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.     

Comparison of once-weekly with twice-daily exenatide in the treatment of type 2 diabetes (DURATION-1 trial)

The safety and efficacy of exenatide once weekly is evaluated over 52 weeks in the DURATION-1 trial in patients with type 2 diabetes. This long-acting glucagon-like peptide 1 receptor agonist given as a once weekly subcutaneous injection was found to produce better glycemic control as compared to twice daily exenatide and had a good safety profile over the trial period. Its use can help to reduce the complexity of drug regimen in patients with type 2 diabetes while maintaining a good safety and efficacy profile.     

An evaluation of liraglutide including its efficacy and safety for the treatment of obesity

ABSTRACT

Introduction: The prevalence of obesity is increasing worldwide and associated conditions, particularly type 2 diabetes mellitus (T2DM), also show increasing prevalence. Lifestyle intervention should be the first line of management for obesity but additional pharmacotherapy is often required and bariatric surgery is appropriate in more severe cases. Drugs acting as glucagon-like peptide-1 receptor agonists (GLP-1RAs) developed for the management of T2DM reduce body weight and liraglutide is the first GLP-1RA to be approved for the treatment of obesity in patients with and without T2DM.

Areas covered: In this review of relevant published material, the authors summarize the pharmacokinetics, pharmacodynamics, clinical efficacy and safety of liraglutide for the treatment of obesity.

Expert opinion: Liraglutide effectively reduces body weight and body fat through mechanisms involving reduced appetite and lowered energy intake, independent of its glucose-lowering effects. Like most of the other medications currently available for obesity, liraglutide has some common adverse effects, although generally not serious ones. Liraglutide has additional benefits in reducing cardiovascular events in patients with T2DM but the cost and the need for daily injections may limit its use in obesity. Newer GLP-1RAs, such as semaglutide, or other drugs in development for obesity may have advantages over liraglutide.     

艾塞那肽联合吡格列酮治疗肥胖2型糖尿病患者的疗效观察

目的观察艾塞那肽联合吡格列酮治疗肥胖2型糖尿病（T2DM）患者的疗效及安全性。方法 68例肥胖T2DM患者,在口服吡格列酮一段时间后血糖控制不理想的情况下,加用艾塞那肽,疗程3个月,观察治疗前后空腹血糖（FPG）,餐后2 h血糖（2hPG）、糖化血糖蛋白（HbA1C）、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）、C肽（C-P）、体重指数（BMI）等变化情况,计算胰岛素抵抗（H0MA-R）,胰岛β细胞功能（H0MA-β）。结果治疗后BMI、FPG、2hPG、HbA1C、HoMA-IR、TC、TG均下降;C-P,HOMA-β高于治疗前（P〈0.05）。结论艾塞那肽联合吡格列酮可显著改善肥胖T2DM患者血糖控制水平,同时能降低患者的体重,改善患者的生活质量。     

2型糖尿病治疗药物艾塞那肽及其开发

艾塞那肽是首个获准上市的肠促胰岛素类似物,可模拟人体自身胰高血糖素样肽-1的功能,降低2型糖尿病患者的空腹和餐后血糖。本文简要综述2型糖尿病治疗新药艾塞那肽及其开发。     

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.     

Exenatide once weekly in type 2 diabetes mellitus

Introduction: Exenatide once weekly (EQW) is an injectable glucagon-like peptide-1 receptor agonist that is pending approval at present by regulatory authorities for treatment of type 2 diabetes mellitus. Its glucose-reducing and weight-loss properties, together with minimal hypoglycemia and a once-weekly dosing schedule, make it a potentially attractive treatment option for overweight type 2 diabetics.

Areas covered: A literature search using PubMed resulted in a search for all published clinical trials with EQW, entitled the DURATION trials, which are reviewed in this paper. Efficacy and safety data are compared with other available antidiabetes agents. Molecular structure, pharmacokinetics, pharmacodynamics and mechanism of action are also reviewed.

Expert opinion: EQW is a potentially attractive medication for overweight type 2 diabetics with efficacy in both glycemic control and weight loss, as well as minimal hypoglycemia. Owing to its route of administration and expected cost compared with generic metformin, it will probably have a role as add-on therapy rather than monotherapy. Additional studies are ongoing to compare its efficacy against liraglutide.     

