs also have many pleiotropic properties, due to the presence of many direct and indirect points of application. The purpose of this paper is to provide an overview of the currently best studied neuroprotective effects of this class of drugs. As materials in the course of the work, studies of foreign colleagues published in the period 2008–2022 were used. Analysis of the works showed that the neuroprotective effect of gliflozins is associated with many different mechanisms. Thus, gliflozins realize an anti-inflammatory effect by activating the M2 subpopulation of macrophages, reducing pro-inflammatory neurotransmitters (related primarily to the inflammasome). In addition, by reducing the activity of the mTOR signaling pathway, the drugs reduce the amount of beta-amyloid and improve neurotransmission. A group of works also showed the antiacetylcholinesterase effect of gliflozins, not to mention the decrease in the intensity of non-enzymatic protein glycation and insulin resistance. All of the above mechanisms provide an anti-inflammatory, anti-atherogenic effect, improve cognitive abilities in patients, reduce the frequency of hemorrhagic stroke, and can also potentially improve prognosis in patients with Alzheimer’s disease (AD). The effects described above were obtained during preclinical trials and many experimental studies, and some effects have already demonstrated their consistency in prospective clinical trials. However, the data obtained are still insufficient to form clear indications for this class of drugs in neurology, so the topic requires further study and clinical trials.

нейропротекцияболезнь Альцгеймераглифлозиныингибиторы натрий-глюкозного котранспортера-2сахарный диабетгеморрагический инсульткогнитивные нарушенияneuroprotectionAlzheimer’s diseasegliflozinssodium-glucose cotransporter-2 inhibitorsdiabetes mellitushemorrhagic strokecognitive impairmentReferencesNasiri-Ansari N, Nikolopoulou C, Papoutsi K, et al. Empagliflozin attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in high fat diet fed ApoE(-/-) mice by activating autophagy and reducing er stress and apoptosis. Int J Mol Sci. 2021;22(2):818. doi: https://doi.org/10.3390/ijms22020818Nasiri-Ansari N, Nikolopoulou C, Papoutsi K, et al. Empagliflozin attenuates Non-Alcoholic Fatty Liver Disease (NAFLD) in high fat diet fed ApoE(-/-) mice by activating autophagy and reducing er stress and apoptosis. Int J Mol Sci. 2021;22(2):818. doi: https://doi.org/10.3390/ijms22020818Wright EM, Loo DDF, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733-794. doi: https://doi.org/10.1152/physrev.00055.2009Wright EM, Loo DDF, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733-794. doi: https://doi.org/10.1152/physrev.00055.2009Deng D, Yan N. GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters. Protein Science. 2016;25(3):546-558. doi: https://doi.org/10.1002/pro.2858Deng D, Yan N. GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters. Protein Science. 2016;25(3):546-558. doi: https://doi.org/10.1002/pro.2858Lehmann A, Hornby PJ. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Liver Physiol. 2016;310(11):G887-G898. doi: https://doi.org/10.1152/ajpgi.00068.2016Lehmann A, Hornby PJ. Intestinal SGLT1 in metabolic health and disease. Am J Physiol Liver Physiol. 2016;310(11):G887-G898. doi: https://doi.org/10.1152/ajpgi.00068.2016Hu G, Wang X, Meng L, et al. SGLT1/2 as the potential biomarkers of renal damage under Apoe−/− and chronic stress via the BP neural network model and support vector machine. Front Cardiovasc Med. 2022;9. doi: https://doi.org/10.3389/fcvm.2022.948909Hu G, Wang X, Meng L, et al. SGLT1/2 as the potential biomarkers of renal damage under Apoe−/− and chronic stress via the BP neural network model and support vector machine. Front Cardiovasc Med. 2022;9. doi: https://doi.org/10.3389/fcvm.2022.948909Poppe R, Karbach U, Gambaryan S, et al. Expression of the Na+-d-Glucose Cotransporter SGLT1 in Neurons. J Neurochem. 