Login Register Cart 0
Generic placeholder image

Cardiovascular & Hematological Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5257
ISSN (Online): 1875-6182

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

Potential Therapeutic Benefits of Sodium-Glucose Cotransporter 2 Inhibitors in the Context of Ischemic Heart Failure: A State-of-the-Art Review

Author(s): Mauro Gitto, Dimitrios A. Vrachatis*, Gianluigi Condorelli, Konstantinos Papathanasiou, Bernhard Reimers, Spyridon Deftereos and Giulio G Stefanini

Volume 20, Issue 2, 2022

Published on: 29 November, 2021

Page: [90 - 102] Pages: 13

DOI: 10.2174/1871525719666210809121016

Price: $65

Abstract

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are a class of anti-diabetic agents that block the reabsorption of glucose in the proximal convoluted tubule of the nephron, thereby contributing to glycosuria and lowering blood glucose levels. SGLT2 inhibitors have been associated with improved cardiovascular outcomes in patients with diabetes, including a reduced risk of cardiovascular death and hospitalizations for heart failure. Recently, DAPA-HF and EMPEROR REDUCED trials showed the beneficial cardiovascular effect of SGLT2 inhibitors in patients with heart failure with consistently reduced ejection fraction (HFrEF) regardless of the presence of diabetes. Moreover, some exploratory studies suggested that these drugs improve Left Ventricular (LV) systolic function and oppose LV adverse remodeling in patients with HFrEF. However, the exact mechanisms that mediated for this benefit are not fully understood. Beyond glycemic control, enhanced natriuresis, increased erythropoiesis, improved endothelial function and changes in myocardial metabolism may all play an active role in SGLT2 inhibitors’ cardiovascular benefits. A deep understanding of the pathophysiological interplay is key to define which HF phenotype could benefit more from SGLT2 inhibitors. Current evidence on the comparison of different HF etiologies is limited to posthoc subgroup analysis of DAPA-HF and EMPEROR-REDUCED, which showed similar outcomes in patients with or without ischemic HF. On the other hand, in earlier studies of patients suffering from diabetes, rates of classic ischemic endpoints, such as myocardial infarction, stroke or coronary revascularization, did not differ between patients treated with SGLT2 inhibitors or placebo. The aim of this review is to discuss whether SGLT2 inhibitors may improve prognosis in patients with ischemic HF, not only in terms of reducing re-hospitalizations and improving LV function but also by limiting coronary artery disease progression and ischemic burden.

Keywords: SGLT2 inhibitors, ischemic heart failure, left ventricular remodelling, atherosclerosis, coronary artery disease, type 2 diabetes mellitus.

