Cardiorenal Protections of SGLT2 Inhibitors in the Treatment of Type 2
Diabetes

Somayeh      Nazari; Hossein      Mirkhani
doi:10.2174/1573399819666221222160035
Abstract

Cardiovascular disease and renal complications raise the risk of death and morbidity in patients with type 2 diabetes (T2D). Sodium/glucose cotransporter-2 inhibitors (SGLT2i) are a novel class of glucose-lowering drug that increases urine glucose excretion while decreasing blood glucose levels in type 2 diabetes patients by inhibiting glucose reabsorption. In the present article, we review the discovery and development of SGLT2i as a new T2D treatment approach for T2D; thereafter, we consider different cell-based methods for the evaluation of SGLT2i. Finally, we provide evidences from both clinical and experimental studies which bring up the cardio-renal protective effects of SGLT2i. We performed a literature search using PubMed, Google Scholar, and Web of Science to identify publications on preclinical and clinical studies of cardiorenal protective action of SGLT2i and their suggested mechanisms. SGLT2i have shown good effects in the improvement of cardiovascular and renal complications independent of glucose lowering effects. Besides controlling blood glucose levels, SGLT2i were found to exhibit therapeutic benefits on the kidney and cardiovascular system by lowering diabetic glomerular hyperfiltration, blood pressure (BP), body weight, uric acid concentrations, lipid peroxidation, inflammation, etc. As a result of their distinct mode of action, SGLT2i have emerged as a promising treatment option for T2D and maybe T1D due to their increased urine excretion of glucose. It has been demonstrated that SGLT2i have considerable protective effects on diabetic nephropathy (DN) and cardiomyopathy in well-designed experimental and clinical investigations.
[1]
Atlas D. International diabetes federation IDF Diabetes Atlas.  (7th ed.), Brussels, Belgium: IDF 2015.

[2]
Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med  2015; 66(1): 255-70.
 [http://dx.doi.org/10.1146/annurev-med-051013-110046] [PMID: 25341005]

[3]
Evans MR, Wei S, Posner BA, Unger RH, Roth MG. An AlphaScreen assay for the discovery of synthetic chemical inhibitors of glucagon production. SLAS Discov  2016; 21(4): 325-32.
 [http://dx.doi.org/10.1177/1087057115622201] [PMID: 26676097]

[4]
Levetan C. Oral antidiabetic agents in type 2 diabetes. Curr Med Res Opin  2007; 23(4): 945-52.
 [http://dx.doi.org/10.1185/030079907X178766] [PMID: 17407651]

[5]
Meneses M, Silva B, Sousa M, Sá R, Oliveira P, Alves M. Antidiabetic drugs: Mechanisms of action and potential outcomes on cellular metabolism. Curr Pharm Des  2015; 21(25): 3606-20.
 [http://dx.doi.org/10.2174/1381612821666150710145753] [PMID: 26166608]

[6]
Borges de Melo E, da Silveira Gomes A, Carvalho I. α- and β- Glucosidase inhibitors: chemical structure and biological activity. Tetrahedron  2006; 62(44): 10277-302.
 [http://dx.doi.org/10.1016/j.tet.2006.08.055]

[7]
Kinne RK, Castaneda F. SGLT inhibitors as new therapeutic tools in the treatment of diabetes. Diabetes-Perspectives in Drug Therapy.  Springer 2011; pp. 105-26.

[8]
Abdul-Ghani MA, Norton L, DeFronzo RA. Role of sodium-glucose cotransporter 2 (SGLT 2) inhibitors in the treatment of type 2 diabetes. Endocr Rev  2011; 32(4): 515-31.
 [http://dx.doi.org/10.1210/er.2010-0029] [PMID: 21606218]

[9]
Ehrenkranz JRL, Lewis NG, Ronald Kahn C, Roth J. Phlorizin: a review. Diabetes Metab Res Rev  2005; 21(1): 31-8.
 [http://dx.doi.org/10.1002/dmrr.532] [PMID: 15624123]

