1. Lee WS, Kanai Y, Wells RG, et al. The high affinity Na+/
glucose cotransporter. J Biol Chem 1994; 269: 12032–12039.
2. Wright EM, Loo DD, Hirayama BA. Biology of human
sodium glucose transporters. Physiol Rev 2011; 91: 733–794.
3. Bailey CJ. Renal glucose reabsorption inhibitors to treat
diabetes. Trends Pharmacol Sci 2011; 32: 63–71.
4. Abdul-Ghani M, DeFronzo R, Norton L. Novel hypothesis to
explain why SGLT2 inhibitors inhibit only 30–50% of
filtered glucose load in humans. Diabetes 2013; 62: 3324–
3328.
5. Ferrannini E, Muscelli E, Frascerra S, et al. Metabolic
response to sodium-glucose cotransporter 2 inhibition in
type 2 diabetic patients. J Clin Invest 2013; 124: 499–508.
6. Merovci A, Solis-Herrera C, Daniele G, et al. Dapagliflozin
improves muscle insulin sensitivity but enhances
endogenous glucose production. J Clin Invest 2014; 124:
509–514.
7. Cefalu WT. Paradoxical insights into whole body metabolic
adaptations following SGLT2 inhibition. J Clin Invest 2015;
124: 485–487.
8. Polidori D, Mari A, Ferrannini E. Canagliflozin, a sodium
glucose co- transporter 2 inhibitor, improves model-based
indices of beta cell function in patients with type 2
diabetes. Diabetologia 2014; 57: 891–901.
9. Rossetti L, Smith D, Shulman GI, et al. Correction of
hyperglycemia with phlorizin normalizes tissue sensitivity to
insulin. J Clin Invest 1987; 79: 1510–1515.
10. Takahara M, Shiraiwa T, Matsuoka T, et al. Ameliorated
pancreatic b cell dysfunction in type 2 diabetic patients
treated with a sodium-glucose cotransporter 2 inhibitor
ipragliflozin. Endocrine J 2015; 62: 77–86.
11. Leiter LA, Forst T, Polidori D, et al. Effect of canagliflozin on
liver function tests in patients with type 2 diabetes.
Diabetes Metab 2016; 42: 25–32.
12. 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:
512–517.
12
J Diabetes Investig Vol. No. 2020
http://wileyonlinelibrary.com/journal/jdi
13. Chino Y, Samukawa Y, Sakai S, 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.
14. Oliva RV, Bakris GL. Blood pressure effects of sodiumglucose-cotransport 2 (SGLT2) inhibitors. J Am Soc
Hypertens 2014; 8: 330–339.
15. Tikkanen I, Narko K, Zeller C, et al. Empagliflozin reduces
blood pressure in patients with type 2 diabetes and
hypertension. Diabetes Care 2015; 38: 420–428.
16. Kashiwagi A, Yoshida S, Kawamura K, et al. Effects of
ipragliflozin, a selective sodium–glucose co-transporter 2
inhibitor, on blood pressure in Japanese patients with
type 2 diabetes mellitus: a pooled analysis of six
randomized, placebo-controlled clinical trials. Diabetol Int
2017; 8: 76–86.
17. Baker WL, Smyth LR, Riche DM, et al. Effects of sodiumglucose co-transporter 2 inhibitors on blood pressure: a
systematic review and meta-analysis. J Am Soc Hypertens
2014; 8: 262–275.
18. Sha S, Polidori D, Heise T, et al. Effect of the sodium
glucose co-transporter 2 inhibitor canagliflozin on plasma
volume in patients with type 2 diabetes mellitus. Diabetes
Obes Metab 2014; 16: 1087–1095.
19. Bolinder J, Ljunggren O, Kullberg J, et al. 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 2012; 97: 1020–1031.
20. Kashiwagi A, Maegawa H. Metabolic and hemodynamic
effects of sodium dependent glucose cotransporter 2
inhibitors on cardio-renal protection in the treatment of
patients with type 2 diabetes mellitus. J Diabetes Investig
2017; 8: 416–427.
21. Kashiwagi A, Sakatani T, Nakamura I, et al. Improved
cardiometabolic risk factors in Japanese patients with type
2 diabetes treated with ipragliflozin: a pooled analysis of
six randomized, placebo-controlled trials. Endocrine J 2018;
65: 691–705.
