利拉鲁肽与艾塞那肽
艾塞那肽与利拉鲁肽治疗2型糖尿病的研究进展
19 Journal of China Prescription Drug Vol.15 No.4·综述·物在肺内仍有一定的浓度。
该结果表明，配基修饰的脂质体雾化剂可以很好的透过巨噬细胞，使释放的药物浓度迅速达到治疗浓度，因脂质体有控释作用，可以在较长时间内均衡的释放药物，药物半衰期延长，更充分的杀灭结核杆菌以提高疗效[10]。
4.2 阿米卡星脂质体阿米卡星（AMK）脂质体用于治疗小鼠结核分枝杆菌感染，其效果比游离药物或空白脂质体好，其功效可能是胞内寄生菌在抗菌剂脂质体的作用下灭活。
免疫缺陷病的AIDS患者常常是因为其细胞内鸟型结核分枝杆菌感染导致的。
研究发现游离的阿米卡星在绵羊体内的t1/2为2 h，C max为8.3 μg/mL，而阿米卡星脂质体的t1/2却可以增加至10 h，C max降低至3.3 μg/mL，可以减少用药量。
脂质体不但可以提高靶细胞内的药物浓度，而且还可以降低进人体循环的用药量[11-15]。
5 结语与展望目前，抗结核药脂质体肺部给药仍然存在一些问题，尤其是安全问题，需要我们更加深入地研究探讨、解决难题，为深受结核病困扰的患者提供更好的药物治疗，提高他们的生活质量，因此要求我们需要研制新型药、新剂型，能够在特定部位快速达到且长时间维持有效药物浓度，减轻药物的毒副作用，以此提高疗效。
目前用于AIDS患者的弥散性疾病中抗分支杆菌（MAC）感染的脂质体仅有氨基糖苷抗生素脂质体（TLCG-65），而其它的抗结核药物脂质体还没有用于临床治疗中，因此需要我们进行研发探索，并合理应用参考文献[1] 杜听，黄飞陆，陆伟，等. 2010-2012年全国肺结核登记率变化趋势分析. 中国防痨杂志，2013，35（5）：337-342.[2] 陈军，方芸. 脂质体肺部给药的研究. 药学近展，2003，27（2）：85-88.[3] 廖永红，曾宪明. 以氢氟烷为抛射剂的定量吸入气雾剂研究进展. 药学学报，2006，41（3）：197-202.[4] 束家有，全向阳，束怡，等. 月桂酸二乙醇酰胺修饰利福喷丁脂质体的制备、性质及肺部给药. 药学学报，2006，41（8）：761-764.[5] 吕剑，朱颖，江志强. 胰岛素脂质混悬液肺部给药的生物利用度及对肺部损伤的初步考察. 中国生化药物杂志，2002，23（6）：271-274.[6] Vyas SP， Kannan ME， Jain S， et al. Design of lipo-somal aerosols for improved delivery of rifampicin to alveolar macrophages. Int J Pharm，2004， 269（1）：37-49.[7] Lu D， Hickey AJ. Liposomal dry powders as aerosols for pulmonary de-livery of proteins. AAPS Pharm Sci Tech， 2005， 6（4）：E641-E648.[8] Lo YL， Tsai JC， Kuo JH. Liposomes and disaccharides as carriers in spray-dried powder formulations of superoxide dismutase. J Control Release，2004， 94（2-3）：259-272.[9] Sweeney LG， Wang Z， Loebenberg R， et al. Spray-freeze-dried liposo-mal ciprofloxacin powder for inhaled aerosol drug delivery. Int J Pharm， 2005， 305（1-2）：180-185.[10] 陆彬. 药物新剂型与新技术. 第2版. 北京：人民卫生出版社，2005：134.[11] Gangadharam PR， Ashtekar DA， Ghori N， et al. Chemotherautic polential of free and loposome encapsulated strepomycin against ex-perimental myoobacterium avium complex infection in beige mice. J Antimicrob Chemother， 1991， 28（3）：425-435.[12] Düzgüneş N， Ashtekar DR， Flasher DL， et al. Treatment of Myco-bacteirum avium-intracellulare complex infection in beige mice with free and liposome-encapsulated streptomycin: role of liposome type and duration of treatment. J Infect Dis， 1991， 164（1）：143-151.[13] Ashtekar D， Düzgünes N， Gangadharam PR.. Activity offree and liposome encapsulated streptomycin against Mycobacterium avium complex （MAC）inside peritoneal macrophages.J Antimicrob Chemother， 1991， 28（4）：615-617.[14] Onyeji CO， Nightingale CH， Nicolau DP， et al. Efficacies of liposome-encapsulated clarithromycin and ofloxacin against mycobacterium avium-M. intracellulare complex in human macophages. Antimicrob Agents Chemother， 1994， 38（3）：523-527.[15] Tomioka H ， Saito H ， Sato K， et al. Therapeutic efficacy of liposome encapsulated kanamycin agaist mycobacterium intracellulare infection induced in mice. Am Rew Respir Dis， 1991， 144（3ptl）：575.糖尿病临床发病率近年呈持续增长趋势，并且随着生活水平提高，糖尿病发病人群日趋年轻化，糖尿病若未得到及时的对症治疗，病情会呈现进行性加重[1]。
利拉鲁肽、艾塞那肽、度拉糖肽、利司那肽、贝那鲁肽之间的区别！
利拉鲁肽、艾塞那肽、度拉糖肽、利司那肽、贝那鲁肽之间的区别！作者：Gcplive来源：药评中心作为新型降糖药物，GLP-1受体激动剂（GLP-1RA）不仅降糖效果显著，而且兼具减重、降压、改善血脂谱等作用，临床应用越来越广泛。
国内常用的GLP-1RA有利拉鲁肽、艾塞那肽、利司那肽等，它们之间有何区别？丶一、医生开具处方前，别忘记给患者测体重！国内已上市的GLP-1RA有7种，均属于医保目录中“协议期内谈判药品”。
对于医保患者，医生开具处方前，别忘记给患者测体重（见下表）。
二、利拉鲁肽和度拉糖肽，具有心血管保护作用心血管疾病是2型糖尿病（T2DM）患者最主要的死亡原因。
2020年版《中国2型糖尿病防治指南》推荐：无论HbA1c水平是否达标，T2DM合并ASCVD、ASCVD高风险患者，建议首先联合有心血管疾病获益证据的GLP-1RA或SGLT2i（恩格列净等）。
但是，并非所有GLP-1RA都具有心血管保护作用。
2021年版《糖尿病患者合并心血管疾病诊治专家共识》推荐：T2DM合并ASCVD患者可优先考虑二甲双胍联合经证实可带来心血管获益的GLP‐1RA（利拉鲁肽、度拉糖肽）。
三、心血管保护作用，可能与来源有关根据分子结构，GLP-1RA可分为两大类：1.人源性通过对人GLP-1分子结构进行局部修饰加工而成的药物有利拉鲁肽、度拉糖肽、司格美鲁肽、贝那鲁肽，其氨基酸序列与人GLP-1同源性≥90%。
目前已证实利拉鲁肽、度拉糖肽、司格美鲁肽具有心血管保护作用。
贝那鲁肽（与人GLP-1的同源性100%）尚缺乏数据。
2.动物源性通过对美洲毒蜥唾液中的多肽Exendin-4进行局部修饰加工而成的药物有利司那肽、艾塞那肽、洛塞那肽，其氨基酸序列与人GLP-1同源性较低。
已有研究结果显示，利司那肽、艾塞那肽、艾塞那肽对心血管的作用为中性。
洛塞那肽尚缺乏数据。
温馨提示：与其他外源性多肽类药物相似，给予GLP-1受体激动剂后，有小部分患者可能会产生抗体，并可能会影响血糖控制效果。
利拉鲁肽对2型糖尿病患者血脂的影响
利拉鲁肽对 2型糖尿病患者血脂的影响摘要目的：为了评估利拉鲁肽对2型糖尿病患者血脂谱的影响。
方法：共纳入30例2型糖尿病患者，从第0天开始给予利拉鲁肽（每天一次，皮下注射），持续三个月。
分别在0、1和3个月时测量体重，HbA1c，TC，LDL-C，HDL-C，非HDL-C和TG、RC水平。
结果：在利拉鲁肽治疗1个月和3个月时，体重均显著下降，HbA1c水平均显著下降，LDL-C、非HDL-C、TC水平均显著降低，但利拉鲁肽的治疗未改变TG 水平、HDL-C水平、RC水平。
结论：利拉鲁肽治疗3个月可显著降低LDL-C、非HDL-C和TC，在一定程度上改善了糖尿病患者的脂代谢紊乱。
关键词利拉鲁肽；血脂；2型糖尿病引言近年来，二肽基肽酶-4（DPP-4）抑制剂和胰高血糖素样肽1受体激动剂（GLP-1 RA）已广泛应用于2型糖尿病患者的降糖治疗中。
它们的作用机制是以葡萄糖依赖的方式增加血清胰岛素、改善高血糖症[1]。
而控制糖尿病患者的血脂水平对于预防心血管事件非常重要[2]。
据报道，GLP-1 RA，如利拉鲁肽可减少心血管事件[3]。
研究表明，利拉鲁肽在载脂蛋白E基因敲除小鼠中具有抗动脉粥样硬化作用，但具体机制尚不清楚[4]。
在一项meta分析中，发现GLP-1 RA 可降低低密度脂蛋白胆固醇（LDL-C），总胆固醇（TC）和甘油三酯（TG）的水平，但不会改变高密度脂蛋白胆固醇（ HDL-C）；但是，其机制尚不清楚[5]。
为了评估临床中GLP-1 RA的实际降脂能力，本实验探索了利拉鲁肽对2型糖尿病患者血脂谱的影响。
对象和方法1.对象本研究是在上海市普陀区利群医院内分泌科进行的。
我们纳入30例未接受GLP-1 RA治疗的男性和女性2型糖尿病患者（≥20岁，HbA1c≥6.5％）。
所有患者均签署知情同意书。
2．方法本研究共纳入17例男性和13例女性2型糖尿病患者，均按1999年WHO糖尿病诊断标准确诊。
所有纳入对象从第0天开始给予利拉鲁肽（每天一次，皮下注射），持续三个月。
最新关于药品“利拉鲁肽”的认识
通过调节食欲和饱腹
势是其副作用相对较
感，帮助患者改变不
小，大多数患者能够
良的饮食习惯，从而
2
很好地耐受，这使得
3 更好地控制体重，这
其在临床应用中具有
是其在肥胖症治疗中
较大的优势。
的又一重要优势。
3. 利拉鲁肽在其他疾病治疗中的潜力
3. 利拉鲁肽在肿瘤治疗中的潜力也受到关注，可能通过抑制
3
肿瘤细胞的增殖、诱导凋亡和增强免疫系统的功能来抑制肿 瘤的生长和转移。
2. 利拉鲁肽的安全性评价研究显示，其对心血管系统的影响较 小，不会增加心脏病发作的风险。
3. 最新的研究进展表明，利拉鲁肽在长期使用后仍能保持较高 的安全性，没有发现明显的副作用。
感谢观看!
3. 利拉鲁肽对食欲和饱腹 感的调节作用不依赖于胰岛 素分泌，因此对于糖尿病患 者来说也是一种安全有效的 治疗手段。
3. 利拉鲁肽对脂肪代谢的调控
1. 利拉鲁肽能够通过抑制食 欲和增加饱腹感，减少食物的 摄入，从而降低脂肪的积累。
3. 利拉鲁肽还可以调节胰岛素的 分泌，提高身体对葡萄糖的利用 效率，减少脂肪的合成和储存。
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3. 除了糖尿病治疗外，利拉鲁肽还被应用于肥胖症的治疗，通过抑制食欲 和促进脂肪分解来减少体重。
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二、利拉鲁肽的作用机制
1. 利拉鲁肽对胰岛素分泌的影响
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1. 利拉鲁肽能够刺激胰岛β 细胞，增加胰岛素的分泌量 。
2. 利拉鲁肽通过抑制胰高血 糖素的分泌，降低血糖水平 ，从而促进胰岛素的分泌。
2. 利拉鲁肽最初是在研究 肥胖症治疗药物的过程中被 发现的，它能够有效地降低 血糖和减轻体重。
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《GLP-1受体激动剂临床应用专家指导意见》要点
