Comparison of the Anti-Platelet and Anti-Thrombotic Effects of the Dual SGLT1/2 Inhibitor Sotagliflozin to the Relatively Selective SGLT2 Inhibitor Empagliflozin

Cardiovascular disease (CVD) is commonly associated with a wide variety of chronic comorbidities, including type 2 diabetes (T2DM) and chronic kidney disease (CKD). In the past decade, inhibition of sodium-glucose cotransporter (SGLT) 2 has been identified as a target for anti-diabetic medications. In the SCORED trial conducted in patients with T2DM and CKD, sotagliflozin (SOTA), an SGLT inhibitor with dual action at sodium-glucose cotransporters 1 and 2, demonstrated a significant reduction in both myocardial infarction (MI) and stroke. These findings support a potential cardiovascular benefit of SOTA in T2DM and CKD patients with cardiovascular comorbidities. Recently, our lab has shown that SGLT1 and 2 are present in the platelet, and SOTA decreases platelet activation and thrombus formation. However, it is unclear whether targeting SGLT2 is sufficient to observe these effects, or if SGLT1 inhibition is necessary to achieve them. To address this, we compared the anti-platelet and anti-thrombotic effects of SOTA with empagliflozin (EMPA), a selective SGLT 2 inhibitor approved for the treatment of T2DM.

The effects of SOTA and EMPA on platelet activation and thrombus formation were assessed in vitro using washed human platelets and human whole blood as well as in vivo in wild-type mice. Washed platelets were treated with increasing concentrations of SOTA or EMPA prior to activation with collagen, convulxin or thrombin. Platelet activation was assessed by measuring platelet aggregation, integrin αIIbβ3 activation and granule secretion. In human whole blood, the effect of SOTA and EMPA on platelet adhesion and thrombus formation was probed in the Total Thrombus formation Analysis System (TTAS). In vivo, mice were dosed with 1 mg/kg SOTA or EMPA and the cremaster arteriole thrombosis injury model was employed to evaluate the impact on platelet accumulation and fibrin formation at the site of injury. Finally, to assess the effects of SOTA or EMPA on hemostasis, coagulation parameters were measured in human whole blood using thromboelastography (TEG) and tail bleeding time was measured in vivo in mice dosed with 1 mg/kg SOTA or EMPA.

Increasing concentrations of SOTA result in a dose-dependent decrease in platelet aggregation, integrin αIIbβ3 activation and granule secretion in washed human platelets, while EMPA displays minimal inhibitory potential on aggregation and no effect on integrin αIIbβ3 activation or granule secretion. In human whole blood, EMPA has no effect on platelet adhesion and thrombus formation in the TTAS, contrasting with SOTA which demonstrates a dose-dependent inhibitory effect. While EMPA was observed to have a modest effect on thrombus formation in the vessel following injury, SOTA exhibited a highly significant inhibition of platelet accumulation at the site of vascular injury. Finally, neither SOTA nor EMPA impact coagulation parameters or tail bleeding time.

In conclusion, EMPA exhibited only minor effects on platelet activation and thrombus formation, whereas SOTA demonstrated a significant and robust anti-thrombotic profile. The overwhelming majority of the anti-thrombotic effects of SOTA appear to be due to SGLT1 inhibition. While further investigation is warranted, our results underscore the potential of SOTA to reduce cardiovascular outcomes in patients with T2DM and CKD at high risk for thrombotic events.

Pitt:KBP Biosciences: Consultancy, Current equity holder in private company; Cereno Scientific: Consultancy, Current equity holder in publicly-traded company; Bayer: Consultancy; Lexicon Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Boehringer Ingelheim: Consultancy; Vifor Pharma: Consultancy, Current equity holder in publicly-traded company; Bristol Myers Squibb: Consultancy; Sarfez Pharmaceuticals: Consultancy, Current equity holder in private company; scPharmaceuticals: Consultancy, Current equity holder in publicly-traded company; SQ Innovation: Consultancy, Current equity holder in private company; G3 Pharmaceuticals: Consultancy, Current equity holder in private company; Prointel: Consultancy, Current equity holder in private company; SeaStar Medical: Consultancy, Current equity holder in publicly-traded company; BrainStorm Medical: Consultancy, Current equity holder in publicly-traded company. Holinstat:Veralox Therapeutics: Consultancy, Current equity holder in private company, Patents & Royalties, Research Funding; Lexicon Pharmaceuticals: Research Funding; Cereno Scientific: Consultancy, Current equity holder in publicly-traded company, Patents & Royalties, Research Funding.