Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

Ban       Liu; Yuliang       Wang; Yangyang       Zhang; Biao       Yan
Abstract

Type 2 diabetes mellitus is one of the most common forms of the disease worldwide. Hyperglycemia and insulin resistance play key roles in type 2 diabetes mellitus. Renal glucose reabsorption is an essential feature in glycaemic control. Kidneys filter 160 g of glucose daily in healthy subjects under euglycaemic conditions. The expanding epidemic of diabetes leads to a prevalence of diabetes-related cardiovascular disorders, in particular, heart failure and renal dysfunction. Cellular glucose uptake is a fundamental process for homeostasis, growth, and metabolism. In humans, three families of glucose transporters have been identified, including the glucose facilitators GLUTs, the sodium-glucose cotransporter SGLTs, and the recently identified SWEETs. Structures of the major isoforms of all three families were studied. Sodium-glucose cotransporter (SGLT2) provides most of the capacity for renal glucose reabsorption in the early proximal tubule. A number of cardiovascular outcome trials in patients with type 2 diabetes have been studied with SGLT2 inhibitors reducing cardiovascular morbidity and mortality.
The current review article summarises these aspects and discusses possible mechanisms with SGLT2 inhibitors in protecting heart failure and renal dysfunction in diabetic patients. Through glucosuria, SGLT2 inhibitors reduce body weight and body fat, and shift substrate utilisation from carbohydrates to lipids and, possibly, ketone bodies. These pleiotropic effects of SGLT2 inhibitors are likely to have contributed to the results of the EMPA-REG OUTCOME trial in which the SGLT2 inhibitor, empagliflozin, slowed down the progression of chronic kidney disease and reduced major adverse cardiovascular events in high-risk individuals with type 2 diabetes. This review discusses the role of SGLT2 in the physiology and pathophysiology of renal glucose reabsorption and outlines the unexpected logic of inhibiting SGLT2 in the diabetic kidney.
Keywords: Type 2 diabetes mellitus, Insulin resistance, Mechanism- sodium-glucose cotransporter, Proximal tubule, Cardiovascular events, Renal dysfunction, Heart failure.
Graphical Abstract

[1] 
Wild, S.; Roglic, G.; Green, A.; Sicree, R.; King, H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care,  2004, 27(5), 1047-1053.
[http://dx.doi.org/10.2337/diacare.27.5.1047] [PMID:  15111519] 
[2] 
Diabetes Atlas. International diabetes federation., https://idf.org/e-library/epidemiology-research/diabetes-atlas/22-atlas-3rd-edition.html  (Accessed 2006)
[3] 
US Food and Drug Administration. Diabetes mellitus — evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes.. http://www.fda.gov/cder/guidance/index.htm  (Accessed 2008)
[4] 
Bornfeldt, K.E.; Tabas, I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab.,  2011, 14(5), 575-585.
[http://dx.doi.org/10.1016/j.cmet.2011.07.015] [PMID:  22055501] 
[5] 
Saltiel, A.R.; Kahn, C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature,  2001, 414(6865), 799-806.
[http://dx.doi.org/10.1038/414799a] [PMID:  11742412] 
[6] 
Hossain, P.; Kawar, B.; El Nahas, M. Obesity and diabetes in the developing world-A growing challenge. 2009, 356(3), 213-215.
[http://dx.doi.org/10.1056/NEJMp068177] [PMID:  17229948] 
[7] 
Shulman, G.I. Cellular mechanisms of insulin resistance. J. Clin. Invest.,  2000, 106(2), 171-176.
[http://dx.doi.org/10.1172/JCI10583] [PMID:  10903330] 
[8] 
Cavelti-Weder, C.; Babians-Brunner, A.; Keller, C.; Stahel, M.A.; Kurz-Levin, M.; Zayed, H.; Solinger, A.M.; Mandrup-Poulsen, T.; Dinarello, C.A.; Donath, M.Y. Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes. Diabetes Care,  2012, 35(8), 1654-1662.
[http://dx.doi.org/10.2337/dc11-2219] [PMID:  22699287] 
[9] 
Kim, J.A.; Montagnani, M.; Koh, K.K.; Quon, M.J. Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation,  2006, 113(15), 1888-1904.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.105.563213] [PMID:  16618833] 
[10] 
Sarkar, K.; Fox-Talbot, K.; Steenbergen, C.; Bosch-Marcé, M.; Semenza, G.L. Adenoviral transfer of HIF-1alpha enhances vascular responses to critical limb ischemia in diabetic mice. Proc. Natl. Acad. Sci. USA,  2009, 106(44), 18769-18774.
[http://dx.doi.org/10.1073/pnas.0910561106] [PMID:  19841279] 
[11] 
Bento, C.F.; Pereira, P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia,  2011, 54(8), 1946-1956.
[http://dx.doi.org/10.1007/s00125-011-2191-8] [PMID:  21614571] 
[12] 
Chou, E.; Suzuma, I.; Way, K.J.; Opland, D.; Clermont, A.C.; Naruse, K.; Suzuma, K.; Bowling, N.L.; Vlahos, C.J.; Aiello, L.P.; King, G.L. Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic States: a possible explanation for impaired collateral formation in cardiac tissue. Circulation,  2002, 105(3), 373-379.
[http://dx.doi.org/10.1161/hc0302.102143] [PMID:  11804995] 
[13] 
DeFronzo, R.A.; Ferrannini, E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care,  1991, 14(3), 173-194.
[http://dx.doi.org/10.2337/diacare.14.3.173] [PMID:  2044434] 
[14] 
Naudi, A.; Jove, M.; Ayala, V.; Cassanye, A.; Serrano, J.; Gonzalo, H.; Boada, J.; Prat, J.; Portero-Otin, M.; Pamplona, R. Cellular dysfunction in diabetes as maladaptive response to mitochondrial oxidative stress. Exp. Diabetes Res.,  2012, 2012(1) 696215
[http://dx.doi.org/10.1155/2012/696215] [PMID:  22253615] 
[15] 
Paneni, F.; Beckman, J.A.; Creager, M.A.; Cosentino, F. Diabetes and vascular disease: Pathophysiology, clinical consequences and medical therapy: Part I. Eur. Heart J.,  2013, 34(31), 2436-2443.
[http://dx.doi.org/10.1093/eurheartj/eht149] [PMID:  23641007] 
[16] 
Hink, U.; Li, H.; Mollnau, H.; Oelze, M.; Matheis, E.; Hartmann, M.; Skatchkov, M.; Thaiss, F.; Stahl, R.A.; Warnholtz, A.; Meinertz, T.; Griendling, K.; Harrison, D.G.; Forstermann, U.; Munzel, T. Mechanisms underlying endothelial dysfunction in diabetes mellitus. Circ. Res.,  2001, 88(2), E14-E22.
[http://dx.doi.org/10.1161/01.RES.88.2.e14] [PMID:  11157681] 
[17] 
Lerman, A.; Zeiher, A.M. Endothelial function: Cardiac events. Circulation,  2005, 111(3), 363-368.
[http://dx.doi.org/10.1161/01.CIR.0000153339.27064.14] [PMID:  15668353] 
[18] 
Cipollone, F.; Fazia, M.; Iezzi, A.; Zucchelli, M.; Pini, B.; De Cesare, D.; Ucchino, S.; Spigonardo, F.; Bajocchi, G.; Bei, R.; Muraro, R.; Artese, L.; Piattelli, A.; Chiarelli, F.; Cuccurullo, F.; Mezzetti, A. Suppression of the functionally coupled cyclooxygenase-2/prostaglandin E synthase as a basis of simvastatin-dependent plaque stabilization in humans. Circulation,  2003, 107(11), 1479-1485.
[http://dx.doi.org/10.1161/01.CIR.0000056530.03783.81] [PMID:  12654603] 
[19] 
Tanji, N.; Markowitz, G.S.; Fu, C.; Kislinger, T.; Taguchi, A.; Pischetsrieder, M.; Stern, D.; Schmidt, A.M.; D’Agati, V.D. Expression of advanced glycation end products and their cellular receptor RAGE in diabetic nephropathy and nondiabetic renal disease. J. Am. Soc. Nephrol.,  2000, 11(9), 1656-1666.
[PMID:  10966490] 
[20] 
Lynch, J.J.; Ferro, T.J.; Blumenstock, F.A.; Brockenauer, A.M.; Malik, A.B. Increased endothelial albumin permeability mediated by protein kinase C activation. J. Clin. Invest.,  1990, 85(6), 1991-1998.
[http://dx.doi.org/10.1172/JCI114663] [PMID:  2347922] 
[21] 
Inoguchi, T.; Li, P.; Umeda, F.; Yu, H.Y.; Kakimoto, M.; Imamura, M.; Aoki, T.; Etoh, T.; Hashimoto, T.; Naruse, M.; Sano, H.; Utsumi, H.; Nawata, H. High glucose level and free fatty acid stimulate reactive oxygen species production through protein kinase C--dependent activation of NAD(P)H oxidase in cultured vascular cells. Diabetes,  2000, 49(11), 1939-1945.
[http://dx.doi.org/10.2337/diabetes.49.11.1939] [PMID:  11078463] 
[22] 
Cosentino, F.; Francia, P.; Camici, G.G.; Pelicci, P.G.; Lüscher, T.F.; Volpe, M. Final common molecular pathways of aging and cardiovascular disease: Role of the p66Shc protein. Arterioscler. Thromb. Vasc. Biol.,  2008, 28(4), 622-628.
[http://dx.doi.org/10.1161/ATVBAHA.107.156059] [PMID:  18162611] 
[23] 
Paneni, F.; Mocharla, P.; Akhmedov, A.; Costantino, S.; Osto, E.; Volpe, M.; Lüscher, T.F.; Cosentino, F. Gene silencing of the mitochondrial adaptor p66(Shc) suppresses vascular hyperglycemic memory in diabetes. Circ. Res.,  2012, 111(3), 278-289.
[http://dx.doi.org/10.1161/CIRCRESAHA.112.266593] [PMID:  22693349] 
[24] 
Du, X.L.; Edelstein, D.; Dimmeler, S.; Ju, Q.; Sui, C.; Brownlee, M. Hyperglycemia inhibits endothelial nitric oxide synthase activity by posttranslational modification at the Akt site. J. Clin. Invest.,  2001, 108(9), 1341-1348.
[http://dx.doi.org/10.1172/JCI11235] [PMID:  11696579] 
[25] 
Brouwers, O.; Niessen, P.M.; Haenen, G.; Miyata, T.; Brownlee, M.; Stehouwer, C.D.; De Mey, J.G.; Schalkwijk, C.G. Hyperglycaemia-induced impairment of endothelium-dependent vasorelaxation in rat mesenteric arteries is mediated by intracellular methylglyoxal levels in a pathway dependent on oxidative stress. Diabetologia,  2010, 53(5), 989-1000.
[http://dx.doi.org/10.1007/s00125-010-1677-0] [PMID:  20186387] 
[26] 
Sena, C.M.; Matafome, P.; Crisóstomo, J.; Rodrigues, L.; Fernandes, R.; Pereira, P.; Seiça, R.M. Methylglyoxal promotes oxidative stress and endothelial dysfunction. Pharmacol. Res.,  2012, 65(5), 497-506.
[http://dx.doi.org/10.1016/j.phrs.2012.03.004] [PMID:  22425979] 
[27] 
Bierhaus, A.; Humpert, P.M.; Morcos, M.; Wendt, T.; Chavakis, T.; Arnold, B.; Stern, D.M.; Nawroth, P.P. Understanding RAGE, the receptor for advanced glycation end products. J. Mol. Med. (Berl.),  2005, 83(11), 876-886.
[http://dx.doi.org/10.1007/s00109-005-0688-7] [PMID:  16133426] 
[28] 
Giacco, F.; Brownlee, M.; Lam, K.; Lam, K.; Chung, S. Oxidative stress and diabetic complications. Circ. Res.,  2010, 107(9), 1058-1070.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.223545] [PMID:  21030723] 
[29] 
Fülöp, N.; Marchase, R.B.; Chatham, J.C. Role of protein O-linked N-acetyl-glucosamine in mediating cell function and survival in the cardiovascular system. Cardiovasc. Res.,  2007, 73(2), 288-297.
[http://dx.doi.org/10.1016/j.cardiores.2006.07.018] [PMID:  16970929] 
[30] 
Buse, M.G. Hexosamines, insulin resistance, and the complications of diabetes: current status. Am. J. Physiol. Endocrinol. Metab.,  2006, 290(1), E1-E8.
[http://dx.doi.org/10.1152/ajpendo.00329.2005] [PMID:  16339923] 
[31] 
Lee, A.Y.W.; Chung, S.S. Contributions of polyol pathway to oxidative stress in diabetic cataract. FASEB J.,  1999, 13(1), 23-30.
[http://dx.doi.org/10.1096/fasebj.13.1.23] [PMID:  9872926] 
[32] 
Vikramadithyan, R.K.; Hu, Y.; Noh, H.L.; Liang, C.P.; Hallam, K.; Tall, A.R.; Ramasamy, R.; Goldberg, I.J. Human aldose reductase expression accelerates diabetic atherosclerosis in transgenic mice. J. Clin. Invest.,  2005, 115(9), 2434-2443.
[http://dx.doi.org/10.1172/JCI24819] [PMID:  16127462] 
[33] 
Shantikumar, S.; Caporali, A.; Emanueli, C. Role of microRNAs in diabetes and its cardiovascular complications. Cardiovasc. Res.,  2012, 93(4), 583-593.
[http://dx.doi.org/10.1093/cvr/cvr300] [PMID:  22065734] 
[34] 
Zampetaki, A.; Kiechl, S.; Drozdov, I.; Willeit, P.; Mayr, U.; Prokopi, M.; Mayr, A.; Weger, S.; Oberhollenzer, F.; Bonora, E.; Shah, A.; Willeit, J.; Mayr, M. Plasma microRNA profiling reveals loss of endothelial miR-126 and other microRNAs in type 2 diabetes. Circ. Res.,  2010, 107(6), 810-817.
[http://dx.doi.org/10.1161/CIRCRESAHA.110.226357] [PMID:  20651284] 
[35] 
Wang, X.H.; Qian, R.Z.; Zhang, W.; Chen, S.F.; Jin, H.M.; Hu, R.M. MicroRNA-320 expression in myocardial microvascular endothelial cells and its relationship with insulin-like growth factor-1 in type 2 diabetic rats. Clin. Exp. Pharmacol. Physiol.,  2009, 36(2), 181-188.
[http://dx.doi.org/10.1111/j.1440-1681.2008.05057.x] [PMID:  18986336] 
[36] 
Li, Y.; Song, Y.H.; Li, F.; Yang, T.; Lu, Y.W.; Geng, Y.J. MicroRNA-221 regulates high glucose-induced endothelial dysfunction. Biochem. Biophys. Res. Commun.,  2009, 381(1), 81-83.
[http://dx.doi.org/10.1016/j.bbrc.2009.02.013] [PMID:  19351599] 
[37] 
Togliatto, G.; Trombetta, A.; Dentelli, P.; Rosso, A.; Brizzi, M.F. MIR221/MIR222-driven post-transcriptional regulation of P27KIP1 and P57KIP2 is crucial for high-glucose- and AGE-mediated vascular cell damage. Diabetologia,  2011, 54(7), 1930-1940.
