Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Background: Dulaglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist administered subcutaneously once a week, developed through recombinant DNA technology, and prescribed as an add-on to diet and exercise for managing type 2 diabetes mellitus in adults. In several clinical trials, once-weekly dulaglutide has demonstrated reductions in cardiovascular risk associated with diabetes, as well as improvements in glycemic control and weight reduction. The scope of this study was to evaluate the effect of dulaglutide 1.5 mg on glycemic control, weight management, and LDL-cholesterol levels in patients with uncontrolled type 2 diabetes mellitus. Methods: We retrospectively reviewed the medical records of 55 patients with inadequately controlled type 2 diabetes mellitus who were on oral antidiabetic agents and insulin, and who were additionally treated with dulaglutide 1.5 mg. We monitored fasting plasma glucose and glycated hemoglobin (HbA1c) at baseline and at 6, 12, and 24 months after initiating dulaglutide treatment. Weight, body mass index, and LDL-cholesterol were assessed at baseline and after 24 months of dulaglutide therapy. Results: Treatment with dulaglutide resulted in significant improvements in fasting plasma glucose and HbA1c after 6 months (p < 0.001), 12 months (p < 0.001), and 24 months (p < 0.001). A significant weight reduction was observed after 24 months of dulaglutide therapy (-3.3 kg; p < 0.001). In addition, we observed a significant reduction in LDL-cholesterol after 24 months (p < 0.001). Conclusions: Our data demonstrate that dulaglutide 1.5 mg significantly improves glycemic control, reduces body weight, and lowers LDL-cholesterol in Romanian patients with inadequately controlled type 2 diabetes.

The perioperative management of patients using glucagon-like peptide 1 receptor agonists remains a topic of debate. While several multisociety statements have been published recently, the recommendations vary significantly in terms of medication management and preoperative fasting protocols for these patients. This document represents a multidisciplinary consensus statement led by the Society for Perioperative Assessment and Quality Improvement (SPAQI). It provides updated recommendations based on a modified Delphi process and supported by a systematic review of the current literature. The recommendations address management of the glucagon-like peptide 1 receptor agonists perioperatively, and preoperative fasting times for both solids and liquids. SYSTEMATIC REVIEW PROTOCOL: PROSPERO (CRD42023438624).

HEC88473 is a novel long-acting dual agonist of glucagon-like peptide 1 (GLP-1) and fibroblast growth factor 21 (FGF21) receptors. It is a Fc fusion protein containing a fibroblast growth factor 21 and a GLP-1 moiety, fused to the N-terminal and C-terminal of the Fc fragment, respectively.

This study aimed to evaluate the clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of HEC88473.

The clinical safety, tolerability, pharmacokinetics, and preliminary pharmacodynamics of HEC88473 (0.5-62.9 mg) were evaluated in a phase I, single-ascending dose trial with healthy and obese subjects. Serum glucose, lipid, and adiponectin levels were evaluated.

HEC88473 was slowly absorbed and metabolized into Fc-GLP-1 and Fc-FGF21 after dosing. In healthy participants, the median times to observed maximum serum concentration of HEC88473, Fc-GLP-1, and Fc-FGF21 were all in the range of 12.00-14.00 h, and their geomean half-lives were 16.2-22.6, 66.5-119.5, and 28.4-41.6 h, respectively. Their systemic exposure increased slightly more than proportionally to the dose. In healthy subjects, serum glucose decreased from baseline (day 1) in the oral glucose tolerance test at days 3 and 7 after HEC88473 administration with doses ≥ 5.1 mg, and the largest reduction occured in the 47.6-mg dose group, which was -1.829 mmol/L after baseline and placebo adjustment. At doses of ≥ 10.2 mg, adiponectin levels showed an upward trend with the dose and treatment time, and the average percentage increase of adiponectin from baseline was up to 90.71% in the 62.9-mg dose group. At doses of ≥ 17.0 mg, triglyceride levels showed a significant reduction from baseline in a certain dose-dependent manner, and the average percentage of triglyceride decrease from baseline was up to - 43.01% in the 62.9-mg dose group. HEC88473 was well tolerated, with the majority of treatment-related adverse events being gastrointestinal disorders of mild severity.

HEC88473 is well tolerated in healthy and obese subjects, and it shows glucose-lowering and lipid-lowering efficacies. The data support further clinical evaluations of HEC88473 for the treatment of metabolic diseases.

This study was registered at ClinicalTrials.gov (registration number: NCT05943886).

Glucagon-like peptide-1 (GLP-1) and glucagon (GCG) are polypeptides derived from a common precursor (preproglucagon) that modulates the activity of numerous cell types involved in regulating glucose and energy homeostasis. GLP-1 and GCG exert their biological functions via binding to specific G protein-coupled receptors (GLP-1Rs and GCGRs). Ligand-activated GLP-1Rs and GCGRs preferentially activate the heterotrimeric G protein Gs, resulting in increased cytosolic cAMP levels. However, activation of the two receptors also leads to the recruitment of β-arrestin-1 and -2 (βarr1 and βarr2, respectively) to the intracellular surface of the receptor proteins. The binding of β-arrestins to the activated receptors contributes to the termination of receptor-stimulated G protein coupling. In addition, receptor-β-arrestin complexes can act as signaling nodes in their own right by modulating the activity of many intracellular signaling pathways. In this Review, we will discuss the roles of βarr1 and βarr2 in regulating key metabolic functions mediated by activated GLP-1Rs and GCGRs. During the past decade, GLP-1R agonists have emerged as highly efficacious antidiabetic and antiobesity drugs. Moreover, dual agonists that stimulate both GLP-1Rs and GCGRs are predicted to offer additional therapeutic benefits as compared to GLP-1R agonist monotherapy. We will summarize and try to synthesize a series of studies suggesting that the development of G protein-biased GLP-1R and/or GCGR agonists, which do not lead to the recruitment of β-arrestins, may lead to even more efficacious therapeutic agents.

