SGLT2 Inhibitors and Kidney Diseases: A Clinical Perspective

Manoj, A.; Das, S.; Kunnath Ramachandran, A.; Alex, A.T.; Joseph, A. SGLT2 inhibitors, an accomplished development in field of medicinal chemistry: An extensive review. Future Med. Chem., 2020, 12(21), 1961-1990.
[http://dx.doi.org/10.4155/fmc-2020-0154] [PMID: 33124462]

Bakris, G.L.; Fonseca, V.A.; Sharma, K.; Wright, E.M. Renal sodium–glucose transport: Role in diabetes mellitus and potential clinical implications. Kidney Int., 2009, 75(12), 1272-1277.
[http://dx.doi.org/10.1038/ki.2009.87] [PMID: 19357717]

Lee, Y.J.; Lee, Y.J.; Han, H.J. Regulatory mechanisms of Na +/glucose cotransporters in renal proximal tubule cells. Kidney Int., 2007, 72(106), S27-S35.
[http://dx.doi.org/10.1038/sj.ki.5002383] [PMID: 17653207]

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]

Rossetti, L.; Smith, D.; Shulman, G.I.; Papachristou, D.; DeFronzo, R.A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J. Clin. Invest., 1987, 79(5), 1510-1515.
[http://dx.doi.org/10.1172/JCI112981] [PMID: 3571496]

Wright, E.M.I. I. Glucose galactose malabsorption. Am. J. Physiol., 1998, 275(5), G879-G882.
[PMID: 9815014]

Isaji, M. Sodium-glucose cotransporter inhibitors for diabetes. Curr. Opin. Investig. Drugs, 2007, 8(4), 285-292.
[PMID: 17458177]

Meng, W.; Ellsworth, B.A.; Nirschl, A.A.; McCann, P.J.; Patel, M.; Girotra, R.N.; Wu, G.; Sher, P.M.; Morrison, E.P.; Biller, S.A.; Zahler, R.; Deshpande, P.P.; Pullockaran, A.; Hagan, D.L.; Morgan, N.; Taylor, J.R.; Obermeier, M.T.; Humphreys, W.G.; Khanna, A.; Discenza, L.; Robertson, J.G.; Wang, A.; Han, S.; Wetterau, J.R.; Janovitz, E.B.; Flint, O.P.; Whaley, J.M.; Washburn, W.N. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J. Med. Chem., 2008, 51(5), 1145-1149.
[http://dx.doi.org/10.1021/jm701272q] [PMID: 18260618]

Nomura, S.; Sakamaki, S.; Hongu, M.; Kawanishi, E.; Koga, Y.; Sakamoto, T.; Yamamoto, Y.; Ueta, K.; Kimata, H.; Nakayama, K.; Tsuda-Tsukimoto, M. 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), 6355-6360.
[http://dx.doi.org/10.1021/jm100332n] [PMID: 20690635]

Grempler, R.; Thomas, L.; Eckhardt, M.; Himmelsbach, F.; Sauer, A.; Sharp, D.E.; Bakker, R.A.; Mark, M.; Klein, T.; Eickelmann, P. 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]

Mascitti, V.; Maurer, T.S.; Robinson, R.P.; Bian, J.; Boustany-Kari, C.M.; Brandt, T.; Collman, B.M.; Kalgutkar, A.S.; Klenotic, M.K.; Leininger, M.T.; Lowe, A.; Maguire, R.J.; Masterson, V.M.; Miao, Z.; Mukaiyama, E.; Patel, J.D.; Pettersen, J.C.; Préville, C.; Samas, B.; She, L.; Sobol, Z.; Steppan, C.M.; Stevens, B.D.; Thuma, B.A.; Tugnait, M.; Zeng, D.; Zhu, T. Discovery of a clinical candidate from the structurally unique dioxa-bicyclo [3.2.1]octane class of sodium-dependent glucose cotransporter 2 inhibitors. J. Med. Chem., 2011, 54(8), 2952-2960.
[http://dx.doi.org/10.1021/jm200049r] [PMID: 21449606]

Thomas, M.C.; Cooper, M.E.; Zimmet, P. Changing epidemiology of type 2 diabetes mellitus and associated chronic kidney disease. Nat. Rev. Nephrol., 2016, 12(2), 73-81.
[http://dx.doi.org/10.1038/nrneph.2015.173] [PMID: 26553517]

Go, A.S.; Chertow, G.M.; Fan, D.; McCulloch, C.E.; Hsu, C. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N. Engl. J. Med., 2004, 351(13), 1296-1305.
[http://dx.doi.org/10.1056/NEJMoa041031] [PMID: 15385656]

Thomson, S.C.; Vallon, V. Effects of SGLT2 inhibitor and dietary NaCl on glomerular hemodynamics assessed by micropuncture in diabetic rats. Am. J. Physiol. Renal Physiol., 2021, 320(5), F761-F771.
[http://dx.doi.org/10.1152/ajprenal.00552.2020] [PMID: 33645318]

Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Siasos, G.; Tsioufis, K.; Tousoulis, D. The impact of SGLT2 inhibitors on inflammation: A systematic review and meta-analysis of studies in rodents. Int. Immunopharmacol., 2022, 111, 109080.
[http://dx.doi.org/10.1016/j.intimp.2022.109080] [PMID: 35908505]

Ali, B.H.; Al Salam, S.; Al Suleimani, Y.; Al Za'abi, M.; Abdelrahman, A. M.; Ashique, M.; Manoj, P.; Adham, S.A.; Hartmann, C.; Schupp, N.; Nemmar, A. Effects of the SGLT-2 inhibitor canagliflozin on adenine-induced chronic kidney disease in rats. Cell. Physiol. Biochem., 2019, 52(1), 27-39.

Castoldi, G.; Carletti, R.; Ippolito, S.; Colzani, M.; Barzaghi, F.; Stella, A.; Zerbini, G.; Perseghin, G.; Zatti, G.; di Gioia, C.R.T. Sodium-glucose cotransporter 2 inhibition prevents renal fibrosis in cyclosporine nephropathy. Acta Diabetol., 2021, 58(8), 1059-1070.
[http://dx.doi.org/10.1007/s00592-021-01681-2] [PMID: 33760995]

Elkazzaz, S.K.; Khodeer, D.M.; El Fayoumi, H.M.; Moustafa, Y.M. Role of sodium glucose cotransporter type 2 inhibitors dapagliflozin on diabetic nephropathy in rats; Inflammation, angiogenesis and apoptosis. Life Sci., 2021, 280, 119018.
[http://dx.doi.org/10.1016/j.lfs.2021.119018] [PMID: 33549594]

Klimontov, V.V.; Korbut, A.I.; Taskaeva, I.S.; Bgatova, N.P.; Dashkin, M.V.; Orlov, N.B.; Khotskina, A.S.; Zavyalov, E.L.; Klein, T. Empagliflozin alleviates podocytopathy and enhances glomerular nephrin expression in db/db diabetic mice. World J. Diabetes, 2020, 11(12), 596-610.
[http://dx.doi.org/10.4239/wjd.v11.i12.596] [PMID: 33384767]

Leoncini, G.; Russo, E.; Bussalino, E.; Barnini, C.; Viazzi, F.; Pontremoli, R. SGLT2 is and renal protection: From biological mechanisms to real-world clinical benefits. Int. J. Mol. Sci., 2021, 22(9), 4441.
[http://dx.doi.org/10.3390/ijms22094441] [PMID: 33922865]

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]

Li, J.; Woodward, M.; Perkovic, V.; Figtree, G.A.; Heerspink, H.J.L.; Mahaffey, K.W.; de Zeeuw, D.; Vercruysse, F.; Shaw, W.; Matthews, D.R.; Neal, B. Mediators of the effects of canagliflozin on heart failure in patients with type 2 diabetes. JACC Heart Fail., 2020, 8(1), 57-66.
[http://dx.doi.org/10.1016/j.jchf.2019.08.004] [PMID: 31676303]

Mazer, C.D.; Hare, G.M.T.; Connelly, P.W.; Gilbert, R.E.; Shehata, N.; Quan, A.; Teoh, H.; Leiter, L.A.; Zinman, B.; Jüni, P.; Zuo, F.; Mistry, N.; Thorpe, K.E.; Goldenberg, R.M.; Yan, A.T.; Connelly, K.A.; Verma, S. Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation, 2020, 141(8), 704-707.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044235] [PMID: 31707794]

Solak, Y.; Cetiner, M.; Siriopol, D.; Tarim, K.; Afsar, B.; Covic, A.; Kanbay, M. Novel masters of erythropoiesis: hypoxia inducible factors and recent advances in anemia of renal disease. Blood Purif., 2016, 42(2), 160-167.
[http://dx.doi.org/10.1159/000446273] [PMID: 27318465]

Hsu, Y.J.; Hsu, S.C.; Hsu, C.P.; Chen, Y.H.; Chang, Y.L.; Sadoshima, J.; Huang, S.M.; Tsai, C.S.; Lin, C.Y. Sirtuin 1 protects the aging heart from contractile dysfunction mediated through the inhibition of endoplasmic reticulum stress-mediated apoptosis in cardiac-specific Sirtuin 1 knockout mouse model. Int. J. Cardiol., 2017, 228, 543-552.
[http://dx.doi.org/10.1016/j.ijcard.2016.11.247] [PMID: 27875732]

Sciarretta, S.; Volpe, M.; Sadoshima, J. Mammalian target of rapamycin signaling in cardiac physiology and disease. Circ. Res., 2014, 114(3), 549-564.
[http://dx.doi.org/10.1161/CIRCRESAHA.114.302022] [PMID: 24481845]

