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Cardiovascular Drugs and Therapy
Published in: Cardiovascular Drugs and Therapy 6/2022

Open Access 14-09-2021 | Dapagliflozin | Original Article

Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure

Authors: Michele Correale, Pietro Mazzeo, Adriana Mallardi, Alessandra Leopizzi, Lucia Tricarico, Martino Fortunato, Michele Magnesa, Salvatore Tucci, Pasquale Maiellaro, Giuseppe Pastore, Olga Lamacchia, Massimo Iacoviello, Matteo Di Biase, Natale Daniele Brunetti

Published in: Cardiovascular Drugs and Therapy | Issue 6/2022

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Abstract

Purpose

The use of sodium-glucose-cotransporter-type-2 inhibitors (SGLT2i) was associated in previous studies with an improved vascular function in non-human experimental models. We therefore sought to evaluate possible changes in endothelial function assessed by flow-mediated dilation (FMD) in patients with chronic heart failure (CHF) and type-2 diabetes mellitus (T2DM), switching from other oral hypoglycemic agents to SGLT2i in an observational study.

Methods

Twenty-two consecutive outpatients with CHF and T2DM were enrolled after switching to SGLT2i therapy, and compared with 23 consecutive controls from the same registry comparable for principal clinical characteristics. In all patients, endothelial function was assessed by FMD at baseline and after 3 months of follow-up.

Results

Three months of therapy with SGLT2i were associated with a statistically significant improvement in endothelial function (19.0 ± 5.7% vs 8.5 ± 4.1%, p < 0.0001); baseline levels of FMD were comparable between groups (p n.s.). Therapy with SGLT2i was significantly associated to improved FMD levels even at multivariable stepwise regression analysis (p < 0.001).