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。     

Exenatide once weekly for the treatment of type 2 diabetes

Exenatide is the first glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes mellitus (T2DM). Exenatide lowers blood glucose through multiple mechanisms, including enhancement of glucose-dependent insulin secretion, suppression of excess glucagon secretion, reduction of food intake and slowing of gastric emptying. The current formulation of exenatide requires twice-daily dosing (exenatide BID), and an extended-release formulation of exenatide is now in development for use as a once-weekly injection (exenatide QW). The purpose of this report is to review the most current clinical data on the development of exenatide QW for the treatment of T2DM. In clinical trials, exenatide QW significantly improved glycemic control, resulted in patient weight loss, and was well tolerated in patients with T2DM. In a head-to-head clinical trial, exenatide QW caused greater improvements in glycemic control and was better tolerated than exenatide BID. Given the rapidly increasing prevalence of diabetes and obesity worldwide, exenatide QW is a promising development candidate for the treatment of T2DM.     

Pharmacokinetic drug evaluation of exenatide for the treatment of type 2 diabetes

Introduction: Glucagon-like peptide-1 (GLP-1) receptor analogs are a group of therapeutic agents which mimic endogenous GLP-1, exerting their effect by the stimulation of the GLP-1 receptor with a wide distribution. Its activation increases insulin releasing dependent on blood glucose levels, suppression of glucagon secretion and a reduction of hepatic glucose output. It delays gastric emptying and increases satiety. Exenatide is the synthetic version of exendin-4, a natural peptide with similar properties to human GLP-1. There are two pharmaceutical forms, for subcutaneous injection: twice daily and once weekly.

Clinical practice guidelines recommend them because of a high efficacy reducing hyperglycemia, low risk of hypoglycemia and a significative weight loss effect. Gastrointestinal adverse events are the most common beside injection site-related. Their cost is the main limitation to use.

Areas covered: We review the recent literature investigating the pharmacokinetics and pharmacodynamics and efficacy-safety studies of exenatide twice daily and once weekly in type 2 diabetes

Expert opinion: GLP-1 receptor analogs are now positioned as an effective and safe drug for the treatment of type 2 diabetes. Exenatide significally reduces HbA1c and fasting plasma glucose. Additionally, it produces moderate weight loss and decreases blood pressure. One weekly formulation may improve compliance while cost is still a limitation. EXSCEL trial has shown that, despite cardiovascular safety, exenatide do not exhibits cardiovascular benefits.     

Investigational glucagon-like peptide-1 agonists for the treatment of obesity

Introduction: Obesity is a worldwide problem predisposing to type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, cancer and other comorbidities. Lifestyle modification is the first line intervention but adjunctive pharmacotherapy is often required. The GLP-1 receptor agonists (GLP-1RAs) were developed primarily for T2DM and they also reduce body weight. Liraglutide was approved for the treatment of obesity and other GLP-1RAs are likely to be suitable for this indication.

Areas covered: This review describes the GLP-1RAs that have been approved for the treatment of T2DM as potential candidates for the treatment of obesity and the new agents currently under development which may have advantages in patient adherence.

Expert opinion: The GLP-1RAs offer a welcome addition to obesity pharmacotherapy. They appear to be free of serious adverse effects although uncertainty remains about possible risks of pancreatitis and neoplasms. However, they have frequent gastrointestinal side effects, particularly nausea, which limits their tolerability. Cardiovascular outcome studies in T2DM support their use and this is likely to increase in both T2DM and obesity. Other GLP-1RAs which can be given by subcutaneous injection once weekly or less frequently or by oral administration would have advantages especially if nausea is less frequent than with liraglutide.     

肥胖型2型糖尿病的中医药研究进展

中医药在认识肥胖型2型糖尿病的病因病机及治疗方面有整体性、多途径、多环节、多靶点、多层次的综合调节优势。该文主要从病因病机、辨证分型、治疗方面综述了中医药治疗肥胖型2型糖尿病研究的进展,并指出了当前研究存在的现状及今后研究发展的方法。     

Potential use of exenatide for the treatment of obesity

INTRODUCTION: Obesity is a major health threat in the Western world because of its high incidence and prevalence, and its association with metabolic and cardiovascular disease as well as cancer. The reduction of food intake in obese patients can be achieved only transiently (generally for no longer than 6 months), in the absence of concomitant pharmacological therapy. Only bariatric surgery provides a means to increase satiety and/or decrease nutrient absorption in obese patients, in the long term. AREAS COVERED: This article reviews the available pharmacological treatments for obesity as well as the pharmacology and mechanism of action of exenatide in obese type 2 diabetic patients. EXPERT OPINION: Exenatide is a potential new candidate treatment for obesity, possibly in combination with other hormones that increase satiety (leptin) and slow gastric emptying (amylin).     

