Insights into SGLT2 inhibitor treatment of diabetic cardiomyopathy ... - Cardiovascular Diabetology

Ahmed AM. History of diabetes mellitus. Saudi Med J. 2002;23:373–8.
Zheng Y, Ley SH, Hu FB. Global aetiology and epidemiology of type 2 diabetes mellitus and its complications. Nat Rev Endocrinol. 2018;14:88–98.
Jia G, Whaley-Connell A, Sowers JR. Diabetic cardiomyopathy: a hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 2018;61:21–8.
Isfort M, Stevens SC, Schaffer S, Jong CJ, Wold LE. Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail Rev. 2014;19:35–48.
Bugger H, Abel ED. Molecular mechanisms of diabetic cardiomyopathy. Diabetologia. 2014;57:660–71.
Holscher ME, Bode C, Bugger H. Diabetic cardiomyopathy: does the type of diabetes matter? Int J Mol Sci. 2016;17:2136.
Reifsnider OS, Kansal AR, Gandhi PK, Cragin L, Brand SB, Pfarr E, et al. Cost-effectiveness of empagliflozin versus canagliflozin, dapagliflozin, or standard of care in patients with type 2 diabetes and established cardiovascular disease. BMJ Open Diabetes Res Care. 2021;9:e001313.
Cefalo CMA, Cinti F, Moffa S, Impronta F, Sorice GP, Mezza T, et al. Sotagliflozin, the first dual SGLT inhibitor: current outlook and perspectives. Cardiovasc Diabetol. 2019;18:20.
Isaji M. SGLT2 inhibitors: molecular design and potential differences in effect. Kidney Int Suppl. 2011. https://doi.org/10.1038/ki.2010.511.S14-9.
Saisho Y. SGLT2 inhibitors: the star in the treatment of type 2 diabetes? Diseases. 2020;8:14.
Kaji K, Nishimura N, Seki K, Sato S, Saikawa S, Nakanishi K, et al. Sodium glucose cotransporter 2 inhibitor canagliflozin attenuates liver cancer cell growth and angiogenic activity by inhibiting glucose uptake. Int J Cancer. 2018;142:1712–22.
Lin Y, Nan J, Shen J, Lv X, Chen X, Lu X, et al. Canagliflozin impairs blood reperfusion of ischaemic lower limb partially by inhibiting the retention and paracrine function of bone marrow derived mesenchymal stem cells. EBioMedicine. 2020;52:102637.
Kondo H, Akoumianakis I, Badi I, Akawi N, Kotanidis CP, Polkinghorne M, et al. Effects of canagliflozin on human myocardial redox signalling: clinical implications. Eur Heart J. 2021;42:4947–60.
Uthman L, Baartscheer A, Schumacher CA, Fiolet JWT, Kuschma MC, Hollmann MW, et al. Direct cardiac actions of sodium glucose cotransporter 2 inhibitors target pathogenic mechanisms underlying heart failure in diabetic patients. Front Physiol. 2018;9:1575.
Philippaert K, Kalyaanamoorthy S, Fatehi M, Long W, Soni S, Byrne NJ, et al. Cardiac late sodium channel current is a molecular target for the sodium/glucose cotransporter 2 inhibitor empagliflozin. Circulation. 2021;143:2188–204.
Amaral N, Okonko DO. Metabolic abnormalities of the heart in type II diabetes. Diab Vasc Dis Res. 2015;12:239–48.
Dakhili SAT, Greenwell AA, Ussher JR. Pyruvate dehydrogenase complex and glucose oxidation as a therapeutic target in diabetic heart disease. J Lipid Atheroscler. 2023;12:47–57.
Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism. 2017;77:65–72.
Bertrand L, Auquier J, Renguet E, Angé M, Cumps J, Horman S, et al. Glucose transporters in cardiovascular system in health and disease. Pflugers Arch. 2020;472:1385–99.
Mustroph J, Lücht CM, Wagemann O, Sowa T, Hammer KP, Sag CM, et al. Empagliflozin enhances human and murine cardiomyocyte glucose uptake by increased expression of GLUT1. Diabetologia. 2019;62:726–9.
Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl Sci. 2018;3:575–87.
Angelini A, Saha PK, Jain A, Jung SY, Mynatt RL, Pi X, et al. PHDs/CPT1B/VDAC1 axis regulates long-chain fatty acid oxidation in cardiomyocytes. Cell Rep. 2021;37:109767.
