A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus.
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SUBMITTER: Kalra S
PROVIDER: S-EPMC7434819 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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A Review on Semaglutide: An Oral Glucagon-Like Peptide 1 Receptor Agonist in Management of Type 2 Diabetes Mellitus.
Diabetes therapy : research, treatment and education of diabetes and related disorders 20200728 9
Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) are a well-established class of glucose-lowering drugs. GLP-1 RAs can be classified according to their structure, duration of action and mode of administration. This review describes the basic and clinical pharmacology of orally administered semaglutide. It highlights the PIONEER clinical trial programme results, and reviews the efficacy, safety and tolerability. ...[more]
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Project description:Glucagon-like peptide-1 (GLP-1) is a promising target for diabetes mellitus (DM) therapy and reduces the occurrence of diabetes due to obesity. However, GLP-1 will be hydrolyzed soon by the enzyme dipeptidyl peptidase-4 (DPP-4). We tried to design small molecular drugs for GLP-1 receptor agonist from the world's largest traditional Chinese medicine (TCM) Database@Taiwan. According to docking results of virtual screening, we selected 2 TCM compounds, wenyujinoside and 28-deglucosylchikusetsusaponin IV, for further molecular dynamics (MD) simulation. GLP-1 was assigned as the control compound. Based on the results of root mean square deviation (RMSD), solvent accessible surface (SAS), mean square deviation (MSD), Gyrate, total energy, root mean square fluctuation (RMSF), matrices of smallest distance of residues, database of secondary structure assignment (DSSP), cluster analysis, and distance of H-bond, we concluded that all the 3 compounds could bind and activate GLP-1 receptor by computational simulation. Wenyujinoside and 28-deglucosylchikusetsusaponin IV were the TCM compounds that could be GLP-1 receptor agonists.
| S-EPMC4033432 | biostudies-literature
Project description:BackgroundGlucagon-like peptide analogues are a new class of drugs used in the treatment of type 2 diabetes that mimic the endogenous hormone glucagon-like peptide 1 (GLP-1). GLP-1 is an incretin, a gastrointestinal hormone that is released into the circulation in response to ingested nutrients. GLP-1 regulates glucose levels by stimulating glucose-dependent insulin secretion and biosynthesis, and by suppressing glucagon secretion, delayed gastric emptying and promoting satiety.ObjectivesTo assess the effects of glucagon-like peptide analogues in patients with type 2 diabetes mellitus.Search strategyStudies were obtained from electronic searches of The Cochrane Library (last search issue 1, 2011), MEDLINE (last search March 2011), EMBASE (last search March 2011), Web of Science (last search March 2011) and databases of ongoing trials.Selection criteriaStudies were included if they were randomised controlled trials of a minimum duration of eight weeks comparing a GLP-1 analogue with placebo, insulin, an oral anti-diabetic agent, or another GLP-1 analogue in people with type 2 diabetes.Data collection and analysisData extraction and quality assessment of studies were done by one reviewer and checked by a second. Data were analysed by type of GLP-1 agonist and comparison treatment. Where appropriate, data were summarised in a meta-analysis (mean differences and risk ratios summarised using a random-effects model).Main resultsSeventeen randomised controlled trials including relevant analyses for 6899 participants were included in the analysis. Studies were mostly of short duration, usually 26 weeks.In comparison with placebo, all GLP-1 agonists reduced glycosylated haemoglobin A1c (HbA1c) levels by about 1%. Exenatide 2 mg once weekly and liraglutide 1.8 mg reduced it by 0.20% and 0.24% respectively more than insulin glargine. Exenatide 2 mg once weekly reduced HbA1c more than exenatide 10 μg twice daily, sitagliptin and pioglitazone. Liraglutide 1.8 mg reduced HbA1c by 0.33% more than exenatide 10 μg twice daily. Liraglutide led to similar improvements in HbA1c compared to sulphonylureas but reduced it more than sitagliptin and rosiglitazone.Both exenatide and liraglutide led to greater weight loss than most active comparators, including in participants not experiencing nausea. Hypoglycaemia occurred more frequently in participants taking concomitant sulphonylurea. GLP-1 agonists caused gastrointestinal adverse effects, mainly nausea. These adverse events were strongest at the beginning and then subsided. Beta-cell function was improved with GLP-1 agonists but the effect did not persist after cessation of treatment.None of the studies was long enough to assess long-term positive or negative effects.Authors' conclusionsGLP-1 agonists are effective in improving glycaemic control.
