艾塞那肽对肥胖2型糖尿病患者疗效观察

目的观察艾塞那肽对多种口服降糖药物联用和／或胰岛素联合治疗疗效不佳的肥胖2型糖尿病（T2DM）患者的临床疗效和安全性。方法选择对多种口服降糖药联用和／或胰岛素联合治疗疗效不佳的肥胖T2DM患者36例,在原有治疗基础上加用艾塞那肽治疗3个月。比较治疗前后的血糖、血脂、血压、体重及不良反应等指标。结果加用艾塞那肽治疗3个月后,患者的糖化血红蛋白Alc（HbAlc）、空腹血糖（FBG）、餐后2h血糖（2hPBG）、甘油三酯（TG）和体重均明显下降。主要的不良反应为胃肠道反应及低血糖,但两者均较轻微且短暂。结论对多种口服降糖药物联用和／或胰岛素联合治疗后血糖仍控制欠佳的肥胖2型糖尿病患者,艾塞那肽可有效控制血糖,并有助于体重的控制。     

艾塞那肽注射液治疗老年2型糖尿病病人的观察及护理

[目的]总结艾塞那肽注射液治疗老年2型糖尿病病人的观察及护理。[方法]对15例老年2型糖尿病病人应用艾塞那肽注射液治疗,同时加强观察及护理。[结果]1例病人因严重肾功能不全在使用艾塞那肽注射液2个月后停用;艾塞那肽注射液治疗3个月后病人空腹血糖、餐后2h血糖、糖化血红蛋白、体重指数等指标均低于治疗前;出现恶心等轻度胃肠道反应7例,呕吐1例,低血糖1例,胃肠道副反应为一过性且症状较轻。[结论]艾塞那肽注射液能降低老年2型糖尿病病人的血糖水平,是一种安全有效的降糖药物。     

Exenatide Treatment for 6 Months Improves Insulin Sensitivity in Adults With Type 1 Diabetes

OBJECTIVE

Exenatide treatment improves glycemia in adults with type 2 diabetes and has been shown to reduce postprandial hyperglycemia in adolescents with type 1 diabetes. We studied the effects of exenatide on glucose homeostasis in adults with long-standing type 1 diabetes.

RESEARCH DESIGN AND METHODS

Fourteen patients with type 1 diabetes participated in a crossover study of 6 months'' duration on exenatide (10 μg four times a day) and 6 months off exenatide. We assessed changes in fasting and postprandial blood glucose and changes in insulin sensitivity before and after each study period.

RESULTS

High-dose exenatide therapy reduced postprandial blood glucose but was associated with higher fasting glucose concentrations without net changes in hemoglobin A_1c. Exenatide increased insulin sensitivity beyond the effects expected as a result of weight reduction.

CONCLUSIONS

Exenatide is a promising adjunctive agent to insulin therapy because of its beneficial effects on postprandial blood glucose and insulin sensitivity in patients with type 1 diabetes.Glucagon-like peptide 1 (GLP-1) agonists, including exenatide, are promising agents for the treatment of type 2 diabetes. Exenatide, the first GLP-1 agonist to be Food and Drug Administration approved, and other members of this class of drugs have been shown to improve fasting and postprandial blood glucose and hemoglobin A_1c (A1C) and to promote weight loss, resulting in increased insulin sensitivity (1–3). Few reports have focused on GLP-1 agonist treatment in patients with type 1 diabetes. Herein, we report the effects of 6 months of therapy with exenatide in patients with long-standing type 1 diabetes focusing on outcomes related to glucose homeostasis, including fasting and postprandial blood glucose and insulin sensitivity, as determined by the reference glucose clamp method (4).     

Acute Metabolic Effects of Exenatide in Patients With Type 1 Diabetes With and Without Residual Insulin to Oral and Intravenous Glucose Challenges

OBJECTIVE

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is released from the gastrointestinal tract. Treatment with GLP-1 analogs has proven to be of clinical use for patients with type 2 diabetes. Patients with type 1 diabetes, particularly those with residual β-cell function, may also respond to treatment, but the acute metabolic effects of GLP-1 analogs on these patients in reaction to both oral and intravenous glucose challenges are not well understood.

