Exenatide: pharmacokinetics,clinical use,and future directions

Introduction: The first-in-class glucagon-like peptide-1 receptor agonist (GLP-1RA) exenatide, which was initially approved in 2005, is available in twice-daily (BID) and once-weekly (QW) formulations. Clinical trial data suggest both formulations are effective and safe for patients with type 2 diabetes (T2D), both as monotherapy and as part of combination therapy. Since exenatide was approved, several other GLP-1RAs have become available for clinical use.

Areas covered: Many ongoing clinical trials involving exenatide BID and exenatide QW are investigating new indications (exenatide BID) and new end points and combination therapies (exenatide QW). This review provides an overview of the delivery and pharmacokinetics of both formulations of exenatide, reviews existing data in T2D, and summarizes ongoing investigations.

Expert opinion: Exenatide BID and QW have substantial clinical benefits. Comparisons with other GLP-1RAs demonstrate some differences in efficacy and safety profiles that make assessment of benefit:risk ratios complex. Head-to-head comparisons of QW GLP-1RA formulations may assist in the ranking of GLP-1RAs according to efficacy and safety. Results on the impact of exenatide QW on cardiovascular outcomes are eagerly awaited. The potential clinical utility of exenatide BID in other indications will clarify whether exenatide holds clinical promise in diagnoses other than T2D.     

The efficacy and safety of exenatide once weekly in patients with type 2 diabetes

Introduction: Exenatide once weekly (QW) is a glucagon-like peptide 1 receptor agonist (GLP-1RA) that was approved in 2012 in Europe and the U.S.A. for the treatment of type 2 diabetes (T2D).

Areas covered: This review provides an overview of the safety and efficacy of exenatide QW for the treatment of T2D and evaluates the benefit–risk ratio compared to other available long-acting GLP-1RAs. In addition, the authors provide an outline of the novel formulations and delivery methods of exenatide.

Expert opinion: Exenatide QW is an efficacious and safe treatment for T2D. However, head-to-head trials have demonstrated exenatide QW to be inferior to liraglutide and semaglutide with respect to effects on fasting plasma glucose, glycated hemoglobin A1c, and bodyweight. In addition, exenatide QW appears inferior to liraglutide and semaglutide in terms of cardiovascular risk reduction. Currently, the overall risk-benefit profiles for the range of GLP-1RAs point to liraglutide and semaglutide as first-choice for the management of T2D, which has been confirmed by a recently published consensus report on the treatment of T2D from the American Diabetes Association and the European Association for the Study of Diabetes. The pricing of exenatide QW will most likely be a key determinant for its place in the future management of T2D.     

Targeting the pathophysiology of type 2 diabetes: rationale for combination therapy with pioglitazone and exenatide

ABSTRACT

Objective: The objectives of this article are to review the pathophysiology of type 2 diabetes mellitus (T2DM), present the rationale for a pathophysiologically based treatment approach for patients with T2DM and discuss the role of the therapeutic combination of pioglitazone and exenatide in the management of T2DM.

Methods: References were identified from searches of the PubMed database that were conducted in May 2007, October 2007 and March 2008 and updates to product labeling that occurred between May 2007 and December 2007. Information was selected for inclusion on the basis of its relevance to the pathophysiology of T2DM or the clinical use of thiazolidinediones or exenatide. Discussion of other anti-diabetic treatment strategies is not included.

Results: T2DM results from a combination of insulin resistance and beta-cell dysfunction. The combination of a thiazolidinedione and an incretin mimetic offers a combination of characteristics (e.g., glycemic control, reduced insulin resistance, decreased weight, potential cardiovascular benefits, beta-cell preservation) that addresses many of the pathophysiologic underpinnings of T2DM. A recent small placebo-controlled study assessed the effects of exenatide used with a thiazolidinedione (TZD; pioglitazone or rosiglitazone) with or without metformin. Exenatide demonstrated a greater incidence of glycosylated hemoglobin (HbA_1c) <?7%; greater reductions in fasting blood glucose, postprandial plasma glucose and body weight; and improved beta-cell function versus the TZD/placebo group. However, exenatide was associated with a high dropout rate, and the 16-week duration of treatment in this study precluded evaluation of the long-term effects of the exenatide/pioglitazone combination. Furthermore, exenatide/pioglitazone has not been compared with any other anti-diabetic combination in a head-to-head clinical study.

