SGLT2 inhibitors and atherosclerosis in a background of effect of gliflozins and heart failure
Authors:
Josef Kořínek 1,2,3; Miloš Dobiáš 2,3
Authors‘ workplace:
Centrum srdečního selhání, II. interní klinika – kardiologie a angiologie 1. LF UK a VFN v Praze
1; II. chirurgická klinika – kardiovaskulární chirurgie 1. LF UK a VFN v Praze
2; Klinika anesteziologie, resuscitace a intenzivní medicíny (KARIM) 1. LF UK a VFN v Praze
3
Published in:
AtheroRev 2021; 6(2): 76-83
Category:
Reviews
Overview
Sodium/glucose cotransporter 2 inhibitors, gliflozins represent a relatively new class of antidiabetic drugs, which demonstrated its capabilities to significantly reduce mortality and morbidity of cardiovascular diseases in type 2 diabetes mellitus. Their effect was shown in patients with heart failure with reduced ejection fraction in diabetics as well as in non-diabetics. Moreover, gliflozins have also a major nephroprotective actions. This review article describes the effects of SGLT2 inhibitors not only in heart failure, but also mentions potential benefits and mechanisms of action in atherosclerosis. The review also points out the complexity, multilevel character and mutual interconnections of these mechanisms which are reflected in therapeutic effects of the SGLT2 inhibition.
Keywords:
Atherosclerosis – cardiovascular benefit – diabetes mellitus – dyslipidemia – gliflozins – nephroprotection – SGLT2 inhibitors – heart failure
Sources
1. Mahaffey KW, Neal B, Perkovic V et al. [CANVAS Program Collaborative Group]. Canagliflozin for Primary and Secondary Prevention of Cardiovascular Events: Results From the CANVAS Program (Canagliflozin Cardiovascular Assessment Study). Circulation 2018; 137(4): 323–334. Dostupné z DOI: .
2. 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. Dostupné z DOI: .
3. Wiviott SD, Raz I, Bonaca MP et al. [DECLARE–TIMI 58 Investigators]. Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 2019; 380(4): 347–357. Dostupné z DOI: .
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. Dostupné z DOI: .
5. Heerspink HJL, Stefansson BV, Correa-Rotter R et al. [DAPA-CKD Trial Committees and Investigators]. Dapagliflozin in Patients with Chronic Kidney Disease. N Engl J Med 2020; 383(15): 1436–1446. Dostupné z DOI: .
6. Perkovic V, Jardine MJ, Neal B et al. [CREDENCE Trial Investigators]. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 2019; 380(24): 2295–2306. Dostupné z DOI: .
7. Packer M, Anker SD, Butler J et al. [EMPEROR-Reduced Trial Investigators]. Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 2020; 383(15): 1413–1424. Dostupné z DOI: .
8. McMurray JJV, Solomon SD, Inzucchi SE et al. [DAPA-HF Trial Committees and Investigators]. Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 2019; 381(21): 1995–2008. Dostupné z DOI: .
9. Ponikowski P, Voors AA, Anker SD et al. 2016 ESC Guidelines 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)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016; 37(27): 2129–2200. Dostupné z DOI: .
10. Seferovic PM, Petrie MC, Filippatos GS et al. Type 2 diabetes mellitus and heart failure: a position statement from the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2018; 20(5): 853–872. Dostupné z DOI: .
11. 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. Dostupné z DOI: .
12. Zannad F, Ferreira JP, Pocock SJ et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR- Reduced and DAPA-HF trials. Lancet 2020; 396(10254): 819–829. Dostupné z DOI: .
13. Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia 2018; 61(10): 2108–2117. Dostupné z DOI: .
14. Vallon V, Verma S. Effects of SGLT2 Inhibitors on Kidney and Cardiovascular Function. Annu Rev Physiol 2020. Dostupné z DOI: .
15. 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. Dostupné z DOI: .
