SGLT1/2 inhibitor sotagliflozin, but not SGLT2-selective inhibitor empagliflozin, attenuates platelet activation and thrombosis

Livia Stanger; Krista Goerger; Xu Zhang; Pooja Yalavarthi; Andrew Rickenberg; Adriana Yamaguchi; Mariane Flores Nascimento; Ashleigh Kilgore; Heeseo Kim; Xiaokang Wu; Yanhong Guo; Anna R. Dahlgren; Jifeng Zhang; Jordan A. Shavit; Bertram Pitt; Y. Eugene Chen; Michael Holinstat

doi:10.1172/JCI201899

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

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¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

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¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, X. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Yalavarthi, P. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

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¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Yamaguchi, A. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Flores Nascimento, M. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Kilgore, A. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Kim, H. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Wu, X. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Guo, Y. in: PubMed | Google Scholar |

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Dahlgren, A. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Zhang, J. in: PubMed | Google Scholar |

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Shavit, J. in: PubMed | Google Scholar |

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Pitt, B. in: PubMed | Google Scholar

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Chen, Y. in: PubMed | Google Scholar |

¹Department of Pharmacology, University of Michigan Medical Center, Ann Arbor, United States of America

²Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan Medical Center, Ann Arbor, United States of America

³Department of Pediatrics, University of Michigan Medical Center, Ann Arbor, United States of America

Find articles by Holinstat, M. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI201899.
Copyright © 2026, Stanger et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published October 14, 2026 - Version history

As rates of type 2 diabetes mellitus (T2DM) have risen, comorbidities of T2DM and cardiovascular disease (CVD) have similarly increased. The adoption of sodium-glucose cotransporter (SGLT) 2 inhibitors as a treatment for T2DM has provided an effective means of decreasing renal glucose reabsorption. In recent clinical trials, sotagliflozin, the first FDA-approved inhibitor of both isoforms of SGLT (SGLT1 and SGLT2), demonstrated a reduction in myocardial infarction and stroke in patients with T2DM at high cardiovascular risk. The cardiovascular protective effect of sotagliflozin compared to the SGLT2-selective inhibitor, empagliflozin, was investigated by evaluating effects on platelet activation and thrombus formation. Employing ex vivo models using blood from healthy donors or T2DM patients, and in vivo mouse models, we demonstrate an inhibitory effect on platelet activity and thrombus formation with sotagliflozin, while empagliflozin has minor to no effects. Further, no impact on hemostasis was observed with sotagliflozin. Finally, a platelet-specific deletion of SGLT1 via Slc5a1^fl/fl Gp1ba-Cre⁺ mice resulted in reduced platelet integrin activation and thrombus formation. This study provides insight into a potential explanation for the cardiovascular protection conferred by sotagliflozin observed in patients with T2DM at risk of an ischemic event and reveals an added benefit to SGLT2-selective inhibitors.

Version 1 (October 14, 2026): In-Press Preview

SGLT1/2 inhibitor sotagliflozin, but not SGLT2-selective inhibitor empagliflozin, attenuates platelet activation and thrombosis

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SGLT1/2 inhibitor sotagliflozin, but not SGLT2-selective inhibitor empagliflozin, attenuates platelet activation and thrombosis

Livia Stanger,1 Krista Goerger,1 Xu Zhang,2 Pooja Yalavarthi,1 Andrew Rickenberg,1 Adriana Yamaguchi,1 Mariane Flores Nascimento,1 Ashleigh Kilgore,1 Heeseo Kim,1 Xiaokang Wu,2 Yanhong Guo,2 Anna R. Dahlgren,3 Jifeng Zhang,2 Jordan A. Shavit,3 Bertram Pitt,2 Y. Eugene Chen,2 and Michael Holinstat1

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