Conclusions: Dual effects on insulin sensitivity (TZD) and insulin secretion (exenatide) make the TZD/exenatide combination a rational treatment option for patients who do not attain glycemic control with a single agent. Studies undertaken to evaluate the effects on cardiovascular outcomes and the potential for prevention of T2DM with impaired glucose tolerance may reveal additional advantages of this combination approach.     

Discovery and development of exenatide: the first antidiabetic agent to leverage the multiple benefits of the incretin hormone,GLP-1

Introduction: The GLP-1 receptor agonist exenatide is synthetic exendin-4, a peptide originally isolated from the salivary secretions of the Gila monster. Exenatide was developed as a first-in-class diabetes therapy, with immediate- and extended-release formulations. In preclinical diabetes models, exenatide enhanced glucose-dependent insulin secretion, suppressed inappropriately elevated glucagon secretion, slowed gastric emptying, reduced body weight, enhanced satiety, and preserved pancreatic β-cell function. In clinical trials, both exenatide formulations reduced hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and were associated with weight loss.

Areas covered: This article reviews the development of exenatide from its discovery and preclinical investigations, to the elucidation of its pharmacological mechanisms of action in mammalian systems. The article also presents the pharmacokinetic profiling and toxicology studies of exenatide, as well as its validation in clinical trials.

Expert opinion: GLP-1 receptor agonists represent a new paradigm for the treatment of patients with T2DM. By leveraging incretin physiology, a natural regulatory system that coordinates oral nutrient intake with mechanisms of metabolic control, these agents address multiple core defects in the pathophysiology of T2DM. Studies have identified unique benefits including improvements in glycemic control and weight, and the potential for beneficial effects on the cardiometabolic system without the increased risk of hypoglycemia associated with insulin therapy. Peptide hormone therapeutics can offer significant advantages over small molecule drug targets when it comes to specificity, potency, and more predictable side effects. As exemplified by exenatide, injectable peptides can be important drugs for the treatment of chronic diseases, such as T2DM.     

Exenatide

Exenatide is the first in a new class of compounds that exhibit activity similar to the naturally occurring hormone glucagon-like peptide-1 (GLP-1). Released from cells in the gut in response to food, GLP-1 binds to pancreatic beta-cell receptors to stimulate the release of insulin. Exenatide mirrors many of the effects of GLP-1, improving glycemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying, reduced appetite and enhanced beta-cell function. As stimulation of insulin secretion occurs only in the presence of elevated blood glucose concentrations, the risk of hypoglycemia should be greatly reduced with exenatide. In addition to positive therapeutic effects on fasting and postprandial glucose levels, exenatide treatment is associated with significant, dose-dependent reductions in glycated hemoglobin (HbA1c) from baseline and progressive reductions in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but it can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Exenatide may enable patients with type 2 diabetes to achieve glycemic control while reducing or eliminating the risk of hypoglycemia and weight gain. These would represent significant therapeutic gains.     

艾塞那肽的抗糖尿病机制及临床应用进展

艾塞那肽是首个获准上市的肠促胰素类似物药物,可模拟人体自身胰高糖素样肽1(GLP-1)的功能,降低健康受试者和2型糖尿病患者的体重、空腹和餐后血糖,降低糖化血红蛋白,同时促进胰岛β细胞新生、增殖,抑制β细胞凋亡,改善β细胞功能,促进胰岛素分泌,增加机体对胰岛素的敏感性,延缓胃排空和减少摄食量等,因而有着传统治疗糖尿病药物不可比拟的优点,近年来已经成为糖尿病治疗领域的研究热点,应用前景非常广阔。本文对艾塞那肽的药动学、临床疗效及抗糖尿病作用机制作一综述。     

艾塞那肽治疗2型糖尿病临床观察

目的观察艾塞那肽治疗2型糖尿病(T2DM)的临床效果。方法对2型糖尿病患者19例予艾塞那肽治疗。治疗前后比较糖化血红蛋白(HbA1c)、空腹血糖(FBG)、餐后2h血糖(2h PG)、总胆固醇(TC)、三酰甘油(TG)、体质量、空腹C肽及餐后2h C肽水平,并观察其不良反应。结果治疗3个月后患者HbA1c、FBG、2h PG、TG、TC和体质量均显著下降(P<0.01),空腹C肽、餐后2h C肽均显著增加(P<0.01)。其中出现恶心等轻度胃肠道反应5例,低血糖发生率为5.3%。结论艾塞那肽可持续有效控制T2DM患者的血糖,降低患者体质量,改善B细胞功能,且低血糖风险低,值得推广应用。     

