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Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes.

ABSTRACT: Background: Hypoglycemia rates usually increase when insulin treatment is intensified to improve glycemic control. We evaluated (post hoc) hypoglycemic rates in adult patients with type 1 diabetes (T1D) on sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 1 and 2 inhibitor) in two phase 3, 52-week clinical trials (inTandem 1 and 2; NCT02384941 and NCT02421510). Materials and Methods: We analyzed rates of documented hypoglycemia (level 1, blood glucose ?54 to <70?mg/dL) and clinically important hypoglycemia (level 2, glucose <54?mg/dL) in a patient-level pooled analysis (n?=?1362) using a negative binomial model adjusted for hemoglobin A1c (HbA1c) at 52 weeks in patients receiving placebo, sotagliflozin 200?mg, and sotagliflozin 400?mg. Results: Rates of level 1 hypoglycemia events per patient-year were 58.25 (95% confidence interval: 50.26-67.50) with placebo, 44.86 (38.83-51.82; P?=?0.0138 vs. placebo) with sotagliflozin 200?mg, and 45.68 (39.52-52.81; P?=?0.0220) with sotagliflozin 400?mg. Sotagliflozin was also associated with lower rates of level 2 hypoglycemia: 15.95 (14.37-17.70), 11.51 (10.39-12.76; P?

SUBMITTER: Danne T

PROVIDER: S-EPMC6708262 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes.

Danne Thomas T Pettus Jeremy J Giaccari Andrea A Cariou Bertrand B Rodbard Helena H Weinzimer Stuart A SA Bonnemaire Mireille M Sawhney Sangeeta S Stewart John J Wang Stella S Castro Rita de Cassia RC Garg Satish K SK

Diabetes technology & therapeutics 20190901 9

Background: Hypoglycemia rates usually increase when insulin treatment is intensified to improve glycemic control. We evaluated (post hoc) hypoglycemic rates in adult patients with type 1 diabetes (T1D) on sotagliflozin (a dual sodium-glucose cotransporter [SGLT] 1 and 2 inhibitor) in two phase 3, 52-week clinical trials (inTandem 1 and 2; NCT02384941 and NCT02421510). Materials and Methods: We analyzed rates of documented hypoglycemia (level 1, blood glucose ≥54 to < ...[more]

PMID: 31335194

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Project description:BACKGROUND:According to clinical guidelines, advice to stay active despite experiencing pain is recommended to patients with non-specific low back pain (LBP). However, not all patients receive guideline-concordant information and advice, and some patients still believe that activity avoidance will help them recover. The purpose was to study whether guideline-concordant beliefs among patients and other explanatory variables were associated with recovery. The main aim was to investigate whether believing staying active despite having pain is associated with a better functional outcome. METHODS:This was a prospective cohort study involving adults with non-specific LBP referred from general practices to the Spine Centre at Silkeborg Regional Hospital, Denmark. Patients reported on their beliefs about the importance of finding the cause, the importance of diagnostic imaging, perceiving to have received advice to stay active, pain duration, pain intensity, and STarT Back Tool. Agreeing to: 'An increase in pain is an indication that I should stop what I'm doing until the pain decreases' adjusted for age, gender, and education level was the primary explanatory analysis. A 30% improvement in the Roland Morris Disability Questionnaire (RMDQ) score after 52 weeks was the outcome. RESULTS:816 patients were included and 596 (73.0%) agreed that pain is a warning signal to stop being active. Among patients not considering pain as a warning signal, 80 (43.2%) had a favourable functional improvement of ≥30% on the RMDQ compared to 201 (41.2%) among patients considering pain a warning signal. No difference was found between the two groups (adjusted P = 0.542 and unadjusted P = 0.629). However, STarT Back Tool high-risk patients had a less favourable functional outcome (adjusted P = 0.003 and unadjusted P = 0.002). Chronic pain was associated with less favourable functional outcome (adjusted P < 0.001 and unadjusted P < 0.001), whereas beliefs about finding the cause, diagnostic imaging, perceiving to have received advice to stay active, or pain intensity were not significantly associated with outcome. CONCLUSIONS:Holding the single belief that pain is a warning signal to stop being active was not associated with functional outcome. However, patients characterised by having multiple psychological barriers (high-risk according to the STarT Back Tool) had a less favourable functional outcome. TRIAL REGISTRATION:Registered at ClinicalTrials.gov (registration number: NCT03058315), 20 February 2017.