《GLP・1受体激动剂临床应用专家指导意见》姜点胰升血糖素样肽1 （ GLP-1 ）受体激动剂属于肠促胰素类药物，近年来在T2DM治疗领域得到了越来越广泛的应用。
2005年,国际上第一个GLP-1 受体激动剂成功上市，其后10余年来，随着硏发的不断深入和循证医学证据的逐渐积累,该类药物在T2DM治疗中的地位不断得到提升。
《中国2型糖尿病防治指南（2017年版）》也^其列入二联降糖治疗选择之一。
目前，我国已上市的GLP-1受体激动剂包括艾塞那肽、利拉鲁肽、贝那鲁肽、利司那肽和艾塞那肽周制剂。
—、GLP-1受体激动剂发展史及分类肠促胰素是从肠道分泌的可刺激胰岛素分泌的物质的统称。
现已发现的人体内肠促胰素主要有葡萄糖依赖性胰岛素释放肽（GIP ）和GLP-1O GIP 在T2DM 患者中水平正常或升高，对胰岛p细胞的促胰岛素分泌作用弱，其临床应用价值有限。
目前，临床上肠促胰素类药物均基于GLP-1。
根据分子结构特点，GLP-1受体激动剂可分为两大类：第一类是基于exendin-4结构,由人工合成的艾塞那肽和利司那肽，其氨基酸序列与人GLP-1同源性较低；第二类基于天然人GLP-1结构，通过对人GLP-1分子结构局部修饰加工而成，与人GLP-1氨基酸序列同源性较高，如利拉鲁肽。
目前，国内上市的贝那鲁肽为重组人GLP-1分子，与人GLP-1氨基酸序列完全相同。
不同GLP-1受体激动剂的药代动力学和分子结构特点存在差异(附录1丄根据作用时间长短，GLP-1受体激动剂分为短效和长效制剂两大类，短效制剂包括艾塞那肽、利司那肽、贝那鲁肽，长效制剂包括利拉鲁肽和艾塞那肽周制剂。
二、GLP-1受体激动剂的临床应用方法GLP-1受体激动剂临床应用主要推荐意见总结见表：L。
1. 适应证与使用时机：GLP-1受体激动剂适用于成人T2DM患者，该类药物在我国得到药监部门批准的适应证如下。
(1 )艾塞那肽：适用于服用二甲双肌、磺腺类、TZDs、二甲双弧和磺腺类联用、二甲双呱和TZDs联用不能有效控制血糖的T2DM患者的辅助治疗以改善血糖控制。
2型糖尿病患者每周一次艾塞那肽与每日一次利拉鲁肽的有效性和安全性对比
2型糖尿病患者每周一次艾塞那肽与每日一次利拉鲁肽的有效性和安全性对比（Lancet. 2013 Jan 12;381(9861):117-24）题目：2型糖尿病患者每周一次艾塞那肽vs每日一次利拉鲁肽（DURATION-6）：一项随机开放标签的研究（Exenatide once weekly versus liraglutide once daily in patients with type 2 diabetes (DURATION-6): a randomised，open-label study）背景：胰高血糖素样肽1受体激动剂艾塞那肽（exenatide）和利拉鲁肽（liraglutide）对于改善2型糖尿病患者的血糖控制和降低体重表现出了良好的作用。
本研究对2型糖尿病患者每周使用1次艾塞那肽与每日使用一次利拉鲁肽的有效性和安全性进行了对比。
方法：于2010年1月11日～2011年1月17日，在19个国家的105个地区进行了一项26周、开放标签、随机、平行的试验。
通过带有声音应答系统的计算机生成随机序列，将年龄≥18岁，接受改善生活方式和口服降糖药的2型糖尿病患者随机分配（1:1）至接受每日给予一次利拉鲁肽（1.8 mg）组或每周给予1次艾塞那肽（2 mg）组。
受试者和研究者均对治疗分配知情。
主要终点为26周时的糖化血红蛋白（HbA1c）相比基线时的变化。
根据意向治疗分析对结果进行分析。
试验注册网址为，注册码为NCT01029886。
结果：912例随机患者中，911例被纳入意向治疗分析（利拉鲁肽组450名，艾塞那肽461名）。
利拉鲁肽组患者HbA1c的最小二乘变化（-1.48%，SE 0.05；n=386）比艾塞那肽组（-1.28%，0.05；390）大，治疗差异（0.21%，95% CI 0.08-0.33）没有达到预定的非劣效评价标准（CI上限＜0.25%）。
最常见不良事件为恶心（利拉鲁肽组93例[21%] vs艾塞那肽组43例[9%]），腹泻（59例[13%] vs 28例[6%]）和呕吐（48例[11%] vs 17例[4%]），艾塞那肽组的发生率较低，随着时间的推移，两组的不良反应率均有下降。
除了胰岛素，糖友还可以注射这5种药物，你用过哪一种？
除了胰岛素，糖友还可以注射这5种药物，你⽤过哪⼀种？⼀、阿必鲁肽（Albiglutide）1.什么是阿必鲁肽？这是⼀种⼈⼯制造的GLP-1激素。
正常情况下，⼈吃饭的时候肠道就会⽣成GLP-1，它可以帮助控制⾎糖。
2.适⽤⼈群其它治疗⽆效的II型糖尿病患者。
如果打算怀孕，最好先咨询医⽣，因为研究者⽬前还没有研究阿必鲁肽对孕妇有什么影响。
3.作⽤机制吃饭后，阿必鲁肽可以帮助胰腺释放可以调节⾎糖的胰岛素。
它还会限制⼈体⽣成胰⾼⾎糖素的数量，胰⾼⾎糖素会刺激肝脏释放储存的糖。
除此之外，该药还可以减缓消化。
它只需每周注射⼀次。
4.副作⽤最常见的副作⽤是上呼吸道感染、腹泻、恶⼼和注射部位的⽪肤反应。
所有GLP-1药物在动物实验中都有可能引发甲状腺癌，专家还不知道⼈类是否也会出现相同的副作⽤。
除此之外，可能还会出现严重的胰腺炎。
⼆、艾塞那肽（Exenatide）1.什么是艾塞那肽？艾塞那肽是美国⾷品及药物管理局最早批准上市的GLP-1药物。
最早的艾塞那肽类药物是百泌达（Byetta），患者每天需要注射2次。
另⼀种注射液名为Bydureon，⼀周只需注射⼀次。
但是这两种药物不能同时注射。
2.适⽤⼈群其它治疗⽆效的II型糖尿病患者。
如果打算怀孕，最好先咨询医⽣，因为研究者⽬前还没有研究艾塞那肽对孕妇有什么影响。
3.作⽤机制艾塞那肽会促进胰腺释放胰岛素，让⾎液中的葡萄糖进⼊细胞。
它还会限制⼈体⽣成胰⾼⾎糖素的数量，胰⾼⾎糖素会刺激肝脏释放储存的糖。
除此之外，该药还可以减缓消化。
4.副作⽤最常见的副作⽤包括恶⼼、呕吐、腹泻、感觉紧张、头晕、头痛、胃酸过多、便秘和虚弱。
这些通常会在治疗的第⼀个⽉后消失。
除此之外，可能还会出现严重的胰腺炎。
所有GLP-1药物在动物实验中都有可能引发甲状腺癌，专家还不知道⼈类是否也会出现相同的副作⽤。
患者还有可能低⾎糖或产⽣过敏反应。
三、利拉鲁肽（Liraglutide）1.什么是利拉鲁肽？这是另⼀种GLP-1药物，每天需注射⼀次，可以帮助⼈体释放更多胰岛素，让⾎液中的葡萄糖进⼊细胞。
艾塞那肽说明书
【药物名称】中文通用名称：艾塞那肽英文通用名称：Exenatide其他名称：Byetta。
【临床应用】作为辅助用药，用于单服二甲双胍或磺酰脲类药或联用二甲双胍和磺酰脲类药后均未达到充分血糖控制的2型糖尿病患者的血糖控制的改善。
(国外资料)【药理】1.药效学本药是一种合成的肠降血糖素类似物(有抗高血糖作用的肽)，其53%的氨基酸顺序与哺乳动物胰高血糖素样多肽-1(GLP-1)的氨基酸顺序相同，但不是GLP-1的类似物。
GLP-1是一种肠道激素，是肠道L细胞响应营养摄入而分泌的激素，可通过其受体产生降血糖和抗糖尿病作用(如刺激葡萄糖依赖性胰岛素的释放，抑制胰高血糖素的分泌)，但半衰期较短[低于2分钟，主要经蛋白水解酶Ⅳ(二肽酰胺酶Ⅳ)快速降解]。
本药可激动GLP-1受体，产生与GLP-1类似的作用[其许多(或所有)抗糖尿病作用似与GLP-1受体结合有关，但观察到的所有药效学作用与GLP-1的作用并不一致，有研究人员认为，这可能是本药通过功能不同的其他受体而产生的]。
其作用包括：增强葡萄糖依赖性的胰岛素的分泌和抑制葡萄糖依赖性的异常增高的胰高血糖素的分泌、减慢胃排空、减少食物摄入、促进β-细胞增殖和再生、减少脂肪堆积及胰岛素增敏作用(动物模型)。
由于本药相对较能抵抗蛋白水解酶Ⅳ(二肽酰胺酶Ⅳ)的降解(因GLP-1的2位存在一个丙氨酸基团，可被蛋白水解酶Ⅳ识别，而本药2位则为甘氨酸基团)，故有较长的半衰期，体内活性较GLP-1增强。
一项安慰剂对照研究提示，本药可显著降低禁食状态的血浆葡萄糖水平，降低餐后葡萄糖相对于基础值的峰变化；用药后观察到胃排空延迟、热量摄入减少。
资料表明，本药在非糖尿病受试者及2型糖尿病患者中均是一种强效促胰岛素分泌药。
2.药动学予2型糖尿病患者皮下注射本药，可见餐后葡萄糖水平降低持续达5小时，注射后约3小时达最低点。
2型糖尿病患者皮下注射10μg后2.1小时)211pg/ml，曲线下面积(AUC)为1.036(ng·h)/ml。
GLP-1类似物药物进展
GLP-1类似物药物进展-截止20150921胰高血糖素样肽（glucagon-like peptide，GLP）是小肠表皮细胞在食物刺激情况下分泌的单肽类肠促胰岛素，包括GLP-1、GLP-2两种类型。
其中GLP-2具有促进小肠生长，抑制细胞凋亡，促进胃排空，增加食欲的药理作用，临床上可用于治疗小肠短小综合症；而GLP-1具有促进胰岛素分泌，保护胰岛β细胞，抑制胰高血糖素分泌，抑制胃排空，降低食欲的药理作用，GLP-1主要是GLP-1（7-36peptidase-Ⅳ, DPP-对GLP-1结构修饰，掩盖主要方向。
一、已上市目前已上市的5个、利拉鲁肽Aventis/Zealand)2005年4月获得FDA的批准上市。
艾塞那肽源于从蜥蜴唾液中，与GLP-1大约有53%的同源性。
由于其N端第二位由不被DPP-Ⅳ降解，而相对天然GLP-1而言具有较长的半衰期和较强的生物活性，临床使用频率为每日2次。
Astra Zeneca收购Amylin取得艾塞那肽的全球开发销售权后，开发了其缓释混悬制剂Bydureon Pen，并于2014年获得FDA批准。
Bydureon给药频率为一周一次，大大减缓患者注射痛苦。
24周随机、开放标签临床试验证明，一周使用一次Bydureon对糖化血红蛋白（HbA1c）的降低幅度达1.6%，优于一日两次注射的艾塞那肽（0.9%）。
另外，以色列的Oramed公司正在开发艾塞那肽的口服制剂ORMD-0901，目前处于1/2期临床，适应症为2型糖尿病。
2.利拉鲁肽（Liraglutide）利拉鲁肽（商品名Victoza/Saxenda）由Novo Nordisk 1996年开始研发，2009年最早于丹麦上市。
利拉鲁肽是人GLP-1(7-37)链上34位Lys被Arg取代，在26位的Lys上接入经十六烷酸修饰的谷氨酰胺。
经脂肪连修饰后的，增加了与白蛋白之间的亲和力，从而降低了被DPP‐Ⅳ的水解速率和肾清除率，延长生物半衰期到11～15 h，每天只需一次皮下注射给药，大大提高了患者的顺应性。
司美格鲁肽、度拉糖肽、洛塞那肽......GLP-1RA长效制剂怎么选？
司美格鲁肽、度拉糖肽、洛塞那肽......GLP-1RA长效制剂怎么选？目前我国上市的长效胰高血糖素样肽-1 受体激动剂（GLP-1RA）即 GLP-1RA 周制剂主要有：艾塞那肽微球、洛塞那肽、度拉糖肽、司美格鲁肽 4 种。
1. 周制剂的优势：延长药物的作用时间，稳定药动学特性，降低药物使用频次，改善患者生活质量，提升患者用药依从性，从而保障药物疗效。
不同制剂的特点以及临床推荐地位，如下表：4 种周制剂特点及临床推荐图源：作者整理临床结局：（1）降糖效果长效 GLP-1RA（一周 1 次艾塞那肽、度拉糖肽、司美格鲁肽）在推荐剂量下可持续激活 GLP-1 受体。
与短效 GLP-1RA 相比，长效 GLP-1RA 往往对空腹血糖的影响更显著，对胃排空和餐后血糖的影响较小。
（备注：长效 GLP-1RA 降低HbA1c 的幅度大于短效受体激动剂，但头对头比较研究中各药物有相当大的差异。
）（2）体重减轻GLP-1RA 减轻体重的原理机制主要通过减慢胃排空，以及引起恶心和呕吐等公认副作用。
但是胃排空减慢作用会逐渐减弱（至少使用长效 GLP-1RA 时是这样）。
（3）心血管结局迄今为止的心血管研究纳入的都是极高危人群（除部分度拉糖肽相关研究)，以增加重大心血管疾病（CVD）事件的风险率，而且研究时间相对短暂。
因此，尚缺乏足够的证据证明 GLP-1RA 在低危人群中的 CVD 安全性或推定益处。
•ASCVD：2 型糖尿病合并 CVD 的患者中，利拉鲁肽、司美格鲁肽、度拉糖肽相比安慰剂减少了 ASCVD 结局。
•心力衰竭：在确诊心衰的糖尿病患者中，利拉鲁肽不影响心衰结局。
一篇 meta 分析在确诊 CVD 的糖尿病患者中比较了 GLP-1RA (一周1 次艾塞那肽、利拉鲁肽、司美格鲁肽等) 与安慰剂，发现GLP-1RA 并未影响心衰住院风险。
•心血管性死亡：一篇 meta 分析在确诊 CVD 的糖尿病患者中比较了 GLP-1RA（一周 1 次艾塞那肽、利拉鲁肽、司美格鲁肽）与安慰剂，发现 GLP-1RA 降低了心血管性死亡风险，也降低了致死性或非致死性脑卒中风险。
基于肠促胰岛素的抗糖尿病药物发展概况
基于肠促胰岛素的抗糖尿病药物发展概况作者：吴霞来源：《上海医药》2013年第07期摘要肠促胰岛素的发现为糖尿病治疗提供了一个新的途径，各大制药公司已相继推出了自己的药品，根据作用机制可分为二肽基肽酶-4抑制剂和胰高血糖素样肽-1类似物或受体激动剂。
这些药物具有有效降低血糖、安全性和耐受性良好以及不增加体重等优点，是2型糖尿病治疗的新选择。