22. Zimman 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: 2117–2128.
23. Wanner C, Inzucchi SE, Lachin JM, et al. Empagliflozin and
progression of kidney disease in type 2 diabetes. N Engl J
Med 2016; 375: 323–334.
24. Cherney DZ, Zinman B, Inzucchi SE, et al. OUTCOME
Investigators. Effects of empagliflozin on the urinary
albumin-to-creatinine ratio in patients with type 2 diabetes
and established cardiovascular disease: and exploratory
analysis from the EMPA-REG OUTCOME randomized,
placebo-controlled trial. Lancet Diabetes Endocrinol 2017; 5:
610–621.
ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
http://wileyonlinelibrary.com/journal/jdi
25. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and
cardiovascular and renal events in type 2 diabetes. N Engl J
Med 2017; 377: 644–657.
26. Wiviott SD, Bonaca MP, Mosenzon O, et al. Dapagliflozin
and cardiovascular outcomes in type 2 diabetes. N Engl J
Med 2019; 380: 347–357.
27. Perkovic V, Jardine MJ, Neal S, et al. Canagliflozin and renal
outcomes in type 2 diabetes and nephropathy. N Engl J
Med 2019; 380: 2295–2306.
28. Marso SP, Daniels GH, Brown-Frandson K, et al. Liraglutide
and cardiovascular outcomes in type 2 diabetes. New Engl
J Med 2016; 375: 311–322.
29. Marso SP, Bain SC, Consoli A, et al. Semaglutide and
cardiovascular outcomes in patients with type 2 diabetes.
New Engl J Med 2016; 375: 1834–1844.
30. Holman RR, Bethel MA, Mentz RJ, et al. Effects of onceweekly exenatide on cardiovascular outcomes in type 2
diabetes. New Engl J Med 2017; 377: 1228–1239.
31. Mann JFE, Orsted DD, Brown-Frandsen K, et al. Liraglutide
and renal outcomes in type 2 diabetes. N Engl J Med 2017;
377: 839–848.
32. Cosentio F, Grant PJ, Aboyans V, et al. 2019 ESC guidelines
on diabetes, pre-diabetes, and cardiovascular diseases
developed in collaboration with EASD. Eur Heart J 2020; 41:
255–323.
33. Kluger AY, Tecson KM, Lee AY, et al. Class effects of SGLT2
inhibitors on cardiorenal outcomes. Cardiovasc Diabetol
2019; 18: 99.
34. Rabizadeh S, Nakhjavani M, Esteghmati A. Cardiovascular
and renal benefits of SGLT2 inhibitors: a narrative review.
Int J Endocrinol Metab 2019; 17: e84353.
35. Verma S, McMurray JJV. SGLT2 inhibitor and mechanisms
of cardiovascular benefit: a state -of-the-art review.
Diabetologia 2018; 61: 2108–2117.
36. Cavender MA, Norhammar A, Birkeland KI, et al. SGLT2
inhibitors and cardiovascular risk: an analysis of CVD-REAL. J
Am Coll Cardiol 2018; 71: 2497–2506.
37. Kosiborod M, Lam CSP, Kohsaka S, et al. Cardiovascular
events associated with SGLT2 inhibitors versus other
glucose-lowering drugs: the CVD-REAL 2 study. J Am Coll
Cardiol 2018; 71: 2628–2639.
38. Heerspink HL, Karasik A, Thuresson M, et al. Kidney
outcomes associated with use of SGLT2 inhibitors in real
world clinical practice (CVD-REAL 3): a multinational
observational cohort study. Lancet Diabetes Endocrinol 2020;
8: 27–35.
39. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC guideline
for the diagnosis and treatment of acute and chronic heart
failure: the task force for the diagnosis and treatment of
acute and chronic heart failure of the European Society of
cardiology (ESC). Eur Heart J 2016; 37: 2129–2200.
40. Bell DSH. Heart failure: the frequent, forgotten, and often
fetal complication of diabetes. Diabetes Care 2003; 26:
2433–2441.
ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
REVIEW ARTICLE
SGLT2 inhibitors for heart failure prevention
41. Nichols GA, Ephross SA, Gullion CM, et al. The incidence of
congestive heart failure in type 2 diabetes: an update.
Diabetes Care 2004; 27: 1879–1884.
42. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of
cardiomyopathy associated with diabetic
glomerulosclerosis. Am J Cardiol 1972; 30: 595–602.
43. Bell DSH. Diabetic cardiomyopathy. Diabetes Care 2003; 26:
2949–2951.
