The Beneficial Hemodynamic Actions of SGLT-2 Inhibitors beyond the Management of Hyperglycemia

Charalampos       Loutradis; Eirini       Papadopoulou; Elena       Angeloudi; Asterios       Karagiannis; Pantelis       Sarafidis
Abstract

Type 2 diabetes mellitus (DM) is a public health burden and its co-existence with hypertension is long established in the context of the metabolic syndrome. Both DM and hypertension are major risk factors, for end-stage renal disease, cardiovascular events and mortality. Strict blood pressure (BP) control in diabetics has been associated with a cardiovascular and renal risk decrease. Inhibitors of the sodium-glucose co-transporter 2 (SGLT-2) in the proximal tubule is a relatively novel class of agents for the treatment of type 2 DM. Inhibition of SGLT-2 co-transporter combines proximal tubule diuretic and osmotic diuretic action leading to glucose reabsorption reduction and mild natriuretic and diuretic effects. On this basis, several studies showed that treatment with SGLT-2 inhibitors can effectively decrease hyperglycemia but also increase BP control and reduce renal outcomes and cardiovascular mortality. Based on such evidence, the recent guidelines for the management of type 2 DM now suggest that SGLT-2 inhibitors should be preferred among oral agents in combination with metformin, in patients at increased cardiovascular risk, chronic kidney disease or heart failure. This review summarizes the existing data from studies evaluating the effect of SGLT-2 inhibitors on BP, and its potential value for cardio- and nephroprotection.
Keywords: Blood pressure, SGLT-2 inhibitors, empagliflozin, canagliflozin, dapagliflozin, Diabetes mellitus (DM).
[1] 
Bullard, K.M.; Cowie, C.C.; Lessem, S.E.; Saydah, S.H.; Menke, A.; Geiss, L.S.; Orchard, T.J.; Rolka, D.B.; Imperatore, G. Prevalence of diagnosed diabetes in adults by diabetes type - United States, 2016. MMWR Morb. Mortal. Wkly. Rep.,  2018, 67(12), 359-361.
[http://dx.doi.org/10.15585/mmwr.mm6712a2] [PMID: 29596402] 
[2] 
Shaw, J.E.; Sicree, R.A.; Zimmet, P.Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract.,  2010, 87(1), 4-14.
[http://dx.doi.org/10.1016/j.diabres.2009.10.007] [PMID: 19896746] 
[3] 
Ogurtsova, K.; da Rocha Fernandes, J.D.; Huang, Y.; Linnenkamp, U.; Guariguata, L.; Cho, N.H.; Cavan, D.; Shaw, J.E.; Makaroff, L.E. IDF Diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res. Clin. Pract.,  2017, 128, 40-50.
[http://dx.doi.org/10.1016/j.diabres.2017.03.024] [PMID: 28437734] 
[4] 
Martín-Timón, I.; Sevillano-Collantes, C.; Segura-Galindo, A.; Del Cañizo-Gómez, F.J. Type 2 diabetes and cardiovascular disease: Have all risk factors the same strength? World J. Diabetes,  2014, 5(4), 444-470.
[http://dx.doi.org/10.4239/wjd.v5.i4.444] [PMID: 25126392] 
[5] 
Papadopoulou, E.; Angeloudi, E.; Karras, S.; Sarafidis, P. The optimal blood pressure target in diabetes mellitus: a quest coming to an end? J. Hum. Hypertens.,  2018, 32(10), 641-650.
[http://dx.doi.org/10.1038/s41371-018-0079-5] [PMID: 29934621] 
[6] 
IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: Estimates for the year 2013. Diabetes Res. Clin. Pract.,  2015, 109(3), 461-465.
[http://dx.doi.org/10.1016/j.diabres.2015.05.037] [PMID: 26119773] 
[7] 
Sarwar, N.; Gao, P.; Seshasai, S.R.; Gobin, R.; Kaptoge, S.; Di Angelantonio, E.; Ingelsson, E.; Lawlor, D.A.; Selvin, E.; Stampfer, M.; Stehouwer, C.D.; Lewington, S.; Pennells, L.; Thompson, A.; Sattar, N.; White, I.R.; Ray, K.K.; Danesh, J. Emerging risk factors collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet,  2010, 375(9733), 2215-2222.
[http://dx.doi.org/10.1016/S0140-6736(10)60484-9] [PMID: 20609967] 
[8] 
Stamler, J.; Vaccaro, O.; Neaton, J.D.; Wentworth, D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care,  1993, 16(2), 434-444.
[http://dx.doi.org/10.2337/diacare.16.2.434] [PMID: 8432214] 
[9] 
Mancia, G.; Fagard, R.; Narkiewicz, K.; Redon, J.; Zanchetti, A.; Böhm, M.; Christiaens, T.; Cifkova, R.; De Backer, G.; Dominiczak, A.; Galderisi, M.; Grobbee, D.E.; Jaarsma, T.; Kirchhof, P.; Kjeldsen, S.E.; Laurent, S.; Manolis, A.J.; Nilsson, P.M.; Ruilope, L.M.; Schmieder, R.E.; Sirnes, P.A.; Sleight, P.; Viigimaa, M.; Waeber, B.; Zannad, F. Task force for the management of arterial hypertension of the European society of hypertension and the European society of cardiology. 2013 ESH/ESC practice guidelines for the management of arterial hypertension. Blood Press.,  2014, 23(1), 3-16.
[http://dx.doi.org/10.3109/08037051.2014.868629] [PMID: 24359485] 
[10] 
Adler, A.I.; Stratton, I.M.; Neil, H.A.; Yudkin, J.S.; Matthews, D.R.; Cull, C.A.; Wright, A.D.; Turner, R.C.; Holman, R.R. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study. BMJ,  2000, 321(7258), 412-419.
[http://dx.doi.org/10.1136/bmj.321.7258.412] [PMID: 10938049] 
[11] 
UK prospective diabetes study group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ,  1998, 317(7160), 703-713.
[http://dx.doi.org/10.1136/bmj.317.7160.703] [PMID: 9732337] 
[12] 
Hansson, L.; Zanchetti, A.; Carruthers, S.G.; Dahlöf, B.; Elmfeldt, D.; Julius, S.; Ménard, J.; Rahn, K.H.; Wedel, H.; Westerling, S. HOT study group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet,  1998, 351(9118), 1755-1762.