RESEARCH DESIGN AND METHODS

Seventeen patients with type 1 diabetes, half of whom had residual insulin production, underwent two mixed-meal tolerance tests (MMTTs) and two intravenous glucose tolerance tests (IVGTTs), with and without pretreatment with exenatide. No exogenous bolus insulin was administered for the studies. Glucose excursions, insulin secretion rates (ISRs), and levels of glucagon, endogenous GLP-1, and gastric inhibitory polypeptide were measured after the meal or glucose loads.

RESULTS

During the MMTT, glucose levels were suppressed with exenatide in patients with or without residual insulin production (P = 0.0003). Exenatide treatment did not change the absolute ISR, but the ISR to glucose levels were increased (P = 0.0078). Gastric emptying was delayed (P = 0.0017), and glucagon was suppressed (P = 0.0015). None of these hormonal or glucose changes were detected during the IVGTT with exenatide administration.

CONCLUSIONS

Exenatide showed a significant antidiabetogenic effect prior to an oral meal in patients with type 1 diabetes involving glucagon suppression and gastric emptying, while preserving increased insulin secretion. GLP-1 analogs may be useful as an adjunctive treatment in type 1 diabetes.     

Exenatide in type 2 diabetes: treatment effects in clinical studies and animal study data

The therapeutic options for treating type 2 diabetes have been widened by the introduction of exenatide as the first incretin mimetic. Incretins are gut hormones that contribute to the stimulation of insulin secretion after a carbohydrate rich meal. The incretin hormone glucagon-like peptide-1 (GLP-1) not only stimulates insulin secretion under hyperglycaemic conditions, but also suppresses glucagon secretion, slows gastric emptying, induces satiety and improves beta cell function in type 2 diabetes. These beneficial effects have awakened the interest to use GLP-1 for the treatment of type 2 diabetes. Because of its short biological half-life, GLP-1 itself is not practical for type 2 diabetes therapy. Exenatide is a peptide found in the lizard Heloderma suspectum and has a high similarity to GLP-1. Exenatide belongs to the novel class of incretin mimetics because of its incretin-like action. It has a much longer biological half life than GLP-1 and is a GLP-1 receptor agonist that can be used for therapeutic purposes by twice daily injection. Clinical studies and clinical experience with exenatide have shown a significant reduction in HbA1c, fasting- and postprandial glucose and a marked reduction in body weight in type 2 diabetic patients. Animal studies reveal an improvement of beta cell function and an increase in beta cell mass after exenatide treatment. This review gives an overview on exenatide, its pharmacological profile and its role and potential in the therapeutic setting of type 2 diabetes. Furthermore, future developments concerning exenatide application are highlighted.     

Addition of exenatide twice daily to basal insulin for the treatment of type 2 diabetes: clinical studies and practical approaches to therapy

Background: Type 2 diabetes is a progressive disease that requires stepwise additions of non‐insulin and insulin therapies to meet recommended glycaemic goals. The final stage of intensification may require prandial insulin, adding complexity and increased risks of hypoglycaemia and weight gain. Aims: This review assesses the benefits and risks of adding exenatide twice daily, a glucagon‐like peptide 1 receptor agonist, in patients with type 2 diabetes who are currently treated with basal insulin, but have failed to reach their glycaemic goals. Methods and Results: Based on data from published studies, exenatide has a number of actions that complement basal insulin therapy. Exenatide has been shown to increase glucose‐dependent insulin production, suppress abnormal plasma glucagon production, slow gastric emptying, enhance liver uptake of glucose and promote satiety. A recently published randomised clinical trial reported that the addition of exenatide twice daily to titrated basal insulin provided greater glycaemic control than titrated basal insulin alone, and did so without an increase in hypoglycaemic events and with modest weight loss. Exenatide use was associated with gastrointestinal side effects. The recent randomised trial confirmed and extended data from a number of prior observational studies that demonstrated the efficacy and safety of insulin/exenatide combination therapy. Practical considerations for adding exenatide twice daily to ongoing basal insulin are discussed.     