2002;69(1):84-94. doi: https://doi.org/10.1046/j.1471-4159.1997.69010084.xPoppe R, Karbach U, Gambaryan S, et al. Expression of the Na+-d-Glucose Cotransporter SGLT1 in Neurons. J Neurochem. 2002;69(1):84-94. doi: https://doi.org/10.1046/j.1471-4159.1997.69010084.xNguyen T, Wen S, Gong M, et al. Dapagliflozin activates neurons in the Ther. 2020;(13):2781central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice. Diabetes, Metab Syndr Obes Targets -2799. doi: https://doi.org/10.2147/DMSO.S258593Nguyen T, Wen S, Gong M, et al. Dapagliflozin activates neurons in the Ther. 2020;(13):2781central nervous system and regulates cardiovascular activity by inhibiting SGLT-2 in mice. Diabetes, Metab Syndr Obes Targets -2799. doi: https://doi.org/10.2147/DMSO.S258593Pawlos A, Broncel M, Woźniak E, Gorzelak-Pabiś P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. doi: https://doi.org/10.3390/molecules26237213Pawlos A, Broncel M, Woźniak E, Gorzelak-Pabiś P. Neuroprotective effect of SGLT2 inhibitors. Molecules. 2021;26(23):7213. doi: https://doi.org/10.3390/molecules26237213Oerter S, Förster C, Bohnert M. Validation of sodium/ glucose cotransporter proteins in human brain as a potential marker for temporal narrowing of the trauma formation. Int J Legal Med. 2019;133(4):1107-1114. doi: https://doi.org/10.1007/s00414-018-1893-6Oerter S, Förster C, Bohnert M. Validation of sodium/ glucose cotransporter proteins in human brain as a potential marker for temporal narrowing of the trauma formation. Int J Legal Med. 2019;133(4):1107-1114. doi: https://doi.org/10.1007/s00414-018-1893-6Sebastiani A, Greve F, Gölz C, et al. RS1 (Rsc1A1) deficiency limits cerebral SGLT1 expression and delays brain damage after experimental traumatic brain injury. J Neurochem. 2018;147(2):190-203. doi: https://doi.org/10.1111/jnc.14551Sebastiani A, Greve F, Gölz C, et al. RS1 (Rsc1A1) deficiency limits cerebral SGLT1 expression and delays brain damage after experimental traumatic brain injury. J Neurochem. 2018;147(2):190-203. doi: https://doi.org/10.1111/jnc.14551Jayarathne HSM, Debarba LK, Jaboro JJ, et al. Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice. Aging Cell. 2022;21(7):e13653. doi: https://doi.org/10.1111/acel.13653Jayarathne HSM, Debarba LK, Jaboro JJ, et al. Neuroprotective effects of Canagliflozin: Lessons from aged genetically diverse UM-HET3 mice. Aging Cell. 2022;21(7):e13653. doi: https://doi.org/10.1111/acel.13653Rizvi S, Shakil S, Biswas D, et al. Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose Co-transporter 2: Advancement in Alzheimer’s disease diabetes type 2 linkage via an enzoinformatics study. CNS Neurol Disord Drug Targets. 2014;13(3):447-451. doi: https://doi.org/10.2174/18715273113126660160Rizvi S, Shakil S, Biswas D, et al. Invokana (Canagliflozin) as a dual inhibitor of acetylcholinesterase and sodium glucose Co-transporter 2: Advancement in Alzheimer’s disease diabetes type 2 linkage via an enzoinformatics study. CNS Neurol Disord Drug Targets. 2014;13(3):447-451. doi: https://doi.org/10.2174/18715273113126660160Arafa NMS, Ali EHA, Hassan MK. Canagliflozin prevents scopolamineinduced memory impairment in rats: Comparison with galantamine hydrobromide action. Chem Biol Interact. 2017;(277):195-203. doi: https://doi.org/10.1016/j.cbi.2017.08.013Arafa NMS, Ali EHA, Hassan MK. Canagliflozin prevents scopolamineinduced memory impairment in rats: Comparison with galantamine hydrobromide action. Chem Biol Interact. 2017;(277):195-203. doi: https://doi.org/10.1016/j.cbi.2017.08.013Van Skike CE, Galvan V. A perfect sTORm: The role of the mammalian Target of Rapamycin (mTOR) in cerebrovascular dysfunction of Alzheimer’s disease: A mini-review. Gerontology. 2018;64(3):205-211. doi: https://doi.org/10.1159/000485381Van Skike CE, Galvan V. A perfect sTORm: The role of the mammalian Target of Rapamycin (mTOR) in cerebrovascular dysfunction of Alzheimer’s disease: A mini-review. Gerontology. 