[http://dx.doi.org/10.1016/S0140-6736(98)04311-6] [PMID: 9635947] 
[13] 
Cushman, W.C.; Evans, G.W.; Byington, R.P.; Goff, D.C., Jr; Grimm, R.H., Jr; Cutler, J.A.; Simons-Morton, D.G.; Basile, J.N.; Corson, M.A.; Probstfield, J.L.; Katz, L.; Peterson, K.A.; Friedewald, W.T.; Buse, J.B.; Bigger, J.T.; Gerstein, H.C.; Ismail-Beigi, F. ACCORD study group. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N. Engl. J. Med.,  2010, 362(17), 1575-1585.
[http://dx.doi.org/10.1056/NEJMoa1001286] [PMID: 20228401] 
[14] 
Sarafidis, P.A.; Georgianos, P.; Bakris, G.L. Resistant hypertension--its identification and epidemiology. Nat. Rev. Nephrol.,  2013, 9(1), 51-58.
[http://dx.doi.org/10.1038/nrneph.2012.260] [PMID: 23165303] 
[15] 
Standards of medical care in diabetes--2013. Diabetes Care,  2013, 36(Suppl. 1), S11-S66.
[http://dx.doi.org/10.2337/dc13-S011] [PMID: 23264422] 
[16] 
James, P.A.; Oparil, S.; Carter, B.L.; Cushman, W.C.; Dennison-Himmelfarb, C.; Handler, J.; Lackland, D.T.; LeFevre, M.L.; MacKenzie, T.D.; Ogedegbe, O.; Smith, S.C., Jr; Svetkey, L.P.; Taler, S.J.; Townsend, R.R.; Wright, J.T. Jr.; Narva, A.S.; Ortiz, E. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA,  2014, 311(5), 507-520.
[http://dx.doi.org/10.1001/jama.2013.284427] [PMID: 24352797] 
[17] 
Wright, J.T., Jr; Williamson, J.D.; Whelton, P.K.; Snyder, J.K.; Sink, K.M.; Rocco, M.V.; Reboussin, D.M.; Rahman, M.; Oparil, S.; Lewis, C.E.; Kimmel, P.L.; Johnson, K.C.; Goff, D.C. Jr.; Fine, L.J.; Cutler, J.A.; Cushman, W.C.; Cheung, A.K.; Ambrosius, W.T. SPRINT research group. A randomized trial of intensive versus standard blood-pressure control. N. Engl. J. Med.,  2015, 373(22), 2103-2116.
[http://dx.doi.org/10.1056/NEJMoa1511939] [PMID: 26551272] 
[18] 
Whelton, P.K.; Carey, R.M.; Aronow, W.S.; Casey, D.E., Jr; Collins, K.J.; Dennison Himmelfarb, C.; DePalma, S.M.; Gidding, S.; Jamerson, K.A.; Jones, D.W.; MacLaughlin, E.J.; Muntner, P.; Ovbiagele, B.; Smith, S.C., Jr; Spencer, C.C.; Stafford, R.S.; Taler, S.J.; Thomas, R.J.; Williams, K.A., Sr; Williamson, J.D.; Wright, J.T. Jr. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation and management of high blood pressure in adults: executive summary: a report of the American college of cardiology/American heart association task force on clinical practice guidelines. Hypertension,  2018, 71(6), 1269-1324.
[http://dx.doi.org/10.1161/HYP.0000000000000066] [PMID: 29133354] 
[19] 
American diabetes association 9. Cardiovascular Disease and Risk Management: Standards of Medical Care in Diabetes-2018. Diabetes Care,  2018, 41(Suppl. 1), S86-S104.
[http://dx.doi.org/10.2337/dc18-S009] [PMID: 29222380] 
[20] 
Xu, X.; Wang, G.; Zhou, T.; Chen, L.; Chen, J.; Shen, X. Novel approaches to drug discovery for the treatment of type 2 diabetes. Expert Opin. Drug Discov.,  2014, 9(9), 1047-1058.
[http://dx.doi.org/10.1517/17460441.2014.941352] [PMID: 25054271] 
[21] 
Tasyurek, H.M.; Altunbas, H.A.; Balci, M.K.; Sanlioglu, S. Incretins: their physiology and application in the treatment of diabetes mellitus. Diabetes Metab. Res. Rev.,  2014, 30(5), 354-371.
[http://dx.doi.org/10.1002/dmrr.2501] [PMID: 24989141] 
[22] 
Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Inzucchi, S.E. EMPA-REG OUTCOME investigators. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N. Engl. J. Med.,  2015, 373(22), 2117-2128.
[http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978] 
[23] 
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] 
[24] 
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 hyperglycemia in type 2 Diabetes, 2018. A consensus report by the American diabetes association (ADA) and the European association for the study of diabetes (EASD). Diabetes Care,  2018, 41(12), 2669-2701.
[http://dx.doi.org/10.2337/dci18-0033] [PMID: 30291106] 
[25] 
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] 
[26] 
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] 
[27] 
Ferrannini, E. Sodium-glucose co-transporters and their inhibition: clinical physiology. Cell Metab.,  2017, 26(1), 27-38.
[http://dx.doi.org/10.1016/j.cmet.2017.04.011] [PMID: 28506519] 
[28] 
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] 
[29] 
Wright, E.M.; Loo, D.D.; Hirayama, B.A.; Turk, E. Surprising versatility of Na+-glucose cotransporters: SLC5. Physiology (Bethesda),  2004, 19, 370-376.
[http://dx.doi.org/10.1152/physiol.00026.2004] [PMID: 15546855] 
[30] 
Lee, Y.J.; Lee, Y.J.; Han, H.J. Regulatory mechanisms of Na(+)/glucose cotransporters in renal proximal tubule cells. Kidney Int. Suppl.,  2007, (106), S27-S35.
[http://dx.doi.org/10.1038/sj.ki.5002383] [PMID: 17653207] 
[31] 
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] 
[32] 
DeFronzo, R.A.; Davidson, J.A.; Del Prato, S. The role of the kidneys in glucose homeostasis: a new path towards normalizing glycaemia. Diabetes Obes. Metab.,  2012, 14(1), 5-14.
[http://dx.doi.org/10.1111/j.1463-1326.2011.01511.x] [PMID: 21955459] 
[33] 
Wright, E.M.; Hirayama, B.A.; Loo, D.F. Active sugar transport in health and disease. J. Intern. Med.,  2007, 261(1), 32-43.
