Patients with nonalcoholic steatohepatitis were randomly assigned to receive subcutaneous semaglutide or placebo. The incidence of NASH resolution was significantly higher with semaglutide than with ...placebo, but the between-group difference in the incidence of an improvement in fibrosis stage was not significant.
In this article, we will present statistical methods to assess to what extent the effect of a randomised treatment (versus control) on a time‐to‐event endpoint might be explained by the effect of ...treatment on a mediator of interest, a variable that is measured longitudinally at planned visits throughout the trial. In particular, we will show how to identify and infer the path‐specific effect of treatment on the event time via the repeatedly measured mediator levels. The considered proposal addresses complications due to patients dying before the mediator is assessed, due to the mediator being repeatedly measured, and due to posttreatment confounding of the effect of the mediator by other mediators. We illustrate the method by an application to data from the LEADER cardiovascular outcomes trial.
To investigate whether liraglutide added to treat-to-target insulin improves glycemic control and reduces insulin requirements and body weight in subjects with type 1 diabetes.
A 52-week, ...double-blind, treat-to-target trial involving 1,398 adults randomized 3:1 to receive once-daily subcutaneous injections of liraglutide (1.8, 1.2, or 0.6 mg) or placebo added to insulin.
HbA1c level was reduced 0.34-0.54% (3.7-5.9 mmol/mol) from a mean baseline of 8.2% (66 mmol/mol), and significantly more for liraglutide 1.8 and 1.2 mg compared with placebo (estimated treatment differences ETDs: 1.8 mg liraglutide -0.20% 95% CI -0.32; -0.07; 1.2 mg liraglutide -0.15% 95% CI -0.27; -0.03; 0.6 mg liraglutide -0.09% 95% CI -0.21; 0.03). Insulin doses were reduced by the addition of liraglutide 1.8 and 1.2 mg versus placebo (estimated treatment ratios: 1.8 mg liraglutide 0.92 95% CI 0.88; 0.96; 1.2 mg liraglutide 0.95 95% CI 0.91; 0.99; 0.6 mg liraglutide 1.00 95% CI 0.96; 1.04). Mean body weight was significantly reduced in all liraglutide groups compared with placebo ETDs (1.8 mg liraglutide -4.9 kg 95% CI -5.7; -4.2; 1.2 mg liraglutide -3.6 kg 95% CI -4.3; -2.8; 0.6 mg liraglutide -2.2 kg 95% CI -2.9; -1.5). The rate of symptomatic hypoglycemia increased in all liraglutide groups (estimated rate ratios: 1.8 mg liraglutide 1.31 95% CI 1.07; 1.59; 1.2 mg liraglutide 1.27 95% CI 1.03; 1.55; 0.6 mg liraglutide 1.17 95% CI 0.97; 1.43), and hyperglycemia with ketosis increased significantly for liraglutide 1.8 mg only (event rate ratio 2.22 95% CI 1.13; 4.34).
Liraglutide added to insulin therapy reduced HbA1c levels, total insulin dose, and body weight in a population that was generally representative of subjects with type 1 diabetes, accompanied by increased rates of symptomatic hypoglycemia and hyperglycemia with ketosis, thereby limiting clinical use in this group.
We have evaluated the performance of two classes of probabilistic models for substitution rate variation over phylogenetic trees. In the first class, branch rates are considered to be independent and ...identically distributed (i.i.d.) stochastic variables. Three versions with respect to the underlying distribution (Gamma, Inverse Gaussian, and LogNormal) are considered. The i.i.d. models are compared with the autocorrelated (AC) model, where rates of adjacent nodes in the tree are AC, so that a node rate is LogNormal distributed around the rate of the parent node. The performance of different models is evaluated using three empirical data sets. For all data sets, it was clear that all tested models extracted substantial knowledge from data when posterior divergence time distributions were compared with the prior distributions and, furthermore, that they clearly outperformed a molecular clock. Moreover, the descriptive power of the i.i.d. models, as evaluated by Bayes factors, was either equal to or clearly better than that of the AC model. The latter effect increased with extended taxon sampling. Likewise, under none of the models could we find compelling evidence, in any of the data sets, for rate correlation between adjacent branches/nodes. These findings challenge previous suggestions of universality of autocorrelation in sequence evolution. We also performed an additional comparison with a divergence time prior including calibration information from fossil evidence. Adding fossil information to the prior had negligible effect on Bayes factors and mainly affected the width of the posterior distribution of the divergence times, whereas the relative position of the mean divergence times were largely unaffected.
EChO, the Exoplanet Characterisation Observatory, has been one of the five M-class mission candidates competing for the M3 launch slot within the science programme Cosmic Vision 2015–2025 of the ...European Space Agency (ESA). As such, EChO has been the subject of a Phase 0/A study that involved European Industry, research institutes and universities from ESA member states and that concluded in September 2013. EChO is a concept for a dedicated mission to measure the chemical composition and structure of hundreds of exoplanet atmospheres using the technique of transit spectroscopy. With simultaneous and uninterrupted spectral coverage from the visible to infrared wavelengths, EChO targets extend from gas giants (Jupiter or Neptune-like) to super-Earths in the very hot to temperate zones of F to M-type host stars, opening up the way to large-scale, comparative planetology that would place our own solar system in the context of other planetary systems in the Milky Way. A review of the performance requirements of the EChO mission was held at ESA at the end of 2013, with the objective of assessing the readiness of the mission to progress to the Phase B1 study phase. No critical issues were identified from a technical perspective, however a number of recommendations were made for future work. Since the mission was not selected for the M3 launch slot, EChO is no longer under study at ESA. In this paper we give an overview of the final mission concept for EChO as of the end of the study, from scientific, technical and operational perspectives.