Conclusions

Switch to SGLT2i in patients with CHF and T2DM was associated in an observational non-randomized study with an improved endothelial function.
Appendix
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Literature
1.
Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, Colagiuri S, Guariguata L, Motala AA, Ogurtsova K, Shaw JE, Bright D, Williams R; IDF Diabetes Atlas Committee. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843.
2.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE, EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373:2117–28.CrossRefPubMed
3.
Neal B, Perkovic V, Matthews DR, Mahaffey KW, Fulcher G, Meininger G, Erondu N, Desai M, Shaw W, Vercruysse F, Yee J, Deng H, de Zeeuw D, CANVAS-R Trial Collaborative Group. Rationale, design and baseline characteristics of the CANagliflozin cardioVascular Assessment Study-Renal (CANVAS-R): a randomized, placebo-controlled trial. Diabetes Obes Metab. 2017;19:387–93.CrossRefPubMedPubMedCentral
4.
Wiviott SD, Raz I, Bonaca MP, Mosenzon O, Kato ET, Cahn A, Silverman MG, Bansilal S, Bhatt DL, Leiter LA, McGuire DK, Wilding JP, Gause-Nilsson IA, Langkilde AM, Johansson PA, Sabatine MS. The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J. 2018;200:83–9.CrossRefPubMed
5.
Kosiborod M, Cavender MA, Fu AZ, Wilding JP, Khunti K, Holl RW, Norhammar A, Birkeland KI, Jørgensen ME, Thuresson M, Arya N, Bodegård J, Hammar N, Fenici P, CVD-REAL Investigators and Study Group*. 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;136:249–59.CrossRefPubMedPubMedCentral
6.
Ganbaatar B, Fukuda D, Shinohara M, Yagi S, Kusunose K, Yamada H, Soeki T, Hirata KI, Sata M. Empagliflozin ameliorates endothelial dysfunction and suppresses atherogenesis in diabetic apolipoprotein E-deficient mice. Eur J Pharmacol. 2020;875:173040.CrossRefPubMed
7.
Lee DM, Battson ML, Jarrell DK, Hou S, Ecton KE, Weir TL, Gentile CL. SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. Cardiovasc Diabetol. 2018;17:62.CrossRefPubMedPubMedCentral
8.
Gaspari T, Spizzo I, Liu H, Hu Y, Simpson RW, Widdop RE, Dear AE. Dapagliflozin attenuates human vascular endothelial cell activation and induces vasorelaxation: a potential mechanism for inhibition of atherogenesis. Diab Vasc Dis Res. 2018;15:64–73.CrossRefPubMed
9.
Correale M, Totaro A, Greco CA, Musaico F, De Rosa F, Ferraretti A, Ieva R, Di Biase M, Brunetti ND. Tissue Doppler Time Intervals predict the occurrence of re-hospitalization in chronic heart failure: data from the Daunia Heart Failure Registry. Echocardiography. 2012;29:906–13.CrossRefPubMed
10.
Correale M, Brunetti ND, Totaro A, Montrone D, Russo AR, Fanigliulo AM, Ieva R, Di Biase M. Statin therapy blunts inflammatory activation and improves prognosis and left ventricular performance assessed by tissue Doppler imaging in subjects with chronic ischemic heart failure: results from the Daunia Heart Failure Registry. Clinics. 2011;66:777–84.PubMedPubMedCentral
11.
Correale M, Totaro A, Ferraretti A, Musaico F, Passero T, De Rosa F, Abruzzese S, Ieva R, Di Biase M, Brunetti ND. Additional Prognostic Value of EAS index in predicting the occurrence of rehospitalizations in chronic heart failure: data from the Daunia Heart Failure Registry. Eur J Clin Invest. 2015;45:1098–105.CrossRefPubMed
12.
Seferović PM, Petrie MC, Filippatos GS, Anker SD, Rosano G, Bauersachs J, Paulus WJ, Komajda M, Cosentino F, de Boer RA, Farmakis D, Doehner W, Lambrinou E, Lopatin Y, Piepoli MF, Theodorakis MJ, Wiggers H, Lekakis J, Mebazaa A, Mamas MA, Tschöpe C, Hoes AW, Seferović JP, Logue J, McDonagh T, Riley JP, Milinković I, Polovina M, van Veldhuisen DJ, Lainscak M, Maggioni AP, Ruschitzka F, McMurray JJV. 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;20:853–72.CrossRefPubMed
13.
Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, Rossing P, Tsapas A, Wexler DJ, Buse JB, Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2018;2018(61):2461–98.CrossRef
14.
Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, Federici M, Filippatos G, Grobbee DE, Hansen TB, Huikuri HV, Johansson I, Jüni P, Lettino M, Marx N, Mellbin LG, Östgren CJ, Rocca B, Roffi M, Sattar N, Seferović PM, Sousa-Uva M, Valensi P, Wheeler DC, ESC Scientific Document Group. 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.CrossRefPubMed
