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Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.

ABSTRACT: OBJECTIVE:To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes. RESEARCH DESIGN AND METHODS:We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment. RESULTS:In the sotagliflozin-treated group, the percent reduction from baseline in the primary end point of bolus insulin dose was 32.1% (P = 0.007), accompanied by lower mean daily glucose measured by continuous glucose monitoring (CGM) of 148.8 mg/dL (8.3 mmol/L) (P = 0.010) and a reduction of 0.55% (5.9 mmol/mol) (P = 0.002) in HbA1c compared with the placebo group that showed 6.4% reduction in bolus insulin dose, a mean daily glucose of 170.3 mg/dL (9.5 mmol/L), and a decrease of 0.06% (0.65 mmol/mol) in HbA1c. The percentage of time in target glucose range 70-180 mg/dL (3.9-10.0 mmol/L) increased from baseline with sotagliflozin compared with placebo, to 68.2% vs. 54.0% (P = 0.003), while the percentage of time in hyperglycemic range >180 mg/dL (10.0 mmol/L) decreased from baseline, to 25.0% vs. 40.2% (P = 0.002), for sotagliflozin and placebo, respectively. Body weight decreased (1.7 kg) with sotagliflozin compared with a 0.5 kg gain (P = 0.005) in the placebo group. CONCLUSIONS:As adjunct to insulin, dual SGLT1 and SGLT2 inhibition with sotagliflozin improved glycemic control and the CGM profile with bolus insulin dose reduction, weight loss, and no increased hypoglycemia in type 1 diabetes.

SUBMITTER: Sands AT

PROVIDER: S-EPMC4831906 | biostudies-literature | 2015 Jul

REPOSITORIES: biostudies-literature

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Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.

Sands Arthur T AT Zambrowicz Brian P BP Rosenstock Julio J Lapuerta Pablo P Bode Bruce W BW Garg Satish K SK Buse John B JB Banks Phillip P Heptulla Rubina R Rendell Marc M Cefalu William T WT Strumph Paul P

Diabetes care 20150606 7

<h4>Objective</h4>To assess the safety and efficacy of dual sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibition with sotagliflozin as adjunct therapy to insulin in type 1 diabetes.<h4>Research design and methods</h4>We treated 33 patients with sotagliflozin, an oral dual SGLT1 and SGLT2 inhibitor, or placebo in a randomized, double-blind trial assessing safety, insulin dose, glycemic control, and other metabolic parameters over 29 days of treatment.<h4>Results</h4>In the sotagliflozin-tre ...[more]

