The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease.
Humans
Male
Endothelial Progenitor Cells
/ drug effects
Female
Glucosides
/ therapeutic use
Coronary Artery Disease
/ blood
Benzhydryl Compounds
/ therapeutic use
Aged
Sodium-Glucose Transporter 2 Inhibitors
/ therapeutic use
Prospective Studies
Treatment Outcome
Time Factors
Cells, Cultured
Diabetes Mellitus, Type 2
/ blood
Cell Proliferation
/ drug effects
Biomarkers
/ blood
Middle Aged
Cardioprotective effects of anti-diabetic medications
Diabetes and cardiovascular disease
Endothelial progenitor cells
Journal
Cardiovascular diabetology
ISSN: 1475-2840
Titre abrégé: Cardiovasc Diabetol
Pays: England
ID NLM: 101147637
Informations de publication
Date de publication:
28 Oct 2024
28 Oct 2024
Historique:
received:
08
08
2024
accepted:
10
10
2024
medline:
29
10
2024
pubmed:
29
10
2024
entrez:
29
10
2024
Statut:
epublish
Résumé
Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.
Sections du résumé
BACKGROUND
BACKGROUND
Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD.
METHODS
METHODS
A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays.
RESULTS
RESULTS
Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012).
CONCLUSIONS
CONCLUSIONS
Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.
Identifiants
pubmed: 39468546
doi: 10.1186/s12933-024-02466-x
pii: 10.1186/s12933-024-02466-x
doi:
Substances chimiques
empagliflozin
HDC1R2M35U
Glucosides
0
Benzhydryl Compounds
0
Sodium-Glucose Transporter 2 Inhibitors
0
Biomarkers
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
386Informations de copyright
© 2024. The Author(s).
Références
Wong ND, Sattar N. Cardiovascular risk in diabetes mellitus: epidemiology, assessment and prevention. Nat Rev Cardiol. 2023;20:685–95.
pubmed: 37193856
doi: 10.1038/s41569-023-00877-z
Brown E, Rajeev SP, Cuthbertson DJ, Wilding JPH. A review of the mechanism of action, metabolic profile and haemodynamic effects of sodium-glucose co-transporter-2 inhibitors. Diabetes Obes Metab. 2019;21(Suppl 2):9–18.
pubmed: 31081592
doi: 10.1111/dom.13650
Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.
pubmed: 26378978
doi: 10.1056/NEJMoa1504720
Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N Engl J Med. 2017;377:644–57.
pubmed: 28605608
doi: 10.1056/NEJMoa1611925
Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose co-transporter 2 (SGLT2) inhibitors: a state-of-the-art review. JACC Basic Transl Sci. 2020;5(6):632–44.
pubmed: 32613148
pmcid: 7315190
doi: 10.1016/j.jacbts.2020.02.004
Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med. 2019;380(4):347–57.
pubmed: 30415602
doi: 10.1056/NEJMoa1812389
Zelniker TAWS, Raz I, Im K, 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. 2018;393:31–9.
pubmed: 30424892
doi: 10.1016/S0140-6736(18)32590-X
McMurray JJV, 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.
pubmed: 31535829
doi: 10.1056/NEJMoa1911303
Kosiborod M, Cavender MA, Fu AZ, et al. 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;136:989–91.
doi: 10.1161/CIRCULATIONAHA.117.029190
Perseghin G, Solini A. The EMPA-REG outcome study: critical appraisal and potential clinical implications. Cardiovasc Diabetol. 2016;4(15):85.
doi: 10.1186/s12933-016-0403-8
Gao M, Bhatia K, Kapoor A, Badimon J, Pinney SP, Mancini DM, Santos-Gallego CG, Lala A. SGLT2 inhibitors, functional capacity, and quality of life in patients with heart failure: a systematic review and meta-analysis. JAMA Netw Open. 2024;7(4): e245135.
pubmed: 38573633
pmcid: 11192183
doi: 10.1001/jamanetworkopen.2024.5135
Byrne NJ, Matsumura N, Maayah ZH, Ferdaoussi M, Takahara S, Darwesh AM, Levasseur JL, Jahng JWS, Vos D, Parajuli N, El-Kadi AOS, Braam B, Young ME, Verma S, Light PE, Sweeney G, Seubert JM, Dyck JRB. Empagliflozin blunts worsening cardiac dysfunction associated with reduced nlrp3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure. Circ Heart Fail. 2020;13(1): e006277.
