EASD 2018: InTandem 1 Shows Promise for Adjunctive Therapy in Type 1 Diabetes
Sotagliflozin helps patients achieve glycemic targets, lose weight, and improve blood pressure control
October 2, 2018—Berlin, Germany—Sotagliflozin can help patients with type 1 diabetes attain their HbA1c goals without increasing the risk of severe hypoglycemia, according to the results of the InTandem 1 trial presented at the 54th Annual Meeting of the European Association for the Study of Diabetes, taking place here from Oct 1 – 5, 2018.
“There is a huge unmet need in the treatment of patients with type 1 diabetes,” presenter Satish K. Garg, MD, from the University of Colorado in Denver, told Elsevier’s PracticeUpdate. According to a soon-to-be published investigation he is currently working on, “More than two-thirds of patients [with type 1 diabetes] do not achieve target HbA1s, and more than two-thirds of patients in the U.S. are getting overweight and obese. We are not reaching targets and, if anything, things have gotten worse in the last 5 years. … We need to provide additional therapies for patients with type 1 diabetes.”
The ideal agent, he noted, would help patients achieve glycemic targets without causing weight gain, severe hypoglycemia, or diabetic ketoacidosis.
Sotagliflozin is currently under investigation for the treatment of type 1 diabetes. It is the first drug to combine both SGLT-1 inhibitor and SGLT-2 inhibitor-2 effects. SGLT-2 inhibitors are currently available for the treatment of type 2 diabetes. These agents work primarily by inhibiting absorption of glucose by the kidneys, allowing excess glucose to be eliminated from the body via the urine. Sotagliflozin has an additional SGLT-1 inhibitor effect, which acts primarily on the gut, delaying and blunting absorption of glucose and galactose.
“This drug does not require insulin for its action,” said Dr. Garg. This differentiates it from the other antidiabetes drugs that have been unsuccessfully tried for use as adjunctive therapy in type 1 diabetes. These include metformin, GLP-1 receptor agonists, and DPP-4 inhibitors.
For this double-blind, 52-week North American trial, 793 adults with type 1 diabetes who were being treated with multiple daily insulin injections (40%) or an insulin pump (60%) were randomized to placebo (n = 268), sotagliflozin 200 mg (n=263), or sotagliflozin 400 mg (n=262) once daily. Prior to randomization, participants underwent a 6-week insulin optimization phase. Patients were not excluded from the trial if their HbA1c dropped by > 0.5% or to > 7.5% during the optimization phase, which differentiated this trial from several others investigating similar agents. The trial is supported by Lexicon Pharmaceuticals, Inc./Sanofi, manufacturers of sotagliflozin.
The primary endpoint was change from baseline in HbA1c at week 24. During this period, HbA1c levels were masked. Other endpoints included HbA1c, body weight, bolus insulin dose, and fasting plasma glucose changes at week 52 after HbA1c was unmasked. In addition, the investigators evaluated patient-reported outcomes and net clinical benefit, defined as the proportion of patients who had an HbA1c < 7.0% without having severe hypoglycemia or diabetic ketoacidosis.
Baseline characteristics were similar among the three groups of patients. Compared with placebo, patients taking sotagliflozin 200 and 400 mg had improvement in HbA1c and patient satisfaction at week 24. The least squares mean difference in HbA1c, compared with placebo, was -0.36% ± 0.05; P< .001 for the 200 dose of sotagliflozin and -0.41% ± 0.05; P< .001, for the 400 mg dose.
At week 52, patients taking sotagliflozin had significantly reduced HbA1c, weight, bolus insulin, fasting plasma glucose, and patient distress, compared to placebo. For weight loss, the least squares mean difference, compared to placebo, was -3.14 kg ± 0.34; P< .001 for the 200 mg dose and -4.32 kg ± 0.35; P< .001, for the 400 mg dose.
Among patients with systolic blood pressure > 130 mm Hg at baseline, blood pressure also dropped significantly at 24 and 52 weeks.
The proportion of patients who experienced a net clinical benefit was 26.2% with the 200 mg dose of sotagliflozin and 32.4% with the 400 mg dose compared with 19.0% among patients in the placebo group (P < .05 for each comparison with placebo). The highest incidence of severe hypoglycemia occurred in the placebo arm (9.7% vs 6.5% in each sotagliflozin arm).
The rate of treatment-emergent adverse events was 81.7% with 200 mg of sotagliflozin, 79.8% with the 400 mg dose, and 80.6% with placebo. Diarrhea and genital mycotic infections are the most troublesome side effects with currently available SGLT-2 inhibitors. In this study, rates of diarrhea were 8.4% with the 200 mg dose, 10.3% with the higher dose, and 6.7% with placebo. Rates of genital mycotic infections were 9.1% with the 200 mg dose, 13.0% with the 400 mg dose, and 3.4% with placebo. There were also more episodes of diabetic ketoacidosis with sotagliflozin 200 mg (3.4%) and 400 mg (4.2%) compared with placebo (0.4%). Most of the time, ketoacidosis was associated with serum glucose levels above 14 mmol/L. Dr. Garg emphasized the need to minimize the risk of ketoacidosis using proper patient education and monitoring.
“We finally might have a drug that might allow a nearly twofold increase in the number of patients achieving target HbA1cs without increasing hypoglycemia,” said Dr. Garg. “… However, we have to keep in mind that with SGLT-2 inhibitors, there will always be a high risk of genital mycotic infection. So, one must take the necessary precautions … and have a proper mitigation plan [for diabetic ketoacidosis].”
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