« Previous Next »
Graphical Abstract

[1]
Virani, S.S.; Alonso, A.; Benjamin, E.J.; Bittencourt, M.S.; Callaway, C.W.; Carson, A.P.; Chamberlain, A.M.; Chang, A.R.; Cheng, S.; Delling, F.N.; Djousse, L.; Elkind, M.S.V.; Ferguson, J.F.; Fornage, M.; Khan, S.S.; Kissela, B.M.; Knutson, K.L.; Kwan, T.W.; Lackland, D.T.; Lewis, T.T.; Lichtman, J.H.; Longenecker, C.T.; Loop, M.S.; Lutsey, P.L.; Martin, S.S.; Matsushita, K.; Moran, A.E.; Mussolino, M.E.; Perak, A.M.; Rosamond, W.D.; Roth, G.A.; Sampson, U.K.A.; Satou, G.M.; Schroeder, E.B.; Shah, S.H.; Shay, C.M.; Spartano, N.L.; Stokes, A.; Tirschwell, D.L.; VanWagner, L.B.; Tsao, C.W. Heart disease and stroke statistics-2020 update: A report from the American heart association. Circulation, 2020, 141(9), e139-e596.
[http://dx.doi.org/10.1161/CIR.0000000000000757] [PMID: 31992061]
[2]
Ponikowski, P.; Voors, A.A.; Anker, S.D.; Bueno, H.; Cleland, J.G.F.; Coats, A.J.S. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J., 2016, 37, 2129-2200.
[http://dx.doi.org/10.1093/eurheartj/ehw128] [PMID: 27206819]
[3]
Yusuf, S.; Pitt, B.; Davis, C.E.; Hood, W.B.; Cohn, J.N. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N. Engl. J. Med., 1991, 325(5), 293-302.
[http://dx.doi.org/10.1056/NEJM199108013250501] [PMID: 2057034]
[4]
Merit-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet, 1999, 353(9169), 2001-2007.
[http://dx.doi.org/10.1016/S0140-6736(99)04440-2] [PMID: 10376614]
[5]
Investigators, C.I. The Cardiac insufficiency bisoprolol study II (CIBIS-II) a randomised trial. Lancet, 1999, 353(9146), 9-13.
[http://dx.doi.org/10.1016/S0140-6736(98)11181-9] [PMID: 10023943]
[6]
Pitt, B.; Zannad, F.; Remme, W.J.; Cody, R.; Castaigne, A.; Perez, A.; Palensky, J.; Wittes, J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N. Engl. J. Med., 1999, 341(10), 709-717.
[http://dx.doi.org/10.1056/NEJM199909023411001] [PMID: 10471456]
[7]
Packer, M.; Coats, A.J.; Fowler, M.B.; Katus, H.A.; Krum, H.; Mohacsi, P.; Rouleau, J.L.; Tendera, M.; Castaigne, A.; Roecker, E.B.; Schultz, M.K.; DeMets, D.L. Effect of Carvedilol on survival in severe chronic heart failure. N. Engl. J. Med., 2001, 344(22), 1651-1658.
[http://dx.doi.org/10.1056/NEJM200105313442201] [PMID: 11386263]
[8]
Zannad, F.; McMurray, J.J.V.; Krum, H.; van Veldhuisen, D.J.; Swedberg, K.; Shi, H.; Vincent, J.; Pocock, S.J.; Pitt, B. Eplerenone in patients with systolic heart failure and mild symptoms. N. Engl. J. Med., 2011, 364(1), 11-21.
[http://dx.doi.org/10.1056/NEJMoa1009492] [PMID: 21073363]
[9]
McMurray, J.J.V.; Packer, M.; Desai, A.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.L.; Shi, V.C.; Solomon, S.D.; Swedberg, K.; Zile, M.R. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N. Engl. J. Med., 2014, 371(11), 993-1004.
[http://dx.doi.org/10.1056/NEJMoa1409077] [PMID: 25176015]
[10]
Gallo, L.A.; Wright, E.M.; Vallon, V. Probing SGLT2 as a therapeutic target for diabetes: Basic physiology and consequences. Diab. Vasc. Dis. Res., 2015, 12(2), 78-89.
[http://dx.doi.org/10.1177/1479164114561992] [PMID: 25616707]
[11]
Hasan, F.M.; Alsahli, M.; Gerich, J.E. SGLT2 inhibitors in the treatment of type 2 diabetes. Diabetes Res. Clin. Pract., 2014, 104(3), 297-322.
[http://dx.doi.org/10.1016/j.diabres.2014.02.014] [PMID: 24735709]
[12]
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. 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]
[13]
Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R. 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]
[14]
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. 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]
[15]
Wiviott, S.D.; Raz, I.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Silverman, M.G.; Zelniker, T.A.; Kuder, J.F.; Murphy, S.A.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Wilding, J.P.H.; Ruff, C.T.; Gause-Nilsson, I.A.M.; Fredriksson, M.; Johansson, P.A.; Langkilde, A.M.; Sabatine, M.S. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N. Engl. J. Med., 2019, 380(4), 347-357.
[http://dx.doi.org/10.1056/NEJMoa1812389] [PMID: 30415602]
[16]
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. 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]
[17]
Cannon, C.P.; Pratley, R.; Dagogo-Jack, S.; Mancuso, J.; Huyck, S.; Masiukiewicz, U.; Charbonnel, B.; Frederich, R.; Gallo, S.; Cosentino, F.; Shih, W.J.; Gantz, I.; Terra, S.G.; Cherney, D.Z.I.; McGuire, D.K. Cardiovascular outcomes with ertugliflozin in type 2 diabetes. N. Engl. J. Med., 2020, 383(15), 1425-1435.
[http://dx.doi.org/10.1056/NEJMoa2004967] [PMID: 32966714]
[18]
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]
[19]
McMurray, J.J.V.; Solomon, S.D.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; Sabatine, M.S.; Anand, I.S.; Bělohlávek, J.; Böhm, M.; Chiang, C.E.; Chopra, V.K.; de Boer, R.A.; Desai, A.S.; Diez, M.; Drozdz, J.; Dukát, A.; Ge, J.; Howlett, J.G.; Katova, T.; Kitakaze, M.; Ljungman, C.E.A.; Merkely, B.; Nicolau, J.C.; O’Meara, E.; Petrie, M.C.; Vinh, P.N.; Schou, M.; Tereshchenko, S.; Verma, S.; Held, C.; DeMets, D.L.; Docherty, K.F.; Jhund, P.S.; Bengtsson, O.; Sjöstrand, M.; Langkilde, A.M. 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]
[20]
Seferović, P.M.; Fragasso, G.; Petrie, M.; Mullens, W.; Ferrari, R.; Thum, T.; Bauersachs, J.; Anker, S.D.; Ray, R.; Çavuşoğlu, Y.; Polovina, M.; Metra, M.; Ambrosio, G.; Prasad, K.; Seferović, J.; Jhund, P.S.; Dattilo, G.; Čelutkiene, J.; Piepoli, M.; Moura, B.; Chioncel, O.; Ben Gal, T.; Heymans, S.; Jaarsma, T.; Hill, L.; Lopatin, Y.; Lyon, A.R.; Ponikowski, P.; Lainščak, M.; Jankowska, E.; Mueller, C.; Cosentino, F.; Lund, L.H.; Filippatos, G.S.; Ruschitzka, F.; Coats, A.J.S.; Rosano, G.M.C. Heart Failure Association of the European Society of Cardiology update on sodium-glucose co-transporter 2 inhibitors in heart failure. Eur. J. Heart Fail., 2020, 22(11), 1984-1986.
[http://dx.doi.org/10.1002/ejhf.2026] [PMID: 33068051]
[21]
