Top

Published in:

01-05-2018

Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects

Authors: Abdullah Kaplan, Emna Abidi, Ahmed El-Yazbi, Ali Eid, George W. Booz, Fouad A. Zouein

Published in: Heart Failure Reviews | Issue 3/2018

Abstract

Diabetes is a global epidemic and a leading cause of death with more than 422 million patients worldwide out of whom around 392 million alone suffer from type 2 diabetes (T2D). Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are novel and effective drugs in managing glycemia of T2D patients. These inhibitors gained recent clinical and basic research attention due to their clinically observed cardiovascular protective effects. Although interest in the study of various SGLT isoforms and the effect of their inhibition on cardiovascular function extends over the past 20 years, an explanation of the effects observed clinically based on available experimental data is not forthcoming. The remarkable reduction in cardiovascular (CV) mortality (38%), major CV events (14%), hospitalization for heart failure (35%), and death from any cause (32%) observed over a period of 2.6 years in patients with T2D and high CV risk in the EMPA-REG OUTCOME trial involving the SGLT2 inhibitor empagliflozin (Empa) have raised the possibility that potential novel, more specific mechanisms of SGLT2 inhibition synergize with the known modest systemic improvements, such as glycemic, body weight, diuresis, and blood pressure control. Multiple studies investigated the direct impact of SGLT2i on the cardiovascular system with limited findings and the pathophysiological role of SGLTs in the heart. The direct impact of SGLT2i on cardiac homeostasis remains controversial, especially that SGLT1 isoform is the only form expressed in the capillaries and myocardium of human and rodent hearts. The direct impact of SGLT2i on the cardiovascular system along with potential lines of future research is summarized in this review.

Alberti KG, Zimmet PZ (1998) Definition, diagnosis and classification of diabetes mellitus and its complications. Part 1: diagnosis and classification of diabetes mellitus provisional report of a WHO consultation. Diabet Med 15(7):539–553. https://doi.org/10.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S PubMedCrossRef

Nathan DM (1993) Long-term complications of diabetes mellitus. N Engl J Med 328(23):1676–1685. https://doi.org/10.1056/NEJM199306103282306 PubMedCrossRef

Mathers CD, Loncar D (2006) Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 3(11):e442. https://doi.org/10.1371/journal.pmed.0030442 PubMedPubMedCentralCrossRef

Cefalu WT, Leiter LA, Yoon KH, Arias P, Niskanen L, Xie J, Balis DA, Canovatchel W, Meininger G (2013) Efficacy and safety of canagliflozin versus glimepiride in patients with type 2 diabetes inadequately controlled with metformin (CANTATA-SU): 52 week results from a randomised, double-blind, phase 3 non-inferiority trial. Lancet 382(9896):941–950. https://doi.org/10.1016/S0140-6736(13)60683-2 PubMedCrossRef

Forst T, Guthrie R, Goldenberg R, Yee J, Vijapurkar U, Meininger G, Stein P (2014) Efficacy and safety of canagliflozin over 52 weeks in patients with type 2 diabetes on background metformin and pioglitazone. Diabetes Obes Metab 16(5):467–477. https://doi.org/10.1111/dom.12273 PubMedPubMedCentralCrossRef

Purnell JQ, Weyer C (2003) Weight effect of current and experimental drugs for diabetes mellitus: from promotion to alleviation of obesity. Treat Endocrinol 2(1):33–47PubMedCrossRef

Tahrani AA, Bailey CJ, Del Prato S, Barnett AH (2011) Management of type 2 diabetes: new and future developments in treatment. Lancet 378(9786):182–197. https://doi.org/10.1016/S0140-6736(11)60207-9 PubMedCrossRef

Fala L (2015) Jardiance (empagliflozin), an SGLT2 inhibitor, receives FDA approval for the treatment of patients with type 2 diabetes. Am Health Drug Benefits 8(Spec Feature):92–95PubMedPubMedCentral

Vrhovac I, Balen Eror D, Klessen D, Burger C, Breljak D, Kraus O, Radovic N, Jadrijevic S, Aleksic I, Walles T, Sauvant C, Sabolic I, Koepsell H (2015) Localizations of Na(+)-D-glucose cotransporters SGLT1 and SGLT2 in human kidney and of SGLT1 in human small intestine, liver, lung, and heart. Pflugers Arch 467(9):1881–1898. https://doi.org/10.1007/s00424-014-1619-7 PubMedCrossRef

10.

Banerjee SK, McGaffin KR, Pastor-Soler NM, Ahmad F (2009) SGLT1 is a novel cardiac glucose transporter that is perturbed in disease states. Cardiovasc Res 84(1):111–118. https://doi.org/10.1093/cvr/cvp190 PubMedPubMedCentralCrossRef

11.

Elfeber K, Stumpel F, Gorboulev V, Mattig S, Deussen A, Kaissling B, Koepsell H (2004) Na(+)-D-glucose cotransporter in muscle capillaries increases glucose permeability. Biochem Biophys Res Commun 314(2):301–305PubMedCrossRef

12.

Zhou L, Cryan EV, D'Andrea MR, Belkowski S, Conway BR, Demarest KT (2003) Human cardiomyocytes express high level of Na+/glucose cotransporter 1 (SGLT1). J Cell Biochem 90(2):339–346. https://doi.org/10.1002/jcb.10631 PubMedCrossRef

13.

Ferrannini E, Mark M, Mayoux E (2016) CV protection in the EMPA-REG OUTCOME trial: a “Thrifty Substrate” hypothesis. Diabetes Care 39(7):1108–1114. https://doi.org/10.2337/dc16-0330 PubMedCrossRef

14.

Cherney DZ, Perkins BA, Soleymanlou N, Har R, Fagan N, Johansen OE, Woerle HJ, von Eynatten M, Broedl UC (2014) The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol 13:28. https://doi.org/10.1186/1475-2840-13-28 PubMedPubMedCentralCrossRef

15.

Scheerer MF, Rist R, Proske O, Meng A, Kostev K (2016) Changes in HbA1c, body weight, and systolic blood pressure in type 2 diabetes patients initiating dapagliflozin therapy: a primary care database study. Diabetes Metab Syndr Obes 9:337–345. https://doi.org/10.2147/dmso.s116243 PubMedPubMedCentralCrossRef

16.

Chilton R, Tikkanen I, Cannon CP, Crowe S, Woerle HJ, Broedl UC, Johansen OE (2015) Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab 17(12):1180–1193. https://doi.org/10.1111/dom.12572 PubMedPubMedCentralCrossRef

17.

Ott C, Jumar A, Striepe K, Friedrich S, Karg MV, Bramlage P, Schmieder RE (2017) A randomised study of the impact of the SGLT2 inhibitor dapagliflozin on microvascular and macrovascular. Circulation. 16(1):26. https://doi.org/10.1186/s12933-017-0510-1 CrossRef

18.

Daneman D (2006) Type 1 diabetes. Lancet 367(9513):847–858. https://doi.org/10.1016/S0140-6736(06)68341-4 PubMedCrossRef

19.

Disease GBD, Injury I, Prevalence C (2016) Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 388(10053):1545–1602. https://doi.org/10.1016/S0140-6736(16)31678-6 CrossRef

20.

Leiter LA, Yoon K-H, Arias P, Langslet G, Xie J, Balis DA, Millington D, Vercruysse F, Canovatchel W, Meininger G (2015) Canagliflozin provides durable glycemic improvements and body weight reduction over 104 weeks versus glimepiride in patients with type 2 diabetes on metformin: a randomized, double-blind, phase 3 study. Diabetes Care 38(3):355–364. https://doi.org/10.2337/dc13-2762 PubMedCrossRef

21.