[10]
Fernández-Ruiz I. Further insights into SGLT2 inhibitors. Nat Rev Cardiol  2018; 15(1): 2-3.
 [http://dx.doi.org/10.1038/nrcardio.2017.198] [PMID: 29188808]

[11]
Nomura S, Sakamaki S, Hongu M, et al. Discovery of canagliflozin, a novel C-glucoside with thiophene ring, as sodium-dependent glucose cotransporter 2 inhibitor for the treatment of type 2 diabetes mellitus. J Med Chem  2010; 53(17): 6355-60.
 [http://dx.doi.org/10.1021/jm100332n] [PMID: 20690635]

[12]
Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab  2012; 14(1): 83-90.
 [http://dx.doi.org/10.1111/j.1463-1326.2011.01517.x] [PMID: 21985634]

[13]
Zelniker TA, Braunwald E. Mechanisms of cardiorenal effects of sodium-glucose cotransporter 2 inhibitors: JACC state-of-the-art review. J Am Coll Cardiol  2020; 75(4): 422-34.
 [http://dx.doi.org/10.1016/j.jacc.2019.11.031] [PMID: 32000955]

[14]
Chilton RJ. Effects of sodium-glucose cotransporter-2 inhibitors on the cardiovascular and renal complications of type 2 diabetes. Diabetes Obes Metab  2020; 22(1): 16-29.
 [http://dx.doi.org/10.1111/dom.13854] [PMID: 31407866]

[15]
Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med  2019; 380(24): 2295-306.
 [http://dx.doi.org/10.1056/NEJMoa1811744] [PMID: 30990260]

[16]
Wright EM. Glucose transport families SLC5 and SLC50. Mol Aspects Med  2013; 34(2-3): 183-96.
 [http://dx.doi.org/10.1016/j.mam.2012.11.002] [PMID: 23506865]

[17]
DeFronzo RA, Davidson JA, 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]

[18]
Rahmoune H, Thompson PW, Ward JM, Smith CD, 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): 3427-34.
 [http://dx.doi.org/10.2337/diabetes.54.12.3427] [PMID: 16306358]

[19]
Wright EM. Renal Na+ -glucose cotransporters. Am J Physiol Renal Physiol  2001; 280(1): F10-8.
 [http://dx.doi.org/10.1152/ajprenal.2001.280.1.F10] [PMID: 11133510]

[20]
Szalat A, Perlman A, Muszkat M, Khamaisi M, Abassi Z, Heyman SN. Can SGLT2 inhibitors cause acute renal failure? Plausible role for altered glomerular hemodynamics and medullary hypoxia. Drug Saf  2018; 41(3): 239-52.
 [http://dx.doi.org/10.1007/s40264-017-0602-6] [PMID: 28952138]

[21]
Shepard BD, Pluznick JL. Saving the sweetness: renal glucose handling in health and disease. Am J Physiol Renal Physiol  2017; 313(1): F55-61.
 [http://dx.doi.org/10.1152/ajprenal.00046.2017] [PMID: 28356283]

[22]
Wright EM, Hirayama BA, Loo DF. 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]

[23]
Jung CH, Jang JE, Park JY. A novel therapeutic agent for type 2 diabetes mellitus: SGLT2 inhibitor. Diabetes Metab J  2014; 38(4): 261-73.
 [http://dx.doi.org/10.4093/dmj.2014.38.4.261] [PMID: 25215272]

[24]
Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia  2018; 61(10): 2079-86.
 [http://dx.doi.org/10.1007/s00125-018-4654-7] [PMID: 30132033]

[25]
Oku A, Ueta K, Arakawa K, et al. T-1095, an inhibitor of renal Na+-glucose cotransporters, may provide a novel approach to treating diabetes. Diabetes  1999; 48(9): 1794-800.
 [http://dx.doi.org/10.2337/diabetes.48.9.1794] [PMID: 10480610]

[26]
Parent L, Supplisson S, Loo DF, Wright E. Electrogenic properties of the cloned Na+/glucose cotransporter: I. Voltage-clamp studies. J Membr Biol  1992; 125(1): 49-62.
 [http://dx.doi.org/10.1007/BF00235797] [PMID: 1542106]

