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Much interest has focused on the newer incretin-based therapeutic modalities for diabetes, especially GLP-1 analogues. While the comparatively older GLP-1 analogs, exenatide and liraglutide, have been discussed extensively in lite...
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Much interest has focused on the newer incretin-based therapeutic modalities for diabetes, especially GLP-1 analogues. While the comparatively older GLP-1 analogs, exenatide and liraglutide, have been discussed extensively in literature, much less is known about the newer GLP-1 analogues in the pipeline. This review focuses on the newer molecules being studied, the newer routes of administration being tried, some recent patents and potential uses for these multifaceted compounds.
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摘要 :
Much interest has focused on the newer incretin-based therapeutic modalities for diabetes, especially GLP-1 analogues. While the comparatively older GLP-1 analogs, exenatide and liraglutide, have been discussed extensively in lite...
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Much interest has focused on the newer incretin-based therapeutic modalities for diabetes, especially GLP-1 analogues. While the comparatively older GLP-1 analogs, exenatide and liraglutide, have been discussed extensively in literature, much less is known about the newer GLP-1 analogues in the pipeline. This review focuses on the newer molecules being studied, the newer routes of administration being tried, some recent patents and potential uses for these multifaceted compounds.
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Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bi...
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Peptide drugs have the advantages of target specificity and good drugability and have become one of the most increasingly important hotspots in new drug research in biomedical sciences. However, peptide drugs generally have low bioavailability and metabolic stability, and therefore, the modification of existing peptide drugs for the purpose of improving stability and retaining activity is of viable importance. It is known that glucagon is an effective therapy for treating severe hypoglycemia, but its short half-life prevents its wide therapeutic use. Herein, we report that combined unnatural residues and long fatty acid conjugation afford potent alpha/sulfono-gamma-AApeptide hybrid analogues of Glucagon with enhanced stability and prolonged in vivo activity. This strategy could be adopted to develop stabilized analogues of other short-acting bioactive peptides.
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Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral...
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Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists have been used in clinical management of type 2 diabetes since 2005. Currently approved agents were initially developed and approved for combination therapy with oral antidiabetic drugs (OADs). The potential for combined use with insulin has garnered increasing attention due to the potential to reduce side effects associated with insulin therapy and improve glycemic control. Areas covered: We reviewed published and other publicly released data from controlled and uncontrolled studies that included subjects treated with insulin/GLP-1 analog combination therapy. The currently available guidance for clinical practice when combining insulin and GLP-1 analogs was also summarized. Expert opinion: Limited data currently available from placebo-controlled trials support the use of exenatide twice daily or liraglutide once daily in combination with basal insulin and metformin in subjects with type 2 diabetes unable to attain treatment goals. Several randomized controlled trials are currently studying combinations of insulin with various GLP-1 analogs. Additional guidance on the clinical use of these combinations will likely be forthcoming once these studies are reported. Insulin/GLP-1 analog combinations will require optimization of blood glucose monitoring strategies and delivery systems to decrease the risk of administration errors and reduce the potential complexity of these regimens.
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Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The...
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Incretin-based therapy was first made available for the treatment of type 2 diabetes mellitus (T2DM) in the US in 2006 and in Japan in 2009. Four DPP-4 inhibitors and two GLP-1 analog/receptor agonists are currently available. The effects of incretin-based therapy are assumed to be exerted mainly through the hormonal and neuronal actions of one of the incretins, GLP-1, which is secreted from L cells localized in the small intestine. The benefits of this therapy over conventional sulfonylureas or insulin injections, such as fewer hypoglycemic events and reduced body weight gain, derive from the glucose-dependent insulinotropic effect. The protective effects of this therapy on vulnerable pancreatic ??-cells and against micro/macroangiopathy in T2DM are also most welcome. Indications and/or contraindications for incretin-based therapy should be clarified by prospectively studying the experiences of Japanese T2DM patients undergoing this therapy in the clinical setting. ? 2012 Japanese Society of Nephrology.
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Background: Cardiomyocyte apoptosis is closely related to cardiac dysfunction in diabetic patients. Although GLP-1 analogs are used as anti-diabetic drugs, their effects on cardiomyocytes remain unclear. The aim of this study was ...