Lloyd-Jones, D.M.; Larson, M.G.; Leip, E.P.; Beiser, A.; D’Agostino, R.B.; Kannel, W.B.; Murabito, J.M.; Vasan, R.S.; Benjamin, E.J.; Levy, D. Lifetime risk for developing congestive heart failure: the Framingham Heart Study. Circulation, 2002, 106(24), 3068-3072.
[http://dx.doi.org/10.1161/01.CIR.0000039105.49749.6F] [PMID: 12473553]
[22]
Nowbar, A.N.; Gitto, M.; Howard, J.P.; Francis, D.P.; Al-Lamee, R. Mortality from ischemic heart disease. Circ. Cardiovasc. Qual. Outcomes, 2019, 12(6), e005375.
[http://dx.doi.org/10.1161/CIRCOUTCOMES.118.005375] [PMID: 31163980]
[23]
Braunwald, E. Heart failure. JACC Heart Fail., 2013, 1(1), 1-20.
[http://dx.doi.org/10.1016/j.jchf.2012.10.002] [PMID: 24621794]
[24]
Kluger, A.Y.; Tecson, K.M.; Lee, A.Y.; Lerma, E.V.; Rangaswami, J.; Lepor, N.E.; Cobble, M.E.; McCullough, P.A. Class effects of SGLT2 inhibitors on cardiorenal outcomes. Cardiovasc. Diabetol., 2019, 18(1), 99.
[http://dx.doi.org/10.1186/s12933-019-0903-4] [PMID: 31382965]
[25]
Zannad, F.; Ferreira, J.P.; Pocock, S.J.; Anker, S.D.; Butler, J.; Filippatos, G.; Brueckmann, M.; Ofstad, A.P.; Pfarr, E.; Jamal, W.; Packer, M. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: A meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet, 2020, 396(10254), 819-829.
[http://dx.doi.org/10.1016/S0140-6736(20)31824-9] [PMID: 32877652]
[26]
Seferović, P.M.; Polovina, M.M.; Coats, A.J.S. Heart failure in dilated non-ischaemic cardiomyopathy. Eur. Heart J. Suppl., 2019, 21(Suppl. M), M40-M43.
[http://dx.doi.org/10.1093/eurheartj/suz212] [PMID: 31908615]
[27]
Pecini, R.; Møller, D.V.; Torp-Pedersen, C.; Hassager, C.; Køber, L. Heart failure etiology impacts survival of patients with heart failure. Int. J. Cardiol., 2011, 149(2), 211-215.
[http://dx.doi.org/10.1016/j.ijcard.2010.01.011] [PMID: 20193969]
[28]
Frazier, C.G.; Alexander, K.P.; Newby, L.K.; Anderson, S.; Iverson, E.; Packer, M.; Cohn, J.; Goldstein, S.; Douglas, P.S. Associations of gender and etiology with outcomes in heart failure with systolic dysfunction: a pooled analysis of 5 randomized control trials. J. Am. Coll. Cardiol., 2007, 49(13), 1450-1458.
[http://dx.doi.org/10.1016/j.jacc.2006.11.041] [PMID: 17397674]
[29]
Mogensen, U.M.; Køber, L.; Kristensen, S.L.; Jhund, P.S.; Gong, J.; Lefkowitz, M.P.; Rizkala, A.R.; Rouleau, J.L.; Shi, V.C.; Swedberg, K.; Zile, M.R.; Solomon, S.D.; Packer, M.; McMurray, J.J.V. The effects of sacubitril/valsartan on coronary outcomes in PARADIGM-HF. Am. Heart J., 2017, 188, 35-41.
[http://dx.doi.org/10.1016/j.ahj.2017.02.034] [PMID: 28577679]
[30]
Fang, J.C. Heart-failure therapy - New drugs but old habits? N. Engl. J. Med., 2019, 381(21), 2063-2064.
[http://dx.doi.org/10.1056/NEJMe1912180] [PMID: 31535828]
[31]
Jarcho, J.A. More evidence for SGLT2 inhibitors in heart failure. N. Engl. J. Med., 2020, 383(15), 1481-1482.
[http://dx.doi.org/10.1056/NEJMe2027915] [PMID: 32865378]
[32]
Packer, M.; Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Pocock, S.J.; Rocca, H.B.; Janssens, S.; Tsutsui, H.; Zhang, J.; Brueckmann, M.; Jamal, W.; Cotton, D.; Iwata, T.; Schnee, J.; Zannad, F. Influence of neprilysin inhibition on the efficacy and safety of empagliflozin in patients with chronic heart failure and a reduced ejection fraction: The EMPEROR-reduced trial. Eur. Heart J., 2021, 42(6), 671-680.
[http://dx.doi.org/10.1093/eurheartj/ehaa968] [PMID: 33459776]
[33]
Docherty, K.F.; Jhund, P.S.; Inzucchi, S.E.; Køber, L.; Kosiborod, M.N.; Martinez, F.A.; Ponikowski, P.; DeMets, D.L.; Sabatine, M.S.; Bengtsson, O.; Sjöstrand, M.; Langkilde, A.M.; Desai, A.S.; Diez, M.; Howlett, J.G.; Katova, T.; Ljungman, C.E.A.; O’Meara, E.; Petrie, M.C.; Schou, M.; Verma, S.; Vinh, P.N.; Solomon, S.D.; McMurray, J.J.V. Effects of dapagliflozin in DAPA-HF according to background heart failure therapy. Eur. Heart J., 2020, 41(25), 2379-2392.
[http://dx.doi.org/10.1093/eurheartj/ehaa183] [PMID: 32221582]
[34]
Jackson, A.M.; Dewan, P.; Anand, I.S.; Bělohlávek, J.; Bengtsson, O.; de Boer, R.A.; Böhm, M.; Boulton, D.W.; Chopra, V.K.; DeMets, D.L.; Docherty, K.F.; Dukát, A.; Greasley, P.J.; Howlett, J.G.; Inzucchi, S.E.; Katova, T.; Køber, L.; Kosiborod, M.N.; Langkilde, A.M.; Lindholm, D.; Ljungman, C.E.A.; Martinez, F.A.; O’Meara, E.; Sabatine, M.S.; Sjöstrand, M.; Solomon, S.D.; Tereshchenko, S.; Verma, S.; Jhund, P.S.; McMurray, J.J.V. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation, 2020, 142(11), 1040-1054.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047077] [PMID: 32673497]
[35]
Bhatt, D.L.; Szarek, M.; Steg, P.G.; Cannon, C.P.; Leiter, L.A.; McGuire, D.K.; Lewis, J.B.; Riddle, M.C.; Voors, A.A.; Metra, M.; Lund, L.H.; Komajda, M.; Testani, J.M.; Wilcox, C.S.; Ponikowski, P.; Lopes, R.D.; Verma, S.; Lapuerta, P.; Pitt, B. Sotagliflozin in patients with diabetes and recent worsening heart failure. N. Engl. J. Med., 2021, 384(2), 117-128.
[http://dx.doi.org/10.1056/NEJMoa2030183] [PMID: 33200892]
[36]
Powell, D.R.; Zambrowicz, B.; Morrow, L.; Beysen, C.; Hompesch, M.; Turner, S.; Hellerstein, M.; Banks, P.; Strumph, P.; Lapuerta, P. Sotagliflozin decreases postprandial glucose and insulin concentrations by delaying intestinal glucose absorption. J. Clin. Endocrinol. Metab., 2020, 105(4), e1235-e1249.
[http://dx.doi.org/10.1210/clinem/dgz258] [PMID: 31837264]
[37]
Sands, A.T.; Zambrowicz, B.P.; Rosenstock, J.; Lapuerta, P.; Bode, B.W.; Garg, S.K.; Buse, J.B.; Banks, P.; Heptulla, R.; Rendell, M.; Cefalu, W.T.; Strumph, P. Sotagliflozin, a dual SGLT1 and SGLT2 inhibitor, as adjunct therapy to insulin in type 1 diabetes. Diabetes Care, 2015, 38(7), 1181-1188.
[http://dx.doi.org/10.2337/dc14-2806] [PMID: 26049551]
[38]
Withaar, C.; Meems, L.M.; Markousis-Mavrogenis, G.; Boogerd, C.J.; Silljé, H.H.W.; Schouten, E.M.; Dokter, M.M.; Voors, A.A.; Westenbrink, B.D.; Lam, C.S.P.; de Boer, R.A. The effects of liraglutide and dapagliflozin on cardiac function and structure in a multi-hit mouse model of heart failure with preserved ejection fraction. Cardiovasc. Res., 2021, 117(9), 2108-2124.