Theofilis, P.; Sagris, M.; Oikonomou, E.; Antonopoulos, A.S.; Siasos, G.; Tsioufis, K.; Tousoulis, D. Pleiotropic effects of SGLT2 inhibitors and heart failure outcomes. Diabetes Res. Clin. Pract., 2022, 188, 109927.
[http://dx.doi.org/10.1016/j.diabres.2022.109927] [PMID: 35577035]

Umino, H.; Hasegawa, K.; Minakuchi, H.; Muraoka, H.; Kawaguchi, T.; Kanda, T.; Tokuyama, H.; Wakino, S.; Itoh, H. High basolateral glucose increases sodium-glucose cotransporter 2 and reduces sirtuin-1 in renal tubules through glucose transporter-2 detection. Sci. Rep., 2018, 8(1), 6791.
[http://dx.doi.org/10.1038/s41598-018-25054-y] [PMID: 29717156]

Lee, J.Y.; Lee, M.; Lee, J.Y.; Bae, J.; Shin, E.; Lee, Y.; Lee, B.W.; Kang, E.S.; Cha, B.S. Ipragliflozin, an SGLT2 inhibitor, ameliorates high-fat diet-induced metabolic changes by upregulating energy expenditure through activation of the AMPK/SIRT1 Pathway. Diabetes Metab. J., 2021, 45(6), 921-932.
[http://dx.doi.org/10.4093/dmj.2020.0187] [PMID: 33611885]

Yang, X.; Liu, Q.; Li, Y.; Tang, Q.; Wu, T.; Chen, L.; Pu, S.; Zhao, Y.; Zhang, G.; Huang, C.; Zhang, J.; Zhang, Z.; Huang, Y.; Zou, M.; Shi, X.; Jiang, W.; Wang, R.; He, J. The diabetes medication canagliflozin promotes mitochondrial remodelling of adipocyte via the AMPK-Sirt1-Pgc-1α signalling pathway. Adipocyte, 2020, 9(1), 484-494.
[http://dx.doi.org/10.1080/21623945.2020.1807850] [PMID: 32835596]

Ying, Y.; Jiang, C.; Zhang, M.; Jin, J.; Ge, S.; Wang, X. Phloretin protects against cardiac damage and remodeling via restoring SIRT1 and anti-inflammatory effects in the streptozotocin-induced diabetic mouse model. Aging, 2019, 11(9), 2822-2835.
[http://dx.doi.org/10.18632/aging.101954] [PMID: 31076562]

Mancini, S.J.; Boyd, D.; Katwan, O.J.; Strembitska, A.; Almabrouk, T.A.; Kennedy, S.; Palmer, T.M.; Salt, I.P. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci. Rep., 2018, 8(1), 5276.
[http://dx.doi.org/10.1038/s41598-018-23420-4] [PMID: 29588466]

Osataphan, S.; Macchi, C.; Singhal, G.; Chimene-Weiss, J.; Sales, V.; Kozuka, C.; Dreyfuss, J.M.; Pan, H.; Tangcharoenpaisan, Y.; Morningstar, J.; Gerszten, R.; Patti, M.E. SGLT2 inhibition reprograms systemic metabolism via FGF21-dependent and -independent mechanisms. JCI Insight, 2019, 4(5), e123130.
[http://dx.doi.org/10.1172/jci.insight.123130] [PMID: 30843877]

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. 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]

Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; Cannon, C.P.; Capuano, G.; Chu, P.L.; de Zeeuw, D.; Greene, T.; Levin, A.; Pollock, C.; Wheeler, D.C.; Yavin, Y.; Zhang, H.; Zinman, B.; Meininger, G.; Brenner, B.M.; Mahaffey, K.W.; Investigators, C.T. Canagliflozin and renal outcomes in type 2 diabetes and nephropathy. N. Engl. J. Med., 2019, 380(24), 2295-2306.
[http://dx.doi.org/10.1056/NEJMoa1811744] [PMID: 30990260]

Mosenzon, O.; Wiviott, S.D.; Cahn, A.; Rozenberg, A.; Yanuv, I.; Goodrich, E.L.; Murphy, S.A.; Heerspink, H.J.L.; Zelniker, T.A.; Dwyer, J.P.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Wilding, J.P.H.; Kato, E.T.; Gause-Nilsson, I.A.M.; Fredriksson, M.; Johansson, P.A.; Langkilde, A.M.; Sabatine, M.S.; Raz, I. Effects of dapagliflozin on development and progression of kidney disease in patients with type 2 diabetes: An analysis from the DECLARE–TIMI 58 randomised trial. Lancet Diabetes Endocrinol., 2019, 7(8), 606-617.
[http://dx.doi.org/10.1016/S2213-8587(19)30180-9] [PMID: 31196815]