[http://dx.doi.org/10.1111/j.1365-2796.2006.01746.x] [PMID: 17222166] 
[34] 
American diabetes association. 8. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes-2018. Diabetes Care,  2018, 41(Suppl. 1), S73-S85.
[http://dx.doi.org/10.2337/dc18-S008] [PMID: 29222379] 
[35] 
Nauck, M.A. Update on developments with SGLT2 inhibitors in the management of type 2 diabetes. Drug Des. Devel. Ther.,  2014, 8, 1335-1380.
[http://dx.doi.org/10.2147/DDDT.S50773] [PMID: 25246775] 
[36] 
Abdul-Ghani, M.A.; Norton, L.; DeFronzo, R.A. Efficacy and safety of SGLT2 inhibitors in the treatment of type 2 diabetes mellitus. Curr. Diab. Rep.,  2012, 12(3), 230-238.
[http://dx.doi.org/10.1007/s11892-012-0275-6] [PMID: 22528597] 
[37] 
Vlotides, G.; Mertens, P.R. Sodium-glucose cotransport inhibitors: mechanisms, metabolic effects and implications for the treatment of diabetic patients with chronic kidney disease. Nephrol. Dial. Transplant.,  2015, 30(8), 1272-1276.
[http://dx.doi.org/10.1093/ndt/gfu299] [PMID: 25230708] 
[38] 
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] 
[39] 
Gu, H.F. Genetic and epigenetic studies in diabetic kidney disease. Front. Genet.,  2019, 10, 507.
[http://dx.doi.org/10.3389/fgene.2019.00507] [PMID: 31231424] 
[40] 
Bai, X.; Geng, J.; Zhou, Z.; Tian, J.; Li, X. MicroRNA-130b improves renal tubulointerstitial fibrosis via repression of Snail-induced epithelial-mesenchymal transition in diabetic nephropathy. Sci. Rep.,  2016, 6, 20475.
[http://dx.doi.org/10.1038/srep20475] [PMID: 26837280] 
[41] 
Barutta, F.; Bellini, S.; Mastrocola, R.; Bruno, G.; Gruden, G. MicroRNA and microvascular complications of diabetes. Int. J. Endocrinol.,  2018, 20186890501
[http://dx.doi.org/10.1155/2018/6890501] [PMID: 29707000] 
[42] 
Keating, S.T.; van Diepen, J.A.; Riksen, N.P.; El-Osta, A. Epigenetics in diabetic nephropathy, immunity and metabolism. Diabetologia,  2018, 61(1), 6-20.
[http://dx.doi.org/10.1007/s00125-017-4490-1] [PMID: 29128937] 
[43] 
O’Neill, J.; Fasching, A.; Pihl, L.; Patinha, D.; Franzén, S.; Palm, F. Acute SGLT inhibition normalizes O2 tension in the renal cortex but causes hypoxia in the renal medulla in anaesthetized control and diabetic rats. Am. J. Physiol. Renal Physiol.,  2015, 309(3), F227-F234.
[http://dx.doi.org/10.1152/ajprenal.00689.2014] [PMID: 26041448] 
[44] 
Marumo, T.; Yagi, S.; Kawarazaki, W.; Nishimoto, M.; Ayuzawa, N.; Watanabe, A.; Ueda, K.; Hirahashi, J.; Hishikawa, K.; Sakurai, H.; Shiota, K.; Fujita, T. Diabetes induces aberrant DNA methylation in the proximal tubules of the kidney. J. Am. Soc. Nephrol.,  2015, 26(10), 2388-2397.
[http://dx.doi.org/10.1681/ASN.2014070665] [PMID: 25653098] 
[45] 
Solini, A.; Seghieri, M.; Giannini, L.; Biancalana, E.; Parolini, F.; Rossi, C.; Dardano, A.; Taddei, S.; Ghiadoni, L.; Bruno, R.M. The effects of dapagliflozin on systemic and renal vascular function display an epigenetic signature. J. Clin. Endocrinol. Metab.,  2019, 104(10), 4253-4263.
[http://dx.doi.org/10.1210/jc.2019-00706] [PMID: 31162549] 
[46] 
Filippatos, T.D.; Tsimihodimos, V.; Elisaf, M.S. Mechanisms of blood pressure reduction with sodium-glucose co-transporter 2 (SGLT2) inhibitors. Expert Opin. Pharmacother.,  2016, 17(12), 1581-1583.
[http://dx.doi.org/10.1080/14656566.2016.1201073] [PMID: 27295549] 
[47] 
Sarafidis, P.A.; Georgianos, P.I.; Lasaridis, A.N. Diuretics in clinical practice. Part I: mechanisms of action, pharmacological effects and clinical indications of diuretic compounds. Expert Opin. Drug Saf.,  2010, 9(2), 243-257.
[http://dx.doi.org/10.1517/14740330903499240] [PMID: 20095917] 
[48] 
Imprialos, K.P.; Sarafidis, P.A.; Karagiannis, A.I. Sodium-glucose cotransporter-2 inhibitors and blood pressure decrease: a valuable effect of a novel antidiabetic class? J. Hypertens.,  2015, 33(11), 2185-2197.
[http://dx.doi.org/10.1097/HJH.0000000000000719] [PMID: 26372321] 
[49] 
Sarafidis, P.A.; Bakris, G.L. The antinatriuretic effect of insulin: an unappreciated mechanism for hypertension associated with insulin resistance? Am. J. Nephrol.,  2007, 27(1), 44-54.
[http://dx.doi.org/10.1159/000098955] [PMID: 17245074] 
[50] 
Bakris, G.; Molitch, M.; Hewkin, A.; Kipnes, M.; Sarafidis, P.; Fakouhi, K.; Bacher, P.; Sowers, J. STAR investigators. Differences in glucose tolerance between fixed-dose antihypertensive drug combinations in people with metabolic syndrome. Diabetes Care,  2006, 29(12), 2592-2597.
[http://dx.doi.org/10.2337/dc06-1373] [PMID: 17130190] 
[51] 
Sarafidis, P.A.; Bakris, G.L. Insulin resistance, hyperinsulinemia, and hypertension: an epidemiologic approach. J. Cardiometab. Syndr.,  2006, 1(5), 334-342.