44. Seferovic PM, Paulus WJ. Clinical diabetic cardiomyopathy:
a two-faced disease with restrictive and dilated
phenotypes. Eur Heart J 2015; 36: 1718–1727.
45. Shah S, Katz DH, Deo RC. Phenotypic spectrum of heart
failure with preserved ejection fraction. Heart Fail Clin 2014;
10: 407–418.
46. Clarke GD, Molina-Wilkins M, Solis-Herrera C, et al. Impaired
left ventricular diastolic function in T2DM patients is closely
related to glycemic control. Endocrine Diab Metab 2018; 1:
e00014.
47. Triposkiadis F, Giamouzis G, Parrissis J, et al. Reframing the
association and significance of co-morbidities in heart
failure. Eur J Heart Fail 2016; 18: 744–58.
48. McMurray JJV, Ostergren J, Swedberg K, et al. Effects of
candesartan in patients with chronic heart failure and
reduced left-ventricular systolic function taking angiotensinconverting-enzyme inhibitors: the CHARM-Added Trial.
Lancet 2003; 362: 767–771.
49. Sandesara PB, O’Neal WT, Kelli HM, et al. The prognostic
significance of diabetes and microvascular complications in
patients with heart failure with preserved ejection fraction.
Diabetes Care 2018; 41: 150–155.
50. Tromp J, Lim SL, Toy WT, et al. Microvascular disease in
patients with diabetes with reduced ejection fraction
versus preserved ejection fraction. Diabetes Care 2019; 42:
1792–1799.
51. Packer M, Kitzman DW. Obesity-related heart failure with a
preserved ejection fraction: the mechanistic rationale for
combining inhibitors of aldosterone, neprilysin, and
sodium-glucose cotransporter-2. J Am Coll Cardiol 2018; 6:
633–639.
52. Bakker W, Eringa EC, Sipkema P, et al. Endothelial
dysfunction and diabetes: roles of hyperglycemia, impaired
insulin signaling and obesity. Cell Tissue Res 2009; 335: 165–
189.
53. Sorop O, Heinonen I, van Kranenburg M, et al. Multiple
common comorbidities produce left ventricular diastolic
dysfunction associated with coronary microvascular
dysfunction, oxidative stress, and myocardial stiffening.
Cardiovasc Res 2018; 114: 954–964.
54. Patel VB, Shah S, Verma S, et al. Epicardial adipose tissue as
a metabolic transducer: role in heart failure and coronary
artery disease. Heart Fail Rev 2007; 22: 889–902.
55. Pitt B, Zannad F, Remme WJ, et al. The effect of
spironolactone on morbidity and mortality in patients with
severe heart failure. N Engl J Med 1999; 341: 709–717.
J Diabetes Investig Vol. No. 2020
13
REVIEW ARTICLE
Kashiwagi et al.
56. Solomon SD, Claggett B, McMurray JJV, et al. Combined
neprilysin and renin-angiotensin system inhibition in heart
failure with reduced ejection fraction: a meta-analysis. Eur J
Heart Fail 2016; 18: 1238–1243.
57. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin
in patients with heart failure and reduced ejection fraction.
N Engl J Med 2019; 381: 1995–2008.
58. Lam CS, Donal E, Kraigher-Krainer E, et al. Epidemiology
and clinical course of heart failure with preserved ejection
fraction. Eur J Heart Fail 2011; 13: 18–28.
59. Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–
neprilysin inhibition in heart failure with preserved ejection
fraction. N Engl J Med 2019; 381: 1609–1620.
60. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for
heart failure with preserved ejection fraction. N Engl J Med
2014; 370: 1383–1392.
61. Kashiwagi A. A new door opens, but it is essential to
accumulate further clinical evidence to control heart failure
in diabetes with preserved ejection fraction. J Diabetes
Investig 2019; 10: 1145–1147.
62. Soga F, Tanaka H, Tatsumi K, et al. Impact of dapagliflozin
on left ventricular diastolic function of patients with type 2
diabetic mellitus with chronic heart failure. Cardiovasc
Diabetol 2018; 17: 132–140.
63. Pabel S, Wagner S, Bollenberg H, et al. Empagliflozin
directly improves diastolic function in human heart failure.
Eur J Heart Fail 2018; 20: 1690–1700.