Pathophysiological and Pharmacological Rationale for the Use of Exenatide Once Weekly in Patients with Type 2 Diabetes

Introduction

A new formulation of exenatide has become available recently that is the first antidiabetic medication for type 2 diabetes mellitus (T2DM) dosed on a weekly schedule. This review summarizes the pharmacology, efficacy, and safety of exenatide once weekly (exenatide QW). The results are interpreted in terms of the pathophysiology of T2DM, as well as the pharmacology of the new formulation.

Methods

Relevant literature on exenatide QW and diabetes was identified through PubMed database searches from inception until September 2013.

Discussion

In the new once-weekly formulation of exenatide, the exenatide molecule is dispersed in microspheres. Following subcutaneous injection, these microspheres degrade in situ and slowly release active agent. In clinical trials, therapy with exenatide QW as monotherapy or in combination with other antidiabetic treatments was associated with reductions in glycated hemoglobin (?1.3% to ?1.9%), fasting plasma glucose (?32 to ?41 mg/dL), and body weight (?2.0 to ?3.7 kg). These outcomes were achieved without an associated increase in the rate of hypoglycemic episodes, except when exenatide QW was used in combination with sulfonylureas. The primary tolerability issues in the trials were gastrointestinal adverse events, particularly during the first weeks of use, although the rate of nausea during startup with exenatide QW was lower than that with the related agents, exenatide twice daily and liraglutide once daily.

Conclusions

Exenatide QW may be particularly well suited to patients who desire the benefits associated with glucagon-like peptide-1 receptor agonists, including significant glycemic control, low risk of hypoglycemia, and moderate weight loss, but prefer the convenience of once-weekly dosing.     

GLP-1受体激动剂对超重肥胖2型糖尿病患者糖脂代谢的影响

目的：探讨胰高血糖素样肽-1受体激动剂艾塞那肽对超重和肥胖2型糖尿病患者糖脂代谢及体质量的影响。方法对22例口服二甲双胍治疗血糖控制不佳的超重肥胖2型糖尿病患者联合艾塞那肽治疗,观察6个月,监测患者治疗前后的血糖、血脂及体质量的变化。结果患者治疗后体质量、体质量指数、空腹血糖、餐后2 h血糖、糖化血红蛋白均呈进行性下降（P＜0．05）;总胆固醇、胰岛素抵抗指数均较治疗前显著下降（P＜0．01）,其他指标与治疗前比较差异均无显著性（P＞0．05）。结论艾塞那肽能显著降低超重肥胖2型糖尿病患者的血糖、血脂水平,减轻体质量,更适用于肥胖的2型糖尿病患者。     

Exenatide: an incretin mimetic for the treatment of type 2 diabetes mellitus

BACKGROUND: Exenatide is a subcutaneously injected incretin mimetic. It is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus (T2DM) who are already receiving therapy with metformin, a sulfonylurea, or both but continue to have suboptimal glycemic control. OBJECTIVE: This article reviews available information on the clinical pharmacology, comparative efficacy, tolerability, drug interactions, contraindications and precautions, dosage and administration, availability and storage, and cost of exenatide. METHODS: MEDLINE (1966-April 2006) and Web of Science (1995-April 2006) were searched for original research and review articles published in the English language. The search terms used were exenatide, exendin-4, glucagon-Like peptide-1, GLP-1, and incretin mimetic. The reference lists of identified articles were also consulted, as was selected information from the package insert for exenatide. All relevant comparative efficacy studies that were available in published form were included in the review. RESULTS: Naturally occurring incretins, such as glucagon-like peptide-1 (GLP-1), exhibit insulinotropic properties after release into the circulation from the gut. As a GLP-1 agonist, exenatide improves glucose homeostasis by mimicking the actions of naturally occurring GLP-1. It improves glycemic control by reducing fasting and postprandial glucose concentrations through a combination of known mechanisms, including glucose-dependent insulin secretion, restoration of first-phase insulin response, regulation of glucagon secretion, delaying gastric emptying, and decreasing food intake. Three Phase III comparative efficacy trials were identified that enrolled a total of 1,446 patients who received exenatide 5 pg SC BID, exenatide 10 mug SC BID, or placebo for 30 weeks in addition to their existing therapy with metformin, sulfonylurea, or both. In these trials, the addition of exenatide was associated with significant reductions in glycosylated hemoglobin (HbA(1c)) values (P < 0.001-P < 0.002), greater proportions of patients achieving an HbA(1c) 10% of patients receiving exenatide were hypoglycemia (19.6%), diarrhea (12.8%), and vomiting (12.8%). CONCLUSIONS: During clinical trials, exenatide added to existing metformin and/or sulfonylurea therapy in patients with T2DM reduced fasting and postprandial glucose concentrations, with improvements in HbA(1c) and modest weight loss. The main adverse effect associated with exenatide therapy was nausea.     

