AFRJMS African Research Journal of Medical Sciences 3006-7421 Bioscience Press afrjms-3-1-001 10.62587/AFRJMS.1.1.2024.72-86 Research Paper The complex interplay between SGLT2 inhibitors and atrial fibrillation: mechanisms and clinical implications FahimiBehzad 1 * BeikmohammadiSomayeh 2 1Cardiologist, Academic Heart Center Duisburg, Duisburg, Nordrhein Westfalen, Germany. E-mail: behzadfahimi@gmail.com 2Cardiologist, Academic Hospital Elisabeth-Krankenhaus, Essen, Nordrhein Westfalen, Germany. E-mail: soman10620@gmail.com *Corresponding author: Behzad Fahimi, Cardiologist, Academic Heart Center Duisburg, Duisburg, Nordrhein Westfalen, Germany. E-mail: behzadfahimi@gmail.com 01 2024 1 1 72 86 Abstract

This comprehensive review delves into the intricate relationship between Sodium-Glucose Co-Transporter 2 (SGLT2) inhibitors and AF, highlighting the multifaceted actions of these drugs and their significant cardiovascular benefits. Mechanisms: SGLT2 inhibitors induce substantial hemodynamic changes, impacting blood pressure, adipose tissue function, and inflammation. They enhance glycemic control while potentially reducing oxidative stress and inflammation, and they modulate atrial electrophysiology, collectively contributing to the reduction of AF risk. Clinical evidence: This review synthesizes a wealth of clinical evidence, drawing from observational studies and randomized controlled trials, consistently demonstrating a correlation between SGLT2 inhibitors, particularly dapagliflozin and empagliflozin, and a decreased risk of AF. This protective effect is most pronounced in patients with type 2 diabetes and heart failure, underscoring their potential as therapeutic agents for high-risk populations. Potential benefits: SGLT2 inhibitors offer a spectrum of potential benefits, including substantial reductions in AF risk, particularly in patients with type 2 diabetes and heart failure. These drugs have consistently demonstrated benefits in reducing heart failure hospitalizations, cardiovascular mortality, and stroke risk, which indirectly contribute to better AF management. Furthermore, SGLT2 inhibitors exhibit renoprotective properties by slowing the progression of chronic kidney disease and reducing albuminuria, offering substantial benefits for AF patients with comorbid kidney disease. Metabolic improvements involving weight loss, blood pressure reduction, and favorable changes in lipid profiles contribute to enhanced cardiovascular health and reduced AF risk. Originally designed for diabetes management, these medications offer a holistic approach to AF risk reduction, particularly in patients with type 2 diabetes and heart failure.