Glucagon-like peptide-1 (GLP-1) receptor agonists delay gastric emptying and are used for the treatment of diabetes (DM) and obesity. Successful treatment of Helicobacter pylori (H. pylori) infection depends upon a precise dosing schedule. We aimed to examine the impact of GLP-1 drugs on antibiotic treatment for H. pylori.

Adults with a new diagnosis of H. pylori infection who received treatment between 2014 and 2023 were identified in the Clalit Health Services database. Subjects were divided into groups based on diagnoses of DM and obesity, and exposure to GLP-1 drugs. A 1:2 propensity-score matched dataset was used to determine the effect of GLP-1 drugs on eradication success.

We identified 426 individuals who received, and 36,436 who did not receive GLP-1 drugs. Eradication among those who did and did not receive GLP-1 drugs was 86.6% and 83.7%, respectively (p = 0.059 across subgroups). Eradication among those who received semaglutide was 93.8% (OR 2.78, 95% CI 1.32-5.83, p = 0.007). Eradication in subjects who received dulaglutide (88.6%) or liraglutide (81.4%) was not significantly changed. When applying a propensity-score-adjusted analysis, eradication remained significantly increased among individuals who received semaglutide (OR 2.89, 95% CI 1.24-6.74, p = 0.014). Additional independent predictors of successful eradication included male sex, high socioeconomic status, quadruple therapy, and older age (p < 0.001 for all).

Co-administration of semaglutide and antibiotics for H. pylori infection is associated with an increased likelihood of successful eradication.

Glucagon-like peptide-1 (GLP-1) receptor agonists and the dual GLP-1- and glucose-dependent insulinotropic polypeptide receptor co-agonist tirzepatide (referred to here collectively as "GLP-1-based therapy") are incretin-based therapies being used increasingly in the management of both type 2 diabetes and obesity. They are now recognized to have beneficial effects beyond improved glycemic control and weight loss, including cardiovascular and renal protection. GLP-1-based therapy also slows gastric emptying, which has benefits (lowering postprandial glucose), but also potential risks (eg, hypoglycemia in individuals on insulin or sulphonylurea therapy). Their effects on the gallbladder may also be beneficial, contributing to reducing postprandial triglycerides, but they also potentially increase the risk of biliary disease. In this review, we summarize the effects of GLP-1 and incretin-based therapeutics on gastric, biliary and small intestinal function. An improved understanding of these effects will optimize the use of these drugs.

Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys and has proven efficacy and safety in patients with diabetic kidney disease. We aimed to evaluate the 1-year efficacy of dulaglutide in patients with diabetic kidney disease who have used the drug for more than 1 year.

This retrospective, observational study comprised 131 patients with an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 who had received dulaglutide for more than one year between June 2016 and May 2023. The primary outcome measures were changes in glycosylated hemoglobin A1c (HbA1c), fasting plasma glucose (FPG), and body weight from baseline to the 12-month follow-up, with assessments performed at six-month intervals. Subgroup analyses were conducted based on age, sex, baseline body mass index, FPG, and HbA1c, and insulin administration at baseline and last follow-up.

The mean age was 60.0 ± 10.2 years, and 61.1% of the participants were males. Baseline HbA1c, FPG, and body weight were 9.1% (76.0 mmol/mol), 186.8 mg/dL, and 79.3 kg, respectively. Dulaglutide significantly reduced HbA1c, FPG, and body weight from baseline to the 12-month follow-up (mean ± standard error: -1.2 ± 0.1%, -34.8 ± 6.9 mg/dL, and -2.3 ± 0.5 kg, respectively; P < 0.001). Subgroup analysis revealed significant differences in HbA1c reduction based on baseline HbA1c.

Dulaglutide exhibited sustained glucose-lowering and weight-reduction effects during the initial 1 year of treatment in patients with diabetic kidney disease. Altogether, dulaglutide could serve as a favorable long-term therapeutic option for patients with diabetic kidney disease in real-world clinical settings.

Diabetes leads to a significantly accelerated incidence of various related macrovascular complications, including peripheral vascular disease and cardiovascular disease (the most common cause of mortality in diabetes), as well as microvascular complications such as kidney disease and retinopathy. Endothelial dysfunction is the main pathogenic event of diabetes-related vascular disease at the earliest stage of vascular injury. Understanding the molecular processes involved in the development of diabetes and its debilitating vascular complications might bring up more effective and specific clinical therapies. Long-acting glucagon-like peptide (GLP)-1 analogs are currently available in treating diabetes with widely established safety and extensively evaluated efficacy. In recent years, autophagy, as a critical lysosome-dependent self-degradative process to maintain homeostasis, has been shown to be involved in the vascular endothelium damage in diabetes. In this review, the GLP-1/GLP-1R system implicated in diabetic endothelial dysfunction and related autophagy mechanism underlying the pathogenesis of diabetic vascular complications are briefly presented. This review also highlights a possible crosstalk between autophagy and the GLP-1/GLP-1R axis in the treatment of diabetic angiopathy.