Exenatide upregulates gene expression of glucagon‐like peptide‐1 receptor and nerve growth factor in streptozotocin/nicotinamide‐induced diabetic mice

Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone that has modulating effects on insulin release. GLP‐1 and receptors for GLP‐1 are widely expressed throughout the body including the brain. The expression of GLP‐1 receptors is very specific to large neurons in hippocampus, neocortex, and cerebellum. GLP‐1 receptor stimulation enhances glucose‐dependent insulin secretion and lowers blood glucose in type 2 diabetes mellitus. Studies on adipobiology of neurotrophins have focused on nerve growth factor (NGF) as an example of adipose‐derived neurotrophins. Compromised trophic factor signaling may underlie neurodegenerative diseases ranging from Alzheimer's disease to diabetic neuropathies. Exenatide, a potent and selective agonist for the GLP‐1 receptor, is currently approved for the treatment of type 2 diabetes mellitus. The aim of this study was to assess the effect of chronic exenatide treatment on the hippocampal gene expression levels of GLP‐1 receptor and NGF in diabetic mice. The effects of chronic exenatide treatment (0.1 μg/kg, s.c., twice daily for 2 weeks) on GLP‐1 receptor and NGF gene expression levels in the hippocampus of streptozotocin/nicotinamide (STZ–NA)‐induced diabetic mice were assessed by quantitative real‐time polymerase chain reaction (RT‐PCR). The results of this study revealed that hippocampal gene expression of GLP‐1 receptor and NGF were downregulated in diabetic mice. Importantly, a significant increase in the gene expression level of GLP‐1 receptor and NGF was determined after 2 weeks of exenatide administration. Increased gene expression level of GLP‐1 receptor and NGF may underlie the beneficial action of exenatide in STZ/NA‐induced diabetes.     

The Role of Adjunctive Exenatide Therapy in Pediatric Type 1 Diabetes

OBJECTIVE

Exenatide improves postprandial glycemic excursions in type 2 diabetes. Exenatide could benefit type 1 diabetes as well. We aimed to determine an effective and safe glucose-lowering adjuvant exenatide dose in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Eight subjects completed a three-part double-blinded randomized controlled study of premeal exenatide. Two doses of exenatide (1.25 and 2.5 μg) were compared with insulin monotherapy. Prandial insulin dose was reduced by 20%. Gastric emptying and hormones were analyzed for 300 min postmeal.

RESULTS

Treatment with both doses of exenatide versus insulin monotherapy significantly reduced glucose excursions over 300 min (P < 0.0001). Exenatide administration failed to suppress glucagon but delayed gastric emptying (P < 0.004).

CONCLUSIONS

Adjunctive exenatide therapy reduces postprandial hyperglycemia in adolescents with type 1 diabetes. This reduction in glucose excursion occurs despite reduction in insulin dose. We suggest that exenatide has therapeutic potential as adjunctive therapy in type 1 diabetes.Intensive insulin therapy delays/prevents complications associated with type 1 diabetes (1,2). However, insulin monotherapy fails to achieve normoglycemia (3). Postprandial hyperglycemia and hypoglycemia (4,5) continue to create impediments to management. Even the closed-loop system fails to normalize postprandial hyperglycemia (6). Additional therapies to insulin are needed to achieve optimal glycemic control.Glucagon-like peptide (GLP)-1 is an incretin secreted in response to nutrient ingestion (7). Physiological GLP-1 enhances insulin secretion, delays gastric emptying, and suppresses glucagon. But because of its short half-life (8), it is unsuitable for clinical application.Exenatide is a long-acting GLP-1 receptor agonist and acts similarly to native GLP-1 (9). Exenatide is effective in decreasing postprandial hyperglycemia in type 2 diabetes (10). However, there are few studies using exenatide in type 1 diabetes and none in adolescents. The objective of our study was to examine the effect of adjuvant premeal exenatide and insulin on postprandial glucose in type 1 diabetes and establish an effective and safe glucose-lowering dose.     