关键词肠促胰岛素胰高血糖素样肽-1受体激动剂二肽基肽酶-4抑制剂 2型糖尿病中图分类号：R977.15 文献标识码：A 文章编号：1006-1533（2013）07-0003-04近年来，随着对糖尿病发病机制的不断研究与认识，肠促胰岛素（incretin）因可促进β细胞复制和再生、抑制其凋亡以及改善α细胞功能而成为研究热点。
肠促胰岛素是一组胃肠激素，主要包括胰高血糖素样肽-1（glucagon-like peptide-1， GLP-1）和葡萄糖依赖性促胰岛素肽（glucose-dependent insulinotropic peptide， GIP）[1]。
因为GLP-1会被GLP-1降解酶二肽基肽酶-4（dipeptidyl peptidase-4， DPP-4）迅速降解且2型糖尿病患者体内或多或少都存在GLP-1水平降低的现象，所以注射GLP-1受体激动剂和口服DPP-4抑制剂能够促进胰岛素分泌和维持血糖水平稳定[2]。
本文简要介绍这两类基于肠促胰岛素的抗糖尿病药物的发展概况。
1 GLP-1受体激动剂1.1 艾塞那肽（exenatide）艾塞那肽是人工合成的含有39个氨基酸的exendin-4类似物，是美国批准的第一个GLP-1受体激动剂。
exendin-4是自希拉毒蜥（Gila monster）的唾液中分离得到的，与人GLP-1在氨基酸序列上具有53%的同源性[3]。
exendin-4不是DPP-4的底物，不会被迅速降解。
艾塞那肽能够激活GLP-1受体、由此发挥类似人GLP-1的作用，但因其N端不能被DPP-4降解，故血浆半衰期更长。
GLP-1类似物Liraglutide（利拉鲁肽）的作用可以持续24小时，每天仅需...
GLP-1类似物Liraglutide（利拉鲁肽）的作用可以持续24小时，每天仅需用药一次，能够提供类似于内源性GLP-1的生理效应，包括根据葡萄糖水平促进胰岛素分泌、抑制胰高糖素、延迟胃排空；在动物实验中，还能防止B细胞凋亡并促进其再生。
由于促进胰岛素分泌的作用是依赖于血糖水平的，因此发生低血糖的危险比较低。
临床试验证实，Liraglutide能够降低空腹及餐后血糖，HbA1C水平能够降低1～2%；某些试验甚至表明，Liraglutide能够降低某些心血管风险的生物标记，明显降低甘油三酯的水平。
当然，还需要进行相关实验验证究竟Liraglutide能否改善2型糖尿病患者的进程。
在过去的30年中，全球和我国的2型糖尿病（T2DM）患病率急剧上升，给社会带来了日益沉重的负担。
总体来说，目前T2DM的控制达标率较低，且在过去5年中未能进一步提高。
目前临床上使用的降糖药物，在保护胰岛β细胞功能方面也尚无突破性进展。
因此寻找新的治疗机制和研发新药物是提高T2DM治疗达标率的希望之一，而胰高血糖素样肽-1（GLP-1）类似物的问世，是这方面的一个成功典范。
GLP—1是一种由胃肠内分泌细胞产生的肽类物质，属于肠促胰素的一种。
它能够通过促进胰岛素分泌、刺激胰岛β细胞增生、阻止胰岛β细胞凋亡、抑制胰高血糖素的释放、抑制胃肠道蠕动和胃液分泌、延迟胃排空、产生饱胀感和食欲下降等多重途径来控制血糖。
无疑，GLP—1将会开启未来糖尿病治疗的新篇章！礼来的产品是GLP-1类似物，其实是南美蜥蜴分泌的GLP-1，在美国使用时因为出现个别急性胰腺炎的病例，被FDA加黑框警告，因此这个产品在国外的销量一直上不去；诺和的产品是GLP-1的化学修饰物，半衰期比天然GLP-1长很多，但因为在动物身上发现细微的致癌性差异，在FDA 专家委员会投票时以6票赞成、6票反对、1票弃权的结果“暂时搁置”。
礼来的艾塞那肽是巨蜥唾液提取，与人类GLP-1同源性仅有50%多诺和的利拉鲁肽是人工修饰的，与人类的GLP-1同源性好像是90%，记不清了。
利拉鲁肽和艾塞那肽临床作用对比
Liraglutide once a day versus exenatide twice a day for type 2 diabetes: a 26-week randomised, parallel-group, multinational, open-label trial (LEAD-6)John B Buse, Julio Rosenstock, Giorgio Sesti, Wolfgang E Schmidt, Eduard Montanya, Jason H Brett, Marcin Zychma, Lawrence Blonde, for the LEAD-6 Study Group*SummaryBackground Unlike most antihyperglycaemic drugs, glucagon-like peptide-1 (GLP-1) receptor agonists have a glucose-dependent action and promote weight loss. We compared the effi cacy and safety of liraglutide, a human GLP-1 analogue, with exenatide, an exendin-based GLP-1 receptor agonist.Methods Adults with inadequately controlled type 2 diabetes on maximally tolerated doses of metformin, sulphonylurea, or both, were stratifi ed by previous oral antidiabetic therapy and randomly assigned to receive additional liraglutide 1·8 mg once a day (n=233) or exenatide 10 μg twice a day (n=231) in a 26-week open-label, parallel-group, multinational (15 countries) study. The primary outcome was change in glycosylated haemoglobin (HbA1c). Effi cacy analyses were by intention to treat. The trial is registered with , number NCT00518882.Findings Mean baseline HbA1c for the study population was 8·2%. Liraglutide reduced mean HbA1csignifi cantly morethan did exenatide (–1·12% [SE 0·08] vs –0·79% [0·08]; estimated treatment diff erence –0·33; 95% CI –0·47 to –0·18; p<0·0001) and more patients achieved a HbA1cvalue of less than 7% (54% vs 43%, respectively; odds ratio 2·02; 95% CI 1·31 to 3·11; p=0·0015). Liraglutide reduced mean fasting plasma glucose more than did exenatide (–1·61 mmol/L [SE 0·20] vs –0·60 mmol/L [0·20]; estimated treatment diff erence –1·01 mmol/L; 95% CI –1·37 to –0·65; p<0·0001) but postprandial glucose control was less eff ective after breakfast and dinner. Both drugs promoted similar weight losses (liraglutide –3·24 kg vs exenatide –2·87 kg). Both drugs were well tolerated, but nausea was less persistent (estimated treatment rate ratio 0·448, p<0·0001) and minor hypoglycaemia less frequent with liraglutide than with exenatide (1·93 vs 2·60 events per patient per year; rate ratio 0·55; 95% CI 0·34 to 0·88; p=0·0131; 25·5% vs 33·6% had minor hypoglycaemia). Two patients taking both exenatide and a sulphonylurea had a major hypoglycaemic episode.Interpretation Liraglutide once a day provided significantly greater improvements in glycaemic control than did exenatide twice a day, and was generally better tolerated. The results suggest that liraglutide might be a treatment option for type 2 diabetes, especially when weight loss and risk of hypoglycaemia are major considerations.Funding Novo Nordisk A/S.IntroductionType 2 diabetes is an increasingly common chronic disease. Although diagnosed on the basis of hyperglycaemia, it is associated with broad metabolic abnormalities that contribute to microvascular and macrovascular complications. Importantly, unmet pharma c ological needs remain despite great advances in diabetes care and treatment, and availability of ten diff erent antihyperglycaemic medication classes.To reach glycaemic targets, various antihyperglycaemic drugs—alone or in combination—are commonly required in addition to lifestyle interventions. Some agents are eventually combined with insulin in complex regimens that need daily titration based on glucose monitoring. Careful selection of therapies and follow-up is crucial to achieve glycaemic control while avoiding other substantial problems, particularly weight gain and hypoglycaemia.1 Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L-cells, mainly in response to food intake. It has broad physiological effects, including stimulation of insulinsecretion and reduction of glucagon secretion, both in aglucose-dependent manner, and resulting in reducedhepatic glucose production. F urthermore, GLP-1 slowsgastrointestinal motility and increases satiety withreduced food intake. In animal models, it promotes β-cellproliferation and probably neogenesis, while