Research progress of sodium-glucose cotransporter-2 inhibitors in heart failure with preserved ejection fraction_West China Medical Journal

Authors：

MA Lanhu ¹ , LAN Qingsu ¹ , WU Fengchao ¹ ,  YAO Yali ^1,2

1. The First Clinical Medical College of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;
2. Heart Center, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

YAO Yali, Email: yaoyalifs@163.com

Keywords：

Heart failure with preserved ejection fraction; Sodium-glucose cotransporter-2 inhibitors; Treatment

DOI：

10.7507/1002-0179.202010070

Video：

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Sodium-glucose cotransporter (SGLT) -2 inhibitors is a new type of oral sugar-lowering drug. Instead of relying on insulin, it lowers blood sugar by inhibiting the reabsorption of near-curvy tube glucose, which is drained from the urine. SGLT-2 inhibitors not only have a sugar-lowering effect, but also benefit significantly in cardiovascular disease, and this drug has the advantages of permeable diuretic, reducing capacity load, and improving ventricular remodeling. SGLT-2 inhibitors can improve the diastolic function of patients with heart failure with preserved ejection fraction (HFpEF) and reduce the risk of adverse cardiovascular events. SGLT-2 inhibitors can benefit patients with HFpEF. Therefore, this article will discuss the progress of SGLT-2 inhibitors in HFpEF.

Citation： MA Lanhu, LAN Qingsu, WU Fengchao, YAO Yali. Research progress of sodium-glucose cotransporter-2 inhibitors in heart failure with preserved ejection fraction. West China Medical Journal, 2021, 36(9): 1288-1292. doi: 10.7507/1002-0179.202010070 Copy

1.	McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J, 2021: ehab368.
2.	中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南2018. 中华心血管病杂志, 2018, 46(10): 760-789.
3.	Shimokawa H, Miura M, Nochioka K, et al. Heart failure as a general pandemic in Asia. Eur J Heart Fail, 2015, 17(9): 884-892.
4.	王华, 李莹莹, 柴坷, 等. 中国住院心力衰竭患者流行病学及治疗现状. 中华心血管病杂志, 2019, 47(11): 865-874.
5.	McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med, 2019, 381(21): 1995-2008.
6.	Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol, 2017, 14(10): 591-602.
7.	Shah SJ, Borlaug BA, Kitzman DW, et al. Research priorities for heart failure with preserved ejection fraction: national heart, lung, and blood institute working group summary. Circulation, 2020, 141(12): 1001-1026.
8.	Lindman BR, Dávila-Román VG, Mann DL, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol, 2014, 64(6): 541-549.
9.	Zile MR, Gaasch WH, Anand IS, et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in heart failure with preserved ejection fraction study (Ⅰ-preserve) trial. Circulation, 2010, 121(12): 1393-1405.
10.	Kristensen SL, Mogensen UM, Jhund PS, et al. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-preserve trial (Irbesartan in heart failure with preserved ejection fraction). Circulation, 2017, 135(8): 724-735.
11.	Ge J. Coding proposal on phenotyping heart failure with preserved ejection fraction: a practical tool for facilitating etiology-oriented therapy. Cardiol J, 2020, 27(1): 97-98.
12.	Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia, 2018, 61(10): 2079-2086.
13.	Ni L, Yuan C, Chen G, et al. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol, 2020, 19(1): 98.
14.	You G, Lee WS, Barros EJ, et al. Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney. J Biol Chem, 1995, 270(49): 29365-29371.
15.	Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol, 2018, 72(15): 1845-1855.
16.	Fukami K, Yamagishi S, Okuda S. Role of AGEs-RAGE system in cardiovascular disease. Curr Pharm Des, 2014, 20(14): 2395-2402.
17.	Willemsen S, Hartog JW, Hummel YM, et al. Tissue advanced glycation end products are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients. Eur J Heart Fail, 2011, 13(1): 76-82.
18.	Butler J, Hamo CE, Filippatos G, et al. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail, 2017, 19(11): 1390-1400.
19.	Batzias K, Antonopoulos AS, Oikonomou E, et al. Effects of newer antidiabetic drugs on endothelial function and arterial stiffness: a systematic review and meta-analysis. J Diabetes Res, 2018, 2018: 1232583.
20.	Amaral N, Okonko DO. Metabolic abnormalities of the heart in typeⅡdiabetes. Diab Vasc Dis Res, 2015, 12(4): 239-248.
21.	Kappel BA, Lehrke M, Schütt K, et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation, 2017, 136(10): 969-972.
22.	Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol, 2019, 73(15): 1931-1944.
23.	Wang X, Ni J, Guo R. SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism. Heart Fail Rev, 2021. doi: 10.1007/s10741-021-10096-8.
24.	Tong M, Saito T, Zhai P, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res, 2019, 124(9): 1360-1371.
25.	Weber MA, Mansfield TA, Cain VA, et al. 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.
26.	Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-transporter 2 inhibitors (SGLT2is): more than osmotic diuresis. Curr Hypertens Rep, 2019, 21(2): 12.
27.	Karg MV, Bosch A, Kannenkeril D, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol, 2018, 17(1): 5.
28.	Anker SD, Butler J, Filippatos GS, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med, 2021. doi: 10.1056/NEJMoa2107038.
29.	Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox biol, 2017, 13: 370-385.
30.	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.
31.	Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med, 2021, 384(2): 117-128.
32.	Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Eng J Med, 2021, 384(2): 129-139.
33.	Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomised clinical trials. Lancet Diabetes Endocrinol, 2018, 6(9): 691-704.
34.	Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2019, 380(4): 347-357.
35.	Dave CV, Schneeweiss S, Kim D, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med, 2019, 171(4): 248-256.
36.	Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet, 2019, 393(10166): 31-39.
37.	Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med, 2019, 380(24): 2295-2306.
38.	Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ, 2018, 363: k4365.
39.	Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG outcome trial. Diabetes care, 2018, 41(1): e4-e5.

1. McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J, 2021: ehab368.
2. 中华医学会心血管病学分会心力衰竭学组, 中国医师协会心力衰竭专业委员会, 中华心血管病杂志编辑委员会. 中国心力衰竭诊断和治疗指南2018. 中华心血管病杂志, 2018, 46(10): 760-789.
3. Shimokawa H, Miura M, Nochioka K, et al. Heart failure as a general pandemic in Asia. Eur J Heart Fail, 2015, 17(9): 884-892.
4. 王华, 李莹莹, 柴坷, 等. 中国住院心力衰竭患者流行病学及治疗现状. 中华心血管病杂志, 2019, 47(11): 865-874.
5. McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med, 2019, 381(21): 1995-2008.
6. Dunlay SM, Roger VL, Redfield MM. Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol, 2017, 14(10): 591-602.
7. Shah SJ, Borlaug BA, Kitzman DW, et al. Research priorities for heart failure with preserved ejection fraction: national heart, lung, and blood institute working group summary. Circulation, 2020, 141(12): 1001-1026.
8. Lindman BR, Dávila-Román VG, Mann DL, et al. Cardiovascular phenotype in HFpEF patients with or without diabetes: a RELAX trial ancillary study. J Am Coll Cardiol, 2014, 64(6): 541-549.
9. Zile MR, Gaasch WH, Anand IS, et al. Mode of death in patients with heart failure and a preserved ejection fraction: results from the Irbesartan in heart failure with preserved ejection fraction study (Ⅰ-preserve) trial. Circulation, 2010, 121(12): 1393-1405.
10. Kristensen SL, Mogensen UM, Jhund PS, et al. Clinical and echocardiographic characteristics and cardiovascular outcomes according to diabetes status in patients with heart failure and preserved ejection fraction: a report from the I-preserve trial (Irbesartan in heart failure with preserved ejection fraction). Circulation, 2017, 135(8): 724-735.
11. Ge J. Coding proposal on phenotyping heart failure with preserved ejection fraction: a practical tool for facilitating etiology-oriented therapy. Cardiol J, 2020, 27(1): 97-98.
12. Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia, 2018, 61(10): 2079-2086.
13. Ni L, Yuan C, Chen G, et al. SGLT2i: beyond the glucose-lowering effect. Cardiovasc Diabetol, 2020, 19(1): 98.
14. You G, Lee WS, Barros EJ, et al. Molecular characteristics of Na(+)-coupled glucose transporters in adult and embryonic rat kidney. J Biol Chem, 1995, 270(49): 29365-29371.
15. Zelniker TA, Braunwald E. Cardiac and renal effects of sodium-glucose co-transporter 2 inhibitors in diabetes: JACC state-of-the-art review. J Am Coll Cardiol, 2018, 72(15): 1845-1855.
16. Fukami K, Yamagishi S, Okuda S. Role of AGEs-RAGE system in cardiovascular disease. Curr Pharm Des, 2014, 20(14): 2395-2402.
17. Willemsen S, Hartog JW, Hummel YM, et al. Tissue advanced glycation end products are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients. Eur J Heart Fail, 2011, 13(1): 76-82.
18. Butler J, Hamo CE, Filippatos G, et al. The potential role and rationale for treatment of heart failure with sodium-glucose co-transporter 2 inhibitors. Eur J Heart Fail, 2017, 19(11): 1390-1400.
19. Batzias K, Antonopoulos AS, Oikonomou E, et al. Effects of newer antidiabetic drugs on endothelial function and arterial stiffness: a systematic review and meta-analysis. J Diabetes Res, 2018, 2018: 1232583.