2018;64(3):205-211. doi: https://doi.org/10.1159/000485381Stanciu GD, Rusu RN, Bild V, et al. Systemic actions of SGLT2 inhibition on chronic mTOR activation as a shared pathogenic mechanism between Alzheimer’s disease and diabetes. Biomedicines. 2021;9(5):576. doi: https://doi.org/10.3390/biomedicines9050576Stanciu GD, Rusu RN, Bild V, et al. Systemic actions of SGLT2 inhibition on chronic mTOR activation as a shared pathogenic mechanism between Alzheimer’s disease and diabetes. Biomedicines. 2021;9(5):576. doi: https://doi.org/10.3390/biomedicines9050576Packer M. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: A paradigm shift in understanding their mechanism of action. Diabetes Care. 2020;43(3):508-511. doi: https://doi.org/10.2337/dci19-0074Packer M. SGLT2 inhibitors produce cardiorenal benefits by promoting adaptive cellular reprogramming to induce a state of fasting mimicry: A paradigm shift in understanding their mechanism of action. Diabetes Care. 2020;43(3):508-511. doi: https://doi.org/10.2337/dci19-0074Uddin MdS, Rahman MdA, Kabir MdT, et al. Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer’s disease. IUBMB Life. 2020;72(9):1843-1855. doi: https://doi.org/10.1002/iub.2324Uddin MdS, Rahman MdA, Kabir MdT, et al. Multifarious roles of mTOR signaling in cognitive aging and cerebrovascular dysfunction of Alzheimer’s disease. IUBMB Life. 2020;72(9):1843-1855. doi: https://doi.org/10.1002/iub.2324Bi C, Fu Y, Li B. Brain-derived neurotrophic factor alleviates diabetes mellitus-accelerated atherosclerosis by promoting M2 polarization of macrophages through repressing the STAT3 pathway. Cell Signal. 2020;70:109569. doi: https://doi.org/10.1016/j.cellsig.2020.109569Bi C, Fu Y, Li B. Brain-derived neurotrophic factor alleviates diabetes mellitus-accelerated atherosclerosis by promoting M2 polarization of macrophages through repressing the STAT3 pathway. Cell Signal. 2020;70:109569. doi: https://doi.org/10.1016/j.cellsig.2020.109569Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empaglifl zin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13(1):148. doi: https://doi.org/10.1186/s12933-014-0148-1Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empaglifl zin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13(1):148. doi: https://doi.org/10.1186/s12933-014-0148-1Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Archives of Medical Science. 2015;6:1164-1178. doi: https://doi.org/10.5114/aoms.2015.56342Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications. Archives of Medical Science. 2015;6:1164-1178. doi: https://doi.org/10.5114/aoms.2015.56342Zhen YF, Zhang J, Liu XY, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology (Berl). 2013;227(1):93-100. doi: https://doi.org/10.1007/s00213-012-2942-3Zhen YF, Zhang J, Liu XY, et al. Low BDNF is associated with cognitive deficits in patients with type 2 diabetes. Psychopharmacology (Berl). 2013;227(1):93-100. doi: https://doi.org/10.1007/s00213-012-2942-3Liu Z, Ma X, Ilyas I, et al. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to preclinical and clinical therapeutics. Theranostics. 2021;11(9):4502-4515. doi: https://doi.org/10.7150/thno.54498Liu Z, Ma X, Ilyas I, et al. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to preclinical and clinical therapeutics. Theranostics. 2021;11(9):4502-4515. doi: https://doi.org/10.7150/thno.54498Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20(13):3328. doi: https://doi.org/10.3390/ijms20133328Kelley N, Jeltema D, Duan Y, He Y. The NLRP3 inflammasome: An overview of mechanisms of activation and regulation. Int J Mol Sci. 2019;20(13):3328. doi: https://doi.org/10.3390/ijms20133328Kim SR, Lee SG, Kim SH, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11(1):2127. doi: https://doi.org/10.1038/s41467-020-15983-6Kim SR, Lee SG, Kim SH, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11(1):2127. doi: https://doi.org/10.1038/s41467-020-15983-6Tejera D, Mercan D, Sanchez‐Caro JM, et al. Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome. EMBO J. 2019;38(17). doi: https://doi.org/10.15252/embj.2018101064Tejera D, Mercan D, Sanchez‐Caro JM, et al. Systemic inflammation impairs microglial Aβ clearance through NLRP 3 inflammasome. EMBO J. 2019;38(17). doi: https://doi.org/10.15252/embj.2018101064Sim AY, Barua S, Kim JY, et al. Role of DPP-4 and SGLT2 inhibitors connected to Alzheimer disease in type 2 diabetes mellitus. Front Neurosci. 2021;15. doi: https://doi.org/10.3389/fnins.2021.708547Sim AY, Barua S, Kim JY, et al. Role of DPP-4 and SGLT2 inhibitors connected to Alzheimer disease in type 2 diabetes mellitus. Front Neurosci. 2021;15. doi: https://doi.org/10.3389/fnins.2021.708547Langbaum JBS, Chen K, Lee W, et al. Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuroimage. 2009;45(4):1107-1116. doi: https://doi.org/10.1016/j.neuroimage.2008.12.072Langbaum JBS, Chen K, Lee W, et al. Categorical and correlational analyses of baseline fluorodeoxyglucose positron emission tomography images from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Neuroimage. 2009;45(4):1107-1116. doi: https://doi.org/10.1016/j.neuroimage.2008.12.072Cork SC, Richards JE, Holt MK, et al. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718-731. doi: https://doi.org/10.1016/j.molmet.2015.07.008Cork SC, Richards JE, Holt MK, et al. Distribution and characterisation of Glucagon-like peptide-1 receptor expressing cells in the mouse brain. Mol Metab. 2015;4(10):718-731. doi: https://doi.org/10.1016/j.molmet.2015.07.008Mone P, Lombardi A, Gambardella J, et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022;45(5):1247-1251. doi: https://doi.org/10.2337/dc21-2434Mone P, Lombardi A, Gambardella J, et al. Empagliflozin improves cognitive impairment in frail older adults with type 2 diabetes and heart failure with preserved ejection fraction. Diabetes Care. 2022;45(5):1247-1251. doi: https://doi.org/10.2337/dc21-2434Yabe D, Shiki K, Suzaki K, et al. Rationale and design of the EMPAELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodiumglucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes. BMJ Open. 2021;11(4):e045844. doi: https://doi.org/10.1136/bmjopen-2020-045844Yabe D, Shiki K, Suzaki K, et al. Rationale and design of the EMPAELDERLY trial: a randomised, double-blind, placebo-controlled, 52-week clinical trial of the efficacy and safety of the sodiumglucose cotransporter-2 inhibitor empagliflozin in elderly Japanese patients with type 2 diabetes. BMJ Open. 2021;11(4):e045844. doi: https://doi.org/10.1136/bmjopen-2020-045844Lee SG, Lee SJ, Lee JJ, et al. Anti-Inflammatory Effect for atherosclerosis progression by Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitor in a normoglycemic rabbit model. Korean Circ J. 2020;50(5):443. doi: https://doi.org/10.4070/kcj.2019.0296Lee SG, Lee SJ, Lee JJ, et al. Anti-Inflammatory Effect for atherosclerosis progression by Sodium-Glucose Cotransporter 2 (SGLT-2) inhibitor in a normoglycemic rabbit model. Korean Circ J. 2020;50(5):443. doi: https://doi.org/10.4070/kcj.2019.0296Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empaglifl zin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol Res. 2021;2021:1-11. doi: https://doi.org/10.1155/2021/9944880Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empaglifl zin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling pathways. J Immunol Res. 2021;2021:1-11. doi: https://doi.org/10.1155/2021/9944880Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. 2020;40(1):20-33. doi: https://doi.org/10.1161/ATVBAHA.119.312802Barrett TJ. Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. 2020;40(1):20-33. doi: https://doi.org/10.1161/ATVBAHA.119.312802Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet. 2019;393(10166):31-39. doi: https://doi.org/10.1016/S0140-6736(18)32590-XZelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. The Lancet. 2019;393(10166):31-39. doi: https://doi.org/10.1016/S0140-6736(18)32590-XRay KK, Seshasai SRK, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. The Lancet. 