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Background: Cardiomyocyte apoptosis is closely related to cardiac dysfunction in diabetic patients. Although GLP-1 analogs are used as anti-diabetic drugs, their effects on cardiomyocytes remain unclear. The aim of this study was to assess the effects of the GLP-1 analog liraglutide on high glucose-induced cardiomyocyte apoptosis.Methods: Wistar rats were divided into normal (N), diabetes mellitus (DM), and liraglutide (LIR) groups. H9c2 cardiomyocytes were divided into normal (NG) and high glucose (HG) groups, 4 liraglutide groups (Lir1-4), 3 Epac-1 agonist intervention groups (CPT1-3), and 2 Epac-1 shRNA transfection groups (sh21 and sh22). Apoptosis was measured using TUNEL assays, and the apoptotic indices were calculated. Intracellular ROS levels were measured using a DCFH-DA probe. Epac-1, Akt, and P-Akt (Ser473) expression were measured by immunoblotting.Results: The apoptotic index and intracellular ROS levels were higher in the HG than NG group (P<0.01). Liraglutide decreased both parameters in a dose- and time-dependent manner. Liraglutide increased the expression of Epac-1 in the myocardium of diabetic rats and H9c2 cells (P<0.05), and increased Akt phosphorylation in the myocardium of diabetic rats (P<0.05). Liraglutide treatment also increased the P-Akt (Ser473)/Akt ratio (P<0.05). An Epac-1 agonist increased Epac-1 expression (P<0.05) and the P-Akt (Ser473)/Akt ratio (P<0.05) in a dose-dependent manner, and subsequently decreased apoptosis and intracellular ROS. Conversely, Epac-1shRNA knocked-down Epac-1 expression (P<0.01) and decreased the P-Akt (Ser473)/Akt ratio (P<0.05), but had no effect on apoptosis and intracellular ROS levels.Conclusions: Liraglutide protects cardiomyocytes from high glucose-induced apoptosis by activating the Epac-1/Akt pathway.
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? 2022GZR18 is a novel analog of glucagon-like peptide-1 (GLP-1). This study evaluates the pharmacology, pharmacokinetics, and efficacy of GZR18, and its potential for the treatment of Type 2 diabetes mellitus (T2DM). In vitro pha...
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? 2022GZR18 is a novel analog of glucagon-like peptide-1 (GLP-1). This study evaluates the pharmacology, pharmacokinetics, and efficacy of GZR18, and its potential for the treatment of Type 2 diabetes mellitus (T2DM). In vitro pharmacology and activity of GZR18 were characterized by a binding assay of GZR18 using human serum albumin (HSA), an activation assay in human GLP-1 receptor-expressing cell lines, and its effect on glucose-stimulated insulin secretion (GSIS) in primary mice islets. Pharmacokinetic profiling was performed in Sprague Dawley rats and cynomolgus monkeys, and efficacy evaluated using GZR18 single or repeated doses in db/db mice. GZR18 showed similar binding affinity for HSA and GLP-1 receptor compared with semaglutide and liraglutide. GZR18 increased GSIS, which was confirmed by dynamic islet perifusion and fluorescence imaging using PKZnR-5 for real-time detection. In cynomolgus monkeys, the average GZR18 maximal concentration was 527 nmol L?1, the terminal half-life (T1/2) was 61.3 h, and the time to maximum concentration was 14 h. Single-dose GZR18 lowered blood glucose levels and reduced body weight over 72 h in db/db mice. GZR18 successive administration (every three days for 33 days, i.e. 11 doses) lowered nonfasting and fasting blood glucose levels (p < 0.05 versus control) and glycated hemoglobin, following the 11th dose. Food and water consumption in db/db mice was lowered following repeated doses of GZR18 (p < 0.05 versus control), without a reduction in body weight. These results demonstrate the potential of GZR18 as a long-acting GLP-1 analog for the treatment of T2DM.
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Aim: In Japan, liraglutide is approved for use alone or in combination with sulfonylureas, and the approved maximum dosage is 0.9 mg/day. This restriction could limit the glucose-lowering effect of liraglutide in Japanese patients...