Cherney, D.Z.I.; Charbonnel, B.; Cosentino, F.; Dagogo-Jack, S.; McGuire, D.K.; Pratley, R.; Shih, W.J.; Frederich, R.; Maldonado, M.; Pong, A.; Cannon, C.P.; Investigators, V.C. VERTIS CV Investigators. Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial. Diabetologia, 2021, 64(6), 1256-1267.
[http://dx.doi.org/10.1007/s00125-021-05407-5] [PMID: 33665685]

Cannon, C.P.; Perkovic, V.; Agarwal, R.; Baldassarre, J.; Bakris, G.; Charytan, D.M.; de Zeeuw, D.; Edwards, R.; Greene, T.; Heerspink, H.J.L.; Jardine, M.J.; Levin, A.; Li, J.W.; Neal, B.; Pollock, C.; Wheeler, D.C.; Zhang, H.; Zinman, B.; Mahaffey, K.W. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%. Circulation, 2020, 141(5), 407-410.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044359] [PMID: 31707795]

Jardine, M.J.; Zhou, Z.; Mahaffey, K.W.; Oshima, M.; Agarwal, R.; Bakris, G.; Bajaj, H.S.; Bull, S.; Cannon, C.P.; Charytan, D.M.; de Zeeuw, D.; Di Tanna, G.L.; Greene, T.; Heerspink, H.J.L.; Levin, A.; Neal, B.; Pollock, C.; Qiu, R.; Sun, T.; Wheeler, D.C.; Zhang, H.; Zinman, B.; Rosenthal, N.; Perkovic, V.; Investigators, C.S. Renal, cardiovascular, and safety outcomes of canagliflozin by baseline kidney function: a secondary analysis of the credence randomized trial. J. Am. Soc. Nephrol., 2020, 31(5), 1128-1139.
[http://dx.doi.org/10.1681/ASN.2019111168] [PMID: 32354987]

Bakris, G.; Oshima, M.; Mahaffey, K.W.; Agarwal, R.; Cannon, C.P.; Capuano, G.; Charytan, D.M.; de Zeeuw, D.; Edwards, R.; Greene, T.; Heerspink, H.J.L.; Levin, A.; Neal, B.; Oh, R.; Pollock, C.; Rosenthal, N.; Wheeler, D.C.; Zhang, H.; Zinman, B.; Jardine, M.J.; Perkovic, V. Effects of canagliflozin in patients with baseline eGFR <30 ml/min per 1.73 m2. Clin. J. Am. Soc. Nephrol., 2020, 15(12), 1705-1714.
[http://dx.doi.org/10.2215/CJN.10140620] [PMID: 33214158]

Oshima, M.; Jardine, M.J.; Agarwal, R.; Bakris, G.; Cannon, C.P.; Charytan, D.M.; de Zeeuw, D.; Edwards, R.; Greene, T.; Levin, A.; Lim, S.K.; Mahaffey, K.W.; Neal, B.; Pollock, C.; Rosenthal, N.; Wheeler, D.C.; Zhang, H.; Zinman, B.; Perkovic, V.; Heerspink, H.J.L. Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice. Kidney Int., 2021, 99(4), 999-1009.
[http://dx.doi.org/10.1016/j.kint.2020.10.042] [PMID: 33316282]

Oshima, M.; Neuen, B.L.; Jardine, M.J.; Bakris, G.; Edwards, R.; Levin, A.; Mahaffey, K.W.; Neal, B.; Pollock, C.; Rosenthal, N.; Wada, T.; Wheeler, D.C.; Perkovic, V.; Heerspink, H.J.L. Effects of canagliflozin on anaemia in patients with type 2 diabetes and chronic kidney disease: a post-hoc analysis from the CREDENCE trial. Lancet Diabetes Endocrinol., 2020, 8(11), 903-914.
[http://dx.doi.org/10.1016/S2213-8587(20)30300-4] [PMID: 33065060]

Ye, N.; Jardine, M.J.; Oshima, M.; Hockham, C.; Heerspink, H.J.L.; Agarwal, R.; Bakris, G.; Schutte, A.E.; Arnott, C.; Chang, T.I.; Górriz, J.L.; Cannon, C.P.; Charytan, D.M.; de Zeeuw, D.; Levin, A.; Mahaffey, K.W.; Neal, B.; Pollock, C.; Wheeler, D.C.; Luca Di Tanna, G.; Cheng, H.; Perkovic, V.; Neuen, B.L. Blood pressure effects of canagliflozin and clinical outcomes in type 2 diabetes and chronic kidney disease. Circulation, 2021, 143(18), 1735-1749.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.048740] [PMID: 33554616]