16. Hallow KM, Helmlinger G, Greasley PJ et al. Why do SGLT2 inhibitors reduce heart failure hospitalization? A differential volume regulation hypothesis. Diabetes Obes Metab 2018; 20(3): 479–487. Dostupné z DOI: .
17. Lambers Heerspink HJ, de Zeeuw D, Wie L et al. Dapagliflozin a glucose- regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 2013; 15(9): 853–862. Dostupné z DOI: .
18. Ghanim H, Abuaysheh S, Hejna J et al. Dapagliflozin Suppresses Hepcidin And Increases Erythropoiesis. J Clin Endocrinol Metab 2020; 105(4): dgaa057. Dostupné z DOI: .
19. Mazer CD, Hare GMT, Connelly PW et al. Effect of Empagliflozin on Erythropoietin Levels, Iron Stores, and Red Blood Cell Morphology in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease. Circulation 2020; 141(8): 704–707. Dostupné z DOI: .
20. Verma S, Rawat S, Ho KL et al. Empagliflozin Increases Cardiac Energy Production in Diabetes: Novel Translational Insights Into the Heart Failure Benefits of SGLT2 Inhibitors. JACC Basic Transl Sci 2018; 3(5): 575–587. Dostupné z DOI: .
21. 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. Dostupné z DOI: .
22. Uthman L, Baartscheer A, Bleijlevens B et al. Class effects of SGLT2 inhibitors in mouse cardiomyocytes and hearts: inhibition of Na(+)/H(+) exchanger, lowering of cytosolic Na(+) and vasodilation. Diabetologia 2018; 61(3): 722–726. Dostupné z DOI: .
23. Verma S, Mazer CD, Yan AT et al. Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The EMPA-HEART CardioLink-6 Randomized Clinical Trial. Circulation 2019; 140(21): 1693–1702. Dostupné z DOI: .
24. Kang S, Verma S, Hassanabad AF et al. Direct Effects of Empagliflozin on Extracellular Matrix Remodelling in Human Cardiac Myofibroblasts: Novel Translational Clues to Explain EMPA-REG OUTCOME Results. Can J Cardiol 2020; 36(4): 543–553. Dostupné z DOI: .
25. Byrne NJ, Soni S, Takahara S et al. Chronically Elevating Circulating Ketones Can Reduce Cardiac Inflammation and Blunt the Development of Heart Failure. Circ Heart Fail 2020; 13(6): e006573. Dostupné z DOI: .
26. Ansary TM, Nakano D, Nishiyama A. Diuretic Effects of Sodium Glucose Cotransporter 2 Inhibitors and Their Influence on the Renin-Angiotensin System. Int J Mol Sci 2019; 20(3). Dostupné z DOI: .
27. Verma S. Are the Cardiorenal Benefits of SGLT2 Inhibitors Due to Inhibition of the Sympathetic Nervous System? JACC Basic Transl Sci 2020; 5(2): 180–182. Dostupné z DOI: .
28. Nasiri-Ansari N, Dimitriadis GK, Agrogiannis G et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol 2018; 17(1): 106. Dostupné z DOI: .
29. Liu Z, Ma X, Ilyas I et al. Impact of sodium glucose cotransporter 2 (SGLT2) inhibitors on atherosclerosis: from pharmacology to pre-clinical and clinical therapeutics. Theranostics 2021; 11(9): 4502–4515. Dostupné z DOI: .
30. Shigiyama F, Kumashiro N, Miyagi M et al. Effectiveness of dapagliflozin on vascular endothelial function and glycemic control in patients with early- stage type 2 diabetes mellitus: DEFENCE study. Cardiovasc Diabetol 2017; 16(1): 84. Dostupné z DOI: .
31. Zainordin NA, Hatta S, Mohamed Shah FZ et al. Effects of Dapagliflozin on Endothelial Dysfunction in Type 2 Diabetes With Established Ischemic Heart Disease (EDIFIED). J Endocr Soc 2020; 4(1): bvz017. Dostupné z DOI: .
32. Ganbaatar B, Fukuda D, Shinohara M et al. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur J Pharmacol 2020; 875: 173040. Dostupné z DOI: .
