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Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect...
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Clinical and nonclinical studies have implicated glucagon-like peptide-1 (GLP-1) receptor agonist therapy as a risk factor for acute pancreatitis in patients with type 2 diabetes. Therefore, it is critical to understand the effect that dulaglutide, an approved GLP-1 receptor agonist, has on the exocrine pancreas. Dulaglutide 8.15 mg/kg (approximately 500 times the maximum recommended human dose based on plasma exposure) was administered twice weekly for 12 months to cynomolgus monkeys. Serum amylase and lipase activities were measured and 6 sections of each pancreas were examined microscopically. Ductal epithelial cell proliferation was estimated using Ki67 labeling. Dulaglutide administration did not alter serum amylase or lipase activities measured at the end of treatment compared to control values. An extensive histologic evaluation of the pancreas revealed no changes in the acinar or endocrine portions and no evidence of pancreatitis, necrosis, or pancreatic intraepithelial neoplasia. An increase in goblet cells noted in 4 of the 19 treated monkeys was considered an effect of dulaglutide but was not associated with dilation, blockage, or accumulation of mucin in the pancreatic duct. There was no difference in cell proliferation in ductal epithelium between control and dulaglutide-treated monkeys. These data reveal that chronic dosing of nondiabetic primates with dulaglutide does not induce inflammatory or preneoplastic changes in exocrine pancreas.
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AimsTo compare the once-weekly glucagon-like peptide-1 (GLP-1) receptor dulaglutide with the dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin after 104weeks of treatment.
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Aims: To evaluate the efficacy and safety of dulaglutide 1.5 and 0.75 mg in elderly patients (aged >= 65 years) with type 2 diabetes (T2D) in six phase III clinical trials.
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Abstract Aim To assess the relationship between baseline body mass index (BMI) and glycaemic control in dulaglutide‐treated patients, a post hoc analysis was conducted on HbA1c and baseline BMI data from eight AWARD studies, with...
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Abstract Aim To assess the relationship between baseline body mass index (BMI) and glycaemic control in dulaglutide‐treated patients, a post hoc analysis was conducted on HbA1c and baseline BMI data from eight AWARD studies, with a total of 5770 patients. Materials and methods Changes from baseline in HbA1c data from patients treated with 1.5 mg or 0.75?mg dulaglutide, active comparator or placebo, were analyzed in each study (AWARD‐1 to ?6, ?8 and???9) at approximately 6 months (26, 24 and 28?weeks, respectively). Within each study, data were analyzed by the following baseline BMI categories: <30, ≥30 to <35, and?≥?35?kg/m 2 . Results In this post hoc analysis, 1.5 mg or 0.75?mg dulaglutide treatment achieved statistically significant HbA1c reductions from baseline in all BMI categories (least‐squares mean change from ?0.62 to ?1.75%) across the AWARD studies. No statistically significant treatment‐by‐BMI category interactions were found for reductions in HbA1c. Conclusion This post hoc analysis of eight AWARD studies indicates that baseline BMI does not affect the relative treatment efficacy of dulaglutide as measured by HbA1c change from baseline in any study. Dulaglutide is an effective treatment option for adult patients with type 2 diabetes regardless of their baseline BMI category.
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Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (H...
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Dulaglutide glycaemic efficacy has been demonstrated in the AWARD clinical trial programme. The objective of the present analysis was to determine the major baseline factors associated with the reduction in glycated haemoglobin (HbA1c) in response to dulaglutide. Baseline covariates from patients receiving dulaglutide in six phase III studies (n = 2806) were analysed using a gradient-boosting method to assess their relative influence on the change in HbA1c after 26 weeks of treatment. Influential variables (relative influence >5%) were further evaluated in univariate and multivariable modelling. The gradient-boosting analysis showed that the top influential baseline factors associated with HbA1c reduction were: HbA1c (48.8%), age (9.1%), fasting serum glucose (FSG; 8.2%), fasting serum insulin (FSI; 6.7%) and estimated glomerular filtration rate (eGFR; 5.4%). Multivariable regression showed that higher baseline HbA1c was the major factor associated with greater HbA1c reduction [coefficient estimates: -0.6% (-6.6 mmol/mol); p < 0.0001]. Age ]收起
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Abstract Aims Dulaglutide, a once weekly GLP‐1 receptor agonist, is approved at two doses (1.5 and 0.75?mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and ef...