reducingapoptosis.2–4 Because GLP-1 is rapidly degraded bydipeptidyl peptidase-4,5 GLP-1 receptor agonists based onexendin or human analogues resistant to dipeptidylpeptidase-4 have been developed.The current consensus statement from the AmericanDiabetes Association (ADA) and the European Associationfor the Study of Diabetes (EASD) about the medicalmanagement of hyperglycaemia in type 2 diabetessuggests that comprehensive lifestyle managementcombined with metformin should be initiated at diagnosis,except in cases of severely uncontrolled hyperglycaemia.1Subsequently, treatment should be intensifi ed promptly ifLancet 2009; 374: 39–47Published OnlineJune 8, 2009DOI:10.1016/S0140-6736(09)60659-0See Comment page 4Division of Endocrinology,University of North CarolinaSchool of Medicine, Chapel Hill,NC, USA (Prof J B Buse MD);Dallas Diabetes and EndocrineCenter at Medical City, Dallas,TX, USA (J Rosenstock MD);Department of Experimentaland Clinical Medicine, MagnaGraecia University ofCatanzaro, Catanzaro, Italy(Prof G Sesti MD);Departmentof Medicine I, St Josef-Hospital,Ruhr-University MedicalFaculty, Bochum, Germany(Prof W E Schmidt MD);HospitalUniversitari Bellivtge-IDIBELL,University of Barcelona, CIBERde Diabetes y EnfermedadesMetabólicas Asociadas(CIBERDEM), Barcelona, Spain(Prof E Montanya MD);NovoNordisk, Princeton, NJ, USA(J H Brett MD);Novo Nordisk,Bagsvaerd, Denmark(M Zychma MD);and OchsnerDiabetes Clinical Research Unit,Department of Endocrinology,Ochsner Medical Center, NewOrleans, LA, USA (L Blonde MD)Correspondence to:Prof John B Buse, Division ofEndocrinology, University ofNorth Carolina School ofMedicine, Chapel Hill, NC, USAjbuse@glycosylated haemoglobin (HbA1c) values exceed the ADA target of less than 7%. Recently, the consensus panel added GLP-1 receptor agonists as options when weight loss or risk of hypoglycaemia are major considerations. This decision was based on clinical data for the exendin-based GLP-1 receptor agonist exenatide, a molecule with 53% aminoacid identity with human GLP-1. Exenatide causes a decrease in HbA1cvalues of 0·5–1·0%, and treatment is associated with weight loss1 and with frequent gastrointestinal side-eff ects that tend to subside over time but can lead to treatment discontinuation. With elimination by glomerular fi ltration and a half-life of 2·4 h, administration of exenatide twice a day 0–60 min before meals is recommended.6 The drug’s predominant effect is the reduction of postprandial glucose concentration, especially after breakfast and dinner.7 Liraglutide is a human GLP-1 analogue with one aminoacid substitution (Arg34Lys) and a C-16 palmitic-acid side chain attached via a glutamyl spacer. These modifications result in slower absorption from sub-cutaneous tissue, reversible albumin binding, and resistance to GLP-1 inactivation by dipeptidyl peptidase-4. Unlike exenatide, liraglutide is 99% bound to albumin, with free liraglutide degraded by endogenous peptidases, and not via renal elimination.8 Liraglutide injection produces maximal concentrations within 10–14 h after administration, with a half-life of 13 h.9 Liraglutide has been developed as a once-a-day treatment for type 2 diabetes, as an adjunct to lifestyle therapy and in combination with oral antidiabetic drugs.7Because the molecular structure, aminoacid sequence identity shared with human GLP-1, metabolism, and pharmacokinetics of exenatide and liraglutide diff er, we designed the liraglutide eff ect and action in our diabetes (LEAD-6) study to compare their effi cacy and safety. We report the results of the 26-week randomised comparator trial.MethodsParticipantsParticipants aged 18–80 years with type 2 diabetes were eligible if their HbA1cvalue was 7–11% and if they had a body-mass index (BMI) of 45·0 kg/m² or less on stable treatment with maximally tolerated doses of metformin, sulphonylurea, or both, for 3 months or more. Exclusion criteria included previous insulin treatment (except short-term treatment for intercurrent illness), previous exposure to exenatide or liraglutide, impaired liver or renal function, clinically significant cardiovascular disease, retinopathy or maculopathy requiring acute treatment, uncontrolled hypertension (≥180/100 mm Hg), or cancer.All participants provided written consent before any procedure. The trial was done in accordance with the Declaration of Helsinki10 and Good Clinical Practice guidelines.11 Before trial initiation, the protocol, its amendments, consent form, and patient information sheets were approved by independent local ethics committees. The study is registered with ClinicalTrials. gov, number NCT00518882.Trial design and interventionsThis study was a 26-week randomised, open-label, active-comparator, p arallel-group, m ultinational (132 offi ce-based sites across 15 countries) trial. Participants were screened for eligibility and enrolled by investigators. They were randomly assigned (1:1) to subcutaneous liraglutide 1·8 mg once a day (Novo Nordisk A/S, Bagsvaerd, Denmark) or subcutaneous exenatide 10 μg twice a day (Byetta, Amylin Pharmaceuticals Inc, San Diego, CA, USA), and were stratifi ed by previous oral antidiabetic drug treatment. Randomisation was done with telephone-based or web-based systems. Participants were randomly assigned by investigators to the lowest available number from the range of numbers allocated to the site. The study began on Aug 24, 2007, and was completed on April 9, 2008.After randomisation, participants underwent a 2-week liraglutide dose-escalation period (during which the initial dose of 0·6 mg was increased by 0·6 mg