pubmed: 31957470
doi: 10.1161/CIRCHEARTFAILURE.119.006277
Connelly KA, Zhang Y, Visram A, Advani A, Batchu SN, Desjardins JF, Thai K, Gilbert RE. Empagliflozin improves diastolic function in a nondiabetic rodent model of heart failure with preserved ejection fraction. JACC Basic Transl Sci. 2019;4(1):27–37.
pubmed: 30847416
pmcid: 6390677
doi: 10.1016/j.jacbts.2018.11.010
Inzucchi SE, Zinman B, Wanner C, Ferrari R, Fitchett D, Hantel S, Espadero RM, Woerle HJ, Broedl UC, Johansen OE. SGLT-2 inhibitors and cardiovascular risk: proposed pathways and review of ongoing outcome trials. Diab Vasc Dis Res. 2015;12:90–100.
pubmed: 25589482
doi: 10.1177/1479164114559852
Lioudaki E, Androulakis ES, Whyte M, Stylianou KG, Daphnis EK, Ganotakis ES. The effect of sodium-glucose co-transporter-2 (SGLT-2) inhibitors on cardiometabolic profile; beyond the hypoglycaemic action. Cardiovasc Drugs Ther. 2017;31:215–25.
pubmed: 28444472
doi: 10.1007/s10557-017-6724-3
Cowie MR, Fisher M. SGLT2 inhibitors: mechanisms of cardiovascular benefit beyond glycaemic control. Nat Rev Cardiol. 2020;17:761–72.
pubmed: 32665641
doi: 10.1038/s41569-020-0406-8
Verma S, McMurray JJV. SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review. Diabetologia. 2018;61:2108–17.
pubmed: 30132036
doi: 10.1007/s00125-018-4670-7
Angermann CE, Santos-Gallego CG, Requena-Ibanez JA, Sehner S, Zeller T, Gerhardt LMS, Maack C, Sanz J, Frantz S, Fuster V, Ertl G, Badimon JJ. Empagliflozin effects on iron metabolism as a possible mechanism for improved clinical outcomes in non-diabetic patients with systolic heart failure. Nat Cardiovasc Res. 2023;2(11):1032–43.
pubmed: 39196095
pmcid: 11358002
doi: 10.1038/s44161-023-00352-5
Spigoni V, Fantuzzi F, Carubbi C, Pozzi G, Masselli E, Gobbi G, Solini A, Bonadonna RC, Dei CA. 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.
pubmed: 32264868
pmcid: 7140327
doi: 10.1186/s12933-020-01016-5
Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G, Isner JM. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964–7.
pubmed: 9020076
doi: 10.1126/science.275.5302.964
Heinisch PP, Bello C, Emmert MY, Carrel T, Dreßen M, Hörer J, Winkler B and Luedi MM. Endothelial Progenitor Cells as Biomarkers of Cardiovascular Pathologies: A Narrative Review. Cells. 2022;11.
Ng CY, Cheung C. Origins and functional differences of blood endothelial cells. Semin Cell Dev Biol. 2024;155:23–9.
pubmed: 37202277
doi: 10.1016/j.semcdb.2023.05.001
Vega FM, Gautier V, Fernandez-Ponce CM, Extremera MJ, Altelaar AFM, Millan J, Tellez JC, Hernandez-Campos JA, Conejero R, Bolivar J, Pardal R, Garcia-Cózar FJ, Aguado E, Heck AJR, Duran-Ruiz MC. The atheroma plaque secretome stimulates the mobilization of endothelial progenitor cells ex vivo. J Mol Cell Cardiol. 2017;105:12–23.
pubmed: 28223221
doi: 10.1016/j.yjmcc.2017.02.001
Huang PH, Chen JW, Lin SJ. Effects of cardiovascular risk factors on endothelial progenitor cell. Acta Cardiol Sin. 2014;30:375–81.
pubmed: 27122814
pmcid: 4834954
Benítez-Camacho J, Ballesteros A, Beltrán-Camacho L, Rojas-Torres M, Rosal-Vela A, Jimenez-Palomares M, Sanchez-Gomar I, Durán-Ruiz MC. Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications. Stem Cell Res Ther. 2023;14:324.
