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.     

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.     

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.     

度拉糖肽治疗2型糖尿病的临床研究进展

目前,我国老年糖尿病患者的发病人数越来越多。GLP-1受体激动剂是一类新型作用靶点的降糖药物。新型长效GLP-1受体激动剂度拉糖肽具有改善血糖水平、降低患者体质量、每周注射1次的临床应用特点,同时该药物也具有胃肠道不适等相关的不良反应。对度拉糖肽在临床研究中的应用现状进行综述,供临床医生参考。     

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.     

Dulaglutide (LY-2189265) for the treatment of type 2 diabetes

Dulaglutide is a new once-weekly glucagon-like peptide-1 receptor agonist for the management of hyperglycemia in adult patients with type 2 diabetes. It stimulates dose-dependent insulin secretion and reduces glucagon secretion, both in a glucose-dependent manner. Efficacy on blood glucose control and safety were demonstrated in the large AWARD program in type 2 diabetic patients treated with diet, metformin, dual oral therapy or insulin lispro with or without metformin, confirming findings of pilot studies in Caucasian patients and data in Japanese patients. Dulaglutide 1.5 mg once weekly was superior to metformin, sitagliptin, insulin glargine and exenatide twice daily, and non-inferior to liraglutide 1.8 mg once daily regarding the reduction in glycated hemoglobin. A modest but significant weight loss was consistently observed. Most frequent adverse events were transient and generally mild gastrointestinal disturbances. Clinical outcomes of dulaglutide will not be known until the large prospective cardiovascular outcome trial REWIND is complete.     

An overview of new GLP-1 receptor agonists for type 2 diabetes

Introduction: The increasing prevalence of type 2 diabetes mellitus (T2DM) and the eventual need for multiple medications in most patients stimulated the development of new drug classes to reduce plasma glucose levels. The GLP-1 receptor agonists (GLP-1RAs) are established as an option for treatment of T2DM after metformin. They are also effective in reducing body weight but current GLP-1RAs have to be given by subcutaneous injection daily or once weekly.

Areas covered: This review focuses on the new GLP-1RAs currently undergoing development, some of which require less frequent subcutaneous administration and others that are being developed in oral formulations that may favor patient adherence.

Expert opinion: The new GLP-1RAs may have the benefit of requiring less frequent subcutaneous dosing or being active by oral administration. However, cardiovascular outcome trials have shown that DPP4 inhibitors are neutral for cardiovascular events and the first cardiovascular outcome trial with lixisenatide reported similar results, whereas the trial with the SGLT2 inhibitor empagliflozin showed a reduction in cardiovascular events. These findings in patients with high cardiovascular risk may favor the use of SGLT2 inhibitors as a second line treatment after metformin but there should still be an important role for novel GLP-1RAs, especially when weight reduction is required.     

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。     

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.     

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.     

Fixed-ratio combination therapy with GLP-1 receptor agonist liraglutide and insulin degludec in people with type 2 diabetes

Introduction: A fixed combination of basal insulin degludec and glucagon-like peptide-1 receptor agonist (GLP-1RA) liraglutide (IDegLira; 50 units degludec/1.8 mg liraglutide) has been developed as a once daily injection for the treatment of type 2 diabetes (T2D). In the phase 3a trial programme ‘Dual action of liraglutide and insulin degludec in type 2 diabetes’ (DUAL?), five trials of 26 weeks duration and one trial of 32 weeks duration have evaluated the efficacy and safety of IDegLira compared with administration of insulin degludec, insulin glargine, liraglutide alone or placebo.

Areas covered: Combination therapy with IDegLira reduces HbA1c more than monotherapy with a GLP-1RA (liraglutide) or insulin (degludec or glargine). Combination therapy leads also to weight loss, or a stable body weight, with no increase in hypoglycaemia. Rates of adverse events did not differ between treatment groups; however, gastrointestinal side effects were fewer with IDegLira compared with liraglutide treatment alone. A limitation of the DUAL? development programme is that patients receiving basal insulin doses in excess of 50 units were excluded from the studies.