 Keywords Atrial fibrillation SGLT2 inhibitors Cardiovascular outcomes Hemodynamic effects AF risk reduction References AbdullahKaplan.EmnaAbidi.AhmedF.El-YazbiAhmedF.El-YazbiAliH.EidAliH., Eid., GeorgeW.BoozFouadA.Zouein (2018). Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects. Heart Failure Reviews. doi: 10.1007/S10741-017-9665-9 AdrianaSánchez-GarcíaMarioSimental-MendíaJuanManuelMillán-AlanísLuisE.Simental-Mendía (2020). Effect of sodium-glucose co-transporter 2 inhibitors on lipid profile: A systematic review and meta-analysis of 48 randomized controlled trials. Pharmacological Research. doi: 10.1016/J.-PHRS.2020.105068 AlexAliSayour.MihályRuppert.AttilaOláh.KálmánBenke.BálintAndrásBarta., Eszter, Zsáry., BélaMerkely.TamásRadovits. (2021). Effects of SGLT2 Inhibitors beyond Glycemic Control—Focus on Myocardial SGLT1. International Journal of Molecular Sciences. doi: 10.3390/IJMS22189852 AnjaSchork.JanineSaynisch.AndreasVosseler.BenjaminAssadJaghutriz.NilsHeyne.AndreasPeter.Hans-UlrichHäring.NorbertStefan.AndreasFritsche.FerruhArtunc. (2019). Effect of SGLT2 inhibitors on body composition, fluid status and renin-angiotensin-aldosterone system in type 2 diabetes: a prospective study using bioimpedance spectroscopy. Cardiovascular Diabetology. doi: 10.1186/S12933-019-0852-Y AsadurRahman.HirofumiHitomi.AkiraNishiyama. (2017). Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. Hypertension Research. doi:10.1038/HR.2016.193 AshishVerma.AnkitB. Patel.SushrutS. Waikar. (2020). SGLT2 Inhibitor: Not a traditional diuretic for heart failure. Cell Metabolism. doi: 10.1016/J.CMET.2020.06.014 AtsushiTanaka.TakumiImai.ShigeruToyoda.KazuhiroSugimoto.RukaYoshida.MachiFuruta.KoichiNode. (2023). Long-term observation of estimated fluid volume reduction after the initiation of ipragliflozin in patients with type 2 diabetes mellitus: a sub-analysis from a randomized controlled trial (PROTECT). Diabetology & Metabolic Syndrome doi: 10.1186/s13098-023-01129-3 BloseJ.P. Stickles., A.Battaglino., A.Trumbetti., J.James., K.Cooper., A.SchadeMelissaA.ReedSelenRazon.MelissaA.Whidden (2020). The effects of a six-week weight loss program on blood lipid profiles and cardiovascular health. Journal of Exercise and Nutrition, 3(4): 16. BorianiG.MeiD.A.ImbertiJ.F. (2023). Therapeutic effects of sodium-glucose cotransporter 2 inhibitors in patients with heart failure with preserved ejection fraction: From outcome improvement to potentially favourable influences on atrial fibrillation burden, atrial fibrillation progression and atrial cardiomyopathy. Eur. J Heart Fail., 25(7): 978–980. doi: 10.1002/ejhf.2891. Epub 2023 May 25. PMID: 37191122 BrendonL. Neuen.MinJun.JamesWick.S.KotwalSunilBadve.MegJardine.M.GallagherJohnChalmers.KellieNallaiah.VladoPerkovic.D.PeirisA.RodgersMarkWoodward.PaulE. Ronksley. (2023). Estimating the population-level kidney benefits of improved uptake of SGLT2 inhibitors in patients with chronic kidney disease in Australian primary care. Med-Rxiv doi: 10.1101/ 2023.06.26.23291881 ChoM.S.NamG.B.KimY.N.KimJ.ChoiK.J.KimY.H. (2020). Clinical implications of ventricular repolarization parameters on long-term risk of a trial fibrillation Longitudinal Follow-up Data From a General Ambulatory Korean Population. Circulation Journal, 84(7): 1067–1074. ChristopherRedford.LauraDoherty.JamieSmith. (2015). SGLT2 inhibitors and the risk of diabetic ketoacidosis. Practical Diabetes. doi: 10.1002/PDI.1969 Chung-ChuanChou.PengShengChen.DelonWu.DelonWu. (2008). Intracellular calcium dynamics and autonomic stimulation in