15.
Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, Vallance P, Vita J, Vogel R, International Brachial Artery Reactivity Task Force. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. J Am Coll Cardiol. 2002;39:257–65.CrossRefPubMed
16.
Correale M, Leopizzi A, Mallardi A, Ranieri A, Suriano MP, D’Alessandro D, Tricarico L, Mazzeo P, Tucci S, Pastore G, Maulucci G, Di Biase M, Brunetti ND. Switch to direct anticoagulants and improved endothelial function in patients with chronic heart failure and atrial fibrillation. Thromb Res. 2020;195:16–20.CrossRefPubMed
17.
Maulucci G, Cipriani F, Russo D, Casavecchia G, Di Staso C, Di Martino L, Ruggiero A, Di Biase M, Brunetti ND. Improved endothelial function after short term therapy with evolocumab. J Clin Lipidol. 2018;12:669–73.CrossRefPubMed
18.
Correale M, Paolillo S, Mercurio V, Limongelli G, Barillà F, Ruocco G, Palazzuoli A, Scrutinio D, Lagioia R, Lombardi C, Lupi L, Magrì D, Masarone D, Pacileo G, Scicchitano P, Matteo Ciccone M, Parati G, Tocchetti CG, Nodari S. Comorbidities in chronic heart failure: an update from Italian Society of Cardiology (SIC) Working Group on Heart Failure. Eur J Intern Med. 2020;71:23–31.CrossRefPubMed
19.
Correale M, Brunetti ND, Totaro A, Montrone D, Russo AR, Fanigliulo AM, Ieva R, Di Biase M. Statin therapy blunts inflammatory activation and improves prognosis and left ventricular performance assessed by Tissue Doppler Imaging in subjects with chronic ischemic heart failure: results from the Daunia Heart Failure Registry. Clinics. 2011;66:777–84.PubMedPubMedCentral
20.
Tsutsui H, Kinugawa S, Matsushima S. Oxidative stress and heart failure. Am J Physiol Heart Circ Physiol. 2011;301:H2181–90.CrossRefPubMed
21.
Osorio H, Coronel I, Arellano A, Pacheco U, Bautista R, Franco M, Escalante B. Sodium–glucose cotransporter inhibition prevents oxidative stress in the kidney of diabetic rats. Oxid Med Cell Longev. 2012;2012:542042.CrossRefPubMedPubMedCentral
22.
Lin B, Koibuchi N, Hasegawa Y, Sueta D, Toyama K, Uekawa K, Ma M, Naka-gawa T, Kusaka H, Kim-Mitsuyama S. 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.CrossRefPubMedPubMedCentral
23.
Tahara A, Kurosaki E, Yokono M, Yamajuku D, Kihara R, Hayashizaki Y, Takasu T, Imamura M, Li Q, Tomiyama H, Kobayashi Y, Noda A, Sasamata M, Shibasaki M. Effects of SGLT2 selective inhibitor ipraglifozin on hyperglycemia, hyperlipidemia, hepatic steatosis, oxidative stress, inflammation, and obesity in type 2 diabetic mice. Eur J Pharmacol. 2013;715:246–55.CrossRefPubMed
24.
Oelze M, Kroller-Schon S, Welschof P, Jansen T, Hausding M, Mikhed Y, 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.CrossRefPubMedPubMedCentral
25.
Salim HM, Fukuda D, Yagi S, Soeki T, Shimabukuro M, Sata M. Glycemic control with ipragliflozin, a novel selective SGLT2 inhibitor, ameliorated endothelial dysfunction in streptozotocin-induced diabetic mouse. Front Cardiovasc Med. 2016;3:43.CrossRefPubMedPubMedCentral
26.
Juni RP, Kuster DWD, Goebel M, Helmes M, Musters RJP, van der Velden J, Koolwijk P, Paulus WJ, van Hinsbergh VWM. Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. JACC Basic Transl Sci. 2019;4:575–91.CrossRefPubMedPubMedCentral
27.
Shigiyama F, Kumashiro N, Miyagi M, Ikehara K, Kanda E, Uchino H, Hirose T. 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.CrossRefPubMedPubMedCentral
28.
Solini A, Giannini L, Seghieri M, Vitolo E, Taddei S, Ghiadoni L. Bruno RM Dapagliflozin acutely improves endothelial dysfunction, reduces aortic stiffness and renal resistive index in type 2 diabetic patients: a pilot study. Cardiovasc Diabetol. 2017;16:138.CrossRefPubMedPubMedCentral
29.
Tanaka, et al. Rationale and design of a multicenter placebo-controlled double-blind randomized trial to evaluate the effect of empagliflozin on endothelial function: the EMBLEM trial. Cardiovasc Diabetol. 2017;16:48.CrossRefPubMedPubMedCentral
30.