[27]
Castaneda F, Kinne RKH. A 96-well automated method to study inhibitors of human sodium-dependent D-glucose transport. Mol Cell Biochem  2005; 280(1-2): 91-8.
 [http://dx.doi.org/10.1007/s11010-005-8235-y] [PMID: 16311909]

[28]
Tsytsarev V, Maslov KI, Yao J, Parameswar AR, Demchenko AV, Wang LV. In vivo imaging of epileptic activity using 2-NBDG, a fluorescent deoxyglucose analog. J Neurosci Methods  2012; 203(1): 136-40.
 [http://dx.doi.org/10.1016/j.jneumeth.2011.09.005] [PMID: 21939688]

[29]
Ryan MJ, Johnson G, Kirk J, Fuerstenberg SM, Zager RA, Torok-Storb B. HK-2: An immortalized proximal tubule epithelial cell line from normal adult human kidney. Kidney Int  1994; 45(1): 48-57.
 [http://dx.doi.org/10.1038/ki.1994.6] [PMID: 8127021]

[30]
Lu YT, Ma XL, Xu YH, et al. A fluorescent glucose transport assay for screening SGLT2 inhibitors in endogenous SGLT2-expressing HK-2 cells. Nat Prod Bioprospect  2019; 9(1): 13-21.
 [http://dx.doi.org/10.1007/s13659-018-0188-4] [PMID: 30387082]

[31]
Kanwal A, Singh SP, Grover P, Banerjee SK. Development of a cell-based nonradioactive glucose uptake assay system for SGLT1 and SGLT2. Anal Biochem  2012; 429(1): 70-5.
 [http://dx.doi.org/10.1016/j.ab.2012.07.003] [PMID: 22796500]

[32]
Fioretto P, Mauer M, Eds. Histopathology of diabetic nephropathy. Seminars in nephrology.  Elsevier 2007; pp. 195-207.

[33]
Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia  1996; 39(12): 1569-76.
 [http://dx.doi.org/10.1007/s001250050616] [PMID: 8960844]

[34]
Ziyadeh FN, Goldfarb S. The renal tubulointerstitium in diabetes mellitus. Kidney Int  1991; 39(3): 464-75.
 [http://dx.doi.org/10.1038/ki.1991.57] [PMID: 2062033]

[35]
Kohan DE, Fioretto P, Tang W, List JF. Long-term study of patients with type 2 diabetes and moderate renal impairment shows that dapagliflozin reduces weight and blood pressure but does not improve glycemic control. Kidney Int  2014; 85(4): 962-71.
 [http://dx.doi.org/10.1038/ki.2013.356] [PMID: 24067431]

[36]
Fioretto P, Del Prato S, Buse JB, et al. Efficacy and safety of dapagliflozin in patients with type 2 diabetes and moderate renal impairment (chronic kidney disease stage 3A): The DERIVE Study. Diabetes Obes Metab  2018; 20(11): 2532-40.
 [http://dx.doi.org/10.1111/dom.13413] [PMID: 29888547]

[37]
Dekkers CCJ, Wheeler DC, Sjöström CD, Stefansson BV, Cain V, Heerspink HJL. Effects of the sodium-glucose co-transporter 2 inhibitor dapagliflozin in patients with type 2 diabetes and Stages 3b-4 chronic kidney disease. Nephrol Dial Transplant  2018; 33(11): 2005-11.
 [http://dx.doi.org/10.1093/ndt/gfx350] [PMID: 29370424]

[38]
Pollock C, Stefánsson B, Reyner D, et al. Albuminuria-lowering effect of dapagliflozin alone and in combination with saxagliptin and effect of dapagliflozin and saxagliptin on glycaemic control in patients with type 2 diabetes and chronic kidney disease (DELIGHT): a randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol  2019; 7(6): 429-41.
 [http://dx.doi.org/10.1016/S2213-8587(19)30086-5] [PMID: 30992195]

