Effect of upper gastrointestinal disease on the pharmacokinetics of oral semaglutide in subjects with type 2 diabetes.

AIM: To investigate whether upper gastrointestinal (GI) disease has any effect on the exposure of oral semaglutide, an important consideration given that its absorption occurs primarily in the stomach. MATERIALS AND METHODS: In an open-label, parallel-group trial (NCT02877355), subjects aged 18-80 years with type 2 diabetes with mild-to-moderate upper GI disease (N = 36; chronic gastritis [n = 5], gastroesophageal reflux disease [n = 8], and both [n = 23]) or without upper GI disease (N = 19) received oral semaglutide 3 mg once daily for 5 days, followed by 7 mg for 5 days. The primary and key supportive endpoints were the area under the semaglutide plasma concentration-time curve (AUC) from 0 to 24 hours after last trial product administration on day 10 (AUC0-24h,day10 ) and the maximum semaglutide plasma concentration (Cmax,day10 ), respectively. RESULTS: Semaglutide exposure was not statistically significantly different between subjects with and without upper GI disease. Estimated group ratios (subjects with/without upper GI disease) were 1.18 (95% confidence interval [CI], 0.80, 1.75) for AUC0-24h,day10 and 1.16 (95% CI, 0.77, 1.76) for Cmax . Time to Cmax and semaglutide half-life were similar in subjects with and without upper GI disease. Oral semaglutide was well tolerated; all adverse events were mild-to-moderate, with no withdrawals because of adverse events. CONCLUSIONS: There was no significant difference in exposure to oral semaglutide in subjects with or without upper GI disease, hence no dose adjustment is required.

Maintenance of glycaemic control with liraglutide versus oral antidiabetic drugs as add-on therapies in patients with type 2 diabetes uncontrolled with metformin alone: A randomized clinical trial in primary care (LIRA-PRIME).

AIM: To compare (in the LIRA-PRIME [NCT02730377], a randomized open-label trial), the efficacy of liraglutide in controlling glycaemia versus an oral antidiabetic drug (OAD) in patients with uncontrolled type 2 diabetes (T2D), despite metformin use in a primary care setting (n = 219 sites, n = 9 countries). MATERIALS AND METHODS: Adults (n = 1991) with T2D (HbA1c 7.5%-9.0%) receiving metformin were randomized 1:1 to liraglutide (≤1.8 mg/d) or one OAD, selected by the investigator, added to metformin, for up to 104 weeks. Primary endpoint: time to inadequate glycaemic control (HbA1c > 7.0%) at two scheduled consecutive visits after week 26. Outcomes were assessed for liraglutide versus a pooled OAD group, and (post hoc) liraglutide versus sodium-glucose co-transporter-2 inhibitors, dipeptidyl peptidase-4 inhibitors, and sulphonylureas individually. RESULTS: Among randomized patients (liraglutide, n = 996; OAD, n = 995), 47.6% were female, mean age was 57.4 years and mean HbA1c was 8.2%. Median time to inadequate glycaemic control was 44 weeks longer with liraglutide versus OAD (109 weeks [25% percentile, 38; 75% percentile, not available] vs. 65 weeks [25% percentile, 35; 75% percentile, 107], P < .0001). Changes in HbA1c and body weight at week 104 or at premature treatment discontinuation significantly favoured liraglutide over OAD. Hypoglycaemia rates were comparable between groups and few patients discontinued because of adverse events (liraglutide, 7.9% [n = 79]; OAD, 4.1% [n = 41]). Similar results were observed in the post hoc analysis for liraglutide versus individual OAD classes. CONCLUSIONS: Glycaemic control was better maintained with liraglutide versus OAD, supporting liraglutide use when intensifying therapy in primary care patients with T2D.

Efficacy of liraglutide added to sodium-glucose cotransporter-2 inhibitors in type 2 diabetes, stratified by baseline characteristics: Post-hoc analysis of LIRA-ADD2SGLT2i.

AIMS: The LIRA-ADD2SGLT2i trial demonstrated that liraglutide + sodium-glucose cotransporter-2 inhibitors (SGLT2is) ± metformin significantly improved glycaemic control (not body weight) versus placebo in adults with type 2 diabetes (T2D). This post-hoc analysis assessed whether baseline characteristics influenced these findings. MATERIALS AND METHODS: LIRA-ADD2SGLT2i (NCT02964247) was a placebo-controlled, double-blind, multinational trial, wherein participants received liraglutide (≤1.8 mg/day) or placebo (randomized 2:1). Changes from baseline to week 26 in haemoglobin A1c (HbA1c), body weight and waist circumference stratified by HbA1c, body mass index (BMI), diabetes duration, duration of pre-trial SGLT2i use and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) were analysed. These five baseline characteristics were divided into tertiles, and the treatment effect was evaluated using the trial product estimand. RESULTS: Data from all 303 participants were analysed. There was a significant interaction between baseline HbA1c tertiles (7.0%-<7.6%; 7.6%-8.1%; ≥8.2%-9.5%) and glycaemic control at week 26 (p[interaction]  = .011), with the lowest HbA1c estimated treatment difference (95% confidence interval) observed in patients with lowest baseline HbA1c [-0.20% (-0.59, 0.19); -0.68% (-1.03, -0.33); -0.98% (-1.33, -0.64), respectively]. There were no significant interactions in glycaemic control across baseline BMI, diabetes duration, insulin resistance determined by HOMA-IR or SGLT2i use duration (p[interaction] > .05, all). Across the five characteristics assessed, no significant interactions were found for body weight or waist circumference changes from baseline (p[interaction] > .05, all). CONCLUSION: For individuals with T2D and inadequate glycaemic control despite therapy with SGLT2is ± metformin, liraglutide 1.8 mg would provide an effective treatment intensification option, irrespective of HbA1c, BMI, diabetes duration, insulin resistance determined by HOMA-IR and SGLT2i use duration.