Clinical implications of exenatide as a twice-daily or once-weekly therapy for type 2 diabetes

Exenatide (exendin-4) is a 39-amino acid peptide belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class that has been demonstrated to improve glycemic control in patients with type 2 diabetes mellitus. Exenatide can be injected twice daily (ExBID) before meals or once weekly (ExQW) when encompassed within dissolvable poly-(D,L-lactide-co-glycolide) microspheres. The primary difference between these formulations is the plasma concentration of exenatide over time, with the long-acting form providing continuous delivery. Clinical trials have examined the similarities and differences in the efficacy and safety/tolerability outcomes of these formulations. In 2 clinical studies spanning 24 and 30 weeks, significant (P < 0.05) reductions from baseline were observed in fasting plasma glucose (ExBID, -12 and -25 mg/dL; ExQW, -35 and -41 mg/dL), postprandial glucose (ExBID, -124 mg/dL; ExQW, -95 mg/dL), and glycated hemoglobin (HbA1c) (ExBID, -0.9% and -1.5%; ExQW, -1.6% and -1.9%). Reductions in body weight from baseline were significant and similar with both treatments (ExBID, -1.4 and -3.6 kg; ExQW, -2.3 and -3.7 kg). Reductions in systolic blood pressure from baseline were observed with both formulations, particularly in patients who were hypertensive at baseline. Beneficial improvements in lipid profiles were small and fluctuated in significance. Patients reported greater treatment satisfaction with ExQW compared with ExBID dosing. Gastrointestinal adverse events were commonly observed with both formulations but were less frequent with ExQW. These events were of mild-to-moderate intensity and rarely led to discontinuation. Real-world data for ExBID demonstrated decreases in HbA1c, fasting plasma glucose, and body weight that were consistent with clinical trial results. Cases of pancreatitis or renal impairment have been reported in patients treated with ExBID, although no causal relationship with treatment has been shown. This review describes the similarities and differences between exenatide delivered as a twice-daily or as a once-weekly injection to provide a better understanding of the clinical effects and potential clinical uses of each.     

Exenatide: a novel approach for treatment of type 2 diabetes

Exenatide (synthetic exendin-4) is the analog of glucagon-like peptide 1 (GLP-1), the major physiologic incretin. The latter is an intestinal hormone that enhances glucose-induced insulin secretion after meals. In addition, GLP-1 stimulates insulin synthesis, inhibits glucagon secretion, delays gastric emptying, and may promote satiety. These glucoregulatory actions help control plasma glucose in the postprandial period. However, in diabetes, the GLP-1 response to nutrient intake is impaired, leading to exacerbation of postprandial hyperglycemia. Exenatide was recently approved as adjunctive therapy in diabetic patients failing sulfonylureas and/or metformin. In clinical trials lasting 30 weeks, exenatide therapy was associated with moderate reduction in mean hemoglobin A1c (HbA1c) levels of approximately 0.8%, and an average weight loss of approximately 2 kg compared with baseline. Hypoglycemia was generally mild and occurred more commonly when exenatide was used in conjunction with sulfonylureas. The requirement of subcutaneous injections twice a day, and the frequent occurrence of nausea and vomiting, represent the main limitations of exenatide. Nevertheless, this agent may be a useful add-on therapy in obese diabetic patients with suboptimal control as a result of continuing weight gain and/or severe postprandial hyperglycemia. The introduction of GLP-1-based antidiabetic drugs is a novel and promising strategy to treat diabetes.     