Neuen, B.L.; Oshima, M.; Perkovic, V.; Agarwal, R.; Arnott, C.; Bakris, G.; Cannon, C.P.; Charytan, D.M.; Edwards, R.; Górriz, J.L.; Jardine, M.J.; Levin, A.; Neal, B.; De Nicola, L.; Pollock, C.; Rosenthal, N.; Wheeler, D.C.; Mahaffey, K.W.; Heerspink, H.J.L. Effects of canagliflozin on serum potassium in people with diabetes and chronic kidney disease: The CREDENCE trial. Eur. Heart J., 2021, 42(48), 4891-4901.
[http://dx.doi.org/10.1093/eurheartj/ehab497] [PMID: 34423370]

Heerspink, H.J.L.; Stefánsson, B.V.; Correa-Rotter, R.; Chertow, G.M.; Greene, T.; Hou, F.F.; Mann, J.F.E.; McMurray, J.J.V.; Lindberg, M.; Rossing, P.; Sjöström, C.D.; Toto, R.D.; Langkilde, A.M.; Wheeler, D.C. Dapagliflozin in patients with chronic kidney disease. N. Engl. J. Med., 2020, 383(15), 1436-1446.
[http://dx.doi.org/10.1056/NEJMoa2024816] [PMID: 32970396]

Wheeler, D.C.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Toto, R.D.; Sjöström, C.D.; Langkilde, A.M.; Heerspink, H.J.L. Effects of dapagliflozin on major adverse kidney and cardiovascular events in patients with diabetic and non-diabetic chronic kidney disease: a prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol., 2021, 9(1), 22-31.
[http://dx.doi.org/10.1016/S2213-8587(20)30369-7] [PMID: 33338413]

Heerspink, H.J.L.; Jongs, N.; Chertow, G.M.; Langkilde, A.M.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Sjöström, C.D.; Stefansson, B.V.; Toto, R.D.; Wheeler, D.C.; Greene, T. Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol., 2021, 9(11), 743-754.
[http://dx.doi.org/10.1016/S2213-8587(21)00242-4] [PMID: 34619108]

Jongs, N.; Greene, T.; Chertow, G.M.; McMurray, J.J.V.; Langkilde, A.M.; Correa-Rotter, R.; Rossing, P.; Sjöström, C.D.; Stefansson, B.V.; Toto, R.D.; Wheeler, D.C.; Heerspink, H.J.L. Effect of dapagliflozin on urinary albumin excretion in patients with chronic kidney disease with and without type 2 diabetes: A prespecified analysis from the DAPA-CKD trial. Lancet Diabetes Endocrinol., 2021, 9(11), 755-766.
[http://dx.doi.org/10.1016/S2213-8587(21)00243-6] [PMID: 34619106]

Sen, T.; Li, J.; Neuen, B.L.; Neal, B.; Arnott, C.; Parikh, C.R.; Coca, S.G.; Perkovic, V.; Mahaffey, K.W.; Yavin, Y.; Rosenthal, N.; Hansen, M.K.; Heerspink, H.J.L. Effects of the SGLT2 inhibitor canagliflozin on plasma biomarkers TNFR-1, TNFR-2 and KIM-1 in the CANVAS trial. Diabetologia, 2021, 64(10), 2147-2158.
[http://dx.doi.org/10.1007/s00125-021-05512-5] [PMID: 34415356]

Heerspink, H.J.L.; Cherney, D.; Postmus, D.; Stefansson, B.V.; Chertow, G.M.; Dwyer, J.P.; Greene, T.; Kosiborod, M.; Langkilde, A.M.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Sjostrom, C.D.; Toto, R.D.; Wheeler, D.C. Committees, D.-C. T.; Investigators A pre-specified analysis of the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized controlled trial on the incidence of abrupt declines in kidney function. Kidney Int., 2022, 101(1), 174-184.