pubmed: 37950274
pmcid: 10636846
doi: 10.1186/s13287-023-03537-8
Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593–600.
pubmed: 12584367
doi: 10.1056/NEJMoa022287
Werner N, Kosiol S, Schiegl T, et al. Circulating endothelial progenitor cells and cardiovascular outcomes. N Engl J Med. 2005;353(10):999–1007.
pubmed: 16148285
doi: 10.1056/NEJMoa043814
Schmidt-Lucke C, Rössig L, Fichtlscherer S, Vasa M, Britten M, Kämper U, Dimmeler S, Zeiher AM. Reduced number of circulating endothelial progenitor cells predicts future cardiovascular events: proof of concept for the clinical importance of endogenous vascular repair. Circulation. 2005;111(22):2981–7.
pubmed: 15927972
doi: 10.1161/CIRCULATIONAHA.104.504340
Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, Prescott E, Storey RF, Deaton C, Cuisset T, Agewall S, Dickstein K, Edvardsen T, Escaned J, Gersh BJ, Svitil P, Gilard M, Hasdai D, Hatala R, Mahfoud F, Masip J, Muneretto C, Valgimigli M, Achenbach S, Bax JJ. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020;41:407–77.
pubmed: 31504439
doi: 10.1093/eurheartj/ehz425
Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, Christodorescu RM, Crawford C, Di Angelantonio E, Eliasson B, Espinola-Klein C, Fauchier L, Halle M, Herrington WG, Kautzky-Willer A, Lambrinou E, Lesiak M, Lettino M, McGuire DK, Mullens W, Rocca B, Sattar N. 2023 ESC Guidelines for the management of cardiovascular disease in patients with diabetes. Eur Heart J. 2023;44:4043–140.
pubmed: 37622663
doi: 10.1093/eurheartj/ehad192
Fadini GP, Losordo D, Dimmeler S. Critical reevaluation of endothelial progenitor cell phenotypes for therapeutic and diagnostic use. Circ Res. 2012;110:624–37.
pubmed: 22343557
pmcid: 3382070
doi: 10.1161/CIRCRESAHA.111.243386
Friedrich EB, Walenta K, Scharlau J, Nickenig G, Werner N. CD34-/CD133+/VEGFR-2+ endothelial progenitor cell subpopulation with potent vasoregenerative capacities. Circ Res. 2006;98:e20–5.
pubmed: 16439688
doi: 10.1161/01.RES.0000205765.28940.93
Chen JZ, Zhu JH, Wang XX, Zhu JH, Xie XD, Sun J, Shang YP, Guo XG, Dai HM, Hu SJ. Effects of homocysteine on number and activity of endothelial progenitor cells from peripheral blood. J Mol Cell Cardiol. 2004;36:233–9.
pubmed: 14871551
doi: 10.1016/j.yjmcc.2003.10.005
Peichev M, Naiyer AJ, Pereira D, et al. Expression of VEGFR-2 and AC133 by circulating human CD34(+) cells identifies a population of functional endothelial precursors. Blood. 2000;95:952–8.
pubmed: 10648408
doi: 10.1182/blood.V95.3.952.003k27_952_958
Basile DP, Yoder MC. Circulating and tissue resident endothelial progenitor cells. J Cell Physiol. 2014;229:10–6.
pubmed: 23794280
pmcid: 3867575
George J, Afek A, Abashidze A, et al. Transfer of endothelial progenitor and bone marrow cells influences atherosclerotic plaque size and composition in apolipoprotein E knockout mice. Arterioscler Thromb Vasc Biol. 2005;25:2636–41.
pubmed: 16195475
doi: 10.1161/01.ATV.0000188554.49745.9e
Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89:E1-7.
pubmed: 11440984
doi: 10.1161/hh1301.093953
Güven H, Shepherd RM, Bach RG, Capoccia BJ, Link DC. The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease. J Am Coll Cardiol. 2006;48:1579–87.
pubmed: 17045891
doi: 10.1016/j.jacc.2006.04.101
Bahlmann FH, de Groot K, Mueller O, Hertel B, Haller H, Fliser D. Stimulation of endothelial progenitor cells: a new putative therapeutic effect of angiotensin II receptor antagonists. Hypertension. 2005;45:526–9.