Exenatide twice daily: analysis of effectiveness and safety data stratified by age, sex, race, duration of diabetes, and body mass index

Background: Exenatide, a glucagon-like peptide-1 receptor agonist, is used twice daily (BID) as monotherapy or adjunctive therapy for the improvement of glycemic control in patients with type 2 diabetes mellitus. The purpose of this pooled analysis was to evaluate the safety and efficacy of exenatide BID in patients stratified by various demographic characteristics. Methods: This post hoc analysis included data from 16 randomized controlled trials in which patients with type 2 diabetes mellitus were treated with 10-μg exenatide BID. Each patient was classified into subgroups on the basis of his or her baseline values for age (< 65 or ≥ 65 years), sex (male or female), race (white, black, Asian, or Hispanic), duration of diabetes (< 10 years or ≥ 10 years), and body mass index (BMI; ≥ 20 to < 25, ≥ 25 to < 30, ≥ 30 to < 35, or ≥ 35 kg/m2). Results: A total of 2067 patients were included. All groups experienced significant improvements in glycated hemoglobin, fasting plasma glucose levels (other than black patients, who had a relatively low baseline fasting plasma glucose level), and body weight from baseline to endpoint. Most groups had significant improvements in systolic blood pressure. All of the age, sex, and duration of diabetes groups experienced significant improvements in lipid levels (other than high-density lipoprotein cholesterol). Whites and Asians generally experienced significant improvements in lipid levels, whereas blacks and Hispanics did not. Significant improvements in lipid levels were generally seen across BMI groups. The most common adverse events overall were nausea (38.6%), hypoglycemia (28.4%), and vomiting (14.0%). Hypoglycemia was more common overall in patients who were taking a concomitant sulfonylurea than it was in patients who were not. Conclusion: In this pooled analysis, exenatide BID improved glycemic control and body weight, and had generally beneficial effects on blood pressure and lipid levels in patients regardless of baseline age, sex, race, duration of diabetes, or BMI. Gastrointestinal events were the most common adverse events.Trial registration: www.ClinicalTrials.gov [NCT00039026, NCT00039013, NCT00082381, NCT00035984, NCT00082407, NCT00381342, NCT00360334, NCT00375492, NCT00603239, NCT00765817, NCT00577824, NCT00434954].     

Pharmacology and tolerability of a single dose of exenatide in adolescent patients with type 2 diabetes mellitus being treated with metformin: A randomized,placebo-controlled,single-blind,dose-escalation,crossover study

Objective: This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single doses of exenatide in adolescent patients with type 2 diabetes mellitus (T2DM).Methods: This was a randomized, single-blind, dose-escalation, crossover study in adolescent (age 10–16 years) patients with T2DM who were being treated with diet and exercise or a stable dose of metformin, a sulfonylurea, or a combination of metformin and a sulfonylurea for at least 3 months before screening. Eligible patients were allocated to receive single subcutaneous doses of exenatide 2.5 μg, exenatide 5 μg, and placebo, each followed by a standardized meal, on 3 separate days (maximum interval between first and third doses, 5 weeks). Exenatide 2.5 μg always preceded exenatide 5 μg in each treatment sequence. The primary end points were the pharmacokinetics and safety profile of exenatide; secondary end points included postprandial plasma glucose, serum insulin, and plasma glucagon concentrations.Results: The study enrolled 13 adolescent patients with T2DM (7 females, 6 males; mean [SD] age, 15 [1] years; body mass index, 32.5 [5.0] kg/m²; glycosylated hemoglobin, 8.2% [1.5%]). After administration of exenatide 5 μg, the geometric mean (SE) exenatide AUC_0?∞ and C_max were 339.5 (39.6) pg · h/mL and 85.1 (11.5) pg/mL, respectively (n = 12). The exenatide AUC appeared to be dose dependent, although exenatide was not quantifiable in all patients at the 2.5-μg dose; after administration of exenatide 2.5-μg, the geometric mean AUC_0?∞) was 159.2 (23.1) pg · h/mL (n = 6) and the geometric mean C_max was 56.3 (10.1) pg/mL (n = 9). Both exenatide doses were associated with significant reductions in postprandialplasma glucose excursions compared with placebo (P < 0.01); the incremental mean (SE) AUC_15–360min was ?3465.6 (1587.3) mg · min/dL for exenatide 2.5 pg, ?4422.2 (2434.4) mg · min/dL for exenatide 5 μg, and 3457.4 (1615.5) mg · min/dL for placebo. The 2 exenatide doses were also associated with significant reductions in postprandial plasma glucagon concentrations compared with placebo (P < 0.01); the respective incremental mean values for AUC_15–180min were 125.5 (658.4), ?1403.8 (632.1), and 1843.1 (540.6) pg · min/mL. There were no significant differences in serum insulin concentrations between exenatide and placebo. Exenatide was generally well tolerated, with no hypoglycemic events recorded during the study.Conclusions: In these adolescent patients with T2DM, administration of single 2.5- and 5-μg doses of exenatide were associated with dose-dependent increases in plasma exenatide concentrations and improved postprandial glucose concentrations compared with placebo. Both doses appeared to be well tolerated. ClinicalTrials.gov Identifier: NCT00254254.     