[http://dx.doi.org/10.1111/j.1559-4564.2006.05795.x] [PMID: 17679789] 
[52] 
Tamura, K.; Wakui, H.; Azushima, K.; Uneda, K.; Umemura, S. Circadian blood pressure rhythm as a possible key target of SGLT2 inhibitors used for the treatment of Type 2 diabetes. Hypertens. Res.,  2016, 39(6), 396-398.
[http://dx.doi.org/10.1038/hr.2016.1] [PMID: 26818654] 
[53] 
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] 
[54] 
Cefalu, W.T.; Stenlöf, K.; Leiter, L.A.; Wilding, J.P.; Blonde, L.; Polidori, D.; Xie, J.; Sullivan, D.; Usiskin, K.; Canovatchel, W.; Meininger, G. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia,  2015, 58(6), 1183-1187.
[http://dx.doi.org/10.1007/s00125-015-3547-2] [PMID: 25813214] 
[55] 
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] 
[56] 
Jordan, J.; Tank, J.; Heusser, K.; Heise, T.; Wanner, C.; Heer, M.; Macha, S.; Mattheus, M.; Lund, S.S.; Woerle, H.J.; Broedl, U.C. The effect of empagliflozin on muscle sympathetic nerve activity in patients with type II diabetes mellitus. J. Am. Soc. Hypertens.,  2017, 11(9), 604-612.
[http://dx.doi.org/10.1016/j.jash.2017.07.005] [PMID: 28757109] 
[57] 
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] 
[58] 
Muskiet, M.H.; Tonneijck, L.; Smits, M.M.; Kramer, M.H.; Heerspink, H.J.; van Raalte, D.H. Pleiotropic effects of type 2 diabetes management strategies on renal risk factors. Lancet Diabetes Endocrinol.,  2015, 3(5), 367-381.
[http://dx.doi.org/10.1016/S2213-8587(15)00030-3] [PMID: 25943756] 
[59] 
Pandey, J.; Tamrakar, A.K. SGLT2 inhibitors for the treatment of diabetes: a patent review (2013-2018). Expert Opin. Ther. Pat.,  2019, 29(5), 369-384.
[http://dx.doi.org/10.1080/13543776.2019.1612879] [PMID: 31026402] 
[60] 
Ferrannini, E.; Ramos, S.J.; Salsali, A.; Tang, W.; List, J.F. Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care,  2010, 33(10), 2217-2224.
[http://dx.doi.org/10.2337/dc10-0612] [PMID: 20566676] 
[61] 
Wilding, J.P.; Woo, V.; Soler, N.G.; Pahor, A.; Sugg, J.; Rohwedder, K.; Parikh, S. Dapagliflozin 006 study group. Long-term efficacy of dapagliflozin in patients with type 2 diabetes mellitus receiving high doses of insulin: a randomized trial. Ann. Intern. Med.,  2012, 156(6), 405-415.
[http://dx.doi.org/10.7326/0003-4819-156-6-201203200-00003] [PMID: 22431673] 
[62] 
Strojek, K.; Yoon, K.H.; Hruba, V.; Sugg, J.; Langkilde, A.M.; Parikh, S. Dapagliflozin added to glimepiride in patients with type 2 diabetes mellitus sustains glycemic control and weight loss over 48 weeks: a randomized, double-blind, parallel-group, placebo-controlled trial. Diabetes Ther.,  2014, 5(1), 267-283.
[http://dx.doi.org/10.1007/s13300-014-0072-0] [PMID: 24920277] 
[63] 
Nauck, M.A.; Del Prato, S.; Meier, J.J.; Durán-García, S.; Rohwedder, K.; Elze, M.; Parikh, S.J. Dapagliflozin versus glipizide as add-on therapy in patients with type 2 diabetes who have inadequate glycemic control with metformin: a randomized, 52-week, double-blind, active-controlled noninferiority trial. Diabetes Care,  2011, 34(9), 2015-2022.
[http://dx.doi.org/10.2337/dc11-0606] [PMID: 21816980] 
[64] 
Nauck, M.A.; Del Prato, S.; Durán-García, S.; Rohwedder, K.; Langkilde, A.M.; Sugg, J.; Parikh, S.J. Durability of glycaemic efficacy over 2 years with dapagliflozin versus glipizide as add-on therapies in patients whose type 2 diabetes mellitus is inadequately controlled with metformin. Diabetes Obes. Metab.,  2014, 16(11), 1111-1120.
[http://dx.doi.org/10.1111/dom.12327] [PMID: 24919526] 
[65] 
Weber, M.A.; Mansfield, T.A.; Cain, V.A.; Iqbal, N.; Parikh, S.; Ptaszynska, A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol.,  2016, 4(3), 211-220.
[http://dx.doi.org/10.1016/S2213-8587(15)00417-9] [PMID: 26620248] 
[66] 
Weber, M.A.; Mansfield, T.A.; Alessi, F.; Iqbal, N.; Parikh, S.; Ptaszynska, A. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press.,  2016, 25(2), 93-103.
[http://dx.doi.org/10.3109/08037051.2015.1116258] [PMID: 26623980] 
[67] 
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] 
[68] 
Kadowaki, T.; Haneda, M.; Inagaki, N.; Terauchi, Y.; Taniguchi, A.; Koiwai, K.; Rattunde, H.; Woerle, H.J.; Broedl, U.C. Empagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a randomized, 12-week, double-blind, placebo-controlled, phase II trial. Adv. Ther.,  2014, 31(6), 621-638.
[http://dx.doi.org/10.1007/s12325-014-0126-8] [PMID: 24958326] 
[69] 
Roden, M.; Weng, J.; Eilbracht, J.; Delafont, B.; Kim, G.; Woerle, H.J.; Broedl, U.C. EMPA-REG MONO trial investigators. Empagliflozin monotherapy with sitagliptin as an active comparator in patients with type 2 diabetes: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Diabetes Endocrinol.,  2013, 1(3), 208-219.
[http://dx.doi.org/10.1016/S2213-8587(13)70084-6] [PMID: 24622369] 
[70] 
Ridderstråle, M.; Andersen, K.R.; Zeller, C.; Kim, G.; Woerle, H.J.; Broedl, U.C. EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol.,  2014, 2(9), 691-700.
[http://dx.doi.org/10.1016/S2213-8587(14)70120-2] [PMID: 24948511] 
[71] 
Tikkanen, I.; Narko, K.; Zeller, C.; Green, A.; Salsali, A.; Broedl, U.C.; Woerle, H.J. EMPA-REG BP investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care,  2015, 38(3), 420-428.
