Cardiovascular effects of sodium glucose cotransporter 2 inhibitors

Diabetes, Metabolic Syndrome and Obesity

Volumn 11, Issue , 2018, Pages 133-148

  Santos Cavaiola, Tricia ^a   Pettus, Jeremy ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

Canagliflozin; Cardiovascular outcomes; Dapagliflozin; Empagliflozin; Mechanisms; Sodium glucose cotransporter 2 inhibitors

Indexed keywords

ALBIGLUTIDE; CANAGLIFLOZIN; DAPAGLIFLOZIN; EMPAGLIFLOZIN; ERTUGLIFLOZIN; EXENDIN 4; GLIMEPIRIDE; GLUCAGON; INSULIN DEGLUDEC; INSULIN GLARGINE; LIPID; LIRAGLUTIDE; LIXISENATIDE; NITRIC OXIDE; SAXAGLIPTIN; SEMAGLUTIDE; SITAGLIPTIN; SODIUM GLUCOSE COTRANSPORTER 1; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SULFONYLUREA DERIVATIVE;

BLOOD PRESSURE; BODY WEIGHT; CARDIOVASCULAR EFFECT; CARDIOVASCULAR RISK; CLINICAL OUTCOME; DIURESIS; ENERGY METABOLISM; GLUCAGON RELEASE; GLYCEMIC CONTROL; HEMATOCRIT; HEMODYNAMICS; HUMAN; INFLAMMATION; KIDNEY FUNCTION; LIPID BLOOD LEVEL; NON INSULIN DEPENDENT DIABETES MELLITUS; NONHUMAN; OBESITY; REVIEW; RISK REDUCTION; URIC ACID BLOOD LEVEL;

EID: 85056781319     PISSN: None     EISSN: 11787007     Source Type: Journal    
DOI: 10.2147/DMSO.S154602     Document Type: Review

References (103)