[39]
Barnett AH, Mithal A, Manassie J, et al. 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): 369-84.
 [http://dx.doi.org/10.1016/S2213-8587(13)70208-0] [PMID: 24795251]

[40]
Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med  2016; 375(4): 323-34.
 [http://dx.doi.org/10.1056/NEJMoa1515920] [PMID: 27299675]

[41]
Wanner C, Inzucchi SE, Zinman B, et al. Consistent effects of empagliflozin on cardiovascular and kidney outcomes irrespective of diabetic kidney disease categories: Insights from the EMPA-REG OUTCOME trial. Diabetes Obes Metab  2020; 22(12): 2335-47.
 [http://dx.doi.org/10.1111/dom.14158] [PMID: 32744354]

[42]
Yale JF, Bakris G, Cariou B, et al. 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): 1016-27.
 [http://dx.doi.org/10.1111/dom.12348] [PMID: 24965700]

[43]
Heerspink HJL, Perkins BA, Fitchett DH, Husain M, Cherney DZI. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation  2016; 134(10): 752-72.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.116.021887] [PMID: 27470878]

[44]
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med  2017; 377(7): 644-57.
 [http://dx.doi.org/10.1056/NEJMoa1611925] [PMID: 28605608]

[45]
Grunberger G, Camp S, Johnson J, et al. Ertugliflozin in patients with stage 3 chronic kidney disease and type 2 diabetes mellitus: the VERTIS RENAL randomized study. Diabetes Ther  2018; 9(1): 49-66.
 [http://dx.doi.org/10.1007/s13300-017-0337-5] [PMID: 29159457]

[46]
Tang H, Li D, Zhang J, et al. Sodium-glucose co-transporter-2 inhibitors and risk of adverse renal outcomes among patients with type 2 diabetes: A network and cumulative meta-analysis of randomized controlled trials. Diabetes Obes Metab  2017; 19(8): 1106-15.
 [http://dx.doi.org/10.1111/dom.12917] [PMID: 28240446]

[47]
Horii T, Oikawa Y, Kunisada N, Shimada A, Atsuda K. Acute kidney injury in Japanese type 2 diabetes patients receiving sodium-glucose cotransporter 2 inhibitors: A nationwide cohort study. J Diabetes Investig  2022; 13(1): 42-6.
 [http://dx.doi.org/10.1111/jdi.13630] [PMID: 34255919]

[48]
Thomson SC, Vallon V, Blantz RC. Kidney function in early diabetes: the tubular hypothesis of glomerular filtration. Am J Physiol Renal Physiol  2004; 286(1): F8-F15.
 [http://dx.doi.org/10.1152/ajprenal.00208.2003] [PMID: 14656757]

[49]
Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia: the pleiotropic effects of SGLT2 inhibition. Diabetologia  2017; 60(2): 215-25.
 [http://dx.doi.org/10.1007/s00125-016-4157-3] [PMID: 27878313]

[50]
Nespoux J, Vallon V. SGLT2 inhibition and kidney protection. Clin Sci (Lond)  2018; 132(12): 1329-39.
 [http://dx.doi.org/10.1042/CS20171298] [PMID: 29954951]

[51]
Vallon V, Rose M, Gerasimova M, et al. Knockout of Na-glucose transporter SGLT2 attenuates hyperglycemia and glomerular hyperfiltration but not kidney growth or injury in diabetes mellitus. Am J Physiol Renal Physiol  2013; 304(2): F156-67.
 [http://dx.doi.org/10.1152/ajprenal.00409.2012] [PMID: 23152292]

[52]
Vallon V, Gerasimova M, Rose MA, et al. SGLT2 inhibitor empagliflozin reduces renal growth and albuminuria in proportion to hyperglycemia and prevents glomerular hyperfiltration in diabetic Akita mice. Am J Physiol Renal Physiol  2014; 306(2): F194-204.
 [http://dx.doi.org/10.1152/ajprenal.00520.2013] [PMID: 24226524]