33. Tahara A, Takasu T, Yokono M et al. Characterization and comparison of SGLT2 inhibitors: Part 3. Effects on diabetic complications in type 2 diabetic mice. Eur J Pharmacol 2017; 809: 163–171. Dostupné z DOI: .
34. Behnammanesh G, Durante GL, Khanna YP et al. Canagliflozin inhibits vascular smooth muscle cell proliferation and migration: Role of heme oxygenase-1. Redox Biol 2020; 32: 101527. Dostupné z DOI: .
35. Terasaki M, Hiromura M, Mori Y et al. Amelioration of Hyperglycemia with a Sodium-Glucose Cotransporter 2 Inhibitor Prevents Macrophage- Driven Atherosclerosis through Macrophage Foam Cell Formation Suppression in Type 1 and Type 2 Diabetic Mice. PLoS One 2015; 10(11): e0143396. Dostupné z DOI: .
36. Xu L, Nagata N, Nagashimada M et al. SGLT2 Inhibition by Empagliflozin Promotes Fat Utilization and Browning and Attenuates Inflammation and Insulin Resistance by Polarizing M2 Macrophages in Diet-induced Obese Mice. EBioMedicine 2017; 20: 137–149. Dostupné z DOI: .
37. Dimitriadis GK, Nasiri-Ansari N, Agrogiannis G et al. Empagliflozin improves primary haemodynamic parameters and attenuates the development of atherosclerosis in high fat diet fed APOE knockout mice. Mol Cell Endocrinol 2019; 494: 110487. Dostupné z DOI: .
38. Leng W, Ouyang X, Lei X et al. The SGLT-2 Inhibitor Dapagliflozin Has a Therapeutic Effect on Atherosclerosis in Diabetic ApoE(-/-) Mice. Mediators Inflamm 2016; 2016: 6305735. Dostupné z DOI: .
39. Spigoni V, Fantuzzi F, Carubbi C et al. Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: potential relevance to prevention of cardiovascular events. Cardiovasc Diabetol 2020; 19(1): 46. Dostupné z DOI: .
40. Sakurai S, Jojima T, Iijima T et al. Empagliflozin decreases the plasma concentration of plasminogen activator inhibitor-1 (PAI-1) in patients with type 2 diabetes: Association with improvement of fibrinolysis. J Diabetes Complications 2020; 34(11): 107703. Dostupné z DOI: .
41. Uthman L, Homayr A, Juni RP et al. Empagliflozin and Dapagliflozin Reduce ROS Generation and Restore NO Bioavailability in Tumor Necrosis Factor alpha-Stimulated Human Coronary Arterial Endothelial Cells. Cell Physiol Biochem 2019; 53(5): 865–886. Dostupné z DOI: .
42. Iannantuoni F, de Maranon A, Diaz-Morales N et al. The SGLT2 Inhibitor Empagliflozin Ameliorates the Inflammatory Profile in Type 2 Diabetic Patients and Promotes an Antioxidant Response in Leukocytes. J Clin Med 2019; 8(11): 1814. Dostupné z DOI: .
43. Xu C, Wang W, Zhong J et al. Canagliflozin exerts anti-inflammatory effects by inhibiting intracellular glucose metabolism and promoting autophagy in immune cells. Biochem Pharmacol 2018; 152: 45–59. Dostupné z DOI: .
44. Aragon-Herrera A, Feijoo-Bandin S, Otero Santiago M et al. Empagliflozin reduces the levels of CD36 and cardiotoxic lipids while improving autophagy in the hearts of Zucker diabetic fatty rats. Biochem Pharmacol 2019; 170: 113677. Dostupné z DOI: .
45. Filippas-Ntekouan S, Tsimihodimos V, Filippatos T et al. SGLT-2 inhibitors: pharmacokinetics characteristics and effects on lipids. Expert Opin Drug Metab Toxicol 2018; 14(11): 1113–1121. Dostupné z DOI: .
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