Heerspink, H.J.L.; Sjöström, C.D.; Jongs, N.; Chertow, G.M.; Kosiborod, M.; Hou, F.F.; McMurray, J.J.V.; Rossing, P.; Correa-Rotter, R.; Kurlyandskaya, R.; Stefansson, B.V.; Toto, R.D.; Langkilde, A.M.; Wheeler, D.C.; Heerspink, H.J.L.; Wheeler, D.C.; Chertow, G.; Correa-Rotter, R.; Greene, T.; Fan Hou, F. McMurray, J.; Rossing, P.; Toto, R.; Stefansson, B.; Maria Langkilde, A.; Maffei, L.E.; Raffaele, P.; Solis, S.E.; Arias, C.A.; Aizenberg, D.; Luquez, C.; Zaidman, C.; Cluigt, N.; Mayer, M.; Alvarisqueta, A.; Wassermann, A.; Maldonado, R.; Bittar, J.; Maurich, M.; Gaite, L.E.; Garcia, N.; Sivak, L.; Ramallo, P.O.; Santos, J.C.; Garcia Duran, R.; Oddino, J.A.; Maranon, A.; Maia, L.N.; D Avila, D.; Barros, E.J.G.; Vidotti, M.H.; Panarotto, D.; Noronha, I.D.L.; Turatti, L A A.; Deboni, L.; Canziani, M.E.; Riella, M.C.; Bacci, M.R.; Paschoalin, R.P.; Franco, R.J.; Goldani, J.C.; St-Amour, E.; Steele, A.W.; Goldenberg, R.; Pandeya, S.; Bajaj, H.; Cherney, D.; Kaiser, S.M.; Conway, J.R.; Chow, S.S.; Bailey, G.; Lafrance, J.; Winterstein, J.; Cournoyer, S.; Gaudet, D.; Madore, F.; Houlden, R.L.; Dowell, A.; Langlois, M.; Muirhead, N.; Khandwala, H.; Levin, A.; Hou, F.; Xue, Y.; Zuo, L.; Hao, C.; Ni, Z.; Xing, C.; Chen, N.; Dong, Y.; Zhou, R.; Xiao, X.; Zou, Y.; Wang, C.; Liu, B.; Chen, Q.; Lin, M.; Luo, Q.; Zhang, D.; Wang, J.; Chen, M.; Wang, X.; Zhong, A.; Dong, J.; Zhu, C.; Yan, T.; Luo, P.; Ren, Y.; Pai, P.; Li, D.; Zhang, R.; Zhang, J.; Xu, M.; Zhuang, Y.; Kong, Y.; Yao, X.; Peng, X.; Persson, F.I.; Hansen, T.K.; Borg, R.; Pedersen Bjergaard, U.; Hansen, D.; Hornum, M.; Haller, H.; Klausmann, G.; Tschope, D.; Kruger, T.; Gross, P.; Hugo, C.; Obermuller, N.; Rose, L.; Mertens, P.; Zeller-Stefan, H.; Fritsche, A.; Renders, L.; Muller, J.; Budde, K.; Schroppel, B.; Wittmann, I.; Voros, P.; Dudas, M.; Tabak, G.A.; Kirschner, R.; Letoha, A.; Balku, I.; Hermanyi, Z.; Zakar, G.; Mezei, I.; Nagy, G.G.; Lippai, J.; Nemeth, A.; Khullar, D.; Gowdaiah, P.K.; Fernando Mervin, E.; Rao, V.A.; Dewan, D.; Maddi, V.S.K.; Vyawahare, M.S.; Pulichikkat, R.K.; Sonkar, S.K.; Gupta, V.K.; Agarwal, S.; Asirvatham, A.J.; Ignatius, A.; Chaubey, S.; Melemadathil, S.; Alva, H.; Kadam, Y.; Shimizu, H.; Sueyoshi, A.; Takeoka, H.; Abe, Y.; Imai, T.; Onishi, Y.; Fujita, Y.; Tokita, Y.; Makita, Y.; Idogaki, A.; Koyama, R.; Kikuchi, H.; Kashihara, N.; Hayashi, T.; Ando, Y.; Tanaka, T.; Shimizu, M.; Hidaka, S.; Gohda, T.; Tamura, K.; Abe, M.; Kamijo, Y.; Imasawa, T.; Takahashi, Y.; Nakayama, M.; Tomita, M.; Hirano, F.; Nakayama, M.; Fukushima, Y.; Kiyosue, A.; Kurioka, S.; Imai, E.; Kitagawa, K.; Waki, M.; Wada, J.; Uehara, K.; Iwatani, H.; Ota, K.; Shibazaki, S.; Tamura, K.; Katayama, K.; Narita, I.; Iinuma, M.; Matsueda, S.; Sasaki, S.; Yokochi, A.; Tsukamoto, T.; Yoshimura, T.; Kang, S.; Lee, S.; Lim, C.S.; Chin, H.; Joo, K.W.; Han, S.Y.; Chang, T.I.; Park, S.; Park, H.; Park, C.W.; Han, B.G.; Cha, D.R.; Yoon, S.A.; Kim, W.; Kim, S.W.; Ryu, D.; Correa Rotter, R.; Irizar Santana, S.S.; Hernandez Llamas, G.; Valdez Ortiz, R.; Secchi Nicolas, N.C.; Gonzalez