[http://dx.doi.org/10.1093/cvr/cvaa256] [PMID: 32871009]
[39]
Packer, M. Lessons learned from the DAPA-HF trial concerning the mechanisms of benefit of SGLT2 inhibitors on heart failure events in the context of other large-scale trials nearing completion. Cardiovasc. Diabetol., 2019, 18(1), 129.
[http://dx.doi.org/10.1186/s12933-019-0938-6] [PMID: 31585532]
[40]
Nissen, S.E.; Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med., 2007, 356(24), 2457-2471.
[http://dx.doi.org/10.1056/NEJMoa072761] [PMID: 17517853]
[41]
Lincoff, A.M.; Wolski, K.; Nicholls, S.J.; Nissen, S.E. Pioglitazone and risk of cardiovascular events in patients with type 2 diabetes mellitus: a meta-analysis of randomized trials. JAMA, 2007, 298(10), 1180-1188.
[http://dx.doi.org/10.1001/jama.298.10.1180] [PMID: 17848652]
[42]
Zelniker, T.A.; Wiviott, S.D.; Raz, I.; Im, K.; Goodrich, E.L.; Bonaca, M.P.; Mosenzon, O.; Kato, E.T.; Cahn, A.; Furtado, R.H.M.; Bhatt, D.L.; Leiter, L.A.; McGuire, D.K.; Wilding, J.P.H.; Sabatine, M.S. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: A systematic review and meta-analysis of cardiovascular outcome trials. Lancet, 2019, 393(10166), 31-39.
[http://dx.doi.org/10.1016/S0140-6736(18)32590-X] [PMID: 30424892]
[43]
Fitchett, D.; Butler, J.; van de Borne, P.; Zinman, B.; Lachin, J.M.; Wanner, C.; Woerle, H.J.; Hantel, S.; George, J.T.; Johansen, O.E.; Inzucchi, S.E. Effects of empagliflozin on risk for cardiovascular death and heart failure hospitalization across the spectrum of heart failure risk in the EMPA-REG OUTCOME OUTCOME® trial. Eur. Heart J., 2018, 39(5), 363-370.
[http://dx.doi.org/10.1093/eurheartj/ehx511] [PMID: 29020355]
[44]
Wu, J.H.Y.; Foote, C.; Blomster, J.; Toyama, T.; Perkovic, V.; Sundström, J.; Neal, B. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes: A systematic review and meta-analysis. Lancet Diabetes Endocrinol., 2016, 4(5), 411-419.
[http://dx.doi.org/10.1016/S2213-8587(16)00052-8] [PMID: 27009625]
[45]
Zhou, Z.; Lindley, R.I.; Rådholm, K.; Jenkins, B.; Watson, J.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Shaw, W.; Oh, R.; Desai, M.; Matthews, D.R.; Neal, B. Canagliflozin and stroke in type 2 diabetes mellitus. Stroke, 2019, 50(2), 396-404.
[http://dx.doi.org/10.1161/STROKEAHA.118.023009] [PMID: 30591006]
[46]
Sano, M.; Goto, S. Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation, 2019, 139(17), 1985-1987.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.038881] [PMID: 31009585]
[47]
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]
[48]
Imprialos, K.P.; Boutari, C.; Stavropoulos, K.; Doumas, M.; Karagiannis, A.I. Stroke paradox with SGLT-2 inhibitors: A play of chance or a viscosity-mediated reality? J. Neurol. Neurosurg. Psychiatry, 2017, 88(3), 249-253.
[http://dx.doi.org/10.1136/jnnp-2016-314704] [PMID: 27895093]
[49]
Irace, C.; Casciaro, F.; Scavelli, F.B.; Oliverio, R.; Cutruzzolà, A.; Cortese, C.; Gnasso, A. Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. Cardiovasc. Diabetol., 2018, 17(1), 52.
[http://dx.doi.org/10.1186/s12933-018-0695-y] [PMID: 29631585]
[50]
Fei, Y.; Tsoi, M.F.; Cheung, B.M.Y. Cardiovascular outcomes in trials of new antidiabetic drug classes: A network meta-analysis. Cardiovasc. Diabetol., 2019, 18(1), 112.
[http://dx.doi.org/10.1186/s12933-019-0916-z] [PMID: 31462224]
[51]
Pfeffer, M.A.; Braunwald, E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation, 1990, 81(4), 1161-1172.
[http://dx.doi.org/10.1161/01.CIR.81.4.1161] [PMID: 2138525]
[52]
Chareonthaitawee, P.; Christian, T.F.; Hirose, K.; Gibbons, R.J.; Rumberger, J.A. Relation of initial infarct size to extent of left ventricular remodeling in the year after acute myocardial infarction. J. Am. Coll. Cardiol., 1995, 25(3), 567-573.
[http://dx.doi.org/10.1016/0735-1097(94)00431-O] [PMID: 7860898]
[53]
Sutton, M.G.; Sharpe, N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation, 2000, 101(25), 2981-2988.
[http://dx.doi.org/10.1161/01.CIR.101.25.2981] [PMID: 10869273]
[54]
Burchfield, J.S.; Xie, M.; Hill, J.A. Pathological ventricular remodeling: Mechanisms: part 1 of 2. Circulation, 2013, 128(4), 388-400.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.001878] [PMID: 23877061]
[55]
Bhatt, A.S.; Ambrosy, A.P.; Velazquez, E.J. Adverse remodeling and reverse remodeling after myocardial infarction. Curr. Cardiol. Rep., 2017, 19(8), 71.
[http://dx.doi.org/10.1007/s11886-017-0876-4] [PMID: 28660552]
[56]
Pepine, C.J.; Nichols, W.W. The pathophysiology of chronic ischemic heart disease. Clin. Cardiol., 2007, 30(2)(S1), 4-9.
[http://dx.doi.org/10.1002/clc.20048] [PMID: 18373328]
[57]
Konstam, M.A.; Kramer, D.G.; Patel, A.R.; Maron, M.S.; Udelson, J.E. Left ventricular remodeling in heart failure: Current concepts in clinical significance and assessment. JACC Cardiovasc. Imaging, 2011, 4(1), 98-108.
[http://dx.doi.org/10.1016/j.jcmg.2010.10.008] [PMID: 21232712]
[58]
Elgendy, I.Y.; Mahtta, D.; Pepine, C.J. Medical therapy for heart failure caused by ischemic heart disease. Circ. Res., 2019, 124(11), 1520-1535.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.313568] [PMID: 31120824]
[59]
Verma, S.; Mazer, C.D.; Yan, A.T.; Mason, T.; Garg, V.; Teoh, H.; Zuo, F.; Quan, A.; Farkouh, M.E.; Fitchett, D.H.; Goodman, S.G.; Goldenberg, R.M.; Al-Omran, M.; Gilbert, R.E.; Bhatt, D.L.; Leiter, L.A.; Jüni, P.; Zinman, B.; Connelly, K.A. Effect of Empagliflozin on left ventricular mass in patients with type 2 diabetes mellitus and Coronary artery disease: The EMPA-HEART cardiolink-6 randomized clinical trial. Circulation, 2019, 140(21), 1693-1702.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042375] [PMID: 31434508]
[60]
Singh, J.S.S.; Mordi, I.R.; Vickneson, K.; Fathi, A.; Donnan, P.T.; Mohan, M.; Choy, A.M.J.; Gandy, S.; George, J.; Khan, F.; Pearson, E.R.; Houston, J.G.; Struthers, A.D.; Lang, C.C. Dapagliflozin versus placebo on left ventricular remodeling in patients with diabetes and heart failure: The REFORM trial. Diabetes Care, 2020, 43(6), 1356-1359.