Matthaei S, Bowering K, Rohwedder K, Grohl A, Parikh S (2015) Dapagliflozin improves glycemic control and reduces body weight as add-on therapy to metformin plus sulfonylurea: a 24-week randomized, double-blind clinical trial. Diabetes Care 38(3):365–372. https://doi.org/10.2337/dc14-0666 PubMedCrossRef

22.

Cefalu WT, Riddle MC (2015) SGLT2 inhibitors: the latest “new kids on the block”! Diabetes Care 38(3):352–354. https://doi.org/10.2337/dc14-3048 PubMedPubMedCentralCrossRef

23.

Kitada M, Zhang Z, Mima A, King GL (2010) Molecular mechanisms of diabetic vascular complications. J Diabetes Investig 1(3):77–89. https://doi.org/10.1111/j.2040-1124.2010.00018.x PubMedPubMedCentralCrossRef

24.

American_Diabetes_Association (2016) Standards of medical care in diabetes-2016: glycemic targets. Diabetes Care 39(Supplement 1):S39–S46. https://doi.org/10.2337/dc16-S008 CrossRef

25.

Holman RR, Sourij H, Califf RM (2014) Cardiovascular outcome trials of glucose-lowering drugs or strategies in type 2 diabetes. Lancet 383(9933):2008–2017. https://doi.org/10.1016/S0140-6736(14)60794-7 PubMedCrossRef

26.

Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HAW (2008) 10-Year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 359(15):1577–1589. https://doi.org/10.1056/NEJMoa0806470 PubMedCrossRef

27.

Jax TW (2010) Metabolic memory: a vascular perspective. Cardiovasc Diabetol 9:51. https://doi.org/10.1186/1475-2840-9-51 PubMedPubMedCentralCrossRef

28.

Basnet S, Kozikowski A, Makaryus AN, Pekmezaris R, Zeltser R, Akerman M, Lesser M, Wolf-Klein G (2015) Metformin and myocardial injury in patients with diabetes and ST-segment elevation myocardial infarction: a propensity score matched analysis. J Am Heart Assoc 4(10):e002314. https://doi.org/10.1161/JAHA.115.002314 PubMedPubMedCentralCrossRef

29.

Lexis CP, van der Horst IC, Lipsic E, Wieringa WG, de Boer RA, van den Heuvel AF, van der Werf HW, Schurer RA, Pundziute G, Tan ES, Nieuwland W, Willemsen HM, Dorhout B, Molmans BH, van der Horst-Schrivers AN, Wolffenbuttel BH, ter Horst GJ, van Rossum AC, Tijssen JG, Hillege HL, de Smet BJ, van der Harst P, van Veldhuisen DJ, Investigators G-I (2014) Effect of metformin on left ventricular function after acute myocardial infarction in patients without diabetes: the GIPS-III randomized clinical trial. JAMA 311(15):1526–1535. https://doi.org/10.1001/jama.2014.3315 PubMedCrossRef

30.

Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JFE, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, Steinberg WM, Stockner M, Zinman B, Bergenstal RM, Buse JB (2016) Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med 375(4):311–322. https://doi.org/10.1056/NEJMoa1603827 PubMedPubMedCentralCrossRef

31.

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE (2015) Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 373(22):2117–2128. https://doi.org/10.1056/NEJMoa1504720 PubMedCrossRef

32.

Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ (2015) Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care 38(3):420–428. https://doi.org/10.2337/dc14-1096 PubMedCrossRef

33.

Neal B, Perkovic V, Mahaffey KW, de Zeeuw D, Fulcher G, Erondu N, Shaw W, Law G, Desai M, Matthews DR, Group CPC (2017) Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med 377(7):644–657. https://doi.org/10.1056/NEJMoa1611925 PubMedCrossRef

34.

Fitchett D, Zinman B, Wanner C, Lachin JM, Hantel S, Salsali A, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, investigators E-ROt (2016) Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME(R) trial. Eur Heart J 37(19):1526–1534. https://doi.org/10.1093/eurheartj/ehv728 PubMedPubMedCentralCrossRef

35.

Fowler MJ (2008) Microvascular and macrovascular complications of diabetes. Clin Diabetes 26(2):77–82. https://doi.org/10.2337/diaclin.26.2.77 CrossRef

36.

Kannel WB, McGee DL (1979) Diabetes and glucose tolerance as risk factors for cardiovascular disease: the Framingham study. Diabetes Care 2(2):120–126PubMedCrossRef

37.

Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, Das SR, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Isasi CR, Jimenez MC, Judd SE, Kissela BM, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Magid DJ, McGuire DK, Mohler ER 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Rosamond W, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C, Stroke Statistics S (2016) Executive summary: heart disease and stroke statistics-2016 update: a report from the American Heart Association. Circulation 133(4):447–454. https://doi.org/10.1161/CIR.0000000000000366 PubMedCrossRef

38.

Stamler J, Vaccaro O, Neaton JD, Wentworth D (1993) Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16(2):434–444PubMedCrossRef

39.

Ishihara M (2012) Acute hyperglycemia in patients with acute myocardial infarction. Circ J 76(3):563–571PubMedCrossRef

40.

Oswald GA, Corcoran S, Yudkin JS (1984) Prevalence and risks of hyperglycaemia and undiagnosed diabetes in patients with acute myocardial infarction. Lancet 1(8389):1264–1267PubMedCrossRef

41.

Cid-Alvarez B, Gude F, Cadarso-Suarez C, Gonzalez-Babarro E, Rodriguez-Alvarez MX, Garcia-Acuna JM, Gonzalez-Juanatey JR (2009) Admission and fasting plasma glucose for estimating risk of death of diabetic and nondiabetic patients with acute coronary syndrome: nonlinearity of hazard ratios and time-dependent comparison. Am Heart J 158(6):989–997. https://doi.org/10.1016/j.ahj.2009.10.004 PubMedCrossRef

42.

Dirkali A, van der Ploeg T, Nangrahary M, Cornel JH, Umans VA (2007) The impact of admission plasma glucose on long-term mortality after STEMI and NSTEMI myocardial infarction. Int J Cardiol 121(2):215–217. https://doi.org/10.1016/j.ijcard.2006.08.107 PubMedCrossRef

43.

Capes SE, Hunt D, Malmberg K, Gerstein HC (2000) Stress hyperglycaemia and increased risk of death after myocardial infarction in patients with and without diabetes: a systematic overview. Lancet 355(9206):773–778. https://doi.org/10.1016/S0140-6736(99)08415-9 PubMedCrossRef

44.

Malmberg K, Norhammar A, Wedel H, Ryden L (1999) Glycometabolic state at admission: important risk marker of mortality in conventionally treated patients with diabetes mellitus and acute myocardial infarction: long-term results from the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction (DIGAMI) study. Circulation 99(20):2626–2632PubMedCrossRef

45.

Dziewierz A, Giszterowicz D, Siudak Z, Rakowski T, Dubiel JS, Dudek D (2010) Admission glucose level and in-hospital outcomes in diabetic and non-diabetic patients with acute myocardial infarction. Clin Res Cardiol 99(11):715–721. https://doi.org/10.1007/s00392-010-0175-1 PubMedCrossRef

46.

Stranders I, Diamant M, van Gelder RE, Spruijt HJ, Twisk JW, Heine RJ, Visser FC (2004) Admission blood glucose level as risk indicator of death after myocardial infarction in patients with and without diabetes mellitus. Arch Intern Med 164(9):982–988. https://doi.org/10.1001/archinte.164.9.982 PubMedCrossRef

47.

