GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond - New Insights 2015.
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SUBMITTER: Gallwitz B
PROVIDER: S-EPMC5819057 | biostudies-literature | 2015 Apr
REPOSITORIES: biostudies-literature
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GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond - New Insights 2015.
European endocrinology 20150411 1
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long-acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has bee ...[more]
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Project description:BackgroundGLP-1 receptor agonists (GLP-1 RAs) with exenatide b.i.d. first approved to treat type 2 diabetes in 2005 have been further developed to yield effective compounds/preparations that have overcome the original problem of rapid elimination (short half-life), initially necessitating short intervals between injections (twice daily for exenatide b.i.d.).Scope of reviewTo summarize current knowledge about GLP-1 receptor agonist.Major conclusionsAt present, GLP-1 RAs are injected twice daily (exenatide b.i.d.), once daily (lixisenatide and liraglutide), or once weekly (exenatide once weekly, dulaglutide, albiglutide, and semaglutide). A daily oral preparation of semaglutide, which has demonstrated clinical effectiveness close to the once-weekly subcutaneous preparation, was recently approved. All GLP-1 RAs share common mechanisms of action: augmentation of hyperglycemia-induced insulin secretion, suppression of glucagon secretion at hyper- or euglycemia, deceleration of gastric emptying preventing large post-meal glycemic increments, and a reduction in calorie intake and body weight. Short-acting agents (exenatide b.i.d., lixisenatide) have reduced effectiveness on overnight and fasting plasma glucose, but maintain their effect on gastric emptying during long-term treatment. Long-acting GLP-1 RAs (liraglutide, once-weekly exenatide, dulaglutide, albiglutide, and semaglutide) have more profound effects on overnight and fasting plasma glucose and HbA1c, both on a background of oral glucose-lowering agents and in combination with basal insulin. Effects on gastric emptying decrease over time (tachyphylaxis). Given a similar, if not superior, effectiveness for HbA1c reduction with additional weight reduction and no intrinsic risk of hypoglycemic episodes, GLP-1RAs are recommended as the preferred first injectable glucose-lowering therapy for type 2 diabetes, even before insulin treatment. However, GLP-1 RAs can be combined with (basal) insulin in either free- or fixed-dose preparations. More recently developed agents, in particular semaglutide, are characterized by greater efficacy with respect to lowering plasma glucose as well as body weight. Since 2016, several cardiovascular (CV) outcome studies have shown that GLP-1 RAs can effectively prevent CV events such as acute myocardial infarction or stroke and associated mortality. Therefore, guidelines particularly recommend treatment with GLP-1 RAs in patients with pre-existing atherosclerotic vascular disease (for example, previous CV events). The evidence of similar effects in lower-risk subjects is not quite as strong. Since sodium/glucose cotransporter-2 (SGLT-2) inhibitor treatment reduces CV events as well (with the effect mainly driven by a reduction in heart failure complications), the individual risk of ischemic or heart failure complications should guide the choice of treatment. GLP-1 RAs may also help prevent renal complications of type 2 diabetes. Other active research areas in the field of GLP-1 RAs are the definition of subgroups within the type 2 diabetes population who particularly benefit from treatment with GLP-1 RAs. These include pharmacogenomic approaches and the characterization of non-responders. Novel indications for GLP-1 RAs outside type 2 diabetes, such as type 1 diabetes, neurodegenerative diseases, and psoriasis, are being explored. Thus, within 15 years of their initial introduction, GLP-1 RAs have become a well-established class of glucose-lowering agents that has the potential for further development and growing impact for treating type 2 diabetes and potentially other diseases.