| S-EPMC6486297 | biostudies-literature
Project description:IntroductionGlucagon-like peptide-1 receptor agonists (GLP-1RAs) differ in efficacy, side effects, dosing frequency, and device-related attributes. This study assessed the relative importance of treatment-related attributes in influencing preferences for GLP-1RAs among injection-naïve patients with type 2 diabetes mellitus (T2DM).MethodsInjection-naïve T2DM patients from five countries completed a Web-based discrete choice experiment (DCE) survey. Patients chose between hypothetical treatment profiles reflecting important and differentiating attributes of GLP-1RAs. Eight attributes were included: efficacy, side effects, device size, needle size, titration, preparation, evidence of long-term efficacy/safety, and dosing frequency. Odds ratios (ORs) and 95% confidence intervals were calculated using a conditional logit model to indicate the likelihood of choosing a treatment with a given attribute level versus a reference attribute level. The influence of individual attributes when considering full treatment profiles was examined using exenatide once weekly (QW) and liraglutide once daily (QD) as case examples.ResultsA total of 1482 patients with T2DM completed the DCE survey. Side effects, efficacy, and dosing frequency were the three most important attributes influencing preferences; needle size, device size, and required preparation were least important. Total sample analysis indicated that a profile of GLP-1RA approximating exenatide QW (single pen) was preferred over a profile approximating liraglutide QD (OR 3.36; p < 0.001), when efficacy was assumed to be equal.ConclusionThe most influential drivers of treatment preferences for a hypothetical GLP-RA profile were side effects, efficacy, and dosing frequency among injection-naïve T2DM patients. Preference elicitation can promote patient-centered care and inform new generations of T2DM treatments, which can lead to improved adherence and health outcomes.
| S-EPMC5380493 | biostudies-literature
Project description:IntroductionTo complement results of the SUSTAIN program, this study assessed effectiveness and safety of once weekly subcutaneous semaglutide in people with type 2 diabetes (T2D) managed under routine care.MethodsThis was a multicenter, observational, retrospective study including all patients treated with semaglutide. Changes in clinical outcomes from baseline to 6 and 12 months were assessed in patients who were glucagon-like peptide receptor agonist (GLP-1RA) naïve or switching from another GLP-1RA. Discontinuation rate was assessed.ResultsOverall, 216 patients (mean age 64 years, 65.7% men) were evaluated: 135 (61.5%) naïve and 81 (38.5%) switchers from another GLP-1RA. In the naïve cohort, after 6 months from semaglutide initiation, levels of HbA1c significantly decreased by - 1.31% (p < 0.0001). All obesity indices improved, with mean reductions in body weight of - 3.92 kg, in BMI of - 1.43 kg/m2, and in waist circumference of - 5.03 cm. In the switcher cohort, statistically significant improvements in HbA1c (- 0.78%), body weight (- 2.64 kg), and waist circumference (- 3.03 cm) were obtained after 6 months. Reductions were sustained after 12 months in both cohorts (mean semaglutide dose: 0.86 mg in naïve and 0.96 mg in switcher cohort). Blood pressure and lipid profile mean levels decreased after 12 months from semaglutide initiation in both cohorts. No severe hypoglycemia occurred; 6.5% of patients discontinued semaglutide (2.8% due to gastrointestinal side effects).ConclusionEffectiveness and tolerability of semaglutide have been confirmed in the real world irrespective of diabetes duration and severity. As expected, more marked reductions in HbA1c and obesity indices were obtained in naïve patients, but it is noteworthy that relevant improvements were also obtained in patients already treated with GLP-1RAs.
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Project description:Aims/introductionGlucagon-like peptide-1 receptor agonists (GLP-1 RA) might be less effective in patients with severe hyperglycemia, because hyperglycemia downregulated the GLP-1 receptor in an animal study. To examine this hypothesis clinically, we compared the glucose-lowering effects of GLP-1 receptor agonist liraglutide with and without prior glycemic control.Materials and methodsIn an open-label, parallel trial, participants with poorly controlled type 2 diabetes were recruited and randomized to receive once-daily insulin therapy, degludec (Insulin-GLP-1 RA relay group, mean 16.8 ± 11.4 IU/day), for 12 weeks and then liraglutide for 12 weeks or subcutaneous injections of GLP-1 RA, liraglutide (GLP-1 RA first group, 0.9 mg), for 24 weeks. The primary efficacy end-points consisted of changes in the levels of fasting plasma glucose and glycated hemoglobin (HbA1c).ResultsThe median fasting plasma glucose and HbA1c before the study were 210.0 mg/dL and 9.8%, respectively. The levels of fasting plasma glucose and HbA1c significantly decreased in the Insulin-GLP-1 RA relay group (P < 0.001) and GLP-1 RA first group (P < 0.001) by week 24, although no intergroup differences were observed. The reduction of HbA1c in the Insulin-GLP-1 RA relay group tended to be larger than that in the GLP-1 RA first group in the lowest CPR (C-peptide immunoreactivity) quartile (P = 0.072). The adverse events consisted of gastrointestinal problems, followed by hypoglycemia.ConclusionsThe GLP-1 receptor agonist is overall effective without prior glycemic control with insulin in participants with poorly controlled type 2 diabetes. However, in participants with insulinopenic type 2 diabetes, prior glycemic control with insulin might overcome glucose toxicity-induced GLP-1 resistance.