Glucagon-like Peptide-1 (GLP-1) receptor agonists (GLP-1RAs) emerged as a primary treatment for type-2 diabetes mellitus (T2DM), however, their multifaceted effects on various target organs beyond glycemic control opened a new era of treatment. We conducted a comprehensive literature search using databases including Scopus, Google Scholar, PubMed, and the Cochrane Library to identify clinical, in-vivo, and in-vitro studies focusing on the diverse effects of GLP-1 receptor agonists. Eligible studies were selected based on their relevance to the varied roles of GLP-1RAs in T2DM management and their impact on other physiological functions. Numerous studies have reported the efficacy of GLP-1RAs in improving outcomes in T2DM, with demonstrated benefits including glucose-dependent insulinotropic actions, modulation of insulin signaling pathways, and reductions in glycemic excursions. Additionally, GLP-1 receptors are expressed in various tissues and organs, suggesting their widespread physiological functions beyond glycemic control potentially include neuroprotective, anti-inflammatory, cardioprotective, and metabolic benefits. However, further scientific studies are still underway to maximize the benefits of GLP-1RAs and to discover additional roles in improving health benefits. This article sought to review not only the actions of GLP1RAs in the treatment of T2DM but also explore its effects on potential targets in other disorders.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) significantly reduce postprandial blood glucose, inhibit appetite, and delay gastrointestinal emptying. However, it is controversial that some patients are intolerant to GLP-1RAs.

PubMed, Embase, Web of Science, and Cochrane Library were searched for randomized controlled trials (RCTs) using GLP-1RAs with documented withdrawal due to gastrointestinal adverse reactions (GI AEs) from their inception to September 28, 2022. After extracting the information incorporated into the studies, a random-effects network meta-analysis was performed within a frequentist framework.

64 RCTs were finally enrolled, which included six major categories of the GLP-1RA. The sample size of the GLP-1RAs treatment group was 16,783 cases. The risk of intolerable gastrointestinal adverse reactions of Liraglutide and Semaglutide was higher than that of Dulaglutide. Meanwhile, the higher the dose of the same GLP-1RA preparation, the more likely to cause these adverse reactions. These intolerable GI AEs were not significantly related to drug homology or formulations and may be related to the degree of suppression of the appetite center.

Dulaglutide caused the lowest intolerable GI AEs, while Liraglutide and Semaglutide were the highest. For Semaglutide, the higher the dose, the more likely it is to drive GI AEs. Meanwhile, the risk of these GI AEs is independent of the different formulations of the drug. All these findings can effectively guide individualized treatment.

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022359346, identifier CRD42022359346.

Obesity is a complex disease characterized by excessive fat accumulation which is caused by genetic, environmental and other factors. In recent years, there has been an increase in the morbidity, disability rate,and mortality due to obesity, making it great threat to people's health and lives, and increasing public health care expenses. Evidence from previous studies show that weight loss can significantly reduce the risk of obesity-related complications and chronic diseases. Diet control, moderate exercise, behavior modification programs, bariatric surgery and prescription drug treatment are the major interventions used to help people lose weight. Among them, anti-obesity drugs have high compliance rates and cause noticeable short-term effects in reducing obese levels. However, given the safety or effectiveness concerns of anti-obesity drugs, many of the currently used drugs have limited clinical use. Glucagon-like peptide-1 receptor (GLP-1R) agonists are a group of drugs that targets incretin hormone action, and its receptors are widely distributed in nerves, islets, heart, lung, skin, and other organs. Several animal experiments and clinical trials have demonstrated that GLP-1R agonists are more effective in treating or preventing obesity. Therefore, GLP-1R agonists are promising agents for the treatment of obese individuals. This review describes evidence from previous research on the effects of GLP-1R agonists on obesity. We anticipate that this review will generate data that will help biomedical researchers or clinical workers develop obesity treatments based on GLP-1R agonists.

With an increasing prevalence of obesity, there is a need for new therapies to improve body weight management and metabolic health. Multireceptor agonists in development may provide approaches to fulfill this unmet medical need. LY3437943 is a novel triple agonist peptide at the glucagon receptor (GCGR), glucose-dependent insulinotropic polypeptide receptor (GIPR), and glucagon-like peptide-1 receptor (GLP-1R). In vitro, LY3437943 shows balanced GCGR and GLP-1R activity but more GIPR activity. In obese mice, administration of LY3437943 decreased body weight and improved glycemic control. Body weight loss was augmented by the addition of GCGR-mediated increases in energy expenditure to GIPR- and GLP-1R-driven calorie intake reduction. In a phase 1 single ascending dose study, LY3437943 showed a safety and tolerability profile similar to other incretins. Its pharmacokinetic profile supported once-weekly dosing, and a reduction in body weight persisted up to day 43 after a single dose. These findings warrant further clinical assessment of LY3437943.

We demonstrated recently that supaglutide, a novel GLP-1 mimetic generated by recombinant fusion protein techniques, exerted hypoglycemic effects in type 2 diabetes db/db mice and spontaneous diabetic monkeys. In this study, we investigated the pharmacokinetics and pharmacodynamics of supaglutide by single subcutaneous and intravenous injection(s) in rats and rhesus monkeys, as well as fourconsecutive subcutaneous injections in monkeys.We found the half-life (t1/2) of supaglutide was 39.7 hours and 35.8 hours at dosing 0.1 mg/kg upon subcutaneous or intravenous administration respectively, in rhesus monkeys. The plasma supaglutide peaked at 8-10 hours, while the plasma drug exposure levels increased with the increase of dose, showing approximately a linear pharmacokinetic characteristic. The elimination kinetics (Ke) were found to be similar between subcutaneous (∼0.025 in rats and ∼0.018 in monkeys) and intravenous administration (0.021 in rats and 0.020 in monkeys), whereas the bioavailability was found to be 31.1% in rats and 63.9% in monkeys. In monkeys, a single dose injection of supaglutide markedly decreased the random blood glucose levels that reaching the maxima effects in 14-16 hours, gradually recovered and returned to the baseline level approximately after 72 hours. 125I-supaglutide was found mainly distributed in the serum and organs rich in blood supply. Urine was found to be the primary excretion route of supaglutide, following by feces, but mostly not in bile.Our results show that supaglutide possess linear pharmacokinetic characteristics associated with prolonged hypoglycemic effects inanimals,suggestinga potential weekly dosing therapeutic reagent for the treatment of type 2 diabetes and metabolic diseases.