pubmed: 15767470
doi: 10.1161/01.HYP.0000159191.98140.89
Dimmeler S, Aicher A, Vasa M, et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PI 3-kinase/Akt pathway. J Clin Invest. 2001;108:391–7.
pubmed: 11489932
pmcid: 209365
doi: 10.1172/JCI200113152
Heeschen C, Aicher A, Lehmann R, et al. Erythropoietin is a potent physiologic stimulus for endothelial progenitor cell mobilization. Blood. 2003;102:1340–6.
pubmed: 12702503
doi: 10.1182/blood-2003-01-0223
Pelliccia F, Pasceri V, Zimarino M, et al. Endothelial progenitor cells in coronary atherosclerosis and percutaneous coronary intervention: a systematic review and meta-analysis. Cardiovasc Revasc Med. 2022;42:94–9.
pubmed: 35246408
doi: 10.1016/j.carrev.2022.02.025
Min TQ, Zhu CJ, Xiang WX, Hui ZJ, Peng SY. Improvement in endothelial progenitor cells from peripheral blood by ramipril therapy in patients with stable coronary artery disease. Cardiovasc Drugs Ther. 2004;18:203–9.
pubmed: 15229388
doi: 10.1023/B:CARD.0000033641.33503.bd
Pelliccia F, Pasceri V, Cianfrocca C, et al. Angiotensin II receptor antagonism with telmisartan increases number of endothelial progenitor cells in normotensive patients with coronary artery disease: a randomized, double-blind, placebo-controlled study. Atherosclerosis. 2010;210:510–5.
pubmed: 20044087
doi: 10.1016/j.atherosclerosis.2009.12.005
Altabas V, Biloš LSK. The role of endothelial progenitor cells in atherosclerosis and impact of anti-lipemic treatments on endothelial repair. Int J Mol Sci. 2022;23:2663.
pubmed: 35269807
pmcid: 8910333
doi: 10.3390/ijms23052663
Fadini GP, Miorin M, Facco M, et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol. 2005;45:1449–57.
pubmed: 15862417
doi: 10.1016/j.jacc.2004.11.067
Kondo T, Hayashi M, Takeshita K, Numaguchi Y, Kobayashi K, Iino S, Inden Y, Murohara T. Smoking cessation rapidly increases circulating progenitor cells in peripheral blood in chronic smokers. Arterioscler Thromb Vasc Biol. 2004;24(8):1442–7.
pubmed: 15191940
doi: 10.1161/01.ATV.0000135655.52088.c5
Balistreri CR, Buffa S, Pisano C, Lio D, Ruvolo G, Mazzesi G. Are endothelial progenitor cells the real solution for cardiovascular diseases? focus on controversies and perspectives. Biomed Res Int. 2015;2015: 835934.
pubmed: 26509164
pmcid: 4609774
doi: 10.1155/2015/835934
Laufs U, Werner N, Link A, et al. Physical training increases endothelial progenitor cells, inhibits neointima formation, and enhances angiogenesis. Circulation. 2004;109:220–6.
pubmed: 14691039
doi: 10.1161/01.CIR.0000109141.48980.37
Itzhaki-Ben-Zadok O, Mager A, Leshem-Lev D, Lev E, Kornowski R, Eisen A. The effect of proprotein convertase subtilisin kexin type 9 inhibitors on circulating endothelial progenitor cells in patients with cardiovascular disease. Cardiovasc Drugs Ther. 2022;36:85–92.
pubmed: 33394363
doi: 10.1007/s10557-020-07119-1
Foresta C, Lana A, Cabrelle A, et al. PDE-5 inhibitor, Vardenafil, increases circulating progenitor cells in humans. Int J Impot Res. 2005;17:377–80.
pubmed: 15829988
doi: 10.1038/sj.ijir.3901325
Berezin AE, Kremzer AA, Martovitskaya YV, Samura TA. The effect of angiotensin-2 receptor blocker valsartan on circulating level of endothelial progenitor cells in diabetic patients with asymptomatic coronary artery disease. Diabetes Metab Syndr. 2015;9:305–9.