Tanaka A, Shimabukuro M, Machii N, Teragawa H, Okada Y, Shima KR, Takamura T, Taguchi I, Hisauchi I, Toyoda S, Matsuzawa Y, Tomiyama H, Yamaoka-Tojo M, Ueda S, Higashi Y, Node K. Secondary analyses to assess the profound effects of empagliflozin on endothelial function in patients with type 2 diabetes and established cardiovascular diseases: the placebo-controlled double-blind randomized effect of empagliflozin on endothelial function in cardiovascular high risk diabetes mellitus: Multi-center placebo-controlled double-blind randomized trial. J Diabetes Investig. 2020. https://​doi.​org/​10.​1111/​jdi.​13289.
31.
Tanaka A, Shimabukuro M, Okada Y, Sugimoto K, Kurozumi A, Torimoto K, Hirai H, Node K, PROCEED trial investigators. Rationale and design of an investigator-initiated, multicenter, prospective open-label, randomized trial to evaluate the effect of ipragliflozin on endothelial dysfunction in type 2 diabetes and chronic kidney disease: the PROCEED trial. Cardiovasc Diabetol. 2020;19:85.CrossRefPubMedPubMedCentral
32.
Breder I, Cunha Breder J, Bonilha I, Munhoz DB, Medorima STK, Oliveira DC, do Carmo HR, Moreira C, Kontush A, Zimetti F, Zanotti I, Carvalho LSF, Nadruz W, Muscelli E, Quinaglia T, Sposito AC, EXCEED-BHS3 Trial Investigator. Rationale and design of the expanded combination of evolocumab plus empagliflozin in diabetes: EXCEED-BHS3 trial. Ther Adv Chronic Dis. 2020;11:2040622320959248.CrossRefPubMedPubMedCentral
33.
Sposito AC, Breder I, Soares AAS, Kimura-Medorima ST, Munhoz DB, Cintra RMR, Bonilha I, Oliveira DC, Breder JC, Cavalcante P, Moreira C, Moura FA, de Lima-Junior JC, do Carmo HRP, Barreto J, Nadruz W, Carvalho LSF, Quinaglia T, ADDENDA-BHS2 trial investigators. Dapagliflozin effect on endothelial dysfunction in diabetic patients with atherosclerotic disease: a randomized active-controlled trial. Cardiovasc Diabetol. 2021;20:74.CrossRefPubMedPubMedCentral
34.
Lee HC, Shiou YL, Jhuo SJ, Chang CY, Liu PL, Jhuang WJ, Dai ZK, Chen WY, Chen YF, Lee AS. The sodium-glucose co-transporter 2 inhibitor empagliflozin attenuates cardiac fibrosis and improves ventricular hemodynamics in hypertensive heart failure rats. Cardiovasc Diabetol. 2019;18:45.CrossRefPubMedPubMedCentral
35.
Loutradis C, Papadopoulou E, Theodorakopoulou M, Karagiannis A, Sarafidis P. The effect of SGLT-2 inhibitors on blood pressure: a pleiotropic action favoring cardio- and nephroprotection. Future Med Chem. 2019;11:1285–303.CrossRefPubMed
36.
Filippatos TD, Liontos A, Papakitsou I, Elisaf MS. SGLT2 inhibitors and cardioprotection: a matter of debate and multiple hypotheses. Postgrad Med. 2019;131:82–8.CrossRefPubMed
37.
Irace C, Cutruzzolà A, Parise M, Fiorentino R, Frazzetto M, Gnasso C, Casciaro F, Gnasso A. Effect of empagliflozin on brachial artery shear stress and endothelial function in subjects with type 2 diabetes: results from an exploratory study. Diab Vasc Dis Res. 2020;17:1479164119883540.CrossRefPubMed
38.
Irace C, Casciaro F, Scavelli FB, et al. Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. Cardiovasc Diabetol. 2018;17:52.CrossRefPubMedPubMedCentral
39.
Li H, Shin SE, Seo MS, An JR, Choi IW, Jung WK, Firth AL, Lee DS, Yim MJ, Choi G, Lee JM, Na SH, Park WS. The anti-diabetic drug dapagliflozin induces vasodilation via activation of PKG and Kv channels. Life Sci. 2018;197:46–55.CrossRefPubMed
40.
Sano M. Sodium glucose cotransporter (SGLT)-2 inhibitors alleviate the renal stress responsible for sympathetic activation. Ther Adv Cardiovasc Dis. 2020;14:1753944720939383.CrossRefPubMedPubMedCentral
41.
Scheen AJ. Effect of SGLT2 inhibitors on the sympathetic nervous system and blood pressure. Curr Cardiol Rep. 2019;21:70.CrossRefPubMed
Metadata
Title
Switch to SGLT2 Inhibitors and Improved Endothelial Function in Diabetic Patients with Chronic Heart Failure
Authors
Michele Correale
Pietro Mazzeo
Adriana Mallardi
Alessandra Leopizzi
Lucia Tricarico
Martino Fortunato
Michele Magnesa
Salvatore Tucci
Pasquale Maiellaro
Giuseppe Pastore
Olga Lamacchia
Massimo Iacoviello
Matteo Di Biase
Natale Daniele Brunetti
Publication date
14-09-2021
Publisher
Springer US
Published in
Cardiovascular Drugs and Therapy / Issue 6/2022
Print ISSN: 0920-3206
Electronic ISSN: 1573-7241
DOI
https://doi.org/10.1007/s10557-021-07254-3

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