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Aim: In Japan, liraglutide is approved for use alone or in combination with sulfonylureas, and the approved maximum dosage is 0.9 mg/day. This restriction could limit the glucose-lowering effect of liraglutide in Japanese patients with type 2 diabetes mellitus (T2DM). This study was designed to identify predictors of response to liraglutide therapy at the approved dosage.
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Background Randomized controlled clinical trials (RCT) have demonstrated varied efficacy of glucagon-like peptide-1 receptor (GLP-1R) agonists for cardiovascular outcomes. We sought to evaluate the efficacy and safety of GLP-1R ag...
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Background Randomized controlled clinical trials (RCT) have demonstrated varied efficacy of glucagon-like peptide-1 receptor (GLP-1R) agonists for cardiovascular outcomes. We sought to evaluate the efficacy and safety of GLP-1R agonists among patients with Type 2 diabetes mellitus (DM) for stroke prevention. Methods We conducted a systematic review and meta-analysis of RCTs reporting the following outcomes among patients with Type 2 DM treated with GLP-1R agonists (vs. placebo): nonfatal or fatal strokes, all-cause or cardiovascular mortality, myocardial infarction (MI) and major adverse cardiovascular events (MACE). The protocol of our systematic review and meta-analysis was registered to the PROSPERO database. We pooled odds ratios (OR) using random-effect models, and assessed the heterogeneity using Cochran Q and I-2 statistics. Results We identified 8 RCTs, comprising 56,251 patients. In comparison to placebo, GLP-1R agonists reduced nonfatal strokes (OR 0.84; 95% CI 0.76-0.94, p = 0.002; I-2 = 0%) and all strokes (OR 0.84; 95% CI 0.75-0.93, p = 0.001; I-2 = 0%) by 16%. Overall, GLP-1R agonists reduced MACE by 13% (OR 0.87; 95% CI 0.81-0.94, p = 0.0003; I-2 = 42%), cardiovascular mortality by 12% (OR 0.88; 95% CI 0.81-0.95; p = 0.002; I-2 = 0%) and all-cause mortality by 12% (OR 0.88; 95% CI 0.82-0.95, p = 0.0007; I-2 = 15%). Additional analyses demonstrated that GLP-1R agonists reduced the risk of incident MACE (OR 0.86; 95% CI 0.80-0.92; p < 0.0001; I-2 = 0%) among patients with prior history of MI or nonfatal strokes. Conclusions Among patients with type 2 DM, GLP-1R agonists are beneficial for primary stroke, MACE, and cardiovascular mortality prevention. Further RCTs are needed to evaluate their role for secondary stroke prevention.
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Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postpr...
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Glucagon-like peptide 1 (GLP-1) has incretin effects that are well-documented, but the independent role of GLP-1 action in human satiety perception is debated. We hypothesized that blockade of GLP-1 receptors would suppress postprandial satiety and increase voluntary food intake. After an overnight fast, eight normal weight participants (seven men, BMI 19-24,7 kg/m2, age 19-29 year) were enrolled in a double-blind, placebo-controlled, randomized crossover study of the GLP-1 antagonist Exendin-[9-39] (Ex-9) to determine if the satiating effects of a meal are dependent on GLP-1 signaling in humans. Following a fasting blood draw, iv infusion of Ex-9 (600-750 pmol/kg/min) or saline began. Thirty minutes later, subjects consumed a standardized breakfast followed 90 min later (at the predicted time of maximal endogenous circulating GLP-1) by an ad libitum buffet meal to objectively measure satiety. Infusions ended once the buffet meal was complete. Visual analog scale ratings of hunger and fullness and serial assessments of plasma glucose, insulin, and GLP-1 concentrations were done throughout the experiment. Contrary to the hypothesis, during Ex-9 infusion subjects reported a greater decrease in hunger due to consumption of the breakfast (Ex-9 -62 ± 5; placebo -41 ± 9; P=0.01) than during placebo. There were no differences in ad libitum caloric intake between Ex-9 and placebo. Ex-9 increased glucose, insulin, and endogenous GLP-1, which may have counteracted any effects of Ex-9 infusion to block satiety signaling. Blockade of GLP-1 receptors failed to suppress subjective satiety following a standardized meal or increase voluntary food intake in healthy, normal-weight subjects.
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