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.     

Exendin-4对非糖尿病小鼠的血糖和糖耐量的影响

目的:观察exendin4对非糖尿病小鼠的血糖和糖耐量的影响。方法:非糖尿病小鼠分为exendin4(Exe4)各剂量组和生理盐水(NS)组。腹腔内注射Exe40.1μg·g-1,观察注射1h后、连续注射10d期间和停药后2wk内血糖,并于停药后20d行腹腔葡萄糖耐量试验(IPGTT)。另外,非糖尿病小鼠每日注射不同剂量Exe40.1,0.2,0.4μg·g-1×3d,观察每日血糖。结果:非糖尿病小鼠注射Exe40.1μg·g-11h后血糖为(6.2±s1.3)mmol·L-1,低于NS组(10.6±1.1)mmol·L-1,P<0.01。连续注射Exe4期间的平均血糖以及停药后2wk内的平均血糖与NS组比较,均无明显差异,P>0.05;且IPGTT中2组各点血糖差异无显著意义,不同剂量Exe4注射组小鼠的3d平均血糖与NS组比较也无明显差别。结论:Exe4对非糖尿病小鼠的血糖具有即刻降低作用,但是每日1次腹腔内注射对非糖尿病小鼠的血糖和糖耐量无明显影响。     

利拉鲁肽的药理及临床研究进展

 利拉鲁肽是一种酰化胰高血糖素样肽-1（GLP-1）类似物,通过激活GLP-1受体,以葡萄糖依赖性刺激胰岛素分泌并抑制胰高血糖素分泌,临床用于2型糖尿病的二线治疗,可与其他口服降糖药联合使用,但不用于1型糖尿病的治疗。文中通过Medline对利拉鲁肽进行文献检索,并对其药理作用、药动学、临床研究、安全性和药物相互作用等进行综述。     

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.     

利拉鲁肽和阿必鲁泰治疗2型糖尿病临床研究进展

利拉鲁肽和阿必鲁泰是治疗2型糖尿病的新靶点药物,较已有的口服降糖药降糖效果好、副作用较小,而且可以减轻体质量,因此有广阔的应用前景。作为新一代降糖新药,利拉鲁肽是一种短效胰高血糖素样肽-1（GLP-1）类似物,阿必鲁泰是一种长效GLP-1类似物,两者既有共同之处,又有区别。总结这二种抗糖尿病新药的临床应用和不良反应研究进展,为临床合理用药以及新药研发提供思路。     

人GLP-1类似物治疗2型糖尿病的研究进展

人胰高血糖素样肽1（GLP-1）类似物已成为新一代降糖药。无论是上市的艾塞那肽和利拉鲁肽,还是处于临床研究阶段的taspoglutide,均在2型糖尿病临床研究中取得显著成果,如有效降糖、减轻体重和减少低血糖发生等。同时,人GLP—1类似物潜在的益处与风险还有待进一步研究。     

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。     

胰岛素联合治疗的新选择——基础胰岛素+GLP-1受体激动剂

胰岛素治疗可提高外周葡萄糖的利用率, 减少肝糖原输出, 能有效降低空腹血糖, 但往往会引起低血糖、胰岛素抵抗等不良反应。胰高血糖素样肽-1（GLP-1)受体激动剂（GLP-1RA）和二肽基肽酶-4（DPP-4）抑制剂（DPP-4I）作为治疗2型糖尿病的新型药物也越来越受到关注。此类药物能够促进内源胰岛素的分泌, 抑制胰高血糖素的分泌, 同时还可延缓胃排空时间、增加饱腹感、降低食欲, 从而有效地降低餐后血糖, 其与胰岛素联合应用, 可扬长避短, 发挥协同互补的作用, 同时降低低血糖风险。从用药前后糖化血红蛋白的变化和低血糖的发生率方面论述GLP-1RA和DPP-4I对胰岛素血糖控制不良的2型糖尿病患者的有效性和安全性,以期为临床治疗提供参考。