[http://dx.doi.org/10.1007/s00125-011-2125-5] [PMID:  21461636] 
[38] 
Caporali, A.; Meloni, M.; Völlenkle, C.; Bonci, D.; Sala-Newby, G.B.; Addis, R.; Spinetti, G.; Losa, S.; Masson, R.; Baker, A.H.; Agami, R.; le Sage, C.; Condorelli, G.; Madeddu, P.; Martelli, F.; Emanueli, C. Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation,  2011, 123(3), 282-291.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.952325] [PMID:  21220732] 
[39] 
Meng, S.; Cao, J.T.; Zhang, B.; Zhou, Q.; Shen, C.X.; Wang, C.Q. Downregulation of microRNA-126 in endothelial progenitor cells from diabetes patients, impairs their functional properties, via target gene Spred-1. J. Mol. Cell. Cardiol.,  2012, 53(1), 64-72.
[http://dx.doi.org/10.1016/j.yjmcc.2012.04.003] [PMID:  22525256] 
[40] 
Davies, M.J.; D’Alessio, D.A.; Fradkin, J.; Kernan, W.N.; Mathieu, C.; Mingrone, G.; Rossing, P.; Tsapas, A.; Wexler, D.J.; Buse, J.B. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia,  2018, 61(12), 2461-2498.
[http://dx.doi.org/10.1007/s00125-018-4729-5] [PMID:  30288571] 
[41] 
Holman, R.R.; Paul, S.K.; Bethel, M.A.; Matthews, D.R.; Neil, H.A.W. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med.,  2008, 359(15), 1577-1589.
[http://dx.doi.org/10.1056/NEJMoa0806470] [PMID:  18784090] 
[42] 
Maruthur, N.M.; Tseng, E.; Hutfless, S.; Wilson, L.M.; Suarezcuervo, C.; Berger, Z.; Chu, Y.; Iyoha, E.; Segal, J.B.; Bolen, S. Diabetes medications as monotherapy or metformin-based combination therapy for type 2 diabetes: A systematic review and meta-analysis. Ann. Intern. Med.,  2016, 164(11), 740-751.
[http://dx.doi.org/10.7326/M15-2650] [PMID:  27088241] 
[43] 
Stirban, A. O.; Tschoepe, D. Cardiovascular complications in diabetes: targets and interventions. Diabetes Care,  2008, 31 Suppl 2(Supplement 2), S215-S221.
[http://dx.doi.org/10.2337/dc08-s257] 
[44] 
Hugel, B.; Martínez, M.C.; Kunzelmann, C.; Freyssinet, J.M. Membrane microparticles: Two sides of the coin. Physiology (Bethesda),  2005, 20(1), 22-27.
[http://dx.doi.org/10.1152/physiol.00029.2004] [PMID:  15653836] 
[45] 
Koga, H.; Sugiyama, S.; Kugiyama, K.; Watanabe, K.; Fukushima, H.; Tanaka, T.; Sakamoto, T.; Yoshimura, M.; Jinnouchi, H.; Ogawa, H. Elevated levels of VE-cadherin-positive endothelial microparticles in patients with type 2 diabetes mellitus and coronary artery disease. J. Am. Coll. Cardiol.,  2005, 45(10), 1622-1630.
[http://dx.doi.org/10.1016/j.jacc.2005.02.047] [PMID:  15893178] 
[46] 
Ross, R.; Glomset, J.A. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science,  1973, 180(4093), 1332-1339.
[http://dx.doi.org/10.1126/science.180.4093.1332] [PMID:  4350926] 
[47] 
Marwick, T.H. Diabetic heart disease. Heart,  2006, 92(3), 296-300.
[PMID:  16159978] 
[48] 
Rakusan, K.; Flanagan, M.F.; Geva, T.; Southern, J.; Van Praagh, R. Morphometry of human coronary capillaries during normal growth and the effect of age in left ventricular pressure-overload hypertrophy. Circulation,  1992, 86(1), 38-46.
[http://dx.doi.org/10.1161/01.CIR.86.1.38] [PMID:  1535573] 
[49] 
Alter, D.A.; Khaykin, Y.; Austin, P.C.; Tu, J.V.; Hux, J.E. Processes and outcomes of care for diabetic acute myocardial infarction patients in Ontario: Do physicians undertreat? Diabetes Care,  2003, 26(5), 1427-1434.
[http://dx.doi.org/10.2337/diacare.26.5.1427] [PMID:  12716800] 
[50] 
Woodfield, S.L.; Lundergan, C.F.; Reiner, J.S.; Greenhouse, S.W.; Thompson, M.A.; Rohrbeck, S.C.; Deychak, Y.; Simoons, M.L.; Califf, R.M.; Topol, E.J.; Ross, A.M. Angiographic findings and outcome in diabetic patients treated with thrombolytic therapy for acute myocardial infarction: the GUSTO-I experience. J. Am. Coll. Cardiol.,  1996, 28(7), 1661-1669.
[http://dx.doi.org/10.1016/S0735-1097(96)00397-X] [PMID:  8962549] 
[51] 
Zhao, F.Q.; Keating, A.F. Functional properties and genomics of glucose transporters. Curr. Genomics,  2007, 8(2), 113-128.
[http://dx.doi.org/10.2174/138920207780368187] [PMID:  18660845] 
[52] 
Mauer, S.M. Structural-functional correlations of diabetic nephropathy. Kidney Int.,  1994, 45(2), 612-622.
[http://dx.doi.org/10.1038/ki.1994.80] [PMID:  8164451] 
[53] 
Fine, L.G.; Bandyopadhay, D.; Norman, J.T. Is there a common mechanism for the progression of different types of renal diseases other than proteinuria? Towards the unifying theme of chronic hypoxia. Kidney Int. Suppl.,  2000, 75(s75), S22-S26.
[http://dx.doi.org/10.1046/j.1523-1755.2000.07512.x] [PMID:  10828757] 
[54] 
Gómez, O.; Ballester-Lurbe, B.; Poch, E.; Mesonero, J.E.; Terrado, J. Developmental regulation of glucose transporters GLUT3, GLUT4 and GLUT8 in the mouse cerebellar cortex. J. Anat.,  2010, 217(5), 616-623.
[http://dx.doi.org/10.1111/j.1469-7580.2010.01291.x] [PMID:  20819112] 
[55] 
Dawson, P.A.; Mychaleckyj, J.C.; Fossey, S.C.; Mihic, S.J.; Craddock, A.L.; Bowden, D.W. Sequence and functional analysis of GLUT10: A glucose transporter in the Type 2 diabetes-linked region of chromosome 20q12-13.1. Mol. Genet. Metab.,  2001, 74(1-2), 186-199.
[http://dx.doi.org/10.1006/mgme.2001.3212] [PMID:  11592815] 
[56] 
Chandler, J.D.; Williams, E.D.; Slavin, J.L.; Best, J.D.; Rogers, S. Expression and localization of GLUT1 and GLUT12 in prostate carcinoma. Cancer,  2003, 97(8), 2035-2042.
[http://dx.doi.org/10.1002/cncr.11293] [PMID:  12673735] 
[57] 
You, G.; Lee, W.S.; Barros, E.J.; Kanai, Y.; Huo, T.L.; Khawaja, S.; Wells, R.G.; Nigam, S.K.; Hediger, M.A. Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney. J. Biol. Chem.,  1995, 270(49), 29365-29371.
[http://dx.doi.org/10.1074/jbc.270.49.29365] [PMID:  7493971] 
[58] 
Ng, C.Y.; Heist, E.K. Cardiac resynchronization therapy: Maximizing the response to biventricular pacing. Cardiol. Rev.,  2017, 25(1), 6-11.
[http://dx.doi.org/10.1097/CRD.0000000000000127] [PMID:  27861420] 
[59] 
Nativi-Nicolau, J.; Ryan, J.J.; Fang, J.C. Current therapeutic approach in heart failure with preserved ejection fraction. Heart Fail. Clin.,  2014, 10(3), 525-538.
[http://dx.doi.org/10.1016/j.hfc.2014.04.007] [PMID:  24975914] 
[60] 
Borlaug, B.A. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ. J.,  2014, 78(1), 20-32.
[http://dx.doi.org/10.1253/circj.CJ-13-1103] [PMID:  24305634] 
[61] 
Rogers, F.J.; Gundala, T.; Ramos, J.E.; Serajian, A. Heart failure with preserved ejection fraction. J. Am. Osteopath. Assoc.,  2015, 115(7), 432-442.
[http://dx.doi.org/10.7556/jaoa.2015.089] [PMID:  26111131] 
[62] 
Shakib, S.; Clark, R.A. Heart failure pharmacotherapy and supports in the elderly-A short review. Curr. Cardiol. Rev.,  2016, 12(3), 180-185.
[http://dx.doi.org/10.2174/1573403X12666160622102802] [PMID:  27338867] 
[63] 
Liu, Y.; Haddad, T.; Dwivedi, G. Heart failure with preserved ejection fraction: Current understanding and emerging concepts. Curr. Opin. Cardiol.,  2013, 28(2), 187-196.
[http://dx.doi.org/10.1097/HCO.0b013e32835c5492] [PMID:  23274284] 
[64] 
Meng, Q.; Lai, Y.C.; Kelly, N.J.; Bueno, M.; Baust, J.; Bachman, T.; Goncharov, D.; Vanderpool, R.R.; Radder, J.E.; Hu, J. Development of a mouse model of metabolic syndrome, pulmonary hypertension, and heart failure with preserved ejection fraction. (PH-HFpEF). Am. J. Respir. Cell Mol. Biol.,  2017, 56(4), 497-505.
[http://dx.doi.org/10.1165/rcmb.2016-0177OC] [PMID:  28118022] 
[65] 
von Lueder, T.G.; Krum, H. New medical therapies for heart failure. Nat. Rev. Cardiol.,  2015, 12(12), 730-740.
[http://dx.doi.org/10.1038/nrcardio.2015.137] [PMID:  26416006] 
[66] 
Lam, C.S.; Donal, E.; Kraigher-Krainer, E.; Vasan, R.S. Epidemiology and clinical course of heart failure with preserved ejection fraction. Eur. J. Heart Fail.,  2011, 13(1), 18-28.
[http://dx.doi.org/10.1093/eurjhf/hfq121] [PMID:  20685685] 
[67] 
Kannel, W.B.; McGee, D.L. Diabetes and cardiovascular disease. The framingham study. JAMA,  1979, 241(19), 2035-2038.
[http://dx.doi.org/10.1001/jama.1979.03290450033020] [PMID:  430798] 
[68] 
Kannel, W.B.; Hjortland, M.; Castelli, W.P. Role of diabetes in congestive heart failure: The framingham study. Am. J. Cardiol.,  1974, 34(1), 29-34.
[http://dx.doi.org/10.1016/0002-9149(74)90089-7] [PMID:  4835750] 
[69] 
Echouffo-Tcheugui, J.B.; Masoudi, F.A.; Bao, H.; Spatz, E.S.; Fonarow, G.C. Diabetes mellitus and outcomes of cardiac resynchronization with implantable cardioverter-defibrillator therapy in older patients with heart failure. Circ Arrhythm Electrophysiol,  2016, 9(8) e004132
[http://dx.doi.org/10.1161/CIRCEP.116.004132] [PMID:  27489243] 
[70] 
Erqou, S.; Lee, C.T.; Suffoletto, M.; Echouffo-Tcheugui, J.B.; de Boer, R.A.; van Melle, J.P.; Adler, A.I. Association between glycated haemoglobin and the risk of congestive heart failure in diabetes mellitus: systematic review and meta-analysis. Eur. J. Heart Fail.,  2013, 15(2), 185-193.
[http://dx.doi.org/10.1093/eurjhf/hfs156] [PMID:  23099356] 
[71] 
Loffredo, F.S.; Nikolova, A.P.; Pancoast, J.R.; Lee, R.T. Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ. Res.,  2014, 115(1), 97-107.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.302929] [PMID:  24951760] 
[72] 
Rigolli, M.; Whalley, G.A. Heart failure with preserved ejection fraction. J. Geriatr. Cardiol.,  2013, 10(4), 369-376.
[PMID:  24454331] 
[73] 
Lindman, B.R.; Dávila-Román, V.G.; Mann, D.L.; McNulty, S.; Semigran, M.J.; Lewis, G.D.; de las Fuentes, L.; Joseph, S.M.; Vader, J.; Hernandez, A.F.; Redfield, M.M. Cardiovascular phenotype in HFpEF patients with or without diabetes: A RELAX trial ancillary study. J. Am. Coll. Cardiol.,  2014, 64(6), 541-549.
[http://dx.doi.org/10.1016/j.jacc.2014.05.030] [PMID:  25104521] 
[74] 
Lindman, B.R. The diabetic heart failure with preserved ejection fraction phenotype. Circulation,  2017, 135(8), 736-740.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.025957] [PMID:  28052978] 
[75] 
De Keulenaer, G.W.; Brutsaert, D.L. Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. Circulation,  2011, 123(18), 1996-2004.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.110.981431] [PMID:  21555722] 
[76] 
Kristensen, S.L.; Mogensen, U.M.; Jhund, P.S.; Petrie, M.C.; Preiss, D.; Win, S.; Køber, L.; Mckelvie, R.S.; Zile, M.R.; Anand, I.S. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction. A report from the irbesartan in heart failure with preserved ejection fraction trial I. Circulation,  2017, 135(8), 724-735.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.024593] [PMID:  28052977] 
[77] 
Hegab, Z.; Gibbons, S.; Neyses, L.; Mamas, M.A. Role of advanced glycation end products in cardiovascular disease. World J. Cardiol.,  2012, 4(4), 90-102.
[http://dx.doi.org/10.4330/wjc.v4.i4.90] [PMID:  22558488] 
[78] 
Fukami, K.; Yamagishi, S.; Okuda, S. Role of AGEs-RAGE system in cardiovascular disease. Curr. Pharm. Des.,  2014, 20(14), 2395-2402.
[http://dx.doi.org/10.2174/13816128113199990475] [PMID:  23844818] 
[79] 
Twigg, S.M.; Joly, A.H.; Chen, M.M.; Tsubaki, J.; Kim, H.S.; Hwa, V.; Oh, Y.; Rosenfeld, R.G. Connective tissue growth factor/IGF-binding protein-related protein-2 is a mediator in the induction of fibronectin by advanced glycosylation end-products in human dermal fibroblasts. Endocrinology,  2002, 143(4), 1260-1269.
[http://dx.doi.org/10.1210/endo.143.4.8741] [PMID:  11897682] 
[80] 
Zieman, S.J.; Melenovsky, V.; Kass, D.A. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler. Thromb. Vasc. Biol.,  2005, 25(5), 932-943.
[http://dx.doi.org/10.1161/01.ATV.0000160548.78317.29] [PMID:  15731494] 
[81] 
Bayeva, M.; Sawicki, K.T.; Ardehali, H. Taking diabetes to heart--deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J. Am. Heart Assoc.,  2013, 2(6) e000433
[http://dx.doi.org/10.1161/JAHA.113.000433] [PMID:  24275630] 
[82] 
McGavock, J.M.; Lingvay, I.; Zib, I.; Tillery, T.; Salas, N.; Unger, R.; Levine, B.D.; Raskin, P.; Victor, R.G.; Szczepaniak, L.S. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation,  2007, 116(10), 1170-1175.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.645614] [PMID:  17698735] 
[83] 
Levelt, E.; Pavlides, M.; Banerjee, R.; Mahmod, M.; Kelly, C.; Sellwood, J.; Ariga, R.; Thomas, S.; Francis, J.; Rodgers, C.; Clarke, W.; Sabharwal, N.; Antoniades, C.; Schneider, J.; Robson, M.; Clarke, K.; Karamitsos, T.; Rider, O.; Neubauer, S. Ectopic and visceral fat deposition in lean and obese patients with type 2 diabetes. J. Am. Coll. Cardiol.,  2016, 68(1), 53-63.