pubmed: 25470647
doi: 10.1016/j.dsx.2014.04.006
Menegazzo L, Albiero M, Avogaro A, Fadini GP. Endothelial progenitor cells in diabetes mellitus. BioFactors. 2012;38:194–202.
pubmed: 22488933
doi: 10.1002/biof.1016
Benítez-Camacho J, Ballesteros A, Beltrán-Camacho L, et al. Endothelial progenitor cells as biomarkers of diabetes-related cardiovascular complications. Stem Cell Res Ther. 2023;14:324.
pubmed: 37950274
pmcid: 10636846
doi: 10.1186/s13287-023-03537-8
Longo M, Scappaticcio L, Bellastella G, et al. Alterations in the levels of circulating and endothelial progenitor cells levels in young adults with type 1 diabetes: a 2-year follow-up from the observational METRO study. Diabetes Metab Syndr Obes. 2020;13:777–84.
pubmed: 32256094
pmcid: 7090196
doi: 10.2147/DMSO.S238588
Maiorino MI, Casciano O, Della Volpe E, Bellastella G, Giugliano D, Esposito K. Reducing glucose variability with continuous subcutaneous insulin infusion increases endothelial progenitor cells in type 1 diabetes: an observational study. Endocrine. 2016;52:244–52.
pubmed: 26184417
doi: 10.1007/s12020-015-0686-7
Zhang W, Wang H, Liu F, et al. Effects of early intensive insulin therapy on endothelial progenitor cells in patients with newly diagnosed type 2 diabetes. Diabetes Ther. 2022;13:679–90.
pubmed: 34894328
doi: 10.1007/s13300-021-01185-w
Chen LL, Yu F, Zeng TS, Liao YF, Li YM, Ding HC. Effects of gliclazide on endothelial function in patients with newly diagnosed type 2 diabetes. Eur J Pharmacol. 2011;659:296–301.
pubmed: 21453695
doi: 10.1016/j.ejphar.2011.02.044
Ahmed FW, Rider R, Glanville M, Narayanan K, Razvi S, Weaver JU. Metformin improves circulating endothelial cells and endothelial progenitor cells in type 1 diabetes: MERIT study. Cardiovasc Diabetol. 2016;15:116.
pubmed: 27561827
pmcid: 5000450
doi: 10.1186/s12933-016-0413-6
Chen LL, Liao YF, Zeng TS, Yu F, Li HQ, Feng Y. Effects of metformin plus gliclazide compared with metformin alone on circulating endothelial progenitor cell in type 2 diabetic patients. Endocrine. 2010;38:266–75.
pubmed: 20972736
doi: 10.1007/s12020-010-9383-8
Pistrosch F, Herbrig K, Oelschlaegel U, et al. PPARgamma-agonist rosiglitazone increases number and migratory activity of cultured endothelial progenitor cells. Atherosclerosis. 2005;183:163–7.
pubmed: 15907852
doi: 10.1016/j.atherosclerosis.2005.03.039
Wang CH, Ting MK, Verma S, et al. Pioglitazone increases the numbers and improves the functional capacity of endothelial progenitor cells in patients with diabetes mellitus. Am Heart J. 2006;152(1051):e1-8.
Fadini GP, Boscaro E, Albiero M, et al. The oral dipeptidyl peptidase-4 inhibitor sitagliptin increases circulating endothelial progenitor cells in patients with type 2 diabetes: possible role of stromal-derived factor-1alpha. Diabetes Care. 2010;33:1607–9.
pubmed: 20357375
pmcid: 2890368
doi: 10.2337/dc10-0187
Xu M, Zhao X, Zheng M, et al. Acute effects of sitagliptin on progenitor cells and soluble mediators in newly diagnosed type 2 diabetes. Int J Clin Pharmacol Ther. 2020;58:491–503.
pubmed: 32567544
doi: 10.5414/CP203665
De Ciuceis C, Agabiti-Rosei C, Rossini C, et al. Microvascular density and circulating endothelial progenitor cells before and after treatment with incretin mimetics in diabetic patients. High Blood Press Cardiovasc Prev. 2018;25:369–78.
pubmed: 30203268
doi: 10.1007/s40292-018-0279-7
Xie D, Li Y, Xu M, Zhao X, Chen M. Effects of dulaglutide on endothelial progenitor cells and arterial elasticity in patients with type 2 diabetes mellitus. Cardiovasc Diabetol. 2022;21:200.