Rimonabant: the evidence for its use in the treatment of obesity and the metabolic syndrome

Introduction:

Obesity and overweight affect over 1 billion people worldwide and are leading causes of morbidity and mortality. Clinical features of obesity converge with those of the metabolic syndrome and type 2 diabetes, greatly increasing the risk of long-term adverse outcomes.

Aims:

To review the evidence on rimonabant, a novel CB1 receptor antagonist, for the treatment of obese and overweight patients.

Evidence review:

There is clear evidence that rimonabant 20 mg/day in conjunction with a hypocaloric diet causes a mean weight loss of 4.6 kg in obese and overweight patients after 1 year’s treatment, with approximately 50% of patients achieving a weight loss of ≥5%. One study demonstrated that weight loss is maintained for up to 2 years. The drug also improves lipid and glycemic cardiovascular risk factors, including high-density lipoprotein cholesterol and insulin resistance, and reduces waist circumference, thus reducing the prevalence of metabolic syndrome. Treatment of obese and overweight diabetic patients with rimonabant decreases glycosylated hemoglobin (HbA_1c), including patients previously untreated for diabetes. The effect of rimonabant appears to be partly independent of weight loss.Rimonabant 20 mg/day is generally well tolerated, with mild to moderate transient adverse effects including nausea, diarrhea, dizziness, and anxiety. Approximately 14% of patients receiving rimonabant 20 mg/day discontinued due to adverse effects, primarily depressed mood, although overall rates of depression did not differ significantly compared with placebo.

Place in therapy:

The evidence supports the use of rimonabant 20 mg/day along with dietary modification to reduce cardiovascular risk factors in obese and overweight patients, including those with diabetes. The drug is contraindicated in patients receiving antidepressants. Long-term data on cardiovascular outcomes, morbidity, and mortality are eagerly awaited.     

前列地尔联合艾塞那肽对2型糖尿病的疗效

目的探讨前列地尔联合艾塞那肽对2型糖尿病患者的疗效及对血清脂肪特异性丝氨酸蛋白内抑制剂(vaspin)和内抑素(NES)的影响。方法选取130例糖尿病患者,随机均分为观察组和对照组,每组65例。对照组给予艾塞那肽治疗,观察组给予艾塞那肽联合前列地尔治疗,治疗2周后观察2组患者的生化功能、血管功能、肾功能及血清Vaspin和NES水平。结果治疗前2组患者的生化功能、血管功能、肾功能及血清vaspin和NES水平比较差异无统计学意义,治疗后2组患者的空腹血糖(FBG)、餐后2 h血糖(2 h PG)、糖化血红蛋白(HbA1C)、体质量指数(BMI)、空腹C肽、餐后2 h C肽、三酰甘油(TG)和总胆固醇(TC)均显著下降,观察组下降更显著(P<0.05);治疗后2组患者的尿总蛋白、尿素氮(BUN)和血肌酐(SCr)均显著下降,观察组下降更显著(P<0.05);治疗后2组患者的收缩期血管峰值血流速度(PSV)和内膜中层厚度(IMT)均降低,且观察组下降更显著,狭窄率均升高,且观察组升高更显著(P<0.05);治疗后2组患者的血清vaspin和NES水平均显著升高,且观察组升...     

Investigational treatments for Type 2 diabetes mellitus: exenatide and liraglutide

Although a number of compounds are currently used to treat Type 2 diabetes mellitus, achieving a sustained glycaemic control over time is often not possible using oral antidiabetics. Endogenous incretins exhibit beneficial effects that could be useful for Type 2 diabetes mellitus treatment, such as stimulating insulin secretion during hyperglycaemia, improving β-cell mass and function, reducing glucagon secretion, delaying gastric emptying, reducing postprandial hyperglycaemia and diminishing body weight; however, their short half-life makes them unsuitable for treatment. Incretin mimetics such as liraglutide and exenatide were developed to overcome this limitation. This review discusses the effects of these compounds and their potential as a new class of antidiabetic agents.     