[http://dx.doi.org/10.1016/j.jacc.2016.03.597] [PMID:  27364051] 
[84] 
Lopaschuk, G.D.; Ussher, J.R.; Folmes, C.D.; Jaswal, J.S.; Stanley, W.C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev.,  2010, 90(1), 207-258.
[http://dx.doi.org/10.1152/physrev.00015.2009] [PMID:  20086077] 
[85] 
Young, M.E.; McNulty, P.; Taegtmeyer, H. Adaptation and maladaptation of the heart in diabetes: Part II: Potential mechanisms. Circulation,  2002, 105(15), 1861-1870.
[http://dx.doi.org/10.1161/01.CIR.0000012467.61045.87] [PMID:  11956132] 
[86] 
Stanley, W.C.; Recchia, F.A.; Lopaschuk, G.D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev.,  2005, 85(3), 1093-1129.
[http://dx.doi.org/10.1152/physrev.00006.2004] [PMID:  15987803] 
[87] 
Poornima, I.G.; Parikh, P.; Shannon, R.P. Diabetic cardiomyopathy: the search for a unifying hypothesis. Circ. Res.,  2006, 98(5), 596-605.
[http://dx.doi.org/10.1161/01.RES.0000207406.94146.c2] [PMID:  16543510] 
[88] 
Koya, D.; King, G.L. Protein kinase C activation and the development of diabetic complications. Diabetes,  1998, 47(6), 859-866.
[http://dx.doi.org/10.2337/diabetes.47.6.859] [PMID:  9604860] 
[89] 
Wakasaki, H.; Koya, D.; Schoen, F.J.; Jirousek, M.R.; Ways, D.K.; Hoit, B.D.; Walsh, R.A.; King, G.L. Targeted overexpression of protein kinase C beta2 isoform in myocardium causes cardiomyopathy. Proc. Natl. Acad. Sci. USA,  1997, 94(17), 9320-9325.
[http://dx.doi.org/10.1073/pnas.94.17.9320] [PMID:  9256480] 
[90] 
Durpès, M.C.; Morin, C.; Paquin-Veillet, J.; Beland, R.; Paré, M.; Guimond, M.O.; Rekhter, M.; King, G.L.; Geraldes, P. PKC-β activation inhibits IL-18-binding protein causing endothelial dysfunction and diabetic atherosclerosis. Cardiovasc. Res.,  2015, 106(2), 303-313.
[http://dx.doi.org/10.1093/cvr/cvv107] [PMID:  25808972] 
[91] 
Civitarese, R.A.; Kapus, A.; McCulloch, C.A.; Connelly, K.A. Role of integrins in mediating cardiac fibroblast-cardiomyocyte cross talk: A dynamic relationship in cardiac biology and pathophysiology. Basic Res. Cardiol.,  2017, 112(1), 6.
[http://dx.doi.org/10.1007/s00395-016-0598-6] [PMID:  28000001] 
[92] 
Talior-Volodarsky, I.; Connelly, K.A.; Arora, P.D.; Gullberg, D.; McCulloch, C.A. α11 integrin stimulates myofibroblast differentiation in diabetic cardiomyopathy. Cardiovasc. Res.,  2012, 96(2), 265-275.
[http://dx.doi.org/10.1093/cvr/cvs259] [PMID:  22869616] 
[93] 
Talior-Volodarsky, I.; Arora, P.D.; Wang, Y.; Zeltz, C.; Connelly, K.A.; Gullberg, D.; McCulloch, C.A. Glycated collagen induces α11 integrin expression through TGF-β2 and Smad3. J. Cell. Physiol.,  2015, 230(2), 327-336.
[http://dx.doi.org/10.1002/jcp.24708] [PMID:  24962729] 
[94] 
Civitarese, R.A.; Talior-Volodarsky, I.; Desjardins, J.F.; Kabir, G.; Switzer, J.; Mitchell, M.; Kapus, A.; Mcculloch, C.A.; Gullberg, D.; Connelly, K.A. The α11 integrin mediates fibroblast- extracellular matrix- cardiomyocyte interactions in health and disease. Am. J. Physiol. Heart Circ. Physiol.,  2016, 311(1), H96-H106.
[http://dx.doi.org/10.1152/ajpheart.00918.2015] [PMID:  27199132] 
[95] 
Barczyk, M.; Carracedo, S.; Gullberg, D. Integrins. Cell Tissue Res.,  2010, 339(1), 269-280.
[http://dx.doi.org/10.1007/s00441-009-0834-6] [PMID:  19693543] 
[96] 
Augustin, R.; Mayoux, E. Mammalian sugar transporters. Glucose homeostass; InTech, 2014. 
[http://dx.doi.org/10.5772/58325] 
[97] 
Uldry, M.; Ibberson, M.; Horisberger, J.D.; Chatton, J.Y.; Riederer, B.M.; Thorens, B. Identification of a mammalian H(+)-myo-inositol symporter expressed predominantly in the brain. EMBO J.,  2001, 20(16), 4467-4477.
[http://dx.doi.org/10.1093/emboj/20.16.4467] [PMID:  11500374] 
[98] 
Maher, F.; Harrison, L.C. Hexose specificity for downregulation of HepG2/brain-type glucose transporter gene expression in L6 myocytes. Diabetologia,  1990, 33(11), 641-648.
[http://dx.doi.org/10.1007/BF00400564] [PMID:  2076796] 
[99] 
So, A.; Thorens, B. Uric acid transport and disease. J. Clin. Invest.,  2010, 120(6), 1791-1799.
[http://dx.doi.org/10.1172/JCI42344] [PMID:  20516647] 
[100] 
Lee, Y.C.; Huang, H.Y.; Chang, C.J.; Cheng, C.H.; Chen, Y.T. Mitochondrial GLUT10 facilitates dehydroascorbic acid import and protects cells against oxidative stress: Mechanistic insight into arterial tortuosity syndrome. Hum. Mol. Genet.,  2010, 19(19), 3721-3733.
[http://dx.doi.org/10.1093/hmg/ddq286] [PMID:  20639396] 
[101] 
Mueckler, M.; Caruso, C.; Baldwin, S.A.; Panico, M.; Blench, I.; Morris, H.R.; Allard, W.J.; Lienhard, G.E.; Lodish, H.F. Sequence and structure of a human glucose transporter. Science,  1985, 229(4717), 941-945.
[http://dx.doi.org/10.1126/science.3839598] [PMID:  3839598] 
[102] 
Uldry, M.; Ibberson, M.; Hosokawa, M.; Thorens, B. GLUT2 is a high affinity glucosamine transporter. FEBS Lett.,  2002, 524(1-3), 199-203.
[http://dx.doi.org/10.1016/S0014-5793(02)03058-2] [PMID:  12135767] 
[103] 
Nagamatsu, S.; Kornhauser, J.M.; Burant, C.F.; Seino, S.; Mayo, K.E.; Bell, G.I. Glucose transporter expression in brain. cDNA sequence of mouse GLUT3, the brain facilitative glucose transporter isoform, and identification of sites of expression by in situ hybridization. J. Biol. Chem.,  1992, 267(1), 467-472.
[PMID:  1730609] 
[104] 
Huang, S.; Czech, M.P. The GLUT4 glucose transporter. Cell Metab.,  2007, 5(4), 237-252.
[http://dx.doi.org/10.1016/j.cmet.2007.03.006] [PMID:  17403369] 
[105] 
Wu, X.; Freeze, H.H. GLUT14, a duplicon of GLUT3, is specifically expressed in testis as alternative splice forms. Genomics,  2002, 80(6), 553-557.
[http://dx.doi.org/10.1006/geno.2002.7010] [PMID:  12504846] 
[106] 
Kayano, T.; Burant, C.F.; Fukumoto, H.; Gould, G.W.; Fan, Y.S.; Eddy, R.L.; Byers, M.G.; Shows, T.B.; Seino, S.; Bell, G.I. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J. Biol. Chem.,  1990, 265(22), 13276-13282.
[PMID:  1695905] 
[107] 
Drozdowski, L.A.; Thomson, A.B. Intestinal sugar transport. World J. Gastroenterol.,  2006, 12(11), 1657-1670.
[http://dx.doi.org/10.3748/wjg.v12.i11.1657] [PMID:  16586532] 
[108] 
Li, Q.; Manolescu, A.; Ritzel, M.; Yao, S.; Slugoski, M.; Young, J.D.; Chen, X.Z.; Cheeseman, C.I. Cloning and functional characterization of the human GLUT7 isoform SLC2A7 from the small intestine. Am. J. Physiol. Gastrointest. Liver Physiol.,  2004, 287(1), G236-G242.
[http://dx.doi.org/10.1152/ajpgi.00396.2003] [PMID:  15033637] 
[109] 
Wu, X.; Li, W.; Sharma, V.; Godzik, A.; Freeze, H.H. Cloning and characterization of glucose transporter 11, a novel sugar transporter that is alternatively spliced in various tissues. Mol. Genet. Metab.,  2002, 76(1), 37-45.
[http://dx.doi.org/10.1016/S1096-7192(02)00018-5] [PMID:  12175779] 
[110] 
Scheepers, A.; Schmidt, S.; Manolescu, A.; Cheeseman, C.I.; Bell, A.; Zahn, C.; Joost, H-G.; Schürmann, A. Characterization of the human SLC2A11 (GLUT11) gene: alternative promoter usage, function, expression, and subcellular distribution of three isoforms, and lack of mouse orthologue. Mol. Membr. Biol.,  2005, 22(4), 339-351.
[http://dx.doi.org/10.1080/09687860500166143] [PMID:  16154905] 
[111] 
Sasaki, T.; Minoshima, S.; Shiohama, A.; Shintani, A.; Shimizu, A.; Asakawa, S.; Kawasaki, K.; Shimizu, N. Molecular cloning of a member of the facilitative glucose transporter gene family GLUT11 (SLC2A11) and identification of transcription variants. Biochem. Biophys. Res. Commun.,  2001, 289(5), 1218-1224.
[http://dx.doi.org/10.1006/bbrc.2001.6101] [PMID:  11741323] 
[112] 
Bibert, S.; Hess, S.K.; Firsov, D.; Thorens, B.; Geering, K.; Horisberger, J-D.; Bonny, O. Mouse GLUT9: Evidences for a urate uniporter. Am. J. Physiol. Renal Physiol.,  2009, 297(3), F612-F619.
[http://dx.doi.org/10.1152/ajprenal.00139.2009] [PMID:  19587147] 
[113] 
Doege, H.; Bocianski, A.; Joost, H.G.; Schürmann, A. Activity and genomic organization of human glucose transporter 9 (GLUT9), a novel member of the family of sugar-transport facilitators predominantly expressed in brain and leucocytes. Biochem. J.,  2000, 350(Pt 3), 771-776.
[http://dx.doi.org/10.1042/bj3500771] [PMID:  10970791] 
[114] 
Ibberson, M.; Uldry, M.; Thorens, B. GLUTX1, A novel mammalian glucose transporter expressed in the central nervous system and insulin-sensitive tissues. J. Biol. Chem.,  2000, 275(7), 4607-4612.
[http://dx.doi.org/10.1074/jbc.275.7.4607] [PMID:  10671487] 
[115] 
Rogers, S.; Chandler, J.D.; Clarke, A.L.; Petrou, S.; Best, J.D. Glucose transporter GLUT12-functional characterization in Xenopus laevis oocytes. Biochem. Biophys. Res. Commun.,  2003, 308(3), 422-426.
[http://dx.doi.org/10.1016/S0006-291X(03)01417-7] [PMID:  12914765] 
[116] 
Wells, R.G.; Pajor, A.M.; Kanai, Y.; Turk, E.; Wright, E.M.; Hediger, M.A. Cloning of a human kidney cDNA with similarity to the sodium-glucose cotransporter. Am. J. Physiol.,  1992, 263(3 Pt 2), F459-F465.
[PMID:  1415574] 
[117] 
Dai, G.; Levy, O.; Carrasco, N. Cloning and characterization of the thyroid iodide transporter. Nature,  1996, 379(6564), 458-460.
[http://dx.doi.org/10.1038/379458a0] [PMID:  8559252] 
[118] 
Kwon, H.M.; Yamauchi, A.; Uchida, S.; Preston, A.S.; Garcia-Perez, A.; Burg, M.B.; Handler, J.S. Cloning of the cDNa for a Na+/myo-inositol cotransporter, a hypertonicity stress protein. J. Biol. Chem.,  1992, 267(9), 6297-6301.
[PMID:  1372904] 
[119] 
Prasad, P.D.; Wang, H.; Kekuda, R.; Fujita, T.; Fei, Y.J.; Devoe, L.D.; Leibach, F.H.; Ganapathy, V. Cloning and functional expression of a cDNA encoding a mammalian sodium-dependent vitamin transporter mediating the uptake of pantothenate, biotin, and lipoate. J. Biol. Chem.,  1998, 273(13), 7501-7506.
[http://dx.doi.org/10.1074/jbc.273.13.7501] [PMID:  9516450] 
[120] 
Turk, E.; Wright, E.M. Membrane topology motifs in the SGLT cotransporter family. J. Membr. Biol.,  1997, 159(1), 1-20.
[http://dx.doi.org/10.1007/s002329900264] [PMID:  9309206] 
[121] 
Wright, E.M. Glucose transport families SLC5 and SLC50. Mol. Aspects Med.,  2013, 34(2-3), 183-196.
[http://dx.doi.org/10.1016/j.mam.2012.11.002] [PMID:  23506865] 
[122] 
Santer, R.; Calado, J. Familial renal glucosuria and SGLT2: From a mendelian trait to a therapeutic target. Clin. J. Am. Soc. Nephrol.,  2010, 5(1), 133-141.
[http://dx.doi.org/10.2215/CJN.04010609] [PMID:  19965550] 
[123] 
Zhou, L.; Cryan, E.V.; D’Andrea, M.R.; Belkowski, S.; Conway, B.R.; Demarest, K.T. Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J. Cell. Biochem.,  2003, 90(2), 339-346.
[http://dx.doi.org/10.1002/jcb.10631] [PMID:  14505350] 
[124] 
Sabino-Silva, R.; Mori, R.C.; David-Silva, A.; Okamoto, M.M.; Freitas, H.S.; Machado, U.F. The Na(+)/glucose cotransporters: from genes to therapy. Braz. J. Med. Biol. Res.,  2010, 43(11), 1019-1026.
[http://dx.doi.org/10.1590/S0100-879X2010007500115] [PMID:  21049241] 
[125] 
Wright, E.M. Renal Na(+)-glucose cotransporters. Am. J. Physiol. Renal Physiol.,  2001, 280(1), F10-F18.
[http://dx.doi.org/10.1152/ajprenal.2001.280.1.F10] [PMID:  11133510] 
[126] 
Wright, E.M.; Turk, E. The sodium/glucose cotransport family SLC5. Pflugers Arch.,  2004, 447(5), 510-518.
[http://dx.doi.org/10.1007/s00424-003-1202-0] [PMID:  12748858] 
[127] 
Kanai, Y.; Lee, W.S.; You, G.; Brown, D.; Hediger, M.A. The human kidney low affinity Na+/glucose cotransporter SGLT2. Delineation of the major renal reabsorptive mechanism for D-glucose. J. Clin. Invest.,  1994, 93(1), 397-404.