[http://dx.doi.org/10.2337/dc19-2187] [PMID: 32245746]
[61]
Santos-Gallego, C.G.; Vargas-Delgado, A.P.; Requena-Ibanez, J.A.; Garcia-Ropero, A.; Mancini, D.; Pinney, S.; Macaluso, F.; Sartori, S.; Roque, M.; Sabatel-Perez, F.; Rodriguez-Cordero, A.; Zafar, M.U.; Fergus, I.; Atallah-Lajam, F.; Contreras, J.P.; Varley, C.; Moreno, P.R.; Abascal, V.M.; Lala, A.; Tamler, R.; Sanz, J.; Fuster, V.; Badimon, J.J. Randomized trial of Empagliflozin in nondiabetic patients with heart failure and reduced ejection fraction. J. Am. Coll. Cardiol., 2021, 77(3), 243-255.
[http://dx.doi.org/10.1016/j.jacc.2020.11.008] [PMID: 33197559]
[62]
Lee, M.M.Y.; Brooksbank, K.J.M.; Wetherall, K.; Mangion, K.; Roditi, G.; Campbell, R.T.; Berry, C.; Chong, V.; Coyle, L.; Docherty, K.F.; Dreisbach, J.G.; Labinjoh, C.; Lang, N.N.; Lennie, V.; McConnachie, A.; Murphy, C.L.; Petrie, C.J.; Petrie, J.R.; Speirits, I.A.; Sourbron, S.; Welsh, P.; Woodward, R.; Radjenovic, A.; Mark, P.B.; McMurray, J.J.V.; Jhund, P.S.; Petrie, M.C.; Sattar, N. Effect of Empagliflozin on left ventricular volumes in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF). Circulation, 2021, 143(6), 516-525.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.052186] [PMID: 33186500]
[63]
Omar, M.; Jensen, J.; Ali, M.; Frederiksen, P.H.; Kistorp, C.; Videbæk, L.; Poulsen, M.K.; Tuxen, C.D.; Möller, S.; Gustafsson, F.; Køber, L.; Schou, M.; Møller, J.E. Associations of Empagliflozin with left ventricular volumes, mass, and function in patients with heart failure and reduced ejection fraction: A substudy of the empire HF randomized clinical trial. JAMA Cardiol., 2021, 6(7), 836-840.
[http://dx.doi.org/10.1001/jamacardio.2020.6827] [PMID: 33404637]
[64]
Verma, A.; Patel, A.B.; Waikar, S.S. SGLT2 Inhibitor: Not a traditional diuretic for heart failure. Cell Metab., 2020, 32(1), 13-14.
[http://dx.doi.org/10.1016/j.cmet.2020.06.014] [PMID: 32640243]
[65]
Goldberg, L.R. The pleiotropic effects of SGLT2 inhibitors: Remodeling the treatment of heart failure. J. Am. Coll. Cardiol., 2021, 77(3), 256-258.
[http://dx.doi.org/10.1016/j.jacc.2020.11.029] [PMID: 33478648]
[66]
Jensen, J.; Omar, M.; Kistorp, C.; Poulsen, M.K.; Tuxen, C.; Gustafsson, I.; Køber, L.; Gustafsson, F.; Faber, J.; Fosbøl, E.L.; Bruun, N.E.; Brønd, J.C.; Forman, J.L.; Videbæk, L.; Møller, J.E.; Schou, M. Twelve weeks of treatment with empagliflozin in patients with heart failure and reduced ejection fraction: A double-blinded, randomized, and placebo-controlled trial. Am. Heart J., 2020, 228, 47-56.
[http://dx.doi.org/10.1016/j.ahj.2020.07.011] [PMID: 32798787]
[67]
Nassif, M.E.; Windsor, S.L.; Tang, F.; Khariton, Y.; Husain, M.; Inzucchi, S.E.; McGuire, D.K.; Pitt, B.; Scirica, B.M.; Austin, B.; Drazner, M.H.; Fong, M.W.; Givertz, M.M.; Gordon, R.A.; Jermyn, R.; Katz, S.D.; Lamba, S.; Lanfear, D.E.; LaRue, S.J.; Lindenfeld, J.; Malone, M.; Margulies, K.; Mentz, R.J.; Mutharasan, R.K.; Pursley, M.; Umpierrez, G.; Kosiborod, M. Dapagliflozin effects on biomarkers, symptoms, and functional status in patients with heart failure with reduced ejection fraction: The DEFINE-HF trial. Circulation, 2019, 140(18), 1463-1476.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042929] [PMID: 31524498]
[68]
Tripolt, N.J.; Kolesnik, E.; Pferschy, P.N.; Verheyen, N.; Ablasser, K.; Sailer, S.; Alber, H.; Berger, R.; Kaulfersch, C.; Leitner, K.; Lichtenauer, M.; Mader, A.; Moertl, D.; Oulhaj, A.; Reiter, C.; Rieder, T.; Saely, C.H.; Siller-Matula, J.; Weidinger, F.; Zechner, P.M.; von Lewinski, D.; Sourij, H. Impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MY ocardial infarction-The EMMY trial. Am. Heart J., 2020, 221, 39-47.
[http://dx.doi.org/10.1016/j.ahj.2019.12.004] [PMID: 31901799]
[69]
Griffin, M.; Rao, V.S.; Ivey-Miranda, J.; Fleming, J.; Mahoney, D.; Maulion, C.; Suda, N.; Siwakoti, K.; Ahmad, T.; Jacoby, D.; Riello, R.; Bellumkonda, L.; Cox, Z.; Collins, S.; Jeon, S.; Turner, J.M.; Wilson, F.P.; Butler, J.; Inzucchi, S.E.; Testani, J.M. Empagliflozin in heart failure: Diuretic and cardiorenal effects. Circulation, 2020, 142(11), 1028-1039.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045691] [PMID: 32410463]
[70]
Cowie, M.R.; Fisher, M. SGLT2 inhibitors: Mechanisms of cardiovascular benefit beyond glycaemic control. Nat. Rev. Cardiol., 2020, 17(12), 761-772.
[http://dx.doi.org/10.1038/s41569-020-0406-8] [PMID: 32665641]
[71]
Nikolic, M.; Zivkovic, V.; Jovic, J.J.; Sretenovic, J.; Davidovic, G.; Simovic, S.; Djokovic, D.; Muric, N.; Bolevich, S.; Jakovljevic, V. SGLT2 inhibitors: A focus on cardiac benefits and potential mechanisms. Heart Fail. Rev., 2021, 1-5.
[http://dx.doi.org/10.1007/s10741-021-10079-9] [PMID: 33534040]
[72]
Tikkanen, I.; Chilton, R.; Johansen, O.E. Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension. Curr. Opin. Nephrol. Hypertens., 2016, 25(2), 81-86.
[http://dx.doi.org/10.1097/MNH.0000000000000199] [PMID: 26808705]
[73]
Zhao, D.; Liu, H.; Dong, P. Empagliflozin reduces blood pressure and uric acid in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. J. Hum. Hypertens., 2019, 33(4), 327-339.
[http://dx.doi.org/10.1038/s41371-018-0134-2] [PMID: 30443007]
[74]
Mancia, G; Cannon, CP; Tikkanen, I; Zeller, C; Ley, L; Woerle, HJ. Impact of Empagliflozin on blood pressure in patients with type 2 diabetes mellitus and hypertension by background antihypertensive medication. Hypertension, 2016, 68, 1355-1364.
[75]
Sano, M. A new class of drugs for heart failure: SGLT2 inhibitors reduce sympathetic overactivity. J. Cardiol., 2018, 71(5), 471-476.
[http://dx.doi.org/10.1016/j.jjcc.2017.12.004] [PMID: 29415819]
[76]
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), 8.
[http://dx.doi.org/10.1186/s12933-017-0654-z] [PMID: 29301520]
[77]