[http://dx.doi.org/10.2337/dc14-1096] [PMID: 25271206] 
[72] 
Stenlöf, K.; Cefalu, W.T.; Kim, K.A.; Alba, M.; Usiskin, K.; Tong, C.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise. Diabetes Obes. Metab.,  2013, 15(4), 372-382.
[http://dx.doi.org/10.1111/dom.12054] [PMID: 23279307] 
[73] 
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] 
[74] 
Forst, T.; Guthrie, R.; Goldenberg, R.; Yee, J.; Vijapurkar, U.; Meininger, G.; Stein, P. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes. Metab.,  2014, 16(5), 467-477.
[http://dx.doi.org/10.1111/dom.12273] [PMID: 24528605] 
[75] 
Neal, B.; Perkovic, V.; de Zeeuw, D.; Mahaffey, K.W.; Fulcher, G.; Ways, K.; Desai, M.; Shaw, W.; Capuano, G.; Alba, M.; Jiang, J.; Vercruysse, F.; Meininger, G.; Matthews, D. CANVAS trial collaborative group. Efficacy and safety of canagliflozin, an inhibitor of sodium-glucose cotransporter 2, when used in conjunction with insulin therapy in patients with type 2 diabetes. Diabetes Care,  2015, 38(3), 403-411.
[http://dx.doi.org/10.2337/dc14-1237] [PMID: 25468945] 
[76] 
Leiter, L.A.; Yoon, K.H.; Arias, P.; Langslet, G.; Xie, J.; Balis, D.A.; Millington, D.; Vercruysse, F.; Canovatchel, W.; Meininger, G. Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care,  2015, 38(3), 355-364.
[http://dx.doi.org/10.2337/dc13-2762] [PMID: 25205142] 
[77] 
Lavalle-González, F.J.; Januszewicz, A.; Davidson, J.; Tong, C.; Qiu, R.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin compared with placebo and sitagliptin in patients with type 2 diabetes on background metformin monotherapy: a randomised trial. Diabetologia,  2013, 56(12), 2582-2592.
[http://dx.doi.org/10.1007/s00125-013-3039-1] [PMID: 24026211] 
[78] 
Townsend, R.R.; Machin, I.; Ren, J.; Trujillo, A.; Kawaguchi, M.; Vijapurkar, U.; Damaraju, C.V.; Pfeifer, M. Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with Canagliflozin in patients with type 2 diabetes mellitus and hypertension. J. Clin. Hypertens. (Greenwich),  2016, 18(1), 43-52.
[http://dx.doi.org/10.1111/jch.12747] [PMID: 26663712] 
[79] 
Sarafidis, P.A.; Lazaridis, A.A.; Ruiz-Hurtado, G.; Ruilope, L.M. Blood pressure reduction in diabetes: lessons from ACCORD, SPRINT and EMPA-REG OUTCOME. Nat. Rev. Endocrinol.,  2017, 13(6), 365-374.
[http://dx.doi.org/10.1038/nrendo.2016.209] [PMID: 28106149] 
[80] 
Wanner, C.; Inzucchi, S.E.; Lachin, J.M.; Fitchett, D.; von Eynatten, M.; Mattheus, M.; Johansen, O.E.; Woerle, H.J.; Broedl, U.C.; Zinman, B. EMPA-REG OUTCOME investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N. Engl. J. Med.,  2016, 375(4), 323-334.
[http://dx.doi.org/10.1056/NEJMoa1515920] [PMID: 27299675] 
[81] 
Multicenter trial to evaluate the effect of dapagliflozin on the incidence of cardiovascular events (DECLARETIMI58). ClinicalTrials.gov, NCT01730534, 2018.
[82] 
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] 
[83] 
Phase 3 CREDENCE renal outcomes trial of INVOKANA ® (canagliflozin) is being stopped early for positive efficacy findings,  2018.
[84] 
A study to evaluate the effect of dapagliflozin on renal outcomes and cardiovascular mortality in patients with chronic kidney disease (Dapa-CKD). ClinicalTrials.gov, NCT03036150, 2017.
[85] 
EMPA-KIDNEY (the study of heart and kidney protection with empagliflozin). ClinicalTrials.gov, NCT03594110, 2018.
[86] 
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] 
[87] 
Marx, N.; McGuire, D.K. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur. Heart J.,  2016, 37(42), 3192-3200.
[http://dx.doi.org/10.1093/eurheartj/ehw110] [PMID: 27153861] 
[88] 
Flores, E.; Santos-Gallego, C.G.; Diaz-Mejía, N.; Badimon, J.J. Do the SGLT-2 Inhibitors Offer More than Hypoglycemic Activity? Cardiovasc. Drugs Ther.,  2018, 32(2), 213-222.
[http://dx.doi.org/10.1007/s10557-018-6786-x] [PMID: 29679303] 
[89] 
Baartscheer, A.; Schumacher, C.A.; Wüst, R.C.; Fiolet, J.W.; Stienen, G.J.; 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] 
[90] 
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] 
[91] 
Verma, S.; McMurray, J.J.V. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia,  2018, 61(10), 2108-2117.
[http://dx.doi.org/10.1007/s00125-018-4670-7] [PMID: 30132036] 
[92] 
Sarafidis, P.A.; Tsapas, A. Empagliflozin, cardiovascular outcomes and mortality in type 2 diabetes. N. Engl. J. Med.,  2016, 374(11), 1092.
[http://dx.doi.org/10.1056/NEJMc1600827] [PMID: 26981941] 
[93] 
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] 
[94] 
Moser, M.; Hebert, P.R. Prevention of disease progression, left ventricular hypertrophy and congestive heart failure in hypertension treatment trials. J. Am. Coll. Cardiol.,  1996, 27(5), 1214-1218.
[http://dx.doi.org/10.1016/0735-1097(95)00606-0] [PMID: 8609345] 
[95] 
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] 
[96] 
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, 288(23), 2981-2997.
[http://dx.doi.org/10.1001/jama.288.23.2981] [PMID: 12479763] 
[97] 
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] 
[98] 
Heerspink, H.J.L.; Kosiborod, M.; Inzucchi, S.E.; Cherney, D.Z.I. Renoprotective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int.,  2018, 94(1), 26-39.