| S-EPMC8085572 | biostudies-literature
Project description:The ever-increasing number of drugs available to treat type 2 diabetes and the complexity of patients with this condition present a constant challenge when it comes to identifying the most appropriate treatment approach. The more recent glucagon-like peptide-1 receptor agonists (GLP-1RAs) are non-insulin injectable options for the management of type 2 diabetes. Effective at improving glycaemic control with a low intrinsic risk of hypoglycaemia and the potential for weight reduction, this agent class is an important addition to the prescribing armamentarium. However, understanding their place in therapy may prove confusing for many primary care practitioners, especially given the common belief that 'injectables' are a last-resort treatment option, which puts them at risk of being niched alongside insulin. This review summarises the clinical evidence for GLP-1RAs and how they compare to other glucose-lowering agents in managing type 2 diabetes. It also provides practical and case-driven opinions and recommendations on the optimal use of GLP-1RAs by discussing important patient factors and clinical considerations that will help to identify those who are most likely to benefit from this class of agents.Funding: Eli Lilly Australia.
| S-EPMC6612351 | biostudies-literature
Project description:PurposePrevious research suggests that treatment process can have an influence on patient preference and health state utilities. This study examined preferences and estimated utilities for treatment processes of two daily oral treatment regimens and two weekly injectable regimens for treatment of type 2 diabetes (T2D).MethodsParticipants with T2D in the UK reported preferences and valued four health state vignettes in time trade-off utility interviews. The vignettes had identical descriptions of T2D but differed in treatment process: (1) daily simple oral treatment (tablets without administration requirements), (2) daily oral semaglutide (with administration requirements per product label), (3) weekly dulaglutide injection, (4) weekly semaglutide injection.ResultsInterviews were completed by 201 participants (52.7% male; mean age = 58.7). Preferences between treatment processes varied widely. Mean utilities were 0.890 for simple oral, 0.880 for oral semaglutide, 0.878 for dulaglutide injection, and 0.859 for semaglutide injection (with higher scores indicating greater preference). All pairwise comparisons found statistically significant differences between utilities (p < 0.01), except the comparison between oral semaglutide and the dulaglutide injection (p = 0.49).ConclusionsResults suggest that routes of administration cannot be compared using only the simplest descriptions (e.g., oral versus injectable). Dose frequency and specific details of the treatment process administration had an impact on patient preference and health state utilities. The utilities estimated in this study may be useful in cost-utility models comparing these treatments for T2D. Results also suggest that it may be helpful to consider patient preferences for treatment process when selecting medications for patients in clinical settings.
| S-EPMC8233232 | biostudies-literature
Project description:Along the obesity pandemic, the prevalence of non-alcoholic fatty liver disease (NAFLD), often regarded as the hepatic manifestation of the metabolic syndrome, increases worldwide representing now the prevalent liver disease in western countries. No pharmacotherapy is approved for the treatment of NAFLD and, currently, the cornerstone treatment is lifestyle modifications focusing on bodyweight loss, notoriously difficult to obtain and even more difficult to maintain. Thus, novel therapeutic approaches are highly demanded. Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) are approved for the treatment of type 2 diabetes and obesity. They exert their body weight-lowering effect by reducing satiety and food intake. GLP-1RAs have also been shown to reduce liver inflammation and fibrosis. Furthermore, glucagon receptor agonism is being investigated for the treatment of NAFLD due to its appetite and food intake-reducing effects, as well as its ability to increase lipid oxidation and thermogenesis. Recent studies suggest that glucagon receptor signaling is disrupted in NAFLD, indicating that supra-physiological glucagon receptor agonism might represent a new NAFLD treatment target. The present review provides (1) an overview in the pathophysiology of NAFLD, including the potential involvement of GLP-1 and glucagon, (2) an introduction to the currently available GLP-1RAs and (3) outlines the potential of emerging GLP-1RAs and GLP-1/glucagon receptor co-agonists in the treatment of NAFLD.