[53]
Faulhaber-Walter R, Chen L, Oppermann M, et al. Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury. J Am Soc Nephrol  2008; 19(4): 722-30.
 [http://dx.doi.org/10.1681/ASN.2007060721] [PMID: 18256360]

[54]
Magee GM, Bilous R, Cardwell CR, et al. Is hyperfiltration associated with the future risk of developing diabetic nephropathy? A meta-analysis. Springer 2009.
 [http://dx.doi.org/10.1007/s00125-009-1268-0]

[55]
Layton AT, Vallon V, Edwards A. Predicted consequences of diabetes and SGLT inhibition on transport and oxygen consumption along a rat nephron. Am J Physiol Renal Physiol  2016; 310(11): F1269-83.
 [http://dx.doi.org/10.1152/ajprenal.00543.2015] [PMID: 26764207]

[56]
Pirklbauer M, Schupart R, Fuchs L, et al. Unraveling reno-protective effects of SGLT2 inhibition in human proximal tubular cells. Am J Physiol Renal Physiol  2019; 316(3): F449-62.
 [http://dx.doi.org/10.1152/ajprenal.00431.2018] [PMID: 30539648]

[57]
Vallon V, Komers R. Pathophysiology of the diabetic kidney. Compr Physiol  2011; 1(3): 1175-232.
 [http://dx.doi.org/10.1002/cphy.c100049] [PMID: 23733640]

[58]
Gembardt F, Bartaun C, Jarzebska N, et al. The SGLT2 inhibitor empagliflozin ameliorates early features of diabetic nephropathy in BTBR ob / ob type 2 diabetic mice with and without hypertension. Am J Physiol Renal Physiol  2014; 307(3): F317-25.
 [http://dx.doi.org/10.1152/ajprenal.00145.2014] [PMID: 24944269]

[59]
Gangadharan Komala M, Gross S, Mudaliar H, et al. Inhibition of kidney proximal tubular glucose reabsorption does not prevent against diabetic nephropathy in type 1 diabetic eNOS knockout mice. PLoS One  2014; 9(11): e108994.
 [http://dx.doi.org/10.1371/journal.pone.0108994] [PMID: 25369239]

[60]
Maki T, Maeno S, Maeda Y, et al. Amelioration of diabetic nephropathy by SGLT2 inhibitors independent of its glucose-lowering effect: A possible role of SGLT2 in mesangial cells. Sci Rep  2019; 9(1): 4703.
 [http://dx.doi.org/10.1038/s41598-019-41253-7] [PMID: 30886225]

[61]
Forbes JM, Cooper ME. Glycation in diabetic nephropathy. Amino Acids  2012; 42(4): 1185-92.
 [http://dx.doi.org/10.1007/s00726-010-0771-4] [PMID: 20963456]

[62]
Wendt TM, Tanji N, Guo J, et al. RAGE drives the development of glomerulosclerosis and implicates podocyte activation in the pathogenesis of diabetic nephropathy. Am J Pathol  2003; 162(4): 1123-37.
 [http://dx.doi.org/10.1016/S0002-9440(10)63909-0] [PMID: 12651605]

[63]
Ojima A, Matsui T, Nishino Y, Nakamura N, Yamagishi S. Empagliflozin, an inhibitor of sodium-glucose cotransporter 2 exerts anti-inflammatory and antifibrotic effects on experimental diabetic nephropathy partly by suppressing AGEs-receptor axis. Horm Metab Res  2015; 47(9): 686-92.
 [http://dx.doi.org/10.1055/s-0034-1395609] [PMID: 25611208]

[64]
Woods TC, Satou R, Miyata K, et al. Canagliflozin prevents intrarenal angiotensinogen augmentation and mitigates kidney injury and hypertension in mouse model of type 2 diabetes mellitus. Am J Nephrol  2019; 49(4): 331-42.
 [http://dx.doi.org/10.1159/000499597] [PMID: 30921791]

[65]
Bessho R, Takiyama Y, Takiyama T, et al. Hypoxia-inducible factor-1α is the therapeutic target of the SGLT2 inhibitor for diabetic nephropathy. Sci Rep  2019; 9(1): 14754.
 [http://dx.doi.org/10.1038/s41598-019-51343-1] [PMID: 30626917]

