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

Diabetes Care. 2020 Nov;43(11):2713-2720. doi: 10.2337/dc20-0924. Epub 2020 Sep 14.

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.

Trial registration: ClinicalTrials.gov NCT02384941 NCT02421510.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • 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

Associated data

  • figshare/10.2337/figshare.12824342
  • ClinicalTrials.gov/NCT02384941
  • ClinicalTrials.gov/NCT02421510