Schneider, M.P.; Raff, U.; Kopp, C.; Scheppach, J.B.; Toncar, S.; Wanner, C.; Schlieper, G.; Saritas, T.; Floege, J.; Schmid, M.; Birukov, A.; Dahlmann, A.; Linz, P.; Janka, R.; Uder, M.; Schmieder, R.E.; Titze, J.M.; Eckardt, K.U. Skin sodium concentration correlates with left ventricular hypertrophy in CKD. J. Am. Soc. Nephrol., 2017, 28(6), 1867-1876.
[http://dx.doi.org/10.1681/ASN.2016060662] [PMID: 28154199]
[78]
Lee, P.C.; Ganguly, S.; Goh, S-Y. Weight loss associated with sodium-glucose cotransporter-2 inhibition: A review of evidence and underlying mechanisms. Obes. Rev., 2018, 19(12), 1630-1641.
[http://dx.doi.org/10.1111/obr.12755] [PMID: 30253050]
[79]
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]
[80]
Maruyama, T.; Takashima, H.; Oguma, H.; Nakamura, Y.; Ohno, M.; Utsunomiya, K.; Furukawa, T.; Tei, R.; Abe, M. Canagliflozin Improves erythropoiesis in diabetes patients with anemia of chronic kidney disease. Diabetes Technol. Ther., 2019, 21(12), 713-720.
[http://dx.doi.org/10.1089/dia.2019.0212] [PMID: 31385724]
[81]
Ali-Hassan-Sayegh, S.; Mirhosseini, S.J.; Tahernejad, M.; Mahdavi, P.; Haddad, F.; Shahidzadeh, A.; Lotfaliani, M.R.; Sedaghat-Hamedani, F.; Kayvanpour, E.; Weymann, A.; Sabashnikov, A.; Popov, A.F. Administration of erythropoietin in patients with myocardial infarction: Does it make sense? An updated and comprehensive meta-analysis and systematic review. Cardiovasc. Revasc. Med., 2015, 16(3), 179-189.
[http://dx.doi.org/10.1016/j.carrev.2015.01.008] [PMID: 25704158]
[82]
Ott, I.; Schulz, S.; Mehilli, J.; Fichtner, S.; Hadamitzky, M.; Hoppe, K.; Ibrahim, T.; Martinoff, S.; Massberg, S.; Laugwitz, K.L.; Dirschinger, J.; Schwaiger, M.; Kastrati, A.; Schmig, A. Erythropoietin in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: A randomized, double-blind trial. Circ. Cardiovasc. Interv., 2010, 3(5), 408-413.
[http://dx.doi.org/10.1161/CIRCINTERVENTIONS.109.904425] [PMID: 20736448]
[83]
Steppich, B.; Groha, P.; Ibrahim, T.; Schunkert, H.; Laugwitz, K-L.; Hadamitzky, M.; Kastrati, A.; Ott, I. Effect of Erythropoietin in patients with acute myocardial infarction: five-year results of the REVIVAL-3 trial. BMC Cardiovasc. Disord., 2017, 17(1), 38.
[http://dx.doi.org/10.1186/s12872-016-0464-3] [PMID: 28109258]
[84]
Zelniker, T.A.; 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), 422-434.
[http://dx.doi.org/10.1016/j.jacc.2019.11.031] [PMID: 32000955]
[85]
Arima, Y.; Izumiya, Y.; Ishida, T.; Takashio, S.; Ishii, M.; Sueta, D.; Fujisue, K.; Sakamoto, K.; Kaikita, K.; Tsujita, K. Myocardial ischemia suppresses ketone body utilization. J. Am. Coll. Cardiol., 2019, 73(2), 246-247.
[http://dx.doi.org/10.1016/j.jacc.2018.10.040] [PMID: 30408507]
[86]
Shimizu, W.; Kubota, Y.; Hoshika, Y.; Mozawa, K.; Tara, S.; Tokita, Y.; Yodogawa, K.; Iwasaki, Y.K.; Yamamoto, T.; Takano, H.; Tsukada, Y.; Asai, K.; Miyamoto, M.; Miyauchi, Y.; Kodani, E.; Ishikawa, M.; Maruyama, M.; Ogano, M.; Tanabe, J. Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: The EMBODY trial. Cardiovasc. Diabetol., 2020, 19(1), 148.
[http://dx.doi.org/10.1186/s12933-020-01127-z] [PMID: 32977831]
[87]
Lim, V.G.; Bell, R.M.; Arjun, S.; Kolatsi-Joannou, M.; Long, D.A.; Yellon, D.M. 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]
[88]
Abdurrachim, D.; Teo, X.Q.; Woo, C.C.; Chan, W.X.; Lalic, J.; Lam, C.S.P.; Lee, P.T.H. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: A hyperpolarized 13 C magnetic resonance spectroscopy study. Diabetes Obes. Metab., 2019, 21(2), 357-365.
[http://dx.doi.org/10.1111/dom.13536] [PMID: 30225964]
[89]
Packer, M. Activation and inhibition of sodium-hydrogen exchanger is a mechanism that links the pathophysiology and treatment of diabetes mellitus with that of heart failure. Circulation, 2017, 136(16), 1548-1559.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.117.030418] [PMID: 29038209]
[90]
Karmazyn, M.; Gan, X.T.; Humphreys, R.A.; Yoshida, H.; Kusumoto, K. The myocardial Na(+)-H(+) exchange: structure, regulation, and its role in heart disease. Circ. Res., 1999, 85(9), 777-786.
[http://dx.doi.org/10.1161/01.RES.85.9.777] [PMID: 10532945]
[91]
Di Franco, A.; Cantini, G.; Tani, A.; Coppini, R.; Zecchi-Orlandini, S.; Raimondi, L.; Luconi, M.; Mannucci, E. Sodium-dependent glucose transporters (SGLT) in human ischemic heart: A new potential pharmacological target. Int. J. Cardiol., 2017, 243, 86-90.
[http://dx.doi.org/10.1016/j.ijcard.2017.05.032] [PMID: 28526540]
[92]
Mentzer, R.M.J., Jr; Bartels, C.; Bolli, R.; Boyce, S.; Buckberg, G.D.; Chaitman, B.; Haverich, A.; Knight, J.; Menasché, P.; Myers, M.L.; Nicolau, J.; Simoons, M.; Thulin, L.; Weisel, R.D. Sodium-hydrogen exchange inhibition by cariporide to reduce the risk of ischemic cardiac events in patients undergoing coronary artery bypass grafting: Results of the expedition study. Ann. Thorac. Surg., 2008, 85(4), 1261-1270.
[http://dx.doi.org/10.1016/j.athoracsur.2007.10.054] [PMID: 18355507]
[93]
Zeymer, U.; Suryapranata, H.; Monassier, J.P.; Opolski, G.; Davies, J.; Rasmanis, G.; Linssen, G.; Tebbe, U.; Schröder, R.; Tiemann, R.; Machnig, T.; Neuhaus, K.L. The Na(+)/H(+) exchange inhibitor eniporide as an adjunct to early reperfusion therapy for acute myocardial infarction. Results of the evaluation of the safety and cardioprotective effects of eniporide in acute myocardial infarction (ESCAMI) trial. J. Am. Coll. Cardiol., 2001, 38(6), 1644-1650.
[http://dx.doi.org/10.1016/S0735-1097(01)01608-4] [PMID: 11704395]
[94]
Davies, M.J.; Trujillo, A.; Vijapurkar, U.; Damaraju, C.V.; Meininger, G. Effect of canagliflozin on serum uric acid in patients with type 2 diabetes mellitus. Diabetes Obes. Metab., 2015, 17(4), 426-429.
[http://dx.doi.org/10.1111/dom.12439] [PMID: 25600248]
[95]
Zhao, Y.; Xu, L.; Tian, D.; Xia, P.; Zheng, H.; Wang, L.; Chen, L. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibitors on serum uric acid level: A meta-analysis of randomized controlled trials. Diabetes Obes. Metab., 2018, 20(2), 458-462.