64. Figtree GA, Radholm K, Barrett TD, et al. Effects of
canagliflozin on heart failure outcomes associated with
preserved and reduced ejection fraction in type 2 diabetes
mellitus: results from the CAVAS program. Circulation 2019;
139: 2591–2593.
65. Kato ET, Silverman MG, Mosenzon O, et al. Effect of
dapagliflozin on heart failure and mortality in type 2
diabetes mellitus. Circulation 2019; 139: 2528–2536.
66. Milton Packer M, Butler J, Filippatos GS, et al. Evaluation of
the effect of sodium glucose co-transporter 2 inhibition
with empagliflozin on morbidity and mortality of patients
with chronic heart failure and a reduced ejection fraction:
rationale for and design of the EMPEROR-Reduced Trial. Eur
J Heart Fail 2019; 21: 1270–1278.
67. Anker SD, Butler J, Filippatos GS, et al. Evaluation of the
effects of sodium-glucose cotransporter 2 inhibition with
empagliflozin on morbidity and mortality in patients with
chronic heart failure and a preserved ejection fraction:
rationale for and design of the EMPEROR-Preserved Trial.
Eur J Heart Fail 2019; 21: 1279–1287.
68. Jensen J, Omar M, Kistorp C, et al. Empagliflozin in
heart failure patients with reduced ejection fraction:
a randomized clinical trial (Empire HF). Trials 2019;
20: 374.
69. Shinozaki K, Kashiwagi A, Nishio Y, et al. Abnormal
biopterin metabolism is a major cause of impaired
endothelial-dependent relaxation through nitric oxide/O214
J Diabetes Investig Vol. No. 2020
http://wileyonlinelibrary.com/journal/jdi
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
imbalance in insulin-resistant rat aorta. Diabetes 1999; 48:
2437–2445.
Kashiwagi A, Shibozaki K, Nishio Y, et al. Free radical
production in endothelial cells as a pathogenetic factor for
vascular dysfunction in the insulin-resistance state. Diabetes
Res Clin Pract 1999; 45: 199–203.
Shinozaki K, Hirayama A, Nishio Y, et al. Coronary
endothelial dysfunction in the insulin-resistant state is
linked to abnormal pteridine metabolism and vascular
oxidative stress. J Am Coll Cardiol 2001; 38: 1821–1828.
Aoyagi T, Matsui T. The cardiomyocytes as a source of
cytokines in cardiac injury. J Cell Sci Ther 2011.
https://doi.org/10.4172/2157-7013.S5-003
Salim HM, Fukuda D, Yagi S, et al. Gylcemic control with
ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated
endothelial dysfunction in streptozotocin-induced diabetic
mouse. Front Cardiovasc Med 2016; 3: 1–9.
Sprague AH, Khalil RA. Inflammatory cytokines in vascular
dysfunction and vascular disease. Biochem Pharmacol 2009;
15: 539–552.
L, Barroso E, et al. An overview of the
Palomer X, Salvado
crosstalk between inflammatory processes and metabolic
dysregulation during diabetic cardiomyopathy. Int J Cardiol
2013; 168: 3160–3172.
Ansley DM, Wang B. Oxidative stress and myocardial injury
in the diabetic heart”. J Pathol 2013; 229: 232–241.
Balligand J-L, Ungureanu-Longrois D, Simmons WW, et al.
Cytokine-inducible nitric oxide synthase (iNOS) expression
in cardiac myocytes: characterization and regulation of
iNOS expression and detection of iNOS activity in single
cardiac myocytes in vitro. J Biol Chem 1994; 269: 27580–
27588.
Liu T, Zhang L, Joo D, et al. NF-kB signaling in
inflammation. Signal Transduct Target Ther 2017; 2: 17023.
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: 246–255.
Li C, Zhang J, Xue M, et al. SGLT2 inhibition with
empagliflozin attenuates myocardial oxidative stress and
fibrosis in diabetic heart. Cardiovasc Diabetol 2019; 18: 15.
Garvey WT, Gaal LV, Leiter LA, et al. Effects of canagliflozin
versus glimepiride on adipokines and inflammatory
biomarkers in type 2 diabetes. Metabolism 2018; 85: 32–37.
Paulus WJ. Unfolding discoveries in heart failure. New Engl
J Med 2020; 382: 679–682.
Schiattarella GG, Altamirano F, Tong D, et al. Nitrosative
stress drives heart failure with preserved ejection fraction.
Nature 2019; 568: 351–356.