2009;373(9677):1765-1772. doi: https://doi.org/10.1016/S0140-6736(09)60697-8Ray KK, Seshasai SRK, Wijesuriya S, et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. The Lancet. 2009;373(9677):1765-1772. doi: https://doi.org/10.1016/S0140-6736(09)60697-8Kimura G. Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors and stroke. Circ J. 2017;81(6):898. doi: https://doi.org/10.1253/circj.CJ-17-0040Kimura G. Sodium-Glucose Cotransporter 2 (SGLT2) inhibitors and stroke. Circ J. 2017;81(6):898. doi: https://doi.org/10.1253/circj.CJ-17-0040Sato K, Mano T, Iwata A, Toda T. Subtype‐dependent reporting of stroke With SGLT2 inhibitors: implications from a Japanese pharmacovigilance study. J Clin Pharmacol. 2020;60(5):629-635. doi: https://doi.org/10.1002/jcph.1561Sato K, Mano T, Iwata A, Toda T. Subtype‐dependent reporting of stroke With SGLT2 inhibitors: implications from a Japanese pharmacovigilance study. J Clin Pharmacol. 2020;60(5):629-635. doi: https://doi.org/10.1002/jcph.1561Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6(9):691-704. doi: https://doi.org/10.1016/S2213-8587(18)30141-4Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS Program randomised clinical trials. Lancet Diabetes Endocrinol. 2018;6(9):691-704. doi: https://doi.org/10.1016/S2213-8587(18)30141-4Zhou Z, Jardine MJ, Li Q, et al. Effect of SGLT2 Inhibitors on stroke and atrial fibrillation in diabetic kidney disease. Stroke. 2021;52(5):1545-1556. doi: https://doi.org/10.1161/STROKEAHA.120.031623Zhou Z, Jardine MJ, Li Q, et al. Effect of SGLT2 Inhibitors on stroke and atrial fibrillation in diabetic kidney disease. Stroke. 2021;52(5):1545-1556. doi: https://doi.org/10.1161/STROKEAHA.120.031623Zinman 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: https://doi.org/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: https://doi.org/10.1056/NEJMoa1504720Zinman B, Inzucchi SE, Lachin JM, et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48(5):1218-1225. doi: https://doi.org/10.1161/STROKEAHA.116.015756Zinman B, Inzucchi SE, Lachin JM, et al. Empagliflozin and cerebrovascular events in patients with type 2 diabetes mellitus at high cardiovascular risk. Stroke. 2017;48(5):1218-1225. doi: https://doi.org/10.1161/STROKEAHA.116.015756Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi: https://doi.org/10.1056/NEJMoa1811744Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N Engl J Med. 2019;380(24):2295-2306. doi: https://doi.org/10.1056/NEJMoa1811744Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: https://doi.org/10.1056/NEJMoa1812389Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347-357. doi: https://doi.org/10.1056/NEJMoa1812389Kaze AD, Jaar BG, Fonarow GC, Echouffo-Tcheugui JB. Diabetic kidney disease and risk of incident stroke among adults with type 2 diabetes. BMC Med. 2022;20(1):127. doi: https://doi.org/10.1186/s12916-022-02317-0Kaze AD, Jaar BG, Fonarow GC, Echouffo-Tcheugui JB. Diabetic kidney disease and risk of incident stroke among adults with type 2 diabetes. BMC Med. 2022;20(1):127. doi: https://doi.org/10.1186/s12916-022-02317-0Tsai WH, Chuang SM, Liu SC, et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci Rep. 2021;11(1):15364. doi: https://doi.org/10.1038/s41598-021-94945-4Tsai WH, Chuang SM, Liu SC, et al. Effects of SGLT2 inhibitors on stroke and its subtypes in patients with type 2 diabetes: a systematic review and meta-analysis. Sci Rep. 2021;11(1):15364. doi: https://doi.org/10.1038/s41598-021-94945-4Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: A systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262-275.e9. doi: https://doi.org/10.1016/j.jash.2014.01.007Baker WL, Smyth LR, Riche DM, et al. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: A systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262-275.e9. doi: https://doi.org/10.1016/j.jash.2014.01.007

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