     

Adding prandial GLP-1 receptor agonists to basal insulin: a promising option for type 2 diabetes therapy

Background: Diabetes mellitus is a serious and increasingly prevalent condition in Canada and around the world. Treatment strategies have become increasingly complex, with a widening array of pharmacological agents available for glycemic management in type 2 diabetes mellitus (T2DM). New therapies that act in concert with available basal insulins may represent alternatives to basal insulin intensification with prandial or pre-mixed insulin. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have recently shown promise as useful additions to basal insulin, with significant reductions in glycated hemoglobin and potentially beneficial effects on body weight. This review will focus on pivotal clinical trials to assess the potential benefits of adding prandial GLP-1 RAs to basal insulin in patients with T2DM.

Methods: Clinical studies combining prandial GLP-1 RAs and basal insulin (published between 2011 and July 2017) were identified and reviewed in PubMed, the Cochrane Central Register of Clinical Trials (Issue 6, June 2017), and clinicaltrials.gov.

Results: Most of the studies presented in this review show that the addition of a prandial GLP-1 RA to basal insulin results in equal or slightly superior efficacy compared to the addition of prandial insulin, together with weight loss and less hypoglycemia.

Conclusions: The results of the studies suggest that a prandial GLP-1 RA as an add-on to basal insulin may be a safe and effective treatment intensification option (vs basal-plus or basal-bolus insulin).     

胰高血糖素样肽1与糖尿病的治疗

胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)是由肠道L细胞分泌的一种重要的肠促胰岛素激素,其在体内的主要生理作用有刺激胰岛素的分泌和释放、抑制胰高血糖素的分泌、促进胰腺β细胞的增殖并抑制其凋亡、抑制胃的排空、促进饱食感的产生等。GLP-1对糖尿病和肥胖具有很好的治疗前景。由于GLP-1在体内很快被二肽酰基肽酶Ⅳ降解,血浆半衰期很短,因而限制了其临床应用。现已发现了促进GLP-1分泌的物质,开发了多种GLP-1的衍生物和二肽酰基肽酶Ⅳ抑制剂,为开发新型糖尿病治疗药物开辟了新的天地。     

Alogliptin: a new,highly selective dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes

Background: Alogliptin is a potent, highly selective dipeptidyl peptidase-4 inhibitor now undergoing clinical testing to support a new drug application for the treatment of type 2 diabetes. Objective: To provide an overview of the mechanism by which alogliptin reduces hyperglycemia and to summarize the pharmacology, efficacy and safety of the drug. Methods: A Medline search was conducted and abstracts and presentations from recent American Diabetes Association and European Association for the Study of Diabetes (EASD) meetings were reviewed. The results of Phase II and Phase III human studies were evaluated for clinical efficacy, safety and tolerability in patients with type 2 diabetes. Results/conclusions: Alogliptin is effective as a treatment for type 2 diabetes, either as monotherapy or in combination with metformin, thiazolidinediones, sulfonylureas and insulin. It is well tolerated and has an excellent safety profile. Additional studies are needed to evaluate the long-term safety and efficacy of alogliptin.     

降糖药利拉鲁肽及其临床评价

利拉鲁肽(Iiraglutide)是新一代以肠促胰素为基础的降糖药,具有良好的降糖效果,无论单独应用还是与其他口服降糖药联用,均能迅速、高效地降低血糖和糖化血红蛋白(HbA1c)水平.其降糖作用依赖于葡萄糖浓度,即仅在血糖水平升高时刺激胰岛素释放达到治疗效果,因此发生低血糖的概率非常低.此外,利拉鲁肽能改善B细胞功能,降低血压,延缓糖尿病进展,减低糖尿病心血管并发症危险.与其他大多数降糖药相比,利拉鲁肽能帮助患者减轻体重.利拉鲁肽具有超越现有糖尿病治疗药物的多种特点.     