1. American Diabetes Association. 9. Cardiovascular disease and risk management. Diabetes Care. 2017;40 (Suppl 1):S75–S87.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–853. Erratum: Lancet. 1999;354(9178):602.
3. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359(15):1577–1589.
4. Skyler JS, Bergenstal R, Bonow RO, et al. Intensive glycemic control and the prevention of cardiovascular events: implications of the ACCORD, ADVANCE, and VA diabetes trials: a position statement of the American Diabetes Association and a scientific statement of the American College of Cardiology Foundation and the American Heart Association. Diabetes Care. 2009;32(1):187–192.
5. Action to Control Cardiovascular Risk in Diabetes Study Group, Gerstein HC, Miller ME, Byington RP, et al. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med. 2008;358(24): 2545–2559.
6. ADVANCE Collaborative Group, Patel A, MacMahon S, Chalmers J, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–2572.
7. Duckworth W, Abraira C, Moritz T, et al; VADT Investigators. Glucose control and vascular complications in veterans with type 2 diabetes. N Engl J Med. 2009;360(2):129–139.
8. ACCORD Study Group, Gerstein HC, Miller ME, Genuth S, et al. Long-term effects of intensive glucose lowering on cardiovascular outcomes. N Engl J Med. 2011;364(9):818–828.
9. Giorgino F, Home PD, Tuomilehto J. Glucose control and vascular outcomes in type 2 diabetes: is the picture clear? Diabetes Care. 2016;39(Suppl 2):S187–S195.
10. Nissen SE, 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. Erratum: N Engl J Med. 2007;357(1):100.
11. Food and Drug Administration. Guidance for industry: diabetes mellitus–evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available from: http://www.fda.gov/down-loads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm071627.pdf. Accessed February 22, 2017.
12. Singh AK, Singh R. SAVOR-TIMI to SUSTAIN-6: a critical comparison of cardiovascular outcome trials of antidiabetic drugs. Expert Rev Clin Pharmacol. 2017;10(4):429–442.
13. Scirica BM, Bhatt DL, Braunwald E, et al; SAVOR-TIMI 53 Steering Committee and Investigators. Saxagliptin and cardiovascular outcomes in patients with type 2 diabetes mellitus. N Engl J Med. 2013;369(14):1317–1326.
14. White WB, Cannon CP, Heller SR, et al; EXAMINE Investigators. Alogliptin after acute coronary syndrome in patients with type 2 diabetes. N Engl J Med. 2013;369(14):1327–1335.
15. Green JB, Bethel MA, Armstrong PW, et al; TECOS Study Group. Effect of sitagliptin on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2015;373(3):232–242.
16. Pfeffer MA, Claggett B, Diaz R, et al; ELIXA Investigators. Lixisenatide in patients with type 2 diabetes and acute coronary syndrome. N Engl J Med. 2015;373(23):2247–2257.
17. Marso SP, Daniels GH, Brown-Frandsen K, et al; LEADER Steering Committee; LEADER Trial Investigators. Liraglutide and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2016;375(4): 311–322.
18. Marso SP, Bain SC, Consoli A, et al; SUSTAIN-6 Investigators. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834–1844.
19. Holman RR, Bethel MA, Mentz RJ, et al; EXSCEL Study Group. Effects of once-weekly exenatide on cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2017;377(13):1228–1239.
20. Fellner C. Novel treatments target type-2 diabetes. P T. 2016;41(10): 650–653.
21. Marso SP, McGuire DK, Zinman B, et al; DEVOTE Study Group. Efficacy and safety of degludec versus glargine in type 2 diabetes. N Engl J Med. 2017;377(8):723–732.
22. Vaccaro O, Masulli M, Nicolucci A, et al; Thiazolidinediones Or Sulfonylureas Cardiovascular Accidents Intervention Trial (TOSCA. IT) study group; Italian Diabetes Society. Effects on the incidence of cardiovascular events of the addition of pioglitazone versus sulfonylureas in patients with type 2 diabetes inadequately controlled with metformin (TOSCA.IT): a randomised, multicentre trial. Lancet Diabetes Endocrinol. 2017;5(11):887–897.
23. Zinman B, Wanner C, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–2128.
24. Neal B, Perkovic V, Mahaffey KW, et al; CANVAS Program Collaborative Group. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377(7):644–657.
25. Kosiborod M, Cavender MA, Fu AZ, et al; CVD-REAL Investigators and Study Group. Lower risk of heart failure and death in patients initiated on sodium-glucose cotransporter-2 inhibitors versus other glucose-lowering drugs: the CVD-REAL study (Comparative effectiveness of cardiovascular outcomes in new users of sodium-glucose cotransporter-2 inhibitors). Circulation. 2017;136(3):249–259.