a week to a maximum dose of 1·8 mg once a day) or 4-week exenatide dose-escalation period (during which 5 μg twice a day was increased to 10 μg twice a day after 4 weeks).6 This was followed by a 22–24-week maintenance period when no dose reduction of liraglutide or exenatide was allowed. Intolerance to these doses required study discontinuation. Background oral antidiabetic drugs were maintained at prestudy doses unless unacceptable hypoglycaemia occurred, in which case sulphonylurea doses could be reduced to no less than 50% of the starting dose.Both liraglutide and exenatide were injected in the upper arm, abdomen, or thigh with a pre-fi lled pen. Participants were encouraged to take liraglutide at the same time each day. Exenatide was administered 0–60 min before breakfast and dinner (or before each of the two main daily meals, about 6 h or more apart). Participants completing this study could enrol in a 52-week liraglutide 1·8-mg extension phase. Assessments and endpointsThe primary effi cacy outcome was change in HbA1cvalues from baseline to week 26. Secondary effi cacy endpoints included proportion of patients reaching HbA1ctargets (<7·0% and ≤6·5%), changes in fasting plasma glucose, self-measured 7-point plasma glucose profi les, bodyweight, β-cell function, glucagon, blood pressure, and lipid profiles. Assays were done by central laboratories (MDS Pharma Services in Canada, F rance, Germany, Switzerland, and USA). Participants used Precision Xceed or Precision Xtra glucose meters (Abbott Diagnostics Inc, Abbott Park, IL, USA) to measure plasma glucose, and values were recorded in diaries. Overall treatment satisfaction was assessed with the Diabetes Treatment Satisfaction Questionnaire in a subgroup of participants.12 Overall treatment satisfactionwas based on six of the eight items in the questionnaire (each item was scored on a scale from +3 [better] to –3 [worse]).Safety variables included adverse events, vital signs,measures, and patient-reported hypoglycaemic episodes.A serious adverse event was defi ned as an adverse event that resulted in death, hospitalisation, disability, a birth defect, was life-threatening, or that required medical or surgical intervention to prevent one of the other outcomes.A severe adverse event was defi ned as an adverse event causing unacceptable and considerable interference with the patient’s daily activities. Major hypoglycaemic episodes were defi ned as requiring third-party assistance with food only, glucagon, or intravenous glucose. Minor episodes were defi ned as those that the participant could self-treat and for which the plasma glucose concentration was less than 3·1 mmol/L. At glucose concentrations of 3·1 mmol/L or more,or in the absence of glucose measurements, episodes were regarded as symptoms only. Because of the nature of the antibody assay, analysis of emergent antibodies against liraglutide cannot be completed until participants have been through a washing-out period from therapy. Antibody data are not reported here and will be analysed once the liraglutide extension phase is completed.Statistical analysisThe primary endpoint was the diff erence between treatment groups in HbA1cvalues from baseline toweek 26. 163 individuals in each group were needed for 85% power to detect a diff erence of 0·4% between groups (assuming a SD of 1·2%), a clinically meaningful margin for non-inferiority. Assuming a 25% drop-out rate, 434 participants (217 per group) were needed at randomisation.Analyses of efficacy outcomes were based on the intention-to-treat population. The primary endpoint was also analysed for the per-protocol population. We analysed most endpoints with the analysis of covariance (ANCOVA) with treatment, country, and current antidiabetic drug as explanatory variables, and baseline HbA1cvalues as covariate. We imputed missing values by carrying the last observation forward. We did hierarchical tests for non-inferiority and superiority of liraglutide and back-ground oral antidiabetic drugs versus exenatide and background oral antidiabetic drugs. We fi rst established non-inferiority and then tested superiority, each at 2·5% significance level. We assumed non-inferiority if the upper limit of the two-sided 95% CI for treatment difference was less than 0·4%, and superiority if the upper limit was less than 0. We compared the proportions of patients achieving HbA1ctarget values using logistic regression with treatment, country, and background oral antidiabetic drug as explanatory variables, and baseline HbA1cvalues as covariate. We developed estimates of overall treatment satisfaction from an ANCOVA model with treatment, country, and background oral antidiabeticdrug as fi xed eff ects, and baseline Diabetes TreatmentSatisfaction Questionnaire summary score as covariate.Missing data were not imputed.We analysed hypoglycaemic episodes using ageneralised linear model with treatment, backgroundoral antidiabetic drug, and country as fi xed eff ects. Wecompared other safety data with descriptive statistics.Significance level was set at p<0·05, and data areexpressed as least square means (SE) unless statedotherwise.Role of the funding sourceThe sponsor was involved in study design, data collection,data review, and data analysis. All authors had full accessto the data and had fi nal responsibility for the content ofthe manuscript; JBB had final decision to submit forpublication.Results464 participants were randomly assigned to treatment(fi gure 1). Three participants received treatment withoutrandomisation (2 in the liraglutide group, 1 in exenatidegroup), and they were included in the safety but notintention-to-treat populations. 