Sotagliflozin combined with insulin for type 1 diabetes: one-year results of inTandem1 study show decreased HbA1c levels, lower risk of severe hypoglycemia.
Sotagliflozin is the second SGLT-2 inhibitor to show positive results when adding it to insulin for T1D. What makes it unique is that it is the only SGLT-2 inhibitor that is a dual inhibitor with SGLT-1.
People with type 1 diabetes (T1D) who take 200 mg or 400 mg of sotagliflozin in addition to optimized insulin therapy have statistically lower HbA1c levels and weight, as well as low incidence of severe hypoglycemia after a year of treatment, compared to those who take a placebo with optimized insulin, according to the study, “Fifty-Two-Week Efficacy and Safety of Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Adults with Type 1 Diabetes (inTandem1),” presented at the American Diabetes Association’s (ADA’s) 78th Scientific Sessions at the Orange County Convention Center. The study results are outlined in detail in an article published online in Diabetes Care, the ADA’s peer-reviewed research journal dedicated to diabetes treatment and prevention.
Sotagliflozin is an investigational dual inhibitor of sodium glucose transport proteins 1 and 2 (SGLT-1 and SGLT-2)—two proteins responsible for glucose regulation. Inhibition of SGLT-1 delays and reduces glucose absorption in the proximal intestine, improving postprandial (post meal) glycemic management. SGLT-2 inhibition results in loss of glucose into the urine. Sotagliflozin is the first dual SGLT-1/SGLT-2 inhibitor to be extensively studied in humans.
The inTandem1 study, a double-blind, phase 3 trial conducted at 75 sites in the U.S. and Canada, compared the safety and efficacy of two different doses of oral sotagliflozin—each used in addition to optimized insulin—to optimized insulin alone. The study enrolled a total of 793 adults with T1D who used an insulin pump or were on multiple-injection therapy. The participants had HbA1c levels between 7.0 and 11 percent prior to the study. After six weeks of insulin optimization, participants were randomly assigned to one of three groups: 268 received a placebo; 263 received 200 mg of sotagliflozin; and 262 received 400 mg of sotagliflozin, each taken once daily before the first meal of the day.
In 2017, a comparison of the treatment groups after 24 weeks was reported, and the results for the primary endpoints of inTandem 1, 2 and 3 were disclosed. After 24 weeks, HbA1c levels, body weight, and systolic blood pressure were significantly reduced with sotagliflozin added to optimized insulin compared to optimized insulin alone.
After 52 weeks, patients who received sotagliflozin in addition to optimized insulin had sustained reduction in HbA1c levels and body weight, and lower total daily insulin dose compared to optimized insulin alone.
Sotagliflozin use was also associated with fewer low glucose events requiring assistance (severe hypoglycemia), despite lower average blood glucose. A total of 17 participants, each from the 200 mg sotagliflozin and 400 mg groups (6.5 percent from each group), reported episodes of severe hypoglycemia compared to 26 participants (9.7 percent) from the placebo group, who reported severe hypoglycemia events.
Researchers noted that there is an increased risk of diabetic ketoacidosis (DKA) through SGLT-2 inhibition, and the study results showed that DKA was seen in a greater proportion of patients treated with sotagliflozin and insulin. Of the participants, nine patients (3.4 percent) from the 200 mg group and 11 patients (4.2 percent) in the 400 mg group experienced DKA compared to one patient (0.4 percent) from the placebo group. According to the study authors, this increased risk of DKA could potentially be managed with patient education and increased monitoring.
Overall, the data indicated that more of the patients taking sotagliflozin added to optimized insulin therapy achieved the combined goal of an average blood glucose below the ADA-recommended target without severe hypoglycemia and without DKA. For net clinical benefit, 69 patients (26.2 percent) from the 200 mg group and 85 (32.4 percent) from the 400 mg group achieved this endpoint compared to 51 (19 percent) from the placebo group at 52 weeks.
Lead study investigator John Buse, MD, PhD, director of the Diabetes Center, director of the NC Translational and Clinical Sciences Institute, and executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill added that, “More than 1.25 million adults in the U.S. live with T1D, and more than 75 percent of these people who use insulin alone have glucose levels above target…. Despite recent advances, the challenges of T1D management, specifically hypoglycemia or fear of hypoglycemia, weight gain, glucose variability, and patient burden, prevent many patients from reaching their treatment goals. The profile of sotagliflozin to improve glucose management beyond what can be achieved with intensified insulin alone while addressing these challenges has the potential to improve the lives of people with T1D.”
The final results showed that in a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo.
- Sotagliflozin is the first dual inhibitor submitted to the FDA for approval; its expected FDA action date under the Prescription Drug User Fee Act (PDUFA) is anticipated to be March 22, 2019.
- Adding sotagliflozin combined with insulin therapy allowed for less insulin, which means there will most likely be less hypoglycemia, improved glycemia and weight loss. Among patients with a baseline HbA1c ≥7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively, at 24 weeks.
ADA Scientific Meeting June 24, 2018