26. Birkeland KI, Jorgensen ME, Carstensen B, et al. Cardiovascular mortality and morbidity in patients with type 2 diabetes following initiation of sodium-glucose co-transporter-2 inhibitors versus other glucose-lowering drugs (CVD-REAL Nordic): a multinational observational analysis. Lancet Diabetes Endocrinol. 2017;5(9):709–717.
27. Marx N, Rosenstock J, Kahn SE, et al. Design and baseline characteristics of the CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes (CAROLINA®). Diab Vasc Dis Res. 2015;12(3):164–174.
28. Jardine MJ, Mahaffey KW, Neal B, et al; CREDENCE study investigators. The canagliflozin and renal endpoints in diabetes with established nephropathy clinical evaluation (CREDENCE) study rationale, design, and baseline characteristics. Am J Nephrol. 2017;46(6):462–472.
29. Novo Nordisk US. Victoza® (liraglutide) is approved in the US as the only type 2 diabetes treatment indicated to reduce the risk of three major adverse cardiovascular events. Available from: http://press. novonordisk-us.com/2017-08-25-Victoza-R-liraglutide-is-approved-in-the-US-as-the-only-type-2-diabetes-treatment-indicated-to-reduce-the-risk-of-three-major-adverse-cardiovascular-events. Accessed October 11, 2017.
30. CardioBrief. Clinical trial expert’s deep dive into the important new liraglutide trial. Available from: http://www.cardiobrief. org/2016/06/13/clinical-trial-experts-deep-dive-into-the-important-new-liraglutide-trial/. Accessed October 11, 2017.
31. Abdul-Ghani M, Del Prato S, Chilton R, DeFronzo RA. SGLT2 inhibitors and cardiovascular risk: lessons learned from the EMPA-REG OUTCOME study. Diabetes Care. 2016;39(5):717–725.
32. Pitt B, Remme W, Zannad F, et al; Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study Investigators. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003;348(14):1309–1321.
33. Fitchett D, Zinman B, Wanner C, et al; EMPA-REG OUTCOME® trial investigators. Heart failure outcomes with empagliflozin in patients with type 2 diabetes at high cardiovascular risk: results of the EMPA-REG OUTCOME® trial. Eur Heart J. 2016;37(19):1526–1534.
34. Raz I, Cahn A. Heart failure: SGLT2 inhibitors and heart failure – clinical implications. Nat Rev Cardiol. 2016;13(4):185–186.
35. Baartscheer A, Schumacher CA, Wust RC, et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia. 2017;60(3): 568–573.
36. Verma S, Garg A, Yan AT, et al. Effect of empagliflozin on left ventricular mass and diastolic function in individuals with diabetes: an important clue to the EMPA-REG OUTCOME trial? Diabetes Care. 2016;39(12):e212–e213.
37. Tucker ME. CANVAS: experts spar on canagliflozin risk/benefit in diabetes. Available from: http://www.medscape.com/viewarticle/881719. Accessed July 10, 2017.
38. Schilsky RL. Finding the evidence in real-world evidence: moving from data to information to knowledge. J Am Coll Surg. 2017;224(1):1–7.
39. Fitchett D. SGLT2 inhibitors in the real world: too good to be true? Lancet Diabetes Endocrinol. 2017;5(9):673–675.
40. Vallon V. The mechanisms and therapeutic potential of SGLT2 inhibitors in diabetes mellitus. Annu Rev Med. 2015;66:255–270.
41. Vestri S, Okamoto MM, de Freitas HS, et al. Changes in sodium or glucose filtration rate modulate expression of glucose transporters in renal proximal tubular cells of rat. J Membr Biol. 2001;182(2):105–112.
42. Tabatabai NM, Sharma M, Blumenthal SS, Petering DH. Enhanced expressions of sodium-glucose cotransporters in the kidneys of diabetic Zucker rats. Diabetes Res Clin Pract. 2009;83(1):e27–e30.
43. STEGLATRO™ (ertugliflozin) tablets, for oral use [prescribing information]. Kenilworth, NJ: Merck Sharp & Dohme Corp; 2018. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/209803s000lbl.pdf. Accessed January 3, 2018.
44. Storgaard H, Gluud LL, Bennett C, et al. Benefits and harms of sodium-glucose co-transporter 2 inhibitors in patients with type 2 diabetes: a systematic review and meta-analysis. PLoS One. 2016;11(11):e0166125.
45. Scheen AJ. Reduction in cardiovascular and all-cause mortality in the EMPA-REG OUTCOME trial: a critical analysis. Diabetes Metab. 2016;42(2):71–76.
46. Heise T, Seewaldt-Becker E, Macha S, et al. Safety, tolerability, pharmacokinetics and pharmacodynamics following 4 weeks’ treatment with empagliflozin once daily in patients with type 2 diabetes. Diabetes Obes Metab. 2013;15(7):613–621.
47. Cefalu WT, Leiter LA, Yoon KH, et al. 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. 2013;382(9896):941–950.