Project description:Type 2 diabetes mellitus (T2DM) is often associated with cardiovascular (CV) risk factors such as obesity, hypertension and dyslipidemia. The objective of this analysis was to evaluate potential effects of exenatide once weekly (ExQW), a GLP-1 receptor agonist, on glycaemic control and CV risk factors.This analysis included 675 Intent-to-Treat patients with T2DM [baseline (mean ± SD) HbA1c, 8.1?±?1.2%; fasting blood glucose (FBG), 166?±?48 mg/dl; weight, 94.3?±?19.4 kg; systolic/diastolic blood pressure (SBP/DBP), 129?±?15/78 ± 9 mm?Hg; total cholesterol, 178.5?±?41.9 mg/dl; low-density lipoprotein (LDL), 100.1?±?35.0 mg/dl; high-density lipoprotein (HDL), 44.5?±?11.6 mg/dl; triglycerides, 155.6?±?3.3 mg/dl; alanine aminotransferase (ALT), 32.1?±?19.5 U/l] treated with diet and exercise alone or in combination with metformin, sulfonylurea, and/or thiazolidinedione who received 52 weeks of ExQW in four clinical trials.At 52 weeks, ExQW significantly improved HbA1c [mean (SE) change from baseline, -1.3 (0.05)%], FBG [-36.3 (2.02) mg/dl], body weight [-2.6 (0.19) kg], SBP/DBP [-3.6 (0.56) mm?Hg/-1.2 (0.34) mm?Hg], total cholesterol, -4.4 (1.33) mg/dl; LDL, -2.6 (1.08) mg/dl; HDL, 1.1 (0.31) mg/dl; triglycerides, -7 (1.6)%], and ALT [-4.3 (0.71) IU/l] concentrations, with greater improvements in patients with elevated analyte levels at baseline. Improvements were observed across a range of background antihyperglycaemia therapies. Of patients completing 52 weeks, 19% achieved the composite American Diabetes Association goal (HbA1c < 7.0%, BP < 130/80 mm?Hg, LDL?<?100 mg/dl), compared to 1% at baseline. Nearly half (48%) achieved HbA1c < 7.0% without weight gain or major/minor hypoglycaemia. Nausea was the most frequent adverse event and was predominantly mild. Hypoglycaemia was infrequent, and more common with a sulfonylurea.With 52 weeks of ExQW, patients experienced sustained improvements in glycaemic control and CV risk factors, with an increased likelihood of achieving both a clinically relevant composite outcome (HbA1c?<?7% without weight gain or increased risk of hypoglycaemia) and a composite of key therapeutic goals (HbA1c?<?7%, BP < 130/80 mm?Hg, LDL?<?100 mg/dl).

Project description:PurposeThis pragmatic clinical study aimed to assess goal attainment among patients with schizophrenia treated with paliperidone palmitate 3-monthly (PP3M) and its relation to their level of disability, and whether patients achieved symptomatic remission at the study endpoint.Patients and methodsGoal attainment was assessed as a secondary endpoint using Goal Attainment Scaling (GAS) within a 52-week, prospective, single-arm, non-randomized, open-label, international, multicenter study evaluating the impact of transitioning stable patients with schizophrenia from paliperidone palmitate 1-monthly (PP1M) to PP3M. Additional exploratory analyses were performed to investigate the relationship between disability and functioning as measured by the World Health Organization Disability Assessment Schedule (WHODAS), Version 2.0, symptomatic remission, and goal attainment.ResultsOverall, 305 patients were enrolled, of whom 281 (92.1%) provided GAS data at baseline. Of these, 160 achieved symptomatic remission at the last observation carried forward (LOCF) endpoint. The most common category of goals was "self" related, of which work-related was most frequent. Two-thirds of patients (67.7%) achieved at least one goal at the LOCF endpoint. Goal achievement was positively associated with lower baseline symptoms and symptomatic remission at LOCF endpoint, and with lower WHODAS scores at baseline and LOCF endpoint and greater WHODAS score improvements from baseline. Age, duration of disease, and duration of PP1M treatment before the switch did not impact goal setting and goal attainment. The proportion of patients with remunerated work status increased by 11.3% at LOCF endpoint.ConclusionThe results of this secondary endpoint analysis indicate that continued treatment of patients with schizophrenia with PP3M following stabilization with PP1M may facilitate attainment of patients' personal goals and reduce disability, especially, but not exclusively, in patients with symptomatic remission achieved at LOCF.

Project description:Infants undergo extensive developments during their first year of life. Although the biological mechanisms involved are not yet fully understood, changes in the DNA methylation in mammals are believed to play a key role. This study was designed to investigate changes in infant DNA methylation that occurs between 6 and 52 weeks. A total of 214 infant saliva samples from 6 or 52 weeks were assessed using principal component analyses and t-distributed stochastic neighbor-embedding algorithms. Between the two time points, there were clear differences in DNA methylation. To further investigate these findings, paired two-sided student's t-tests were performed. Differently methylated regions were defined as at least two consecutive probes that showed significant differences, with a q-value?<?0.01 and a mean difference?>?0.2. After correcting for false discovery rates, changes in the DNA methylation levels were found in 42 genes. Of these, 36 genes showed increased and six decreased DNA methylation. The overall DNA methylation changes indicated decreased gene expression. This was surprising because infants undergo such profound developments during their first year of life. The results were evaluated by taking into consideration the extensive development that occurs during pregnancy. During the first year of life, infants have an overall three-fold increase in weight, while the fetus develops from a single cell into a viable infant in 9 months, with an 875-million-fold increase in weight. It is possible that the findings represent a biological slowing mechanism in response to extensive fetal development. In conclusion, our study provides evidence of DNA methylation changes during the first year of life, representing a possible biological slowing mechanism. We encourage future studies of DNA methylation changes in infants to replicate the findings by using a repeated measures model and less stringent criteria to see if the same genes can be found, as well as investigating whether other genes are involved in development during this period.

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).

Dataset Information

Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes.

Publications

Sotagliflozin Added to Optimized Insulin Therapy Leads to Lower Rates of Clinically Relevant Hypoglycemic Events at Any HbA1c at 52 Weeks in Adults with Type 1 Diabetes.

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