[http://dx.doi.org/10.1111/dom.13101] [PMID: 28846182]
[96]
Biscaglia, S.; Ceconi, C.; Malagù, M.; Pavasini, R.; Ferrari, R. Uric acid and coronary artery disease: An elusive link deserving further attention. Int. J. Cardiol., 2016, 213, 28-32.
[http://dx.doi.org/10.1016/j.ijcard.2015.08.086] [PMID: 26318389]
[97]
Grebe, A.; Hoss, F.; Latz, E. NLRP3 Inflammasome and the IL-1 Pathway in Atherosclerosis. Circ. Res., 2018, 122(12), 1722-1740.
[http://dx.doi.org/10.1161/CIRCRESAHA.118.311362] [PMID: 29880500]
[98]
Birnbaum, Y.; Bajaj, M.; Yang, H-C.; Ye, Y. Combined SGLT2 and DPP4 inhibition reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic nephropathy in mice with type 2 diabetes. Cardiovasc. Drugs Ther., 2018, 32(2), 135-145.
[http://dx.doi.org/10.1007/s10557-018-6778-x] [PMID: 29508169]
[99]
Maeda, S.; Matsui, T.; Takeuchi, M.; Yamagishi, S. Sodium-glucose cotransporter 2-mediated oxidative stress augments advanced glycation end products-induced tubular cell apoptosis. Diabetes Metab. Res. Rev., 2013, 29(5), 406-412.
[http://dx.doi.org/10.1002/dmrr.2407] [PMID: 23508966]
[100]
Yan, S.F.; Ramasamy, R.; Naka, Y.; Schmidt, A.M. Glycation, inflammation, and RAGE: A scaffold for the macrovascular complications of diabetes and beyond. Circ. Res., 2003, 93(12), 1159-1169.
[http://dx.doi.org/10.1161/01.RES.0000103862.26506.3D] [PMID: 14670831]
[101]
Paradela-Dobarro, B.; Agra, R.M.; Álvarez, L.; Varela-Román, A.; García-Acuña, J.M.; González-Juanatey, J.R.; Álvarez, E.; García-Seara, F.J. The different roles for the advanced glycation end products axis in heart failure and acute coronary syndrome settings. Nutr. Metab. Cardiovasc. Dis., 2019, 29(10), 1050-1060.
[http://dx.doi.org/10.1016/j.numecd.2019.06.014] [PMID: 31371263]
[102]
Nikolaou, P.E.; Efentakis, P.; Abu Qourah, F.; Femminò, S.; Makridakis, M.; Kanaki, Z.; Varela, A.; Tsoumani, M.; Davos, C.H.; Dimitriou, C.A.; Tasouli, A.; Dimitriadis, G.; Kostomitsopoulos, N.; Zuurbier, C.J.; Vlahou, A.; Klinakis, A.; Brizzi, M.F.; Iliodromitis, E.K.; Andreadou, I. Chronic Empagliflozin treatment reduces myocardial infarct size in nondiabetic mice through STAT-3-mediated protection on microvascular endothelial cells and reduction of oxidative stress. Antioxid. Redox Signal., 2021, 34(7), 551-571.
[http://dx.doi.org/10.1089/ars.2019.7923] [PMID: 32295413]
[103]
Andreadou, I.; Efentakis, P.; Balafas, E.; Togliatto, G.; Davos, C.H.; Varela, A.; Dimitriou, C.A.; Nikolaou, P.E.; Maratou, E.; Lambadiari, V.; Ikonomidis, I.; Kostomitsopoulos, N.; Brizzi, M.F.; Dimitriadis, G.; Iliodromitis, E.K. Empagliflozin limits myocardial infarction in vivo and cell death in vitro: Role of STAT3, mitochondria, and redox aspects. Front. Physiol., 2017, 8, 1077.
[http://dx.doi.org/10.3389/fphys.2017.01077] [PMID: 29311992]
[104]
Esterline, R.L.; Vaag, A.; Oscarsson, J.; Vora, J. Mechanisms in Endocrinology: SGLT2 inhibitors: Clinical benefits by restoration of normal diurnal metabolism? Eur. J. Endocrinol., 2018, 178(4), R113-R125.
[http://dx.doi.org/10.1530/EJE-17-0832] [PMID: 29371333]
[105]
Liu, C-Y.; Zhang, Y-H.; Li, R-B.; Zhou, L-Y.; An, T.; Zhang, R-C.; Zhai, M.; Huang, Y.; Yan, K.W.; Dong, Y.H.; Ponnusamy, M.; Shan, C.; Xu, S.; Wang, Q.; Zhang, Y.H.; Zhang, J.; Wang, K. LncRNA CAIF inhibits autophagy and attenuates myocardial infarction by blocking p53-mediated myocardin transcription. Nat. Commun., 2018, 9(1), 29.
[http://dx.doi.org/10.1038/s41467-017-02280-y] [PMID: 29295976]
[106]
Xie, M.; Kong, Y.; Tan, W.; May, H.; Battiprolu, P.K.; Pedrozo, Z.; Wang, Z.V.; Morales, C.; Luo, X.; Cho, G.; Jiang, N.; Jessen, M.E.; Warner, J.J.; Lavandero, S.; Gillette, T.G.; Turer, A.T.; Hill, J.A. Histone deacetylase inhibition blunts ischemia/reperfusion injury by inducing cardiomyocyte autophagy. Circulation, 2014, 129(10), 1139-1151.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002416] [PMID: 24396039]
[107]
Mizuno, M.; Kuno, A.; Yano, T.; Miki, T.; Oshima, H.; Sato, T.; Nakata, K.; Kimura, Y.; Tanno, M.; Miura, T. Empagliflozin normalizes the size and number of mitochondria and prevents reduction in mitochondrial size after myocardial infarction in diabetic hearts. Physiol. Rep., 2018, 6(12), e13741.
[http://dx.doi.org/10.14814/phy2.13741] [PMID: 29932506]
[108]
Li, L.; Xu, J.; He, L.; Peng, L.; Zhong, Q.; Chen, L.; Jiang, Z. The role of autophagy in cardiac hypertrophy. Acta Biochim. Biophys. Sin., 2016, 48(6), 491-500.
[http://dx.doi.org/10.1093/abbs/gmw025] [PMID: 27084518]
[109]
Jiang, K.; Xu, Y.; Wang, D.; Chen, F.; Tu, Z.; Qian, J.; Xu, S.; Xu, Y.; Hwa, J.; Li, J.; Shang, H.; Xiang, Y. Cardioprotective mechanism of SGLT2 inhibitor against myocardial infarction is through reduction of autosis. Protein Cell, 2021, 1-24.
[http://dx.doi.org/10.1007/s13238-020-00809-4] [PMID: 33417139]
[110]
Ren, C.; Sun, K.; Zhang, Y.; Hu, Y.; Hu, B.; Zhao, J.; He, Z.; Ding, R.; Wang, W.; Liang, C. Sodium-glucose CoTransporter-2 inhibitor empagliflozin ameliorates Sunitinib-induced cardiac dysfunction via regulation of AMPK-mTOR signaling pathway-mediated autophagy. Front. Pharmacol., 2021, 12, 664181.
[http://dx.doi.org/10.3389/fphar.2021.664181] [PMID: 33995090]
[111]
Packer, M. Autophagy-dependent and -independent modulation of oxidative and organellar stress in the diabetic heart by glucose-lowering drugs. Cardiovasc. Diabetol., 2020, 19(1), 62.
[http://dx.doi.org/10.1186/s12933-020-01041-4] [PMID: 32404204]
[112]
Giannitsi, S.; Bougiakli, M.; Bechlioulis, A.; Naka, K. Endothelial dysfunction and heart failure: A review of the existing bibliography with emphasis on flow mediated dilation. JRSM Cardiovasc. Dis., 2019, 8, 2048004019843047.
[http://dx.doi.org/10.1177/2048004019843047] [PMID: 31007907]
[113]