| S-EPMC6232120 | biostudies-literature
Project description: Not available
| S-EPMC7390475 | biostudies-literature
Project description:Type 2 diabetes mellitus (T2DM) is closely associated with cardiovascular diseases (CVD), including atherosclerosis, hypertension and heart failure. Some anti-diabetic medications are linked with an increased risk of weight gain or hypoglycemia which may reduce the efficacy of the intended anti-hyperglycemic effects of these therapies. The recently developed receptor agonists for glucagon-like peptide-1 (GLP-1RAs), stimulate insulin secretion and reduce glycated hemoglobin levels without having side effects such as weight gain and hypoglycemia. In addition, GLP1-RAs demonstrate numerous cardiovascular protective effects in subjects with or without diabetes. There have been several cardiovascular outcomes trials (CVOTs) involving GLP-1RAs, which have supported the overall cardiovascular benefits of these drugs. GLP1-RAs lower plasma lipid levels and lower blood pressure (BP), both of which contribute to a reduction of atherosclerosis and reduced CVD. GLP-1R is expressed in multiple cardiovascular cell types such as monocyte/macrophages, smooth muscle cells, endothelial cells, and cardiomyocytes. Recent studies have indicated that the protective properties against endothelial dysfunction, anti-inflammatory effects on macrophages and the anti-proliferative action on smooth muscle cells may contribute to atheroprotection through GLP-1R signaling. In the present review, we describe the cardiovascular effects and underlying molecular mechanisms of action of GLP-1RAs in CVOTs, animal models and cultured cells, and address how these findings have transformed our understanding of the pharmacotherapy of T2DM and the prevention of CVD.
| S-EPMC8193264 | biostudies-literature
Project description:AimWe aimed to integrate evidence from all randomized controlled trials (RCTs) and assess the impact of different doses of exenatide or liraglutide on major gastrointestinal adverse events (GIAEs) in type 2 diabetes (T2DM).MethodsRCTs evaluating different doses of exenatide and liraglutide against placebo or an active comparator with treatment duration ≥4 weeks were searched and reviewed. A total of 35, 32 and 28 RCTs met the selection criteria evaluated for nausea, vomiting, and diarrhea, respectively. Pairwise random-effects meta-analyses and mixed treatment comparisons (MTC) of all RCTs were performed.ResultsAll GLP-1 dose groups significantly increased the probability of nausea, vomiting and diarrhea relative to placebo and conventional treatment. MTC meta-analysis showed that there was 99.2% and 85.0% probability, respectively, that people with exenatide 10 μg twice daily (EX10BID) was more vulnerable to nausea and vomiting than those with other treatments. There was a 78.90% probability that liraglutide 1.2 mg once daily (LIR1.2) has a higher risk of diarrhea than other groups. A dose-dependent relationship of exenatide and liraglutide on GIAEs was observed.ConclusionsOur MTC meta-analysis suggests that patients should be warned about these GIAEs in early stage of treatment by GLP-1s, especially by EX10BID and LIR1.2, to promote treatment compliance.
| S-EPMC3540917 | biostudies-literature
Project description:IntroductionSemaglutide once-weekly (QW) is a novel glucagon-like peptide-1 (GLP-1) analogue administered at a 0.5 or 1.0 mg dose. In the absence of head-to-head trials between semaglutide QW and other GLP-1 receptor agonists (GLP-1 RAs) in a Japanese population, a network meta-analysis (NMA) was performed. The objective was to assess the relative efficacy and safety of semaglutide QW vs GLP-1 RAs in Japanese patients with type 2 diabetes (T2DM), with a specific focus on the comparison between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.MethodsA systematic review (SR) and supplementary Japanese searches were conducted to identify trials of GLP-1 RAs in Japanese patients on diet and exercise, who have previously received 0-1 oral antidiabetic drugs (OADs). Data at 52-56 weeks were extracted for the following outcomes (feasible for analysis in an NMA): glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), weight, systolic blood pressure (SBP), and overall hypoglycemia. The data were synthesized using an NMA and a Bayesian framework.ResultsFour trials, identified from the SR and Japanese-specific searches, were relevant for inclusion in the NMA. When compared to dulaglutide 0.75 mg QW, semaglutide 0.5 mg QW was shown to provide significant reductions in HbA1c [- 0.61% (12.3 mmol/mol)], weight (- 1.45 kg), SBP (- 5.03 mmHg), and FPG (- 1.26 mmol/L). No significant differences in the proportion of patients achieving a HbA1c level < 7% (53 mmol/mol) or the risk of overall hypoglycemia were observed between semaglutide 0.5 mg QW and dulaglutide 0.75 mg QW.ConclusionOverall, semaglutide 0.5 mg QW was associated with significant reductions from baseline in HbA1c, weight, SBP, and FPG compared with dulaglutide 0.75 mg QW in Japanese patients with T2DM. These data may provide valuable evidence for clinical decision-making, cost-effectiveness analyses, and health technology appraisal (HTA) requirements.FundingNovo Nordisk Pharma Ltd.
