Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure - Proposal of a novel mechanism of action

JAMA Cardiology

Volumn 2, Issue 9, 2017, Pages 1025-1029

  Packer, Milton ^a   Anker, Stefan D ^b   Butler, Javed ^c   Filippatos, Gerasimos ^d   Zannad, Faiez ^e  

^a BAYLOR UNIVERSITY MEDICAL CENTER   (United States)

^b CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^c STONY BROOK UNIVERSITY   (United States)

^d UNIVERSITY OF ATHENS MEDICAL SCHOOL   (Greece)

^e UNIVERSITÉ DE LORRAINE   (France)

Author keywords

[No Author keywords available]

Indexed keywords

DAPAGLIFLOZIN; EMPAGLIFLOZIN; SODIUM GLUCOSE COTRANSPORTER 2 INHIBITOR; SODIUM PROTON EXCHANGE PROTEIN; BENZHYDRYL DERIVATIVE; GLUCOSIDE;

ARTICLE; BLOOD PRESSURE REGULATION; BODY WEIGHT; CEREBROVASCULAR ACCIDENT; DIABETES MELLITUS; DRUG MECHANISM; FLUID RETENTION; GLOMERULUS FILTRATION; GLYCEMIC CONTROL; HEART FAILURE; HEART FAILURE WITH PRESERVED EJECTION FRACTION; HEART INFARCTION; HEART PROTECTION; OSMOTIC DIURESIS; PRIORITY JOURNAL; BLOOD VESSEL; CARDIAC MUSCLE; HUMAN; KIDNEY; KIDNEY PROXIMAL TUBULE; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS;

BENZHYDRYL COMPOUNDS; BLOOD VESSELS; DIABETES MELLITUS, TYPE 2; GLUCOSIDES; HEART FAILURE; HUMANS; KIDNEY; KIDNEY TUBULES, PROXIMAL; MYOCARDIUM; SODIUM-GLUCOSE TRANSPORTER 2 INHIBITORS; SODIUM-HYDROGEN EXCHANGERS;

EID: 85032620814     PISSN: 23806583     EISSN: 23806591     Source Type: Journal    
DOI: 10.1001/jamacardio.2017.2275     Document Type: Article

References (75)