atrial fibrillation: Mechanisms and implications. Journal of Arrhythmia. doi: 10.1016/S1880-4276(08)80010-5 DavidZ.I.CherneyAyodeleOdutayo.RonnieAronson.JustinA.EzekowitzJohnD.Parker (2019). Sodium glucose cotransporter-2 inhibition and cardiorenal protection: JACC review topic of the week. Journal of the American College of Cardiology. doi: 10.1016/JJACC.2019.09.022 DobromirDobrev.StanleyNattel. (2008). Calcium handling abnormalities in atrial fibrillation as a target for innovative therapeutics. Journal of Cardiovascular Pharmacology. doi: 10.1097/FJC.0B013E318171924D DobromirDobrev.XanderH.T.Wehrens (2017). Calcium-mediated cellular triggered activity in atrial fibrillation. The Journal of Physiology. doi: 10.1113/JP273048 DuranteWilliam.GhazalehBehnammanesh.KellyJ. Peyton. (2021). Effects of sodium-glucose cotransporter 2 inhibitors on vascular cell function and arterial remodeling. International Journal of Molecular Sciences, 22(16): 8786. https://doi.org/10.3390/ijms22168786 EdoardoGronda.GaryD., Lopaschuk., ArduinoArduini.AntonioSantoro.GiudittaBenincasa.AlbertoPalazzuoli.DomenicoGabrielli.ClaudioNapoli. (2022). Mechanisms of action of SGLT2 inhibitors and their beneficial effects on the cardiorenal axis. Canadian Journal of Physiology and Pharmacology. doi: 10.1139/cjpp-2021-0399 FatimaAlzahra.AlHamed.HazemElewa. (2020). Potential therapeutic effects of sodium glucose-linked cotransporter 2 inhibitors in stroke. Clinical Therapeutics. doi: 10.1016/J.CLINTHERA.2020.09.008 FernandBonnet.AndréScheen (2018). Effects of SGLT2 inhibitors on systemic and tissue low-grade inflammation: The potential contribution to diabetes complications and cardiovascular disease. Diabetes & Metabolism. doi:10.1016/J.DIABET.2018.09.005 FranciscoGarcía-CarrizoSebastiàGalmés.CatalinaPico.AndreuPalou.AnaM.Rodríguez (2022). Supplementation with the prebiotic high-esterified pectin improves blood pressure and cardiovascular risk biomarker profile, counteracting metabolic malprogramming. Journal of Agricultural and Food Chemistry. doi: 10.1021/acs.jafc.2c03143 Funsho, EFakuade.VanessaSteckmeister.F.SeibertzJudithGronwald.StefanieKestel.JuliaMenzel.JuliusRyanD.ProntoKarimTaha.FereshtehHaghighi.GeorgeKensah.CharlesM.PearmanFelixWiedmann.ArcoJ.TeskeConstanzeSchmidt.KatharineM.Dibb.AschrafEl-EssawiBernhardC., Danner., HassinaBaraki.BlancheSchwappach.IngoKutschka.FleurE.MasonNielsVoigt. (2021). Altered atrial cytosolic calcium handling contributes to the development of postoperative atrial fibrillation. Cardiovascular Research. doi: 10.1093/CVR/CV AA162 GailinYe.ShuaiWang.DaoquanPeng. (2021). Effects of SGLT2 inhibitor on ischemic events stemming from atherosclerotic coronary diseases: A systematic review and meta-analysis with trial sequential analysis of randomized controlled trials. Journal of Cardiovascular Pharmacology. doi:10.1097/FJC.0000000000001018 GaryL.AistrupRishiArora.SørenGrubb.ShinYoo.BenjaminToren.ManvinderKumar.AaronKunamalla.WilliamMarszalec.TejMotiwala.ShannonTai.SeanYamakawa.SatyaYerrabolu.FranciscoJ., Alvarado., HéctorH.ValdiviaJonathanM.CordeiroYohannesShiferaw.J. WasserstromA. (2017). Triggered