Once-weekly insulin efsitora alfa: Design and rationale for the QWINT phase 3 clinical development programme.

Aims: Insulin efsitora alfa (efsitora) is a once-weekly basal insulin. This review describes the study design and rationale of the efsitora phase 3 Once Weekly (QW) Insulin Therapy (QWINT) clinical development programme, including the five trials, QWINT-1 through QWINT-5.

Materials And Methods: The five trials included insulin-naïve adults (QWINT-1 and -2) with type 2 diabetes (T2D), adults with T2D previously treated with basal insulin (QWINT-3 and -4), and QWINT-5 in adults with type 1 diabetes.

Dulaglutide and Kidney Function-Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis.

Objective: Dulaglutide (DU) 1.5 mg was associated with improved composite renal outcomes that included new-onset macroalbuminuria in people with type 2 diabetes with previous cardiovascular disease or cardiovascular risk factors in the REWIND (Researching cardiovascular Events with a Weekly INcretin in Diabetes) trial. This exploratory post hoc analysis evaluated kidney function-related outcomes, excluding the new-onset macroalbuminuria component, among the REWIND participants.

Indicators of Kidney Fibrosis in Patients with Type 2 Diabetes and Chronic Kidney Disease Treated with Dulaglutide.

Introduction: In the AWARD-7 study in patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide slowed the decline in estimated glomerular filtration rate (eGFR) and decreased the urine albumin/creatinine ratio compared to insulin glargine at the end of 52 weeks of treatment. In this exploratory post hoc analysis, changes in two fibrosis biomarkers, serum PRO-C6 (type VI collagen formation) and urine C3M (type III collagen degradation), were evaluated.

Methods: In the groups treated with dulaglutide 1.

Efficacy and safety outcomes of dulaglutide by baseline HbA1c: A post hoc analysis of the REWIND trial.

Aim: To assess cardiovascular, glycaemic, weight and safety outcomes of long-term treatment with dulaglutide 1.5 mg compared with placebo in patients with a baseline HbA1c of less than 7% versus 7% or higher.

Materials And Methods: Intention-to-treat analyses were performed on REWIND participants with a baseline HbA1c measurement, using Cox proportional hazards regression and mixed model for repeated measures.

A thrombin-PAR1/2 feedback loop amplifies thromboinflammatory endothelial responses to the viral RNA analogue poly(I:C).

Activation of blood coagulation and endothelial inflammation are hallmarks of respiratory infections with RNA viruses that contribute significantly to the morbidity and mortality of patients with severe disease. We investigated how signaling by coagulation proteases affects the quality and extent of the response to the TLR3-ligand poly(I:C) in human endothelial cells. Genome-wide RNA profiling documented additive and synergistic effects of thrombin and poly(I:C) on the expression level of many genes.

Follow-up of SARS-CoV-2 positive subgroup from the Asymptomatic novel CORonavirus iNFection study.

A nested longitudinal study within theAsymptomatic novel CORonavirus iNFfection study followed participants with positive nasopharyngeal swab to query for development of symptoms and assess duration of positive reverse transcription-polymerase chain reaction (RT-PCR) test results. Of the 91 participants initially testing positive, 86 participated in follow-up approximately 14 days after study enrollment; of those 86 participants, 19 (22.1%) developed at least one symptom at any time after the initial positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result.

Clinical Outcomes by Albuminuria Status with Dulaglutide versus Insulin Glargine in Participants with Diabetes and CKD: AWARD-7 Exploratory Analysis.

Background: In the AWARD-7 trial of participants with type 2 diabetes (T2DM) and moderate-to-severe CKD, dulaglutide (DU) treatment slowed decline in eGFR compared with insulin glargine (IG). Treatment with doses of either DU or IG resulted in similar levels of glycemic control and BP. The aim of this analysis was to determine the risk of clinical event outcomes between treatment groups.

A cross-sectional community-based observational study of asymptomatic SARS-CoV-2 prevalence in the greater Indianapolis area.

The Asymptomatic novel CORonavirus iNfection (ACORN) study was designed to investigate the prevalence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the asymptomatic adult population of the Indianapolis metropolitan area, to follow individuals testing positive for the development of symptoms, and to understand duration of positive test results. ACORN is a cross-sectional community-based observational study of adult residents presenting asymptomatic for COVID-like illness, defined as the self-reported absence of the following three symptoms in the last 7 days: fever (≥100°F), new-onset or worsening cough, and new-onset or worsening shortness of breath. SARS-CoV-2 infection was determined by real-time reverse transcription-polymerase chain reaction in nasopharyngeal swab samples.

The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial.

Background: Cardiovascular outcome trials have suggested that glucagon-like peptide 1 (GLP-1) receptor agonists might reduce strokes. We analysed the effect of dulaglutide on stroke within the researching cardiovascular events with a weekly incretin in diabetes (REWIND) trial.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial done at 371 sites in 24 countries.

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial.

Background: Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term effect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the effect of dulaglutide on cardiovascular disease.

Methods: REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries.

Body weight and eGFR during dulaglutide treatment in type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7).

In patients with type 2 dibetes and moderate-to-severe chronic kidney disease, dulaglutide treatment led to body weight (BW) loss and lesser eGFR decline compared to insulin glargine. As BW may affect muscle mass, creatinine-based eGFR can be altered independently of kidney function. Cystatin C-based eGFR is not affected by muscle mass.

The association between the severity of chronic kidney disease and medical costs among patients with type 2 diabetes.

Aims: Examine healthcare costs across chronic kidney disease (CKD) stages for US patients with type 2 diabetes (T2D).