Exenatide effects on diabetes,obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years

ABSTRACT

Background: Exenatide, an incretin mimetic for adjunctive treatment of type 2 diabetes (T2DM), reduced hemoglobin A_1c (A1C) and weight in clinical trials. The objective of this study was to evaluate the effects of?≥?3 years exenatide therapy on glycemic control, body weight, cardiometabolic markers, and safety.

Methods: Patients from three placebo-controlled trials and their open-label extensions were enrolled into one open-ended, open-label clinical trial. Patients were randomized to twice daily (BID) placebo, 5?µg exenatide, or 10?µg exenatide for 30 weeks, followed by 5?µg exenatide BID for 4 weeks, then 10?µg exenatide BID for ≥3 years of exenatide exposure. Patients continued metformin and/or sulfonylureas.

Results: 217 patients (64% male, age 58?±?10 years, weight 99?±?18?kg, BMI 34?±?5?kg/m², A1C 8.2?±?1.0% [mean?±?SD]) completed 3 years of exenatide exposure. Reductions in A1C from baseline to week 12 (?1.1?±?0.1% [mean?±?SEM]) were sustained to 3 years (?1.0?±?0.1%; p?<?0.0001), with 46% achieving A1C?≤?7%. Exenatide progressively reduced body weight from baseline (?5.3?±?0.4?kg at 3 years; p?<?0.0001). Patients with elevated serum alanine aminotransferase (ALT) at baseline (n?=?116) had reduced ALT (?10.4?±?1.5?IU/L; p?<?0.0001) and 41% achieved normal ALT. Patients with elevated ALT at baseline tended to lose more weight than patients with normal ALT at baseline (?6.1?±?0.6?kg vs. ?4.4?±?0.5?kg; p?=?0.03), however weight change was minimally correlated with baseline ALT (r?=??0.01) or ALT change (r?=?0.31). Homeostasis Model Assessment B (HOMA-B), blood pressure, and aspartate aminotransferase (AST) all improved. A subset achieved 3.5 years of exenatide exposure and had serum lipids available for analysis (n?=?151). Triglycerides decreased 12% (p?=?0.0003), total cholesterol decreased 5% (p?=?0.0007), LDL-C decreased 6% (p?<?0.0001), and HDL-C increased 24% (p <?0.0001). Exenatide was generally well tolerated. The most frequent adverse event was mild-to-moderate nausea. The main limitation of this study is the open-label, uncontrolled nature of the study design which does not provide a placebo group for comparison.

Conclusion: Adjunctive exenatide treatment for ≥3 years in T2DM patients resulted in sustained improvements in glycemic control, cardiovascular risk factors, and hepatic biomarkers, coupled with progressive weight reduction.     

Do glucagon-like peptide-1 receptor (GLP-1R) agonists have potential as adjuncts in the treatment of type 1 diabetes?

ABSTRACT

Introduction: Glucagon-like peptide-1 (GLP-1) is produced by the gut, stimulates insulin secretion from the pancreatic β-cells, and inhibits glucagon secretion from the α-cells. The GLP-1 receptor (GLP-1R) agonists are used in the treatment of type 2 diabetes (T2DM).

Area covered: This review covers the clinical trials of the GLP-1R agonists (exenatide and liraglutide) and their potential as adjunct treatment in type 1 diabetes mellitus (T1DM).

Expert opinion: GLP-1R agonists are unable to increase insulin secretion, in subjects with T1DM, who are C-peptide negative. Also, the GLP-1R agonists either have no effect or cause a small inhibition of glucagon secretion in subjects with T1DM. There is no evidence that the GLP-1R agonists cause a major reduction in HbA1c, or have a major effect on hypo- or hyperglycemia in subjects with TD1M. The main beneficial effect of the GLP-1R agonists is probably the modest weight loss, which may underlie the reduction in dose of insulin used. Given that the GLP-1R agonists cause gastrointestinal adverse effects, and with reduced insulin doses, increase the risk of ketosis, it seems to me that the risk with these agents may outweigh any benefit in T1DM, and that they have little potential as adjuncts in the treatment of T1DM.     