[http://dx.doi.org/10.1172/JCI116972] [PMID:  8282810] 
[128] 
Diez-Sampedro, A.; Hirayama, B.A.; Osswald, C.; Gorboulev, V.; Baumgarten, K.; Volk, C.; Wright, E.M.; Koepsell, H. A glucose sensor hiding in a family of transporters. Proc. Natl. Acad. Sci. USA,  2003, 100(20), 11753-11758.
[http://dx.doi.org/10.1073/pnas.1733027100] [PMID:  13130073] 
[129] 
Lin, X.; Ma, L.; Fitzgerald, R.L.; Ostlund, R.E. Jr Human sodium/inositol cotransporter 2 (SMIT2) transports inositols but not glucose in L6 cells. Arch. Biochem. Biophys.,  2009, 481(2), 197-201.
[http://dx.doi.org/10.1016/j.abb.2008.11.008] [PMID:  19032932] 
[130] 
Chen, L.Q.; Hou, B.H.; Lalonde, S.; Takanaga, H.; Hartung, M.L.; Qu, X.Q.; Guo, W.J.; Kim, J.G.; Underwood, W.; Chaudhuri, B.; Chermak, D.; Antony, G.; White, F.F.; Somerville, S.C.; Mudgett, M.B.; Frommer, W.B. Sugar transporters for intercellular exchange and nutrition of pathogens. Nature,  2010, 468(7323), 527-532.
[http://dx.doi.org/10.1038/nature09606] [PMID:  21107422] 
[131] 
Chiang, C.E.; Lin, S.Y.; Lin, T.H.; Wang, T.D.; Yeh, H.I.; Chen, J.F.; Tsai, C.T.; Hung, Y.J.; Li, Y.H.; Liu, P.Y.; Chang, K.C.; Wang, K.L.; Chao, T.H.; Shyu, K.G.; Yang, W.S.; Ueng, K.C.; Chu, P.H.; Yin, W.H.; Wu, Y.W.; Cheng, H.M.; Shin, S.J.; Huang, C.N.; Chuang, L.M.; Lin, S.J.; Yeh, S.J.; Sheu, W.H.; Lin, J.L. 2018 consensus of the taiwan society of cardiology and the diabetes association of republic of china (taiwan) on the pharmacological management of patients with type 2 diabetes and cardiovascular diseases. J. Chin. Med. Assoc.,  2018, 81(3), 189-222.
[132] 
Bays, H. Sodium Glucose Co-transporter type 2 (SGLT2) inhibitors: Targeting the kidney to improve glycemic control in diabetes mellitus. Diabetes Ther.,  2013, 4(2), 195-220.
[http://dx.doi.org/10.1007/s13300-013-0042-y] [PMID:  24142577] 
[133] 
Prentki, M.; Nolan, C.J. Islet beta cell failure in type 2 diabetes. J. Clin. Invest.,  2006, 116(7), 1802-1812.
[http://dx.doi.org/10.1172/JCI29103] [PMID:  16823478] 
[134] 
Kaiser, N.; Leibowitz, G.; Nesher, R. Glucotoxicity and beta-cell failure in type 2 diabetes mellitus. J. Pediatr. Endocrinol. Metab.,  2003, 16(1), 5-22.
[http://dx.doi.org/10.1515/JPEM.2003.16.1.5] [PMID:  12585335] 
[135] 
Defronzo, R.A. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes,  2009, 58(4), 773-795.
[http://dx.doi.org/10.2337/db09-9028] [PMID:  19336687] 
[136] 
Thomas, M.C.; Jandeleit-Dahm, K.; Bonnet, F. Beyond glycosuria: Exploring the intrarenal effects of SGLT-2 inhibition in diabetes. Diabetes Metab.,  2014, 40(6)(Suppl. 1), S17-S22.
[http://dx.doi.org/10.1016/S1262-3636(14)72691-6] [PMID:  25554067] 
[137] 
Gallo, L.A.; Wright, E.M.; Vallon, V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diab. Vasc. Dis. Res.,  2015, 12(2), 78-89.
[http://dx.doi.org/10.1177/1479164114561992] [PMID:  25616707] 
[138] 
Rahmoune, H.; Thompson, P.W.; Ward, J.M.; Smith, C.D.; Hong, G.; Brown, J. 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.
[http://dx.doi.org/10.2337/diabetes.54.12.3427] [PMID:  16306358] 
[139] 
Lee, Y.J.; Lee, Y.J.; Han, H.J.; Kung, A.W.C. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int. Suppl.,  2007, 72(106), S27-S35.
[http://dx.doi.org/10.1038/sj.ki.5002383] [PMID:  17653207] 
[140] 
Barfuss, D.W.; Schafer, J.A. Differences in active and passive glucose transport along the proximal nephron. Am. J. Physiol.,  1981, 241(3), F322-F332.
[PMID:  7282931] 
[141] 
Turner, R.J.; Moran, A. Heterogeneity of sodium-dependent D-glucose transport sites along the proximal tubule: evidence from vesicle studies. Am. J. Physiol.,  1982, 242(4), F406-F414.
[PMID:  6278960] 
[142] 
Wright, E.M.; Loo, D.D.; Hirayama, B.A. Biology of human sodium glucose transporters. Physiol. Rev.,  2011, 91(2), 733-794.
[http://dx.doi.org/10.1152/physrev.00055.2009] [PMID:  21527736] 
[143] 
Abdul-Ghani, M.A.; DeFronzo, R.A.; Norton, L. Novel hypothesis to explain why SGLT2 inhibitors inhibit only 30-50% of filtered glucose load in humans. Diabetes,  2013, 62(10), 3324-3328.
[http://dx.doi.org/10.2337/db13-0604] [PMID:  24065789] 
[144] 
Abdul-Ghani, M.A.; Norton, L.; Defronzo, R.A. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr. Rev.,  2011, 32(4), 515-531.
[http://dx.doi.org/10.1210/er.2010-0029] [PMID:  21606218] 
[145] 
Wallner, E.I.; Wada, J.; Tramonti, G.; Lin, S.; Kanwar, Y.S. Status of glucose transporters in the mammalian kidney and renal development. Ren. Fail.,  2001, 23(3-4), 301-310.
[http://dx.doi.org/10.1081/JDI-100104714] [PMID:  11499546] 
[146] 
Farber, S.J.; Berger, E.Y.; Earle, D.P. Effect of diabetes and insulin of the maximum capacity of the renal tubules to reabsorb glucose. J. Clin. Invest.,  1951, 30(2), 125-129.
[http://dx.doi.org/10.1172/JCI102424] [PMID:  14814204] 
[147] 
Oku, A.; Ueta, K.; Arakawa, K.; Ishihara, T.; Nawano, M.; Kuronuma, Y.; Matsumoto, M.; Saito, A.; Tsujihara, K.; Anai, M.; Asano, T.; Kanai, Y.; Endou, H. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes,  1999, 48(9), 1794-1800.
[http://dx.doi.org/10.2337/diabetes.48.9.1794] [PMID:  10480610] 
[148] 
Bernard, Z.; Christoph, W.; Lachin, J.M.; David, F.; Erich, B.; Stefan, H.; Michaela, M.; Theresa, D.; Odd Erik, J.; Woerle, H.J. Empagliflozin, cardiovascular outcomes, and mortality in Type 2 diabetes. N. Engl. J. Med.,  2016, 373(22), 2117-2128.
[PMID:  27959769] 
[149] 
Rajagopalan, S.; Brook, R. Canagliflozin and cardiovascular and renal events in Type 2 diabetes. N. Engl. J. Med.,  2017, 377(21), 2098-2099.
[PMID:  29182250] 
[150] 
Norhammar, A.; Bodegård, J.; Nyström, T.; Thuresson, M.; Nathanson, D.; Eriksson, J.W. Dapagliflozin and cardiovascular mortality and disease outcomes in a population with type 2 diabetes similar to that of the DECLARE-TIMI 58 trial: A nationwide observational study. Diabetes Obes. Metab.,  2019, 21(5), 1136-1145.
[http://dx.doi.org/10.1111/dom.13627] [PMID:  30609272] 
[151] 
Kosiborod, M.; Cavender, M.A.; Fu, A.Z.; Wilding, J.P.; Khunti, K.; Holl, R.W.; Norhammar, A.; Birkeland, K.I.; Jørgensen, M.E.; Thuresson, M. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugsclinical perspective: The CVD-REAL study (comparative effectiveness of cardiovascular outcomes in new users of sodiuM. Circulation,  2017, 136(3), 249-259.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029190] [PMID:  28522450] 
[152] 
Nyström, T.; Bodegard, J.; Nathanson, D.; Thuresson, M.; Norhammar, A.; Eriksson, J.W. Novel oral glucose-lowering drugs are associated with lower risk of all-cause mortality, cardiovascular events and severe hypoglycaemia compared with insulin in patients with type 2 diabetes. Diabetes Obes. Metab.,  2017, 19(6), 831-841.
[http://dx.doi.org/10.1111/dom.12889] [PMID:  28116795] 
[153] 
Kostis, J.B.; Wilson, A.C.; Freudenberger, R.S.; Cosgrove, N.M.; Pressel, S.L.; Davis, B.R. SHEP Collaborative Research Group. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am. J. Cardiol.,  2005, 95(1), 29-35.
[http://dx.doi.org/10.1016/j.amjcard.2004.08.059] [PMID:  15619390] 
[154] 
Patel, A.; MacMahon, S.; Chalmers, J.; Neal, B.; Woodward, M.; Billot, L.; Harrap, S.; Poulter, N.; Marre, M.; Cooper, M.; Glasziou, P.; Grobbee, D.E.; Hamet, P.; Heller, S.; Liu, L.S.; Mancia, G.; Mogensen, C.E.; Pan, C.Y.; Rodgers, A.; Williams, B. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet,  2007, 370(9590), 829-840.
[http://dx.doi.org/10.1016/S0140-6736(07)61303-8] [PMID:  17765963] 
[155] 
Fitchett, D.; Lee, J.; George, J.; Mattheus, M.; Woerle, H. Empagliflozin (empa) reduces heart failure outcomes irrespective of blood pressure (BP), low density lipoprotein cholesterol (LDL-C) and HBA1C control. Diabetes,  2017, 66, a312-a313.
[156] 
Wanner, C.; Lachin, J.M.; Inzucchi, S.E.; Fitchett, D.; Mattheus, M.; George, J.; Woerle, H.J.; Broedl, U.C.; von Eynatten, M.; Zinman, B. EMPA-REG OUTCOME Investigators. Empagliflozin and clinical outcomes in patients with type 2 diabetes mellitus, established cardiovascular disease, and chronic kidney disease. Circulation,  2018, 137(2), 119-129.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.028268] [PMID:  28904068] 
[157] 
Al-Jobori, H.; Daniele, G.; Cersosimo, E.; Triplitt, C.; Mehta, R.; Norton, L.; DeFronzo, R.A.; Abdul-Ghani, M. Empagliflozin and kinetics of renal glucose transport in healthy individuals and individuals with type 2 diabetes. Diabetes,  2017, 66(7), 1999-2006.
[http://dx.doi.org/10.2337/db17-0100] [PMID:  28428225] 
[158] 
Heise, 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 empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes. Metab.,  2013, 15(7), 613-621.
[http://dx.doi.org/10.1111/dom.12073] [PMID:  23356556] 
[159] 
Seman, L.; Macha, S.; Nehmiz, G.; Simons, G.; Ren, B.; Pinnetti, S.; Woerle, H.J.; Dugi, K. Empagliflozin (BI 10773), a potent and selective SGLT2 inhibitor, induces dose-dependent glucosuria in healthy subjects. Clin. Pharmacol. Drug Dev.,  2013, 2(2), 152-161.
[http://dx.doi.org/10.1002/cpdd.16] [PMID:  27121669] 
[160] 
Byrne, N.J.; Parajuli, N.; Levasseur, J.L.; Boisvenue, J.; Beker, D.L.; Masson, G.; Fedak, P.W.M.; Verma, S.; Dyck, J.R.B. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. JACC Basic Transl. Sci.,  2017, 2(4), 347-354.
[http://dx.doi.org/10.1016/j.jacbts.2017.07.003] [PMID:  30062155] 
[161] 
Shi, X.; Verma, S.; Yun, J.; Brand-Arzamendi, K.; Singh, K.K.; Liu, X.; Garg, A.; Quan, A.; Wen, X.Y. Effect of empagliflozin on cardiac biomarkers in a zebrafish model of heart failure: Clues to the EMPA-REG OUTCOME trial? Mol. Cell. Biochem.,  2017, 433(1-2), 97-102.
[http://dx.doi.org/10.1007/s11010-017-3018-9] [PMID:  28391552] 
[162] 
Verma, S.; McMurray, J.J.V.; Cherney, D.Z.I. The Metabolodiuretic Promise of sodium-dependent glucose cotransporter 2 inhibition: The search for the sweet spot in heart failure. JAMA Cardiol.,  2017, 2(9), 939-940.
[http://dx.doi.org/10.1001/jamacardio.2017.1891] [PMID:  28636701] 
[163] 
Sattar, N.; McLaren, J.; Kristensen, S.L.; Preiss, D.; McMurray, J.J. SGLT2 Inhibition and cardiovascular events: Why did EMPA-REG Outcomes surprise and what were the likely mechanisms? Diabetologia,  2016, 59(7), 1333-1339.
[http://dx.doi.org/10.1007/s00125-016-3956-x] [PMID:  27112340] 
[164] 
Karg, M.V.; Bosch, A.; Kannenkeril, D.; Striepe, K.; Ott, C.; Schneider, M.P.; Boemke-Zelch, F.; Linz, P.; Nagel, A.M.; Titze, J.; Uder, M.; Schmieder, R.E. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc. Diabetol.,  2018, 17(1), 5.
[http://dx.doi.org/10.1186/s12933-017-0654-z] [PMID:  29301520] 
[165] 
Inzucchi, S.E.; Zinman, B.; Fitchett, D.; Wanner, C.; Ferrannini, E.; Schumacher, M.; Schmoor, C.; Ohneberg, K.; Johansen, O.E.; George, J.T.; Hantel, S.; Bluhmki, E.; Lachin, J.M. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care,  2018, 41(2), 356-363.
[http://dx.doi.org/10.2337/dc17-1096] [PMID:  29203583] 
[166] 
Lambers Heerspink, H.J.; de Zeeuw, D.; Wie, L.; Leslie, B.; List, J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes. Metab.,  2013, 15(9), 853-862.
[http://dx.doi.org/10.1111/dom.12127] [PMID:  23668478] 
[167] 
Hallow, K.M.; Helmlinger, G.; Greasley, P.J.; Jjv, M.M.; Boulton, D.W. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes. Metab.,  2018, 20(3), 479-487.