33 of 235 participantswithdrew from liraglutide and 45 of 232 from exenatidetreatment; withdrawal rates were not signifi cantlyFigure 1: Trial profi leOf the adverse events leading to withdrawal, nausea was the most common (14 patients in the liraglutide group and 16 in the exenatide group). Participants were exposed to treatment if they had received at least one dose of study medication.diff erent between groups. Adverse events were the most common reason for withdrawal in both groups. The characteristics of the study population were typical for participants with type 2 diabetes, and baseline characteristics were well matched between treatment groups (table 1).HbA 1c values decreased more in the group treated with liraglutide 1·8 mg once a day than in that treated with exenatide 10 μg twice a day over 26 weeks (fi gure 2A). The mean change from baseline to week 26 was signifi cantly greater in the group treated with liraglutide than in that treated with exenatide (–1·12% [0·08] vs –0·79% [0·08]; estimated treatment diff erence [ETD] –0·33; 95% CI –0·47 to –0·18; fi gure 2B). Reduction of HbA 1c values with liraglutide was statistically superior to that seen with exenatide. Diff erences in HbA 1c values between treatment groups did not depend on baseline therapy, BMI, country, sex, ethnic origin, or age because the interaction eff ects were not signifi cant (p>0·05). The signifi cance oftreatment-by-race interaction (p=0·0256) might be due to the small number of non-white participants (table 1). Data in the intention-to-treat population were similar to those in the per-protocol population (change from baseline toweek 26 HbA 1c : liraglutide –1·16% [0·09] vs exenatide –0·87% [0·09]; ETD –0·29%; 95% CI –0·45 to –0·13; p<0·0001). We confi rmed robustness of the ETD using last-observation carried-forward data withrepeated-measures analysis and multiple imputation methods (data not shown). Mean reductions in HbA 1c values were generally greater for the liraglutide group than for the exenatide group across the spectrum of HbA 1c values. However, the diff erence was greatest for patients with baseline HbA 1c of 10% or more (liraglutide –2·4% [SE 0·21] vs exenatide –1·2% [0·37]).The proportion of participants achieving HbA 1c targets was signifi cantly higher in the liraglutide than in the exenatide group (target of <7%: 54% vs 43%; odds ratio [OR] 2·02; 95% CI 1·31 to 3·11; target of ≤6·5%: 35% vs21%; OR 2·73; 95% CI 1·68 to 4·43; fi gure 2C). Liraglutidealso reduced fasting plasma glucose from baseline signifi cantly more than did exenatide (–1·61 mmol/L [0·20] vs –0·60 mmol/L [0·20]; ETD –1·01 mmol/L; 95% CI –1·37 to –0·65; p<0·0001; fi gure 2D). In contrast, exenatide reduced postprandial plasma glucose increment more than did liraglutide (self-measured with 7-point plasma glucose profi les; fi gure 2E) after breakfast and dinner (breakfast: ETD 1·33 mmol/L; 95% CI 0·80 to 1·86; p<0·0001; dinner: ETD 1·01 mmol/L; 95% CI0·44 to 1·57; p=0·0005); treatment diff erences after lunchwere not signifi cant.Liraglutide and exenatide were associated with similarweight losses (liraglutide –3·24 kg [0·33] vs exenatide–2·87 kg [0·33]; ETD –0·38 kg; 95% CI –0·99 to 0·23; p=0·2235; fi gure 2) and similar proportions of participants who lost weight (liraglutide 78% [182 of 233]vs exenatide 76% [176 of 231]). Mean reductions in HbA 1c values were clinically meaningful irrespective of whetherparticipants lost weight (weight loss: liraglutide –1·3% vs exenatide –0·9%; no weight loss: liraglutide –1·0% vs exenatide –0·5%).Table 2 shows changes in islet function, blood pressure, and lipids. Increases in fasting insulin and the associatedhomoeostasis model assessment index of β-cell function (HOMA-B) were significantly greater for the liraglutide than for the exenatide group. Treatment differences for fasting C-peptide or proinsulin-to-insulin ratio were notsignificant. F asting glucagon and blood pressure decreased with both treatments, and differences between treatments were not significant for fasting glucagon or either systolic or diastolic blood pressures. Reductions oftriglycerides and free fatty acid values were significantly greater in the liraglutide group than in the exenatide group, and increases in very low-density lipoprotein cholesterol were smaller in the liraglutide group than in the exenatide group.Overall treatment satisfaction was signifi cantly better in the liraglutide group (n=161) than in the exenatide group (n=143) (15·18 [0·58] vs 13·30 [0·58]; ETD 1·89; 95% CI 0·85 to 2·92; p=0·0004).Despite an overall lower reporting of adverse events in the liraglutide group than in the exenatide group (74·9% vs 78·9%), the liraglutide group had more serious and severe adverse events (serious: 5·1% vs 2·6%; severe:7·2% vs 4·7%; table 3). Serious adverse events showed no consistent pattern for system organ class and onlyone event (severe hypoglycaemia requiring medical attention in the exenatide group) was judged probably related to study medication by the investigator. The most frequent severe adverse events were dyspepsia in the liraglutide group (n=3) and nausea in the exenatide group (n=4). The distribution of most adverse events was similar between groups (table 3). Although the incidence of nausea was similar initially, it was less persistent with liraglutide (estimated treatment rate ratio 0·448 for liraglutide vs exenatide; proportion of participants with nausea at week 26, 5 of 202 [3%] vs 16 of 186 [9%]; fi gure 3).Figure 2: Effi cacy of treatment with