Wahab NN, Cowden EA, Pearce NJ, Gardner MJ, Merry H, Cox JL, Investigators I (2002) Is blood glucose an independent predictor of mortality in acute myocardial infarction in the thrombolytic era? J Am Coll Cardiol 40(10):1748–1754PubMedCrossRef

48.

Lejay A, Fang F, John R, Van JA, Barr M, Thaveau F, Chakfe N, Geny B, Scholey JW (2016) Ischemia reperfusion injury, ischemic conditioning and diabetes mellitus. J Mol Cell Cardiol 91:11–22. https://doi.org/10.1016/j.yjmcc.2015.12.020 PubMedCrossRef

49.

Kuehl M, Stevens MJ (2012) Cardiovascular autonomic neuropathies as complications of diabetes mellitus. Nat Rev Endocrinol 8(7):405–416. https://doi.org/10.1038/nrendo.2012.21 PubMedCrossRef

50.

Vinik AI, Maser RE, Ziegler D (2011) Autonomic imbalance: prophet of doom or scope for hope? Diabet Med 28(6):643–651. https://doi.org/10.1111/j.1464-5491.2010.03184.x PubMedPubMedCentralCrossRef

51.

Xuan YL, Wang Y, Xue M, Hu HS, Cheng WJ, Li XR, Yin J, Yang N, Yan SH (2015) In rats the duration of diabetes influences its impact on cardiac autonomic innervations and electrophysiology. Auton Neurosci 189:31–36. https://doi.org/10.1016/j.autneu.2015.01.003 PubMedCrossRef

52.

Despa S, Bers DM (2013) Na(+) transport in the normal and failing heart—remember the balance. J Mol Cell Cardiol 61:2–10. https://doi.org/10.1016/j.yjmcc.2013.04.011 PubMedPubMedCentralCrossRef

53.

Lambert R, Srodulski S, Peng X, Margulies KB, Despa F, Despa S (2015) Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. J Am Heart Assoc 4(9):e002183. https://doi.org/10.1161/JAHA.115.002183 PubMedPubMedCentralCrossRef

54.

Bugger H, Abel ED (2014) Molecular mechanisms of diabetic cardiomyopathy. Diabetologia 57(4):660–671. https://doi.org/10.1007/s00125-014-3171-6 PubMedPubMedCentralCrossRef

55.

Hattori Y, Matsuda N, Kimura J, Ishitani T, Tamada A, Gando S, Kemmotsu O, Kanno M (2000) Diminished function and expression of the cardiac Na+-Ca2+ exchanger in diabetic rats: implication in Ca2+ overload. J Physiol 527(Pt 1):85–94PubMedPubMedCentralCrossRef

56.

Shattock MJ, Ottolia M, Bers DM, Blaustein MP, Boguslavskyi A, Bossuyt J, Bridge JH, Chen-Izu Y, Clancy CE, Edwards A, Goldhaber J, Kaplan J, Lingrel JB, Pavlovic D, Philipson K, Sipido KR, Xie ZJ (2015) Na+/Ca2+ exchange and Na+/K+-ATPase in the heart. J Physiol 593(6):1361–1382. https://doi.org/10.1113/jphysiol.2014.282319 PubMedPubMedCentralCrossRef

57.

Kho C, Lee A, Hajjar RJ (2012) Altered sarcoplasmic reticulum calcium cycling—targets for heart failure therapy. Nat Rev Cardiol 9(12):717–733. https://doi.org/10.1038/nrcardio.2012.145 PubMedPubMedCentralCrossRef

58.

Bers DM (2002) Cardiac excitation-contraction coupling. Nature 415(6868):198–205. https://doi.org/10.1038/415198a PubMedCrossRef

59.

Cingolani HE, Ennis IL (2007) Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 115(9):1090–1100. https://doi.org/10.1161/CIRCULATIONAHA.106.626929 PubMedCrossRef

60.

Anzawa R, Bernard M, Tamareille S, Baetz D, Confort-Gouny S, Gascard JP, Cozzone P, Feuvray D (2006) Intracellular sodium increase and susceptibility to ischaemia in hearts from type 2 diabetic db/db mice. Diabetologia 49(3):598–606. https://doi.org/10.1007/s00125-005-0091-5 PubMedCrossRef

61.

Chattou S, Diacono J, Feuvray D (1999) Decrease in sodium-calcium exchange and calcium currents in diabetic rat ventricular myocytes. Acta Physiol Scand 166(2):137–144. https://doi.org/10.1046/j.1365-201x.1999.00547.x PubMedCrossRef

62.

Darmellah A, Baetz D, Prunier F, Tamareille S, Rucker-Martin C, Feuvray D (2007) Enhanced activity of the myocardial Na+/H+ exchanger contributes to left ventricular hypertrophy in the Goto-Kakizaki rat model of type 2 diabetes: critical role of Akt. Diabetologia 50(6):1335–1344. https://doi.org/10.1007/s00125-007-0628-x PubMedCrossRef

63.

Hansen PS, Clarke RJ, Buhagiar KA, Hamilton E, Garcia A, White C, Rasmussen HH (2007) Alloxan-induced diabetes reduces sarcolemmal Na+-K+ pump function in rabbit ventricular myocytes. Am J Physiol Cell Physiol 292(3):C1070–C1077. https://doi.org/10.1152/ajpcell.00288.2006 PubMedCrossRef

64.

Kjeldsen K, Braendgaard H, Sidenius P, Larsen JS, Norgaard A (1987) Diabetes decreases Na+-K+ pump concentration in skeletal muscles, heart ventricular muscle, and peripheral nerves of rat. Diabetes 36(7):842–848PubMedCrossRef

65.

Lee TM, Chang NC, Lin SZ (2017) Dapagliflozin, a selective SGLT2 Inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med 104:298–310. https://doi.org/10.1016/j.freeradbiomed.2017.01.035 PubMedCrossRef

66.

Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Nakagawa T, Kusaka H, Kim-Mitsuyama S (2014) Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol 13:148. https://doi.org/10.1186/s12933-014-0148-1 PubMedPubMedCentralCrossRef

67.

Kusaka H, Koibuchi N, Hasegawa Y, Ogawa H, Kim-Mitsuyama S (2016) Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol 15(1):157. https://doi.org/10.1186/s12933-016-0473-7 PubMedPubMedCentralCrossRef

68.

Benetti E, Mastrocola R, Vitarelli G, Cutrin JC, Nigro D, Chiazza F, Mayoux E, Collino M, Fantozzi R (2016) Empagliflozin protects against diet-induced NLRP-3 inflammasome activation and lipid accumulation. J Pharmac Exp Ther 359(1):45–53. https://doi.org/10.1124/jpet.116.235069 CrossRef

69.

Joubert M, Jagu B, Montaigne D, Marechal X, Tesse A, Ayer A, Dollet L, Le May C, Toumaniantz G, Manrique A, Charpentier F, Staels B, Magre J, Cariou B, Prieur X (2017) The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes 66(4):1030–1040. https://doi.org/10.2337/db16-0733 PubMedCrossRef

70.

Hammoudi N, Jeong D, Singh R, Farhat A, Komajda M, Mayoux E, Hajjar R, Lebeche D (2017) Empagliflozin improves left ventricular diastolic dysfunction in a genetic model of type 2 diabetes. Cardiovasc Drugs Ther. https://doi.org/10.1007/s10557-017-6734-1

71.