Oshima H, Miki T, Kuno A, Mizuno M, Sato T, Tanno M, et al. Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and antioxidants in diabetic rats. J Pharmacol Exp Ther. 2019;368:524–34.
Huang CC, Chou CA, Chen WY, Yang JL, Lee WC, Chen JB, et al. Empagliflozin ameliorates free fatty acid induced-lipotoxicity in renal proximal tubular cells via the PPARγ/CD36 pathway in obese mice. Int J Mol Sci. 2021;22:12408.
Aragon-Herrera A, Feijoo-Bandin S, Santiago MO, Barral L, Campos-Toimil M, Gil-Longo J, et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol. 2019;170:113677.
Pepino MY, Kuda O, Samovski D, Abumrad NA. Structure-function of CD36 and importance of fatty acid signal transduction in fat metabolism. Annu Rev Nutr. 2014;34:281–303.
Wang L, Cai Y, Jian L, Cheung CW, Zhang L, Xia Z. Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy. Cardiovasc Diabetol. 2021;20:2.
Wei D, Liao L, Wang H, Zhang W, Wang T, Xu Z. Canagliflozin ameliorates obesity by improving mitochondrial function and fatty acid oxidation via PPARα in vivo and in vitro. Life Sci. 2020;247:117414.
Yanai H, Yoshida H. Beneficial effects of adiponectin on glucose and lipid metabolism and atherosclerotic progression: mechanisms and perspectives. Int J Mol Sci. 2019;20:1190.
Wu P, Wen W, Li J, Xu J, Zhao M, Chen H, et al. Systematic review and meta-analysis of randomized controlled trials on the effect of SGLT2 inhibitor on blood leptin and adiponectin level in patients with type 2 diabetes. Horm Metab Res. 2019;51:487–94.
Krauss RM. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care. 2004;27:1496–504.
Liu L, Mu Y, Han W, Wang C. Association of hypercholesterolemia and cardiac function evaluated by speckle tracking echocardiography in a rabbit model. Lipids Health Dis. 2014;13:128.
Huang Y, Walker KE, Hanley F, Narula J, Houser SR, Tulenko TN. Cardiac systolic and diastolic dysfunction after a cholesterol-rich diet. Circulation. 2004;109:97–102.
Kim JH, Lee M, Kim SH, Kim SR, Lee BW, Kang ES, et al. Sodium-glucose cotransporter 2 inhibitors regulate ketone body metabolism via inter-organ crosstalk. Diabetes Obes Metab. 2019;21:801–11.
Pietschner R, Kolwelter J, Bosch A, Striepe K, Jung S, Kannenkeril D, et al. Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure. Cardiovasc Diabetol. 2021;20:219.
Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a "thrifty substrate" hypothesis. Diabetes Care. 2016;39:1108–14.
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73:1931–44.
Galloway CA, Yoon Y. Mitochondrial dynamics in diabetic cardiomyopathy. Antioxid Redox Signal. 2015;22:1545–62.
Wu S, Lu Q, Ding Y, Wu Y, Qiu Y, Wang P, et al. Hyperglycemia-driven inhibition of AMP-activated protein kinase α2 induces diabetic cardiomyopathy by promoting mitochondria-associated endoplasmic reticulum membranes in vivo. Circulation. 2019;139:1913–36.
Zheng H, Zhu H, Liu X, Huang X, Huang A, Huang Y. Mitophagy in diabetic cardiomyopathy: roles and mechanisms. Front Cell Dev Biol. 2021;9:750382.
Bereiter-Hahn J, Vöth M. Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria. Microsc Res Tech. 1994;27:198–219.
Zemirli N, Morel E, Molino D. Mitochondrial dynamics in basal and stressful conditions. Int J Mol Sci. 2018;19:564.
Yu T, Robotham JL, Yoon Y. Increased production of reactive oxygen species in hyperglycemic conditions requires dynamic change of mitochondrial morphology. Proc Natl Acad Sci USA. 2006;103:2653–8.
Tanajak P, Sa-Nguanmoo P, Sivasinprasasn S, Thummasorn S, Siri-Angkul N, Chattipakorn SC, et al. Cardioprotection of dapagliflozin and vildagliptin in rats with cardiac ischemia-reperfusion injury. J Endocrinol. 2018;236:69–84.
Chang CR, Blackstone C. Dynamic regulation of mitochondrial fission through modification of the dynamin-related protein Drp1. Ann N Y Acad Sci. 2010;1201:34–9.
Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2018;15:335–46.
Tilokani L, Nagashima S, Paupe V, Prudent J. Mitochondrial dynamics: overview of molecular mechanisms. Essays Biochem. 2018;62:341–60.
Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC. Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol. 2003;160:189–200.
Sun S, Erchova I, Sengpiel F, Votruba M. Opa1 deficiency leads to diminished mitochondrial bioenergetics with compensatory increased mitochondrial motility. Invest Ophthalmol Vis Sci. 2020;61:42.
Durak A, Olgar Y, Degirmenci S, Akkus E, Tuncay E, Turan B. A SGLT2 inhibitor dapagliflozin suppresses prolonged ventricular-repolarization through augmentation of mitochondrial function in insulin-resistant metabolic syndrome rats. Cardiovasc Diabetol. 2018;17:144.
Shao Q, Meng L, Lee S, Tse G, Gong M, Zhang Z, et al. Empagliflozin, a sodium glucose co-transporter-2 inhibitor, alleviates atrial remodeling and improves mitochondrial function in high-fat diet/streptozotocin-induced diabetic rats. Cardiovasc Diabetol. 2019;18:165.
Jornayvaz FR, Shulman GI. Regulation of mitochondrial biogenesis. Essays Biochem. 2010;47:69–84.
Scarpulla RC. Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta. 2011;1813:1269–78.
Virbasius JV, Scarpulla RC. Activation of the human mitochondrial transcription factor A gene by nuclear respiratory factors: a potential regulatory link between nuclear and mitochondrial gene expression in organelle biogenesis. Proc Natl Acad Sci USA. 1994;91:1309–13.
Irrcher I, Adhihetty PJ, Sheehan T, Joseph AM, Hood DA. PPARgamma coactivator-1alpha expression during thyroid hormone- and contractile activity-induced mitochondrial adaptations. Am J Physiol Cell Physiol. 2003;284:C1669–77.
Croston TL, Thapa D, Holden AA, Tveter KJ, Lewis SE, Shepherd DL, et al. Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol. 2014;307:H54-65.
Secker PF, Beneke S, Schlichenmaier N, Delp J, Gutbier S, Leist M, et al. Canagliflozin mediated dual inhibition of mitochondrial glutamate dehydrogenase and complex I: an off-target adverse effect. Cell Death Dis. 2018;9:226.
Hu Y, Suarez J, Fricovsky E, Wang H, Scott BT, Trauger SA, et al. Increased enzymatic O-GlcNAcylation of mitochondrial proteins impairs mitochondrial function in cardiac myocytes exposed to high glucose. J Biol Chem. 2009;284:547–55.
Hodrea J, Balogh DB, Hosszu A, Lenart L, Besztercei B, Koszegi S, et al. Reduced O-GlcNAcylation and tubular hypoxia contribute to the antifibrotic effect of SGLT2 inhibitor dapagliflozin in the diabetic kidney. Am J Physiol Renal Physiol. 2020;318:F1017–29.
Huang D, Refaat M, Mohammedi K, Jayyousi A, Al Suwaidi J, Abi KC. Macrovascular complications in patients with diabetes and prediabetes. Biomed Res Int. 2017;2017:7839101.
Kibel A, Selthofer-Relatic K, Drenjancevic I, Bacun T, Bosnjak I, Kibel D, et al. Coronary microvascular dysfunction in diabetes mellitus. J Int Med Res. 2017;45:1901–29.
Henning RJ. Type-2 diabetes mellitus and cardiovascular disease. Future Cardiol. 2018;14:491–509.
Poznyak AV, Litvinova L, Poggio P, Sukhorukov VN, Orekhov AN. Effect of glucose levels on cardiovascular risk. Cells. 2022;11:3034.
Forrester SJ, Preston KJ, Cooper HA, Boyer MJ, Escoto KM, Poltronetti AJ, et al. Mitochondrial fission mediates endothelial inflammation. Hypertension. 2020;76:267–76.
Gimbrone MA Jr, García-Cardeña G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circ Res. 2016;118:620–36.
Wang Q, Zhang M, Torres G, Wu S, Ouyang C, Xie Z, et al. Metformin suppresses diabetes-accelerated atherosclerosis via the inhibition of Drp1-mediated mitochondrial fission. Diabetes. 2017;66:193–205.