This study evaluated the pharmacokinetics, pharmacodynamics, and safety of a single dulaglutide dose in Chinese healthy subjects and of multiple dulaglutide doses in Chinese patients with type 2 diabetes mellitus (T2DM).

This two-part, double-blind, placebo-controlled study included 16 healthy subjects randomized to receive a single dose of placebo and two of three dulaglutide doses (0.5 mg, 0.75 mg, or 1.5 mg) in three treatment periods, and 42 patients with T2DM randomized to receive placebo or one of the three dulaglutide doses once weekly for 4 weeks. Pharmacokinetics and safety parameters were assessed in all participants, and pharmacodynamics effects were investigated in patients with T2DM.

Following a single-dose administration of 0.5 mg, 0.75 mg, or 1.5 mg dulaglutide in healthy subjects, geometric mean maximum concentrations (C_max) were 29.4, 44.2, and 81.5 ng/mL, respectively. Following weekly administration in patients with T2DM for 4 weeks, C_max were 26.3, 41.4, and 70.2 ng/mL, respectively, with accumulation ratios of 1.33-1.39. Geometric mean for half-life of 4-5 days and median time to C_max (t_max) of approximately 48 h were observed in both study populations. Dose-proportional increases in drug exposure were observed after both single and multiple dosing. Significant reductions in baseline-corrected fasting glucose and hemoglobin A1c (HbA1c) were observed in patients with T2DM who received dulaglutide 0.75 mg and 1.5 mg. Dulaglutide was well tolerated, with the majority of adverse events being gastrointestinal disorders of mild severity.

Pharmacokinetics, pharmacodynamics, and safety profiles of dulaglutide demonstrated in the present study support a once-weekly dosing regimen in Chinese patients with T2DM.

NCT01667900 (ClinicalTrials.gov).

Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are promising weight-loss drugs, but real-world data concerning the liability of GLP-1RAs in gastrointestinal safety are lacking. We examined the differences in gastrointestinal safety between semaglutide and liraglutide.

We used the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database and retrieved data during the first three years of semaglutide and liraglutide approved by the FDA. Thirteen main gastrointestinal adverse drug reactions (GADRs) were evaluated. Patient demographics, treatment information, and outcome of events were summarized. Disproportionality analyses were conducted by estimating the reporting odds ratios (RORs) and 95% confidence intervals (CIs).

In the reported cases of semaglutide (n = 2047) and liraglutide (n = 4175), semaglutide had a higher pooled ROR and later pooled time-to-onset median of GADRs compared with those of liraglutide (5.53, 95% CI 5.23-5.85 vs 3.95, 95% CI 3.81-4.10; 7 days, Q1-Q3: 0-48 vs 4 days, Q1-Q3: 0-34.5). The thirteen GADRs associated with these two GLP-1RAs showed a significant difference in the profile of reporting risk and time-to-onset.

GLP-1RAs produce a spectrum of distinct classes of GADRs. The individual properties of GADRs between semaglutide and liraglutide might enable incretin-based treatment of obesity to be "tailored" to the needs of each patient.

Dulaglutide is a long-acting glucagon-like peptide 1 receptor agonist that is administered once weekly for the treatment of type 2 diabetes. However, the immediate glucose-lowering effect of dulaglutide after the first administration and the factors affecting the efficacy of the drug remain unclear.

This study was a retrospective and observational study of 80 subjects with type 2 diabetes conducted in a hospitalized setting. The changes (Δ) in the blood glucose (BG) levels at six time points (6-point BG levels) from the baseline (day - 1) to the day after the first administration of 0.75 mg of dulaglutide (day 1) were evaluated. The associations of the Δ 6-point BG levels with the patients' characteristics and laboratory data were also analyzed.

Significant reduction of the fasting BG, preprandial BG, postprandial BG, and standard deviation (SD) of the 6-point BG levels was observed on day 1 as compared to day - 1 (P < 0.0001) and the reduced BG levels were maintained throughout the remaining observation period of 5 days. The baseline serum hemoglobin A1c and glycoalbumin levels were positively correlated with the reduction of the fasting BG. The Δ BG levels were not related to the parameters of insulin-secreting capacity. Insulin treatment was positively associated with the reduction of the 6-point BG levels. Patients without cerebrovascular disease and patients without diabetic retinopathy showed greater improvements of the fasting BG and SD of the 6-point BG levels, respectively. Urinary microalbumin level was positively correlated with improvements of the 6-point BG levels. Dulaglutide reduced the BG levels, irrespective of the previously used class of antidiabetic medication(s).

Dulaglutide achieved reduction in glucose level within 24 h of the first injection. The improvement in the BG levels remained stable for a week in the hospitalized clinical setting.

After years of intensive investigation, the definition of glycaemic variability remains unclear and the term variability in glucose homoeostasis might be more appropriate covering both short and long-term glycaemic variability. For the latter, we remain in the search of an accurate definition and related targets. Recent work leads us to consider that the within-subject variability of HbA1c calculated from consecutive determinations of HbA1c at regular time-intervals could be the most relevant index for assessing the long-term variability with a threshold value of 5% (%CV = SD of HbA1c/mean HbA1c) to separate stability from lability of HbA1c. Presently, no one can deny that short- and long-term glucose variability should be maintained within their lower ranges to limit the incidence of hypoglycaemia. Usually, therapeutic strategies aimed at reducing post-meal glucose excursions, i.e. the major contributor to daily glucose fluctuations, exert a beneficial effect on the short-term glucose variability. This explains the effectiveness of adjunct therapies with either GLP- receptor agonists or SGLT inhibitors in type 2 diabetes. In type 1 diabetes, the application of a CGM device alone reduces the short-term glycaemic variability. In contrast, sophisticated insulin delivery does not necessarily lead to such reductions despite marked downward shifts of 24-hour glycaemic profiles. Such contrasting observations raise the question as to whether the prolonged wear of CGM devices is or not the major causative factor for improvement in glucose variability among intensively insulin-treated persons with type 1 diabetes.