pubmed: 36199064
pmcid: 9533545
doi: 10.1186/s12933-022-01634-1
Patti AM, Rizvi AA, Giglio RV, Stoian AP, Ligi D, Mannello F. Impact of glucose-lowering medications on cardiovascular and metabolic risk in type 2 diabetes. J Clin Med. 2020;9:912.
pubmed: 32225082
pmcid: 7230245
doi: 10.3390/jcm9040912
Cannon CP, Perkovic V, Agarwal R, et al. Evaluating the effects of canagliflozin on cardiovascular and renal events in patients with type 2 diabetes mellitus and chronic kidney disease according to baseline HbA1c, including those with HbA1c <7%: results from the CREDENCE trial. Circulation. 2020;141:407–10.
pubmed: 31707795
doi: 10.1161/CIRCULATIONAHA.119.044359
Fadini GP, Bonora BM, Zatti G, Vitturi N, Iori E, Marescotti MC, Albiero M, Avogaro A. Effects of the SGLT2 inhibitor dapagliflozin on HDL cholesterol, particle size, and cholesterol efflux capacity in patients with type 2 diabetes: a randomized placebo-controlled trial. Cardiovasc Diabetol. 2017;16(1):42.
pubmed: 28376855
pmcid: 5379610
doi: 10.1186/s12933-017-0529-3
Heerspink HJ, Perkins BA, Fitchett DH, Husain M, Cherney DZ. Sodium glucose cotransporter 2 inhibitors in the treatment of diabetes mellitus: cardiovascular and kidney effects, potential mechanisms, and clinical applications. Circulation. 2016;134(10):752–72.
pubmed: 27470878
doi: 10.1161/CIRCULATIONAHA.116.021887
Takahashi H, Nomiyama T, Terawaki Y, et al. Combined treatment with DPP-4 inhibitor linagliptin and SGLT2 inhibitor empagliflozin attenuates neointima formation after vascular injury in diabetic mice. Biochem Biophys Rep. 2019;18: 100640.
pubmed: 31032431
pmcid: 6477163
Behnammanesh G, Durante GL, Khanna YP, Peyton KJ, Durante W. Canagliflozin inhibits vascular smooth muscle cell proliferation and migration: Role of heme oxygenase-1. Redox Biol. 2020;32: 101527.
pubmed: 32278282
pmcid: 7152682
doi: 10.1016/j.redox.2020.101527
Adingupu DD, Göpel SO, Grönros J, et al. SGLT2 inhibition with empagliflozin improves coronary microvascular function and cardiac contractility in prediabetic ob/ob(-/-) mice. Cardiovasc Diabetol. 2019;18:16.
pubmed: 30732594
pmcid: 6366096
doi: 10.1186/s12933-019-0820-6
Rahadian A, Fukuda D, Salim HM, et al. Canagliflozin prevents diabetes-induced vascular dysfunction in ApoE-deficient mice. J Atheroscler Thromb. 2020;27:1141–51.
pubmed: 32101837
pmcid: 7803832
doi: 10.5551/jat.52100
Mori K, Tsuchiya K, Nakamura S, et al. Ipragliflozin-induced adipose expansion inhibits cuff-induced vascular remodeling in mice. Cardiovasc Diabetol. 2019;18:83.
pubmed: 31234839
pmcid: 6589884
doi: 10.1186/s12933-019-0886-1
Lee DM, Battson ML, Jarrell DK, et al. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol. 2018;17:62.
pubmed: 29703207
pmcid: 5921754
doi: 10.1186/s12933-018-0708-x
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:bvz017.
pubmed: 31993550
doi: 10.1210/jendso/bvz017
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;16:84.
pubmed: 28683796
pmcid: 5500953
doi: 10.1186/s12933-017-0564-0
Oelze M, Kröller-Schön S, Welschof P, et al. The sodium-glucose co-transporter 2 inhibitor empagliflozin improves diabetes-induced vascular dysfunction in the streptozotocin diabetes rat model by interfering with oxidative stress and glucotoxicity. PLoS ONE. 2014;9: e112394.