[http://dx.doi.org/10.1111/dom.13126] 
[168] 
Wilcox, C.S.; Shen, W.; Boulton, D.W.; Leslie, B.R.; Griffen, S.C. Interaction between the sodium-glucose-linked transporter 2 inhibitor dapagliflozin and the loop diuretic bumetanide in normal human subjects. J. Am. Heart Assoc.,  2018, 7(4) e007046
[http://dx.doi.org/10.1161/JAHA.117.007046] [PMID:  29440005] 
[169] 
Striepe, K.; Jumar, A.; Ott, C.; Karg, M.V.; Schneider, M.P.; Kannenkeril, D.; Schmieder, R.E. Effects of the selective sodium-glucose cotransporter 2 inhibitor empagliflozin on vascular function and central hemodynamics in patients with type 2 diabetes mellitus. Circulation,  2017, 136(12), 1167-1169.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029529] [PMID:  28923906] 
[170] 
Chilton, R.; Tikkanen, I.; Cannon, C.P.; Crowe, S.; Woerle, H.J.; Broedl, U.C.; Johansen, O.E. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes. Metab.,  2015, 17(12), 1180-1193.
[http://dx.doi.org/10.1111/dom.12572] [PMID:  26343814] 
[171] 
Li, H.; Shin, S.E.; Seo, M.S.; An, J.R.; Choi, I.W.; Jung, W.K.; Firth, A.L.; Lee, D.S.; Yim, M.J.; Choi, G.; Lee, J.M.; Na, S.H.; Park, W.S. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci.,  2018, 197, 46-55.
[http://dx.doi.org/10.1016/j.lfs.2018.01.032] [PMID:  29409796] 
[172] 
Solini, A.; Giannini, L.; Seghieri, M.; Vitolo, E.; Taddei, S.; Ghiadoni, L.; Bruno, R.M. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc. Diabetol.,  2017, 16(1), 138.
[http://dx.doi.org/10.1186/s12933-017-0621-8] [PMID:  29061124] 
[173] 
Ferrannini, E.; Mark, M.; Mayoux, E. CV Protection in the EMPA-REG OUTCOME trial: A “Thrifty Substrate” hypothesis. Diabetes Care,  2016, 39(7), 1108-1114.
[http://dx.doi.org/10.2337/dc16-0330] [PMID:  27289126] 
[174] 
Lopaschuk, G.D.; Verma, S. Empagliflozin’s fuel hypothesis: Not so soon. Cell Metab.,  2016, 24(2), 200-202.
[http://dx.doi.org/10.1016/j.cmet.2016.07.018] [PMID:  27508868] 
[175] 
Mizuno, Y.; Harada, E.; Nakagawa, H.; Morikawa, Y.; Shono, M.; Kugimiya, F.; Yoshimura, M.; Yasue, H. The diabetic heart utilizes ketone bodies as an energy source. Metabolism,  2017, 77, 65-72.
[http://dx.doi.org/10.1016/j.metabol.2017.08.005] [PMID:  29132539] 
[176] 
Gormsen, L.C.; Svart, M.; Thomsen, H.H.; Søndergaard, E.; Vendelbo, M.H.; Christensen, N.; Tolbod, L.P.; Harms, H.J.; Nielsen, R.; Wiggers, H.; Jessen, N.; Hansen, J.; Bøtker, H.E.; Møller, N. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J. Am. Heart Assoc.,  2017, 6(3) e005066
[http://dx.doi.org/10.1161/JAHA.116.005066] [PMID:  28242634] 
[177] 
Santos-Gallego, C.G.; Ibanez, J.A.R.; Antonio, R.S.; Ishikawa, K.; Watanabe, S.; Picatoste Botija, M.B.; Salvo, A.J.S.; Hajjar, R.; Fuster, V.; Badimon, J. Empagliflozin induces a myocardial metabolic shift from glucose consumption to ketone metabolism that mitigates adverse cardiac remodeling and improves myocardial contractility. J. Am. Coll. Cardiol.,  2018, 71(11), A674.
[http://dx.doi.org/10.1016/S0735-1097(18)31215-4] 
[178] 
Kappel, B.A.; Lehrke, M.; Schütt, K.; Artati, A.; Adamski, J.; Lebherz, C.; Marx, N. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation,  2017, 136(10), 969-972.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.029166] [PMID:  28874423] 
[179] 
Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Zannad, F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol.,  2017, 2(9), 1025-1029.
[http://dx.doi.org/10.1001/jamacardio.2017.2275] [PMID:  28768320] 
[180] 
Uthman, L.; Baartscheer, A.; Bleijlevens, B.; Schumacher, C.A.; Fiolet, J.W.T.; Koeman, A.; Jancev, M.; Hollmann, M.W.; Weber, N.C.; Coronel, R.; Zuurbier, C.J. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na+/H+ exchanger, lowering of cytosolic Na+ and vasodilation. Diabetologia,  2018, 61(3), 722-726.
[http://dx.doi.org/10.1007/s00125-017-4509-7] [PMID:  29197997] 
[181] 
Baartscheer, A.; Schumacher, C.A.; Wüst, R.C.I.; Fiolet, J.W.T.; Stienen, G.J.M.; Coronel, R.; Zuurbier, C.J. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia,  2017, 60(3), 568-573.
[http://dx.doi.org/10.1007/s00125-016-4134-x] [PMID:  27752710] 
[182] 
Fedak, W.M.P.; Verma, S.; D.Weisel, R. Ren-KeLi, Cardiac remodeling and failure. Cardiovasc. Pathol.,  2005, 14(2), 49-60.
[http://dx.doi.org/10.1016/j.carpath.2005.01.005] [PMID:  15780796] 
[183] 
Kang, S.; Verma, S.; Teng, G.; Belke, D.; Svystonyuk, D.; Guzzardi, D.; Park, D.; Turnbull, J.; Malik, G.; Fedak, P. Direct effects of empagliflozin on extracellular matrix remodeling in human cardiac fibroblasts: Novel translational clues to EMPA-REG outcome. Can. J. Cardiol.,  2017, 33(10), S169.
[http://dx.doi.org/10.1016/j.cjca.2017.07.330] 
[184] 
Lau, D.C.; Dhillon, B.; Yan, H.; Szmitko, P.E.; Verma, S. Adipokines: molecular links between obesity and atheroslcerosis. Am. J. Physiol. Heart Circ. Physiol.,  2005, 288(5), H2031-H2041.
[http://dx.doi.org/10.1152/ajpheart.01058.2004] [PMID:  15653761] 
[185] 
Patel, V.B.; Shah, S.; Verma, S.; Oudit, G.Y. Epicardial adipose tissue as a metabolic transducer: Role in heart failure and coronary artery disease. Heart Fail. Rev.,  2017, 22(6)(Suppl. 2), 889-902.
[http://dx.doi.org/10.1007/s10741-017-9644-1] [PMID:  28762019] 
[186] 
Packer, M. Do Sodium-glucose cotransporter-2 inhibitors prevent heart failure with a preserved ejection fraction by counterbalancing the effects of leptin? A novel hypothesis. Diabetes Obesity & Metabolism,  2018, 20(6), 1361-1366.
[http://dx.doi.org/10.1111/dom.13229] [PMID:  29359851] 
[187] 
Garvey, W.T.; Van Gaal, L.; Leiter, L.A.; Vijapurkar, U.; List, J.; Cuddihy, R.; Ren, J.; Davies, M.J. Effects of canagliflozin versus glimepiride on adipokines and inflammatory biomarkers in type 2 diabetes. Metabolism,  2018, 85, 32-37.
[http://dx.doi.org/10.1016/j.metabol.2018.02.002] [PMID:  29452178] 
[188] 
Sato, T.; Aizawa, Y.; Yuasa, S.; Kishi, S.; Fuse, K.; Fujita, S.; Ikeda, Y.; Kitazawa, H.; Takahashi, M.; Sato, M.; Okabe, M. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc. Diabetol.,  2018, 17(1), 6.
[http://dx.doi.org/10.1186/s12933-017-0658-8] [PMID:  29301516] 
[189] 
Verma, S.; Garg, A.; Yan, A.T.; Gupta, A.K.; Al-Omran, M.; Sabongui, A.; Teoh, H.; Mazer, C.D.; Connelly, K.A. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: An important clue to the EMPA-REG OUTCOME Trial? Diabetes Care,  2016, 39(12), e212-e213.
[http://dx.doi.org/10.2337/dc16-1312] [PMID:  27679584] 
[190] 
Singh, J.S.S.; Fathi, A.; Vickneson, K.; Mordi, I.; Mohan, M.; Houston, J.G.; Pearson, E.R.; Struthers, A.D.; Lang, C.C. Research into the effect Of SGLT2 inhibition on left ventricular remodelling in patients with heart failure and diabetes mellitus (REFORM) trial rationale and design. Cardiovasc. Diabetol.,  2016, 15(1), 97.
[http://dx.doi.org/10.1186/s12933-016-0419-0] [PMID:  27422625] 
[191] 
Januzzi, J.L., Jr; Butler, J.; Jarolim, P.; Sattar, N.; Vijapurkar, U.; Desai, M.; Davies, M.J. Effects of canagliflozin on cardiovascular biomarkers in older adults with type 2 diabetes. J. Am. Coll. Cardiol.,  2017, 70(6), 704-712.
[http://dx.doi.org/10.1016/j.jacc.2017.06.016] [PMID:  28619659] 
[192] 
Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R. CANVAS program collaborative group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med.,  2017, 377(7), 644-657.
[http://dx.doi.org/10.1056/NEJMoa1611925] [PMID:  28605608] 
[193] 
Inzucchi, S.E.; Iliev, H.; Pfarr, E.; Zinman, B. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG OUTCOME Trial. Diabetes Care,  2018, 41(1), e4-e5.
[http://dx.doi.org/10.2337/dc17-1551] [PMID:  29133344] 
[194] 
Verma, S.; Mazer, C.D.; Al-Omran, M.; Inzucchi, S.E.; Fitchett, D.; Hehnke, U.; George, J.T.; Zinman, B. Cardiovascular outcomes and safety of empagliflozin in patients with type 2 diabetes mellitus and peripheral artery disease: A Subanalysis of EMPA-REG OUTCOME. Circulation,  2018, 137(4), 405-407.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032031] 
[195] 
Verma, S.; Bhatt, D.L.; Bain, S.C.; Buse, J.B.; Mann, J.F.E.; Marso, S.P.; Nauck, M.A.; Poulter, N.R.; Pratley, R.E.; Zinman, B.; Michelsen, M.M.; Monk Fries, T.; Rasmussen, S.; Leiter, L.A. LEADER Publication Committee on behalf of the LEADER trial investigators. Effect of liraglutide on cardiovascular events in patients with type 2 diabetes mellitus and polyvascular disease: Results of the LEADER trial. Circulation,  2018, 137(20), 2179-2183.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033898] [PMID:  29760228] 
[196] 
Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Bansilal, S.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Wilding, J.P.; Gause-Nilsson, I.A.; Langkilde, A.M.; Johansson, P.A.; Sabatine, M.S. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am. Heart J.,  2018, 200, 83-89.
[http://dx.doi.org/10.1016/j.ahj.2018.01.012] [PMID:  29898853] 
[197] 
Jardine, M.J.; Mahaffey, K.W.; Neal, B.; Agarwal, R.; Bakris, G.L.; Brenner, B.M.; Bull, S.; Cannon, C.P.; Charytan, D.M.; de Zeeuw, D.; Edwards, R.; Greene, T.; Heerspink, H.J.L.; Levin, A.; Pollock, C.; Wheeler, D.C.; Xie, J.; Zhang, H.; Zinman, B.; Desai, M.; Perkovic, V. CREDENCE study investigators. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am. J. Nephrol.,  2017, 46(6), 462-472.
[http://dx.doi.org/10.1159/000484633] [PMID:  29253846] 
[198] 
Verma, S.; Mazer, C.D.; Fitchett, D.; Inzucchi, S.E.; Pfarr, E.; George, J.T.; Zinman, B. Empagliflozin reduces cardiovascular events, mortality and renal events in participants with type 2 diabetes after coronary artery bypass graft surgery: subanalysis of the EMPA-REG OUTCOME® randomised trial. Diabetologia,  2018, 61(8), 1712-1723.
[http://dx.doi.org/10.1007/s00125-018-4644-9] [PMID:  29777264] 
[199] 
Fitchett, D.; Butler, J.; van de Borne, P.; Zinman, B.; Lachin, J.M.; Wanner, C.; Woerle, H.J.; Hantel, S.; George, J.T.; Johansen, O.E.; Inzucchi, S.E. EMPA-REG OUTCOME® trial investigators. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME® trial. Eur. Heart J.,  2018, 39(5), 363-370.
[http://dx.doi.org/10.1093/eurheartj/ehx511] [PMID:  29020355] 
[200] 
Fitchett, D.; Zinman, B.; Wanner, C.; Lachin, J.M.; Hantel, S.; Salsali, A.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E. EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur. Heart J.,  2016, 37(19), 1526-1534.
[http://dx.doi.org/10.1093/eurheartj/ehv728] [PMID:  26819227] 
[201] 
Radholm, K.; Figtree, G.; Perkovic, V.; Solomon, S.D.; Mahaffey, K.W.; De, Z.D.; Fulcher, G.; Barrett, T.D.; Shaw, W.; Desai, M. Canagliflozin and Heart Failure in Type 2 Diabetes Mellitus: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation,  2018, 138(5), 458-468.
[202] 
Jorsal, A.; Wiggers, H.; McMurray, J.J.V. Heart failure: epidemiology, pathophysiology, and management of heart failure in diabetes mellitus. Endocrinol. Metab. Clin. North Am.,  2018, 47(1), 117-135.
[http://dx.doi.org/10.1016/j.ecl.2017.10.007] [PMID:  29407047] 
[203] 
McMurray, J.J.V.; Gerstein, H.C.; Holman, R.R.; Pfeffer, M.A. Heart failure: A cardiovascular outcome in diabetes that can no longer be ignored. Lancet Diabetes Endocrinol.,  2014, 2(10), 843-851.
[http://dx.doi.org/10.1016/S2213-8587(14)70031-2] [PMID:  24731668] 
[204] 
Seferović, P.M.; Petrie, M.C.; Filippatos, G.S.; Anker, S.D.; Rosano, G.; Bauersachs, J.; Paulus, W.J.; Komajda, M.; Cosentino, F.; Boer, R.A.d. Type 2 diabetes mellitus and heart failure: A position statement from the heart failure association of the european society of cardiology. Eur. J. Heart Fail.,  2018, 20(5), 853-872.
[http://dx.doi.org/10.1002/ejhf.1170] 
[205] 
Greene, S.J.; Vaduganathan, M.; Khan, M.S.; Bakris, G.L.; Weir, M.R.; Seltzer, J.H.; Sattar, N.; McGuire, D.K.; Januzzi, J.L.; Stockbridge, N.; Butler, J. Prevalent and incident heart failure in cardiovascular outcome trials of patients with type 2 diabetes. J. Am. Coll. Cardiol.,  2018, 71(12), 1379-1390.
[http://dx.doi.org/10.1016/j.jacc.2018.01.047] [PMID:  29534825] 
[206] 
Jia, G.; Hill, M.A.; Sowers, J.R. Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ. Res.,  2018, 122(4), 624-638.
[http://dx.doi.org/10.1161/CIRCRESAHA.117.311586] [PMID:  29449364] 
[207] 
Seferović, P.M.; Paulus, W.J. Clinical diabetic cardiomyopathy: A two-faced disease with restrictive and dilated phenotypes. Eur. Heart J.,  2015, 36(27), 1718-1727.1727a-1727c.  [http://dx.doi.org/10.1093/eurheartj/ehv134] [PMID: 25888006]
[208] 
Farkouh, M.E.; Verma, S. Prevention of heart failure with SGLT-2 Inhibition: Insights From CVD-REAL. J. Am. Coll. Cardiol.,  2018, 71(22), 2507-2510.