Habibi J, Aroor AR, Sowers JR, Jia G, Hayden MR, Garro M, Barron B, Mayoux E, Rector RS, Whaley-Connell A, DeMarco VG (2017) Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol 16(1):9. https://doi.org/10.1186/s12933-016-0489-z PubMedPubMedCentralCrossRef

72.

Baartscheer A, Schumacher CA, Wust RC, Fiolet JW, Stienen GJ, Coronel R, Zuurbier CJ (2017) Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60(3):568–573. https://doi.org/10.1007/s00125-016-4134-x PubMedCrossRef

73.

Hamouda NN, Sydorenko V, Qureshi MA, Alkaabi JM, Oz M, Howarth FC (2015) Dapagliflozin reduces the amplitude of shortening and Ca(2+) transient in ventricular myocytes from streptozotocin-induced diabetic rats. Mol Cell Biochem 400(1-2):57–68. https://doi.org/10.1007/s11010-014-2262-5 PubMedCrossRef

74.

Han Y, Cho YE, Ayon R, Guo R, Youssef KD, Pan M, Dai A, Yuan JX, Makino A (2015) SGLT inhibitors attenuate NO-dependent vascular relaxation in the pulmonary artery but not in the coronary artery. Am J Physiol Lung Cell Mol Physiol 309(9):L1027–L1036. https://doi.org/10.1152/ajplung.00167.2015 PubMedPubMedCentralCrossRef

75.

Di Franco A, Cantini G, Tani A, Coppini R, Zecchi-Orlandini S, Raimondi L, Luconi M, Mannucci E (2017) Sodium-dependent glucose transporters (SGLT) in human ischemic heart: a new potential pharmacological target. Int J Cardiol 243:86–90. https://doi.org/10.1016/j.ijcard.2017.05.032 PubMedCrossRef

76.

Avkiran M, Cook AR, Cuello F (2008) Targeting Na+/H+ exchanger regulation for cardiac protection: a RSKy approach? Curr Opin Pharmacol 8(2):133–140. https://doi.org/10.1016/j.coph.2007.12.007 PubMedCrossRef

77.

Gumina RJ, Mizumura T, Beier N, Schelling P, Schultz JJ, Gross GJ (1998) A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmac Exp Ther 286(1):175–183

78.

Rohmann S, Weygandt H, Minck KO (1995) Preischaemic as well as postischaemic application of a Na+/H+ exchange inhibitor reduces infarct size in pigs. Cardiovasc Res 30(6):945–951PubMedCrossRef

79.

Bolli R (2003) The role of sodium-hydrogen ion exchange in patients undergoing coronary artery bypass grafting. J Card Surg 18(Suppl 1):21–26PubMedCrossRef

80.

Boyce SW, Bartels C, Bolli R, Chaitman B, Chen JC, Chi E, Jessel A, Kereiakes D, Knight J, Thulin L, Theroux P, Investigators GDIANS (2003) Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients: results of the CABG surgery cohort of the GUARDIAN study. J Thorac Cardiovasc Surg 126(2):420–427PubMedCrossRef

81.

Rupprecht HJ, vom Dahl J, Terres W, Seyfarth KM, Richardt G, Schultheibeta HP, Buerke M, Sheehan FH, Drexler H (2000) Cardioprotective effects of the Na(+)/H(+) exchange inhibitor cariporide in patients with acute anterior myocardial infarction undergoing direct PTCA. Circulation 101(25):2902–2908PubMedCrossRef

82.

Theroux P, Chaitman BR, Danchin N, Erhardt L, Meinertz T, Schroeder JS, Tognoni G, White HD, Willerson JT, Jessel A (2000) Inhibition of the sodium-hydrogen exchanger with cariporide to prevent myocardial infarction in high-risk ischemic situations. Main results of the GUARDIAN trial. Guard during ischemia against necrosis (GUARDIAN) Investigators. Circulation 102(25):3032–3038PubMedCrossRef

83.

Sano M (2017) Hemodynamic effects of sodium-glucose cotransporter 2 inhibitors. J Clin Med Res 9(6):457–460. https://doi.org/10.14740/jocmr3011w PubMedPubMedCentralCrossRef

84.

Martens P, Mathieu C, Verbrugge FH (2017) Promise of SGLT2 inhibitors in heart failure: diabetes and beyond. Curr Treat Options Cardiovasc Med 19(3):23. https://doi.org/10.1007/s11936-017-0522-x PubMedCrossRef

85.

Rahman A, Hitomi H, Nishiyama A (2017) Cardioprotective effects of SGLT2 inhibitors are possibly associated with normalization of the circadian rhythm of blood pressure. Hypertens Res. https://doi.org/10.1038/hr.2016.193

86.

Aoyama T, Matsui T, Novikov M, Park J, Hemmings B, Rosenzweig A (2005) Serum and glucocorticoid-responsive kinase-1 regulates cardiomyocyte survival and hypertrophic response. Circulation 111(13):1652–1659. https://doi.org/10.1161/01.CIR.0000160352.58142.06 PubMedCrossRef

87.

Das S, Aiba T, Rosenberg M, Hessler K, Xiao C, Quintero PA, Ottaviano FG, Knight AC, Graham EL, Bostrom P, Morissette MR, del Monte F, Begley MJ, Cantley LC, Ellinor PT, Tomaselli GF, Rosenzweig A (2012) Pathological role of serum- and glucocorticoid-regulated kinase 1 in adverse ventricular remodeling. Circulation 126(18):2208–2219. https://doi.org/10.1161/CIRCULATIONAHA.112.115592 PubMedPubMedCentralCrossRef

88.

Lang F, Shumilina E (2013) Regulation of ion channels by the serum- and glucocorticoid-inducible kinase SGK1. FASEB J 27(1):3–12. https://doi.org/10.1096/fj.12-218230 PubMedCrossRef

89.

Mudaliar S, Alloju S, Henry RR (2016) Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care 39(7):1115–1122. https://doi.org/10.2337/dc16-0542 PubMedCrossRef

90.

Labbe SM, Grenier-Larouche T, Noll C, Phoenix S, Guerin B, Turcotte EE, Carpentier AC (2012) Increased myocardial uptake of dietary fatty acids linked to cardiac dysfunction in glucose-intolerant humans. Diabetes 61(11):2701–2710. https://doi.org/10.2337/db11-1805 PubMedPubMedCentralCrossRef

91.

Ferre P (2004) The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes 53(Suppl 1):S43–S50PubMedCrossRef

92.

Rijzewijk LJ, van der Meer RW, Lamb HJ, de Jong HW, Lubberink M, Romijn JA, Bax JJ, de Roos A, Twisk JW, Heine RJ, Lammertsma AA, Smit JW, Diamant M (2009) Altered myocardial substrate metabolism and decreased diastolic function in nonischemic human diabetic cardiomyopathy: studies with cardiac positron emission tomography and magnetic resonance imaging. J Am Coll Cardiol 54(16):1524–1532. https://doi.org/10.1016/j.jacc.2009.04.074 PubMedCrossRef

93.

Huang B, Wu P, Bowker-Kinley MM, Harris RA (2002) Regulation of pyruvate dehydrogenase kinase expression by peroxisome proliferator-activated receptor-alpha ligands, glucocorticoids, and insulin. Diabetes 51(2):276–283PubMedCrossRef

94.

Wieland O, Siess E, Schulze-Wethmar FH, von Funcke HG, Winton B (1971) Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting, and refeeding on pyruvate dehydrogenase interconversion. Arch Biochem Biophys 143(2):593–601PubMedCrossRef

95.