[66]
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): F227-34.
 [http://dx.doi.org/10.1152/ajprenal.00689.2014] [PMID: 26041448]

[67]
Layton AT, Vallon V. Cardiovascular benefits of SGLT2 inhibition in diabetes and chronic kidney diseases. Acta physiol (Oxford, England)  2018; 222(4): e13050.
 [http://dx.doi.org/10.1111/apha.13050]

[68]
Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res  2016; 8(12): 844-7.
 [http://dx.doi.org/10.14740/jocmr2760w] [PMID: 27829948]

[69]
Kuno A, Kimura Y, Mizuno M, et al. Empagliflozin attenuates acute kidney injury after myocardial infarction in diabetic rats. Sci Rep  2020; 10(1): 7238.
 [http://dx.doi.org/10.1038/s41598-020-64380-y] [PMID: 32350374]

[70]
Manne NDPK, Ginjupalli GK, Rice KM, et al. Long-term treatment with empagliflozin attenuates renal damage in obese zucker rat. Exp Clin Endocrinol Diabetes  2020; 128(8): 512-9.
 [http://dx.doi.org/10.1055/a-0815-4908] [PMID: 30616241]

[71]
Oraby MA, El-Yamany MF, Safar MM, Assaf N, Ghoneim HA. Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats. Biomed Pharmacother  2019; 109: 910-20.
 [http://dx.doi.org/10.1016/j.biopha.2018.10.100] [PMID: 30551545]

[72]
Chung S, Kim S, Son M, et al. Empagliflozin contributes to polyuria via regulation of sodium transporters and water channels in diabetic rat kidneys. Front Physiol  2019; 10: 271.
 [http://dx.doi.org/10.3389/fphys.2019.00271] [PMID: 30941057]

[73]
Onishi A, Fu Y, Patel R, et al. A role for tubular Na+/H+ exchanger NHE3 in the natriuretic effect of the SGLT2 inhibitor empagliflozin. Am J Physiol Renal Physiol  2020; 319(4): F712-28.
 [http://dx.doi.org/10.1152/ajprenal.00264.2020] [PMID: 32893663]

[74]
Li J, Neal B, Perkovic V, et al. Mediators of the effects of canagliflozin on kidney protection in patients with type 2 diabetes. Kidney Int  2020; 98(3): 769-77.
 [http://dx.doi.org/10.1016/j.kint.2020.04.051] [PMID: 32470492]

[75]
Herat LY, Magno AL, Rudnicka C, et al. SGLT2 inhibitor-induced sympathoinhibition: A novel mechanism for cardiorenal protection. JACC Basic Transl Sci  2020; 5(2): 169-79.
 [http://dx.doi.org/10.1016/j.jacbts.2019.11.007] [PMID: 32140623]

[76]
Kinguchi S, Wakui H, Ito Y, et al. Improved home BP profile with dapagliflozin is associated with amelioration of albuminuria in Japanese patients with diabetic nephropathy: the Yokohama add-on inhibitory efficacy of dapagliflozin on albuminuria in Japanese patients with type 2 diabetes study (Y-AIDA study). Cardiovasc Diabetol  2019; 18(1): 110.
 [http://dx.doi.org/10.1186/s12933-019-0912-3] [PMID: 31455298]

[77]
Novikov A, Fu Y, Huang W, et al. SGLT2 inhibition and renal urate excretion: role of luminal glucose, GLUT9, and URAT1. Am J Physiol Renal Physiol  2019; 316(1): F173-85.
 [http://dx.doi.org/10.1152/ajprenal.00462.2018] [PMID: 30427222]

[78]
Gouda M, Arakawa K, Inagaki M, Ushirogawa Y. Effect of sodium-glucose cotransporter 2 inhibitor medication on new prescriptions of antihypertensives, antigout/antihyperuricemics and antidyslipidemics in Japan: Analysis using the JMDC Claims Database. J Diabetes Investig  2022; 13(11): 1842-51.
 [http://dx.doi.org/10.1111/jdi.13887] [PMID: 35854644]

