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LISBON -- Among patients with type 1 diabetes, oral sotagliflozin -- a combination SGLT1 and SGLT2 inhibitor -- when added to insulin therapy helped to reduce hemoglobin A1c levels, researchers reported here.

Patients treated with 400 mg/day of sotagliflozin for 24 weeks in additional to pump or injectable insulin were more likely to achieve the primary composite endpoint of HbA1c less than 7% with no episodes of severe hypoglycemia or diabetic ketoacidosis, compared to those on placebo, according to lead author Satish K. Garg, MD of the University of Colorado Denver, and colleagues.

Meeting this endpoint were 200 of 699 patients or 28.6% in the active drug group versus 107 of 703 or 15.2% taking placebo. The between-group difference of 13.4 percentage points was highly significant (95% CI 9.0-17.8, P<0.001).

Findings from the global were presented here at the European Association for the Study of Diabetes meeting and simultaneously published online in the .

If approved, sotagliflozin would be the first oral medication for type 1 diabetes to reach the market, the investigators noted in the NEJM paper.

"The rationale for this double-blind clinical trial, other than to achieve regulatory approval, was to address the inability of more than two thirds of people with type 1 diabetes to achieve a glycated hemoglobin level of less than 7%," wrote David M. Nathan, MD, of Massachusetts General Hospital, in an .

Following a 2-week run-in period, 1,402 participants were randomized 1:1 to 400 mg/day of sotagliflozin or placebo groups, all of whom had type 1 diabetes for a minimum of 1 year, HbA1c of 7.0%-11.0%, BMI ≥18.5, and were receiving basal insulin at a stable dose for 2 weeks prior.

Regardless of type of insulin -- pump or multiple daily injections -- more participants on sotagliflozin treatment reached the "net benefit" represented by the composite endpoint:

• Insulin pump users (15.9% between group difference, 95% CI 8.6%-23.3%)
• Others (11.8%, 6.1%-17.4%)

A higher proportion of patients on sotagliflozin treatment also reported benefits regarding HbA1c alone (difference -0.46 percentage points), body weight (difference −2.98 kg [6.57 lb]), systolic blood pressure (−3.5 mm Hg), and mean daily bolus dose of insulin (−2.8 units/day) after 24 weeks versus placebo (P≤0.002 for all comparisons).

Garg told 番茄社区 that his group wasn't surprised that sotagliflozin treatment reached its primary endpoint, as yielded similar results. However, his group was surprised to see all prespecified secondary endpoints reflect in favor of sotagliflozin treatment.

Although the overall rate of adverse events were generally similar between both groups (55.1% sotagliflozin versus 52.5% placebo), serious adverse events were more common with the active drug (6.9% versus 3.3%). The rate of acidosis-related adverse events was also higher in the treatment groups at 24 weeks (8.6% versus 2.4%), as well as the overall rate of at least one positively adjudicated episodes of diabetic ketoacidosis (3.0% versus 0.6%). Incidence of at least one episode of severe hypoglycemia was slightly higher with sotagliflozin (3.0% versus 2.4%).

These risks should not be taken lightly, Nathan suggested, noting that these risks have both "immediate and potentially serious clinical effects."

"Unfortunately, the results of this trial suggest that the increased risk of ketoacidosis counterbalances the increased likelihood of achieving a glycated hemoglobin level of less than 7%," he wrote, adding that "there is little to suggest that the risk of ketoacidosis would be mitigated over time."

Despite the promising findings of the trial findings, these studies have not been able to look at cardiovascular outcomes in the type 1 population. However, "there may be some post-marketing studies if and when the drug is approved by the FDA next year," said Garg.

Drugmaker Lexicon Pharmaceuticals said it planned to file marketing applications worldwide in the first half of 2018 for the type 1 diabetes indication. A licensing agreement between Lexicon and Sanofi gives the latter firm sole responsibility for developing sotagliflozin for type 2 diabetes. Phase III studies for that indication are .