Tracheal Fibroxanthoma in a Child

Abstract

Exenatide (exendin-4) is a 39-amino acid peptide belonging to the glucagon-like peptide-1 (GLP-1) receptor agonist class that has been demonstrated to improve glycemic control in patients with type 2 diabetes mellitus. Exenatide can be injected twice daily (ExBID) before meals or once weekly (ExQW) when encompassed within dissolvable poly-(D,L -lactide-co-glycolide) microspheres. The primary difference between these formulations is the plasma concentration of exenatide over time, with the long-acting form providing continuous delivery. Clinical trials have examined the similarities and differences in the efficacy and safety/tolerability outcomes of these formulations. In 2 clinical studies spanning 24 and 30 weeks, significant (P < 0.05) reductions from baseline were observed in fasting plasma glucose (ExBID, ?12 and ?25 mg/dL; ExQW, ?35 and ?41 mg/dL), postprandial glucose (ExBID, ?124 mg/dL; ExQW, ?95 mg/dL), and glycated hemoglobin (HbA1) (ExBID, ?0.9% and ?1.5%; ExQW, ?1.6% and ?1.9%). Reductions in body weight from baseline were significant and similar with both treatments (ExBID, ?1.4 and ?3.6 kg; ExQW, ?2.3 and ?3.7 kg). Reductions in systolic blood pressure from baseline were observed with both formulations, particularly in patients who were hypertensive at baseline. Beneficial improvements in lipid profiles were small and fluctuated in significance. Patients reported greater treatment satisfaction with ExQW compared with ExBID dosing. Gastrointestinal adverse events were commonly observed with both formulations but were less frequent with ExQW. These events were of mild-to-moderate intensity and rarely led to discontinuation. Real-world data for ExBID demonstrated decreases in HbA_1c, fasting plasma glucose, and body weight that were consistent with clinical trial results. Cases of pancreatitis or renal impairment have been reported in patients treated with ExBID, although no causal relationship with treatment has been shown. This review describes the similarities and differences between exenatide delivered as a twice-daily or as a once-weekly injection to provide a better understanding of the clinical effects and potential clinical uses of each.     

Baseline factors associated with glycemic control and weight loss when exenatide twice daily is added to optimized insulin glargine in patients with type 2 diabetes

OBJECTIVE

To determine variables associated with glycemic and body weight responses when adding exenatide to basal insulin–treated type 2 diabetes.

RESEARCH DESIGN AND METHODS

Exploratory subgroup analyses based on baseline A1C, disease duration, and BMI of a 30-week study comparing exenatide twice daily to placebo, added to optimized insulin glargine (intent-to-treat analysis: 137 exenatide; 122 placebo).

RESULTS

Exenatide participants had greater A1C reductions compared with optimized insulin glargine alone, irrespective of baseline A1C (P < 0.001). Exenatide participants with longer diabetes duration and those with lower BMI had greater A1C reductions (P < 0.01). Exenatide participants lost more weight, regardless of baseline A1C or BMI (P < 0.05). Exenatide participants with longer diabetes duration lost the most weight (P < 0.001).

CONCLUSIONS

Exenatide added to optimized basal insulin was associated with improved glycemic control and weight loss, irrespective of baseline A1C, diabetes duration, and BMI. Changes were evident in modestly obese patients and in those with longer diabetes duration.The combined use of glucagon-like peptide 1 (GLP-1) receptor agonists and insulin is of growing clinical interest (1–6), and the combined use of insulin glargine with exenatide is now approved in the U.S. In this recent study, exenatide twice daily added to optimized titration of glargine resulted in greater A1C improvements with weight loss and lesser increase in insulin dose than placebo plus optimized glargine (5). The current exploratory post hoc analysis assessed the relationship of baseline A1C, duration of diabetes, and BMI with glucose control, body weight changes, and insulin doses in that study.     