Tian K, Xu Y, Sahebkar A, Xu S. CD36 in atherosclerosis: pathophysiological mechanisms and therapeutic implications. Curr Atheroscler Rep. 2020;22:59.
Blagov AV, Markin AM, Bogatyreva AI, Tolstik TV, Sukhorukov VN, Orekhov AN. The role of macrophages in the pathogenesis of atherosclerosis. Cells. 2023;12:522.
Pennig J, Scherrer P, Gissler MC, Anto-Michel N, Hoppe N, Füner L, et al. Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci Rep. 2019;9:17937.
Koyani CN, Plastira I, Sourij H, Hallstrom S, Schmidt A, Rainer PP, et al. Empagliflozin protects heart from inflammation and energy depletion via AMPK activation. Pharmacol Res. 2020;158:104870.
Shan H, Bai X, Chen X. Angiotensin II induces endothelial cell senescence via the activation of mitogen-activated protein kinases. Cell Biochem Funct. 2008;26:459–66.
Khemais-Benkhiat S, Belcastro E, Idris-Khodja N, Park SH, Amoura L, Abbas M, et al. Angiotensin II-induced redox-sensitive SGLT1 and 2 expression promotes high glucose-induced endothelial cell senescence. J Cell Mol Med. 2020;24:2109–22.
Lee BY, Han JA, Im JS, Morrone A, Johung K, Goodwin EC, et al. Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006;5:187–95.
Lv Q, Meng XF, He FF, Chen S, Su H, Xiong J, et al. High serum uric acid and increased risk of type 2 diabetes: a systemic review and meta-analysis of prospective cohort studies. PLoS ONE. 2013;8:e56864.
Katsiki N, Papanas N, Fonseca VA, Maltezos E, Mikhailidis DP. Uric acid and diabetes: is there a link? Curr Pharm Des. 2013;19:4930–7.
Albu A, Para I, Porojan M. Uric acid and arterial stiffness. Ther Clin Risk Manag. 2020;16:39–54.
Chino Y, Samukawa Y, Sakai S, Nakai Y, Yamaguchi J, Nakanishi T, et al. SGLT2 inhibitor lowers serum uric acid through alteration of uric acid transport activity in renal tubule by increased glycosuria. Biopharm Drug Dispos. 2014;35:391–404.
Shah AS, Urbina EM. Vascular and endothelial function in youth with type 2 diabetes mellitus. Curr Diab Rep. 2017;17:36.
Gallinoro E, Paolisso P, Candreva A, Bermpeis K, Fabbricatore D, Esposito G, et al. Microvascular dysfunction in patients with type II diabetes mellitus: invasive assessment of absolute coronary blood flow and microvascular resistance reserve. Front Cardiovasc Med. 2021;8:765071.
Shigiyama F, Kumashiro N, Miyagi M, Ikehara K, Kanda E, Uchino H, et al. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early-stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc Diabetol. 2017;16:84.
Sancho P, Martin-Sanz P, Fabregat I. Reciprocal regulation of NADPH oxidases and the cyclooxygenase-2 pathway. Free Radic Biol Med. 2011;51:1789–98.
Ardanaz N, Pagano PJ. Hydrogen peroxide as a paracrine vascular mediator: regulation and signaling leading to dysfunction. Exp Biol Med. 2006;231:237–51.
Oelze M, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Mikhed Y, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE. 2014;9:e112394.
Santiago E, Martínez MP, Climent B, Muñoz M, Briones AM, Salaices M, et al. Augmented oxidative stress and preserved vasoconstriction induced by hydrogen peroxide in coronary arteries in obesity: role of COX-2. Br J Pharmacol. 2016;173:3176–95.
Hasan R, Jaggar JH. KV channel trafficking and control of vascular tone. Microcirculation. 2018. https://doi.org/10.1111/micc.12418.
Li H, Shin SE, Seo MS, An JR, Choi IW, Jung WK, et al. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci. 2018;197:46–55.
Ko EA, Park WS, Firth AL, Kim N, Yuan JX, Han J. Pathophysiology of voltage-gated K+ channels in vascular smooth muscle cells: modulation by protein kinases. Prog Biophys Mol Biol. 2010;103:95–101.
Akash MSH, Rehman K, Liaqat A. Tumor necrosis factor-alpha: role in development of insulin resistance and pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2018;119:105–10.
Uthman L, Homayr A, Juni RP, Spin EL, Kerindongo R, Boomsma M, et al. 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;53:865–86.