liraglutide 1·8 mg once a day or exenatide 10 μg twice a day(A) Glycosylated haemoglobin (HbA1c ) values from baseline to week 26. (B) Change in HbA1cvalues from baseline to week 26. (C) Percentage of patients achievingHbA1ctarget values. (D) Fasting plasma glucose (FPG) concentrations from baseline to week 26. (E) 7-point self-measured plasma glucose profi les. (F) Bodyweight from baseline to week 26. Data are mean (1·96 SE) unless stated otherwise, with last observation carried forward (except for panel E, observed case).One episode of mild pancreatitis, which the investigator regarded as chronic and unlikely to be related to study drug, was diagnosed after 88 days of liraglutide therapy in a 69-year-old man with a history of abdominal distension and hypercholesterolaemia. No data for pancreatic enzyme concentrations were reported. Liraglutide was continuedfor another 10 weeks until the patient was withdrawnbecause of lung adenocarcinoma (unlikely to be related totreatment). No episodes of acute pancreatitis were reportedwith either agent.No major hypoglycaemia occurred with liraglutide butthere were two episodes in patients receiving exenatideand a sulphonylurea. The proportion of patients who hadminor hypoglycaemia (26% [60 out of 235] with liraglutidevs 34% [78 out of 232] with exenatide) and event rate forminor hypoglycaemia(1·932 vs 2·600 events perparticipant per year; rate ratio 0·55, 95% CI 0·34 to 0·88;p=0·0131) were lower with liraglutide than with exenatide,with greater diff erences between treatments during theevening (fi gure 4). The proportion of patients who hadepisodes of minor hypoglycaemia was lower in thesubgroups using metformin as background therapy (6%[4 out of 64] and 11% [7 out of 63] for liraglutide andexenatide groups, respectively) than in those taking asulphonylurea with or without metformin (33% [56 outof 171] and 42% [71 out of 169], respectively). However,most patients could continue sulphonylurea treatment atthe dose used in the period before enrolment (liraglutide89% [150 of 169] and exenatide 85% [142 of 168]).Calcitonin concentrations were monitored in allparticipants to assess any effect of GLP-1 receptoragonists on C-cell function. At baseline, mean calcitoninconcentrations were less than 1 ng/L, below the uppernormal reference range for both women (5·0 ng/L) andmen (8·4 ng/L). Small decreases in calcitonin occurredduring the trial in both treatment groups, withoutsignifi cant diff erence between groups at any timepoint.Heart rates increased slightly in both treatment groups(liraglutide 3·28 [0·83] beats per minute; exenatide 0·69[0·84] beats per minute) but the increase was signifi cantlygreater for liraglutide (ETD: 2·58; 95% CI 1·03 to 4·13;p=0·0012).DiscussionThis trial provides a direct comparison of effi cacy andsafety between liraglutide and exenatide, both of whichinteract with the GLP-1 receptor but diff er in aminoacididentity with human GLP-1, frequency and timing ofadministration, clearance, and especially pharma-cokinetics. The results show that liraglutide providessuperior overall glycaemic control on the basis of HbA1c data.We show HbA1creductions that are consistent withthose from other studies with liraglutide and exenatide.Liraglutide 1·8 mg once a day reduced HbA1cvalues by1·12% in the present study compared with 1·14% in theLEAD-3 monotherapy study13 and 1·00–1·48% in LEADstudies in which it was administered together with oralantidiabetic drugs.14–17 Exenatide 10 μg twice a day reducedHbA1cvalues by 0·79%, which is consistent withreductions of 0·78–0·89% reported elsewhere.18–21Greater mean reductions were shown in a recent studyFigure 3: Proportion of patients with an episode of nausea between baseline and week 26(–1·5%), but these were significantly less than thoseachieved with exenatide once a week (–1·9%).22 Althoughliraglutide has been compared with glimepiride,13rosiglitazone,14 and insulin glargine,17 showing superiorityin lowering HbA1cvalues, exenatide twice a day has beencompared with insulin glargine23 and premixed analogueinsulin,24 showing non-inferiority in lowering HbA1c values.The greater reduction of HbA1cvalues with liraglutidethan that with exenatide is likely to be related to greaterreduction of fasting plasma glucose. In fact, postprandialglucose increments were reduced slightly more byexenatide than by liraglutide after breakfast and dinner,the meals before which exenatide is usually admini-stered. Liraglutide also increased the HOMA index ofβ-cell function more than did exenatide. Glucagon con-centrations were modestly reduced by both drugs andtreatment diff erences were not signifi cant. Changes inC-peptide and the proinsulin-to-insulin ratio were smalland similar between treatments. Although assessmentof β-cell function with fasting measures is challengingand the clinical signifi cance is uncertain, the results areconsistent and likely to indicate more-sustained GLP-1receptor activation with liraglutide than with exenatide.Weight losses (~3 kg) were similar for both treatments.Treatment differences for the various lipid parameterswere not significant except for greater reductions intriglycerides and free fatty acids, and a smaller increase invery low-density lipoprotein cholesterol, with liraglutidethan with exenatide. Other studies have reported similarresults for these parameters for both agents.13,15,18,21Treatments were well tolerated, with most adverseevents being mild or moderate in severity and seriousadverse events mainly judged unlikely to be related totreatment. Gastrointestinal adverse events are ofspecial interest for this