The class B G-protein-coupled GLP-1 receptor: an important target for the treatment of type-2 diabetes mellitus.
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ABSTRACT:
SUBMITTER: Miller LJ
PROVIDER: S-EPMC4850583 | biostudies-other | 2014 Jul
REPOSITORIES: biostudies-other
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Project description:IntroductionThe incidence and prevalence of type 2 diabetes mellitus (T2D) are increasing in Japan, and glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are commonly used to treat the disease. The objective of this study was to use a discrete choice experiment (DCE) to characterize patient preferences for clinical treatment features of two GLP-1 RAs-dulaglutide 0.75 mg and semaglutide 0.50 mg-among patients with T2D in Japan.MethodsAdult patients with T2D in Japan were administered the DCE via a web-based survey. The DCE examined patient preferences for five treatment attributes (each described by two or three levels), including method of administration, HbA1c change, reduction in cardiovascular (CV) risk, weight change, and common side effects (i.e., nausea). Results were analyzed using multinomial and mixed logit models, and predicted choice probability was calculated to determine the overall probability that either dulaglutide or semaglutide DCE levels were preferred. One DCE choice task included a direct comparison of the dulaglutide 0.75 mg versus semaglutide 0.50 mg treatment profiles.Results190 subjects completed the survey; 29 were excluded after failing the predefined internal validity assessments. In the final analysis sample (N = 161), the attribute with the largest effect on the subjects' choices was reduction in CV risk, followed by HbA1c change and common side effects. Patients' predicted choice probability for the semaglutide profile was 78%, versus 22% for the dulaglutide profile. 28% of patients were "very willing" to initiate treatment with semaglutide's product profile, versus 6% for dulaglutide.ConclusionIn this study, reduction in CV risk and HbA1c change were the key drivers of GLP-1 RA medication preference in Japanese patients with T2D. Overall, the majority of the patients preferred a product with attribute levels reflecting the semaglutide 0.50 mg profile, with a known CV risk reduction benefit and superior HbA1c reduction.FundingNovo Nordisk.
| S-EPMC6437254 | biostudies-literature
Project description:Effects of glucagon-like peptide-1 (GLP-1) receptor agonist on cardiovascular complications of diabetes mellitus (DM) were investigated. In total, 132 DM patients treated in Tengzhou Central People's Hospital from April 2013 to September 2016 were included. Of these, 71 cases treated with basic drugs plus GLP-1 were the research group, and 61 cases treated with glipizide controlled release tablets the control group. The improvement of clinical efficacy of patients in the two groups after treatment was observed. The concentrations of FPG, HbAlc, TC, LDL-C, and HDL-C in serum of patients in the two groups before and after treatment were compared, and the incidence rate of cardiovascular disease complications of diabetes was recorded. Expression of FPG, HbAlc, TC, LDL-C, and HDL-C of patients in the two groups were further detected. ROC curve was drawn to analyze its predictive value. In terms of markedly effective treatment rate and overall effective rate, the research group was significantly better than the control group (P<0.05). After treatment, the concentrations of FPG, HbAlc, TC, LDL-C, and HDL-C in serum of patients in the research group were significantly lower than those in the control group (P<0.05). The incidence rate of cardiovascular diseases and residual vascular risks in the research group were significantly higher than those in the control group (P<0.05). After treatment, the AUC of FPG, HbAlc, TC, LDL-C, and HDL-C in serum for predicting cardiovascular complications in DM patients were, respectively, 0.742, 0.780, 0.737, 0.726, and 0.721. In conclusion, GLP-1 receptor agonist can improve the clinical efficacy of patients. Through ROC curve, FPG, HbAlc, TC, LDL-C and HDL-C can be used as predictors of cardiovascular complications in DM patients, which has high clinical value.
| S-EPMC7027309 | 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:GPR119 is a G protein-coupled receptor expressed predominantly in the pancreas (beta-cells) and gastrointestinal tract (enteroendocrine cells) in humans. De-orphanization of GPR119 has revealed two classes of possible endogenous ligands, viz., phospholipids and fatty acid amides. Of these, oleoylethanolamide (OEA) is one of the most active ligands tested so far. This fatty acid ethanolamide is of particular interest because of its known effects of reducing food intake and body weight gain when administered to rodents. Agonists at the GPR119 receptor cause an increase in intracellular cAMP levels via G(alphas) coupling to adenylate cyclase. In vitro studies have indicated a role for GPR119 in the modulation of insulin release by pancreatic beta-cells and of GLP-1 secretion by gut enteroendocrine cells. The effects of GPR119 agonists in animal models of diabetes and obesity are reviewed, and the potential value of such compounds in future therapies for these conditions is discussed.
| S-EPMC2268073 | biostudies-literature
Project description:IntroductionExenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA), approved for treatment of type 2 diabetes mellitus (T2DM). There is limited direct evidence comparing the efficacy and tolerability of exenatide 2 mg once weekly (QW) to other GLP-1 RAs. A network meta-analysis (NMA) was conducted to estimate the relative efficacy and tolerability of exenatide QW versus other GLP-1 RAs for the treatment of adults with T2DM inadequately controlled on metformin monotherapy.MethodsA systematic literature review was conducted to identify randomized controlled trials (RCTs) that investigated GLP-1 RAs (albiglutide, dulaglutide, exenatide, liraglutide, and lixisenatide) at approved doses in the United States/Europe, added on to metformin only and of 24 ± 6 weeks treatment duration. A Bayesian NMA was conducted.ResultsFourteen RCTs were included in the NMA. Exenatide QW obtained a statistically significant reduction in glycated hemoglobin (HbA1c) relative to lixisenatide 20 µg once daily. No other comparisons of exenatide QW to other GLP-1 RAs were statistically significant for change in HbA1c. No statistically significant differences in change in weight, systolic blood pressure, risk of nausea or discontinuation due to adverse events were observed for exenatide QW versus other GLP-1 RAs.ConclusionExenatide QW demonstrated similar effectiveness and tolerability compared to other GLP-1 RAs, for the treatment of T2DM in adults inadequately controlled on metformin alone.
| S-EPMC4801811 | biostudies-literature
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:OBJECTIVE: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). METHODS: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. RESULTS: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. CONCLUSIONS: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.
| S-EPMC6308032 | 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:SGLT2 inhibitors are plausible second-line drugs that provide powerful additional A1c-lowering effects while inducing weight loss without hypoglycemia.
| S-EPMC6375399 | biostudies-literature
Project description:To achieve good metabolic control in diabetes and keep long term, a combination of changes in lifestyle and pharmacological treatment is necessary. Achieving near-normal glycated hemoglobin significantly, decreases risk of macrovascular and microvascular complications. At present there are different treatments, both oral and injectable, available for the treatment of type 2 diabetes mellitus (T2DM). Treatment algorithms designed to reduce the development or progression of the complications of diabetes emphasizes the need for good glycaemic control. The aim of this review is to perform an update on the benefits and limitations of different drugs, both current and future, for the treatment of T2DM. Initial intervention should focus on lifestyle changes. Moreover, changes in lifestyle have proven to be beneficial, but for many patients is a complication keep long term. Physicians should be familiar with the different types of existing drugs for the treatment of diabetes and select the most effective, safe and better tolerated by patients. Metformin remains the first choice of treatment for most patients. Other alternative or second-line treatment options should be individualized depending on the characteristics of each patient. This article reviews the treatments available for patients with T2DM, with an emphasis on agents introduced within the last decade.
| S-EPMC5027002 | biostudies-other