PMID: 26049551

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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:ObjectiveTo assess the efficacy and safety of dual sodium glucose cotransporter (SGLT) 1/2 inhibitor sotagliflozin in type 1 diabetes mellitus.DesignMeta-analysis of randomised controlled trials.Data sourcesMedline; Cochrane Library; Embase; international meeting abstracts; international and national clinical trial registries; and websites of US, European, and Japanese regulatory authorities, up to 10 January 2019.Eligibility criteria for selecting studiesRandomised controlled trials evaluating the effect of sotagliflozin versus active comparators or placebo on glycaemic and non-glycaemic outcomes and on adverse events in type 1 diabetes in participants older than 18. Three reviewers extracted data for study characteristics, outcomes of interest, and risk of bias and summarised strength of evidence using the grading of recommendations assessment, development, and evaluation approach. Main outcomes were pooled using random effects models.ResultsOf 739 records identified, six randomised placebo controlled trials (n=3238, duration 4-52 weeks) were included. Sotagliflozin reduced levels of glycated haemoglobin (HbA1c; weighted mean difference -0.34% (95% confidence interval -0.41% to -0.27%), P<0.001); fasting plasma glucose (-16.98 mg/dL, -22.1 to -11.9; 1 mg/dL=0.0555 mmol/L) and two hour-postprandial plasma glucose (-39.2 mg/dL, -50.4 to -28.1); and daily total, basal, and bolus insulin dose (-8.99%, -10.93% to -7.05%; -8.03%, -10.14% to -5.93%; -9.14%, -12.17% to -6.12%; respectively). Sotagliflozin improved time in range (weighted mean difference 9.73%, 6.66% to 12.81%) and other continuous glucose monitoring parameters, and reduced body weight (-3.54%, -3.98% to -3.09%), systolic blood pressure (-3.85 mm Hg, -4.76 to -2.93), and albuminuria (albumin:creatinine ratio -14.57 mg/g, -26.87 to -2.28). Sotagliflozin reduced hypoglycaemia (weighted mean difference -9.09 events per patient year, -13.82 to -4.36) and severe hypoglycaemia (relative risk 0.69, 0.49 to 0.98). However, the drug increased the risk of ketoacidosis (relative risk 3.93, 1.94 to 7.96), genital tract infections (3.12, 2.14 to 4.54), diarrhoea (1.50, 1.08 to 2.10), and volume depletion events (2.19, 1.10 to 4.36). Initial HbA1c and basal insulin dose adjustment were associated with the risk of diabetic ketoacidosis. A sotagliflozin dose of 400 mg/day was associated with a greater improvement in most glycaemic and non-glycaemic outcomes than the 200 mg/day dose, without increasing the risk of adverse events. The quality of evidence was high to moderate for most outcomes, but low for major adverse cardiovascular events and all cause death. The relatively short duration of trials prevented assessment of long term outcomes.ConclusionsIn type 1 diabetes, sotagliflozin improves glycaemic and non-glycaemic outcomes and reduces hypoglycaemia rate and severe hypoglycaemia. The risk of diabetic ketoacidosis could be minimised by appropriate patient selection and down-titration of the basal insulin dose.

Project description:BackgroundDespite the number of medications for type 2 diabetes, many people with the condition do not achieve good glycaemic control. Some existing glucose-lowering agents have adverse effects such as weight gain or hypoglycaemia. Type 2 diabetes tends to be a progressive disease, and most patients require treatment with combinations of glucose-lowering agents. The sodium glucose co-transporter 2 (SGLT2) receptor inhibitors are a new class of glucose-lowering agents.ObjectiveTo assess the clinical effectiveness and safety of the SGLT2 receptor inhibitors in dual or triple therapy in type 2 diabetes.Data sourcesMEDLINE, Embase, Cochrane Library (all sections); Science Citation Index; trial registries; conference abstracts; drug regulatory authorities; bibliographies of retrieved papers.Inclusion criteriaRandomised controlled trials of SGLT2 receptor inhibitors compared with placebo or active comparator in type 2 diabetes in dual or combination therapy.MethodsSystematic review. Quality assessment used the Cochrane risk of bias score.ResultsSeven trials, published in full, assessed dapagliflozin and one assessed canagliflozin. Trial quality appeared good. Dapagliflozin 10 mg reduced HbA1c by -0.54% (weighted mean differences (WMD), 95% CI -0.67 to -0.40) compared to placebo, but there was no difference compared to glipizide. Canagliflozin reduced HbA1c slightly more than sitagliptin (up to -0.21% vs sitagliptin). Both dapagliflozin and canagliflozin led to weight loss (dapagliflozin WMD -1.81 kg (95% CI -2.04 to -1.57), canagliflozin up to -2.3 kg compared to placebo).LimitationsLong-term trial extensions suggested that effects were maintained over time. Data on canagliflozin are currently available from only one paper. Costs of the drugs are not known so cost-effectiveness cannot be assessed. More data on safety are needed, with the Food and Drug Administration having concerns about breast and bladder cancers.ConclusionsDapagliflozin appears effective in reducing HbA1c and weight in type 2 diabetes, although more safety data are needed.

Dataset Information

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.

Publications

Sotagliflozin, a Dual SGLT1 and SGLT2 Inhibitor, as Adjunct Therapy to Insulin in Type 1 Diabetes.

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