intracellular calcium waves in dog and human left atrial myocytes from normal and failing hearts. Cardiovascular Research. doi: 10.1093/CVR/CVX167 GiuseppeCannella.S.GhielmiMassimoSandrini.ClaudioPoiesi.MarioGaggiotti.A.RodellaRosarioMaiorca. (1988). Effect of reduction of blood volume on plasma immunoreactive atrial natriuretic factor concentrations in normal man. Nephrology Dialysis Transplantation. doi: 10.1093/ OXFORDJOURNALS.NDT.A091712 GumprechtJ.DomekM.LipG.Y.H.et al. (2019). Invited review: hypertension and atrial fibrillation: epidemiology, pathophysiology, and implications for management. J Hum Hypertens, 33: 824–836. https://doi.org/10.1038/s41371-019-0279-7 GuoXue-Yuan; MaChang-Sheng (2017). Atrial fibrillation ablation: Indications, outcomes, complications, and future directions. Chinese Medical Journal, 130(16): 1891–1893, August 20. doi: 10.4103/03666999.211900 HannySawaf.MoarijQaz.JeedaIsmail.AliMehdi. (2022). The Renal Effects of SGLT2 Inhibitors. doi: 10.33590/emjnephrol/22-00080 JamieL.BenhamJaneE.BoothRonaldJ.SigalStellaS., Daskalopoulou., AlexanderA.LeungDoreenM., Rabi. (2021). Systematic review and meta-analysis: SGLT2 inhibitors, blood pressure and cardiovascular outcomes. IJC Heart & Vasculature. doi: 10.1016/J.IJCHA.2021.100725 JasonR.B.DyckSamuelSossalla.NazhaHamdani.RubenCoronel.NinaC.WeberPeterE., Light. CoertJ., Zuurbier. (2022). Cardiac mechanisms of the beneficial effects of SGLT2 inhibitors in heart failure: Evidence for potential off-target effects. Journal of Molecular and Cellular Cardiology. doi:10.1016/ j.yjmcc.2022.03.005 JosselinNespoux.VolkerVallon. (2020). Renal effects of SGLT2 inhibitors: an update. Current Opinion in Nephrology and Hypertension. doi: 10.1097/MNH.0000000000000584 JulietaLazarte.TharsanKanagalingam.RobertA.Hegele (2021). Lipid effects of sodium-glucose cotransporter 2 inhibitors. Current Opinion in Lipidology. doi: 10.1097/MOL.0000000000000751 KanetoHideaki.AtsushiObataTomohikoKimuraMasashiShimodaTomeKinoshitaTaka-akiMatsuokaKoheiKaku. (2021). Unexpected pleiotropic effects of SGLT2 inhibitors: Pearls and pitfalls of this novel antidiabetic class. International Journal of Molecular Sciences, 22(6): 3062. https://doi.org/10.3390/ijms22063062 KazuomiKario.KeithC., Ferdinand., JamesH.O’Keefe (2020). Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Progress in Cardiovascular Diseases. doi: 10.1016/ J.PCAD.2020.04.003 KhialiS.Taban-SadeghiM.SarbakhshP.et al. (2023). SGLT2 inhibitors’ cardiovascular benefits in individuals without diabetes, heart failure, and/or chronic kidney disease: A systematic review. Journal of Clinical Pharmacy and Therapeutics, Published online July 16, 2023. https://doi.org/10.1002/jcph.2311 KochharS. (2016). Atrial fibrillation: An update. Independent Nurse, 2016(2): 30. Published Online:2 Feb 2016. https://doi.org/10.12968/indn.2016.2.30 KristinaJohnsson.EvaJohnsson.TAMansfield.YshaiYavin.AgataPtaszynska.ShamikParikh. (2016). Osmotic diuresis with SGLT2 inhibition: analysis of events related to volume reduction in dapagliflozin clinical trials. Postgraduate Medicine. doi: 