Could a diabetes medication be the next wonder drug?

For millions living with type 2 diabetes, heart disease remains one of the greatest threats to their health. 

Researchers at Michigan Medicine have uncovered a mechanism that may explain why sotagliflozin, an FDA-approved diabetes medication marketed as Inpefa, reduces the risk of heart attack and stroke. In a series of laboratory experiments, the research team found that the drug helps prevent excessive platelet activation, a process that can lead to dangerous blood clots that block flow to the heart and brain. 

The findings, published in the Journal of Clinical Investigation, provide new insight into cardiovascular benefits of the drug that extend beyond blood sugar control.

“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 University of Michigan Medical School.

Sotagliflozin and heart attack, stroke risk

Sotagliflozin belongs to a class of medications known as sodium-glucose cotransporter (SGLT) inhibitors, which lower blood sugar by blocking the proteins responsible for glucose reabsorption. Unlike the widely used SGLT2 inhibitors, which primary act in the kidneys, sotagliflozin, targets both SGLT2 proteins in the kidneys and SGLT1 proteins in other organs.

Over the past decade, SGLT2 inhibitors such as empagliflozin (Jardiance) and dapagliflozin (Farxiga), have become a mainstay of type 2 diabetes treatment. Over 20% of patients are taking the medications. 

Sotagliflozin has demonstrated an unusual ability in clinical trials. Unlike medications that only target SGLT2, the drug reduced the risk of ischemic events such as heart attack and stroke.

To better understand why, researchers conducted a head-to-head comparison between sotagliflozin and the empagliflozin, or Jardiance. While sotagliflozin limited platelet activation in blood samples from both healthy volunteers and people with type 2 diabetes, empagliflozin had little to no effect.

The team also found that sotagliflozin made platelets less likely to stick together and form blood clots. In mice with injured blood vessels, the drug reduced clot formation by approximately 60%, compared with just 5-10% in animals treated with empagliflozin. 

“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 U-M Medical School. 

“Sotagliflozin may offer additional protection against blood clots, potentially lowering the risk of heart attack and stroke.”

What makes sotagliflozin different?

Researchers then asked whether SGLT1 inhibition alone could explain the drug’s anti-clotting effect.

Removing SGLT1 from platelets in mice reduced blood clot formation by about 40%. However, removing it genetically or blocking it with a SGLT1-selective inhibitor drug called mizagliflozin did not fully reproduce the effects of sotagliflozin. 

This suggests that sotagliflozin may help prevent blood clots through additional mechanisms beyond blocking SGLT1 in platelets.

They also believe SGLT1 in endothelial cells, which line blood vessels, may influence platelet interactions and clot formation, a possibility that warrants further study.

“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 U-M Medical School.

“We think this could be a wonder drug with potential to offer benefit for many conditions.”

Sotagliflozin is approved for treatment in adults with heart failure, as well as those with type 2 diabetes, chronic kidney disease and other cardiovascular risk factors.

Researchers say in future studies of the drug, they would also like to evaluate the effects on patients with other conditions, such as chronic kidney disease and atrial fibrillation.

“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.” 

Holinstat and Chen are both members of the Caswell Diabetes Institute.

Paper Cited: “SGLT1/2 inhibitor sotagliflozin, but not SGLT2-selective inhibitor empagliflozin, attenuates platelet activation and thrombosis,” Journal of Clinical Investigation. DOI: 10.1172/JCI201899

Additional authors: Livia Stanger, Ph.D., Krista Goerger, Xu Zhang, M.D., Ph.D., Pooja Yalavarthi, Andrew Rickenberg, Adriana Yamaguchi, Ph.D., Mariane Flores Nascimento, Ph.D., Ashleigh Kilgore, Heeseo Kim, PharmD, Xiaokang Wu, M.D., Ph.D., Yanhong Guo, M.D., Ph.D., Anna R. Dahlgren, Ph.D., Jifeng Zhang, Ph.D., Jordan A. Shavit, M.D., Ph.D., all of University of Michigan.

Funding/disclosures: 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.