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Abstract Aims Dulaglutide, a once weekly GLP‐1 receptor agonist, is approved at two doses (1.5 and 0.75?mg) for treatment of type 2 diabetes (T2D). Two higher doses of dulaglutide (3.0 and 4.5 mg) were evaluated for safety and efficacy to determine whether these doses warrant further study for improved control of glucose and body weight. Materials and methods This 18‐week, double‐blind, phase 2 trial randomized 318 patients with T2D using ≥1500?mg metformin, to receive subcutaneous injection of placebo (n?=?82), dulaglutide 1.5 mg (n?=?81), dulaglutide 3.0 mg (n?=?79) or dulaglutide 4.5 mg (n?=?76). The primary objective was superiority of dulaglutide doses over placebo in reduction of HbA1c at 18?weeks. Secondary objectives included superiority of dulaglutide over placebo in change from baseline in body weight and fasting serum glucose (FSG) at 18?weeks. Investigational doses of dulaglutide were compared to the 1.5 mg dose as an exploratory objective. Results HbA1c reduction at 18?weeks was significantly greater with dulaglutide vs placebo (placebo, ?0.44%?±?0.10% [?4.8?±?1.1 mmol/mol]; dulaglutide 1.5 mg, ?1.23%?±?0.10% [?13.5?±?1.1 mmol/mol]; dulaglutide 3.0 mg, ?1.31%?±?0.10% [?14.3?±?1.1 mmol/mol]; dulaglutide 4.5 mg, ?1.40%?±?0.10% [?15.3?±?1.1 mmol/mol]; P ?<?0.001, each dose), as were changes in body weight (placebo, ?1.6?±?0.39?kg; dulaglutide 1.5 mg, ?2.8?±?0.39?kg; dulaglutide 3.0 mg, ?3.9?±?0.39?kg; dulaglutide 4.5 mg, ?4.1?±?0.41?kg; P ?<?0.001, each dose). All three dulaglutide doses significantly reduced FSG from baseline (1.5 mg, ?36.2?±?4.7 mg/dL [?2.0?±?0.3 mmol/L]; 3.0 mg, ?34.5?±?4.5 mg/dL [?1.9?±?0.3 mmol/L]; 4.5 mg, ?38.0?±?4.7 mg/dL [?2.1?±?0.3 mmol/L]) vs placebo (?12.4?±?4.5 mg/dL [?0.7?±?0.3 mmol/L]) ( P ?<?0.001, all). Safety profiles of the higher doses were consistent with the established safety profile for dulaglutide. Gastrointestinal events were mostly mild to moderate, and was dose‐related for nausea. Conclusion All three dulaglutide doses were superior to placebo in improving glycaemic control and reducing body weight in participants with T2D using metformin. The potential for doses of dulaglutide of 3.0 and 4.5 mg to provide additional glycaemic benefit and weight reduction with an acceptable safety profile, compared with the 1.5 mg dose, warrants further study in a phase 3 trial.
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Aim: To evaluate the impact of dulaglutide 3.0 and 4.5 mg versus 1.5 mg on body weight in patients with type 2 diabetes (T2D) based on exploratory analyses of the AWARD-11 trial. Materials and Methods: Patients were randomized to ...
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Aim: To evaluate the impact of dulaglutide 3.0 and 4.5 mg versus 1.5 mg on body weight in patients with type 2 diabetes (T2D) based on exploratory analyses of the AWARD-11 trial. Materials and Methods: Patients were randomized to once-weekly dulaglutide 1.5 (n = 612), 3.0 (n = 616) or 4.5 mg (n = 614) for 52 weeks. The primary objective was superiority of dulaglutide 3.0 and/or 4.5 mg over 1.5 mg in HbA1c reduction at 36 weeks. Secondary and exploratory assessments included weight reduction in the overall trial population and baseline body mass index (BMI) and HbA1c subgroups. Results: At baseline, patients had a mean age of 57.1 years, HbA1c 8.6% (70 mmol/ mol), weight 95.7 kg and BMI 34.2 kg/m2. At 36 weeks, dulaglutide 3.0 and 4.5 mg were superior to 1.5 mg for weight change from baseline (1.5 mg, —3.1 kg; 3.0 mg, -4.0 kg [P = .001]; 4.5 mg, -4.7 kg [P < .001]). Higher dulaglutide doses were associated with numerically greater weight reduction compared with 1.5 mg in each baseline BMI and HbA1c subgroup. Absolute weight reduction increased with increasing BMI category, but percentage weight loss was similar between subgroups. Weight reductions with dulaglutide were greater in patients with lower versus higher baseline HbA1c. Conclusions: In patients with T2D, inadequately controlled by metformin, incremental weight loss was observed with dulaglutide 1.5, 3.0 and 4.5 mg doses regardless of baseline BMI or HbA1c. Although absolute weight loss was numerically greater in patients with higher baseline BMI, percentage of weight loss was similar between BMI subgroups.
