SGLT-2 inhibition by empagliflozin has no effect on experimental arterial thrombosis in a murine model of low-grade inflammation.

Autor:	Liberale L; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy., Kraler S; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland., Puspitasari YM; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland., Bonetti NR; University Heart Center, Department of Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland., Akhmedov A; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland., Ministrini S; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; Internal Medicine, Angiology and Atherosclerosis, Department of Medicine and Surgery, University of Perugia, 06123 Perugia, Italy., Montecucco F; First Clinic of Internal Medicine, Department of Internal Medicine, University of Genoa, 16132 Genoa, Italy.; IRCCS Ospedale Policlinico San Martino Genoa - Italian Cardiovascular Network, 16132 Genoa, Italy., Marx N; Department of Internal Medicine I, University Hospital Aachen, RWTH, 52074 Aachen, Germany., Lehrke M; Department of Internal Medicine I, University Hospital Aachen, RWTH, 52074 Aachen, Germany., Hartmann NK; Department of Internal Medicine I, University Hospital Aachen, RWTH, 52074 Aachen, Germany., Beer JH; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; Department of Internal Medicine, Cantonal Hospital of Baden, 5404 Baden, Switzerland., Wenzl FA; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland., Paneni F; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; University Heart Center, Department of Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland.; Department of Research and Education, University Hospital Zurich, 8091 Zurich, Switzerland., Lüscher TF; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; Royal Brompton and Harefield Hospitals and Imperial College, SW3 6NP London, UK., Camici GG; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, 8952 Schlieren, Switzerland.; University Heart Center, Department of Cardiology, University Hospital Zurich, 8091 Zurich, Switzerland.; Department of Research and Education, University Hospital Zurich, 8091 Zurich, Switzerland.
Jazyk:	angličtina
Zdroj:	Cardiovascular research [Cardiovasc Res] 2023 May 02; Vol. 119 (3), pp. 843-856.
DOI:	10.1093/cvr/cvac126
Abstrakt:	Aims: Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD. Methods and Results: Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, -9.82 to 8.85 and -9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up. Conclusion: SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis. Competing Interests: Conflict of interest: L.L. and G.G.C. are coinventors on the International Patent (WO/2020/226993) filed in April 2020 and relating to the use of antibodies, which specifically bind IL-1α to reduce various sequelae of ischaemia–reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. L.L. has received speaker fees outside of this work from Daichi-Sankyo. T.F.L. has received honoraria and educational grants from Boehringer Ingelheim Switzerland and Ingelheim, FRG, respectively. N.M. has received support for clinical trial leadership from Boehringer Ingelheim, served as a consultant to Boehringer Ingelheim, Merck, AstraZeneca, BMS, received grant support from Boehringer Ingelheim, Merck, and served as a speaker for Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. M.L. received grants and personal fees from Boehringer Ingelheim, MSD, Novo Nordisk and personal fees from Amgen, Sanofi, Astra Zeneca, Bayer, Lilly, Daiichi Sankyo, Novarits, Amarin. The other authors report no conflict of interest. (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
Databáze:	MEDLINE
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