Gliptins: A New Class of Oral Antidiabetic Agents

India has the largest population of patients with type 2 diabetes mellitus. The conventional agents used to treat type 2 diabetes frequently exhibit reduced efficacy over time leading to inadequate glycaemic control and are also associated with adverse effects. Hence, there is a need for alternative therapies that can overcome the limitations associated with conventional antidiabetic agents. This review focuses on Gliptins, which have become a research area of intense focus and present an alternative therapeutic strategy for patients with type 2 diabetes. Gliptins show significant improvements in glycaemic control and are well tolerated, particularly with regard to weight change and hypoglycemia. Hence, gliptins are considered as useful agents for the treatment of type 2 diabetes mellitus.     

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.     

新型糖尿病治疗药物exendin-4的研究进展

Exendin-4(降血糖药)是首个在美国获准上市用于治疗2型糖尿病的肠促胰岛素拟似物。临床研究表明,其与二甲双胍、磺酰脲类药物、或噻唑烷二酮类药物合用,能有效地控制2型糖尿病患者的血糖。Exendin-4的作用机制包括葡萄糖依赖的促胰岛素分泌、抑制胰高血糖素分泌、增加β细胞质量、减缓胃排空和抑制食欲。近来还发现,exendin-4可增加胰岛移植受者的胰岛素分泌量。Exendin-4对中枢神经系统也有保护作用。本文对ex-endin-4的药理作用及其机制、药物特点等作一综述。     

利拉鲁肽治疗超重的2型糖尿病24例临床观察

目的观察胰高糖素样激动剂1（GLP-1）的类似物利拉鲁肽治疗超重或肥胖的2型糖尿病的有效性及安全性。方法选择于2011—01—12～2013—01—20在本院接受治疗的超重2型糖尿病患者24例,所有患者在二甲双胍及吡咯列酮治疗的基础上加用利拉鲁肽,最初1周给予患者利拉鲁肽0．6mg晚上睡前皮下注射,第2周加量至1．6mg。观察患者的临床疗效,每2周随访1次,观察治疗12周后患者的FPG、2h-PPG、HbAlc、体重、收缩压及舒张压水平变化和不良反应情况。结果治疗12周后患者的FPG、2h-PPG、HbAIc、体重、收缩压及舒张压与治疗前比较,均有明显的改善,差异有统计学意义（P〈0．05）。无严重的不良反应。结论利拉鲁肽治疗超重或肥胖的2型糖尿病疗效肯定,安全,不增加体重,无明显不良反应的另一类糖尿病合适选择的治疗方法。     

二肽基肽酶Ⅳ抑制剂的研究进展

胰高血糖素样肽-1(GLP-1)是一种肠促胰岛素,它通过刺激和保护胰岛B细胞,促进胰岛素的合成和分泌,降低餐后血糖.二肽基肽酶Ⅳ(DPP-Ⅳ)抑制剂能增强GLP-1的活性,降低2型糖尿病患者的高血糖症状,是一类新型的抗糖尿病治疗药物.临床研究表明DPP-Ⅳ单用或与二甲双胍、吡格列酮合用都有明显的降血糖作用,具有治疗效果显著、服用安全,耐受性好,不良反应少等特点,近年来已经成为糖尿病药物研究开发的热点.文中就其作用机制、国内外开发现状、构效关系及研究进展等进行综述.     

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。     

胰高血糖素样肽-1对糖尿病心血管病变的影响

目的:综述近年胰高血糖素样肽1及其类似物的研究进展,为糖尿病心血管病变的临床防治提出新的思路。方法:通过检索近10余年的相关文献,总结胰高血糖素样肽1及其类似物对糖尿病心血管病的作用及其相关机制。结果结论:目前研究提示胰高血糖素样肽1除了可以有效降低血糖以外,还通过多种机制影响心脏和血管的功能,此类活性物质以其独特的作用机制,为糖尿病心血管病变的治疗掀开新的一页。