[http://dx.doi.org/10.1016/j.kint.2017.12.027] [PMID: 29735306] 
[99] 
Terami, N.; Ogawa, D.; Tachibana, H.; Hatanaka, T.; Wada, J.; Nakatsuka, A.; Eguchi, J.; Horiguchi, C.S.; Nishii, N.; Yamada, H.; Takei, K.; Makino, H. Long-term treatment with the sodium glucose cotransporter 2 inhibitor, dapagliflozin, ameliorates glucose homeostasis and diabetic nephropathy in db/db mice. PLoS One,  2014, 9(6)e100777
[http://dx.doi.org/10.1371/journal.pone.0100777] [PMID: 24960177] 
[100] 
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] 
[101] 
Brenner, B.M.; Lawler, E.V.; Mackenzie, H.S. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int.,  1996, 49(6), 1774-1777.
[http://dx.doi.org/10.1038/ki.1996.265] [PMID: 8743495] 
[102] 
Sarafidis, P.A.; Khosla, N.; Bakris, G.L. Antihypertensive therapy in the presence of proteinuria. Am. J. Kidney Dis.,  2007, 49(1), 12-26.
[http://dx.doi.org/10.1053/j.ajkd.2006.10.014] [PMID: 17185142] 
[103] 
Norton, L.; Shannon, C.E.; Fourcaudot, M.; Hu, C.; Wang, N.; Ren, W.; Song, J.; Abdul-Ghani, M.; DeFronzo, R.A.; Ren, J.; Jia, W. Sodium-glucose co-transporter (SGLT) and glucose transporter (GLUT) expression in the kidney of type 2 diabetic subjects. Diabetes Obes. Metab.,  2017, 19(9), 1322-1326.
[http://dx.doi.org/10.1111/dom.13003] [PMID: 28477418] 
[104] 
Solini, A.; Rossi, C.; Mazzanti, C.M.; Proietti, A.; Koepsell, H.; Ferrannini, E. Sodium-glucose co-transporter (SGLT)2 and SGLT1 renal expression in patients with type 2 diabetes. Diabetes Obes. Metab.,  2017, 19(9), 1289-1294.
[http://dx.doi.org/10.1111/dom.12970] [PMID: 28419670] 
[105] 
Skrtić, M.; Yang, G.K.; Perkins, B.A.; Soleymanlou, N.; Lytvyn, Y.; von Eynatten, M.; Woerle, H.J.; Johansen, O.E.; Broedl, U.C.; Hach, T.; Silverman, M.; Cherney, D.Z. Characterisation of glomerular haemodynamic responses to SGLT2 inhibition in patients with type 1 diabetes and renal hyperfiltration. Diabetologia,  2014, 57(12), 2599-2602.
[http://dx.doi.org/10.1007/s00125-014-3396-4] [PMID: 25280671] 
[106] 
Cherney, D.Z.; 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] 
[107] 
Piperidou, A.; Sarafidis, P.; Boutou, A.; Thomopoulos, C.; Loutradis, C.; Alexandrou, M.E.; Tsapas, A.; Karagiannis, A. The effect of SGLT-2 inhibitors on albuminuria and proteinuria in diabetes mellitus: a systematic review and meta-analysis of randomized controlled trials. J. Hypertens.,  2019, 37(7), 1334-1343.
[http://dx.doi.org/10.1097/HJH.0000000000002050] [PMID: 31145707] 
[108] 
Heerspink, H.J.; Desai, M.; Jardine, M.; Balis, D.; Meininger, G.; Perkovic, V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J. Am. Soc. Nephrol.,  2017, 28(1), 368-375.
[http://dx.doi.org/10.1681/ASN.2016030278] [PMID: 27539604] 
[109] 
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] 
[110] 
Kohan, D.E.; Fioretto, P.; Tang, W.; List, J.F. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int.,  2014, 85(4), 962-971.
[http://dx.doi.org/10.1038/ki.2013.356] [PMID: 24067431] 
[111] 
Jabbour, S.A.; Hardy, E.; Sugg, J.; Parikh, S. Study 10 Group. Dapagliflozin is effective as add-on therapy to sitagliptin with or without metformin: a 24-week, multicenter, randomized, double-blind, placebo-controlled study. Diabetes Care,  2014, 37(3), 740-750.
[http://dx.doi.org/10.2337/dc13-0467] [PMID: 24144654] 
[112] 
Kaku, K.; Maegawa, H.; Tanizawa, Y.; Kiyosue, A.; Ide, Y.; Tokudome, T.; Hoshino, Y.; Yang, J.; Langkilde, A.M. Dapagliflozin as monotherapy or combination therapy in Japanese patients with type 2 diabetes: an open-label study. Diabetes Ther.,  2014, 5(2), 415-433.
[http://dx.doi.org/10.1007/s13300-014-0086-7] [PMID: 25341477] 
[113] 
Leiter, L.A.; Cefalu, W.T.; de Bruin, T.W.; Gause-Nilsson, I.; Sugg, J.; Parikh, S.J. Dapagliflozin added to usual care in individuals with type 2 diabetes mellitus with preexisting cardiovascular disease: a 24-week, multicenter, randomized, double-blind, placebo-controlled study with a 28-week extension. J. Am. Geriatr. Soc.,  2014, 62(7), 1252-1262.
[http://dx.doi.org/10.1111/jgs.12881] [PMID: 24890683] 
[114] 
Del Prato, S.; Nauck, M.; Durán-Garcia, S.; Maffei, L.; Rohwedder, K.; Theuerkauf, A.; Parikh, S. Long-term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add-on therapy to metformin in patients with type 2 diabetes: 4-year data. Diabetes Obes. Metab.,  2015, 17(6), 581-590.
[http://dx.doi.org/10.1111/dom.12459] [PMID: 25735400] 
[115] 
Matthaei, S.; Bowering, K.; Rohwedder, K.; Grohl, A.; Parikh, S. Study 05 Group. Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care,  2015, 38(3), 365-372.
[http://dx.doi.org/10.2337/dc14-0666] [PMID: 25592197] 
[116] 
Bailey, C.J.; Morales Villegas, E.C.; Woo, V.; Tang, W.; Ptaszynska, A.; List, J.F. Efficacy and safety of dapagliflozin monotherapy in people with Type 2 diabetes: a randomized double-blind placebo-controlled 102-week trial. Diabet. Med.,  2015, 32(4), 531-541.