Summary
Background
Obesity and type 2 diabetes are drivers of non‐alcoholic fatty liver disease (NAFLD). Glucagon‐like peptide‐1 analogues effectively treat obesity and type 2 diabetes and may offer ...potential for NAFLD treatment.
Aim
To evaluate the effect of the glucagon‐like peptide‐1 analogue, semaglutide, on alanine aminotransferase (ALT) and high‐sensitivity C‐reactive protein (hsCRP) in subjects at risk of NAFLD.
Methods
Data from a 104‐week cardiovascular outcomes trial in type 2 diabetes (semaglutide 0.5 or 1.0 mg/week) and a 52‐week weight management trial (semaglutide 0.05‐0.4 mg/day) were analysed. Treatment ratios vs placebo were estimated for ALT (both trials) and hsCRP (weight management trial only) using a mixed model for repeated measurements, with or without adjustment for change in body weight.
Results
Elevated baseline ALT (men >30 IU/L; women >19 IU/L) was present in 52% (499/957) of weight management trial subjects. In this group with elevated ALT, end‐of‐treatment ALT reductions were 6%‐21% (P<0.05 for doses≥0.2 mg/day) and hsCRP reductions 25%‐43% vs placebo (P < 0.05 for 0.2 and 0.4 mg/day). Normalisation of elevated baseline ALT occurred in 25%‐46% of weight management trial subjects, vs 18% on placebo. Elevated baseline ALT was present in 41% (1325/3268) of cardiovascular outcomes trial subjects. In this group with elevated ALT, no significant ALT reduction was noted at end‐of‐treatment for 0.5 mg/week, while a 9% reduction vs placebo was seen for 1.0 mg/week (P = 0.0024). Treatment ratios for changes in ALT and hsCRP were not statistically significant after adjustment for weight change.
Conclusions
Semaglutide significantly reduced ALT and hsCRP in clinical trials in subjects with obesity and/or type 2 diabetes.
The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) ...events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial.
We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: glycated hemoglobin (HbA
), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors.
Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA
(up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates.
These analyses identify HbA
and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation.
The Spitz Gneiss, located near the Danube in the southern sector of the Variscan Bohemian Massif, represents a ~13 km2 large Late Proterozoic Bt ± Hbl bearing orthogneiss body in the Lower Austrian ...Drosendorf Unit (Moldanubian Zone). Its formation age (U-Pb zircon) has been determined previously as 614 ± 10 Ma. Based on 21 new geochemical analyses, the Spitz Gneiss can be described as a granodioritic I-type rock (64-71 wt. % SiO2) with medium-K composition (1.1-3.2 wt. % K2O) and elevated Na2O (4.1-5.6 wt. %). Compared to average granodiorite, the Spitz Gneiss is slightly depleted in Large-Ion Lithophile (LIL) elements (Rb 46-97 ppm, Cs 0.95-1.5 ppm), Sr (248-492 ppm), Nb (6-10 ppm), Th (3-10 ppm), the LREE (e.g. La 10-30 ppm), Y (6-19 ppm) and first row transitional metals (e.g. Cr 10-37 ppm). The Zr content (102-175 ppm) is close to average granodiorite. The major- and trace-element signature of the Spitz Gneiss is similar to some Late Proterozoic granodiorite suites in the Moravo-Silesian Unit (e.g. the Passendorf-Neudegg suite in the Thaya Batholith). However, granodiorites of such type and age do not occur elsewhere in the Moldanubian Zone of the Bohemian Massif. This observation fits existing tectonic models in which the Austrian Drosendorf Unit is considered allochthonous and part of the Moravo-Silesian Unit and the Avalonian Superterrane. Mineral chemistry data for amphibole, plagioclase and biotite allow an estimation of the Variscan peak regional metamorphic conditions for the Spitz Gneiss at ~700 °C and 7 kbar. Amphibole and plagioclase show hardly any signs of retrograde reequilibration, implying a fast late-Variscan exhumation. Partial chloritization of biotite indicates late fluid activity at T ~ 250 °C.
Non-alcoholic steatohepatitis (NASH) is a chronic liver disease. There is a clear need to develop pharmacological treatment for patients with NASH as well as biomarkers that can diagnose the disease. ...We describe a trial of semaglutide treatment for NASH, identify key patient characteristics and compare the relationship of patient characteristics and non-invasive biomarkers/scores.
NCT02970942 is a randomised, double-blind, placebo-controlled, multi-national Phase 2 trial of daily subcutaneous semaglutide (0.1 mg, 0.2 mg, 0.4 mg) in patients with biopsy-confirmed NASH, F1–F3 fibrosis, NAFLD Activity Score ≥ 4, and body mass index (BMI) > 25 kg/m2. Exploratory analyses were performed to evaluate correlations between baseline parameters and biomarkers in NASH.
Mean (standard deviation SD) age of 320 randomised patients was 55 (11) years, mean BMI was 36 (6) kg/m2, and 199 (62%) had type 2 diabetes. Of the total patients, 28% had F1 fibrosis, 23% had F2 fibrosis and 49% had F3 fibrosis. The highest area under the receiver operating characteristic curve (0.69) for accuracy in classifying fibrosis stage, F2–3 versus F1, was observed for Fib-4 and Enhanced Liver Fibrosis (ELF). No substantial correlation between BMI or other clinical or biochemical parameters and fibrosis stage was observed.
In this large Phase 2 trial of semaglutide treatment for NASH, the clinical profile of enrolled patients was typical for patients with NASH. Of the investigated biomarkers/scores, ELF and Fib-4 showed the most apparent correlation in classifying fibrosis stage, but had only moderate predictive value.
•Liver fibrosis in patients with NASH is associated with disease complications.•Fib-4 and ELF were better able to classify fibrosis stage than other biomarkers.•BMI did not appear to be related to fibrosis stage.
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