Clin Res Cardiol 107, Suppl 1, April 2018

Dapagliflozin reduces platelet activation and thrombin generation

C. Kohlmorgen1, K. Feldmann2, S. Twarock2, S. Hartwig3, S. Lehr3, C. Helten4, P. Keul5, A. Polzin4, M. Kelm4, B. Levkau5, J. W. Fischer2, M. Grandoch2

1Institut für Molekulare Kardiologie, Universitätsklinikum Düsseldorf, Düsseldorf; 2Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum Düsseldorf, Düsseldorf; 3Institut für Klinische Biochemie und Pathobiochemie, Deutsches Diabetes-Zentrum an der Heinrich-Heine-Universität Düsseldorf, Düsseldorf; 4Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf; 5Zentrum Innere Medizin/Institut für Pathophysiologie, Universitätsklinikum Essen, Essen;

Aims: Dapagliflozin, an inhibitor of the sodium glucose co-transporter-2 (SGLT2), is used for treatment of type 2 diabetes mellitus (T2DM). Recent clinical trials report reduced cardiovascular event rates due to SGLT2 inhibition with empagliflozin and canagliflozin. However, the underlying mechanisms still remain unclear and a class effect of the substances is not confirmed yet. Thrombin generation and platelet activation are increased in patients with T2DM driving atherosclerosis and the cardiovascular risk. Therefore, this study aimed to investigate the impact of the SGLT2 inhibitor dapagliflozin on thrombin and platelet function. Methods: Healthy human volunteers were treated with dapagliflozin (10 mg/d) for 4 weeks. Platelet activation was measured before and after SGLT2 inhibition. In order to elucidate the effects on platelet activation in detail, male, 8 week-old low density lipoprotein receptor deficient (Ldlr-/-) mice, a model of accelerated atherosclerosis, were fed a diabetogenic diet supplemented with or without 25 mg/kg dapagliflozin to induce insulin resistance. Mice were analyzed after 8 and 25 weeks, respectively. Results: After 4 weeks of treatment, dapagliflozin decreased the percentage of CD62P-positive platelets in healthy humans indicating reduced platelet activation. Importantly, plasma fibrin D-dimer levels as well as platelet aggregation were not influenced by the treatment. In line, dapagliflozin decreased percentage of activated CD62P-positive platelets also in atherosclerotic Ldlr-/- mice. This probably contributes to dapagliflozin-mediated atheroprotection as determined by en face Oil Red O staining of the total aorta and reduced inflammatory cell numbers as shown by Mac2-staining at the aortic root and flow cytometric analysis of the aorta. In addition, the endogenous thrombin potential was reduced. Besides dapagliflozin directly reduces CD62P expression on isolated platelets. Despite the significant effects on platelet activation, bleeding time was unaffected in dapagliflozin-treated mice. Furthermore, dapagliflozin increased levels of high density lipoprotein-cholesterol (HDL) and modulated hepatic gene expression of HDL metabolism associated genes. HDL directly reduced the endogenous thrombin potential in human plasma. Conclusion: Dapagliflozin decreases thrombin generation and platelet activation by raising HDL and subsequently reduces monocyte/macrophage recruitment into atherosclerotic lesions thereby ameliorating atherogenesis and –progression.

http://www.abstractserver.de/dgk2018/jt/abstracts//P1408.htm