Wu P, Peters JM, Harris RA (2001) Adaptive increase in pyruvate dehydrogenase kinase 4 during starvation is mediated by peroxisome proliferator-activated receptor alpha. Biochem Biophys Res Commun 287(2):391–396. https://doi.org/10.1006/bbrc.2001.5608 PubMedCrossRef

96.

Glenn DJ, Wang F, Nishimoto M, Cruz MC, Uchida Y, Holleran WM, Zhang Y, Yeghiazarians Y, Gardner DG (2011) A murine model of isolated cardiac steatosis leads to cardiomyopathy. Hypertension 57(2):216–222. https://doi.org/10.1161/HYPERTENSIONAHA.110.160655 PubMedPubMedCentralCrossRef

97.

Oka T, Topper YJ (1972) Dynamics of insulin action on mammary epithelium. Nat New Biol 239(94):216–217PubMedCrossRef

98.

Rijzewijk LJ, van der Meer RW, Smit JW, Diamant M, Bax JJ, Hammer S, Romijn JA, de Roos A, Lamb HJ (2008) Myocardial steatosis is an independent predictor of diastolic dysfunction in type 2 diabetes mellitus. J Am Coll Cardiol 52(22):1793–1799. https://doi.org/10.1016/j.jacc.2008.07.062 PubMedCrossRef

99.

Szczepaniak LS, Dobbins RL, Metzger GJ, Sartoni-D’Ambrosia G, Arbique D, Vongpatanasin W, Unger R, Victor RG (2003) Myocardial triglycerides and systolic function in humans: in vivo evaluation by localized proton spectroscopy and cardiac imaging. Magn Reson Med 49(3):417–423. https://doi.org/10.1002/mrm.10372 PubMedCrossRef

100.

Szczepaniak LS, Victor RG, Orci L, Unger RH (2007) Forgotten but not gone: the rediscovery of fatty heart, the most common unrecognized disease in America. Circ Res 101(8):759–767. https://doi.org/10.1161/CIRCRESAHA.107.160457 PubMedCrossRef

101.

Zhou YT, Grayburn P, Karim A, Shimabukuro M, Higa M, Baetens D, Orci L, Unger RH (2000) Lipotoxic heart disease in obese rats: implications for human obesity. Proc Natl Acad Sci U S A 97(4):1784–1789PubMedPubMedCentralCrossRef

102.

Chung SS, Ho EC, Lam KS, Chung SK (2003) Contribution of polyol pathway to diabetes-induced oxidative stress. J Am Soc Nephrol 14(8 Suppl 3):S233–S236PubMedCrossRef

103.

Laughlin MR, Petit WA Jr, Shulman RG, Barrett EJ (1990) Measurement of myocardial glycogen synthesis in diabetic and fasted rats. Am J Physiol 258(1 Pt 1):E184–E190PubMed

104.

McNulty PH (2007) Hexosamine biosynthetic pathway flux and cardiomyopathy in type 2 diabetes mellitus. Focus on “Impact of type 2 diabetes and aging on cardiomyocyte function and O-linked N-acetylglucosamine levels in the heart.”. Am J Physiol Cell Physiol 292(4):C1243–C1244. https://doi.org/10.1152/ajpcell.00521.2006 PubMedCrossRef

105.

Sochor M, Gonzalez AM, McLean P (1984) Regulation of alternative pathways of glucose metabolism in rat heart in alloxan diabetes: changes in the pentose phosphate pathway. Biochem Biophys Res Commun 118(1):110–116PubMedCrossRef

106.

Brownlee M (1995) Advanced protein glycosylation in diabetes and aging. Annu Rev Med 46:223–234. https://doi.org/10.1146/annurev.med.46.1.223 PubMedCrossRef

107.

Petrova R, Yamamoto Y, Muraki K, Yonekura H, Sakurai S, Watanabe T, Li H, Takeuchi M, Makita Z, Kato I, Takasawa S, Okamoto H, Imaizumi Y, Yamamoto H (2002) Advanced glycation endproduct-induced calcium handling impairment in mouse cardiac myocytes. J Mol Cell Cardiol 34(10):1425–1431PubMedCrossRef

108.

Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ, Neufer PD (2009) Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J Am Coll Cardiol 54(20):1891–1898. https://doi.org/10.1016/j.jacc.2009.07.031 PubMedPubMedCentralCrossRef

109.

Croston TL, Thapa D, Holden AA, Tveter KJ, Lewis SE, Shepherd DL, Nichols CE, Long DM, Olfert IM, Jagannathan R, Hollander JM (2014) Functional deficiencies of subsarcolemmal mitochondria in the type 2 diabetic human heart. Am J Physiol Heart Circ Physiol 307(1):H54–H65. https://doi.org/10.1152/ajpheart.00845.2013 PubMedPubMedCentralCrossRef

110.

Montaigne D, Marechal X, Coisne A, Debry N, Modine T, Fayad G, Potelle C, El Arid JM, Mouton S, Sebti Y, Duez H, Preau S, Remy-Jouet I, Zerimech F, Koussa M, Richard V, Neviere R, Edme JL, Lefebvre P, Staels B (2014) Myocardial contractile dysfunction is associated with impaired mitochondrial function and dynamics in type 2 diabetic but not in obese patients. Circulation 130(7):554–564. https://doi.org/10.1161/CIRCULATIONAHA.113.008476 PubMedCrossRef

111.

Zorzano A, Liesa M, Palacin M (2009) Role of mitochondrial dynamics proteins in the pathophysiology of obesity and type 2 diabetes. Int J Biochem Cell Biol 41(10):1846–1854. https://doi.org/10.1016/j.biocel.2009.02.004 PubMedCrossRef

112.

Diamant M, Lamb HJ, Groeneveld Y, Endert EL, Smit JW, Bax JJ, Romijn JA, de Roos A, Radder JK (2003) Diastolic dysfunction is associated with altered myocardial metabolism in asymptomatic normotensive patients with well-controlled type 2 diabetes mellitus. J Am Coll Cardiol 42(2):328–335PubMedCrossRef

113.

Andreyev AY, Kushnareva YE, Starkov AA (2005) Mitochondrial metabolism of reactive oxygen species. Biochemistry (Mosc) 70(2):200–214CrossRef

114.

Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, Giardino I, Brownlee M (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature 404(6779):787–790. https://doi.org/10.1038/35008121 PubMedCrossRef

115.

Savabi F, Kirsch A (1991) Alteration of the phosphocreatine energy shuttle components in diabetic rat heart. J Mol Cell Cardiol 23(11):1323–1333PubMedCrossRef

116.

Ballinger SW, Patterson C, Yan CN, Doan R, Burow DL, Young CG, Yakes FM, Van Houten B, Ballinger CA, Freeman BA, Runge MS (2000) Hydrogen peroxide- and peroxynitrite-induced mitochondrial DNA damage and dysfunction in vascular endothelial and smooth muscle cells. Circ Res 86(9):960–966PubMedCrossRef

117.

Devasagayam TP, Tilak JC, Boloor KK, Sane KS, Ghaskadbi SS, Lele RD (2004) Free radicals and antioxidants in human health: current status and future prospects. J Assoc Physicians India 52:794–804PubMed

118.

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

119.

Balasse EO, Fery F (1989) Ketone body production and disposal: effects of fasting, diabetes, and exercise. Diabetes Metab Rev 5(3):247–270PubMedCrossRef

120.

Stanley WC, Recchia FA, Lopaschuk GD (2005) Myocardial substrate metabolism in the normal and failing heart. Physiol Rev 85(3):1093–1129. https://doi.org/10.1152/physrev.00006.2004 PubMedCrossRef

121.

