Diabetic Ketoacidosis and Related Events With Sotagliflozin Added to Insulin in Adults With Type 1 Diabetes: A Pooled Analysis of the inTandem 1 and 2 Studies.

Abstract

OBJECTIVE:

To evaluate the incidence and risk factors for diabetic ketoacidosis (DKA) and related adverse events (AEs) in adults with type 1 diabetes treated with sotagliflozin adjunctive to insulin.

RESEARCH DESIGN AND METHODS:

Data from two identically designed, 52-week, randomized studies were pooled and analyzed for DKA, changes in β-hydroxybutyrate (BHB), and percentage of patients with BHB >0.6 and >1.5 mmol/L. The patients were administered placebo, sotagliflozin 200 mg, or sotagliflozin 400 mg once daily.

RESULTS:

A total of 191 ketosis-related AEs were reported, and 98 underwent adjudication. Of these, 37 events (36 patients) were adjudicated as DKA, with an exposure-adjusted incidence rate of 0.2, 3.1, and 4.2 events per 100 patient-years for placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively. No patient died of a DKA event. From a baseline BHB of ∼0.13 mmol/L, sotagliflozin treatment led to a small median increase over 52 weeks (≤0.05 mmol/L at all time points). Of sotagliflozin-treated patients, approximately 47% and 7% had ≥1 BHB measurement >0.6 mmol/L and >1.5 mmol/L, respectively (vs. 20% and 2%, respectively, of placebo-treated patients). Subsequent to the implementation of a risk mitigation plan, annualized DKA incidence was lower versus preimplementation in both the sotagliflozin 200 and 400 mg groups.

CONCLUSIONS:

In patients with type 1 diabetes, confirmed DKA incidence increased when sotagliflozin was added to insulin compared with insulin alone. A lower incidence of DKA was observed following the implementation of an enhanced risk mitigation plan, suggesting that this risk can be managed with patient education.

• Authors: Anne L Peters, Darren K McGuire, Thomas Danne, Jake A Kushner, Helena W Rodbard, Ketan Dhatariya, Sangeeta Sawhney, Phillip Banks, Wenjun Jiang, Michael J Davies, Pablo Lapuerta
• Journal: Diabetes care (Diabetes Care) Vol. 43 Issue 11 Pg. 2713-2720 (11 2020) ISSN: 1935-5548 [Electronic] United States
• PMID: 32928957 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 by the American Diabetes Association.

Chemical References

• Glycosides
• Insulin, Regular, Human
• SLC5A1 protein, human
• Sodium-Glucose Transporter 1
• Sodium-Glucose Transporter 2 Inhibitors
• (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol
• 3-Hydroxybutyric Acid

Topics

• 3-Hydroxybutyric Acid (blood)
• Adult
• Diabetes Mellitus, Type 1 (drug therapy)
• Diabetic Ketoacidosis (blood, chemically induced, epidemiology)
• Double-Blind Method
• Drug Therapy, Combination (adverse effects)
• Female
• Follow-Up Studies
• Glycosides (administration & dosage, adverse effects)
• Humans
• Incidence
• Insulin, Regular, Human (administration & dosage)
• Male
• Sodium-Glucose Transporter 1 (antagonists & inhibitors)
• Sodium-Glucose Transporter 2 Inhibitors (administration & dosage, adverse effects)
• Treatment Outcome