艾塞那肽联合二甲双胍治疗口服降糖药控制不佳的2型糖尿病疗效观察

目的观察艾塞那肽联合二甲双胍治疗对口服降糖药(OAD)控制不佳的2型糖尿病(T2DM)患者的临床疗效。方法 31例既往使用OAD控制不佳的T2DM患者,改用艾塞那肽联合二甲双胍治疗3个月,观察治疗前后空腹血糖(FPG)、餐后2h血糖(2hPG)、糖化血红蛋白(HbA1c)、体重、体质指数(BMI)、C-肽(空腹及餐后2h)、总胆固醇(TC)、甘油三酯(TG)、高密度脂蛋白胆固醇(HDL-C)、低密度脂蛋白胆固醇(LDL-C)的变化。结果治疗后FPG、2hPG、HbA1c、体重、BMI、TC、TG、LDL-C均有明显下降(P均<0.01)。C-肽(空腹及餐后2h)未发现明显变化(P>0.05)。低血糖发生率为3.23%。结论艾塞那肽联合二甲双胍能有效地控制T2DM患者的血糖,减轻体重,且发生低血糖的风险低。     

The effects of pharmacologic agents for type 2 diabetes mellitus on body weight

Type 2 diabetes mellitus and obesity share a pathogenic relationship, and both have rapidly increased in prevalence over the past decade. This review evaluates the effects of antidiabetes therapies on weight and glycemic control in the type 2 diabetes mellitus population. A PubMed search was conducted to identify randomized controlled trials that reported the weight effects of antidiabetes treatments. The search focused on the newer incretin-based therapies, including dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) agonists. Antiobesity drugs and treatment options potentially available to patients with type 2 diabetes mellitus, including bariatric surgery, were also examined. Most of the established antidiabetes therapies (eg, sulfonylureas, thiazolidinediones) promote weight gain, thereby exacerbating insulin resistance and glucose intolerance. Dipeptidyl peptidase-4 inhibitors exhibit a weight-neutral profi le, however, and GLP-1 receptor agonists (eg, exenatide, liraglutide) have achieved signifi cant body weight reductions in spite of improved glycemic control, which is often accompanied by weight gain. Antiobesity drugs, such as orlistat and sibutramine, are effective weight-lowering agents in patients with type 2 diabetes mellitus, but safety and tolerability concerns may limit their use. Bariatric surgery in obese patients is associated with improved glycemic values and decreased mortality. Clinical evidence substantiating the weight-neutral effects of DPP-4 inhibitors and the weight-loss effects of GLP-1 agonists is promising, offering an expansion of therapeutic options for overweight and obese patients with type 2 diabetes mellitus. Evidence on the clinical utility of antiobesity drugs is more equivocal, and more data are needed to evaluate the safety and tolerability of these agents.     

Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes

OBJECTIVE: This study evaluated the ability of the incretin mimetic exenatide (exendin-4) to improve glycemic control in patients with type 2 diabetes failing maximally effective doses of a sulfonylurea as monotherapy. RESEARCH DESIGN AND METHODS: This was a triple-blind, placebo-controlled, 30-week study conducted at 101 sites in the U.S. After a 4-week, single-blind, placebo lead-in period, 377 subjects were randomized (60% men, age 55 +/- 11 years, BMI 33 +/- 6 kg/m(2), HbA(1c) 8.6 +/- 1.2% [+/-SD]) and began 4 weeks at 5 microg subcutaneous exenatide twice daily (before breakfast and dinner; arms A and B) or placebo. Subsequently, subjects in arm B were escalated to 10 microg b.i.d. exenatide. All subjects continued sulfonylurea therapy. RESULTS: At week 30, HbA(1c) changes from baseline were -0.86 +/- 0.11, -0.46 +/- 0.12, and 0.12 +/- 0.09% (+/-SE) in the 10-microg, 5-microg, and placebo arms, respectively (adjusted P < 0.001). Of evaluable subjects with baseline HbA(1c) > 7% (n = 237), 41% (10 microg), 33% (5 microg), and 9% (placebo) achieved HbA(1c) 相似文献