The processing of proglucagon in intestinal L cells results in the formation of glucagon, GLP-1, and GLP-2. The GLP-1 molecule becomes active through the effect of proconvertase 1, and it is inactivated by dipeptidyl peptidase IV (DPP-IV), so that the half-life of endogenous GLP-1 is 2-3 min. GLP-1 stimulates insulin secretion from β cells in the islets of Langerhans. Human studies show that infusion of GLP-1 results in slowing of gastric emptying and increased fasting and postprandial gastric volumes. Retardation of gastric emptying reduces postprandial glycemia. Exendin-4 is a peptide agonist of the GLP-1 receptor that promotes insulin secretion. Chemical modifications of exendin-4 and GLP-1 molecules have been accomplished to prolong the half-life of GLP-1 agonists or analogs. This chapter reviews the effects of GLP-1-related drugs used in treatment of diabetes or obesity on gastric motor functions, chiefly gastric emptying. The literature shows that diverse methods have been used to measure effects of the GLP-1-related drugs on gastric emptying, with most studies using the acetaminophen absorption test which essentially measures gastric emptying of liquids during the first hour and capacity to absorb the drug over 4-6 h, expressed as AUC. The most valid measurements by scintigraphy (solids or liquids) and acetaminophen absorption at 30 or 60 min show that GLP-1-related drugs used in diabetes or obesity retard gastric emptying, and this is associated with reduced glycemia and variable effects on food intake and appetite. GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity. The effects on gastric emptying are reduced with long-acting preparations or long-term use of short-acting preparations as a result of tachyphylaxis. The dual agonists targeting GLP-1 and another receptor (GIP) do not retard gastric emptying, based on reports to date. In summary, GLP-1 agonists and analogs are integral to the management of patients with type 2 diabetes mellitus and obesity, and their effects are mediated, at least in part, by retardation of gastric emptying.

The aim of this study was to evaluate amino acids as glucagon receptor (GCGR)-specific biomarkers in rodents and cynomolgus monkeys in the presence of agonism of both glucagon-like peptide-1 receptor (GLP1R) and GCGR with a variety of dual agonist compounds.

Primary hepatocytes, rodents (normal, diet-induced obese and GLP1R knockout) and cynomolgus monkeys were treated with insulin (hepatocytes only), glucagon (hepatocytes and cynomolgus monkeys), the GLP1R agonist, dulaglutide, or a variety of dual agonists with varying GCGR potencies.

A long-acting dual agonist, Compound 2, significantly decreased amino acids in both wild-type and GLP1R knockout mice in the absence of changes in food intake, body weight, glucose or insulin, and increased expression of hepatic amino acid transporters. Dulaglutide, or a variant of Compound 2 lacking GCGR agonism, had no effect on amino acids. A third variant with ~31-fold less GCGR potency than Compound 2 significantly decreased amino acids, albeit to a significantly lesser extent than Compound 2. Dulaglutide (with saline infusion) had no effect on amino acids, but an infusion of glucagon dose-dependently decreased amino acids on the background of GLP1R engagement (dulaglutide) in cynomolgus monkeys, as did Compound 2.

These results show that amino acids are sensitive and translatable GCGR-specific biomarkers.

Although patient-reported outcome (PRO) measures provide important information beyond clinical data, studies that assess the PROs of type 2 diabetes mellitus (T2DM) patients initiating injectable glucose-lowering medications in routine clinical practice are limited. We describe the perspectives of patients based on a diversified panel of generic and disease-specific PRO measures at the time of enrollment (baseline) in the TROPHIES study.

TROPHIES is a 24-month prospective observational study performed in France, Germany, and Italy in patients with T2DM who initiated their first injectable glucose-lowering medication with once-weekly dulaglutide or once-daily liraglutide. To better understand the perspectives of these patients regarding their overall health, treatment satisfaction, and quality of life and work, the patients' responses to the following questionnaires were collected at baseline before they initiated treatment with dulaglutide or liraglutide: EQ-5D-5L (scale: 0-1), EQ-VAS (visual analog scale: 0-100), Impact of Weight on Self-Perceptions Questionnaire (IW-SP; scale: 0-100), Diabetes Treatment Satisfaction Questionnaire Status (DTSQs; scale: 0-36), and Diabetes Productivity Measure (DPM; scale: 0-100). Analyses were descriptive in nature, with higher scores reflecting better outcomes.

Data from patients at the time of enrollment were analyzed. At baseline, patients initiating dulaglutide (N = 1130) or liraglutide (N = 1051) rated their quality of life in terms of mean EQ-5D-5L index as 0.84 and 0.83, and in terms of mean EQ-VAS as 67.5 and 67.5, respectively. The mean baseline scores in patients initiating dulaglutide or liraglutide were 59.8 and 61.3 for IW-SP, 24.6 and 25.8 for DTSQs, 78.6 and 79.5 for DPM Life Productivity, and 87.5 and 86.8 for DPM Work Productivity, respectively.

The information from this varied panel of PRO instruments collected at baseline complements clinical outcomes data.

