Do the risks of sotagliflozin outweigh benefits for type 1 diabetes?

Last Updated: 2017-09-18

By Marilynn Larkin

NEW YORK (Reuters Health) - Adding sotagliflozin to insulin may help improve insulin control, weight, and blood pressure in people with type 1 diabetes, but the drug also increases the rates of ketoacidosis, gastrointestinal problems and other adverse events, according to results of a phase III trial.

Sotagliflozin, an oral inhibitor of sodium-glucose cotransporters (SGLT) 1 and 2, is being codeveloped by Lexicon Pharmaceuticals, which funded the trial, and Sanofi.

Dr. Paul Strumph, Lexicon's VP of Clinical Development, led the multicenter study, which randomized patients with type 1 diabetes on any type of insulin treatment to receive sotagliflozin 400 mg daily (699 participants) or placebo (703).

For both groups, mean age was 43, about half were women, 88% were white, and mean duration of diabetes was about 20 years. Glycated hemoglobin, weight, fasting glucose, blood pressure, daily insulin dose, and type of therapy (about 60% subcutaneous, 40% pump) also were similar between the groups.

The primary endpoint was a glycated hemoglobin level <7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary endpoints included the change from baseline in glycated hemoglobin level, body weight, systolic blood pressure, and mean daily bolus dose of insulin.

As reported September 13 at the European Association for the Study of Diabetes 2017 annual meeting and published simultaneously in the New England Journal of Medicine, significantly more sotagliflozin than placebo recipients reached the primary endpoint (28.6% vs. 15.2%).

Similarly, mean reductions from baseline were significantly greater with sotagliflozin than with placebo for glycated hemoglobin (by 0.46 percentage points), weight (by 2.98 kg), systolic blood pressure (by 3.5 mmHg), and mean daily bolus dose of insulin (by 2.8 units per day).

The rate of severe hypoglycemia was similar in both groups, whereas the rate of hypoglycemia with a blood glucose level of 55 mg/dL or lower was significantly lower in the sotagliflozin group.

However, the rate of diabetic ketoacidosis was higher with sotagliflozin than with placebo (3.0% vs. 0.6%), as were acidosis-related adverse events at week 24 (8.6% vs. 2.4%). Similarly, the rate of gastrointestinal events was higher in the sotagliflozin group (diarrhea occurred in 4.1% vs. 2.3% with placebo), as was the rate of genital mycotic infections (6.4% vs. 2.1%).

More sotagliflozin recipients than placebo recipients had serious adverse events (6.9% vs. 3.3%), including two major adverse cardiovascular events with the drug. Withdrawal from the trial because of an adverse event also was more common with sotagliflozin (6.3% vs. 2.3%).

"We look forward to aggressively moving ahead toward filing for marketing approval both in the United States and in Europe in the first half of 2018 for type 1 diabetes," Dr. Strumph told Reuters Health by email. "Our plan is to make sotagliflozin available as soon as possible following approval."

"While it's too early to speculate on what the label for sotagliflozin would be if approved," he added, "it is being evaluated as an adjunct to insulin in type 1 diabetes and is not being studied as an insulin replacement in this patient population."

Dr. David Nathan, author of an accompanying editorial, said in an email to Reuters Health, "The addition of (this) currently unapproved SGLT-2 dual inhibitor to type 1 diabetes care modestly improves glycemic control, but at a cost of substantially more cases of diabetic ketoacidosis, dehydration and genital mycotic infections, not to mention the added financial cost of adjunctive therapy."

"The ancient caution of primum non nocere - first, do no harm - should be kept in mind," stated Dr. Nathan, director of the Diabetes Center and the Clinical Research Center at Massachusetts General Hospital in Boston.

"In our enthusiastic pursuit of lower HbA1c levels, which remains very important, clinicians must be cautious not to adopt therapies that cause more or different complications," he concluded.

Many of the study authors have received fees from Lexicon, Sanofi, or both companies.

SOURCES: http://bit.ly/2yjiEt7 and http://bit.ly/2fuIkLA

N Engl J Med 2017.