Kashiwaya Y, King MT, Veech RL (1997) Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am J Cardiol 80(3A):50A–64APubMedCrossRef

122.

Sato K, Kashiwaya Y, Keon CA, Tsuchiya N, King MT, Radda GK, Chance B, Clarke K, Veech RL (1995) Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J 9(8):651–658PubMedCrossRef

123.

Stanley WC, Meadows SR, Kivilo KM, Roth BA, Lopaschuk GD (2003) beta-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content. Am J Physiol Heart Circ Physiol 285(4):H1626–H1631. https://doi.org/10.1152/ajpheart.00332.2003 PubMedCrossRef

124.

Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV Jr, de Cabo R, Ulrich S, Akassoglou K, Verdin E (2013) Suppression of oxidative stress by beta-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science 339(6116):211–214. https://doi.org/10.1126/science.1227166 PubMedCrossRef

125.

Cotter DG, Schugar RC, Crawford PA (2013) Ketone body metabolism and cardiovascular disease. Am J Physiol Heart Circ Physiol 304(8):H1060–H1076. https://doi.org/10.1152/ajpheart.00646.2012 PubMedPubMedCentralCrossRef

126.

Suzuki M, Takeda M, Kito A, Fukazawa M, Yata T, Yamamoto M, Nagata T, Fukuzawa T, Yamane M, Honda K, Suzuki Y, Kawabe Y (2014) Tofogliflozin, a sodium/glucose cotransporter 2 inhibitor, attenuates body weight gain and fat accumulation in diabetic and obese animal models. Nutr Diabetes 4:e125. https://doi.org/10.1038/nutd.2014.20 PubMedPubMedCentralCrossRef

127.

Yokono M, Takasu T, Hayashizaki Y, Mitsuoka K, Kihara R, Muramatsu Y, Miyoshi S, Tahara A, Kurosaki E, Li Q, Tomiyama H, Sasamata M, Shibasaki M, Uchiyama Y (2014) SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. Eur J Pharmacol 727:66–74. https://doi.org/10.1016/j.ejphar.2014.01.040 PubMedCrossRef

128.

Devenny JJ, Godonis HE, Harvey SJ, Rooney S, Cullen MJ, Pelleymounter MA (2012) Weight loss induced by chronic dapagliflozin treatment is attenuated by compensatory hyperphagia in diet-induced obese (DIO) rats. Obesity (Silver Spring) 20(8):1645–1652. https://doi.org/10.1038/oby.2012.59 CrossRef

129.

Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, Mari A, Pieber TR, Muscelli E (2016) Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes 65(5):1190–1195. https://doi.org/10.2337/db15-1356 PubMedCrossRef

130.

Inagaki N, Kondo K, Yoshinari T, Takahashi N, Susuta Y, Kuki H (2014) Efficacy and safety of canagliflozin monotherapy in Japanese patients with type 2 diabetes inadequately controlled with diet and exercise: a 24-week, randomized, double-blind, placebo-controlled, phase III study. Expert Opin Pharmacother 15(11):1501–1515. https://doi.org/10.1517/14656566.2014.935764 PubMedCrossRef

131.

Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, Broedl UC, Woerle HJ (2014) Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest 124(2):499–508. https://doi.org/10.1172/JCI72227 PubMedPubMedCentralCrossRef

132.

Fukao T, Lopaschuk GD, Mitchell GA (2004) Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fatty Acids 70(3):243–251. https://doi.org/10.1016/j.plefa.2003.11.001 PubMedCrossRef

133.

Bouchi R, Terashima M, Sasahara Y, Asakawa M, Fukuda T, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y (2017) Luseogliflozin reduces epicardial fat accumulation in patients with type 2 diabetes: a pilot study. Cardiovasc Diabetol 16(1):32. https://doi.org/10.1186/s12933-017-0516-8 PubMedPubMedCentralCrossRef

134.

Fukuda T, Bouchi R, Terashima M, Sasahara Y, Asakawa M, Takeuchi T, Nakano Y, Murakami M, Minami I, Izumiyama H, Hashimoto K, Yoshimoto T, Ogawa Y (2017) Ipragliflozin reduces epicardial fat accumulation in non-obese type 2 diabetic patients with visceral obesity: a pilot study. Diabetes Ther. https://doi.org/10.1007/s13300-017-0279-y

135.

Iacobellis G, Leonetti F (2005) Epicardial adipose tissue and insulin resistance in obese subjects. J Clin Endocrinol Metab 90(11):6300–6302. https://doi.org/10.1210/jc.2005-1087 PubMedCrossRef

136.

Rijzewijk LJ, Jonker JT, van der Meer RW, Lubberink M, de Jong HW, Romijn JA, Bax JJ, de Roos A, Heine RJ, Twisk JW, Windhorst AD, Lammertsma AA, Smit JW, Diamant M, Lamb HJ (2010) Effects of hepatic triglyceride content on myocardial metabolism in type 2 diabetes. J Am Coll Cardiol 56(3):225–233. https://doi.org/10.1016/j.jacc.2010.02.049 PubMedCrossRef

137.

Kibbey RG (2015) SGLT-2 inhibition and glucagon: Cause for alarm? Trends Endocrinol Metab 26(7):337–338. https://doi.org/10.1016/j.tem.2015.05.011 PubMedPubMedCentralCrossRef

138.

Ogawa W, Sakaguchi K (2016) Euglycemic diabetic ketoacidosis induced by SGLT2 inhibitors: possible mechanism and contributing factors. J Diabetes Investig 7(2):135–138. https://doi.org/10.1111/jdi.12401 PubMedCrossRef

139.

Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB (2015) Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition. Diabetes Care 38(9):1687–1693. https://doi.org/10.2337/dc15-0843 PubMedPubMedCentralCrossRef

140.

Dinh W, Futh R, Nickl W, Krahn T, Ellinghaus P, Scheffold T, Bansemir L, Bufe A, Barroso MC, Lankisch M (2009) Elevated plasma levels of TNF-alpha and interleukin-6 in patients with diastolic dysfunction and glucose metabolism disorders. Cardiovasc Diabetol 8:58. https://doi.org/10.1186/1475-2840-8-58 PubMedPubMedCentralCrossRef

141.

Haffner SM (2006) The metabolic syndrome: inflammation, diabetes mellitus, and cardiovascular disease. Am J Cardiol 97(2A):3A–11A. https://doi.org/10.1016/j.amjcard.2005.11.010 PubMedCrossRef

142.

Khullar M, Al-Shudiefat AA, Ludke A, Binepal G, Singal PK (2010) Oxidative stress: a key contributor to diabetic cardiomyopathy. Can J Physiol Pharmacol 88(3):233–240. https://doi.org/10.1139/Y10-016 PubMedCrossRef

143.

Rochette L, Zeller M, Cottin Y, Vergely C (2014) Diabetes, oxidative stress and therapeutic strategies. Biochim Biophys Acta 1840(9):2709–2729. https://doi.org/10.1016/j.bbagen.2014.05.017 PubMedCrossRef

144.

Paoletti R, Bolego C, Poli A, Cignarella A (2006) Metabolic syndrome, inflammation and atherosclerosis. Vasc Health Risk Manag 2(2):145–152PubMedPubMedCentralCrossRef

145.

Sena CM, Pereira AM, Seica R (2013) Endothelial dysfunction - a major mediator of diabetic vascular disease. Biochim Biophys Acta 1832(12):2216–2231. https://doi.org/10.1016/j.bbadis.2013.08.006 PubMedCrossRef

146.