Given the limited efficacy of available pharmacotherapies for treatment of alcohol use disorder (AUD), the need for new medications is substantial. Preclinical studies have shown that acute administration of glucagon-like peptide-1 receptor (GLP-1R) agonists inhibits various ethanol-related behaviours, indicating this system as a potential target for AUD. However, the effects of long-term systemic treatment of GLP-1R agonists on ethanol intake in male and female rodents are to date unknown. Therefore, we investigated the effects of 9 or 5 weeks of once weekly administration of dulaglutide, a long-acting GLP-1R agonist, on ethanol intake in male and female rats. The ethanol intake during treatment discontinuation was also monitored. In an initial attempt to identify preliminary underlying mechanisms, the effects of 9 weeks of once weekly dulaglutide treatment on monoaminergic signalling in reward-related areas were explored in both sexes. We found that 9 or 5 weeks of once weekly dulaglutide treatment reduced ethanol intake and preference in male and female rats. Following discontinuation of dulaglutide treatment, the decrease in ethanol consumption was prolonged in males, but not females. We demonstrated that 9 weeks of dulaglutide treatment differentially influenced monoaminergic signalling in reward-related areas of male and female rats. Collectively, these data imply that the GLP-1R attracts interest as a potential molecular target in the medical treatment of AUD in humans: more specifically, dulaglutide should be evaluated as a potential medication for treatment thereof.

To identify potential application of GLP1-RAs (glucagon-like peptide-1 receptor agonists) and SGLT2-Is (sodium-dependent glucose cotrasnsporter-2 inhibitors) in cardiovascular medicine, we performed PubMed search until March 31, 2020 and selected placebo-controlled randomized trials (RCTs) in patients with type 2 diabetes mellitus. Twenty-four hour ambulatory and office blood pressure (BP), major adverse cardiovascular events (MACE), progression of chronic kidney disease (CKD), and changes in glycated hemoglobin and body weight were aggregated across RCTs using random-effect models. In 2238 patients (7 RCTs), SGLT2-Is lowered 24-hour systolic/diastolic BP by 4.4/1.9 mm Hg (95% CI, 3.4-5.5/1.2-2.6 mm Hg), whereas 2 GLP1-RAs RCTs produced contradictory BP results. Over 1.3 to 5.4 years of follow-up of 56 004 patients (7 RCTs), aggregate hazard ratios associated with GLP1-RA treatment were 0.88 (0.84-0.93) for MACE, 0.84 (0.74-0.89) for CKD, and ranged from 0.84 to 0.90 for individual MACE end points (P≤0.01). Across 5 SGLT2-Is RCTs, including 43 467 patients with 1.5 to 4.2 years follow-up, hazard ratios were 0.87 (0.82-0.93) for MACE, 0.68 (0.62-0.75) for HF, 0.82 (0.72-0.93) for cardiovascular death, 0.87 (0.79-0.96) for myocardial infarction, and 0.61 (0.56-0.67) for worsening CKD. The risk of HF and CKD, but not MACE, decreased with more BP lowering. Stricter glycemic control was associated with higher HF risk, but unrelated to MACE or CKD. The aggregate effect sizes on systolic BP, body weight, and glycated hemoglobin were -1.61 mm Hg, -2.40 kg, and -0.69% for GLP1-RAs, and -2.53 mm Hg, -1.15 kg and -0.24%, for SGLT2-Is (P<0.001). In conclusion, GLP1-RAs and SGLT2-Is reduced cardiovascular risk with differential benefit profiles.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits. In order to encourage its wide dissemination this article is freely accessible on the BMJ and Trials journal websites."To maximise the benefit to society, you need to not just do research but do it well" Douglas G Altman.

Adaptive designs (ADs) allow pre-planned changes to an ongoing trial without compromising the validity of conclusions and it is essential to distinguish pre-planned from unplanned changes that may also occur. The reporting of ADs in randomised trials is inconsistent and needs improving. Incompletely reported AD randomised trials are difficult to reproduce and are hard to interpret and synthesise. This consequently hampers their ability to inform practice as well as future research and contributes to research waste. Better transparency and adequate reporting will enable the potential benefits of ADs to be realised.This extension to the Consolidated Standards Of Reporting Trials (CONSORT) 2010 statement was developed to enhance the reporting of randomised AD clinical trials. We developed an Adaptive designs CONSORT Extension (ACE) guideline through a two-stage Delphi process with input from multidisciplinary key stakeholders in clinical trials research in the public and private sectors from 21 countries, followed by a consensus meeting. Members of the CONSORT Group were involved during the development process.The paper presents the ACE checklists for AD randomised trial reports and abstracts, as well as an explanation with examples to aid the application of the guideline. The ACE checklist comprises seven new items, nine modified items, six unchanged items for which additional explanatory text clarifies further considerations for ADs, and 20 unchanged items not requiring further explanatory text. The ACE abstract checklist has one new item, one modified item, one unchanged item with additional explanatory text for ADs, and 15 unchanged items not requiring further explanatory text.The intention is to enhance transparency and improve reporting of AD randomised trials to improve the interpretability of their results and reproducibility of their methods, results and inference. We also hope indirectly to facilitate the much-needed knowledge transfer of innovative trial designs to maximise their potential benefits.

The metabolic syndrome (MetS) encompasses medical conditions such as obesity, hyperglycemia, high blood pressure, and dyslipidemia that are major drivers for the ever-increasing prevalence of type 2 diabetes, cardiovascular diseases, and certain types of cancer. At the core of clinical strategies against the MetS is weight loss, induced by bariatric surgery, lifestyle changes based on calorie reduction and exercise, or pharmacology. This Review summarizes the past, current, and future efforts of targeting the MetS by pharmacological agents. Major emphasis is given to drugs that target the CNS as a key denominator for obesity and its comorbid sequelae.