pubmed: 25402275
pmcid: 4234367
doi: 10.1371/journal.pone.0112394
Sayour AA, Korkmaz-Icöz S, Loganathan S, et al. Acute canagliflozin treatment protects against in vivo myocardial ischemia-reperfusion injury in non-diabetic male rats and enhances endothelium-dependent vasorelaxation. J Transl Med. 2019;17:127.
pubmed: 30992077
pmcid: 6469222
doi: 10.1186/s12967-019-1881-8
Mone P, Lombardi A, Kansakar U, Varzideh F, Jankauskas SS, Pansini A, Marzocco S, De Gennaro S, Famiglietti M, Macina G, Frullone S, Santulli G. Empagliflozin improves the MicroRNA signature of endothelial dysfunction in patients with heart failure with preserved ejection fraction and diabetes. J Pharmacol Exp Ther. 2023;384(1):116–22.
pubmed: 36549862
pmcid: 9827502
doi: 10.1124/jpet.121.001251
Balleza Alejandri LR, Grover Páez F, González Campos E, Ramos Becerra CG, Cardona Muñóz EG, Pascoe González S, Ramos Zavala MG, Reynoso Roa AS, Suárez Rico DO, Beltrán Ramírez A, García Galindo JJ, Cardona Müller D, Galán Ruíz CY. Empagliflozin and dapagliflozin improve endothelial function in mexican patients with type 2 diabetes mellitus: a double-blind clinical trial. J Cardiovasc Dev Dis. 2024;11(6):182.
pubmed: 38921682
pmcid: 11204032
Sposito AC, Breder I, Barreto J, Breder J, Bonilha I, Lima M, Oliveira A, Wolf V, Luchiari B, Do-Carmo HR, Munhoz D, Oliveira D, Coelho-Filho OR, Coelho OR, Matos-Souza JR, Moura FA, De-Carvalho LSF, Nadruz W, Quinaglia T, Kimura-Medorima ST. EXCEED-BHS3 group evolocumab on top of empagliflozin improves endothelial function of individuals with diabetes: randomized active-controlled trial. Cardiovasc Diabetol. 2022;21(1):147.
pubmed: 35933413
pmcid: 9356512
doi: 10.1186/s12933-022-01584-8
Lin B, Koibuchi N, Hasegawa Y, et al. Glycemic control with empagliflozin, a novel selective SGLT2 inhibitor, ameliorates cardiovascular injury and cognitive dysfunction in obese and type 2 diabetic mice. Cardiovasc Diabetol. 2014;13:148.
pubmed: 25344694
pmcid: 4219031
doi: 10.1186/s12933-014-0148-1
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: e0143396.
pubmed: 26606676
pmcid: 4659635
doi: 10.1371/journal.pone.0143396
Mancini SJ, Boyd D, Katwan OJ, et al. Canagliflozin inhibits interleukin-1β-stimulated cytokine and chemokine secretion in vascular endothelial cells by AMP-activated protein kinase-dependent and -independent mechanisms. Sci Rep. 2018;8:5276.
pubmed: 29588466
pmcid: 5869674
doi: 10.1038/s41598-018-23420-4
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;20:137–49.
pubmed: 28579299
pmcid: 5478253
doi: 10.1016/j.ebiom.2017.05.028
Nakatsu Y, Kokubo H, Bumdelger B, et al. The SGLT2 inhibitor luseogliflozin rapidly normalizes aortic mRNA levels of inflammation-related but not lipid-metabolism-related genes and suppresses atherosclerosis in diabetic ApoE KO mice. Int J Mol Sci. 2017;18:1704.
pubmed: 28777298
pmcid: 5578094
doi: 10.3390/ijms18081704
Nasiri-Ansari Ν, Dimitriadis GK, Agrogiannis G, et al. Canagliflozin attenuates the progression of atherosclerosis and inflammation process in APOE knockout mice. Cardiovasc Diabetol. 2018;17:106.
pubmed: 30049285
doi: 10.1186/s12933-018-0749-1
Day EA, Ford RJ, Lu JH, et al. The SGLT2 inhibitor canagliflozin suppresses lipid synthesis and interleukin-1 beta in ApoE deficient mice. Biochem J. 2020;477:2347–61.
pubmed: 32510137
doi: 10.1042/BCJ20200278
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.