Johar S, Cave AC, Narayanapanicker A, Grieve DJ, Shah AM (2006) Aldosterone mediates angiotensin II-induced interstitial cardiac fibrosis via a Nox2-containing NADPH oxidase. FASEB J 20(9):1546–1548. https://doi.org/10.1096/fj.05-4642fje PubMedCrossRef

147.

Suzuki H, Kayama Y, Sakamoto M, Iuchi H, Shimizu I, Yoshino T, Katoh D, Nagoshi T, Tojo K, Minamino T, Yoshimura M, Utsunomiya K (2015) Arachidonate 12/15-lipoxygenase-induced inflammation and oxidative stress are involved in the development of diabetic cardiomyopathy. Diabetes 64(2):618–630. https://doi.org/10.2337/db13-1896 PubMedCrossRef

148.

Zhao W, Zhao T, Chen Y, Ahokas RA, Sun Y (2008) Oxidative stress mediates cardiac fibrosis by enhancing transforming growth factor-beta1 in hypertensive rats. Mol Cell Biochem 317(1-2):43–50. https://doi.org/10.1007/s11010-008-9803-8 PubMedCrossRef

149.

Fukuda M, Nakamura T, Kataoka K, Nako H, Tokutomi Y, Dong YF, Ogawa H, Kim-Mitsuyama S (2010) Potentiation by candesartan of protective effects of pioglitazone against type 2 diabetic cardiovascular and renal complications in obese mice. J Hypertens 28(2):340–352. https://doi.org/10.1097/HJH.0b013e32833366cd PubMedCrossRef

150.

Jadhav A, Tiwari S, Lee P, Ndisang JF (2013) The heme oxygenase system selectively enhances the anti-inflammatory macrophage-M2 phenotype, reduces pericardial adiposity, and ameliorated cardiac injury in diabetic cardiomyopathy in Zucker diabetic fatty rats. J Pharmacol Exp Ther 345(2):239–249. https://doi.org/10.1124/jpet.112.200808 PubMedCrossRef

151.

Wang T, Mao X, Li H, Qiao S, Xu A, Wang J, Lei S, Liu Z, Ng KF, Wong GT, Vanhoutte PM, Irwin MG, Xia Z (2013) N-Acetylcysteine and allopurinol up-regulated the Jak/STAT3 and PI3K/Akt pathways via adiponectin and attenuated myocardial postischemic injury in diabetes. Free Radic Biol Med 63:291–303. https://doi.org/10.1016/j.freeradbiomed.2013.05.043 PubMedCrossRef

152.

Shiraishi D, Fujiwara Y, Komohara Y, Mizuta H, Takeya M (2012) Glucagon-like peptide-1 (GLP-1) induces M2 polarization of human macrophages via STAT3 activation. Biochem Biophys Res Commun 425(2):304–308. https://doi.org/10.1016/j.bbrc.2012.07.086 PubMedCrossRef

153.

Sica A, Bronte V (2007) Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117(5):1155–1166. https://doi.org/10.1172/JCI31422 PubMedPubMedCentralCrossRef

154.

Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10(2):417–426PubMedCrossRef

155.

Davis BK, Wen H, Ting JP (2011) The inflammasome NLRs in immunity, inflammation, and associated diseases. Annu Rev Immunol 29:707–735. https://doi.org/10.1146/annurev-immunol-031210-101405 PubMedPubMedCentralCrossRef

156.

Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, Abela GS, Franchi L, Nunez G, Schnurr M, Espevik T, Lien E, Fitzgerald KA, Rock KL, Moore KJ, Wright SD, Hornung V, Latz E (2010) NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature 464(7293):1357–1361. https://doi.org/10.1038/nature08938 PubMedPubMedCentralCrossRef

157.

Vandanmagsar B, Youm YH, Ravussin A, Galgani JE, Stadler K, Mynatt RL, Ravussin E, Stephens JM, Dixit VD (2011) The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance. Nat Med 17(2):179–188. https://doi.org/10.1038/nm.2279 PubMedPubMedCentralCrossRef

158.

Fuentes-Antras J, Ioan AM, Tunon J, Egido J, Lorenzo O (2014) Activation of toll-like receptors and inflammasome complexes in the diabetic cardiomyopathy-associated inflammation. Int J Endocrinol 2014:847827. https://doi.org/10.1155/2014/847827 PubMedPubMedCentralCrossRef

159.

Luo B, Li B, Wang W, Liu X, Liu X, Xia Y, Zhang C, Zhang Y, Zhang M, An F (2014) Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model. Cardiovasc Drugs Ther 28(1):33–43. https://doi.org/10.1007/s10557-013-6498-1 PubMedCrossRef

160.

Luo B, Li B, Wang W, Liu X, Xia Y, Zhang C, Zhang M, Zhang Y, An F (2014) NLRP3 gene silencing ameliorates diabetic cardiomyopathy in a type 2 diabetes rat model. PloS One 9(8):e104771. https://doi.org/10.1371/journal.pone.0104771 PubMedPubMedCentralCrossRef

161.

Shah MS, Brownlee M (2016) Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ Res 118(11):1808–1829. https://doi.org/10.1161/CIRCRESAHA.116.306923 PubMedPubMedCentralCrossRef

162.

Singh LP (2014) The NLRP3 inflammasome and diabetic cardiomyopathy : editorial to: “Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model” by Beibei Luo et al. Cardiovasc Drugs Ther 28(1):5–6. https://doi.org/10.1007/s10557-013-6501-x PubMedCrossRef

163.

Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y (2017) SGLT-2 inhibition with dapagliflozin reduces the activation of the Nlrp3/ASC inflammasome and attenuates the development of diabetic cardiomyopathy in mice with type 2 diabetes. Further augmentation of the effects with saxagliptin, a DPP4 inhibitor. Cardiovasc Drugs Ther 31(2):119–132. https://doi.org/10.1007/s10557-017-6725-2 PubMedCrossRef

164.

Kahn AM, Lichtenberg RA, Allen JC, Seidel CL, Song T (1995) Insulin-stimulated glucose transport inhibits Ca2+ influx and contraction in vascular smooth muscle. Circulation 92(6):1597–1603PubMedCrossRef

165.

Wakisaka M, Kitazono T, Kato M, Nakamura U, Yoshioka M, Uchizono Y, Yoshinari M (2001) Sodium-coupled glucose transporter as a functional glucose sensor of retinal microvascular circulation. Circ Res 88(11):1183–1188PubMedCrossRef

166.

Li X, Mizuno R, Ono N, Ohhashi T (2008) Glucose and glucose transporters regulate lymphatic pump activity through activation of the mitochondrial ATP-sensitive K+ channel. J Physiol Sci 58(4):249–261. https://doi.org/10.2170/physiolsci.RP004608 PubMedCrossRef

167.

Nishizaki T, Matsuoka T (1998) Low glucose enhances Na+/glucose transport in bovine brain artery endothelial cells. Stroke 29(4):844–849PubMedCrossRef

168.

Berna N, Arnould T, Remacle J, Michiels C (2001) Hypoxia-induced increase in intracellular calcium concentration in endothelial cells: role of the Na(+)-glucose cotransporter. J Cell Biochem 84(1):115–131PubMedCrossRef

169.

Vemula S, Roder KE, Yang T, Bhat GJ, Thekkumkara TJ, Abbruscato TJ (2009) A functional role for sodium-dependent glucose transport across the blood-brain barrier during oxygen glucose deprivation. J Pharmacol Exp Ther 328(2):487–495. https://doi.org/10.1124/jpet.108.146589 PubMedCrossRef

170.

Taubert D, Rosenkranz A, Berkels R, Roesen R, Schomig E (2004) Acute effects of glucose and insulin on vascular endothelium. Diabetologia 47(12):2059–2071. https://doi.org/10.1007/s00125-004-1586-1 PubMedCrossRef

171.