1. Gerstein HC, Bosch J, Dagenais GR, et al; ORIGIN Trial Investigators. Basal insulin and cardiovascular and other outcomes in dysglycemia. N Engl J Med. 2012;367(4):319-328.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. Erdmann E, Charbonnel B, Wilcox RG, et al; PROactive Investigators. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease. Diabetes Care. 2007;30(11):2773-2778.
8. 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.
9. 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. Eur Heart J. 2016;37(19):1526-1534.
10. Sattar N, McLaren J, Kristensen SL, Preiss D, McMurray JJ. SGLT2 Inhibition and cardiovascular events. Diabetologia. 2016;59(7):1333-1339.
11. Saad M, Mahmoud AN, Elgendy IY, et al. Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors in patients with type II diabetes mellitus. Int J Cardiol. 2017;228:352-358.
12. Wu JH, Foote C, Blomster J, et al. Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular events, death, and major safety outcomes in adults with type 2 diabetes. Lancet Diabetes Endocrinol. 2016;4(5):411-419.
13. McMurray J. EMPA-REG - the “diuretic hypothesis.” J Diabetes Complications. 2016;30(1): 3-4.
14. Sciarretta S, Palano F, Tocci G, Baldini R, Volpe M. Antihypertensive treatment and development of heart failure in hypertension: a Bayesian network meta-analysis of studies in patients with hypertension and high cardiovascular risk. Arch Intern Med. 2011;171(5):384-394.
15. van Brummelen P, Man in’t Veld AJ, Schalekamp MA. Hemodynamic changes during long-term thiazide treatment of essential hypertension in responders and nonresponders. Clin Pharmacol Ther. 1980;27(3):328-336.
16. van Brummelen P, Schalekamp MA. Body fluid volumes and the response of renin and aldosterone to short- and long-term thiazide therapy of essential hypertension. Acta Med Scand. 1980;207 (4):259-264.
17. 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.
18. Bilo HJ, Westerman RF, Nicolaas-Merkus AM, Donker AJ. Effects of enalapril with and without hydrochlorothiazide in hypertensive patients with non–insulin-dependent diabetes mellitus. Diabetes Res. 1988;9(1):21-25.
19. Voyaki SM, Staessen JA, Thijs L, et al; Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Follow-up of renal function in treated and untreated older patients with isolated systolic hypertension. J Hypertens. 2001;19(3):511-519.
20. Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus. Circulation. 2016;134(10):752-772.
21. Weir MR, Januszewicz A, Gilbert RE, et al. Effect of canagliflozin on blood pressure and adverse events related to osmotic diuresis and reduced intravascular volume in patients with type 2 diabetes mellitus. J Clin Hypertens (Greenwich). 2014;16(12):875-882.
22. Heise T, Jordan J, Wanner C, et al. Pharmacodynamic effects of single and multiple doses of empagliflozin in patients with type 2 diabetes. Clin Ther. 2016;38(10):2265-2276.
23. 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.
24. 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.
25. Scheen AJ. Reappraisal of the diuretic effect of empagliflozin in the EMPA-REG OUTCOME trial. Diabetes Metab. 2016;42(4):224-233.
26. Vallon V, Thomson SC. Targeting renal glucose reabsorption to treat hyperglycaemia. Diabetologia. 2017;60(2):215-225.
27. Ghezzi C, Yu AS, Hirayama BA, et al. Dapagliflozin binds specifically to sodium-glucose cotransporter 2 in the proximal renal tubule. J Am Soc Nephrol. 2017;28(3):802-810.
28. Fioretto P, Zambon A, Rossato M, Busetto L, Vettor R. SGLT2 inhibitors and the diabetic kidney. Diabetes Care. 2016;39(suppl 2):S165-S171.
29. Ikenaga H, Ishii N, Didion SP, et al. Suppressed impact of nitric oxide on renal arteriolar function in rats with chronic heart failure. Am J Physiol. 1999; 276(1 Pt 2):F79-F87.
30. Dargie H. Sympathetic activity and regional blood flow in heart failure. Eur Heart J. 1990;11(suppl A):39-43.
31. Pessoa TD, Campos LC, Carraro-Lacroix L, Girardi AC, Malnic G. Functional role of glucose metabolism, osmotic stress, and sodium-glucose cotransporter isoform-mediated transport on Na+/H+ exchanger isoform 3 activity in the renal proximal tubule. J Am Soc Nephrol. 2014;25(9): 2028-2039.