| S-EPMC5984907 | biostudies-literature
Project description:Chronic kidney disease (CKD) affects around 10% of the global population and is most often caused by diabetes. Diabetes with CKD (diabetic kidney disease, DKD) is a progressive condition that may cause kidney failure and which contributes significantly to the excess morbidity and mortality in these patients. DKD is treated with direct disease-targeting therapies like blockers of the renin-angiotensin system, sodium-glucose cotransporter-2 (SGLT-2) inhibitors and non-steroidal mineralocorticoid receptor antagonists as well as indirect therapies impacting hyperglycaemia, dyslipidaemia, obesity and hypertension, which all together reduce disease progression. While no glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are currently indicated to improve kidney outcomes, accumulating evidence from cardiovascular outcomes trials (CVOTs) corroborates a kidney-protective effect in people with T2D and CKD, and GLP-1 RAs are now mentioned in international treatment guidelines for type 2 diabetes (T2D) with CKD. GLP-1 RAs are indicated to improve glycaemia in people with T2D; certain GLP-1 RAs are also approved for weight management and to reduce cardiovascular risk in T2D. Ongoing pivotal trials are assessing additional indications, including T2D with CKD. In this article, we review and discuss kidney outcomes from a multitude of completed clinical trials as well as real-world evidence and ongoing clinical trials.
| S-EPMC9301118 | biostudies-literature
Project description:Glucagon-like peptide-1 receptor (GLP-1R) agonists have been shown to regulate blood glucose concentrations by mechanisms including enhanced insulin synthesis/secretion, suppressed glucagon secretion, slowed gastric emptying, and enhanced satiety. GLP-1 receptors have also been identified in the heart, kidneys, and blood vessels, leading to the hypothesis that GLP-1R agonists may affect cardiovascular function or cardiovascular disease (CVD). The aim of this literature review was to assemble and assess preclinical and clinical data of potential medical importance regarding the cardiovascular effects of GLP-1R agonists. Preclinical studies with the GLP-1R agonists GLP-1, exenatide, or liraglutide provided evidence that GLP-1R stimulation favorably affects endothelial function, sodium excretion, recovery from ischemic injury, and myocardial function in animals. Similar observations have been made in exploratory studies on GLP-1 infusion in normal subjects and patients with type 2 diabetes. Post hoc analyses of phase III studies of patients with type 2 diabetes treated with exenatide(bid or qw) or liraglutide(qd) showed that these GLP-1R agonists reduced blood pressure, an effect largely independent of weight loss, and that liraglutide slightly increased heart rate. Preliminary data also indicated that GLP-1R agonists reduced markers of CVD risk such as C-reactive protein and plasminogen activator inhibitor-1. Ongoing studies are examining the effects of administering GLP-1R agonists to patients at risk of CVD, postangioplasty patients, post-CABG patients, and patients with heart failure. Additional studies should provide meaningful data to determine whether GLP-1R agonists provide unique treatment benefits to patients at risk for or with established CVD.
| S-EPMC3488299 | biostudies-literature