Rationale and Design of the SOTA-THROMBOSIS Trial (ATRU-VI): Antithrombotic Activities of Sotagliflozin Compared With Empagliflozin

ABSTRACT: Although selective SGLT2 inhibitors improve heart failure (HF) outcomes, they do not consistently reduce atherothrombotic events (myocardial infarctions and strokes). Clinical trials with sotagliflozin, the first dual SGLT1/2 inhibitor, have shown significant reductions in both HF outcomes and atherothrombotic events: an effect not seen with highly selective SGLT2 inhibitors such as empagliflozin. This effect may be related to SGLT1 inhibition, because SGLT1 is widely expressed in the myocardium, platelets, and endothelial cells, suggesting a potential antithrombotic mechanism. The SOTA-THROMBOSIS trial is a randomized, cross-over study in healthy volunteers (n = 16) comparing the antithrombotic effects of dual SGLT1/2 inhibition with sotagliflozin and selective SGLT2 inhibition with empagliflozin. All participants will receive each treatment for 4 weeks, separated by a 1-month washout. Blood thrombogenicity under high and low shear rate conditions will be assessed using the Badimon perfusion chamber. Additional assessments include platelet aggregation (Multiplate Analyzer) and clot formation kinetics using thromboelastometry (RoTEM). Measurements will be performed at baseline (pretreatment) and at the end of each treatment period. The cross-over design-where each participant receives both study treatments and serves as his/her own control-significantly reduces both, intrasubject and intragroup variability. We hypothesize that both treatments will reduce blood thrombogenicity compared with baseline, with sotagliflozin offering a more marked antithrombotic effect than empagliflozin. This trial will provide novel mechanistic insights into the antithrombotic activity of SGLT1/2 inhibition. If confirmed, these findings may explain the additional cardiovascular protection observed with sotagliflozin and support its use in patients with HF at high thrombotic risk.