[79]
Perkovic V, Jardine M, Vijapurkar U, Meininger G. Renal effects of canagliflozin in type 2 diabetes mellitus. Curr Med Res Opin  2015; 31(12): 2219-31.
 [http://dx.doi.org/10.1185/03007995.2015.1092128] [PMID: 26494163]

[80]
Liu Z, Fu C, Wang W, Xu B. Prevalence of chronic complications of type 2 diabetes mellitus in outpatients - a cross-sectional hospital based survey in urban China. Health Qual Life Outcomes  2010; 8(1): 62.
 [http://dx.doi.org/10.1186/1477-7525-8-62] [PMID: 20579389]

[81]
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med  2015; 373(22): 2117-28.
 [http://dx.doi.org/10.1056/NEJMoa1504720] [PMID: 26378978]

[82]
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med  2019; 380(4): 347-57.
 [http://dx.doi.org/10.1056/NEJMoa1812389] [PMID: 30415602]

[83]
McMurray JJV, Wheeler DC, Stefánsson BV, et al. Effect of dapagliflozin on clinical outcomes in patients with chronic kidney disease, with and without cardiovascular disease. Circulation  2021; 143(5): 438-48.

[84]
Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular events associated with SGLT-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll Cardiol  2018; 71(23): 2628-39.
 [http://dx.doi.org/10.1016/j.jacc.2018.03.009] [PMID: 29540325]

[85]
Jhund PS, Solomon SD, Docherty KF, et al. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction: results of DAPA-HF. Circulation  2021; 143(4): 298-309.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050391] [PMID: 33040613]

[86]
McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med  2019; 381(21): 1995-2008.
 [http://dx.doi.org/10.1056/NEJMoa1911303] [PMID: 31535829]

[87]
Cherney DZI, Cooper ME, Tikkanen I, et al. Pooled analysis of Phase III trials indicate contrasting influences of renal function on blood pressure, body weight, and HbA1c reductions with empagliflozin. Kidney Int  2018; 93(1): 231-44.
 [http://dx.doi.org/10.1016/j.kint.2017.06.017] [PMID: 28860019]

[88]
Mazidi M, Rezaie P, Gao HK, Kengne AP. Effect of sodium-glucose cotransport-2 inhibitors on blood pressure in people with type 2 diabetes mellitus: a systematic review and meta-analysis of 43 randomized control trials with 22 528 patients. J Am Heart Assoc  2017; 6(6): e004007.
 [http://dx.doi.org/10.1161/JAHA.116.004007] [PMID: 28546454]

[89]
Scholtes RA, Muskiet MHA, van Baar MJB, et al. Natriuretic effect of two weeks of dapagliflozin treatment in patients with type 2 diabetes and preserved kidney function during standardized sodium intake: results of the DAPASALT trial. Diabetes Care  2021; 44(2): 440-7.
 [http://dx.doi.org/10.2337/dc20-2604] [PMID: 33318125]

[90]
Ikonomidis I, Pavlidis G, Thymis J, et al. Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors, and their combination on endothelial glycocalyx, arterial function, and myocardial work index in patients with type 2 diabetes mellitus after 12-month treatment. J Am Heart Assoc  2020; 9(9): e015716.
 [http://dx.doi.org/10.1161/JAHA.119.015716] [PMID: 32326806]

[91]
Kong P, Christia P, Frangogiannis NG. The pathogenesis of cardiac fibrosis. Cell Mol Life Sci  2014; 71(4): 549-74.
 [http://dx.doi.org/10.1007/s00018-013-1349-6] [PMID: 23649149]

[92]
Lee TM, Chang NC, Lin SZ. 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]

[93]
Sato T, Aizawa Y, Yuasa S, et al. 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]

[94]
Pouraboli I, Nazari S, Sabet N, Sharififar F, Jafari M. Antidiabetic, antioxidant, and antilipid peroxidative activities of Dracocephalum polychaetum shoot extract in streptozotocin-induced diabetic rats: In vivo and in vitro studies. Pharm Biol  2016; 54(2): 272-8.
 [http://dx.doi.org/10.3109/13880209.2015.1033561] [PMID: 25901731]

[95]
Fathalipour M, Mirkhani H, Goharinia M. Effect of allopurinol and benzbromarone on diabetic cardiomyopathy and vasculopathy in streptozotocin-induced diabetic rats. Physiol Pharmacol  2019; 23(1): 1-8.