Expert commentary: In conclusion, IDegLira combines the clinical advantages of basal insulin and GLP-1RA treatment, and is a treatment strategy that could improve the management of patients with T2D.     

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).     

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。     

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...     

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.     

iGlarLixi,a titratable once-daily fixed-ratio combination of basal insulin and lixisenatide for intensifying type 2 diabetes management for patients inadequately controlled on basal insulin with or without oral agents

Background: Achieving and maintaining glycemic control is important for people with type 2 diabetes (T2D), to reduce disease-related complications and mortality; however, about half of US patients fail to meet glycemic targets. iGlarLixi, a titratable fixed-ratio combination of insulin glargine 100?U/mL (iGlar) and lixisenatide for once-daily administration, was recently approved by the US Food and Drug Administration for use in adults with T2D inadequately controlled on basal insulin (<60?U daily) or lixisenatide. iGlar and lixisenatide have complementary mechanisms of action, primarily targeting fasting plasma glucose and postprandial plasma glucose, respectively. In the US, iGlarLixi is available in a 3:1 ratio of iGlar and lixisenatide, respectively, across the dosage range of 15–60?U of iGlar and 5–20?µg of lixisenatide.

Methods: This study identified phase 3 trials which assessed the efficacy and safety of iGlarLixi. Relevant trials were LixiLan-O, which compared iGlarLixi with iGlar or lixisenatide alone in insulin-naïve patients, and LixiLan-L, which compared iGlarLixi with iGlar alone in insulin-experienced patients.

Results: Patients on iGlarLixi experienced greater A1C reduction and were more likely to achieve A1C <7.0% than its comparators. iGlarLixi mitigated the weight gain associated with iGlar without increasing hypoglycemia risk, and resulted in a lower frequency of gastrointestinal adverse events compared with lixisenatide.

Conclusions: iGlarLixi provides a new approach to therapy intensification in patients with T2D. iGlarLixi showed greater A1C efficacy compared with either iGlar or lixisenatide, mitigating iGlar-associated weight gain, without increasing hypoglycemia risk, and reducing the gastrointestinal side-effects seen with lixisenatide.     

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。     

治疗2型糖尿病的非胰岛素类药物的研究进展

2型糖尿病是一种慢性代谢障碍性疾病,呈进行性发展,很难治愈,占糖尿病的90%以上。目前治疗该病的药物有很多,包括传统药物如磺脲类、格列奈类、噻唑烷二酮类、双胍类和α-葡萄糖苷酶抑制剂,以及近些年出现的新作用机制药物如GLP-1受体激动剂、DDP-IV抑制剂和SGLT2抑制剂。对上述各类药物的研究情况进行综述。     

胰高血糖素样肽1受体激动剂治疗2型糖尿病患者疗效的网状Meta分析

目的：系统评价胰高血糖素样肽1受体激动剂治疗2型糖尿病的临床疗效。方法：根据PICOS原则制定检索策略,计算机检索MEDLINE、EMBASE、CENTRAL等数据库,检索时限从建库至2018年8月。严格按照纳入排除标准筛选随机双盲对照试验,提取纳入文献的基本信息和结局指标,采用Corchrane偏倚风险评估工具对文献进行方法学质量评价。采用软件STATA14.0对各效应指标进行网状Meta分析,连续性变量用均数差（MD）及95% CI计算,二分类变量用比值比（OR）及95% CI计算。结果：共纳入51篇英文研究,合计22 360例患者,涉及19个干预措施。网状Meta分析显示,在疗效方面,索马鲁肽1.0 mg降低糖化血红蛋白、提高HbA1c<7%达标率、降低空腹血糖、减轻体质量、降低收缩压最明显,艾塞那肽10 μg降低舒张压最明显。结论：胰高血糖素样肽1受体激动剂治疗2型糖尿病有良好的疗效。