Exenatide BID Observational Study (ExOS): results for primary and secondary endpoints of a prospective research study to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes in a real-world setting

Abstract

Objective:

The Exenatide BID Observational Study (ExOS) was designed to evaluate the clinical effectiveness of exenatide BID use in patients with type 2 diabetes (T2D) in a real-world clinical practice setting in the United States.     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use.

Areas covered: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials.

Expert opinion: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA_1c reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.     

A comparison of currently available GLP-1 receptor agonists for the treatment of type 2 diabetes

INTRODUCTION: Glucagon-like peptide-1 (GLP-1) receptor agonists are a valuable addition to the type 2 diabetes armamentarium. They increase insulin secretion and reduce glucagon secretion in a glucose-dependent manner, posing a relatively low hypoglycemia risk. GLP-1 receptor agonists also offer weight-loss benefits. Because GLP-1 receptor agonists are relatively new agents, there is limited direction on their use. AREAS COVERED: This article aims to provide guidance to physicians when considering GLP-1 receptor agonist use in individual patients. It examines the clinical profiles of the currently available GLP-1 receptor agonists: exenatide twice-daily (BID), liraglutide once daily and exenatide extended release (ER) once weekly. Phase III clinical trial data on efficacy, safety and patient satisfaction are compared, with a primary focus on head-to-head trials. EXPERT OPINION: Liraglutide seems to be the most effective GLP-1 receptor agonist in terms of HbA(1c) reduction and weight loss. Exenatide BID may offer an advantage where postprandial glucose control is a primary concern. Exenatide ER generally outperforms exenatide BID and is a good option for patients who struggle to adhere to more frequent regimens. The future may hold interesting developments in terms of reduced dosing frequency, oral formulations and alternative therapeutic uses.     

Novel GLP-1 receptor agonists for diabetes

INTRODUCTION: GLP-1 receptor agonists have been shown to be effective in the treatment of type 2 diabetes mellitus (T2DM). Although the first GLP-1 receptor agonist, exenatide, was approved in the mid-2000s, other agents with longer durations of action (that do not require twice-daily dosing) are now being developed. Indeed, liraglutide, a once-daily GLP-1 receptor agonist, was approved in 2010, and more recently, a once-weekly formulation of exenatide was approved in 2011. This review considers the mechanism of action of GLP-1 receptor agonists and considers the various agents in this class. AREAS COVERED: The importance of GLP-1 itself in glycemic control and the use of GLP-1 receptor agonists in T2DM are discussed. An overview of the clinical development of the five GLP-1 receptor agonists (exenatide, liraglutide, lixisenatide, albiglutide and taspoglutide) since 2005 is provided and their mechanisms of action, efficacy in terms of glycemic control and weight loss, and tolerability are reviewed. EXPERT OPINION: GLP-1 receptor agonists result in clinically meaningful weight loss in addition to their beneficial effects on glucose homeostasis. These agents provide substantial clinical benefits for patients compared with sulfonylureas or DPP-4 inhibitors and will, therefore, become one of the major therapeutic choices for patients with T2DM.     

Exenatide

Exenatide is the first in a new class of compounds, which possess similar activity to the naturally-occurring hormone glucagon-like peptide-1 (GLP-1). It mirrors many of the effects of GLP-1, improving glycaemic control through a combination of mechanisms, which include glucose-dependent stimulation of insulin secretion, suppression of glucagon secretion, slowing of gastric emptying and reduced appetite. Phase III clinical trials showed exenatide therapy for 30 weeks significantly reduced glycated haemoglobin, and fasting and postprandial plasma glucose compared with baseline when added to metformin and sulfonylureas or a combination of the two, with an average weight loss of approximately 2 kg. Exenatide can also be used in combination with thiazolidinediones and may be an alternative to insulin in patients requiring additional therapy. In patients with established Type 2 diabetes, control of both glycaemia and body weight are important to minimise the risk of future diabetes complications. Open-label extensions from these pivotal trials demonstrate that patients treated with exenatide for < or = 3 years sustained the reductions in glycaemic control achieved at 30 weeks and had a progressive reduction in body weight. Exenatide is generally well tolerated; nausea is the most commonly reported side effect, but can be significantly reduced when a target dose of exenatide is achieved in patients with gradual dose titration. Hypoglycaemia has been encountered in clinical trials of exenatide, especially on initiation of therapy with sulfonylureas (not with metformin). Exenatide may enable patients with Type 2 diabetes to improve glycaemic control and reduce or eliminate the risk of hypoglycaemia and weight gain.     