32. Fu Y, Gerasimova M, Mayoux E, et al. SGLT2 inhibitor empagliflozin increases renal NHE3 phosphorylation in diabetic Akita mice [abstract 132]. Diabetes. 2014;63(suppl 1):A132.
33. Layton AT, Vallon V, Edwards A. Modeling oxygen consumption in the proximal tubule. Am J Physiol Renal Physiol. 2015;308(12):F1343-F1357.
34. Inoue BH, dos Santos L, Pessoa TD, et al. Increased NHE3 abundance and transport activity in renal proximal tubule of rats with heart failure. Am J Physiol Regul Integr Comp Physiol. 2012;302 (1):R166-R174.
35. Lütken SC, Kim SW, Jonassen T, et al. Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure. Am J Physiol Renal Physiol. 2009;297(6):F1678-F1688.
36. Modi A, Agrawal A, Morgan F. Euglycemic diabetic ketoacidosis. Curr Diabetes Rev. In press.
37. Heise T, Jordan J, Wanner C, et al. Acute pharmacodynamic effects of empagliflozin with and without diuretic agents in patients with type 2 diabetes mellitus. Clin Ther. 2016;38(10): 2248-2264.e5.
38. Imai T, Akimoto T, Ito C, Masuda T, Nagata D. Management of diabetes associated with nephrotic syndrome. Drug Target Insights. 2015;9:29-31.
39. Joubert M, Jagu B, Montaigne D, et al. The sodium-glucose cotransporter 2 inhibitor dapagliflozin prevents cardiomyopathy in a diabetic lipodystrophic mouse model. Diabetes. 2017;66 (4):1030-1040.
40. Kusaka H, Koibuchi N, Hasegawa Y, Ogawa H, Kim-Mitsuyama S. Empagliflozin lessened cardiac injury and reduced visceral adipocyte hypertrophy in prediabetic rats with metabolic syndrome. Cardiovasc Diabetol. 2016;15(1):157.
41. Lee TM, Chang NC, Lin SZ. Dapagliflozin, a selective SGLT2 inhibitor, attenuated cardiac fibrosis by regulating the macrophage polarization via STAT3 signaling in infarcted rat hearts. Free Radic Biol Med. 2017;104:298-310.
42. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study?. Diabetes Care. 2016;39(7):1115-1122.
43. Spencer AG, Labonte ED, Rosenbaum DP, et al. Intestinal inhibition of the Na+/H+ exchanger 3 prevents cardiorenal damage in rats and inhibits Na+ uptake in humans. Sci Transl Med. 2014;6(227): 227ra36.
44. von Lewinski D, Rainer PP, Gasser R, et al. Glucose-transporter-mediated positive inotropic effects in human myocardium of diabetic and nondiabetic patients. Metabolism. 2010;59(7): 1020-1028.
45. Baartscheer A, Schumacher CA, Wüst 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.
46. Yokoyama H, Gunasegaram S, Harding SE, Avkiran M. Sarcolemmal Na+/H+ exchanger activity and expression in human ventricular myocardium. J Am Coll Cardiol. 2000;36(2):534-540.
47. Hui Y, Junzhu C, Jianhua Z. Gap junction and Na+–H+ exchanger alternations in fibrillating and failing atrium. Int J Cardiol. 2008;128(1):147-149.
48. Nakamura TY, Iwata Y, Arai Y, Komamura K, Wakabayashi S. Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res. 2008;103(8):891-899.
49. Despa S, Bers DM. Na+ transport in the normal and failing heart - remember the balance. J Mol Cell Cardiol. 2013;61:2-10.
50. Vettor R, Inzucchi SE, Fioretto P. The cardiovascular benefits of empagliflozin. Diabetologia. 2017;60(3):395-398.
51. Baartscheer A, Hardziyenka M, Schumacher CA, et al. Chronic inhibition of the Na+/H+-exchanger causes regression of hypertrophy, heart failure, and ionic and electrophysiological remodelling. Br J Pharmacol. 2008;154(6):1266-1275.
52. Baartscheer A, Schumacher CA, van Borren MM, et al. Chronic inhibition of Na+/H+-exchanger attenuates cardiac hypertrophy and prevents cellular remodeling in heart failure. Cardiovasc Res. 2005;65(1):83-92.
53. Kilić A, Huang CX, Rajapurohitam V, Madwed JB, Karmazyn M. Early and transient sodium-hydrogen exchanger isoform 1 inhibition attenuates subsequent cardiac hypertrophy and heart failure following coronary artery ligation. J Pharmacol Exp Ther. 2014;351(3):492-499.
54. Darmellah A, Baetz D, Prunier F, Tamareille S, Rücker-Martin C, Feuvray D. Enhanced activity of the myocardial Na+/H+ exchanger contributes to left ventricular hypertrophy in the Goto-Kakizaki rat model of type 2 diabetes. Diabetologia. 2007;50 (6):1335-1344.