48. Bolinder J, Ljunggren Ö, Johansson L, et al. Dapagliflozin maintains glycaemic control while reducing weight and body fat mass over 2 years in patients with type 2 diabetes mellitus inadequately controlled on metformin. Diabetes Obes Metab. 2014;16(2):159–169.
49. Ridderstråle M, Andersen KR, Zeller C, Kim G, Woerle HJ, Broedl UC; EMPA-REG H2H-SU trial investigators. Comparison of empagliflozin and glimepiride as add-on to metformin in patients with type 2 diabetes: a 104-week randomised, active-controlled, double-blind, phase 3 trial. Lancet Diabetes Endocrinol. 2014;2(9):691–700.
50. Ferrannini E, Baldi S, Frascerra S, et al. Shift to fatty substrate utilization in response to sodium-glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65(5):1190–1195.
51. Després JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881–887.
52. Lee MJ, Wu Y, Fried SK. Adipose tissue heterogeneity: implication of depot differences in adipose tissue for obesity complications. Mol Aspects Med. 2013;34(1):1–11.
53. Daniele G, Xiong J, Solis-Herrera C, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care. 2016;39(11):2036–2041.
54. Cahill GF Jr, Veech RL. Ketoacids? Good medicine? Trans Am Clin Climatol Assoc. 2003;114:149–161; discussion 162–163.
55. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies, and mitochondrial energy transduction. FASEB J. 1995;9(8):651–658.
56. Tahara A, Kurosaki E, Yokono M, et al. Effects of sodium-glucose cotransporter 2 selective inhibitor ipragliflozin on hyperglycaemia, oxidative stress, inflammation and liver injury in streptozotocin-induced type 1 diabetic rats. J Pharm Pharmacol. 2014;66(7):975–987.
57. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care. 2016;39(7):1115–1122.
58. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a “thrifty substrate” hypothesis. Diabetes Care. 2016;39(7):1108–1114.
59. Xiong W, Xiao MY, Zhang M, Chang F. Efficacy and safety of canagliflozin in patients with type 2 diabetes: A meta-analysis of randomized controlled trials. Medicine (Baltimore). 2016;95(48):e5473.
60. Kohler S, Zeller C, Iliev H, Kaspers S. Safety and tolerability of empagliflozin in patients with type 2 diabetes: pooled analysis of phase I-III clinical trials. Adv Ther. 2017;34(7):1707–1726.
61. Haas B, Eckstein N, Pfeifer V, Mayer P, Hass MDS. Efficacy, safety and regulatory status of SGLT2 inhibitors: focus on canagliflozin. Nutr Diabetes. 2014;4(11):e143.
62. Briand F, Mayoux E, Brousseau E, et al. Empagliflozin, via switching metabolism toward lipid utilization, moderately increases LDL cholesterol levels through reduced LDL catabolism. Diabetes. 2016;65(7):2032–2038.
63. Wu AH, Gladden JD, Ahmed M, Ahmed A, Filippatos G. Relation of serum uric acid to cardiovascular disease. Int J Cardiol. 2016;213:4–7.
64. Cheeseman C. Solute carrier family 2, member 9 and uric acid homeostasis. Curr Opin Nephrol Hypertens. 2009;18(5):428–432.
65. Inzucchi SE, Zinman B, Wanner C, et al. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12(2):90–100.
66. Tikkanen I, Chilton R, Johansen OE. Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension. Curr Opin Nephrol Hypertens. 2016;25(2):81–86.
67. Tikkanen I, Narko K, Zeller C, et al; EMPA-REG BP Investigators. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420–428.
68. Townsend RR, Machin I, Ren J, et al. Reductions in mean 24-hour ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich). 2016;18(1):43–52.
69. Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 study. Lancet Diabetes Endocrinol. 2016;4(3):211–220.
70. Cook NR, Cohen J, Hebert PR, Taylor JO, Hennekens CH. Implications of small reductions in diastolic blood pressure for primary prevention. Arch Intern Med. 1995;155(7):701–709.
71. Hardy ST, Loehr LR, Butler KR, et al. Reducing the blood pressure-related burden of cardiovascular disease: impact of achievable improvements in blood pressure prevention and control. J Am Heart Assoc. 2015;4(10):e002276.
72. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J. Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab. 2013;15(9):853–862.
73. Kimura G. Importance of inhibiting sodium-glucose cotransporter and its compelling indication in type 2 diabetes: pathophysiological hypothesis. J Am Soc Hypertens. 2016;10(3):271–278.
74. Cefalu WT, Stenlöf K, Leiter LA, et al. Effects of canagliflozin on body weight and relationship to HbA1c and blood pressure changes in patients with type 2 diabetes. Diabetologia. 2015;58(6):1183–1187.
75. Cherney DZ, Perkins BA, Soleymanlou N, et al. The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. Cardiovasc Diabetol. 2014;13:28.
