Development of sotagliflozin, a dual sodium-dependent glucose transporter 1/2 inhibitor

Abstract

The sodium-dependent glucose transporter 2 (SGLT2) inhibitors are an important emerging class for the treatment of diabetes. Development of SGLT2 inhibitors has been oriented around a desire for high selectivity for the SGLT2 protein relative to the SGLT1 protein. More recently, genetic and pharmacology research in mice has indicated that gastrointestinal SGLT1 inhibition may also be an appropriate therapeutic target to treat diabetes. Combining SGLT1 and SGLT2 inhibition in a single molecule would provide complementary insulin-independent mechanisms to treat diabetes. Therefore, sotagliflozin (LX4211) has been developed as a dual inhibitor of SGLT1 and SGLT2. The differentiating clinical features of dual inhibitor of SGLT1 and SGLT2 include a large postprandial glucose reduction, elevation of glucagon-like peptide 1 and modest urinary glucose excretion. These features may have clinical implications for the use of sotagliflozin in the treatment of both type 1 and type 2 diabetes.

Sotagliflozin: a dual sodium‐glucose co‐transporter‐1 and ‐2 inhibitor for the management of Type 1 and Type 2 diabetes mellitus

“…In individuals with Type 2 diabetes, a single 300‐mg dose of sotagliflozin led to a 56‐g increase in 24‐h urinary glucose excretion relative to baseline , consistent with SGLT2 inhibition. This is greater than the highest recorded 24‐h urinary glucose excretion of 44 g/day after a 300‐mg dose in healthy individuals , likely attributable to the upregulation of transporters in people with diabetes. Nonetheless, compared with SGLT2 inhibitors, the effect appears modest , probably as a result of the inhibition of intestinal glucose absorption by SGLT1 leading to a lower concentration of circulating glucose for filtration by the kidneys.…”

Beneficial effects of sodium–glucose cotransporter 2 inhibitors for preservation of pancreatic β‐cell function and reduction of insulin resistance

“…However, we think it remains to be determined whether such differences have a substantial impact on our body. In addition, although it seems that high selectivity for SGLT2 over SGLT1 is superior to low selectivity, dual SGLT1/2 inhibitors have also been developed …”

A Safety Evaluation of Empagliflozin for the Treatment of Type 2 Diabetes

“…Lastly, whether dual inhibition of SGLT1 and SGLT2 would improve upon efficacy and/or safety remains to be determined, and is the focus of the sotagliflozin development program presently limited to Phase III evaluation in patients with type 1 diabetes. [45]…”