pubmed: 32114052
doi: 10.1016/j.ejphar.2020.173040
Pennig J, Scherrer P, Gissler MC, et al. Glucose lowering by SGLT2-inhibitor empagliflozin accelerates atherosclerosis regression in hyperglycemic STZ-diabetic mice. Sci Rep. 2019;9:17937.
pubmed: 31784656
pmcid: 6884628
doi: 10.1038/s41598-019-54224-9
Iannantuoni F, 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;8:1814.
pubmed: 31683785
pmcid: 6912454
doi: 10.3390/jcm8111814
Koyani CN, Plastira I, Sourij H, Hallström S, Schmidt A, Rainer PP, Bugger H, Frank S, Malle E, von Lewinski D. Empagliflozin protects heart from inflammation and energy depletion via AMPK activation. Pharmacol Res. 2020;158: 104870.
pubmed: 32434052
doi: 10.1016/j.phrs.2020.104870
Zou R, Shi W, Qiu J, Zhou N, Du N, Zhou H, Chen X, Ma L. Empagliflozin attenuates cardiac microvascular ischemia/reperfusion injury through improving mitochondrial homeostasis. Cardiovasc Diabetol. 2022;21(1):106.
pubmed: 35705980
pmcid: 9202214
doi: 10.1186/s12933-022-01532-6
Cinquegrani G, Spigoni V, Fantuzzi F, Bonadonna RC, Dei CA. Empagliflozin does not reverse lipotoxicity-induced impairment in human myeloid angiogenic cell bioenergetics. Cardiovasc Diabetol. 2022;21(1):27.
pubmed: 35177077
pmcid: 8851739
doi: 10.1186/s12933-022-01461-4
Schmidt K, Schmidt A, Groß S, Just A, Pfanne A, Fuchs M, Jordan M, Mohr E, Pich A, Fiedler J, Thum T. SGLT2 inhibitors attenuate endothelial to mesenchymal transition and cardiac fibroblast activation. Sci Rep. 2024;14(1):16459.
pubmed: 39013942
pmcid: 11252266
doi: 10.1038/s41598-024-65410-9
Kraakman MJ, Lee MK, Al-Sharea A, et al. Neutrophil-derived S100 calcium-binding proteins A8/A9 promote reticulated thrombocytosis and atherogenesis in diabetes. J Clin Invest. 2017;127:2133–47.
pubmed: 28504650
pmcid: 5451242
doi: 10.1172/JCI92450
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;19:46.
pubmed: 32264868
pmcid: 7140327
doi: 10.1186/s12933-020-01016-5
Bonora BM, Cappellari R, Albiero M, Avogaro A, Fadini GP. Effects of SGLT2 inhibitors on circulating stem and progenitor cells in patients with type 2 diabetes. J Clin Endocrinol Metab. 2018;103:3773–82.
pubmed: 30113651
doi: 10.1210/jc.2018-00824
Nandula SR, Kundu N, Awal HB, et al. Role of Canagliflozin on function of CD34+ve endothelial progenitor cells (EPC) in patients with type 2 diabetes. Cardiovasc Diabetol. 2021;20:44.
pubmed: 33581737
pmcid: 7881606
doi: 10.1186/s12933-021-01235-4
Fadini GP, Baesso I, Albiero M, Sartore S, Agostini C, Avogaro A. Technical notes on endothelial progenitor cells: ways to escape from the knowledge plateau. Atherosclerosis. 2008;197:496–503.
pubmed: 18249408
doi: 10.1016/j.atherosclerosis.2007.12.039
Graziani F, Leone AM, Basile E, Cialdella P, Tritarelli A, Bona RD, Liuzzo G, Nanni G, Iaconelli A, Iaconelli A, Mingrone G, Biasucci LM, Crea F. Endothelial progenitor cells in morbid obesity. Circ J. 2014;78(4):977–85.
pubmed: 24572586
doi: 10.1253/circj.CJ-13-0976
Peyter AC, Armengaud JB, Guillot E, Yzydorczyk C. Endothelial Progenitor cells dysfunctions and cardiometabolic disorders: from mechanisms to therapeutic approaches. Int J Mol Sci. 2021;22(13):6667.
pubmed: 34206404
pmcid: 8267891
doi: 10.3390/ijms22136667