Dulaglutide is a recombinant glucagon-like peptide-1 immunoglobulin G4 Fc fusion protein approved for treating patients with type 2 diabetes (T2D). The aim of this study was to assess postprandial data over 4 weeks for dulaglutide (0.75 mg) versus placebo after a standardized test meal in Japanese patients with T2D.

The pharmacodynamic (PD) effects of once-weekly dulaglutide (0.75 mg) in Japanese patients with T2D on diet and exercise therapy (N = 12) were evaluated by assessing postprandial data up to week 4 in a phase 4, single-center, randomized, cross-over, single-blind, placebo-controlled study. The primary end point was the change in 4-h glucose area under the concentration versus time curve [AUC (0-4 h)] from baseline to week 4. Secondary end points included changes from baseline in other PD parameters (insulin, C-peptide, glucagon, and triglycerides) at weeks 1, 2, and 4 and the safety and tolerability of dulaglutide 0.75 mg. Continuous glucose monitoring (CGM) during the 1st week was performed as an exploratory measure in each treatment period.

The decrease in AUC (0-4 h) from baseline to week 4 following dulaglutide administration was statistically significant compared with placebo at weeks 1, 2, and 4 (P < 0.0001). Insulin and C-peptide levels were also significantly increased (P < 0.05) with dulaglutide versus placebo at weeks 2 and 4. There were no statistically significant differences between groups in glucagon and triglyceride levels. Daily average glucose concentrations were decreased on the day after the first administration of dulaglutide and remained at similar levels for 4 days. The incidence of treatment-emergent adverse events was slightly higher with dulaglutide versus placebo.

In conclusion, dulaglutide decreased postprandial glucose from week 1 in Japanese patients with T2D, indicating that dulaglutide treatment is associated with favorable PD effects soon after treatment begins.

ClinicalTrials.gov identifier: NCT03315780.

Eli Lilly Japan K.K. (Kobe, Japan).

Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are an important class of drugs with a well-established efficacy and safety profile in patients with type 2 diabetes mellitus. Agents in this class are derived from either exendin-4 (a compound present in Gila monster venom) or modifications of human GLP-1 active fragment. Differences among these drugs in duration of action (ie, short-acting vs long-acting), effects on glycaemic control and weight loss, immunogenicity, tolerability profiles, and administration routes offer physicians several options when selecting the most appropriate agent for individual patients. Patient preference is also an important consideration. The aim of this review is to discuss the differences between and similarities of GLP-1 RAs currently approved for clinical use, focusing particularly on the properties characterising the single short-acting and long-acting GLP-1 RAs rather than on their individual efficacy and safety profiles. The primary pharmacodynamic difference between short-acting (ie, exenatide twice daily and lixisenatide) and long-acting (ie, albiglutide, dulaglutide, exenatide once weekly, liraglutide, and semaglutide) GLP-1 RAs is that short-acting agents primarily delay gastric emptying (lowering postprandial glucose) and long-acting agents affect both fasting glucose (via enhanced glucose-dependent insulin secretion and reduced glucagon secretion in the fasting state) and postprandial glucose (via enhanced postprandial insulin secretion and inhibition of glucagon secretion). Other advantages of long-acting GLP-1 RAs include smaller fluctuations in plasma drug concentrations, improved gastrointestinal tolerability profiles, and simpler, more convenient administration schedules (once daily for liraglutide and once weekly for albiglutide, dulaglutide, the long-acting exenatide formulation, and semaglutide), which might improve treatment adherence and persistence.

A novel dual GIP and GLP-1 receptor agonist, LY3298176, was developed to determine whether the metabolic action of GIP adds to the established clinical benefits of selective GLP-1 receptor agonists in type 2 diabetes mellitus (T2DM).

LY3298176 is a fatty acid modified peptide with dual GIP and GLP-1 receptor agonist activity designed for once-weekly subcutaneous administration. LY3298176 was characterised in vitro, using signaling and functional assays in cell lines expressing recombinant or endogenous incretin receptors, and in vivo using body weight, food intake, insulin secretion and glycemic profiles in mice. A Phase 1, randomised, placebo-controlled, double-blind study was comprised of three parts: a single-ascending dose (SAD; doses 0.25-8 mg) and 4-week multiple-ascending dose (MAD; doses 0.5-10 mg) studies in healthy subjects (HS), followed by a 4-week multiple-dose Phase 1 b proof-of-concept (POC; doses 0.5-15 mg) in patients with T2DM (ClinicalTrials.gov no. NCT02759107). Doses higher than 5 mg were attained by titration, dulaglutide (DU) was used as a positive control. The primary objective was to investigate safety and tolerability of LY3298176.

LY3298176 activated both GIP and GLP-1 receptor signaling in vitro and showed glucose-dependent insulin secretion and improved glucose tolerance by acting on both GIP and GLP-1 receptors in mice. With chronic administration to mice, LY3298176 potently decreased body weight and food intake; these effects were significantly greater than the effects of a GLP-1 receptor agonist. A total of 142 human subjects received at least 1 dose of LY3298176, dulaglutide, or placebo. The PK profile of LY3298176 was investigated over a wide dose range (0.25-15 mg) and supports once-weekly administration. In the Phase 1 b trial of diabetic subjects, LY3298176 doses of 10 mg and 15 mg significantly reduced fasting serum glucose compared to placebo (least square mean [LSM] difference [95% CI]: -49.12 mg/dL [-78.14, -20.12] and -43.15 mg/dL [-73.06, -13.21], respectively). Reductions in body weight were significantly greater with the LY3298176 1.5 mg, 4.5 mg and 10 mg doses versus placebo in MAD HS (LSM difference [95% CI]: -1.75 kg [-3.38, -0.12], -5.09 kg [-6.72, -3.46] and -4.61 kg [-6.21, -3.01], respectively) and doses of 10 mg and 15 mg had a relevant effect in T2DM patients (LSM difference [95% CI]: -2.62 kg [-3.79, -1.45] and -2.07 kg [-3.25, -0.88], respectively. The most frequent side effects reported with LY3298176 were gastrointestinal (vomiting, nausea, decreased appetite, diarrhoea, and abdominal distension) in both HS and patients with T2DM; all were dose-dependent and considered mild to moderate in severity.