10.1080/00325481.2016.1153941 KurashinV.K.YuN.Borovkova., V.A.Kurashina., T.BakkaE. (2021). Possibilities of cardio-and nephroprotective eff ects of drugs of the SGLT2 inhibitor group. doi: 10.30629/0023-2149-2021-99-3-172176 LeeS.ZhouJ.ChangC.LiuT.ChangD.WongW.T.LeungK.S.K.WaiA.K.C.CheungB.M.Y.TseG.ZhangQ. (2021). Comparative effects of sodium glucose cotransporter 2 (SGLT2) inhibitors and dipeptidyl peptidase-4 (DPP4) inhibitors on new-onset atrial fibrillation and stroke outcomes. medRxiv. 2021.01.04.21249211. doi: https://doi.org/10.1101/2021.01.04.21249211 LiC.YuJ.HockhamC.PerkovicV.NeuenB.L.BadveS.V.HoustonL.Lee ,V.Y.J.BarracloughJ.Y.FletcherR.A.MahaffeyK.W.HeerspinkH.J.L.CannonC.P.NealB.ArnottC. (2022). Canagliflozin and atrial fibrillation in type 2 diabetes mellitus: A secondary analysis from the CANVAS Program and CREDENCE trial and meta-analysis. Diabetes Obes Metab., 24(10): 1927–1938. doi:10.1111/dom.14772. Epub 2022 Jun 9. PMID: 35589614 LiD.LiuY.HidruT.H.YangX.WangY.ChenC.LiK.H.C.TangY.WeiY.TseG.XiaY. (2021). Protective effects of sodium-glucose transporter 2 inhibitors on atrial fibrillation and atrial flutter: A systematic review and meta-analysis of randomized placebo-controlled trials. Front Endocrinol (Lausanne), 12; 619586. doi: 10.3389/fendo.2021.619586. PMID: 33815278; PMCID:PMC8018283 LiW.J.ChenX.Q.XuL.L.LiY.Q.LuoB.H. (2020). SGLT2 inhibitors and atrial fibrillation in type 2 diabetes: a systematic review with meta-analysis of 16 randomized controlled trials. Cardiovasc Diabetol., 19(1): 130. doi: 10.1186/s12933-020-01105-5. PMID: 32847602; PMCID: PMC7448518 LymperopoulosAnastasios.Jordana I.BorgesNatalieCora.AnastasiyaSizova. (2021). Sympatholytic mechanisms for the beneficial cardiovascular effects of SGLT2 inhibitors: A research hypothesis for dapagliflozin’s effects in the adrenal gland. International Journal of Molecular Sciences, 22(14): 7684. https://doi.org/10.3390/ijms22147684 MadsErsbøllMikkelJürgensPhilipHasbak.AndreasKjaer.EmilWolsk.BoZerahn.NielsHBrandt-JacobsenPeterGædePeterRossing.PeterRossing.JensFaber.SilvioE., Inzucchi., FinnGustafsson.MortenSchou.CarolineKistorp.CarolineKistorp. (2021). Effect of empagliflozin on myocardial structure and function in patients with type 2 diabetes at high cardiovascular risk: the SIMPLE randomized clinical trial. International Journal of Cardiovascular Imaging. doi: 10.1007/ S10554-021-02443-5 MariannaFontana.AnaMartinez-NaharroLizaChacko.DorotaRowczenio.JanetA., Gilbertson., CarolJ.WhelanSvetlaG.StrehinaThirushaLane.JamesC.MoonDavidF.HuttPeterKellman.AvivaPetrie.PhilipN.HawkinsJulianD.Gillmore (2021). Reduction in CMR derived extracellular volume with patisiran indicates cardiac amyloid regression. Jacccardiovascular Imaging. doi: 10.1016/ J.JCMG.2020.07.043 McMurrayJ.J.V.DeMetsD.L.InzucchiS.E.KøberL.KosiborodM.N.LangkildeA.M.MartinezF.A.BengtssonO.PonikowskiP.SabatineM.S.SjöstrandM.SolomonS.D. (2019). DAPA-HF committees and investigators. 