[http://dx.doi.org/10.1016/j.jacc.2018.02.078] [PMID:  29852974] 
[209] 
Swoboda, P.P.; McDiarmid, A.K.; Erhayiem, B.; Ripley, D.P.; Dobson, L.E.; Garg, P.; Musa, T.A.; Witte, K.K.; Kearney, M.T.; Barth, J.H.; Ajjan, R.; Greenwood, J.P.; Plein, S. Diabetes mellitus, microalbuminuria, and subclinical cardiac disease: Identification and monitoring of individuals at risk of heart failure. J. Am. Heart Assoc.,  2017, 6(7), A25-A25.
[http://dx.doi.org/10.1161/JAHA.117.005539] [PMID:  28716801] 
[210] 
Mahaffey, K.W.; Neal, B.; Perkovic, V.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Fabbrini, E.; Sun, T.; Li, Q.; Desai, M.; Matthews, D.R. CANVAS program collaborative group. Canagliflozin for primary and secondary prevention of cardiovascular events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation,  2018, 137(4), 323-334.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032038] [PMID:  29133604] 
[211] 
Kosiborod, M.; Lam, C.S.P.; Kohsaka, S.; Kim, D.J.; Karasik, A.; Shaw, J.; Tangri, N.; Goh, S.Y.; Thuresson, M.; Chen, H. Lower cardiovascular risk associated with SGLT-2i in >400,000 patients: The CVD-REAL 2 study. J. Am. Coll. Cardiol.,  2018, 71(23), 2628-2639.
[http://dx.doi.org/10.1016/j.jacc.2018.03.009] 
[212] 
Boonman-de Winter, L.J.; Rutten, F.H.; Cramer, M.J.; Landman, M.J.; Liem, A.H.; Rutten, G.E.; Hoes, A.W. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia,  2012, 55(8), 2154-2162.
[http://dx.doi.org/10.1007/s00125-012-2579-0] [PMID:  22618812] 
[213] 
Mozaffarian, D.; Benjamin, E.J.; Go, A.S.; Arnett, D.K.; Blaha, M.J.; Cushman, M.; Das, S.R.; de Ferranti, S.; Després, J.P.; Fullerton, H.J.; Howard, V.J.; Huffman, M.D.; Isasi, C.R.; Jiménez, M.C.; Judd, S.E.; Kissela, B.M.; Lichtman, J.H.; Lisabeth, L.D.; Liu, S.; Mackey, R.H.; Magid, D.J.; McGuire, D.K.; Mohler, E.R., III; Moy, C.S.; Muntner, P.; Mussolino, M.E.; Nasir, K.; Neumar, R.W.; Nichol, G.; Palaniappan, L.; Pandey, D.K.; Reeves, M.J.; Rodriguez, C.J.; Rosamond, W.; Sorlie, P.D.; Stein, J.; Towfighi, A.; Turan, T.N.; Virani, S.S.; Woo, D.; Yeh, R.W.; Turner, M.B. Writing group members American heart association statistics committee stroke statistics subcommittee. heart disease and stroke statistics-2016 Update: A report from the american heart association. Circulation,  2016, 133(4), e38-e360.
[http://dx.doi.org/10.1161/CIR.0000000000000350] [PMID:  26673558] 
[214] 
World Health Organization. Global report on diabetes https://apps.who.int/iris/bitstream/handle/10665/204871/9789241565257_eng.pdf?sequence=1WHO press.  (Accessed 2016)
[215] 
Ray, K.K.; Seshasai, S.R.; Wijesuriya, S.; Sivakumaran, R.; Nethercott, S.; Preiss, D.; Erqou, S.; Sattar, N. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: A meta-analysis of randomised controlled trials. Lancet,  2009, 373(9677), 1765-1772.
[http://dx.doi.org/10.1016/S0140-6736(09)60697-8] [PMID:  19465231] 
[216] 
Rao Kondapally Seshasai, S.; Kaptoge, S.; Thompson, A.; Di Angelantonio, E.; Gao, P.; Sarwar, N.; Whincup, P.H.; Mukamal, K.J.; Gillum, R.F.; Holme, I.; Njølstad, I.; Fletcher, A.; Nilsson, P.; Lewington, S.; Collins, R.; Gudnason, V.; Thompson, S.G.; Sattar, N.; Selvin, E.; Hu, F.B.; Danesh, J. Emerging Risk Factors Collaboration. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N. Engl. J. Med.,  2011, 364(9), 829-841.
[http://dx.doi.org/10.1056/NEJMoa1008862] [PMID:  21366474] 
[217] 
Grundy, S.M.; Benjamin, I.J.; Burke, G.L.; Chait, A.; Eckel, R.H.; Howard, B.V.; Mitch, W.; Smith, S.C., Jr; Sowers, J.R. Diabetes and cardiovascular disease: A statement for healthcare professionals from the American Heart Association. Circulation,  1999, 100(10), 1134-1146.
[http://dx.doi.org/10.1161/01.CIR.100.10.1134] [PMID:  10477542] 
[218] 
Komajda, M.; Tavazzi, L.; Francq, B.G.; Böhm, M.; Borer, J.S.; Ford, I.; Swedberg, K. SHIFT Investigators. Efficacy and safety of ivabradine in patients with chronic systolic heart failure and diabetes: an analysis from the SHIFT trial. Eur. J. Heart Fail.,  2015, 17(12), 1294-1301.
[http://dx.doi.org/10.1002/ejhf.347] [PMID:  26377342] 
[219] 
Fitchett, D.H.; Udell, J.A.; Inzucchi, S.E. Heart failure outcomes in clinical trials of glucose-lowering agents in patients with diabetes. Eur. J. Heart Fail.,  2017, 19(1), 43-53.
[http://dx.doi.org/10.1002/ejhf.633] [PMID:  27653447] 
[220] 
Lloyd-Jones, D.M.; Larson, M.G.; Leip, E.P.; Beiser, A.; D’Agostino, R.B.; Kannel, W.B.; Murabito, J.M.; Vasan, R.S.; Benjamin, E.J.; Levy, D. Framingham heart study. Lifetime risk for developing congestive heart failure: The framingham heart study. Circulation,  2002, 106(24), 3068-3072.
[http://dx.doi.org/10.1161/01.CIR.0000039105.49749.6F] [PMID:  12473553] 
[221] 
Swan, J.W.; Anker, S.D.; Walton, C.; Godsland, I.F.; Clark, A.L.; Leyva, F.; Stevenson, J.C.; Coats, A.J. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J. Am. Coll. Cardiol.,  1997, 30(2), 527-532.
[http://dx.doi.org/10.1016/S0735-1097(97)00185-X] [PMID:  9247528] 
[222] 
Owan, T.E.; Hodge, D.O.; Herges, R.M.; Jacobsen, S.J.; Roger, V.L.; Redfield, M.M. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N. Engl. J. Med.,  2006, 355(3), 251-259.
[http://dx.doi.org/10.1056/NEJMoa052256] [PMID:  16855265] 
[223] 
Zhou, L.; Deng, W.; Zhou, L.; Fang, P.; He, D.; Zhang, W.; Liu, K.; Hu, R. Prevalence, incidence and risk factors of chronic heart failure in the type 2 diabetic population: systematic review. Curr. Diabetes Rev.,  2009, 5(3), 171-184.
[http://dx.doi.org/10.2174/157339909788920938] [PMID:  19689252] 
[224] 
Shah, A.D.; Langenberg, C.; Rapsomaniki, E.; Denaxas, S.; Pujades-Rodriguez, M.; Gale, C.P.; Deanfield, J.; Smeeth, L.; Timmis, A.; Hemingway, H. Type 2 diabetes and incidence of cardiovascular diseases: a cohort study in 1·9 million people. Lancet Diabetes Endocrinol.,  2015, 3(2), 105-113.
[http://dx.doi.org/10.1016/S2213-8587(14)70219-0] [PMID:  25466521] 
[225] 
Udell, J.A.; Cavender, M.A.; Bhatt, D.L.; Chatterjee, S.; Farkouh, M.E.; Scirica, B.M. Glucose-lowering drugs or strategies and cardiovascular outcomes in patients with or at risk for type 2 diabetes: a meta-analysis of randomised controlled trials. Lancet Diabetes Endocrinol.,  2015, 3(5), 356-366.
[http://dx.doi.org/10.1016/S2213-8587(15)00044-3] [PMID:  25791290] 
[226] 
Home, P.D.; Pocock, S.J.; Beck-Nielsen, H.; Curtis, P.S.; Gomis, R.; Hanefeld, M.; Jones, N.P.; Komajda, M.; McMurray, J.J.V. RECORD Study Team. Rosiglitazone evaluated for cardiovascular outcomes in oral agent combination therapy for type 2 diabetes (RECORD): a multicentre, randomised, open-label trial. Lancet,  2009, 373(9681), 2125-2135.
[http://dx.doi.org/10.1016/S0140-6736(09)60953-3] [PMID:  19501900] 
[227] 
Lincoff, A.M.; Wolski, K.; Nicholls, S.J.; Nissen, S.E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA,  2007, 298(10), 1180-1188.
[http://dx.doi.org/10.1001/jama.298.10.1180] [PMID:  17848652] 
[228] 
Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.F.; Coats, A.J.S.; Falk, V.; González-Juanatey, J.R.; Harjola, V.P.; Jankowska, E.A.; Jessup, M.; Linde, C.; Nihoyannopoulos, P.; Parissis, J.T.; Pieske, B.; Riley, J.P.; Rosano, G.M.C.; Ruilope, L.M.; Ruschitzka, F.; Rutten, F.H.; van der Meer, P. ESC Scientific Document Group. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J.,  2016, 37(27), 2129-2200.
[http://dx.doi.org/10.1093/eurheartj/ehw128] [PMID:  27206819] 
[229] 
Scirica, B.M.; Bhatt, D.L.; Braunwald, E.; Steg, P.G.; Davidson, J.; Hirshberg, B.; Ohman, P.; Frederich, R.; Wiviott, S.D.; Hoffman, E.B.; Cavender, M.A.; Udell, J.A.; Desai, N.R.; Mosenzon, O.; McGuire, D.K.; Ray, K.K.; Leiter, L.A.; Raz, I. SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N. Engl. J. Med.,  2013, 369(14), 1317-1326.
[http://dx.doi.org/10.1056/NEJMoa1307684] [PMID:  23992601] 
[230] 
McAlister, F.A.; Eurich, D.T.; Majumdar, S.R.; Johnson, J.A. The risk of heart failure in patients with type 2 diabetes treated with oral agent monotherapy. Eur. J. Heart Fail.,  2008, 10(7), 703-708.
[http://dx.doi.org/10.1016/j.ejheart.2008.05.013] [PMID:  18571471] 
[231] 
Rosenstock, J.; Marx, N.; Kahn, S.E.; Zinman, B.; Kastelein, J.J.; Lachin, J.M.; Bluhmki, E.; Patel, S.; Johansen, O.E.; Woerle, H.J. Cardiovascular outcome trials in type 2 diabetes and the sulphonylurea controversy: rationale for the active-comparator CAROLINA trial. Diab. Vasc. Dis. Res.,  2013, 10(4), 289-301.
[http://dx.doi.org/10.1177/1479164112475102] [PMID:  23449634] 
[232] 
Gerstein, H.C.; Miller, M.E.; Byington, R.P.; Goff, D.C., Jr; Bigger, J.T.; Buse, J.B.; Cushman, W.C.; Genuth, S.; Ismail-Beigi, F.; Grimm, R.H., Jr; Probstfield, J.L.; Simons-Morton, D.G.; Friedewald, W.T. Action to Control Cardiovascular Risk in Diabetes Study Group. Effects of intensive glucose lowering in type 2 diabetes. N. Engl. J. Med.,  2008, 358(24), 2545-2559.
[http://dx.doi.org/10.1056/NEJMoa0802743] [PMID:  18539917] 
[233] 
Group, ALLHAT officers and coordinators for the allhat collaborative research group. the antihypertensive and lipid-lowering treatment to prevent heart attack trial.Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA,  2002, 2981-2997.
[234] 
Dahlöf, B.; Devereux, R.B.; Kjeldsen, S.E.; Julius, S.; Beevers, G.; de Faire, U.; Fyhrquist, F.; Ibsen, H.; Kristiansson, K.; Lederballe-Pedersen, O.; Lindholm, L.H.; Nieminen, M.S.; Omvik, P.; Oparil, S.; Wedel, H. LIFE Study Group. Cardiovascular morbidity and mortality in the losartan intervention for endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet,  2002, 359(9311), 995-1003.
[http://dx.doi.org/10.1016/S0140-6736(02)08089-3] [PMID:  11937178] 
[235] 
Wing, L.M.H.; Reid, C.M.; Ryan, P.; Beilin, L.J.; Brown, M.A.; Jennings, G.L.R.; Johnston, C.I.; McNeil, J.J.; Macdonald, G.J.; Marley, J.E.; Morgan, T.O.; West, M.J. Second australian national blood pressure study group. a comparison of outcomes with angiotensin-converting--enzyme inhibitors and diuretics for hypertension in the elderly. N. Engl. J. Med.,  2003, 348(7), 583-592.
[http://dx.doi.org/10.1056/NEJMoa021716] [PMID:  12584366] 
[236] 
Julius, S.; Kjeldsen, S.E.; Weber, M.; Brunner, H.R.; Ekman, S.; Hansson, L.; Hua, T.; Laragh, J.; McInnes, G.T.; Mitchell, L.; Plat, F.; Schork, A.; Smith, B.; Zanchetti, A. VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet,  2004, 363(9426), 2022-2031.
[http://dx.doi.org/10.1016/S0140-6736(04)16451-9] [PMID:  15207952] 
[237] 
Solomon, S.D.; Wang, D.; Finn, P.; Skali, H.; Zornoff, L.; McMurray, J.J.V.; Swedberg, K.; Yusuf, S.; Granger, C.B.; Michelson, E.L.; Pocock, S.; Pfeffer, M.A. Effect of candesartan on cause-specific mortality in heart failure patients: the Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity (CHARM) program. Circulation,  2004, 110(15), 2180-2183.
[http://dx.doi.org/10.1161/01.CIR.0000144474.65922.AA] [PMID:  15466644] 
[238] 
Zile, M.R.; Gaasch, W.H.; Anand, I.S.; Haass, M.; Little, W.C.; Miller, A.B.; Lopez-Sendon, J.; Teerlink, J.R.; White, M.; McMurray, J.J.; Komajda, M.; McKelvie, R.; Ptaszynska, A.; Hetzel, S.J.; Massie, B.M.; Carson, P.E. I-Preserve Investigators. Mode of death in patients with heart failure and a preserved ejection fraction: results from the irbesartan in heart failure with preserved ejection fraction study (I-Preserve) trial. Circulation,  2010, 121(12), 1393-1405.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.109.909614] [PMID:  20231531] 
[239] 
Ahmed, A.; Rich, M.W.; Fleg, J.L.; Zile, M.R.; Young, J.B.; Kitzman, D.W.; Love, T.E.; Aronow, W.S.; Adams, K.F., Jr; Gheorghiade, M. Effects of digoxin on morbidity and mortality in diastolic heart failure: The ancillary digitalis investigation group trial. Circulation,  2006, 114(5), 397-403.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.106.628347] [PMID:  16864724] 
[240] 
Cleland, J.G.F.; Tendera, M.; Adamus, J.; Freemantle, N.; Polonski, L.; Taylor, J. PEP-CHF Investigators. The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur. Heart J.,  2006, 27(19), 2338-2345.