Galvez, G.; Lazcano Soto, J.R.; Bochicchio Riccardelli, T.; Bayram Llamas, E.A.; Ramos Ibarra, D.R.; Melo, M.G.S.; Gonzalez Gonzalez, J.G.; Sanchez Mijangos, J.H.; Madero Robalo, M.; Garcia Castillo, A.; Manrique, H.A.; Farfan, J.C.; Vargas, R.; Valdivia, A.; Dextre, A.; Escudero, E.; Calderon Ticona, J.R.; Gonzales, L.; Villena, J.; Leon, L.; Molina, G.; Saavedra, A.; Garrido, E.; Arbanil, H.; Vargas Marquez, S.; Rodriguez, J.; Isidto, R.; Villaflor, A.J.; Gumba, M.A.; Tirador, L.; Comia, R.S.; Sy, R.A.; Guanzon, M.L.V.V.; Aquitania, G.; De Asis, N.C.; Silva, A.A.; Lim, M.E.; Danguilan, R.A.; Nowicki, M.; Rudzki, H.; Landa, K.; Kucharczyk-Bauman, I.; Gogola-Migdal, B.; Golski, M.; Olech-Cudzik, A.; Stompor, T.; Szczepanik, T.; Miklaszewicz, B.; Sciborski, R.; Kuzniewski, M.; Ciechanowski, K.; Wronska, D.; Klatko, W.; Mazur, S.; Popenda, G.; Myslicki, M.; Bolieva, L.Z.; Berns, S.; Galyavich, A.; Abissova, T.; Karpova, I.; Platonov, D.; Koziolova, N.; Kvitkova, L.; Nilk, R.; Medina, T.; Rebrov, A.; Rossovskaya, M.; Sinitsina, I.; Vishneva, E.; Zagidullin, N.; Novikova, T.; Krasnopeeva, N.; Magnitskaya, O.; Antropenko, N.; Batiushin, M.; Escudero Quesada, V.; Barrios Barrea, C.; Espinel Garauz, E.; Cruzado Garrit, J.M.; Morales Portillo, C.; Gorriz Teruel, J.L.; Cigarran Guldris, S.; Praga Terente, M.; Robles Perez-Monteoliva, N.R.; Infanta Cristina, H.; Tinahones Madueno, F.J.; Soto Gonzalez, A.; Diaz Rodriguez, C.; Furuland, H.; Saeed, A.; Dreja, K.; Spaak, J.; Bruchfeld, A.; Kolesnyk, M.; Levchenko, O.; Pyvovarova, N.; Stus, V.; Doretskyy, V.; Korobova, N.; Horoshko, O.; Katerenchuk, I.; Mostovoy, Y.M.; Orynchak, M.; Legun, O.; Dudar, I.; Bilchenko, O.; Andreychyn, S.; Levchenko, A.; Zub, L.; Tereshchenko, N.; Topchii, I.; Ostapenko, T.; Bezuglova, S.; Kopytsya, M.; Turenko, O.; Mark, P.; Barratt, J.; Bhandari, S.; Fraser, D.; Kalra, P.; Kon, S.P.; Mccafferty, K.; Mikhail, A.; Kon, S.P.; Alvarado, O.P.; Anderson, R.; Andrawis, N.S.; Arif, A.; Benjamin, S.A.; Bueso, G.; Busch, R.S.; Carr, K.W.; Carr, K.W.; Crawford, P.; Daboul, N.; De La Calle, G.M.; Delgado, B.; Earl, J.; El-Shahawy, M.A.; Graf, R.J.; Greenwood, G.; Guevara, A.; Wendland, E.M.; Mayfield, R.K.; Montero, M.; Morin, D.J.; Narayan, P.; Numrungroad, V.; Reddy, A.C.; Reddy, R.; Samson, M.B.; Trejo, R.; Butcher, M.B.; Wise, J.K.; Zemel, L.R.; Raikhel, M.; Weinstein, D.; Hernandez, P.; Wynne, A.; Khan, B.V.; Sterba, G.A.; Jamal, A.; Ross, D.; Rovner, S.F.; Tan, A.; Ovalle, F.; Patel, R.J.; Talano, J.; Patel, D.R.; Burgner, A.; Aslam, N.; Elliott, M.; Goral, S.; Jovanovich, A.; Umanath, K.; Waguespack, D.; Weiner, D.; Yu, M.; Schneider, L.; Le, T.; D, T.; Nguyen, N.; Nguyen, H.; Nguyen, D.; Nguyen, V.; Do, T.; Chu, P.; Ta, D.; Tran, N.; Nguyen, D.; Pfeffer, M.A.; Pocock, S.; Swedberg, K.; Rouleau, J.L.; Chaturvedi, N.; Ivanovich, P.; Levey, A.S.; Held, C.; Christersson, C.; Mann, J.; Varenhorst, C. Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial. Eur. Heart J., 2021, 42(13), 1216-1227.
[http://dx.doi.org/10.1093/eurheartj/ehab094] [PMID: 33792669]