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). Eur J Heart Fail, 21(5): 665–675. doi: 10.1002/ejhf.1432. Epub, Mar 21. PMID: 30895697; PMCID: PMC6607736 MondaV.M.GentileS.PorcellatiF.et al. (2022). Heart failure with preserved ejection fraction and obstructive sleep apnea: A novel paradigm for additional cardiovascular benefit of SGLT2 inhibitors in subjects with or without type 2 diabetes. Adv Ther, 39: 4837–4846. https://doi.org/10.1007/s12325-022-02310-2 MuratZiyrek.MustafaDuran. (2021). Effects of SGLT2 inhibitors as an addon therapy to metformin on electrocardiographic indices of ventricular Repolarization. Acta Cardiologica Sinica. doi: 10.6515/ ACS.202105_37(3).20210308B NielsH.Brandt-JacobsenMikkelJürgensPhillipHasbak., Peter, Gæde., PeterRossing.JonJRasmussen.CamilllaFuchsAndersen.JulieLyngForman.JensFaber.SilvioE., Inzucchi., FinnGustafsson.MortenSchou.CarolineKistorp. (2022). ODP154 reduction of cardiac adipose tissue volume with short-term empagliflozin in patients with type 2 diabetes: Results from the simple randomized clinical trial. Journal of the Endocrine Society. doi: 10.1210/jendso/bvac150.504 OmarMourad.ShabanaVohra.SaraS.Tunes (2023). SGLT2 transcriptomic expression atlas supports a kidney-centric role for empagliflozin’s benefits in heart failure. bioRxiv. doi: 10.1101/2023.07.03.547550 PasqualePaolisso.LucaBergamaschi.ArturoCesaro.EmanueleGallinoro.FeliceGragnano.CelestinoSardu.NiyaMileva.AlbertoFoà.MatteoArmillotta.AngeloSansonetti.S.AmiconeA.ImpellizzeriMartaBelmonte.GiuseppeEsposito.NucciaMorici.GianniCasella.CiroMauro.DobrinVassilev., Nazzareno, Galiè., GaetanoSantulli.PaoloCalabrò.EmanueleBarbato.RaffaeleMarfella.CarminePizzi. (2023). Impact of SGLT2-inhibitors on contrast-induced acute kidney injury in diabetic patients with Acute Myocardial Infarction with and without chronic kidney disease: Insight from SGLT2-I AMI PROTECT Registry. Diabetes Research and Clinical Practice. doi: 10.1016/j.diabres.2023.110766 PawlosAgnieszka., Marlena Broncel., Ewelina WoŸniak. and Paulina Gorzelak-Pabiœ. (2021). Neuroprotective effect of SGLT2 inhibitors. Molecules, 26(23): 7213. https://doi.org/10.3390/molecules26237213 Ping-FanLu. (2023). Efficacy of sacubitril-valsartan and SGLT2 inhibitors in heart failure with reduced ejection fraction: A systematic review and meta-analysis. Clinical Cardiology. doi: 10.1002/clc.24085 QingWang.QingWang.JingWang.PeiWang.LiaoyuanWang.LantingJia.XinyuLing.WangXi.JieMin.HuaShen.JianXiao.JinxiangYuan.ZhinongWang. (2019). Glycemic control is associated with atrial structural remodeling in patients with type 2 diabetes. BMC Cardiovascular Disorders. doi: 10.1186/S12872-019-1249-2 RosalieA.ScholtesMichaёlJ.B.vanBaar.MeganD.KokPetterBjornstad.DavidZ.I., Cherney., JaapA.JolesDaniёlH.vanRaalte.DaniёlH.vanRaalte. (2021). Renal haemodynamic and protective effects of renoactive drugs in type 2 diabetes: Interaction with SGLT2 inhibitors. Nephrology. doi: 10.1111/ NEP.13839 SajadKhiali.MohammadRezaSadeghi.ParvinSarbakhsh., Naser, KhezerlouyAghdam.AfraRezagholizadeh.HilaAsham.TaherEntezariMaleki. (2023). SGLT2 Inhibitors’ cardiovascular benefits in individuals without diabetes, heart failure, and/ or chronic kidney disease: A systematic review. The Journal of Clinical