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Project description:Peptide agonists of the glucagon-like peptide-1 receptor (GLP-1R) have revolutionized diabetes therapy, but their use has been limited because they require injection. Herein, we describe the discovery of the orally bioavailable, small-molecule, GLP-1R agonist PF-06882961 (danuglipron). A sensitized high-throughput screen was used to identify 5-fluoropyrimidine-based GLP-1R agonists that were optimized to promote endogenous GLP-1R signaling with nanomolar potency. Incorporation of a carboxylic acid moiety provided considerable GLP-1R potency gains with improved off-target pharmacology and reduced metabolic clearance, ultimately resulting in the identification of danuglipron. Danuglipron increased insulin levels in primates but not rodents, which was explained by receptor mutagensis studies and a cryogenic electron microscope structure that revealed a binding pocket requiring a primate-specific tryptophan 33 residue. Oral administration of danuglipron to healthy humans produced dose-proportional increases in systemic exposure (NCT03309241). This opens an opportunity for oral small-molecule therapies that target the well-validated GLP-1R for metabolic health.
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Project description:IntroductionThe objective of this study was to evaluate real-world treatment patterns of type 2 diabetes (T2D) patients initiating glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in Germany (GE), the United Kingdom (UK), France (FR), the Netherlands (NE), Belgium (BE), and Sweden (SE).MethodsAdult T2D patients initiating exenatide twice daily (exBID), liraglutide once daily (LIRA) or exenatide once weekly (exQW) were identified using the IMS LifeLink™ (IMS Health, Danbury, CT, USA): Electronic Medical Records (EMR; GE/UK/FR) and IMS LifeLink™: longitudinal prescriptions (LRx; NE/BE/GE/UK) databases, and national health register data (SE), between 2010 and 2012. Therapy initiation date was termed 'index date'. Eligible patients had ≥180-day pre- and variable follow-up (minimum ≥360-day post-index exBID and LIRA, ≥180-day post-index exQW). Treatment modification and persistence were evaluated over 180 days. Kaplan-Meier (KM) survival curves and Cox proportional hazards models (PHMs; EMR databases only) evaluated stopping of the index therapy (measured as first of discontinuation or switch).Results30,206 exBID, 5,401 exQW, and 52,155 LIRA patients were included in the analysis (46.0-66.9% male; mean age range 55.4-59.3 years). Mean follow-up was 20.3-27.4 months for exBID and LIRA, and 7.6-13.9 months for exQW. Across the databases, the proportion experiencing a treatment modification at 180 days was highest among exBID (37.6-81.7%) compared to LIRA (36.8-56.6%) and exQW (32.3-47.7%). The proportion persistent at 180 days was lowest among exBID patients (46.8-73.5%) compared to LIRA (50.6-80.1%) or exQW (57.5-74.6%). In the KM analyses, LIRA patients had a lower proportion stopping therapy at all time points compared to exBID patients, across the databases. In the Cox PHMs, LIRA was associated with a significantly lower risk of stopping compared to exBID; in GE, exQW was associated with a lower risk compared to exBID and LIRA.ConclusionTreatment patterns varied among GLP-1 RA patients, with persistence highest among either LIRA or exQW across countries, and lowest among exBID. Longer-term data would be useful, particularly given limited exQW follow-up due to more recent launch.