Wheeler, D.C.; Toto, R.D.; Stefánsson, B.V.; Jongs, N.; Chertow, G.M.; Greene, T.; Hou, F.F.; McMurray, J.J.V.; Pecoits-Filho, R.; Correa-Rotter, R.; Rossing, P.; Sjöström, C.D.; Umanath, K.; Langkilde, A.M.; Heerspink, H.J.L. A pre-specified analysis of the DAPA-CKD trial demonstrates the effects of dapagliflozin on major adverse kidney events in patients with IgA nephropathy. Kidney Int., 2021, 100(1), 215-224.
[http://dx.doi.org/10.1016/j.kint.2021.03.033] [PMID: 33878338]

Bhatt, D.L.; Szarek, M.; Pitt, B.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Inzucchi, S.E.; Kosiborod, M.N.; Cherney, D.Z.I.; Dwyer, J.P.; Scirica, B.M.; Bailey, C.J.; Díaz, R.; Ray, K.K.; Udell, J.A.; Lopes, R.D.; Lapuerta, P.; Steg, P.G.; Investigators, S. Sotagliflozin in patients with diabetes and chronic kidney disease. N. Engl. J. Med., 2021, 384(2), 129-139.
[http://dx.doi.org/10.1056/NEJMoa2030186] [PMID: 33200891]

Group, E.-K. C. Design, recruitment, and baseline characteristics of the EMPA-KIDNEY trial. Nephrol. Dial. Transplant., 2022.

Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Pocock, S.J.; Carson, P.; Januzzi, J.; Verma, S.; Tsutsui, H.; Brueckmann, M.; Jamal, W.; Kimura, K.; Schnee, J.; Zeller, C.; Cotton, D.; Bocchi, E.; Böhm, M.; Choi, D.J.; Chopra, V.; Chuquiure, E.; Giannetti, N.; Janssens, S.; Zhang, J.; Gonzalez Juanatey, J.R.; Kaul, S.; Brunner-La Rocca, H.P.; Merkely, B.; Nicholls, S.J.; Perrone, S.; Pina, I.; Ponikowski, P.; Sattar, N.; Senni, M.; Seronde, M.F.; Spinar, J.; Squire, I.; Taddei, S.; Wanner, C.; Zannad, F. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med., 2020, 383(15), 1413-1424.
[http://dx.doi.org/10.1056/NEJMoa2022190] [PMID: 32865377]

Jhund, P.S.; Solomon, S.D.; Docherty, K.F.; Heerspink, H.J.L.; Anand, I.S.; Böhm, M.; Chopra, V.; de Boer, R.A.; Desai, A.S.; Ge, J.; Kitakaze, M.; Merkley, B.; O’Meara, E.; Shou, M.; Tereshchenko, S.; Verma, S.; Vinh, P.N.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Bengtsson, O.; Langkilde, A.M.; Sjöstrand, M.; McMurray, J.J.V. Efficacy of dapagliflozin on renal function and outcomes in patients with heart failure with reduced ejection fraction. Circulation, 2021, 143(4), 298-309.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.050391] [PMID: 33040613]

Packer, M.; Butler, J.; Zannad, F.; Pocock, S.J.; Filippatos, G.; Ferreira, J.P.; Brueckmann, M.; Jamal, W.; Zeller, C.; Wanner, C.; Anker, S.D.; Group, E.S. Empagliflozin and major renal outcomes in heart failure. N. Engl. J. Med., 2021, 385(16), 1531-1533.
[http://dx.doi.org/10.1056/NEJMc2112411] [PMID: 34449179]

Kaze, A.D.; Zhuo, M.; Kim, S.C.; Patorno, E.; Paik, J.M. Association of SGLT2 inhibitors with cardiovascular, kidney, and safety outcomes among patients with diabetic kidney disease: A meta-analysis. Cardiovasc. Diabetol., 2022, 21(1), 47.
[http://dx.doi.org/10.1186/s12933-022-01476-x] [PMID: 35321742]

Persson, F.; Rossing, P.; Vart, P.; Chertow, G.M.; Hou, F.F.; Jongs, N.; McMurray, J.J.V.; Correa-Rotter, R.; Bajaj, H.S.; Stefansson, B.V.; Toto, R.D.; Langkilde, A.M.; Wheeler, D.C.; Heerspink, H.J.L. Efficacy and safety of dapagliflozin by baseline glycemic status: A prespecified analysis from the DAPA-CKD trial. Diabetes Care, 2021, 44(8), 1894-1897.
[http://dx.doi.org/10.2337/dc21-0300] [PMID: 34183431]

Chertow, G.M.; Vart, P.; Jongs, N.; Toto, R.D.; Gorriz, J.L.; Hou, F.F.; McMurray, J.J.V.; Correa-Rotter, R.; Rossing, P.; Sjöström, C.D.; Stefánsson, B.V.; Langkilde, A.M.; Wheeler, D.C.; Heerspink, H.J.L. Effects of dapagliflozin in stage 4 chronic kidney disease. J. Am. Soc. Nephrol., 2021, 32(9), 2352-2361.
[http://dx.doi.org/10.1681/ASN.2021020167] [PMID: 34272327]