class of drugs. Nausea was themost frequent adverse event but, although theproportion of patients aff ected was initially similar inthe two groups, nausea resolved more quickly inpatients treated with liraglutide than in those treatedwith exenatide. By week 6, the proportion of participantshaving nausea in the liraglutide group had fallen below10% (8·1% vs 15·8% for exenatide), whereas theexenatide group reached this value after 22 weeks. Atweek 26, only 2·5% of the liraglutide group had nauseacompared with 8·6% of the exenatide group. Similar patterns are apparent in other studies.13–15,18,19Only two major hypoglycaemic episodes occurred (both in the exenatide group). Minor hypoglycaemia was less frequent with liraglutide than with exenatide despite greater reductions in fasting glucose and HbA1c. As expected from the glucose dependence of insulin secretion with GLP-1 receptor agonists, hypoglycaemia with both agents occurred mainly in patients on sulphonylureas. However, most patients could continue their sulphonylurea medication throughout the trial at an unchanged prestudy dose.Acute pancreatitis—including severe and fatal episodes—has been spontaneously reported in patients taking exenatide, raising concerns about a potential association with GLP-1 receptor agonists. However, obesity, hypertriglyceridaemia, and gallstones are all known risk factors for acute pancreatitis, and are all associated with type 2 diabetes. In fact, acute pancreatitis seems to be about three times more common in type 2 diabetes patients than in the general population.25 Although the single case of mild pancreatitis treated with liraglutide in this study has not been well characterised and the diagnosis was based solely on clinical symptoms, the patient continued。
胰高血糖素样肽-1受体激动剂类药物知多少
胰高血糖素样肽-1受体激动剂类药物知多少作者：李鑫来源：《家庭医学》2023年第19期皮下注射胰岛素控制血糖，是许多糖尿病患者日常的治疗方案。
近来，另一种通过皮下注射的降糖药迅速成为众多糖尿病患者关注及热议的焦点。
这类新型降糖药被称为胰高血糖素样肽-1受体激动剂（GLP-1RA）。
此类药物有别于传统降糖药，在有效控制患者血糖的同时，还能帮助患者实现多重获益。
目前临床应用的GLP-1RA是基于人胰高血糖素样肽一1结构和北美毒蜥唾液多肽-4结构研究合成的药物。
前者包括利拉鲁肽、度拉糖肽、司美格鲁肽及贝那鲁肽；后者包括艾塞那肽、艾塞那肽微球（周制剂）、利司那肽及聚乙二醇洛塞那肽。
截至2023年3月，我国批准上市用于治疗2型糖尿病的GLP-1RA类药物共9种，除上述提到的药物外，还有德谷胰岛素与利拉鲁肽组成的复方药物。
根据药物作用的时间长短，可将药物分为短效、长效及超长效制剂。
短效制剂包括贝那鲁肽、艾塞那肽及利司那肽，通常需要每天进行多次皮下注射；长效制剂包括利拉鲁肽和德谷胰岛素利拉鲁肽，每天皮下注射1次即可；超长效制剂包括度拉糖肽、司美格鲁肽、艾塞那肽微球（周制剂）及聚乙二醇洛塞那肽，每周进行1次皮下注射即可。
GLP-1RA类药物除具有显著的降糖作用外，还兼具减轻体重、降低血压、改善患者血脂等作用。
国外大型研究CVOT发现，利拉鲁肽、度拉糖肽和司美格鲁肽具有心血管保护作用，可降低伴有脑血管疾病的2型糖尿病成人患者心血管死亡、非致死性心肌梗死或非致死性卒中的风险。
与此同时，GLP-1RA還可减少2型糖尿病患者尿白蛋白的排泄量，为患者带来潜在的肾脏获益。
GLP-1RA类药物均有不同程度的降低患者体重作用，虽然目前上市的药品尚未获得我国国家药品监督管理局用于减肥治疗的适应证，但利拉鲁肽、司美格鲁肽在美国获批了相关的适应证。
药物都是一把双刃剑，在具有良好治疗作用的同时，不可避免会产生不良反应。
GLP-1RA 类药物胃肠道相关不良反应较为常见，但大部分为轻症，可随应用药物时间增加逐步缓解。
利拉鲁肽简介
利拉鲁肽简介利拉鲁肽是一种人胰高糖素样肽-1（GLP-1)类似物，用于治疗糖尿病。
商品名：诺和力(Victoza) 。
药品名称：利拉鲁肽注射液英文名称：Liraglutide injection 汉语拼音：Lilalutai Zhusheye上市简史2009年7月，在欧盟上市。
2010年1月，在日本上市。
2010年1月25日，美国食品与药物管理局（FDA）批准利拉鲁肽在美国上市。
2011年4月13日，获国家食品药品监督管理局批准，用于治疗成人2型糖尿病。
2011年10月9日，正式在中国上市。
利拉鲁肽的成份活性成份：利拉鲁肽(通过基因重组技术，利用酵母生产的人胰高糖素样肽-1（GLP-1)类似物)。
化学名称：Arg34Lys26- (N-ε-（γ-Glu(N-α-十六酰基)))-GLP-1[7-37] 化学结构式：分子式：C172H265N43O51 分子量：3751. 20 Da 其他成份：二水合磷酸氢二钠、丙二醇、盐酸和/或氢氧化钠(仅作为pH调节剂)、苯酚和注射用水。
利拉鲁肽性状本品为无色或几乎无色的澄明等渗液；pH=8. 15。
适应症本品用于成人2型糖尿病患者控制血糖：适用于单用二甲双胍或磺脲类药物最大可耐受剂量治疗后血糖仍控制不佳的患者，与二甲双胍或磺脲类药物联合应用。
规格3毫升:18毫克(预填充注射笔)。
用法用量用法本品每日注射一次，可在任意时间注射，无需根据进餐时间给药。
本品经皮下注射给药，注射部位可选择腹部、大腿或者上臂。
在改变注射部位和时间时无需进行剂量调整。
然而，推荐本品于每天同一时间注射，应该选择每天最为方便的时间。
更多有关给药的指导参见使用及其他操作的注意事项。
本品不可静脉或肌肉注射。
用量利拉鲁肽的起始剂量为每天0. 6mg。
至少1周后，剂量应增加至1. 2mg。
预计一些患者在将剂量从I.2mg 增加至1. 8mg时可以获益，根据临床应答情况，为了进一步改善降糖效果，在至少一周后可将剂量增加至1. 8mg。
利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标的meta分析
利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标的meta分析张楚辞;赵玉岩;温晶【摘要】Objective To systematically evaluate the effects of glucagon⁃like peptide⁃1(GLP⁃1)analogues exenatide and liraglutide on body weight in patients with type 2 diabetics mellitus. Methods Such databases as PubMed,Embase,CNKI and CMFD(1987⁃2014)were searched for randomized controlled trials. The meta⁃analysis was performed on the extracted related data using the software STATA 11. Results Totally 31 RCTs (7 036 patients)were included. The meta⁃analysis on body weight in these patients showed the following findings:compared tocontrols,liraglutide (1.8 mg)effectively decreased body weight(WMD=-0.45,95%CI:-0.59,-0.31);compared to positive controls,liraglutide(1.2 mg and 1.8 mg) also effectively decreased body weight(WMD=-0.91. 95%CI:-1.07,-0.75;WMD=-0.78,95%CI:-1.02,-0.54). Compared tocontrols,exena⁃tide(5μg and 10μg)effectively decreased bodyweight(WMD=-0.36,95%CI:-0.64,-0.09;WMD=-0.99,95%CI:-1.27,-0.72);compared to positive controls,exenatide(10μg)also effect ively decreased body weight(WMD=-1.14,95%CI:-1.46,-0.82). Conclusion As novel intes⁃tinal pancreatotropic hormone analogues,exenatide and liraglutide can effectively reduce body weight,providing new alternatives of hypoglycemic agents for patients with type 2 diabetics mellitus.%目的：系统评价类胰高血糖素样肽1类似物利拉鲁肽与艾塞那肽治疗2型糖尿病降低体质量指标情况。
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利拉鲁肽（诺和力）是诺和公司通过基因重组技术，利用酵母生产的人胰高糖素样肽-1（GLP-1)类似物。
适用于成人2型糖尿病患者控制血糖；以及单用二甲双胍或磺脲类药物最大可耐受剂量治疗后血糖仍控制不佳的患者，与二甲双胍或磺脲类药物联合应用。
GLP-1是一种内源性肠促胰岛素激素，能够促进胰腺葡萄糖浓度依赖性地分泌胰岛素。
利拉鲁肽与人GLP-1具有97%的序列同源性，保留了GLP-1的全部生物活性，仅在人体血糖高于正常时才刺激胰岛素分泌，抑制胰高血糖素分泌，因此不会引起严重低血糖不良反应。
另外，研究报道，利拉鲁肽还有改善胰岛β细胞功能，抑制食欲，减轻体重，降低心血管疾病风险的作用。
2010年，利拉鲁肽被FDA批准用于治疗2型糖尿病，可单独作为2型糖尿病的二线治疗药物，也可与其他口服降糖药联合使用，但不能作为胰岛素替代品用于1型糖尿病的治疗。
与利拉鲁肽不同，艾塞那肽虽然同属肠促胰素类药物，但它是GLP-1受体激动剂，也具有人GLP-1的相似的作用机理和益处。
用法上，艾塞那肽需要1天两次皮下注射，分别在早餐和晚餐前1小时内注射。
利拉鲁肽则每日仅需注射一次，可在任意时间注射，无需根据进餐时间给药，更方便，依从性好。
有研究报道，利拉鲁肽较艾塞那肽有稍低的恶心发生率以及较低的抗体生成率和抗体水平。
价格上，利拉鲁肽（诺和力）医院价格871.4元，艾塞那肽（百泌达）5ug1530.86元，利拉鲁肽更具有价格优势。