76. Inzucchi SE, Zinman B, Fitchett D, et al. How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care. 2018;41(2): 356–363.
77. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial: comparison with classic diuretics. Diabetes Metab. 2016;42(4):224–233.
78. Marx N, McGuire DK. Sodium-glucose cotransporter-2 inhibition for the reduction of cardiovascular events in high-risk patients with diabetes mellitus. Eur Heart J. 2016;37(42):3192–3200.
79. Mudaliar S, Polidori D, Zambrowicz B, Henry RR. Sodium-glucose cotransporter inhibitors: effects on renal and intestinal glucose transport: from bench to bedside. Diabetes Care. 2015;38(12): 2344–2353.
80. Sano M, Takei M, Shiraishi Y, Suzuki Y. Increased hematocrit during sodium-glucose cotransporter 2 inhibitor therapy indicates recovery of tubulointerstitial function in diabetic kidneys. J Clin Med Res. 2016;8(12):844–847.
81. Cherney DZ, Perkins BA, Soleymanlou N, et al. Renal hemodynamic effect of sodium-glucose cotransporter 2 inhibition in patients with type 1 diabetes mellitus. Circulation. 2014;129(5):587–597.
82. Muskiet MH, van Raalte DH, van Bommel EJ, Smits MM, Tonneijck L. Understanding EMPA-REG OUTCOME. Lancet Diabetes Endocrinol. 2015;3(12):928–929.
83. Wang Y, Katzmarzyk PT, Horswell R, Zhao W, Johnson J, Hu G. Kidney function and the risk of cardiovascular disease in patients with type 2 diabetes. Kidney Int. 2014;85(5):1192–1199.
84. Wanner C, Inzucchi SE, Lachin JM, et al; EMPA-REG OUTCOME Investigators. Empagliflozin and progression of kidney disease in type 2 diabetes. N Engl J Med. 2016;375(4):323–334.
85. Heerspink HJ, Desai M, Jardine M, Balis D, Meininger G, Perkovic V. Canagliflozin slows progression of renal function decline independently of glycemic effects. J Am Soc Nephrol. 2017;28(1):368–375.
86. Ross R. Atherosclerosis–an inflammatory disease. N Engl J Med. 1999;340(2):115–126.
87. Beckman JA, Creager MA, Libby P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA. 2002;287(19):2570–2581.
88. Tahara A, Kurosaki E, Yokono M, et al. Effects of SGLT2 selective inhibitor ipragliflozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013;715(1–3):246–255.
89. Osorio H, Coronel I, Arellano A, et al. Sodium-glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev. 2012;2012:542042.
90. Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M. Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse. Front Cardiovasc Med. 2016;3:43.
91. Larsen EL, Cejvanovic V, Kjaer LK, et al. The effect of empagliflozin on oxidative nucleic acid modifications in patients with type 2 diabetes: protocol for a randomised, double-blinded, placebo-controlled trial. BMJ Open. 2017;7(5):e014728.
92. Tabit CE, Chung WB, Hamburg NM, Vita JA. Endothelial dysfunction in diabetes mellitus: molecular mechanisms and clinical implications. Rev Endocr Metab Disord. 2010;11(1):61–74.
93. Goligorsky MS, Chen J, Brodsky S. Workshop: endothelial cell dysfunction leading to diabetic nephropathy: focus on nitric oxide. Hypertension. 2001;37(2 Pt 2):744–748.
94. Chu S, Bohlen HG. High concentration of glucose inhibits glomerular endothelial eNOS through a PKC mechanism. Am J Physiol Renal Physiol. 2004;287:F384–F392.
95. Jones BJ, Tan T, Bloom SR. Minireview: glucagon in stress and energy homeostasis. Endocrinology. 2012;153(3):1049–1054.
96. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124(2):499–508.
97. Bonner C, Kerr-Conte J, Gmyr V, et al. Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion. Nat Med. 2015;21(5):512–517.
98. Ceriello A, Genovese S, Mannucci E, Gronda E. Glucagon and heart in type 2 diabetes: new perspectives. Cardiovasc Diabetol. 2016;15(1):123.
99. Wright EM, Loo DD, Hirayama BA. Biology of human sodium glucose transporters. Physiol Rev. 2011;91(2):733–794.
100. Cariou B, Charbonnel B. Sotagliflozin as a potential treatment for type 2 diabetes mellitus. Expert Opin Investig Drugs. 2015;24(12):1647–1656.
101. Kashiwagi Y, Nagoshi T, Yoshino T, et al. Expression of SGLT1 in human hearts and impairment of cardiac glucose uptake by phlorizin during ischemia-reperfusion injury in mice. PLoS One. 2015;10(6):e0130605.
102. Grempler R, Thomas L, Eckhardt M, et al. Empagliflozin, a novel selective sodium glucose cotransporter-2 (SGLT-2) inhibitor: characterisation and comparison with other SGLT-2 inhibitors. Diabetes Obes Metab. 2012;14(1):83–90.
103. Tanaka A, Shimabukuro M, Okada Y, et al; EMBLEM Trial Investigators. Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial. Cardiovasc Diabetol. 2017;16(1):48.