Exenatide: from the Gila monster to the pharmacy.

OBJECTIVE: To explain the incretin concept and review the pharmacology and clinical utility of exenatide (Byetta-Amylin; Lilly), a new agent for the treatment of patients with type 2 diabetes mellitus, and provide pharmacists with information necessary for counseling patients in the use of exenatide. DATA SOURCES: Review articles, clinical trials, and data on file with the manufacturers. STUDY SELECTION: By the authors. DATA EXTRACTION: By the authors. DATA SYNTHESIS: Exenatide is a synthetic form of a protein found in the saliva of the Gila monster that mimics the action of glucagon-like peptide-1, an incretin important in glucose homeostasis and deficient in patients with diabetes mellitus. Three pivotal clinical trials of exenatide as an add-on therapy in patients with type 2 diabetes mellitus who were unable to achieve glycemic control with maximum doses of metformin, sulfonylurea, or these drugs in combination demonstrated significant reductions in glycosylated hemoglobin (A1C) levels following twice-daily self-injection of exenatide compared with placebo. Weight loss was observed in patients in conjunction with A1C improvement, which occurred without additional patient instruction, intentional caloric deficit, or exercise. Mild-to-moderate nausea was the most common adverse event with exenatide treatment, occurring at the beginning of therapy, lessening over time, and reduced by titration of the dose. CONCLUSION: Exenatide offers a wide range of beneficial glucoregulatory effects, including enhancement of glucose-dependent insulin secretion, restoration of first-phase insulin response, suppression of inappropriately elevated glucagon secretion, slowing of gastric emptying, and reduction of food intake. These positive effects depend on the patient's understanding of the proper administration technique and timing, the need for continued adherence, and what to do if adverse effects occur, all elements that can be conveyed by pharmacists in their counseling and education of patients with type 2 diabetes mellitus.     

Exenatide effects on statin pharmacokinetics and lipid response

OBJECTIVE: Exenatide is an adjunctive treatment for type 2 diabetes. Many patients with type 2 diabetes have dyslipidemia, which requires treatment with three hydroxy-3-methyl glutaryl coenzyme (HMG-CoA) reductase inhibitors (statins), hence, concurrent use of exenatide and statins is likely. Exenatide slows gastric emptying, which may alter the absorption rate of co-administered oral medications. Thus, the potential interaction between exenatide and statins was evaluated in two study settings. METHODS: In an open-label, fixed-sequence, clinical pharmacology study, the plasma pharmacokinetics of lovastatin (40 mg after breakfast) in the presence and absence of exenatide (10 microg before breakfast and dinner) was evaluated in 21 healthy subjects. In a second clinical setting, changes in lipid profiles and statin dosage over 30 weeks in patients with type 2 diabetes were retrospectively compared (n = 180 exenatide 10 microg twice daily (BID), n = 168 placebo BID) in a combined analysis of three placebo-controlled, randomized exenatide Phase 3 trials. RESULTS: In healthy subjects, exenatide decreased mean lovastatin area under the plasma concentration time curve from zero to infinity (AUC0-infinity) and maximum plasma concentration (Cmax) by 40 and 28%, respectively, and increased median time to maximum plasma concentration (tmax) by 4 hours. In the exenatide Phase 3 trials, 30-week changes from baseline for low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol, triglycerides and statin dosage were not significantly different between the exenatide and placebo groups treated with statins. CONCLUSIONS: Despite observed changes in lovastatin bioavailability in the pharmacokinetic drug interaction study, exenatide did not negatively affect long-term lipid profiles or statin dosage in patients with concurrent statin therapy. Thus, co-administration of exenatide does not require adjustment in statin dosage.     