Pharmacology. doi: 10.1002/jcph.2311 SamarA.NasserNehaArora.KeithC. andFerdinand. (2022). Addressing cardiovascular disparities in racial/ethnic populations: The blood pressure-lowering effects of SGLT2 inhibitors. Reviews in Cardiovascular Medicine. doi: 10.31083/j.rcm2312411 SaraAlbalushi. (2023). Meta-analysis on the effectiveness of SGLT2 inhibitors in heart failure. European Heart Journal. Acute cardiovascular care. doi:10.1093/ehjacc/zuad036.173 SatoT.TakayukiMiki.HirofumiOhnishi.T.YamashitaA.TakadaToshiyukiYano.MasayaTanno.AkihitoTsuchida.TetsujiMiura. (2017). Effect of sodium-glucose co-transporter-2 inhibitors on impaired ventricular repolarization in people with Type 2 diabetes. Diabetic Medicine. doi: 10.1111/ DME.13424 Scheen. (2022). https://doi.org/10.1016/j.diabet.2022.101390 48(6): 101390. doi: 10.1016/j.diabet.2022. 101390. Epub 2022 Sep 25 Shan-JiangChen.RubenCoronel.MarkusW. Hollmann.NinaC. Weber.CoertJ. Zuurbier. (2022). Direct cardiac effects of SGLT2 inhibitors. Cardiovascular Diabetology. doi: 10.1186/s12933-022-01480-1 ShrutiSJoshi.TrishaSingh.DavidE.NewbyJagdeepSingh. (2021). Sodium-glucose co-transporter 2 inhibitor therapy: Mechanisms of action in heart failure. Heart. doi: 10.1136/HEARTJNL-2020-318060 SilvioE.InzucchiBernardZinman.ChristophWanner.RobertoFerrari.DavidFitchett.StefanHantel.Rosa-MariaEspadero.Hans-JuergenWoerle.UliC.BroedlOddErikJohansen. (2015). SGLT-2 inhibitors and cardiovascular risk: Proposed pathways and review of ongoing outcome trials. Diabetes and Vascular Disease Research. doi: 10.1177/1479164114559852 SongS.KoJ.S.LeeH.A.et al. (2022). Clinical implications of heart rate control in heart failure with atrial fibrillation: Multi-center prospective observation registry (CODE-AF Registry). Frontiers in Cardiovascular Medicine 9. https://doi.org/10.3389/fcvm.2022.787869 StevenG. Chrysant. (2017). Promising cardiovascular and blood pressure effects of the SGLT2 inhibitors: a new class of antidiabetic drugs. Drugs of Today. doi: 10.1358/DOT.2017.53.3.2555985 StrooJ. F.van SteenbergenG.J.van StratenA.H.M.HoutermanS.Soliman-HamadM.A. (2023). Longterm outcome of reexploration for bleeding after coronary artery bypass grafting. Journal of Cardiothoracic and Vascular Anesthesia, Published online June 09, 2023. https://doi.org/10.1053/j.jvca.2023.06.008 SubodhVerma.JohnJ.V.McMurray (2018). SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. doi:10.1007/S00125-018-4670-7 SzekeresZsoltKalmanTothEszterSzabados (2021). The effects of SGLT2 inhibitors on lipid metabolism. Metabolites, 11(2): 87. TamiqueMason.OtavioR.Coelho-FilhoSubodhVerma.BiswajitChowdhury.FeiZuo.AdrianQuan.KevinE.ThorpeChristopherBonneau.HweeTeoh.RichardE.GilbertLawrenceA.LeiterPeterJüni.BernardZinman.MichaelJerosch-Herold., C.DavidMazer.AndrewT., Yan., KimA.ConnellyKimA. Connelly. (2021). Empagliflozin reduces myocardial extracellular volume in patients with type 2 diabetes and coronary artery disease. Jacc-cardiovascular Imaging. doi: 10.1016/J.JCMG.2020.10.017 ThorénE.WernrothM.L.ChristerssonC.et al. (2020). Compared with matched controls, patients with postoperative atrial fibrillation (POAF) have increased long-term AF after CABG, and POAF is further associated with increased ischemic stroke, heart failure and mortality even after adjustment for AF. Clin Res Cardiol, 109 1232–1242. https://doi.org/10.1007/s00392-020-01614-z VallonVVermaS (2021). Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annu Rev Physiol., 10(83): 503–528. doi: 10.1146/annurevphysiol-031620-095920. Epub 2020 Nov 16. PMID: 33197224; PMCID:PMC8017904 Vincenzo, DeMarzo.GianluigiSavarese.ItaloPorto.MarcoMetra.PietroAmeri. (2023). Efficacy of SGLT2-inhibitors across different definitions of heart failure with preserved ejection fraction. Journal of Cardiovascular Medicine. doi: 10.2459/JCM.0000000000001504 VolkerVallon.SubodhVerma. (2021). Effects of SGLT2 inhibitors on kidney and cardiovascular function. Annual Review of Physiology. doi: 10.1146/ANNUREV-PHYSIOL-031620-095920 WenjieL.XingqingC.XiangqiX.MinX.LinglingX.PeiyingL.BihuiL. (2022). Comparison of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide receptor agonists for atrial fibrillation in Type 2 diabetes mellitus: Systematic review with network meta-analysis of randomized controlled trials. Journal of Cardiovascular Pharmacology, 79(3): 281–288. doi: 10.1097/FJC.0000000000001197 YukikoHasegawa.TomokoNakagami.JunkoOya.KanakoTakahashi.ChisatoIsago.MoritoshiKurita.YukiTanaka.ArataIto.TadasuKasahara.YasukoUchigata. (2019). Body weight reduction of 5% improved blood pressure and lipid profiles in obese men and blood glucose in obese women: A four-year follow-up observational study. Metabolic Syndrome and Related Disorders. doi: 10.1089/MET.2O18.O115 ZelnikerT.A.BonacaM.P.FurtadoR.H.M.MosenzonO.KuderJ.F.MurphyS.A.BhattD.L.LeiterL.A.McGuireD.K.WildingJ.P.H.BudajA.KissR.G.PadillaF.Gause-NilssonI.LangkildeA.M.RazI.SabatineM.S.WiviottS.D. (2020). Effect of dapagliflozin on atrial fibrillation in patients with type 2 diabetes mellitus: Insights from the DECLARE-TIMI 58 trial. Circulation., 141(15) : 1227–1234. doi: 10.1161?CIRCULATIONAHA.119.044183. Epub 2020 Jan 27. PMID: 31983236 ZhangN.GongM.TseG.ZhangZ.MengL.YanB.P.LiuT. (2018). Prolonged corrected QT interval in predicting atrial fibrillation: a systematic review and meta-analysis. Pacing and Clinical Electrophysiology, 4l(3): 321–327. ZhouZ.JardineM.J.LiQ.NeuenB.L.CannonC.P.de ZeeuwD.EdwardsR.LevinA.MahaffeyK.W.PerkovicV.NealB.LindleyR.I. (2021). Credence trial investigators*. Effect of SGLT2 inhibitors on stroke and atrial fibrillation in diabetic kidney disease: Results from the CREDENCE Trial and MetaAnalysis. Stroke. May; 52(5): 1545–1556. doi: 10.1161/STROKEAHA.120.031623. Epub 2021 Apr 20. PMID: 33874750; PMCID: PMC8078131 ZinmanB.WannerC.LachinJ.M.FitchettD.BluhmkiE.HantelS.MattheusM.DevinsT.JohansenO.E.WoerleH.J.BroedlU.C.InzucchiS.E. (2015). EMPA-REG outcome investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med., 373(22): 2117–28. doi:10.1056/NEJMoal5O4720. Epub 2015 Sep 17. PMID: 26378978. ZsoltSzekeres.KalmanToth.EszterSzabados. (2021). The effects of SGLT2 inhibitors on lipid metabolism. Metabolites. doi: 10.3390/METABO11020087