Mudaliar S, Polidori D, Zambrowicz B, Henry RR (2015) Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care 38(12):2344–2353. https://doi.org/10.2337/dc15-0642 PubMedCrossRef

172.

Shen L, You BA, Gao HQ, Li BY, Yu F, Pei F (2012) Effects of phlorizin on vascular complications in diabetes db/db mice. Chin Med J 125(20):3692–3696PubMed

173.

Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M (2016) Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse. Front Cardiovasc Med 3:43. https://doi.org/10.3389/fcvm.2016.00043 PubMedPubMedCentralCrossRef

174.

Lastra G, Manrique C (2015) Perivascular adipose tissue, inflammation and insulin resistance: link to vascular dysfunction and cardiovascular disease. Horm Mol Biol Clin Invest 22(1):19–26. https://doi.org/10.1515/hmbci-2015-0010 CrossRef

175.

Roma-Lavisse C, Tagzirt M, Zawadzki C, Lorenzi R, Vincentelli A, Haulon S, Juthier F, Rauch A, Corseaux D, Staels B, Jude B, Belle EV, Susen S, Chinetti-Gbaguidi G, Dupont A (2015) M1 and M2 macrophage proteolytic and angiogenic profile analysis in atherosclerotic patients reveals a distinctive profile in type 2 diabetes. Diab Vasc Dis Res 12(4):279–289. https://doi.org/10.1177/1479164115582351 PubMedCrossRef

176.

Bolinder J, Ljunggren Ö, Kullberg J, Johansson L, Wilding J, Langkilde AM, Sugg J, Parikh S (2012) Effects of dapagliflozin on body weight, total fat mass, and regional adipose tissue distribution in patients with type 2 diabetes mellitus with inadequate glycemic control on metformin. J Clin Endocrinol Metab 97(3):1020–1031. https://doi.org/10.1210/jc.2011-2260 PubMedCrossRef

177.

Ferrannini E, Ramos SJ, Salsali A, Tang W, List JF (2010) Dapagliflozin monotherapy in type 2 diabetic patients with inadequate glycemic control by diet and exercise: a randomized, double-blind, placebo-controlled, phase 3 trial. Diabetes Care 33(10):2217–2224. https://doi.org/10.2337/dc10-0612 PubMedPubMedCentralCrossRef

178.

Borlaug BA (2014) The pathophysiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 11(9):507–515. https://doi.org/10.1038/nrcardio.2014.83 PubMedCrossRef

179.

Kemp CD, Conte JV (2012) The pathophysiology of heart failure. Cardiovasc Pathol 21(5):365–371. https://doi.org/10.1016/j.carpath.2011.11.007 PubMedCrossRef

180.

Cherney DZ, Perkins BA, Soleymanlou N, Maione M, Lai V, Lee A, Fagan NM, Woerle HJ, Johansen OE, Broedl UC, von Eynatten M (2014) Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation 129(5):587–597. https://doi.org/10.1161/CIRCULATIONAHA.113.005081 PubMedCrossRef

181.

Clark AL, Fonarow GC, Horwich TB (2014) Obesity and the obesity paradox in heart failure. Prog Cardiovasc Dis 56(4):409–414. https://doi.org/10.1016/j.pcad.2013.10.004 PubMedCrossRef

182.

Monica Reddy RP, Inzucchi SE (2016) SGLT2 inhibitors in the management of type 2 diabetes. Endocrine 53(2):364–372. https://doi.org/10.1007/s12020-016-0943-4 PubMedCrossRef

183.

Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA (2016) SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care 39(5):717–725. https://doi.org/10.2337/dc16-0041 PubMedPubMedCentralCrossRef

184.

Pham SV, Chilton R (2017) EMPA-REG OUTCOME: the cardiologist’s point of view. Am J Med 130(6S):S57–S62. https://doi.org/10.1016/j.amjmed.2017.04.006 PubMedCrossRef

185.

Diabetes Prevention Program Research G (2015) Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 3(11):866–875. https://doi.org/10.1016/S2213-8587(15)00291-0 CrossRef

186.

Kernan WN, Viscoli CM, Furie KL, Young LH, Inzucchi SE, Gorman M, Guarino PD, Lovejoy AM, Peduzzi PN, Conwit R, Brass LM, Schwartz GG, Adams HP Jr, Berger L, Carolei A, Clark W, Coull B, Ford GA, Kleindorfer D, O'Leary JR, Parsons MW, Ringleb P, Sen S, Spence JD, Tanne D, Wang D, Winder TR, Investigators IT (2016) Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 374(14):1321–1331. https://doi.org/10.1056/NEJMoa1506930 PubMedPubMedCentralCrossRef

187.

Balteau M, Tajeddine N, de Meester C, Ginion A, Des Rosiers C, Brady NR, Sommereyns C, Horman S, Vanoverschelde JL, Gailly P, Hue L, Bertrand L, Beauloye C (2011) NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1. Cardiovasc Res 92(2):237–246. https://doi.org/10.1093/cvr/cvr230 PubMedCrossRef

188.

Kanwal A, Nizami HL, Mallapudi S, Putcha UK, Mohan GK, Banerjee SK (2016) Inhibition of SGLT1 abrogates preconditioning-induced cardioprotection against ischemia-reperfusion injury. Biochem Biophys Res Commun 472(2):392–398. https://doi.org/10.1016/j.bbrc.2016.02.016 PubMedCrossRef

189.

Kashiwagi Y, Nagoshi T, Yoshino T, Tanaka TD, Ito K, Harada T, Takahashi H, Ikegami M, Anzawa R, Yoshimura M (2015) Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PloS One 10(6):e0130605. https://doi.org/10.1371/journal.pone.0130605 PubMedPubMedCentralCrossRef

190.

Liu JJ, Lee T, DeFronzo RA (2012) Why Do SGLT2 inhibitors inhibit only 30-50% of renal glucose reabsorption in humans? Diabetes 61(9):2199–2204. https://doi.org/10.2337/db12-0052 PubMedCrossRef

191.

Ohgaki R, Wei L, Yamada K, Hara T, Kuriyama C, Okuda S, Ueta K, Shiotani M, Nagamori S, Kanai Y (2016) Interaction of the sodium/glucose cotransporter (SGLT) 2 inhibitor canagliflozin with SGLT1 and SGLT2. J Pharmacol Exp Ther 358(1):94–102. https://doi.org/10.1124/jpet.116.232025 PubMedCrossRef

Title: Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects
Authors: Abdullah Kaplan
Emna Abidi
Ahmed El-Yazbi
Ali Eid
George W. Booz
Fouad A. Zouein
Publication date: 01-05-2018
Publisher: Springer US
Published in: Heart Failure Reviews / Issue 3/2018
Print ISSN: 1382-4147
Electronic ISSN: 1573-7322
DOI: https://doi.org/10.1007/s10741-017-9665-9

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Direct cardiovascular impact of SGLT2 inhibitors: mechanisms and effects

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 3/2018

Clinical correlates and pharmacological management of Asian patients with concomitant diabetes mellitus and heart failure

Interrelationship between diabetes mellitus and heart failure: the role of peroxisome proliferator-activated receptors in left ventricle performance

SGLT2 inhibition and heart failure—current concepts

Interdisciplinary approach to compensation of hypoglycemia in diabetic patients with chronic heart failure

DPP-4 inhibitors and heart failure: a potential role for pharmacogenomics

Still sour about lactic acidosis years later: role of metformin in heart failure

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page