[http://dx.doi.org/10.1111/dme.12624] [PMID: 25381876] 
[117] 
Schumm-Draeger, P.M.; Burgess, L.; Korányi, L.; Hruba, V.; Hamer-Maansson, J.E.; de Bruin, T.W. Twice-daily dapagliflozin co-administered with metformin in type 2 diabetes: a 16-week randomized, placebo-controlled clinical trial. Diabetes Obes. Metab.,  2015, 17(1), 42-51.
[http://dx.doi.org/10.1111/dom.12387] [PMID: 25200570] 
[118] 
Kosiborod, M.; Gause-Nilsson, I.; Xu, J.; Sonesson, C.; Johnsson, E. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and concomitant heart failure. J. Diabetes Complications,  2017, 31(7), 1215-1221.
[http://dx.doi.org/10.1016/j.jdiacomp.2017.02.001] [PMID: 28284707] 
[119] 
Fadini, G.P.; Bonora, B.M.; Zatti, G.; Vitturi, N.; Iori, E.; Marescotti, M.C.; Albiero, M.; Avogaro, A. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovasc. Diabetol.,  2017, 16(1), 42.
[http://dx.doi.org/10.1186/s12933-017-0529-3] [PMID: 28376855] 
[120] 
Müller-Wieland, D.; Kellerer, M.; Cypryk, K.; Skripova, D.; Rohwedder, K.; Johnsson, E.; Garcia-Sanchez, R.; Kurlyandskaya, R.; Sjöström, C.D.; Jacob, S.; Seufert, J.; Dronamraju, N.; Csomós, K. Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add-on to metformin in patients with type 2 diabetes. Diabetes Obes. Metab.,  2018, 20(11), 2598-2607.
[http://dx.doi.org/10.1111/dom.13437] [PMID: 29947099] 
[121] 
Fadini, G.P.; Zatti, G.; Baldi, I.; Bottigliengo, D.; Consoli, A.; Giaccari, A.; Sesti, G.; Avogaro, A. DARWIN-T2D network. Use and effectiveness of dapagliflozin in routine clinical practice: An Italian multicentre retrospective study. Diabetes Obes. Metab.,  2018, 20(7), 1781-1786.
[http://dx.doi.org/10.1111/dom.13280] [PMID: 29516612] 
[122] 
Yang, W.; Ma, J.; Li, Y.; Li, Y.; Zhou, Z.; Kim, J.H.; Zhao, J.; Ptaszynska, A. Dapagliflozin as add-on therapy in Asian patients with type 2 diabetes inadequately controlled on insulin with or without oral antihyperglycemic drugs: a randomized controlled trial. J. Diabetes,  2018, 10(7), 589-599.
[http://dx.doi.org/10.1111/1753-0407.12634] [PMID: 29215189] 
[123] 
Häring, H.U.; Merker, L.; Seewaldt-Becker, E.; Weimer, M.; Meinicke, T.; Woerle, H.J.; Broedl, U.C. EMPA-REG METSU trial investigators. Empagliflozin as add-on to metformin plus sulfonylurea in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care,  2013, 36(11), 3396-3404.
[http://dx.doi.org/10.2337/dc12-2673] [PMID: 23963895] 
[124] 
Rosenstock, J.; Seman, L.J.; Jelaska, A.; Hantel, S.; Pinnetti, S.; Hach, T.; Woerle, H.J. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes. Metab.,  2013, 15(12), 1154-1160.
[http://dx.doi.org/10.1111/dom.12185] [PMID: 23906374] 
[125] 
Kovacs, C.S.; Seshiah, V.; Swallow, R.; Jones, R.; Rattunde, H.; Woerle, H.J.; Broedl, U.C. EMPA-REG PIO™ trial investigators. Empagliflozin improves glycaemic and weight control as add-on therapy to pioglitazone or pioglitazone plus metformin in patients with type 2 diabetes: a 24-week, randomized, placebo-controlled trial. Diabetes Obes. Metab.,  2014, 16(2), 147-158.
[http://dx.doi.org/10.1111/dom.12188] [PMID: 23906415] 
[126] 
Barnett, A.H.; Mithal, A.; Manassie, J.; Jones, R.; Rattunde, H.; Woerle, H.J.; Broedl, U.C. EMPA-REG RENAL trial investigators. Efficacy and safety of empagliflozin added to existing antidiabetes treatment in patients with type 2 diabetes and chronic kidney disease: a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol.,  2014, 2(5), 369-384.
[http://dx.doi.org/10.1016/S2213-8587(13)70208-0] [PMID: 24795251] 
[127] 
Häring, H.U.; Merker, L.; Seewaldt-Becker, E.; Weimer, M.; Meinicke, T.; Broedl, U.C.; Woerle, H.J. EMPA-REG MET Trial Investigators. Empagliflozin as add-on to metformin in patients with type 2 diabetes: a 24-week, randomized, double-blind, placebo-controlled trial. Diabetes Care,  2014, 37(6), 1650-1659.
[http://dx.doi.org/10.2337/dc13-2105] [PMID: 24722494] 
[128] 
DeFronzo, R.A.; Lewin, A.; Patel, S.; Liu, D.; Kaste, R.; Woerle, H.J.; Broedl, U.C. Combination of empagliflozin and linagliptin as second-line therapy in subjects with type 2 diabetes inadequately controlled on metformin. Diabetes Care,  2015, 38(3), 384-393.
[http://dx.doi.org/10.2337/dc14-2364] [PMID: 25583754] 
[129] 
Nishimura, R.; Tanaka, Y.; Koiwai, K.; Inoue, K.; Hach, T.; Salsali, A.; Lund, S.S.; Broedl, U.C. Effect of empagliflozin monotherapy on postprandial glucose and 24-hour glucose variability in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, placebo-controlled, 4-week study. Cardiovasc. Diabetol.,  2015, 14, 11.
[http://dx.doi.org/10.1186/s12933-014-0169-9] [PMID: 25633683] 
[130] 
Ridderstråle, M.; Rosenstock, J.; Andersen, K.R.; Woerle, H.J.; Salsali, A. EMPA-REG H2H-SU trial investigators. Empagliflozin compared with glimepiride in metformin-treated patients with type 2 diabetes: 208-week data from a masked randomized controlled trial. Diabetes Obes. Metab.,  2018, 20(12), 2768-2777.
