Subgroup evaluation revealed that the chance of quantity depletion occasions was increased in the initial 12 weeks of treatment, but subsided (supplementary desk 3). confidence period ?0.41% to ?0.27%), P 0.001); fasting plasma blood sugar (?16.98 mg/dL, ?22.1 to ?11.9; 1 mg/dL=0.0555 mmol/L) and two hour-postprandial plasma blood sugar (?39.2 mg/dL, ?50.4 to ?28.1); and daily total, basal, and bolus insulin dosage (?8.99%, ?10.93% to ?7.05%; ?8.03%, ?10.14% to ?5.93%; ?9.14%, ?12.17% to ?6.12%; respectively). Sotagliflozin improved amount of time in range (weighted mean difference 9.73%, 6.66% to 12.81%) and various other continuous blood sugar 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. Conclusions In 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. Open in a separate window Introduction Type 1 diabetes mellitus affects 1.5 million people in the United States alone and its prevalence is continuously rising, partly because over 10% of patients initially presumed to have type 2 diabetes at diagnosis subsequently show evidence of islet autoimmunity and progress to insulin dependence later on.1 2 The achievement and maintenance of glycaemic goals in type 1 diabetes has proven both difficult and hazardous. In the T1D Exchange clinic registry, the average level of glycated haemoglobin (HbA1c) was 8%, only 30% of patients with type 1 diabetes achieved FR901464 an HbA1c goal of 7%, and severe hypoglycaemia occurred in up to 20% of patients per year.3 Similarly, in the Diabetes Complications and Control Trial, patients with type 1 diabetes with HbA1c levels within target showed a 2.9-fold increased cardiovascular mortality,4 and patients in the intensive intervention group escalated back to an HbA1c of 8% in the years following the trial.5 Insulin is the mainstay of treatment for type 1 diabetes, but has unwanted effects, including hypoglycaemia and weight gain.6 Severe hypoglycaemia in particular is the main factor limiting optimal glucose control in the disease; it is frequent, adds costs to diabetes management, and is a strong predictor of adverse vascular and non-vascular outcomes and death.6 7 8 9 None of the adjunctive treatments approved (that is, pramlintide) or recently proposed for type 1 diabetes (that is, metformin, incretin analogues, and sodium glucose cotransporter (SGLT) 2 inhibitors) has reduced the incidence of hypoglycaemia and severe hypoglycaemia, which remain the major unresolved issue in the management of these patients.10 11 12 13 14 15 16 17 18 19 20 SGLT1 is responsible for glucose absorption in the proximal intestine, and missense mutations in SGLT1 gene have been associated with protection from glucose intolerance, obesity, and cardiometabolic risk in population based studies.21 Sotagliflozin (LX4211, SAR439954) is a novel, first-in-class, dual inhibitor of SGLT1 and SGLT2; while SGLT2 inhibition reduces glucose reabsorption in the renal tubule, SGLT1 inhibition decreases glucose absorption in the intestine. This dual mechanism of action could offer incremental benefits over selective SGLT2 inhibitors22 by blunting postprandial glycaemic excursions and glycaemic variability, lowering the need for bolus insulin correction doses, and eventually reducing hypoglycaemic risk.23 Furthermore, reduced glucose absorption in the proximal intestine increases glucose delivery to the distal intestine, stimulating incretin glucagon-like peptide-1 (GLP-1).24 In.The 2018 Agency for Healthcare Research and Quality recommendations caution against equating industry sponsorship with high risk of bias and automatically downgrading the evidence for industry sponsorship.43 Therefore, for all included trials, we systematically assessed a prespecified list of eight items in trial designing, conducting, and reporting, which have been empirically linked to the risk of biased outcomes in industry funded trials and are not captured by the six domains of the risk of bias tool44 45 46 47 48 49 50 (supplementary table 1). Data synthesis, analysis, and grading of evidence The analysis was carried out in accordance with the Cochrane handbook of systematic reviews of interventions42 using Stata release 11.2 (StataCorp, College Station, TX, USA) and RevMan version 5.3.5 (Nordic Cochrane Center, Copenhagen, Denmark),51 and was reported according to PRISMA guidelines52 (preferred reporting items for systematic reviews and meta-analyses; see supplementary appendix). development, and evaluation approach. Main outcomes were pooled using random effects models. Results Of 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, FR901464 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. Conclusions In type FR901464 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. Open in a separate window Introduction Type 1 diabetes mellitus affects 1.5 million people in the United States alone and its prevalence is continuously rising, partly because over 10% of patients initially presumed to have type 2 diabetes at diagnosis subsequently show evidence of islet autoimmunity and progress to insulin dependence later on.1 2 The achievement and maintenance of glycaemic goals in type 1 diabetes has proven both difficult and hazardous. In FR901464 the T1D Exchange clinic registry, the average level of glycated haemoglobin (HbA1c) was 8%, only 30% of patients with type 1 diabetes achieved an HbA1c goal of 7%, and severe hypoglycaemia occurred in up to 20% of patients per year.3 Similarly, in the Diabetes Complications and Control Trial, patients with type 1 diabetes with HbA1c levels within target showed a 2.9-fold increased cardiovascular mortality,4 and patients FR901464 in the intensive intervention group escalated back to an HbA1c of 8% in the years following the trial.5 Insulin is the mainstay of treatment for type 1 diabetes, but has unwanted effects, including hypoglycaemia and weight gain.6 Severe hypoglycaemia in particular is the main factor limiting optimal glucose control in the disease; it is frequent, adds costs to diabetes management, and is a strong predictor of adverse vascular and non-vascular outcomes and death.6 7 8 9 None of the adjunctive treatments approved (that is, pramlintide) or recently proposed for type 1 diabetes (that is, metformin, incretin analogues, and sodium glucose cotransporter (SGLT) 2 inhibitors) has reduced the incidence of hypoglycaemia and severe hypoglycaemia, which remain the major unresolved issue in the management of these patients.10 11 12 13 14 15 16 17 18 19 20 SGLT1 is responsible for glucose absorption in the proximal intestine, and missense mutations in SGLT1 gene have been associated with protection from glucose intolerance, obesity, and cardiometabolic risk in population based studies.21 Sotagliflozin (LX4211, SAR439954) is a novel, first-in-class, dual inhibitor of SGLT1 and SGLT2; while SGLT2 inhibition reduces glucose reabsorption in the renal tubule, SGLT1 inhibition decreases glucose absorption in the intestine. This dual mechanism of action could offer incremental benefits over selective SGLT2 inhibitors22 by blunting postprandial glycaemic excursions and glycaemic variability, lowering the need for bolus insulin correction doses, and eventually reducing hypoglycaemic risk.23 Furthermore, reduced glucose absorption in the proximal intestine increases glucose delivery to the distal intestine, stimulating incretin glucagon-like peptide-1 (GLP-1).24 In preclinical models, the increased release of incretin has enhanced weight loss and counteracted glucagon induced ketogenesis,25 which could reduce the risk of diabetic ketoacidosis.23 24 25 Sotagliflozin has recently reached phase III development in patients with type Itga1 1 diabetes26 27 28 29 30 31 but randomised.