A diabetes medication may protect against heart attacks and strokes through an unexpected biological mechanism.
Two medications used in people with type 2 diabetes produced dramatically different results when scientists tested their ability to prevent dangerous blood clots. In mice with injured blood vessels, sotagliflozin reduced clot formation by approximately 60%, compared with just 5% to 10% for the widely prescribed drug empagliflozin.
Researchers at Michigan Medicine also found that sotagliflozin suppresses excessive platelet activity, a process that can block blood flow to the heart or brain. Published in the Journal of Clinical Investigation, the findings suggest a possible explanation for the drug’s ability to reduce heart attack and stroke risk beyond its effects on blood sugar.
Why Sotagliflozin Works Differently
Sotagliflozin, marketed as Inpefa, belongs to a group of medications called sodium-glucose cotransporter (SGLT) inhibitors. These drugs interfere with proteins that transport glucose through the body. Common treatments such as empagliflozin (Jardiance) and dapagliflozin (Farxiga) primarily block SGLT2, a protein that helps the kidneys reabsorb glucose. Sotagliflozin acts on both SGLT2 and SGLT1, which is also present in other tissues.
Although SGLT2 inhibitors have established cardiovascular benefits, clinical trials have shown that sotagliflozin can also reduce ischemic events, including heart attacks and strokes. These occur when blood clots or other blockages restrict circulation. The researchers investigated whether the drug’s broader action on glucose transport proteins might help explain this protection.
“A drug that can both decrease the risk for diabetes along with the risk for having a heart attack or stroke could be a turning point in our ability safely treat this growing population in the US and abroad,” said Michael A. Holinstat, Ph.D., M.S., co-senior author and professor of pharmacology, internal medicine, and surgery at the University of Michigan Medical School.
A Powerful Effect on Blood Platelets
Scientists compared sotagliflozin and empagliflozin using blood samples from healthy volunteers and people with type 2 diabetes. Sotagliflozin significantly reduced platelet activation and made platelets less likely to clump together. Empagliflozin produced little or no comparable effect.
Platelets normally help stop bleeding by gathering at damaged blood vessels. However, excessive activation can produce clots inside arteries, potentially triggering a heart attack or stroke. Sotagliflozin’s ability to suppress this activity may contribute to its cardiovascular benefits.
“These experiments showed that sotagliflozin has a unique effect, and blocking SGLT2 alone is not enough to inhibit platelet aggregation,” said Eugene Chen, M.D., Ph.D., co-senior author and Frederick G. L. Huetwell Professor of Cardiovascular Medicine at the University of Michigan Medical School.
“Sotagliflozin may offer additional protection against blood clots, potentially lowering the risk of heart attack and stroke.”
Blocking SGLT1 Explains Only Part of the Effect
The researchers next investigated whether inhibiting SGLT1 alone could account for sotagliflozin’s effects. When they genetically removed SGLT1 from mouse platelets, blood clot formation decreased by approximately 40%. However, neither this genetic approach nor treatment with mizagliflozin, a drug that selectively blocks SGLT1, fully reproduced sotagliflozin’s results.
This suggests that other biological mechanisms contribute to the drug’s ability to prevent clot formation. One possibility involves SGLT1 in endothelial cells, which form the inner lining of blood vessels and interact with circulating platelets. Researchers have not yet established whether these cells contribute to sotagliflozin’s anti-clotting effects.
“Sotagliflozin appears to be in the sweet spot because compounds that have higher levels of SGLT1-selective inhibitors can cause gastrointestinal issues,” said Bertram Pitt, M.D., co-author and professor emeritus of internal medicine at the University of Michigan Medical School.
“We think this could be a wonder drug with potential to offer benefit for many conditions.”
Could the Benefits Extend Beyond Diabetes?
Sotagliflozin is FDA-approved to reduce certain cardiovascular risks in adults with heart failure and in adults with type 2 diabetes, chronic kidney disease, and additional cardiovascular risk factors. The researchers hope to investigate whether its effects on clotting could benefit patients with other conditions, including chronic kidney disease and atrial fibrillation, an irregular heart rhythm associated with increased stroke risk.
The laboratory and animal findings provide evidence that sotagliflozin affects clotting through mechanisms beyond conventional SGLT2 inhibition. However, further clinical research is needed to determine how much this platelet effect contributes to preventing cardiovascular events in humans and whether it can do so without increasing bleeding complications.
“The search for medications that reduce the risk of life-threatening blood clots without increasing the risk of bleeding has continued for decades,” Holinstat said.
“Sotagliflozin has now been demonstrated to serve both functions and may represent the next advancement in prevention of blood clots, heart failure and stroke in patients with and without diabetes.”
Reference: “SGLT1/2 inhibitor sotagliflozin, but not SGLT2-selective inhibitor empagliflozin, attenuates platelet activation and thrombosis” by 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 and Michael Holinstat, 14 October 2026, The Journal of Clinical Investigation.
DOI: 10.1172/JCI201899
This work was supported by the National Heart, Lung, and Blood Institute (F31HL179940, R35HL150784, R01HL109946), the National Institute of General Medical Sciences (T32GM140223, and the National Center for Advancing Translational Sciences (T32TR004371) of National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH
The work was also supported by the American Heart Association and Lexicon Pharmaceuticals.
Michael Holinstat is a consultant and receives research funding from Lexicon Pharmaceuticals. Bertram Pitt is a consultant for Lexicon Pharmaceuticals. The remaining authors declare no conflicts of interest.
Never miss a breakthrough: Join the SciTechDaily newsletter.
Follow us on Google and Google News.