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Project description:AimsTo evaluate the time-varying cardio-protective effect of glucagon-like peptide-1 receptor agonists (GLP-1RAs) using pooled data from eight contemporary cardiovascular outcome trials using the difference in the restricted mean survival time (ΔRMST) as the effect estimate.Material and methodsData from eight multinational cardiovascular outcome randomized controlled trials of GLP-1RAs for type 2 diabetes mellitus were pooled. Flexible parametric survival models were fit from published Kaplan-Meier plots. The differences between arms in RMST (ΔRMST) were calculated at 12, 24, 36 and 48 months. ΔRMST values were pooled using an inverse variance-weighted random-effects model; heterogeneity was tested with Cochran's Q statistic. The endpoints studied were: three-point major adverse cardiovascular events (MACE), all-cause mortality, stroke, cardiovascular mortality and myocardial infarction.ResultsWe included eight large (3183-14 752 participants, total = 60 080; median follow-up range: 1.5 to 5.4 years) GLP-1RA trials. Among GLP-1RA recipients, we observed an average delay in three-point MACE of 0.03, 0.15, 0.37 and 0.63 months at 12, 24, 36 and 48 months, respectively. At 48 months, while cardiovascular mortality was comparable in both arms (pooled ΔRMST 0.163 [-0.112, 0.437]; P = 0.24), overall survival was higher (ΔRMST = 0.261 [0.08-0.43] months) and stroke was delayed (ΔRMST 0.22 [0.15-0.33]) in patients receiving GLP-1RAs.ConclusionsGlucagon-like peptide-1 receptor agonists may delay the occurrence of MACE by an average of 0.6 months at 48 months, with meaningfully larger gains in patients with cardiovascular disease. This metric may be easier for clinicians and patients to interpret than hazard ratios, which assume a knowledge of absolute risk in the absence of treatment.
| S-EPMC9540124 | biostudies-literature
Project description:Background: To assess the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) used as an adjunct to insulin therapy in adults with type 1 diabetes. Methods: A search of electronic databases (Medline, Embase, and the Cochrane Central Register of Controlled Trials) from 1 January 1950 to 23 May 2021 was conducted to find randomized controlled trials. The primary outcome was the change in HbA1c. Eight efficacy and six safety secondary endpoints were evaluated via meta-analysis. Weighted mean difference (WMD) and odds ratio (OR), alongside 95% confidence interval (CI), were calculated using the random effects model. Results: Among 1,379 candidate studies, 11 trials comprising 2,856 participants satisfied the inclusion criteria. Overall, GLP-1 RA adjunctive therapy reduced HbA1c by -0.21% (95% CI, -0.33 to -0.10), weight by -4.04 kg (-4.8 to -3.27), systolic pressure by -2.57 mmHg (-4.11 to -1.03), and diastolic blood pressure by -1.02 mmHg (-1.99 to -0.06). In addition, there was a decrease in prandial insulin dose (WMD, -4.23 IU; 95% CI, -5.26 to -3.20), basal insulin dose (-2.40 IU; -3.93 to -0.87), and total insulin dose (-5.73 IU; -10.61 to -0.86). Moreover, GLP-1 RAs did not increase the incidence of severe hypoglycemia, diabetic ketoacidosis, or severe adverse events. However, GLP-1 RAs increased the incidence of gastrointestinal adverse events (OR, 2.96; 95% CI, 2.33-3.77). Conclusion: Our meta-analysis of randomized clinical trials suggests moderate beneficial effects of GLP-1 RAs on the metabolic profile in patients with type 1 diabetes, without an increased risk of serious adverse events. Clinical Trial Registration: https://www.crd.york.ac.uk/PROSPERO; Identifier: CRD 42020199840.
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Project description:Glucagon-like peptide-1 (GLP-1) has been evaluated for use in the treatment of type 2 diabetes mellitus (T2DM) due to its role in glucose regulation. Four GLP-1 receptor agonists (RAs) are currently indicated for T2DM in the USA. Exenatide and liraglutide are short-acting and require twice-daily and daily dosing, respectively. Two longer acting agents, exenatide long-acting release (LAR) and albiglutide, were formulated to allow for once-weekly dosing. All four GLP-1 RAs have demonstrated reductions in hemoglobin A1c, fasting blood glucose, and body weight both as monotherapy and in combination with first- and second-line diabetes agents including metformin, sulfonylureas, thiazolidinediones, and insulin. Greater glycemic control was seen with liraglutide compared with the other GLP-1 treatment options; however, the two long-acting agents were superior to exenatide twice daily. All agents were well tolerated with most adverse events being mild or moderate in nature. The most common adverse event was transient nausea which typically resolved 4-8 weeks after treatment initiation. Long-acting agents had lower rates of nausea but an increased incidence of injection site reactions. Trials have suggested GLP-1 RAs may improve cardiovascular risk factors including blood pressure, lipid parameters and inflammatory markers. Future trials are needed to confirm the clinical outcomes of these agents. Overall, GLP-1 RAs will provide benefit for patients with T2DM intolerable to or not reaching glycemic goals with first-line agents, especially in patients in need of weight loss.
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