[http://dx.doi.org/10.1111/dom.13457] [PMID: 29961998] 
[131] 
Mancia, G.; Cannon, C.P.; Tikkanen, I.; Zeller, C.; Ley, L.; Woerle, H.J.; Broedl, U.C.; Johansen, O.E. Impact of empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension,  2016, 68(6), 1355-1364.
[http://dx.doi.org/10.1161/HYPERTENSIONAHA.116.07703] [PMID: 27977392] 
[132] 
Bode, B.; Stenlof, K.; Sullivan, D.; Fung, A.; Usiskin, K. Efficacy and safety of canagliflozin treatment in older subjects with type 2 diabetes mellitus: a randomized trial. Hosp. Pract.,  2013, 41(2), 72-84.
[http://dx.doi.org/10.3810/hp.2013.04.1020] [PMID: 23680739] 
[133] 
Schernthaner, G.; Gross, J.L.; Rosenstock, J.; Guarisco, M.; Fu, M.; Yee, J.; Kawaguchi, M.; Canovatchel, W.; Meininger, G. Canagliflozin compared with sitagliptin for patients with type 2 diabetes who do not have adequate glycemic control with metformin plus sulfonylurea: a 52-week randomized trial. Diabetes Care,  2013, 36(9), 2508-2515.
[http://dx.doi.org/10.2337/dc12-2491] [PMID: 23564919] 
[134] 
Wilding, J.P.; Charpentier, G.; Hollander, P.; González-Gálvez, G.; Mathieu, C.; Vercruysse, F.; Usiskin, K.; Law, G.; Black, S.; Canovatchel, W.; Meininger, G. Efficacy and safety of canagliflozin in patients with type 2 diabetes mellitus inadequately controlled with metformin and sulphonylurea: a randomised trial. Int. J. Clin. Pract.,  2013, 67(12), 1267-1282.
[http://dx.doi.org/10.1111/ijcp.12322] [PMID: 24118688] 
[135] 
Bays, H.E.; Weinstein, R.; Law, G.; Canovatchel, W. Canagliflozin: effects in overweight and obese subjects without diabetes mellitus. Obesity (Silver Spring),  2014, 22(4), 1042-1049.
[http://dx.doi.org/10.1002/oby.20663] [PMID: 24227660] 
[136] 
Sha, S.; Devineni, D.; Ghosh, A.; Polidori, D.; Hompesch, M.; Arnolds, S.; Morrow, L.; Spitzer, H.; Demarest, K.; Rothenberg, P. Pharmacodynamic effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, from a randomized study in patients with type 2 diabetes. PLoS One,  2014, 9(9)e110069
[http://dx.doi.org/10.1371/journal.pone.0110069] [PMID: 25268802] 
[137] 
Sha, S.; Polidori, D.; Heise, T.; Natarajan, J.; Farrell, K.; Wang, S.S.; Sica, D.; Rothenberg, P.; Plum-Mörschel, L. Effect of the sodium glucose co-transporter 2 inhibitor canagliflozin on plasma volume in patients with type 2 diabetes mellitus. Diabetes Obes. Metab.,  2014, 16(11), 1087-1095.
[http://dx.doi.org/10.1111/dom.12322] [PMID: 24939043] 
[138] 
Stenlöf, K.; Cefalu, W.T.; Kim, K.A.; Jodar, E.; Alba, M.; Edwards, R.; Tong, C.; Canovatchel, W.; Meininger, G. Long-term efficacy and safety of canagliflozin monotherapy in patients with type 2 diabetes inadequately controlled with diet and exercise: findings from the 52-week CANTATA-M study. Curr. Med. Res. Opin.,  2014, 30(2), 163-175.
[http://dx.doi.org/10.1185/03007995.2013.850066] [PMID: 24073995] 
[139] 
Weir, M.R.; Januszewicz, A.; Gilbert, R.E.; Vijapurkar, U.; Kline, I.; Fung, A.; Meininger, G. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J. Clin. Hypertens. (Greenwich),  2014, 16(12), 875-882.
[http://dx.doi.org/10.1111/jch.12425] [PMID: 25329038] 
[140] 
Yale, J.F.; Bakris, G.; Cariou, B.; Nieto, J.; David-Neto, E.; Yue, D.; Wajs, E.; Figueroa, K.; Jiang, J.; Law, G.; Usiskin, K.; Meininger, G. DIA3004 Study Group. Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes mellitus and chronic kidney disease. Diabetes Obes. Metab.,  2014, 16(10), 1016-1027.
[http://dx.doi.org/10.1111/dom.12348] [PMID: 24965700] 
[141] 
Ji, L.; Han, P.; Liu, Y.; Yang, G.; Dieu Van, N.K.; Vijapurkar, U.; Qiu, R.; Meininger, G. Canagliflozin in Asian patients with type 2 diabetes on metformin alone or metformin in combination with sulphonylurea. Diabetes Obes. Metab.,  2015, 17(1), 23-31.
[http://dx.doi.org/10.1111/dom.12385] [PMID: 25175734] 
[142] 
Yale, J.F.; Xie, J.; Sherman, S.E.; Garceau, C. Canagliflozin in conjunction with sulfonylurea maintains glycemic control and weight loss over 52 weeks: a randomized, controlled trial in patients with type 2 diabetes mellitus. Clin. Ther.,  2017, 39(11), 2230-2242.e2.
[http://dx.doi.org/10.1016/j.clinthera.2017.10.003] [PMID: 29103664] 
[143] 
Kario, K.; Hoshide, S.; Okawara, Y.; Tomitani, N.; Yamauchi, K.; Ohbayashi, H.; Itabashi, N.; Matsumoto, Y.; Kanegae, H. Effect of canagliflozin on nocturnal home blood pressure in Japanese patients with type 2 diabetes mellitus: The SHIFT-J study. J. Clin. Hypertens. (Greenwich),  2018, 20(10), 1527-1535.
[http://dx.doi.org/10.1111/jch.13367] [PMID: 30246286] 
[144] 
Ramirez, A.J.; Sanchez, M.J.; Sanchez, R.A. Diabetic patients with essential hypertension treated with amlodipine: blood pressure and arterial stiffness effects of canagliflozin or perindopril. J. Hypertens., 2018.
[http://dx.doi.org/10.1097/01.hjh.0000538986.17846.65] [PMID: 30113526] 
Cite As
Current Medicinal Chemistry

The Beneficial Hemodynamic Actions of SGLT-2 Inhibitors beyond the Management of Hyperglycemia

Abstract
