Glucagon-like peptide-1 receptor agonists to expand the healthy lifespan: Current and future potentials.

To help ensure an expanded healthy lifespan for as many people as possible worldwide, there is a need to prevent or manage a number of prevalent chronic diseases directly and indirectly closely related to aging, including diabetes and obesity. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have proven beneficial in type 2 diabetes, are amongst the few medicines approved for weight management, and are also licensed for focused cardiovascular risk reduction. In addition, strong evidence suggests several other beneficial effects of the pleiotropic peptide hormone, including anti-inflammation.

The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease.

Background: Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects.

Pharmacogenomics of GLP-1 receptor agonists: a genome-wide analysis of observational data and large randomised controlled trials.

Background: In the treatment of type 2 diabetes, GLP-1 receptor agonists lower blood glucose concentrations, body weight, and have cardiovascular benefits. The efficacy and side effects of GLP-1 receptor agonists vary between people. Human pharmacogenomic studies of this inter-individual variation can provide both biological insight into drug action and provide biomarkers to inform clinical decision making.

Insulin at 100: still central in protein-based therapy for chronic disease.

The discovery of insulin has inspired several pivotal medical and scientific developments during the past 100 years. Here, we describe how insulin as a model protein will drive future advances in peptide- and protein-based therapies for chronic diseases.

Current and future therapies for type 1 diabetes.

In type 1 diabetes, insulin remains the mature therapeutic cornerstone; yet, the increasing number of individuals developing type 1 diabetes (predominantly children and adolescents) still face severe complications. Fortunately, our understanding of type 1 diabetes is continuously being refined, allowing for refocused development of novel prevention and management strategies. Hitherto, attempts based on immune suppression and modulation have been only partly successful in preventing the key pathophysiological feature in type 1 diabetes: the immune-mediated derangement or destruction of beta cells in the pancreatic islets of Langerhans, leading to low or absent insulin secretion and chronic hyperglycaemia.

Does Islet Size Really Influence Graft Function After Clinical Islet Transplantation?

Background: It has been proposed that islet transplants comprised primarily of small rather than large islets may provide better graft function, due to their lower susceptibility to hypoxic damage. Our aim was to determine whether islet size correlated with in vivo graft function in islet transplant recipients with C peptide-negative type 1 diabetes when islets have undergone pretransplant islet culture.

Methods: Human pancreatic islets were isolated, cultured for 24 hours and infused by standardized protocols.

Insulin degludec/liraglutide (IDegLira) for the treatment of type 2 diabetes.

The progressive nature of type 2 diabetes necessitates that treatment is intensified as the disease advances. Several studies have shown that basal insulin and glucagon-like peptide-1 receptor agonists (GLP-1RAs) can be used in combination to successfully improve glycemic control and this combination is increasingly being considered as an alternative to intensification with prandial insulin. Insulin degludec/liraglutide (IDegLira) is the first fixed-ratio combination of a basal insulin and a GLP-1RA in a single formulation.

Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study.

Background: Glucagon-like peptide-1 (GLP-1) analogues reduce hepatic steatosis, concentrations of liver enzymes, and insulin resistance in murine models of fatty liver disease. These analogues are licensed for type 2 diabetes, but their efficacy in patients with non-alcoholic steatohepatitis is unknown. We assessed the safety and efficacy of the long-acting GLP-1 analogue, liraglutide, in patients with non-alcoholic steatohepatitis.

IDegLira Improves Both Fasting and Postprandial Glucose Control as Demonstrated Using Continuous Glucose Monitoring and a Standardized Meal Test.

Objective: IDegLira is a novel, fixed-ratio combination of the long-acting basal insulin, insulin degludec, and the long-acting glucagon-like peptide-1 analog liraglutide. We studied the effect of IDegLira versus its components on postprandial glucose (PPG) in type 2 diabetes.

Methods: In this substudy, 260 (15.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.

Background & Aims: Insulin resistance and lipotoxicity are pathognomonic in non-alcoholic steatohepatitis (NASH). Glucagon-like peptide-1 (GLP-1) analogues are licensed for type 2 diabetes, but no prospective experimental data exists in NASH. This study determined the effect of a long-acting GLP-1 analogue, liraglutide, on organ-specific insulin sensitivity, hepatic lipid handling and adipose dysfunction in biopsy-proven NASH.

Early postoperative continuous glucose monitoring in pancreas transplant recipients.

Continuous glucose monitoring (CGM) is used in people with type 1 diabetes to help with insulin treatment regimens. Its value in whole-organ pancreas transplantation (PT) is largely unknown. This study aimed to use CGM to assess the metabolic profile of pancreas transplant recipients in the early post-transplant period.

Endothelial nitric oxide synthase single nucleotide polymorphism and left ventricular function in early chronic kidney disease.