[http://dx.doi.org/10.1093/eurheartj/ehl250] [PMID:  16963472] 
[241] 
Pitt, B.; Pfeffer, M.A.; Assmann, S.F.; Boineau, R.; Anand, I.S.; Claggett, B.; Clausell, N.; Desai, A.S.; Diaz, R.; Fleg, J.L.; Gordeev, I.; Harty, B.; Heitner, J.F.; Kenwood, C.T.; Lewis, E.F.; O’Meara, E.; Probstfield, J.L.; Shaburishvili, T.; Shah, S.J.; Solomon, S.D.; Sweitzer, N.K.; Yang, S.; McKinlay, S.M. TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N. Engl. J. Med.,  2014, 370(15), 1383-1392.
[http://dx.doi.org/10.1056/NEJMoa1313731] [PMID:  24716680] 
[242] 
McMurray, J.J.V.; Ostergren, J.; Swedberg, K.; Granger, C.B.; Held, P.; Michelson, E.L.; Olofsson, B.; Yusuf, S.; Pfeffer, M.A. CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet,  2003, 362(9386), 767-771.
[http://dx.doi.org/10.1016/S0140-6736(03)14283-3] [PMID:  13678869] 
[243] 
McMurray, J.J.V.; Packer, M.; Desai, A.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.L.; Shi, V.C.; Solomon, S.D.; Swedberg, K.; Zile, M.R. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med.,  2014, 371(11), 993-1004.
[http://dx.doi.org/10.1056/NEJMoa1409077] [PMID:  25176015] 
[244] 
Fang, J.C. Heart failure with preserved ejection fraction: A kidney disorder? Circulation,  2016, 134(6), 435-437.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.022249] [PMID:  27502906] 
[245] 
Abdul-Ghani, M.; Del Prato, S.; Chilton, R.; DeFronzo, R.A. SGLT2 inhibitors and cardiovascular risk: Lessons learned from the EMPA-REG OUTCOME study. Diabetes Care,  2016, 39(5), 717-725.
[http://dx.doi.org/10.2337/dc16-0041] [PMID:  27208375] 
[246] 
Marso, S.P.; Bain, S.C.; Consoli, A.; Eliaschewitz, F.G.; Jódar, E.; Leiter, L.A.; Lingvay, I.; Rosenstock, J.; Seufert, J.; Warren, M.L.; Woo, V.; Hansen, O.; Holst, A.G.; Pettersson, J.; Vilsbøll, T. SUSTAIN-6 investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N. Engl. J. Med.,  2016, 375(19), 1834-1844.
[http://dx.doi.org/10.1056/NEJMoa1607141] [PMID:  27633186] 
[247] 
Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; Steinberg, W.M.; Stockner, M.; Zinman, B.; Bergenstal, R.M.; Buse, J.B. LEADER steering committee LEADER trial investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med.,  2016, 375(4), 311-322.
[http://dx.doi.org/10.1056/NEJMoa1603827] [PMID:  27295427] 
[248] 
Jorsal, A.; Kistorp, C.; Holmager, P.; Tougaard, R.S.; Nielsen, R.; Hänselmann, A.; Nilsson, B.; Møller, J.E.; Hjort, J.; Rasmussen, J.; Boesgaard, T.W.; Schou, M.; Videbaek, L.; Gustafsson, I.; Flyvbjerg, A.; Wiggers, H.; Tarnow, L. Effect of liraglutide, a glucagon-like peptide-1 analogue, on left ventricular function in stable chronic heart failure patients with and without diabetes (LIVE) - a multicentre, double-blind, randomised, placebo-controlled trial. Eur. J. Heart Fail.,  2017, 19(1), 69-77.
[http://dx.doi.org/10.1002/ejhf.657] [PMID:  27790809] 
[249] 
Heerspink, H.J.; Perkins, B.A.; Fitchett, D.H.; Husain, M.; Cherney, D.Z. 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.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021887] [PMID:  27470878] 
[250] 
Nauck, M.A. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des. Devel. Ther.,  2014, 2014, 1335.
[http://dx.doi.org/10.2147/DDDT.S50773] 
[251] 
Rosengren, A.; Åberg, M.; Robertson, J.; Waern, M.; Schaufelberger, M.; Kuhn, G.; Åberg, D.; Schiöler, L.; Torén, K. Body weight in adolescence and long-term risk of early heart failure in adulthood among men in Sweden. Eur. Heart J.,  2017, 38(24), 1926-1933.
[PMID:  27311731] 
[252] 
Wing, R.R.; Bolin, P.; Brancati, F.L.; Bray, G.A.; Clark, J.M.; Coday, M.; Crow, R.S.; Curtis, J.M.; Egan, C.M.; Espeland, M.A.; Evans, M.; Foreyt, J.P.; Ghazarian, S.; Gregg, E.W.; Harrison, B.; Hazuda, H.P.; Hill, J.O.; Horton, E.S.; Hubbard, V.S.; Jakicic, J.M.; Jeffery, R.W.; Johnson, K.C.; Kahn, S.E.; Kitabchi, A.E.; Knowler, W.C.; Lewis, C.E.; Maschak-Carey, B.J.; Montez, M.G.; Murillo, A.; Nathan, D.M.; Patricio, J.; Peters, A.; Pi-Sunyer, X.; Pownall, H.; Reboussin, D.; Regensteiner, J.G.; Rickman, A.D.; Ryan, D.H.; Safford, M.; Wadden, T.A.; Wagenknecht, L.E.; West, D.S.; Williamson, D.F.; Yanovski, S.Z. Look AHEAD Research Group. Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes. N. Engl. J. Med.,  2013, 369(2), 145-154.
[http://dx.doi.org/10.1056/NEJMoa1212914] [PMID:  23796131] 
[253] 
Shin, S.J.; Chung, S.; Kim, S.J.; Lee, E-M.; Yoo, Y-H.; Kim, J-W.; Ahn, Y-B.; Kim, E-S.; Moon, S-D.; Kim, M-J.; Ko, S.H. Effect of sodium-glucose co-transporter 2 inhibitor, dapagliflozin, on renal renin-angiotensin system in an animal model of type 2 diabetes. PLoS One,  2016, 11(11) e0165703
[http://dx.doi.org/10.1371/journal.pone.0165703] [PMID:  27802313] 
[254] 
Cherney, D.Z.I.; Perkins, B.A.; Soleymanlou, N.; Maione, M.; Lai, V.; Lee, A.; Fagan, N.M.; Woerle, H.J.; Johansen, O.E.; Broedl, U.C.; von Eynatten, M. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation,  2014, 129(5), 587-597.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.005081] [PMID:  24334175] 
[255] 
Vallon, V.; Gerasimova, M.; Rose, M.A.; Masuda, T.; Satriano, J.; Mayoux, E.; Koepsell, H.; Thomson, S.C.; Rieg, T. 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-F204.
[http://dx.doi.org/10.1152/ajprenal.00520.2013] [PMID:  24226524] 
[256] 
Panchapakesan, U.; Pegg, K.; Gross, S.; Komala, M.G.; Mudaliar, H.; Forbes, J.; Pollock, C.; Mather, A. Effects of SGLT2 inhibition in human kidney proximal tubular cells--renoprotection in diabetic nephropathy? PLoS One,  2013, 8(2) e54442
[http://dx.doi.org/10.1371/journal.pone.0054442] [PMID:  23390498] 
[257] 
Chang, Y.K.; Choi, H.; Jeong, J.Y.; Na, K.R.; Lee, K.W.; Lim, B.J.; Choi, D.E. Dapagliflozin, SGLT2 Inhibitor, Attenuates Renal Ischemia-Reperfusion Injury. PLoS One,  2016, 11(7) e0158810
[http://dx.doi.org/10.1371/journal.pone.0158810] [PMID:  27391020] 
[258] 
Hershon, K.S. Options for empagliflozin in combination therapy in type 2 diabetes mellitus. Int. J. Gen. Med.,  2016, 9, 155-172.
[PMID:  27307761] 
[259] 
de Boer, I.H.; Kahn, S.E. SGLT2 Inhibitors-sweet success for diabetic kidney disease? J. Am. Soc. Nephrol.,  2017, 28(1), 7-10.
[http://dx.doi.org/10.1681/ASN.2016060650] [PMID:  27539605] 
[260] 
Merovci, A.; Solis-Herrera, C.; Daniele, G.; Eldor, R.; Fiorentino, T.V.; Tripathy, D.; Xiong, J.; Perez, Z.; Norton, L.; Abdul-Ghani, M.A.; DeFronzo, R.A. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production. J. Clin. Invest.,  2014, 124(2), 509-514.
[http://dx.doi.org/10.1172/JCI70704] [PMID:  24463448] 
[261] 
Inagaki, N.; Kondo, K.; Yoshinari, T.; Takahashi, N.; Susuta, Y.; Kuki, H. Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, Phase III study. Expert Opin. Pharmacother.,  2014, 15(11), 1501-1515.
[http://dx.doi.org/10.1517/14656566.2014.935764] [PMID:  25010793] 
[262] 
Pogwizd, S.M.; Sipido, K.R.; Verdonck, F.; Bers, D.M. Intracellular Na in animal models of hypertrophy and heart failure: contractile function and arrhythmogenesis. Cardiovasc. Res.,  2003, 57(4), 887-896.
[http://dx.doi.org/10.1016/S0008-6363(02)00735-6] [PMID:  12650867] 
[263] 
Liu, T.; O’Rourke, B. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ. Res.,  2008, 103(3), 279-288.
[http://dx.doi.org/10.1161/CIRCRESAHA.108.175919] [PMID:  18599868] 
[264] 
Hamouda, N.N.; Sydorenko, V.; Qureshi, M.A.; Alkaabi, J.M.; Oz, M.; Howarth, F.C. Dapagliflozin reduces the amplitude of shortening and Ca(2+) transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol. Cell. Biochem.,  2015, 400(1-2), 57-68.
[http://dx.doi.org/10.1007/s11010-014-2262-5] [PMID:  25351341] 
[265] 
Di Franco, A.; Cantini, G.; Tani, A.; Coppini, R.; Zecchi-Orlandini, S.; Raimondi, L.; Luconi, M.; Mannucci, E. Sodium-dependent glucose transporters (SGLT) in human ischemic heart: A new potential pharmacological target. Int. J. Cardiol.,  2017, 243, 86-90.
[http://dx.doi.org/10.1016/j.ijcard.2017.05.032] [PMID:  28526540] 
[266] 
Vrhovac, I.; Balen Eror, D.; Klessen, D.; Burger, C.; Breljak, D.; Kraus, O.; Radović, N.; Jadrijević, S.; Aleksic, I.; Walles, T.; Sauvant, C.; Sabolić, I.; Koepsell, H. Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch.,  2015, 467(9), 1881-1898.
[http://dx.doi.org/10.1007/s00424-014-1619-7] [PMID:  25304002] 
[267] 
Liu, T.; Takimoto, E.; Dimaano, V.L.; DeMazumder, D.; Kettlewell, S.; Smith, G.; Sidor, A.; Abraham, T.P.; O’Rourke, B. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ. Res.,  2014, 115(1), 44-54.
[http://dx.doi.org/10.1161/CIRCRESAHA.115.303062] [PMID:  24780171] 
[268] 
Cavender, M.A.; Norhammar, A.; Birkeland, K.I.; Jørgensen, M.E.; Wilding, J.P.; Khunti, K.; Fu, A.Z.; Bodegård, J.; Blak, B.T.; Wittbrodt, E.; Thuresson, M.; Fenici, P.; Hammar, N.; Kosiborod, M. CVD-REAL Investigators and study group. sglt-2 inhibitors and cardiovascular risk: An analysis of CVD-REAL. J. Am. Coll. Cardiol.,  2018, 71(22), 2497-2506.
[http://dx.doi.org/10.1016/j.jacc.2018.01.085] [PMID:  29852973] 
[269] 
Lee, T.M.; Lin, S.Z.; Chang, N.C. Antiarrhythmic effect of lithium in rats after myocardial infarction by activation of Nrf2/HO-1 signaling. Free Radic. Biol. Med.,  2014, 77, 71-81.
[http://dx.doi.org/10.1016/j.freeradbiomed.2014.08.022] [PMID:  25224036] 
[270] 
Lee, T.M.; Lai, P.Y.; Chang, N.C. Effect of N-acetylcysteine on sympathetic hyperinnervation in post-infarcted rat hearts. Cardiovasc. Res.,  2010, 85(1), 137-146.
[http://dx.doi.org/10.1093/cvr/cvp286] [PMID:  19696069] 
[271] 
Hofmann, U.; Knorr, S.; Vogel, B.; Weirather, J.; Frey, A.; Ertl, G.; Frantz, S. Interleukin-13 deficiency aggravates healing and remodeling in male mice after experimental myocardial infarction. Circ Heart Fail,  2014, 7(5), 822-830.
[http://dx.doi.org/10.1161/CIRCHEARTFAILURE.113.001020] [PMID:  24970469] 
[272] 
Jacoby, J.J.; Kalinowski, A.; Liu, M.G.; Zhang, S.S.; Gao, Q.; Chai, G.X.; Ji, L.; Iwamoto, Y.; Li, E.; Schneider, M.; Russell, K.S.; Fu, X.Y. Cardiomyocyte-restricted knockout of STAT3 results in higher sensitivity to inflammation, cardiac fibrosis, and heart failure with advanced age. Proc. Natl. Acad. Sci. USA,  2003, 100(22), 12929-12934.
[http://dx.doi.org/10.1073/pnas.2134694100] [PMID:  14566054] 
[273] 
Chao, E.C.; Henry, R.R. SGLT2 inhibition--a novel strategy for diabetes treatment. Nat. Rev. Drug Discov.,  2010, 9(7), 551-559.
[http://dx.doi.org/10.1038/nrd3180] [PMID:  20508640] 
[274] 
Kashiwagi, Y.; Nagoshi, T.; Yoshino, T.; Tanaka, T.D.; Ito, K.; Harada, T.; Takahashi, H.; Ikegami, M.; Anzawa, R.; Yoshimura, M. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS One,  2015, 10(6)e0130605
[http://dx.doi.org/10.1371/journal.pone.0130605] [PMID:  26121582] 
[275] 
Balteau, M.; Tajeddine, N.; de Meester, C.; Ginion, A.; Des Rosiers, C.; Brady, N.R.; Sommereyns, C.; Horman, S.; Vanoverschelde, J.L.; Gailly, P.; Hue, L.; Bertrand, L.; Beauloye, C. NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1. Cardiovasc. Res.,  2011, 92(2), 237-246.
[http://dx.doi.org/10.1093/cvr/cvr230] [PMID:  21859816] 
[276] 
Banerjee, S.K.; McGaffin, K.R.; Pastor-Soler, N.M.; Ahmad, F. SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc. Res.,  2009, 84(1), 111-118.
[http://dx.doi.org/10.1093/cvr/cvp190] [PMID:  19509029] 
[277] 
Ikari, A.; Nagatani, Y.; Tsukimoto, M.; Harada, H.; Miwa, M.; Takagi, K. Sodium-dependent glucose transporter reduces peroxynitrite and cell injury caused by cisplatin in renal tubular epithelial cells. Biochim. Biophys. Acta,  2005, 1717(2), 109-117.
[http://dx.doi.org/10.1016/j.bbamem.2005.10.003] [PMID:  16288972] 
[278] 
Lee, T.M.; Chang, N.C.; Lin, S.Z. Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic. Biol. Med.,  2017, 104, 298-310.