Based on these results, the pharmacology of LY3298176 translates from preclinical to clinical studies. LY3298176 has the potential to deliver clinically meaningful improvement in glycaemic control and body weight. The data warrant further clinical evaluation of LY3298176 for the treatment of T2DM and potentially obesity.

Glucagon-like peptide 1 (GLP-1) was originally identified as a gut-derived incretin hormone that lowered glycemia through potentiation of glucose-dependent insulin secretion. Subsequent studies expanded the actions of GLP-1 to include inhibition of glucagon secretion, gastric emptying, and appetite, collectively useful attributes for a glucose-lowering agent. The introduction of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes was associated with questions surrounding their safety, principally with regard to medullary thyroid cancer, pancreatitis, and pancreatic cancer, yet cardiovascular outcome trials subsequently revealed reductions in rates of stroke, myocardial infarction, and cardiovascular death with a paucity of major safety signals. We discuss the controversies, unanswered questions, and established use of GLP-1R agonists from a mechanistic and clinical perspective. We highlight methods for detection and cellular sites of GLP-1R expression, key uncertainties, recent insights, and experimental caveats surrounding the use of GLP-1R agonists for the treatment of diabetes and the reduction of diabetes-related complications.

Dulaglutide is a once-weekly glucagon-like peptide-1 receptor agonist, which has been on the market in the USA since 2014. Dulaglutide has performed well in head-to-head studies against metformin, glargine, and sitagliptin, where its A1c lowering ranged from -0.78% to -1.64% over 52-104 weeks, and it consistently outperformed each of these agents. As an add-on therapy, dulaglutide provided additional A1c lowering of -1.4% to -1.44% over monotherapy with glimepiride or glargine at 24 and 28 weeks, respectively. Dulaglutide outperformed exenatide when added to a regimen of metformin with pioglitazone as well as glargine when added to a regimen of metformin with glimepiride. Dulaglutide was shown to be non-inferior to liraglutide when added to metformin. In all AWARD studies other than when compared to liraglutide, dulaglutide at full strength resulted in significantly more patients achieving their A1c goal. Recent class-wide meta-analyses indicate that the incidence of commonly experienced gastrointestinal (GI) side effects is dose dependent, and nausea and vomiting are less common in longer-acting agents such as dulaglutide, but diarrhea may be more common. Pooled data have shown no increased risk of serious side effects such as pancreatitis or neoplasm with the use of dulaglutide. Given the evidence supporting liraglutide's cardiovascular benefits, the highly anticipated REWIND trial will have a significant impact on the future place in the therapy of dulaglutide.

Glucagon-like peptide-1 receptor (GLP-1R) activation promotes insulin secretion from pancreatic beta cells, causes weight loss, and is an important pharmacological target in type 2 diabetes (T2D). Like other G protein-coupled receptors, the GLP-1R undergoes agonist-mediated endocytosis, but the functional and therapeutic consequences of modulating GLP-1R endocytic trafficking have not been clearly defined. Here, we investigate a series of biased GLP-1R agonists with variable propensities for GLP-1R internalization and recycling. Compared to a panel of FDA-approved GLP-1 mimetics, compounds that retain GLP-1R at the plasma membrane produce greater long-term insulin release, which is dependent on a reduction in β-arrestin recruitment and faster agonist dissociation rates. Such molecules elicit glycemic benefits in mice without concomitant increases in signs of nausea, a common side effect of GLP-1 therapies. Our study identifies a set of agents with specific GLP-1R trafficking profiles and the potential for greater efficacy and tolerability as T2D treatments.

The present post hoc analysis investigated whether changes in endogenous glucagon-like peptide-1 (∆GLP-1) levels are associated with weight loss in newly diagnosed diabetes patients.

In all, 784 subjects from the Metformin and AcaRbose in Chinese as initial Hypoglycemic treatment (MARCH) study were stratified according to ∆GLP-1. Changes in clinical and physiological parameters were evaluated across ∆GLP-1 subgroups (low, medium, and high) to assess correlations between ∆GLP-1 and weight loss in acarbose- versus metformin-treated groups.

After 24 weeks treatment, greater ∆GLP-1 was associated with significantly greater weight loss (-2 vs -1 kg in the medium/high vs low ∆GLP-1 groups, respectively) and reduction in body mass index (BMI; -0.88, -0.83, and -0.69 kg/m² in the high, medium, and low ∆GLP-1 groups, respectively). In the acarbose-treated group, there was a significant association between ∆GLP-1 and BMI reductions, and greater ∆GLP-1 across the high, medium, and low ∆GLP-1 groups was correlated with greater weight loss (-2.8, -2.1, and -1.9 kg, respectively) and reductions in fasting plasma glucose (-1.57, -1.28, and -1.02 mmol/L, respectively) at Week 24. No significant differences were found across ∆GLP-1 subgroups in metformin-treated patients (P > 0.05). Multivariate linear regression analysis revealed that gender, baseline BMI, and ∆GLP-1 at Week 24 were associated with weight loss. Baseline BMI and ∆GLP-1 in the acarbose-treated group and baseline BMI in the metformin-treated group predicted weight loss at Week 24.

Changes in GLP-1 levels are associated with weight loss in newly diagnosed Chinese diabetes patients receiving acarbose.