Materials And Methods: IQVIA Real World Data Adjudicated Claims linked electronic medical records and insurance claims from January 1, 2012 through March 31, 2017 were used for this retrospective study. Adults diagnosed with T2D and comorbid CKD were included.

Effects of Dulaglutide and Insulin Glargine on Estimated Glomerular Filtration Rate in a Real-world Setting.

Purpose: The aims of this study were to use real-world treatment results to compare changes in estimated glomerular filtration rate (eGFR) and glycosylated hemoglobin (HbA) among patients with type 2 diabetes who initiated treatment with dulaglutide or insulin glargine and to determine the proportions of patients with renal impairment who initiate each treatment.

Methods: The study used data from the Practice Fusion electronic health records database from October 2013 through June 2017. Adults with type 2 diabetes who initiated dulaglutide or insulin glargine therapy and had multiple recorded serum creatinine and/or HbA laboratory test results were included in the study.

Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial.

Background: Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.

Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme.

Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide-treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles.

Expression of novel "LOCGEF" isoforms of ARHGEF18 in eosinophils.

Genomic, transcriptomic and proteomic databases indicate that the N-terminal 322 residues encoded by the presumptive LOC100996504 gene, which is adjacent to the ARHGEF18 guanine nucleotide exchange factor gene on chromosome 19, constitute the N-terminal portion of a 1361-residue isoform of ARHGEF18, dubbed LOCGEF-X3. LOCGEF-X3 arises from the use of a leukocyte-specific alternative transcriptional start site and splicing that bypasses the initial noncoding exon of the canonical 1015-residue ARHGEF18 isoform, p114. Eosinophil LOCGEF-X3 was amplified and cloned, recombinant LOCGEF-X3 was expressed, and anti-ARHGEF18 antibody was found to recognize a band in immunoblots of eosinophil lysates that co-migrates with recombinant LOCGEF-X3.

Glucagon-Like Peptide-1 Receptor Agonist Use and Renal Impairment: A Retrospective Analysis of an Electronic Health Records Database in the U.S. Population.

Introduction: The study characterizes the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with type 2 diabetes (T2D) with and without renal impairment and examines the effects of such use on the clinical outcomes of estimated glomerular filtration rate (eGFR) and glycated hemoglobin (A1c).

Methods: Data from the Practice Fusion electronic health records database from 1 January 2012 through 30 April 2015 were used. Adults with T2D who received serum creatinine laboratory tests and initiated therapy with a GLP-1 RA (N = 3225) or other glucose-lowering agent (GLA) (N = 37,074) were included in the analysis.

Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program.

Dulaglutide (DU) is a once weekly glucagon-like peptide-1 receptor agonist (GLP-1 RA) approved for the treatment of type 2 diabetes mellitus (T2DM). Glycaemic efficacy and safety characteristics of dulaglutide have been assessed in six Phase 3 studies in the AWARD program. The objective of this review article is to summarize these results from the six completed AWARD studies.

Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials.

Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist approved for the treatment of type 2 diabetes (T2D). Integrated data from 9 phase II and III trials in people with T2D (N = 6005) were used to evaluate the effects of dulaglutide on estimated glomerular filtration rate (eGFR [Chronic Kidney Disease Epidemiology Collaboration]), urine albumin-to-creatinine ratio (UACR) and kidney adverse events (AEs). No significant differences in eGFR were observed during treatment for dulaglutide vs placebo, active comparators or insulin glargine (mean ± standard deviation values: dulaglutide vs placebo: 87.

Baseline factors associated with glycaemic response to treatment with once-weekly dulaglutide in patients with type 2 diabetes.

Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient-boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment.

Cardiovascular safety for once-weekly dulaglutide in type 2 diabetes: a pre-specified meta-analysis of prospectively adjudicated cardiovascular events.

Background: Patients with type 2 diabetes (T2D) have a substantial increased risk for cardiovascular (CV) disease and associated mortality than those without diabetes. Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist that is approved for treatment of T2D.

Methods: This meta-analysis evaluates the CV risk in patients with T2D treated with dulaglutide in 9 randomized safety and efficacy trials.

EPCR-dependent PAR2 activation by the blood coagulation initiation complex regulates LPS-triggered interferon responses in mice.

Infection and inflammation are invariably associated with activation of the blood coagulation mechanism, secondary to the inflammation-induced expression of the coagulation initiator tissue factor (TF) on innate immune cells. By investigating the role of cell-surface receptors for coagulation factors in mouse endotoxemia, we found that the protein C receptor (ProcR; EPCR) was required for the normal in vivo and in vitro induction of lipopolysaccharide (LPS)-regulated gene expression. In cultured bone marrow-derived myeloid cells and in monocytic RAW264.

Prorenin receptor in distal nephron segments of 2-kidney, 1-clip goldblatt hypertensive rats.

Background: The prorenin receptor (PRR) is expressed in the kidneys and has been localized to mesangial cells, renal arterioles, and distal nephron segments. By binding renin or prorenin, this receptor increases renin catalytic activity and activates prorenin. The renin gene is expressed by the principal cells of collecting ducts and is enhanced in angiotensin II (AngII)-dependent hypertension and in both kidneys of 2-kidney, 1-clip (2K1C) Goldblatt hypertensive rats.

Tadalafil for the treatment of pulmonary arterial hypertension: a double-blind 52-week uncontrolled extension study.

Objectives: The aim of this study was to evaluate the long-term safety and durability of efficacy of tadalafil for pulmonary arterial hypertension.

Background: Tadalafil is an oral phosphodiesterase-5 inhibitor approved for PAH treatment. In the multicenter, placebo-controlled, randomized, 16-week PHIRST (Pulmonary Arterial Hypertension and Response to Tadalafil) study, tadalafil 40 mg improved exercise capacity and delayed clinical worsening.