Effects of Sotagliflozin Added to Insulin in Patients with Type 1 Diabetes

Background; In most patients with type 1 diabetes, adequate glycemic control is not achieved with insulin therapy alone. We evaluated the safety and efficacy of sotagliflozin, an oral inhibitor of sodium-glucose cotransporters 1 and 2, in combination with insulin treatment in patients with type 1 diabetes. Methods; In this phase 3, double-blind trial, which was conducted at 133 centers worldwide, we randomly assigned 1402 patients with type 1 diabetes who were receiving treatment with any insulin therapy (pump or injections) to receive sotagliflozin (400 mg per day) or placebo for 24 weeks. The primary end point was a glycated hemoglobin level lower than 7.0% at week 24, with no episodes of severe hypoglycemia or diabetic ketoacidosis after randomization. Secondary end points included the change from baseline in glycated hemoglobin level, weight, systolic blood pressure, and mean daily bolus dose of insulin. Results; A significantly larger proportion of patients in the sotagliflozin group than in the placebo group achieved the primary end point (200 of 699 patients [28.6%] vs. 107 of 703 [15.2%], P<0.001). The least-squares mean change from baseline was significantly greater in the sotagliflozin group than in the placebo group for glycated hemoglobin (difference, -0.46 percentage points), weight (-2.98 kg), systolic blood pressure (-3.5 mm Hg), and mean daily bolus dose of insulin (-2.8 units per day) (P≤0.002 for all comparisons). The rate of severe hypoglycemia was similar in the sotagliflozin group and the placebo group (3.0% [21 patients] and 2.4% [17], respectively). The rate of documented hypoglycemia with a blood glucose level of 55 mg per deciliter (3.1 mmol per liter) or below was significantly lower in the sotagliflozin group than in the placebo group. The rate of diabetic ketoacidosis was higher in the sotagliflozin group than in the placebo group (3.0% [21 patients] and 0.6% [4], respectively). Conclusions; Among patients with type 1 diabetes who were receiving insulin, the proportion of patients who achieved a glycated hemoglobin level lower than 7.0% with no severe hypoglycemia or diabetic ketoacidosis was larger in the group that received sotagliflozin than in the placebo group. However, the rate of diabetic ketoacidosis was higher in the sotagliflozin group. (Funded by Lexicon Pharmaceuticals; inTandem3 ClinicalTrials.gov number, NCT02531035)

Efficacy and Safety of Dapagliflozin by Baseline Insulin Regimen and Dose: Post Hoc Analyses from DECLARE-TIMI 58

   Objective: The cardiorenal benefits of adding SGLT2 inhibitors to patients on insulin, particularly those on intensive regimens which include short acting (SA) insulin have not been explored. Research design and methods: The DECLARE-TIMI 58 trial randomized 17,160 patients with type 2 diabetes to dapagliflozin or placebo for a median follow-up of 4.2 years. Cardiovascular, renal, metabolic and safety outcomes with dapagliflozin vs. placebo by insulin dose and regimen were studied by Cox regression models. Results: The study included 7,013 insulin users at baseline, with 4,650 (66.3%) patients on regimens including SA insulin. Insulin doses varied with 2,443 (34.8%) patients receiving 1 IU/kg. Dapagliflozin reduced cardiovascular death/hospitalization for heart failure among overall insulin users (HR [95% CI] 0.82[0.69-0.97]), and consistently in patients on insulin regimens with or without SA insulin (HR 0.83[0.67-1.03] and 0.78[0.57-1.07] respectively, Pinteraction= 0.75). No heterogeneity was observed by insulin dose (Pinteraction = 0.43). The HR for major adverse cardiovascular events with dapagliflozin among insulin users (HR 0.84[0.74-0.97]) was similar irrespective of regimen or dose (Pinteraction 0.75 and 0.07, respectively). Dapagliflozin reduced the rate of adverse renal outcomes overall, and consistently across subgroups of insulin users. Decreases in HbA1c, weight and systolic blood pressure with dapagliflozin were seen regardless of insulin dose or regimen. The known safety profile of dapagliflozin was unchanged in patients on intensive insulin regimens.  Conclusions: The benefits and safety of dapagliflozin were maintained in high-risk patients receiving high-dose or intensive insulin regimens including SA insulin.</p