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ORLANDO – Treatment with two different doses of sotagliflozin paired with insulin therapy was associated with statistically significant A1C reductions in patients with type 1 diabetes. researchers reported here.

In the inTandem1 trial of patients treated with multiple daily insulin injections (40%) or pump (60%), the 200-mg daily dose of sotagliflozin (Zynquista) lowered HbA1c about 0.25% more than placebo while the 400-mg dose lowered HbA1c 0.31% more than placebo after 52 weeks therapy (P<0.001), according to John Buse, MD, of the University of North Carolina School of Medicine at Chapel Hill, and colleagues.

Net clinical benefit -- the percentage of patients with an HbA1c less than 7% at week 52 who did not experience hypoglycemia or diabetic ketoacidosis -- was also significantly higher than placebo with the high dose of sotagliflozin, Buse said at a press conference American Diabetes Association annual meeting.

At week 52 week, 19% of the 268 patients who had been assigned to placebo had achieved a net benefit compared with 26.2% of the 263 patients treated with sotagliflozin 200 mg (P=0.05) and 32.4% of 262 patients who were taking 400 mg of sotagliflozin (P<0.001), Buse said. The medications were taken once daily before the first meal.

However, treatment with the study drug was associated with increases in diabetic ketoacidosis (DKA).

Sotagliflozin is a combination SGLT1 and SGLT2 inhibitor, developed as adjunct therapy to insulin. The a New Drug Application for sotagliflozin in May 2018. Findings from the inTandem3 trial were presented at the 2017 European Association for the Study of Diabetes meeting and published in the .

"More than 1.25 million adults in the United States live with type 1 diabetes, and more than 75% of these people who use insulin alone have blood glucose levels above target," Buse said. "Despite recent advances, the challenges of type 1 diabetes management -- specifically hypoglycemia or fear of hypoglycemia, weight gain, glucose variability and patient burden -- prevent many patients from reaching treatment goals. The profile of sotagliflozin to improve glucose control beyond what can be achieved with intensified insulin alone, while addressing these challenges has the potential to improve the lives of people with type 1 diabetes."

The inTandem1 trial was conducted at 75 sites in the U.S. and Canada, and enrolled 793 adults with type 1 diabetes treated with multiple daily insulin injections or pump. They were randomized 1:1:1 to placebo (n=268), sotagliflozin 200 mg (n=263), or sotagliflozin 400 mg (n=262) once daily after 6 weeks of insulin optimization.

The primary endpoint was change from baseline in A1C at week 24, with others endpoints being A1C, weight, bolus insulin, and fasting plasma glucose (FPG) changes at week 52, and net clinical benefit, which assessed the proportion of patients with A1C <7.0% without severe hypoglycemia or DKA.

All the patients had insulin intensified during a 6-week run-in phase in which average HbA1c was about 8.2%. The intensification reduced the HbA1c to about 7.5%. After 52 weeks, the placebo patients' HbA1c had barely moved the needle, while the patients treated with sotagliflozin has significant declines in their HbA1C, Buse reported.

Compared with placebo, both doses of the study drug improved A1C and patient satisfaction at week 24, and reduced A1C, weight, bolus insulin, FPG, and patient distress at week 52.

In terms of DKA, 3.4% of the patients on 200 mg sotagliflozin experienced at least one bout, as did 4.2% of patients on the 40- mg dose of sotagliflozin versus one patient in the placebo arm.

Severe hypoglycemia was more common in the placebo patients who were on insulin therapy alone -- about 10% of those patients versus 6.5% of the sotagliflozin patients at both doses.

Buse noted that "the small, but increased, risk of diabetic ketoacidosis can be potentially mitigated with proper education and ketone monitoring."

Bernard Zinman, MD, of Mount Sinai Hospital and the University of Toronto, told 番茄社区app that the incidence of ketoacidosis in the trial was worrisome to him.

"I am concerned about the safety of these drugs when you get to the general population," said Zinman, who was not involved in the study. "In this study, they took incredible care to make sure people monitored their ketones, and a bunch of things, and yet they still had incidents of ketoacidosis. I'd be concerned that in the regular clinical setting the rates of ketoacidosis could be unacceptably high."

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