Use of Silicon T-Tube for Subglottic Stenosis and Tracheal Stenosis.

Introduction: The management of subglottic and tracheal stenosis is challenging for any ENT surgeon. The treatment choice depends on the site, severity of stenosis, patient symptoms, and surgeon preferences. The various options for the management include endoscopic balloon dilatation, various types of laryngotracheoplasty, resection anastomosis, and insertion of a silicon T-tube. Compared to the above, silicon T-tube stenting is a better alternative, as it is a onetime procedure, easy to perform with fewer chances of complications. Shiann Yann lee technique is a form of laryngotracheoplasty with long-term stenting using silicon T-tube. This article analyzed our silicon T-Tube insertion result in patients with subglottic and tracheal stenosis using this technique. Materials and Methods: In this retrospective study, we included a total of 21 patients with subglottic and tracheal stenosis who underwent silicon T-Tube insertion. Data regarding the site of stenosis, procedure, complications, and outcome were analyzed. Results: Out of 21 patients, nine patients had subglottic stenosis (42.8%), 8 had cervical tracheal stenosis (38.09%), 3 had thoracic tracheal stenosis (14.28%), and 1 (4.7%) had combined subglottic and cervical tracheal stenosis. Out of 21 patients,7 (33.3%) have undergone successful removal of silicon T-Tube so far, one death due to medical reasons, and 13 patients (61.9%) are still on Silicon tube on regular follow-up. They are comfortable with the tube in situ. Conclusions: Silicon T-Tube for benign acquired laryngotracheal stenosis with Shiann Yann Lee's technique is effective, safe with less complication, and good acceptability and tolerance by the patient.

Liraglutide for Weight Management in Children and Adolescents With Prader-Willi Syndrome and Obesity.

CONTEXT: Prader-Willi syndrome (PWS) is characterized by lack of appetite control and hyperphagia, leading to obesity. Pharmacological options for weight management are needed. OBJECTIVE: To determine whether liraglutide treatment for weight management is superior to placebo/no treatment in pediatric individuals with PWS. METHODS: This was a multicenter, 52-week, placebo-controlled trial with a 16-week double-blinded period. Adolescents (n = 31, aged 12-17 years; Tanner stage 2-5) and children (n = 24, aged 6-11 years; Tanner stage <2) with PWS and obesity were included. Patients were randomized 2:1 to liraglutide 3.0 mg (or maximum-tolerated dose) or placebo for 16 weeks, after which placebo was stopped. Liraglutide was continued for 52 weeks. All patients followed a structured diet and exercise program throughout the trial. The coprimary endpoints were change in body mass index (BMI) standard deviation score (SDS) from baseline to 16 and 52 weeks. Secondary endpoints included other weight-related parameters, hyperphagia, and safety. RESULTS: Change in BMI SDS from baseline to weeks 16 and 52 was not significantly different between treatments in adolescents (estimated treatment difference: -0.07 at week 16 and -0.14 at week 52) and children (-0.06 and -0.07, respectively). Changes in other weight-related parameters between treatments were not significant. At week 52, hyperphagia total and drive scores were lower in adolescents treated with liraglutide vs no treatment. The most common adverse events with liraglutide were gastrointestinal disorders. CONCLUSION: Although the coprimary endpoints were not met, changes in hyperphagia total and drive scores in adolescents warrant further studies on liraglutide in this population.

Effect of liraglutide treatment on body mass index and weight parameters in children and adolescents with type 2 diabetes: Post hoc analysis of the ellipse trial.

BACKGROUND: Weight loss in children and adolescents with type 2 diabetes (T2D) is associated with improved glycaemic control. OBJECTIVES: To assess the effects of liraglutide vs placebo on body mass index (BMI) and weight parameters in children and adolescents with T2D using data from the ellipse trial (NCT01541215). METHODS: The ellipse trial randomized participants (10-<17 years old, BMI >85th percentile, T2D, glycated haemoglobin [HbA1c ] 7.0%-11.0% [if diet- and exercise-treated] or 6.5% to 11.0% [if treated with metformin, basal insulin or both]) to liraglutide or placebo. This post-hoc analysis evaluated changes from baseline to weeks 26 and 52 in absolute BMI, percent change in BMI and other weight-related parameters. Changes were assessed by liraglutide overall (all doses) and liraglutide by dose (0.6, 1.2 and 1.8 mg/day) vs placebo using a pattern mixture model of observed data, with missing observations imputed from each treatment group. RESULTS: In total, 134 participants were included. There were statistically significant differences between groups in certain parameters, including absolute BMI (estimated treatment difference [ETD] -0.89 kg/m2 ; 95% confidence interval [CI] -1.71,-0.06) and percent change in BMI (ETD -2.73%; 95% CI -5.15,-0.30) at week 52, but none at week 26. Dose-dependent effects were not observed for liraglutide vs placebo for all BMI/weight parameters. CONCLUSIONS: Compared with placebo, liraglutide was associated with statistically significant reductions in BMI/weight parameters at week 52, but not week 26, in children and adolescents with T2D.