维格列汀联合艾塞那肽治疗2型糖尿病的效果及对血清胰岛细胞抗体和胰高血糖素样肽-1的影响

目的探究维格列汀联合艾塞那肽治疗2型糖尿病(T2DM)的效果及对血清胰岛细胞抗体(ICA)和胰高血糖素样肽-1(GLP-1)水平的影响。方法选择二甲双胍控制不佳的T2DM患者共90例,按照随机数字表法均分为对照组和观察组。对照组使用维格列汀治疗,观察组在对照组治疗的基础上联合艾塞那肽治疗。比较2组患者治疗前后血糖、胰岛素和胰岛素抵抗相关指标,检测并比较治疗前后血清GLP-1和ICA的表达水平。结果治疗后2组血糖生化指标均显著降低(P<0.05),且观察组空腹血糖(FPG)、2 h血糖(2 h FPG)和糖化血红蛋白(HbA1c)显著低于对照组(P<0.05)。治疗后2组胰岛素相关指标改善,观察组2 h胰岛素(INS)和胰岛β细胞功能指数(HOMA-β)显著高于对照组,胰岛素抵抗指数(HOMA-IR)显著低于对照组(P<0.05)。治疗前2组血清GLP-1水平和ICA阳性率无显著差异,治疗后均有好转,治疗后观察组的血清GLP-1水平显著高于对照组,ICA阳性率显著低于对照组(P<0.05)。2组不良反应发生情况无显著差异。结论维格列汀联合艾塞那肽能更有效地提高GLP-1水平,并降低ICA表达,提示联合治疗具有改善胰岛β细胞功能的作用。     

Adipokines in the treatment of diabetes mellitus and obesity

Background: The physiology of adipose tissue plays a main role in the pathogenesis of type 2 diabetes mellitus. The secretion of adipocyte-derived hormones, in either an autocrine or a paracrine manner, has been proposed as a relevant mechanism in this process. In this sense, the administration and regulation of hormones derived from adipose tissue arises as an attractive option for treating metabolic disorders. Objective: To review the current understanding of the implication of adipokines in the development of obesity and insulin resistance, as well as their potential use as therapeutic agents. Methodology: Review of scientific literature. Conclusions: This review describes the role of adipokines in generating insulin resistance and the chronic low-grade inflammatory profile accompanying visceral obesity.     

Treatment potential of the GLP-1 receptor agonists in type 2 diabetes mellitus: a review

Over the last decade, the discovery of glucagon-like peptide 1 receptor agonists (GLP-1 RAs) has increased the treatment options for patients with type 2 diabetes mellitus (T2DM). GLP-1 RAs mimic the effects of native GLP-1, which increases insulin secretion, inhibits glucagon secretion, increases satiety and slows gastric emptying. This review evaluates the phase III trials for all approved GLP-1 RAs and reports that all GLP-1 RAs decrease HbA1c, fasting plasma glucose, and lead to a reduction in body weight in the majority of trials. The most common adverse events are nausea and other gastrointestinal discomfort, while hypoglycaemia is rarely reported when GLP-1 RAs not are combined with sulfonylurea or insulin. Treatment options in the near future will include co-formulations of basal insulin and a GLP-1 RA.     

已上市胰高血糖素样肽-1受体激动剂的研究进展

胰高血糖素样肽-1受体激动剂（GLP-1RAs）治疗2型糖尿病受到广泛关注,其不仅具有优异的降糖优势,还有控制体质量,调节血脂,改善胰岛β细胞功能等特点,同时低血糖或体质量增加的不良反应发生率较低。自2005年至今,已经有7个GLP-1RAs经美国食品药品监督管理局批准上市,即艾塞那肽、利拉鲁肽、艾塞那肽长效制剂、阿必鲁肽、度拉糖肽、利西拉来和索马鲁肽;在中国上市的有贝那鲁肽和洛塞那肽。对已经上市的9个GLP-1Ras治疗2型糖尿病的临床研究进展进行综述。