Exenatide extended-release: a review of its use in type 2 diabetes mellitus

Subcutaneous exenatide extended-release (ER; Bydureon?; also known as exenatide once weekly), a glucagon-like peptide-1 receptor agonist, provides a convenient, simple, once-weekly regimen that is approved in adult patients with type 2 diabetes as adjunctive monotherapy to diet plus exercise (in the US; not as first-line therapy) and/or as combination therapy with specific oral antihyperglycaemic drugs (OADs) in patients with inadequately controlled type 2 diabetes despite treatment with these OADs (US and Europe). This article reviews the clinical efficacy and tolerability of exenatide ER in the treatment of adult patients with type 2 diabetes and gives a brief overview of its pharmacological properties. In several short-term (24-30 weeks) well designed trials, adjunctive subcutaneously injectable exenatide ER once weekly, as monotherapy or in combination with OADs, significantly improved glycaemic control, bodyweight and some surrogate markers of cardiovascular risk in adult patients with inadequately controlled type 2 diabetes despite diet and exercise and/or treatment with OADs. Furthermore, the beneficial effects of adjunctive exenatide ER therapy were sustained in extension studies of up to 3 years of treatment. Overall, the intensity of glycaemic control with exenatide ER was generally better than that observed with the exenatide immediate-release formulation (twice daily), sitagliptin or insulin glargine. Exenatide ER was shown to be noninferior to metformin in terms of glycaemic efficacy, but did not meet the criteria for noninferiority versus liraglutide. In treatment-naive patients, exenatide ER treatment did not meet noninferiority criteria versus pioglitazone, whereas in treatment-experienced patients, exenatide ER provided better glycaemic control than pioglitazone. Improvements in glycaemic control with exenatide ER and, in general, with other antihyperglycaemic agents were reflected in significant improvements from baseline in treatment satisfaction and health-related quality-of-life measures. Exenatide ER was generally well tolerated in patients participating in these trials, with most treatment-emergent adverse events being of a gastrointestinal nature, of mild to moderate severity, transient and of a similar nature and incidence to those occurring with the exenatide immediate-release formulation. Thus, exenatide ER is a useful option for the treatment of type 2 diabetes, particularly in patients where bodyweight loss is an essential aspect of the individual patient's management.     

Exenatide.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, drug interactions, and dosage and administration of exenatide are discussed. SUMMARY: Exenatide, derived from a compound found in the saliva of the Gila monster, is an incretin mimetic agent that enhances glucose-dependent insulin secretion and has several other antihyperglycemic actions. The drug is indicated as adjunctive therapy to improve glycemic control in patients with type 2 diabetes mellitus who are taking metformin, a sulfonylurea, or both but who have not achieved adequate glycemic control. Peak plasma concentration following subcutaneous administration of exenatide is attained in 2.1 hours. The mean apparent volume of distribution after administration of a single subcutaneous dose is 28.3 L. The terminal half-life of the drug is 2.4 hours. Based on animal studies, the bioavailability of exenatide after subcutaneous injection has been estimated to be between 65% and 75%. The drug is predominantly eliminated by glomerular filtration followed by proteolytic degradation. Clinical trials have shown that exenatide given subcutaneously twice daily significantly reduced glycosylated hemoglobin values when maximum doses of a sulfonylurea, metformin, or both were ineffective. The most common adverse effects are nausea, vomiting, diarrhea, jitteriness, dizziness, headache, and dyspepsia. Drug-drug interactions with digoxin, lovastatin, lisinopril, and acetaminophen have been documented. The recommended starting dosage is 5 microg subcutaneously twice daily within one hour before the morning and evening meals. CONCLUSION: Exenatide offers a novel treatment option for patients with type 2 diabetes mellitus who are refractory to metformin or sulfonylurea therapy or both.     

Stavudine extended release (once-daily,Bristol-Myers Squibb) for the treatment of HIV/AIDS

Exenatide is a glucagon-like peptide 1 receptor agonist, which has recently received FDA approval in the US for the treatment of Type 2 diabetes. Exenatide is an incretin mimetic that improves glycaemic control in patients with diabetes through acute mechanisms, such as glucose-dependent stimulation of insulin secretion, suppression of inappropriate glucagon secretion and slowing of gastric emptying, as well as chronic mechanisms that include enhancement of β-cell mass in rodent studies and weight loss and inhibition of food intake in humans. This article reviews the mechanisms of exenatide action, as well as its efficacy in the treatment of Type 2 diabetes.     

The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide

Background:

Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared.

Data sources:

Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles.

Findings:

Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size.

Conclusions:

Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.