Franssen C, Chen S, Unger A, et al. Myocardial
microvascular inflammatory endothelial activation in heart
failure with preserved ejection fraction. J Am Coll Cardiol
Heart Fail 2016; 4: 312–24.
ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
http://wileyonlinelibrary.com/journal/jdi
85. Karmazyn M, Gan XT, Humphreys RA, et al. The myocardial
Na+-H+ exchange; structure, regulation, and role in heart
disease. Circ Res 1999; 85: 777–786.
86. Packer M, Anker SD, Butler J, et al. Effects of sodiumglucose cotransporter 2 inhibitors for the treatment of
patients with heart failure: proposal of a novel mechanism
of action. JAMA Cardiol 2017; 2: 1025–1029.
87. Hamouda NN, Sydorenko V, Qureshi MA, et al.
Dapagliflozin reduces the amplitude of shortening and
Ca2+ transient in ventricular myocytes from streptozotocininduced diabetic rats. Mol Cell Biochem 2014; 400: 57–68.
88. Baartscheer A, Schumacher CA, Wust RCI, et al.
Empagliflozin decreases myocardial cytoplasmic Na+
through inhibition of the cardiac Na+/H+ exchanger in rats
and rabbits. Diabetologia 2017; 60: 568–573.
89. Uthman L, Baartscheer A, Bleijlevens B, et al. Class effects of
SGLT2 inhibitors in mouse cardiomyocytes and hearts;
inhibition of Na+/H+ exchange, lowering of cytosolic Na+
and vasodilation. Diabetologia 2018; 61: 722–726.
90. Gallo LA, Wright EM, Vallon V. Probing SGLT2 as a
therapeutic target for diabetes: basic physiology and
consequences. Diab Vasc Dis Res 2015; 12: 78–89.
91. Goldberg IJ, Trent CM, Schulze C. Lipid metabolism and
toxicity in the heart. Cell Metab 2012; 15: 805–812.
92. Mizuno Y, Harada E, Nakagawa H, et al. The diabetic heart
utilizes ketone bodies as an energy source. Metabolism
2017; 77: 65–72.
93. Sato K, Kashiwaya Y, Keon CA, et al. Insulin, ketone bodies,
and mitochondrial energy transduction. FASEB J 1995; 9: 651–
658.
94. Shimazu T, Hirschey MD, Newman J, et al. Suppression of
oxidative stress by b-hydroxybutyrate, an endogenous
histone decarboxylase inhibitor. Science 2013; 339: 211–214.
ª 2020 The Authors. Journal of Diabetes Investigation published by AASD and John Wiley & Sons Australia, Ltd
REVIEW ARTICLE
SGLT2 inhibitors for heart failure prevention
95. Kolwicz SC, Airhart S, Tian R, et al. Ketones step to the
plate: a game changer for metabolic remodeling in heart
failure? Circulation 2016; 133: 689–691.
96. Ferrannini E, Mark M, Mayoux E, et al. CV protection in the
EMPA-REG OUTCOME Trial: a “thrifty substrate” hypothesis.
Diabetes Care 2016; 39: 1108–1114.
97. Aubert G, Martin OJ, Horton JL, et al. The failing heart relies
on ketone bodies as a fuel. Circulation 2016; 133: 698–705.
98. Pachalska P, Crawford PA. Multi-dimensional roles of
ketone bodies in fuel metabolism, signaling, and
therapeutics. Cell Metab 2017; 25: 262–284.
99. Taylor SI, Blau JE, Rother KI. SGLT2 inhibitors may
predispose to ketoacidosis. J Clin Endocrinol Metab 2015;
100: 2849–2852.
100. 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: 1190–1195.
101. 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: 1115–1122.
102. Kaku K, Watada H, Iwamoto Y, et al. Efficacy and safety of
monotherapy with the novel sodium/glucose
cotransporter-2 inhibitor tofogliflozin in Japanese patients
with type 2 diabetes mellitus: a combined Phase 2 and 3
randomized, placebo-controlled, double-blind, parallelgroup comparative study. Cardiovasc Diabetol 2014; 13:
65–80.
103. Nielsen R, Moller N, Gormsen LC, et al. Cardiovascular
effects of treatment with ketone body 3-hydroxybutyrate
in chronic heart failure patients. Circulation 2019; 139:
2129–2141.
J Diabetes Investig Vol. No. 2020
15
...
論文の公開元へ
