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Effects of Sotagliflozin Combined with Intensive Insulin Therapy in Young Adults with Poorly Controlled Type 1 Diabetes: The JDRF Sotagliflozin Study.

ABSTRACT: Background: Young adults with type 1 diabetes (T1D) tend to have higher A1C than older adults and are at increased risk for diabetic ketoacidosis (DKA). Oral adjuncts to insulin have not been previously studied in this population. Methods: In this phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, adults aged 18-30 years with T1D and A1C ≥9.0% were randomly assigned to placebo (n = 42) or sotagliflozin 400 mg (n = 43), in addition to insulin for 12 weeks. Insulin doses were adjusted to meet glucose targets (preprandial 80-130 mg/dL, postprandial <180 mg/dL). The primary endpoint was change from baseline in A1C at week 12. Results: From a baseline of 9.8%, mean A1C decreased by 1.0% with placebo and 1.3% with sotagliflozin (-0.4% [95% confidence interval (CI): -0.8 to 0.1]; P = 0.10 vs. placebo). In the prespecified A1C ≤10.0% subgroup, the treatment difference was -0.8% (-1.3 to -0.2; P = 0.006), favoring sotagliflozin. Overall, relative to placebo, postprandial glucose (PPG) decreased by 56.6 mg/dL (-89.7 to -23.6; P < 0.001) and weight decreased by 2.37 kg (-3.5 to -1.2; P < 0.001). More patients achieved an A1C <7.0% with sotagliflozin (16.3%) than placebo (2.4%; P = 0.026). Rates of documented hypoglycemia and severe hypoglycemia were similar between groups. One DKA event occurred with placebo, and none occurred with sotagliflozin. Conclusions: In young adults with T1D and suboptimal glycemic control, sotagliflozin plus insulin for 12 weeks numerically improved A1C and significantly improved A1C goal attainment, PPG, and body weight. Sotagliflozin plus insulin was generally well tolerated without any episodes of DKA (NCT02383940).

SUBMITTER: Bode BW

PROVIDER: S-EPMC7864092 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:OBJECTIVE:Evaluate the efficacy and safety of the dual sodium-glucose cotransporter 1 (SGLT1) and SGLT2 inhibitor sotagliflozin in combination with optimized insulin in type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:The inTandem1 trial, a double-blind, 52-week phase 3 trial, randomized North American adults with T1D to placebo (n = 268), sotagliflozin 200 mg (n = 263), or sotagliflozin 400 mg (n = 262) after 6 weeks of insulin optimization. The primary end point was HbA1c change from baseline at 24 weeks. HbA1c, weight, and safety were also assessed through 52 weeks. RESULTS:From a mean baseline of 7.57%, placebo-adjusted HbA1c reductions were 0.36% and 0.41% with sotagliflozin 200 and 400 mg, respectively, at 24 weeks and 0.25% and 0.31% at 52 weeks (all P < 0.001). Among patients with a baseline HbA1c ?7.0%, an HbA1c <7% was achieved by 15.7%, 27.2%, and 40.3% of patients receiving placebo, sotagliflozin 200 mg, and sotagliflozin 400 mg, respectively (P ? 0.003 vs. placebo) at 24 weeks. At 52 weeks, mean treatment differences between sotagliflozin 400 mg and placebo were -1.08 mmol/L for fasting plasma glucose, -4.32 kg for weight, and -15.63% for bolus insulin dose and -11.87% for basal insulin dose (all P < 0.001). Diabetes Treatment Satisfaction Questionnaire scores increased significantly by 2.5 points with sotagliflozin versus placebo (P < 0.001) at 24 weeks. Genital mycotic infections and diarrhea occurred more frequently with sotagliflozin. Adjudicated diabetic ketoacidosis (DKA) occurred in 9 (3.4%) and 11 (4.2%) patients receiving sotagliflozin 200 and 400 mg, respectively, and in 1 (0.4%) receiving placebo. Severe hypoglycemia occurred in 17 (6.5%) patients from each sotagliflozin group and 26 (9.7%) patients receiving placebo. CONCLUSIONS:In a 1-year T1D study, sotagliflozin combined with optimized insulin therapy was associated with sustained HbA1c reduction, weight loss, lower insulin dose, fewer episodes of severe hypoglycemia, improved patient-reported outcomes, and more DKA relative to placebo (ClinicalTrials.gov, NCT02384941).

Project description:IntroductionThe hemochorial placenta provides a critical barrier at the maternal-fetal interface to modulate maternal immune tolerance and enable gas and nutrient exchange between mother and conceptus. Pregnancy outcomes are adversely affected by diabetes mellitus; however, the effects of poorly controlled diabetes on placental formation, and subsequently fetal development, are not fully understood.Research design and methodsStreptozotocin was used to induce hyperglycemia in pregnant rats for the purpose of investigating the impact of poorly controlled diabetes on placental formation and fetal development. The experimental paradigm of hypoxia exposure in the pregnant rat was also used to assess properties of placental plasticity. Euglycemic and hyperglycemic rats were exposed to ambient conditions (~21% oxygen) or hypoxia (10.5% oxygen) beginning on gestation day (gd) 6.5 and sacrificed on gd 13.5. To determine whether the interaction of hyperglycemia and hypoxia was directly altering trophoblast lineage development, rat trophoblast stem (TS) cells were cultured in high glucose (25 mM) and/or exposed to low oxygen (0.5% to 1.5%).ResultsDiabetes caused placentomegaly and placental malformation, decreasing placental efficiency and fetal size. Elevated glucose disrupted rat TS cell differentiation in vitro. Evidence of altered trophoblast differentiation was also observed in vivo, as hyperglycemia affected the junctional zone transcriptome and interfered with intrauterine trophoblast invasion and uterine spiral artery remodeling. When exposed to hypoxia, hyperglycemic rats showed decreased proliferation and ectoplacental cone development on gd 9.5 and complete pregnancy loss by gd 13.5. Furthermore, elevated glucose concentrations inhibited TS cell responses to hypoxia in vitro.ConclusionsOverall, these results indicate that alterations in placental development, efficiency, and plasticity could contribute to the suboptimal fetal outcomes in offspring from pregnancies complicated by poorly controlled diabetes.

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Effects of Sotagliflozin Combined with Intensive Insulin Therapy in Young Adults with Poorly Controlled Type 1 Diabetes: The JDRF Sotagliflozin Study.

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