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.

Pharmacokinetics, Pharmacodynamics, Safety and Tolerability of Sotagliflozin After Multiple Ascending Doses in Chinese Healthy Subjects

“… 19 , 30 An increased risk of diabetic ketoacidosis has only been observed with sotagliflozin, specifically in patients with type 1 diabetes. 21 The adverse event profile is generally consistent with other SGLT inhibitors. In the present study, none of these AEs was observed in Chinese healthy subjects.…”

“… 18 , 19 However, sotagliflozin is associated with the following adverse reactions including diarrhoea, genital mycotic infections, urinary tract infections, hypotension/volume depletion, increased serum creatinine and decreased estimated glomerular filtration rate (eGFR) occurred after initiating sotagliflozin, and especially diabetic ketoacidosis (in patients with type 1 diabetes). 13 , 19 , 21 , 22 The safety profile of sotagliflozin is generally consistent with that observed with selective SGLT2 inhibitors, except for an increased incidence of diarrhea likely associated with partial SGLT1 inhibition. 23 …”

“…18,19 However, sotagliflozin is associated with the following adverse reactions including diarrhoea, genital mycotic infections, urinary tract infections, hypotension/volume depletion, increased serum creatinine and decreased estimated glomerular filtration rate (eGFR) occurred after initiating sotagliflozin, and especially diabetic ketoacidosis (in patients with type 1 diabetes). 13,19,21,22 The safety profile of sotagliflozin is generally consistent with that observed with selective SGLT2 inhibitors, except for an increased incidence of diarrhea likely associated with partial SGLT1 inhibition. 23 Sotagliflozin is a new class of medication for the treatment of DM with the unique dual inhibiting effects of both SGLT1 and SGLT2, which has its approval in the European Union (EU) as an adjunct to insulin in patients with T1DM with a body mass index (BMI)≥27 kg/m 2 who have failed to achieve adequate glycaemic control despite optimal insulin therapy.…”

The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes

“…The favorable safety profile of TTP399 stands in contrast to what has been observed in trials of other promising adjunctive agents, such as sodium-glucose co-transporter 1 and 2 inhibitors and glucagon-like peptide-1 receptor agonists, for the treatment of type 1 diabetes ( 25 – 27 ). Although both classes improve glycemic control with placebo-adjusted changes in HbA 1c comparable to those observed with TTP399, sodium-glucose co-transporter inhibitors are associated with increased rates of ketosis and DKA, and glucagon-like peptide-1 receptor agonists are associated with increased rates of hypoglycemia and frequent hyperglycemic episodes associated with ketosis ( 25 – 30 ). The scarcity of AEs during treatment with TTP399 underscores the potential for TTP399 in the treatment of type 1 diabetes.…”

The Reporting Frequency of Ketoacidosis Events with Dapagliflozin from the European Spontaneous Reporting System: The DAPA-KETO Study

“…Moreover, ketoacidosis adverse events result in a complete resolution in most ICSRs despite a little more of 30% had an unknown outcome that could affect the proportion of cases with a complete resolution that, therefore, cannot be perfectly estimated. Accordingly, in the literature, patients are used to restart the treatment with SGLT2 inhibitors following the resolution of the event [ 32 ]. However, we could not establish with our data if the treatment was restarted again due to our study limitations.…”