Background: Chronic kidney disease (CKD) is associated with accelerated cardiovascular disease and heart failure. Endothelial nitric oxide synthase (eNOS) Glu298Asp single nucleotide polymorphism (SNP) genotype has been associated with a worse phenotype amongst patients with established heart failure and in patients with progression of their renal disease. The association of a cardiac functional difference in non-dialysis CKD patients with no known previous heart failure, and eNOS gene variant is investigated.

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes.

Background: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients.

Methods: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day).

Comparison of IFCC-calibrated HbA(1c) from laboratory and point of care testing systems.

Objective: WHO, IDF and ADA recommend HbA(1c) ≥6.5% (48 mmol/mol) for diagnosis of diabetes with pre-diabetes 6.0% (42 mmol/mol) [WHO] or 5.

Recent advances with insulin degludec for the treatment of Type 2 diabetes.

Type 2 diabetes has been referred to as the global epidemic of the 21st century, and is associated with significant morbidity and premature mortality. Estimates suggest that over 50% of people with Type 2 diabetes will at some point need insulin injections to help treat their diabetes. Once daily insulin injections are being increasingly used to initiate insulin in people with Type 2 diabetes and the development of novel, safe, once daily basal insulins with low rates of hypoglycaemia are important to help achieve internationally recommended glycaemic targets for individual patients.

Impact of month of birth on the development of autoimmune thyroid disease in the United Kingdom and Europe.

Context: Viral/bacterial infection is proposed as a trigger for the autoimmune thyroid diseases (AITD): Graves' disease (GD) and Hashimoto's thyroiditis (HT). Previous studies in European Caucasian AITD subjects found higher birth rates in the autumn/winter, suggesting those born in the autumn/winter experience increased viral/bacterial exposure after birth, impacting upon immune system development and predisposing to AITD later in life.

Objective: Month of birth effects were investigated in three independent European Caucasian AITD datasets.

Identification of novel genetic Loci associated with thyroid peroxidase antibodies and clinical thyroid disease.

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals.

Reduced risk of hypoglycemia with insulin degludec versus insulin glargine in patients with type 2 diabetes requiring high doses of basal insulin: a meta-analysis of 5 randomized begin trials.

Objective: This meta-analysis of 5 trials from the Phase 3a insulin degludec (IDeg) clinical trial program evaluated the risk of hypoglycemia in a subset of subjects with type 2 diabetes (T2D) who required high basal insulin doses at the end of the trials.

Methods: This meta-analysis compared glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), basal insulin dose, body weight, and rates of overall and nocturnal confirmed hypoglycemia in a pooled population of T2D subjects using >60 U basal insulin at trial completion. Five Phase 3a, open-label, randomized, treat-to-target, confirmatory 26- or 52-week trials with IDeg (n = 2,262) versus insulin glargine (IGlar) (n = 1,110) administered once daily were included.

Liraglutide efficacy and action in non-alcoholic steatohepatitis (LEAN): study protocol for a phase II multicentre, double-blinded, randomised, controlled trial.

Introduction: Non-alcoholic steatohepatitis (NASH) is now the commonest cause of chronic liver disease. Despite this, there are no universally accepted pharmacological therapies for NASH. Liraglutide (Victoza), a human glucagon-like peptide-1 (GLP-1) analogue, has been shown to improve weight loss, glycaemic control and liver enzymes in type 2 diabetes.

Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis.

Context: A number of small data sets have suggested a potential role for skewed X chromosome activation (XCI), away from the expected 50:50 parent of origin ratio, as an explanation for the strong female preponderance seen in the common autoimmune thyroid diseases (AITD), Graves' disease (GD), and Hashimoto's thyroiditis (HT).

Objective: The objective of the study was to confirm a role for XCI skewing as a potential explanation for the strong female preponderance seen in AITD.

Design: The design of the study was to screen XCI in the largest GD, HT, and control case-control cohort and family cohort to date and undertake a meta-analysis of previous AITD XCI reports.

Elderly patients with diabetes experience a lower rate of nocturnal hypoglycaemia with insulin degludec than with insulin glargine: a meta-analysis of phase IIIa trials.

Background And Objective: Elderly patients with diabetes are more vulnerable to the occurrence and effects of hypoglycaemia; therefore, treatments with low risk of hypoglycaemia are preferred in this population. This study aimed to compare hypoglycaemia rates between insulin degludec (IDeg) and insulin glargine (IGlar) in elderly patients.

Methods: Hypoglycaemia data from patients ≥65 years of age with type 1 (T1DM) or type 2 (T2DM) diabetes from seven randomised, treat-to-target phase IIIa trials were used to compare IDeg and IGlar in a pre-planned meta-analysis.