[http://dx.doi.org/10.1016/j.freeradbiomed.2017.01.035] [PMID:  28132924] 
[279] 
Tong, P.C.; Kong, A.P.; So, W.Y.; Ng, M.H.; Yang, X.; Ng, M.C.; Ma, R.C.; Ho, C.S.; Lam, C.W.; Chow, C.C.; Cockram, C.S.; Chan, J.C. Hematocrit, independent of chronic kidney disease, predicts adverse cardiovascular outcomes in chinese patients with type 2 diabetes. Diabetes Care,  2006, 29(11), 2439-2444.
[http://dx.doi.org/10.2337/dc06-0887] [PMID:  17065681] 
[280] 
Kim, E.J.; Choi, M.J.; Lee, J.H.; Oh, J.E.; Seo, J.W.; Lee, Y.K.; Yoon, J.W.; Kim, H.J.; Noh, J.W.; Koo, J.R. Extracellular fluid/intracellular fluid volume ratio as a novel risk indicator for all-cause mortality and cardiovascular disease in hemodialysis patients. PLoS One,  2017, 12(1) e0170272
[http://dx.doi.org/10.1371/journal.pone.0170272] [PMID:  28099511] 
[281] 
Hasselblad, V.; Gattis Stough, W.; Shah, M.R.; Lokhnygina, Y.; O’Connor, C.M.; Califf, R.M.; Adams, K.F., Jr Relation between dose of loop diuretics and outcomes in a heart failure population: results of the ESCAPE trial. Eur. J. Heart Fail.,  2007, 9(10), 1064-1069.
[http://dx.doi.org/10.1016/j.ejheart.2007.07.011] [PMID:  17719273] 
[282] 
Asada, N.; Takase, M.; Nakamura, J.; Oguchi, A.; Asada, M.; Suzuki, N.; Yamamura, K.; Nagoshi, N.; Shibata, S.; Rao, T.N.; Fehling, H.J.; Fukatsu, A.; Minegishi, N.; Kita, T.; Kimura, T.; Okano, H.; Yamamoto, M.; Yanagita, M. Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice. J. Clin. Invest.,  2011, 121(10), 3981-3990.
[http://dx.doi.org/10.1172/JCI57301] [PMID:  21911936] 
[283] 
Lin, K.C.; Lin, H.Y.; Chou, P. The interaction between uric acid level and other risk factors on the development of gout among asymptomatic hyperuricemic men in a prospective study. J. Rheumatol.,  2000, 27(6), 1501-1505.
[PMID:  10852278] 
[284] 
Talbott, J.H.; Terplan, K.L. The kidney in gout. Medicine (Baltimore),  1960, 39(4), 405-467.
[http://dx.doi.org/10.1097/00005792-196012000-00001] [PMID:  13775026] 
[285] 
Tomita, M.; Mizuno, S.; Yamanaka, H.; Hosoda, Y.; Sakuma, K.; Matuoka, Y.; Odaka, M.; Yamaguchi, M.; Yosida, H.; Morisawa, H.; Murayama, T. Does hyperuricemia affect mortality? A prospective cohort study of Japanese male workers. J. Epidemiol.,  2000, 10(6), 403-409.
[http://dx.doi.org/10.2188/jea.10.403] [PMID:  11210110] 
[286] 
Alper, A.B., Jr; Chen, W.; Yau, L.; Srinivasan, S.R.; Berenson, G.S.L.; Hamm, L.L. Childhood uric acid predicts adult blood pressure: the Bogalusa Heart Study. Hypertension,  2005, 45(1), 34-38.
[http://dx.doi.org/10.1161/01.HYP.0000150783.79172.bb] [PMID:  15569853] 
[287] 
Dehghan, A.; van Hoek, M.; Sijbrands, E.J.; Hofman, A.; Witteman, J.C. High serum uric acid as a novel risk factor for type 2 diabetes. Diabetes Care,  2008, 31(2), 361-362.
[http://dx.doi.org/10.2337/dc07-1276] [PMID:  17977935] 
[288] 
Niskanen, L.; Laaksonen, D.E.; Lindström, J.; Eriksson, J.G.; Keinänen-Kiukaanniemi, S.; Ilanne-Parikka, P.; Aunola, S.; Hämäläinen, H.; Tuomilehto, J.; Uusitupa, M. Serum uric acid as a harbinger of metabolic outcome in subjects with impaired glucose tolerance: The finnish diabetes prevention study. Diabetes Care,  2006, 29(3), 709-711.
[http://dx.doi.org/10.2337/diacare.29.03.06.dc05-1465] [PMID:  16505534] 
[289] 
Bailey, C.J.; Gross, J.L.; Pieters, A.; Bastien, A.; List, J.F. Effect of dapagliflozin in patients with type 2 diabetes who have inadequate glycaemic control with metformin: A randomised, double-blind, placebo-controlled trial. Lancet,  2010, 375(9733), 2223-2233.
[http://dx.doi.org/10.1016/S0140-6736(10)60407-2] [PMID:  20609968] 
[290] 
Cefalu, W.T.; Leiter, L.A.; Yoon, K.H.; Arias, P.; Niskanen, L.; Xie, J.; Balis, D.A.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet,  2013, 382(9896), 941-950.
[http://dx.doi.org/10.1016/S0140-6736(13)60683-2] [PMID:  23850055] 
[291] 
Wilding, J.P.; Ferrannini, E.; Fonseca, V.A.; Wilpshaar, W.; Dhanjal, P.; Houzer, A. Efficacy and safety of ipragliflozin in patients with type 2 diabetes inadequately controlled on metformin: a dose-finding study. Diabetes Obes. Metab.,  2013, 15(5), 403-409.
[http://dx.doi.org/10.1111/dom.12038] [PMID:  23163880] 
[292] 
Ferrannini, E.; Seman, L.; Seewaldt-Becker, E.; Hantel, S.; Pinnetti, S.; Woerle, H.J. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes. Metab.,  2013, 15(8), 721-728.
[http://dx.doi.org/10.1111/dom.12081] [PMID:  23398530] 
[293] 
Choi, H.K.; Ford, E.S. Haemoglobin A1c, fasting glucose, serum C-peptide and insulin resistance in relation to serum uric acid levels--the Third National Health and Nutrition Examination Survey. Rheumatology (Oxford),  2008, 47(5), 713-717.
[http://dx.doi.org/10.1093/rheumatology/ken066] [PMID:  18390895] 
[294] 
Galvan, A. Qui?Ones; Natali, A.; Baldi, S.; Frascerra, S.; Sanna, G.; Ciociaro, D.; Ferrannini, E. Effect of insulin on uric acid excretion in humans. Am. J. Physiol.,  1995, 268(1), 1-5.
[295] 
Skeith, M.D.; Healey, L.A.; Cutler, R.E. Effect of phloridzin on uric acid excretion in man. Am. J. Physiol.,  1970, 219(4), 1080-1082.
[http://dx.doi.org/10.1152/ajplegacy.1970.219.4.1080] [PMID:  5459472] 
[296] 
González-Sicilia, L.; García-Estañ, J.; Martínez-Blázquez, A.; Fernández-Pardo, J.; Quiles, J.L.; Hernández, J. Renal metabolism of uric acid in type I insulin-dependent diabetic patients: Relation to metabolic compensation. Horm. Metab. Res.,  1997, 29(10), 520-523.
[http://dx.doi.org/10.1055/s-2007-979093] [PMID:  9405981] 
[297] 
Herman, J.B.; Medalie, J.H.; Goldbourt, U. Diabetes, prediabetes and uricaemia. Diabetologia,  1976, 12(1), 47-52.
[http://dx.doi.org/10.1007/BF01221964] [PMID:  1254115] 
[298] 
Chino, Y.; Samukawa, Y.; Sakai, S.; Nakai, Y.; Yamaguchi, J.; Nakanishi, T.; Tamai, I. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm. Drug Dispos.,  2014, 35(7), 391-404.
[http://dx.doi.org/10.1002/bdd.1909] [PMID:  25044127] 
[299] 
Verbrugge, F.H.; Dupont, M.; Steels, P.; Grieten, L.; Swennen, Q.; Tang, W.H.W.; Mullens, W. The kidney in congestive heart failure: ‘are natriuresis, sodium, and diuretics really the good, the bad and the ugly?’. Eur. J. Heart Fail.,  2014, 16(2), 133-142.
[http://dx.doi.org/10.1002/ejhf.35] [PMID:  24464967] 
[300] 
Verbrugge, F.H.; Vangoitsenhoven, R.; Mullens, W.; Schueren, B.V.D.; Mathieu, C.; Tang, W.H.W. SGLT-2 Inhibitors: Potential novel strategy to prevent congestive heart failure in diabetes? Curr. Cardiovasc. Risk Rep.,  2015, 9(8), 38.
[http://dx.doi.org/10.1007/s12170-015-0467-0] 
[301] 
Bautista, R.; Manning, R.; Martinez, F. Avila-Casado, Mdel.C.; Soto, V.; Medina, A.; Escalante, B. Angiotensin II-dependent increased expression of Na+-glucose cotransporter in hypertension. Am. J. Physiol. Renal Physiol.,  2004, 286(1), F127-F133.
[http://dx.doi.org/10.1152/ajprenal.00113.2003] [PMID:  14506074] 
[302] 
Vasilakou, D.; Karagiannis, T.; Athanasiadou, E.; Mainou, M.; Liakos, A.; Bekiari, E.; Sarigianni, M.; Matthews, D.R.; Tsapas, A. Sodium-glucose cotransporter 2 inhibitors for type 2 diabetes: a systematic review and meta-analysis. Ann. Intern. Med.,  2013, 159(4), 262-274.
[http://dx.doi.org/10.7326/0003-4819-159-4-201308200-00007] [PMID:  24026259] 
[303] 
Layton, A.T.; Vallon, V.; Edwards, A. Modeling oxygen consumption in the proximal tubule: effects of NHE and SGLT2 inhibition. Am. J. Physiol. Renal Physiol.,  2015, 308(12), F1343-F1357.
[http://dx.doi.org/10.1152/ajprenal.00007.2015] [PMID:  25855513] 
[304] 
Vlachopoulos, C.; Aznaouridis, K.; Stefanadis, C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J. Am. Coll. Cardiol.,  2010, 55(13), 1318-1327.
[http://dx.doi.org/10.1016/j.jacc.2009.10.061] [PMID:  20338492] 
[305] 
Turner, R.; Holman, R.; Matthews, D.; Bassett, P.; Coster, R.; Stratton, I. CULL, C.; Peto, R.; Frighi, V.; Kennedy, I., Hypertension in diabetes study (HDS). 1. Prevalence of hypertension in newly presenting Type-2 diabetic-patients and the association with risk-factors for cardiovascular and diabetic complications. J. Hypertens.,  1993, 11(3), 309-317.
[http://dx.doi.org/10.1097/00004872-199303000-00012] [PMID:  8387089] 
[306] 
Bellien, J.; Favre, J.; Iacob, M.; Gao, J.; Thuillez, C.; Richard, V.; Joannidès, R. Arterial stiffness is regulated by nitric oxide and endothelium-derived hyperpolarizing factor during changes in blood flow in humans. Hypertension,  2010, 55(3), 674-680.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.142190] [PMID:  20083732] 
[307] 
Sasson, A.N.; Cherney, D.Z. Renal hyperfiltration related to diabetes mellitus and obesity in human disease. World J. Diabetes,  2012, 3(1), 1-6.
[http://dx.doi.org/10.4239/wjd.v3.i1.1] [PMID:  22253940] 
[308] 
Manolis, A.J.; Iraklianou, S.; Pittaras, A.; Zaris, M.; Tsioufis, K.; Psaltiras, G.; Psomali, D.; Foussas, S.; Gavras, I.; Gavras, H. Arterial compliance changes in diabetic normotensive patients after angiotensin-converting enzyme inhibition therapy. Am. J. Hypertens.,  2005, 18(1), 18-22.
[http://dx.doi.org/10.1016/j.amjhyper.2004.08.014] [PMID:  15691612] 
[309] 
Kim, S.G.; Ryu, O.H.; Kim, H.Y.; Lee, K.W.; Seo, J.A.; Kim, N.H.; Choi, K.M.; Lee, J.; Baik, S.H.; Choi, D.S. Effect of rosiglitazone on plasma adiponectin levels and arterial stiffness in subjects with prediabetes or non-diabetic metabolic syndrome. Eur. J. Endocrinol.,  2006, 154(3), 433-440.
[http://dx.doi.org/10.1530/eje.1.02100] [PMID:  16498057] 
[310] 
Sims, H.; Smith, K.H.; Bramlage, P.; Minguet, J. Sotagliflozin: a dual sodium-glucose co-transporter-1 and -2 inhibitor for the management of Type 1 and Type 2 diabetes mellitus. Diabet. Med.,  2018, 35(8), 1037-1048.
[http://dx.doi.org/10.1111/dme.13645] [PMID:  29637608] 
[311] 
List, J.F.; Whaley, J.M. Glucose dynamics and mechanistic implications of SGLT2 inhibitors in animals and humans. Kidney Int. Suppl.,  2011, 79(120), S20-S27.
[http://dx.doi.org/10.1038/ki.2010.512] [PMID:  21358698] 
[312] 
Wilkinson, I.B.; McEniery, C.M. Arterial stiffness, endothelial function and novel pharmacological approaches. Clin. Exp. Pharmacol. Physiol.,  2004, 31(11), 795-799.
[http://dx.doi.org/10.1111/j.1440-1681.2004.04074.x] [PMID:  15566396] 
[313] 
Cherney, D.Z.; Perkins, B.A.; Soleymanlou, N.; Har, R.; Fagan, N.; Johansen, O.E.; Woerle, H.J.; von Eynatten, M.; Broedl, U.C. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc. Diabetol.,  2014, 13(1), 28.
[http://dx.doi.org/10.1186/1475-2840-13-28] [PMID:  24475922] 
[314] 
Cooper, J.N.; Buchanich, J.M.; Youk, A.; Brooks, M.M.; Barinas-Mitchell, E.; Conroy, M.B.; Sutton-Tyrrell, K. Reductions in arterial stiffness with weight loss in overweight and obese young adults: potential mechanisms. Atherosclerosis,  2012, 223(2), 485-490.
[http://dx.doi.org/10.1016/j.atherosclerosis.2012.05.022] [PMID:  22703865] 
[315] 
Hughes, T.M.; Althouse, A.D.; Niemczyk, N.A.; Hawkins, M.S.; Kuipers, A.L.; Sutton-Tyrrell, K. Effects of weight loss and insulin reduction on arterial stiffness in the SAVE trial. Cardiovasc. Diabetol.,  2012, 11(1), 114-114.
[http://dx.doi.org/10.1186/1475-2840-11-114] [PMID:  22998737] 
[316] 
Mackenzie, I.S.; McEniery, C.M.; Dhakam, Z.; Brown, M.J.; Cockcroft, J.R.; Wilkinson, I.B. Comparison of the effects of antihypertensive agents on central blood pressure and arterial stiffness in isolated systolic hypertension. Hypertension,  2009, 54(2), 409-413.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.109.133801] [PMID:  19487582] 
Cite As
Current Topics in Medicinal Chemistry

Mechanisms of Protective Effects of SGLT2 Inhibitors in Cardiovascular Disease and Renal Dysfunction

Abstract

Graphical Abstract