Kunadian, V.; Chieffo, A.; Camici, P.G.; Berry, C.; Escaned, J.; Maas, A.H.E.M.; Prescott, E.; Karam, N.; Appelman, Y.; Fraccaro, C.; Louise Buchanan, G.; Manzo-Silberman, S.; Al-Lamee, R.; Regar, E.; Lansky, A.; Abbott, J.D.; Badimon, L.; Duncker, D.J.; Mehran, R.; Capodanno, D.; Baumbach, A. An EAPCI expert consensus document on ischaemia with non-obstructive coronary arteries in collaboration with European society of cardiology working group on coronary pathophysiology & microcirculation endorsed by coronary vasomotor disorders international study group. Eur. Heart J., 2020, 41(37), 3504-3520.
[http://dx.doi.org/10.1093/eurheartj/ehaa503] [PMID: 32626906]
[114]
Ott, C.; Jumar, A.; Striepe, K.; Friedrich, S.; Karg, M.V.; Bramlage, P.; Schmieder, R.E. A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular circulation. Cardiovasc. Diabetol., 2017, 16(1), 26.
[http://dx.doi.org/10.1186/s12933-017-0510-1] [PMID: 28231831]
[115]
Solini, A.; Giannini, L.; Seghieri, M.; Vitolo, E.; Taddei, S.; Ghiadoni, L.; Bruno, R.M. Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc. Diabetol., 2017, 16(1), 138.
[http://dx.doi.org/10.1186/s12933-017-0621-8] [PMID: 29061124]
[116]
Cappetta, D.; De Angelis, A.; Ciuffreda, L.P.; Coppini, R.; Cozzolino, A.; Miccichè, A.; Dell’Aversana, C.; D’Amario, D.; Cianflone, E.; Scavone, C.; Santini, L.; Palandri, C.; Naviglio, S.; Crea, F.; Rota, M.; Altucci, L.; Rossi, F.; Capuano, A.; Urbanek, K.; Berrino, L. Amelioration of diastolic dysfunction by dapagliflozin in a non-diabetic model involves coronary endothelium. Pharmacol. Res., 2020, 157, 104781.
[http://dx.doi.org/10.1016/j.phrs.2020.104781] [PMID: 32360273]
[117]
Uthman, L.; Homayr, A.; Juni, R.P.; Spin, E.L.; Kerindongo, R.; Boomsma, M.; Hollmann, M.W.; Preckel, B.; Koolwijk, P.; van Hinsbergh, V.W.M.; Zuurbier, C.J.; Albrecht, M.; Weber, N.C. Empagliflozin and dapagliflozin reduce ROS generation and restore NO bioavailability in tumor necrosis factor α-stimulated human coronary arterial endothelial cells. Cell. Physiol. Biochem., 2019, 53(5), 865-886.
[http://dx.doi.org/10.33594/000000178] [PMID: 31724838]
[118]
Han, Y.; Cho, Y-E.; Ayon, R.; Guo, R.; Youssef, K.D.; Pan, M.; Dai, A.; Yuan, J.X.; Makino, A. SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am. J. Physiol. Lung Cell. Mol. Physiol., 2015, 309(9), L1027-L1036.
[http://dx.doi.org/10.1152/ajplung.00167.2015] [PMID: 26361875]
[119]
Adingupu, D.D.; Göpel, S.O.; Grönros, J.; Behrendt, M.; Sotak, M.; Miliotis, T.; Dahlqvist, U.; Gan, L.M.; Jönsson-Rylander, A.C. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob-/- mice. Cardiovasc. Diabetol., 2019, 18(1), 16.
[http://dx.doi.org/10.1186/s12933-019-0820-6] [PMID: 30732594]
[120]
Liu, Z.; Ma, X.; Ilyas, I.; Zheng, X.; Luo, S.; Little, P.J.; Kamato, D.; Sahebkar, A.; Wu, W.; Weng, J.; Xu, S. Impact of Sodium Glucose CoTransporter 2 (SGLT2) inhibitors on atherosclerosis: From pharmacology to pre-clinical and clinical therapeutics. Theranostics, 2021, 11(9), 4502-4515.
[http://dx.doi.org/10.7150/thno.54498] [PMID: 33754074]
[121]
Hess, D.A.; Terenzi, D.C.; Trac, J.Z.; Quan, A.; Mason, T.; Al-Omran, M.; Bhatt, D.L.; Dhingra, N.; Rotstein, O.D.; Leiter, L.A.; Zinman, B.; Sabongui, S.; Yan, A.T.; Teoh, H.; Mazer, C.D.; Connelly, K.A.; Verma, S. SGLT2 inhibition with empagliflozin increases circulating provascular progenitor cells in people with type 2 diabetes mellitus. Cell Metab., 2019, 30(4), 609-613.
[http://dx.doi.org/10.1016/j.cmet.2019.08.015] [PMID: 31477497]
[122]
Pennig, J.; Scherrer, P.; Gissler, M.C.; Anto-Michel, N.; Hoppe, N.; Füner, L.; Härdtner, C.; Stachon, P.; Wolf, D.; Hilgendorf, I.; Mullick, A.; Bode, C.; Zirlik, A.; Goldberg, I.J.; Willecke, F. Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci. Rep., 2019, 9(1), 17937.
[http://dx.doi.org/10.1038/s41598-019-54224-9] [PMID: 31784656]
[123]
Spigoni, V.; Fantuzzi, F.; Carubbi, C.; Pozzi, G.; Masselli, E.; Gobbi, G.; Solini, A.; Bonadonna, R.C.; Dei Cas, A. Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: potential relevance to prevention of cardiovascular events. Cardiovasc. Diabetol., 2020, 19(1), 46.
[http://dx.doi.org/10.1186/s12933-020-01016-5] [PMID: 32264868]
[124]
Mancio, J.; Oikonomou, E.K.; Antoniades, C. Perivascular adipose tissue and coronary atherosclerosis. Heart, 2018, 104(20), 1654-1662.
[http://dx.doi.org/10.1136/heartjnl-2017-312324] [PMID: 29853488]
[125]
Ouwens, D.M.; Sell, H.; Greulich, S.; Eckel, J. The role of epicardial and perivascular adipose tissue in the pathophysiology of cardiovascular disease. J. Cell. Mol. Med., 2010, 14(9), 2223-2234.
[http://dx.doi.org/10.1111/j.1582-4934.2010.01141.x] [PMID: 20716126]
[126]
Mori, Y.; Terasaki, M.; Hiromura, M.; Saito, T.; Kushima, H.; Koshibu, M.; Osaka, N.; Ohara, M.; Fukui, T.; Ohtaki, H.; Tsutomu, H.; Yamagishi, S.I. Luseogliflozin attenuates neointimal hyperplasia after wire injury in high-fat diet-fed mice via inhibition of perivascular adipose tissue remodeling. Cardiovasc. Diabetol., 2019, 18(1), 143.
[http://dx.doi.org/10.1186/s12933-019-0947-5] [PMID: 31672147]
[127]
Sato, T.; Aizawa, Y.; Yuasa, S.; Kishi, S.; Fuse, K.; Fujita, S.; Ikeda, Y.; Kitazawa, H.; Takahashi, M.; Sato, M.; Okabe, M. The effect of dapagliflozin treatment on epicardial adipose tissue volume. Cardiovasc. Diabetol., 2018, 17(1), 6.
[http://dx.doi.org/10.1186/s12933-017-0658-8] [PMID: 29301516]
[128]
Katakami, N.; Mita, T.; Yoshii, H.; Shiraiwa, T.; Yasuda, T.; Okada, Y.; Torimoto, K.; Umayahara, Y.; Kaneto, H.; Osonoi, T.; Yamamoto, T.; Kuribayashi, N.; Maeda, K.; Yokoyama, H.; Kosugi, K.; Ohtoshi, K.; Hayashi, I.; Sumitani, S.; Tsugawa, M.; Ryomoto, K.; Taki, H.; Nakamura, T.; Kawashima, S.; Sato, Y.; Watada, H.; Shimomura, I. Tofogliflozin does not delay progression of carotid atherosclerosis in patients with type 2 diabetes: A prospective, randomized, open-label, parallel-group comparative study. Cardiovasc. Diabetol., 2020, 19(1), 110.
[http://dx.doi.org/10.1186/s12933-020-01079-4] [PMID: 32646498]

Rights & Permissions Print Cite
Article Metrics
83
1
Wayfinder Image
© 2025 Bentham Science Publishers | Privacy Policy