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Glucagon-like polypeptide (GLP-1) receptor agonist treatment has multiple effects on glucose metabolism, supports the β cell, and promotes weight loss. There are now five GLP-1 agonists in clinical use with more in development. G...
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Glucagon-like polypeptide (GLP-1) receptor agonist treatment has multiple effects on glucose metabolism, supports the β cell, and promotes weight loss. There are now five GLP-1 agonists in clinical use with more in development. GLP-1 treatment typically can induce a lowering of hemoglobin A1c (HbA1c) of 0.5–1.5% over time with weight loss of 2–5%. In some individuals, a progressive loss of weight occurs. There is evidence that GLP-1 therapy opposes the loss of β cells which is a feature of type 2 diabetes. The chief downside of GLP-1 treatment is the gastrointestinal motility disturbance which is one of the modes of action of the hormone; significant nausea, vomiting, and diarrhea may lead to discontinuation of treatment. Although daily injection of GLP-1 agents is successful, the development of extended release preparations allows for injection once weekly, and perhaps much longer in the future. The indication for GLP-1 use is diabetes, but now, liraglutide has been approved for primary treatment of obesity. When oral agents fail to control glucose levels in type 2 diabetes, there is a choice between long-acting insulin and GLP-1 agonists as additional treatments. The lowering of HbA1c by either modality is equivalent in most studies. Patients lose weight with GLP-1 treatment and gain weight on insulin. There is a lower incidence of hypoglycemia with GLP-1 therapy but a much higher incidence of gastrointestinal complaints. Insulin dosing is flexible while GLP-1 agents have historically been administered at fixed dosages. Now, the use of combined long-acting insulin and GLP-1 agonists is promising a major therapeutic change. Combined therapy takes advantage of the benefits of both insulin and GLP-1 agents. Furthermore, direct admixture of both in the same syringe will permit flexible dosing, improvement of glucose levels, and reduction of both hypoglycemia and gastrointestinal side effects.
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摘要 :
Glucagon-like peptide-1 (GLP-1) receptor agonist therapy has been implicated as a possible risk factor for acute pancreatitis in patients with type 2 diabetes. Dulaglutide is a long-acting GLP-1 receptor agonist in development for...
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Glucagon-like peptide-1 (GLP-1) receptor agonist therapy has been implicated as a possible risk factor for acute pancreatitis in patients with type 2 diabetes. Dulaglutide is a long-acting GLP-1 receptor agonist in development for treatment of type 2 diabetes. The effects of dulaglutide were evaluated in male Zucker diabetic fatty (ZDF) rats to examine whether dulaglutide may induce or modulate pancreatitis. Rats were randomized to dose groups receiving twice-weekly subcutaneously administered dulaglutide 0.5, 1.5, and 5.0 mg/kg/dose (corresponding human plasma exposures following twice-weekly dosing are 3-, 8-, and 30-fold, respectively) for 13 weeks or to vehicle control. Following termination, serially trimmed sections of pancreases were stained with hematoxylin and eosin or co-stained with an epithelial marker and a marker of either proliferation or apoptosis. Efficacious reductions in glucose and hemoglobin A1c occurred at all dulaglutide doses. Lipase activity was unaffected, and there were modest increases in total and pancreatic amylase activities at all doses without individual microscopic inflammatory correlates. Microscopic dulaglutide-related pancreatic changes included increased interlobular ductal epithelium without ductal cell proliferation (0.5 mg/kg), increased acinar atrophy with/without inflammation (1.5 mg/kg), and increased incidence/severity of neutrophilic acinar pancreatic inflammation (5.0 mg/kg). In summary, dulaglutide treatment was associated with mild alterations in ductal epithelium and modest exacerbation of spontaneous lesions of the exocrine pancreas typically found in the ZDF rat model.
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