55. Aker S, Snabaitis AK, Konietzka I, et al. Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbits. Cardiovasc Res. 2004;63(2):273-282.
56. Baartscheer A, Schumacher CA, van Borren MM, Belterman CN, Coronel R, Fiolet JW. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc Res. 2003;57(4):1015-1024.
57. Engelhardt S, Hein L, Keller U, Klämbt K, Lohse MJ. Inhibition of Na+-H+ exchange prevents hypertrophy, fibrosis, and heart failure in beta1-adrenergic receptor transgenic mice. Circ Res. 2002;90(7):814-819.
58. Kusumoto K, Haist JV, Karmazyn M. Na+/H+ exchange inhibition reduces hypertrophy and heart failure after myocardial infarction in rats. Am J Physiol Heart Circ Physiol. 2001;280(2):H738-H745.
59. Ruetten H, Gehring D, Hiss K, et al. Effects of combined inhibition of the Na+-H+ exchanger and angiotensin-converting enzyme in rats with congestive heart failure after myocardial infarction. Br J Pharmacol. 2005;146(5):723-731.
60. Boyce SW, Bartels C, Bolli R, et al; GUARD During Ischemia Against Necrosis (GUARDIAN) Study Investigators. Impact of sodium-hydrogen exchange inhibition by cariporide on death or myocardial infarction in high-risk CABG surgery patients. J Thorac Cardiovasc Surg. 2003;126(2): 420-427.
61. Chang HB, Gao X, Nepomuceno R, Hu S, Sun D. Na+/H+ exchanger in the regulation of platelet activation and paradoxical effects of cariporide. Exp Neurol. 2015;272:11-16.
62. Taniguchi Y, Nakano M, Hasegawa S, et al. Beneficial effect of amiloride, A Na+-H+ exchange blocker, in a murine model of dilated cardiomyopathy. Res Commun Mol Pathol Pharmacol. 1996;92(2):201-210.
63. De Giusti VC, Nolly MB, Yeves AM, et al. Aldosterone stimulates the cardiac Na+/H+ exchanger via transactivation of the epidermal growth factor receptor. Hypertension. 2011;58(5): 912-919.
64. Karmazyn M, Liu Q, Gan XT, Brix BJ, Fliegel L. Aldosterone increases NHE-1 expression and induces NHE-1–dependent hypertrophy in neonatal rat ventricular myocytes. Hypertension. 2003;42 (6):1171-1176.
65. Boonman-de Winter LJ, Rutten FH, Cramer MJ, et al. High prevalence of previously unknown heart failure and left ventricular dysfunction in patients with type 2 diabetes. Diabetologia. 2012;55(8): 2154-2162.
66. Karagodin I, Aba-Omer O, Sparapani R, Strande JL. Aortic stiffening precedes onset of heart failure with preserved ejection fraction in patients with asymptomatic diastolic dysfunction. BMC Cardiovasc Disord. 2017;17(1):62.
67. Eaton CB, Pettinger M, Rossouw J, et al. Risk factors for incident hospitalized heart failure with preserved versus reduced ejection fraction in a multiracial cohort of postmenopausal women. Circ Heart Fail. 2016;9(10):e002883.
68. Maurer MS, King DL, El-Khoury Rumbarger L, Packer M, Burkhoff D. Left heart failure with a normal ejection fraction. J Card Fail. 2005;11(3): 177-187.
69. Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure. J Am Soc Hypertens. 2014;8(4): 262-75.e9.
70. Chilton R, Tikkanen I, Cannon CP, et al. Effects of empagliflozin on blood pressure and markers of arterial stiffness and vascular resistance in patients with type 2 diabetes. Diabetes Obes Metab. 2015;17 (12):1180-1193.
71. Habibi J, Aroor AR, Sowers JR, et al. Sodium glucose transporter 2 (SGLT2) inhibition with empagliflozin improves cardiac diastolic function in a female rodent model of diabetes. Cardiovasc Diabetol. 2017;16(1):9.
72. Pfeffer MA, Claggett B, Assmann SF, et al. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015;131(1):34-42.
73. Carreño JE, Verdugo FJ, Contreras F, et al. Spironolactone inhibits the activity of the Na+/H+ exchanger in the aorta of mineralocorticoid-induced hypertensive rats. J Renin Angiotensin Aldosterone Syst. 2015;16(4):1225-1231.
74. Fujisawa G, Okada K, Muto S, et al. Na/H exchange isoform 1 is involved in mineralocorticoid/ salt-induced cardiac injury. Hypertension. 2003;41 (3):493-498.
75. Young M, Funder J. Mineralocorticoid action and sodium-hydrogen exchange. Endocrinology. 2003;144(9):3848-3851.