[96]
Mirkhani H, Goharinia M, Zareei A, Rahimi M. Can allopurinol improve retinopathy in diabetic rats? Oxidative stress or uric acid; which one is the culprit? Res Pharm Sci  2017; 12(5): 401-8.
 [http://dx.doi.org/10.4103/1735-5362.213985] [PMID: 28974978]

[97]
Bonora BM, Avogaro A, Fadini GP. Extraglycemic effects of SGLT2 inhibitors: A review of the evidence. Diabetes Metab Syndr Obes  2020; 13: 161-74.
 [http://dx.doi.org/10.2147/DMSO.S233538] [PMID: 32021362]

[98]
Tahara A, Kurosaki E, Yokono M, et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol  2014; 66(7): 975-87.
 [http://dx.doi.org/10.1111/jphp.12223] [PMID: 24533859]

[99]
Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox Biol  2017; 13: 370-85.
 [http://dx.doi.org/10.1016/j.redox.2017.06.009] [PMID: 28667906]

[100]
Baartscheer A, Schumacher CA, Wüst RCI, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia  2017; 60(3): 568-73.
 [http://dx.doi.org/10.1007/s00125-016-4134-x] [PMID: 27752710]

[101]
Uthman L, Baartscheer A, Bleijlevens B, et al. 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): 722-6.
 [http://dx.doi.org/10.1007/s00125-017-4509-7] [PMID: 29197997]

[102]
Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes  2016; 65(5): 1190-5.
 [http://dx.doi.org/10.2337/db15-1356] [PMID: 26861783]

[103]
Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med  2015; 21(5): 512-7.
 [http://dx.doi.org/10.1038/nm.3828] [PMID: 25894829]

[104]
Sargent J. SGLT2 inhibitor dapagliflozin promotes glucagon secretion in α islet cells. Nat Rev Endocrinol  2015; 11(7): 382-2.
 [http://dx.doi.org/10.1038/nrendo.2015.70] [PMID: 25942656]

[105]
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol  2019; 73(15): 1931-44.
 [http://dx.doi.org/10.1016/j.jacc.2019.01.056] [PMID: 30999996]

[106]
Kovacs CS, Seshiah V, Swallow R, et al. 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): 147-58.
 [http://dx.doi.org/10.1111/dom.12188] [PMID: 23906415]

[107]
Jurczak MJ, Lee HY, Birkenfeld AL, et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic β-cell function. Diabetes  2011; 60(3): 890-8.
 [http://dx.doi.org/10.2337/db10-1328] [PMID: 21357472]

[108]
Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF. 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): 2217-24.
 [http://dx.doi.org/10.2337/dc10-0612] [PMID: 20566676]

[109]
Kario K, Ferdinand KC, O’Keefe JH. Control of 24-hour blood pressure with SGLT2 inhibitors to prevent cardiovascular disease. Prog Cardiovasc Dis  2020; 63(3): 249-62.
 [http://dx.doi.org/10.1016/j.pcad.2020.04.003] [PMID: 32275926]

[110]
Lim VG, Bell RM, Arjun S, Kolatsi-Joannou M, Long DA, Yellon DM. SGLT2 inhibitor, canagliflozin, attenuates myocardial infarction in the diabetic and nondiabetic heart. JACC Basic Transl Sci  2019; 4(1): 15-26.
 [http://dx.doi.org/10.1016/j.jacbts.2018.10.002] [PMID: 30847415]
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DOI https://dx.doi.org/10.2174/1573399819666221222160035	Print ISSN 1573-3998
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