SAN DIEGO (FRONTLINE MEDICAL NEWS) The addition of 400 mg daily sotagliflozin to optimized insulin therapy significantly improved the chances of lowering hemoglobin A1c levels to less than 7% without severe diabetic ketoacidosis or hypoglycemia, compared with placebo, in a pivotal phase III trial of adults with type 1 diabetes.

After 24 weeks, 58 (22%) of patients on placebo achieved this combined endpoint, compared with 44% of patients who received 400 mg oral daily sotagliflozin (P less than .001) and 34% of those who received 200 mg (P = .002), John B. Buse, MD, PhD, reported at the annual scientific sessions of the American Diabetes Association. “Sotagliflozin significantly reduced hemoglobin A1c in the setting of optimized insulin therapy, with a safety profile that supports further clinical development,” said Dr. Buse, lead investigator of the Tandem1 trial.

Sotagliflozin (LX4211, Lexicon Pharmaceuticals) is an oral dual inhibitor of sodium-glucose transporter 1 (SGLT1), which is the main gastrointestinal transporter of glucose and galactose, and SGLT2, which handles 90% of renal glucose reabsorption, said Dr. Buse, professor of medicine at the University of North Carolina at Chapel Hill. “Inhibition of SGLT1 is done locally as the pill tumbles through the gastrointestinal tract, while SGLT2 inhibition is systemic,” he added. During a phase II placebo-controlled, dose-ranging trial – Tandem4 – patients with type 1 diabetes who received sotagliflozin plus optimized insulin for 12 weeks experienced significant reductions in HbA1c levels, significant rises in 24-hour urinary glucose excretion, and modest but statistically significant, dose-dependent decreases in body weight. However, as a group, sotagliflozin recipients also had three episodes of severe hypoglycemia and one episode of diabetic ketoacidosis (DKA), compared with one episode of DKA and none of severe hypoglycemia during the placebo run-in period.

To further evaluate the efficacy and safety of adjunctive sotagliflozin for type 1 diabetes, Dr. Buse and his associates randomly assigned 793 patients from 75 North American sites to receive either placebo or treatment at 200 mg or 400 mg for 24 weeks. Patients and investigators were blinded as to treatment arm. Patients received optimized insulin, and the trial arms were demographically and clinically similar at baseline. The average age was 46 years, mean body mass index was 30 kg per m2, average daily insulin dose was 0.73 U per kg, and mean baseline HbA1c was 7.58 % (standard deviation, 0.73%).

By week 24, HbA1c levels fell by an average of 8% on placebo, 43% on 200 mg sotagliflozin, and 49% on 400 mg sotagliflozin, Dr. Buse reported. “The decrease from baseline was highly significant at both doses of sotagliflozin, compared with placebo,” he noted. Adjunctive sotagliflozin therapy also led to significant reductions in bolus insulin doses, fasting blood glucose levels, and body weight as compared with placebo. Drops in body weight averaged 1.6 kg at 200 mg and 2.7 kg at 400 mg, while placebo patients gained an average of 0.8 kg.

There were no deaths during the trial. Rates of treatment-associated adverse events were similar across groups, and serious adverse events affected 3% of placebo patients, 4% of 200-mg patients, and 7% of 400-mg patients. In all, 7% of placebo recipients experienced severe hypoglycemia, compared with 4%-5% of patients on sotagliflozin. The incidence of DKA was 0% on placebo and 1%-3% on sotagliflozin, with a higher rate among patients on pumps, Dr. Buse noted. Most cases of DKA were considered mildly to moderately severe, with blood glucose levels under 250 mg per dL, he added. Sotagliflozin also was associated with dose-dependent increases in rates of diarrhea and genital mycotic infections, which reached about 10% in the 400-mg arm. However, less than 1% of patients stopped treatment because of either adverse event.

“This is the first report of a successful phase III trial of an oral antidiabetic as an adjunct to insulin therapy for type 1 diabetes,” Dr. Buse commented. Sotagliflozin met all prespecified endpoints in the trial, and the 400-mg dose significantly outperformed placebo on each endpoint, he added. A second phase III trial of sotagliflozin (inTandem2) is ongoing, and investigators plan to present pooled data from both trials later this year. Meanwhile, a third phase III trial (inTandem3) is comparing 400 mg sotagliflozin or placebo for patients receiving any type of insulin therapy.

Lexicon Pharmaceuticals developed sotagliflozin and funded the study. Dr. Buse disclosed research funding from Lexicon, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, and several other pharmaceutical companies.