20. Amaral N, Okonko DO. Metabolic abnormalities of the heart in typeⅡdiabetes. Diab Vasc Dis Res, 2015, 12(4): 239-248.
21. Kappel BA, Lehrke M, Schütt K, et al. Effect of empagliflozin on the metabolic signature of patients with type 2 diabetes mellitus and cardiovascular disease. Circulation, 2017, 136(10): 969-972.
22. Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, et al. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol, 2019, 73(15): 1931-1944.
23. Wang X, Ni J, Guo R. SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism. Heart Fail Rev, 2021. doi: 10.1007/s10741-021-10096-8.
24. Tong M, Saito T, Zhai P, et al. Mitophagy is essential for maintaining cardiac function during high fat diet-induced diabetic cardiomyopathy. Circ Res, 2019, 124(9): 1360-1371.
25. Weber MA, Mansfield TA, Cain VA, et al. 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.
26. Sternlicht H, Bakris GL. Blood pressure lowering and sodium-glucose co-transporter 2 inhibitors (SGLT2is): more than osmotic diuresis. Curr Hypertens Rep, 2019, 21(2): 12.
27. Karg MV, Bosch A, Kannenkeril D, et al. SGLT-2-inhibition with dapagliflozin reduces tissue sodium content: a randomised controlled trial. Cardiovasc Diabetol, 2018, 17(1): 5.
28. Anker SD, Butler J, Filippatos GS, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med, 2021. doi: 10.1056/NEJMoa2107038.
29. Steven S, Oelze M, Hanf A, et al. The SGLT2 inhibitor empagliflozin improves the primary diabetic complications in ZDF rats. Redox biol, 2017, 13: 370-385.
30. 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.
31. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med, 2021, 384(2): 117-128.
32. Bhatt DL, Szarek M, Pitt B, et al. Sotagliflozin in patients with diabetes and chronic kidney disease. N Eng J Med, 2021, 384(2): 129-139.
33. Perkovic V, de Zeeuw D, Mahaffey KW, et al. Canagliflozin and renal outcomes in type 2 diabetes: results from the CANVAS program randomised clinical trials. Lancet Diabetes Endocrinol, 2018, 6(9): 691-704.
34. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med, 2019, 380(4): 347-357.
35. Dave CV, Schneeweiss S, Kim D, et al. Sodium-glucose cotransporter-2 inhibitors and the risk for severe urinary tract infections: a population-based cohort study. Ann Intern Med, 2019, 171(4): 248-256.
36. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet, 2019, 393(10166): 31-39.
37. Perkovic V, Jardine MJ, Neal B, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med, 2019, 380(24): 2295-2306.
38. Ueda P, Svanström H, Melbye M, et al. Sodium glucose cotransporter 2 inhibitors and risk of serious adverse events: nationwide register based cohort study. BMJ, 2018, 363: k4365.
39. Inzucchi SE, Iliev H, Pfarr E, et al. Empagliflozin and assessment of lower-limb amputations in the EMPA-REG outcome trial. Diabetes care, 2018, 41(1): e4-e5.

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