Sotagliflozin Shows Benefit When Added to Insulin for Type 1 Diabetes

Sotagliflozin added to insulin therapy reduced the risk of hypoglycemia, a potentially life-threatening low-blood-sugar condition, in patients with Type 1 diabetes, according to a post-hoc analysis of clinical study data. The data were presented recently at the 85th Scientific Sessions of the American Diabetes Association meeting. Additionally, the effect appears consistent across eGFR subgroups, suggesting that sotagliflozin maintains this similar trend regardless of kidney function.

Type 1 diabetes is an autoimmune disease that affects about 2 million Americans, about 5% to 10% of all diabetes cases, according to the Centers for Disease Control and Prevention (CDC).

The aim of this post-hoc analysis was to evaluate the effect of kidney function on hypoglycemia risk in patients with Type 1 diabetes who were being treated with Lexicon Pharmaceuticals’ sotagliflozin as an adjunct to optimized insulin therapy.

Sotagliflozin is an inhibitor of SGLT2 and SGLT1, which are responsible for glucose regulation in the kidney and gastrointestinal tract, respectively.

Belinda Hardin, Pharm.D.

This analysis shows that adding sotagliflozin to insulin results in an improvement in A1C, M. Belinda Hardin, Pharm.D., senior director of medical communications at Lexicon, said in an interview. “Type 1 diabetics still desperately need control of A1C, even with the best therapies that they have available to them. We know that about 50% to 60% of patients are not reaching ADA targets for A1C.”

The American Diabetes Association (ADA) recommends a target for A1C of less than 7% for most adults.

Hardin also said that adding sotagliflozin to insulin results in improvement for time-in-range, a measurement to assess how long patients are within a targeted blood glucose range. The ADA recommendation is for at least 70% of a person’s day to be within time-in-range.

At baseline, most patients were only spending somewhere between 10 hours and 12 hours in time-in-range, Hardin said. Sotagliflozin adds between two hours and four hours to the time-in-range.

Researchers analyzed pooled data from inTandem 1 and inTandem 2, identically designed 52-week phase 3 clinical trials in which once-daily 200 mg and 400 mg doses of sotagliflozin were compared with placebo when added to optimized insulin therapy. In these studies, documented hypoglycemia was defined as blood glucose of ≤ 70 mg/dL and ≤ 55 mg/dL, and severe hypoglycemia per the ADA Level 3 definition.

In terms of adverse events, adding sotagliflozin to insulin increases the risk of patients developing diabetic ketoacidosis, a serious complication where the body is not able to use sugar for energy. The liver will begin to break down fat for fuel, which produces acids called ketones.

“Diabetic ketoacidosis was increased in both treatment arms,” Hardin said. “The good news is that it didn’t increase over the baseline that we were aware of.”

Related: FDA Issues Complete Response for Zynquista in Type 1 Diabetes

The increased risk for diabetic ketoacidosis from treatment with sotagliflozin was enough of a concern that it led to the FDA issuing a complete response letter in December 2024 as an adjunct to insulin therapy for glycemic control in adults with Type 1 diabetes and chronic kidney disease (CKD). A regulatory advisory board in October 2024 voted 11 to 3 against approval of sotagliflozin, saying the benefit did not outweigh the risks. If it had been approved, the therapy would have had the brand name of Zynquista.

Hardin said Lexicon is in ongoing discussions with the FDA about the NDA. “Our goal is to continue to collect the scientific data from previous trials, as well as the ongoing studies,” she said. “There are studies that continue with sotagliflozin in this patient population, and we are keeping the door open at the FDA to gather the additional data that they would like to see. The pathway is still open.”

Sotagliflozin was approved by the FDA as Inpefa in May 2023 as a once-daily oral tablet that reduces the risk of cardiovascular death and hospitalization for heart failure in adults with heart failure or Type 2 diabetes, chronic kidney disease, and other cardiovascular risk factors.