糖尿病药物治疗概述课件

Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,糖尿病药物治疗概述,南京市第一医院药学部,糖尿病依然是社会巨大负担,目,前糖尿病及其并发症所致残、致死率仅次于心脑血管疾病和癌症而居第,3,位,心血管疾病是糖尿病的主要致死原因，占大约,50%,3.71,亿,：,2019,年全世界糖尿病患病人数：,3.71,亿,7,秒：平均每,7,秒钟就有一个人因糖尿病失去生命,460,万：每年约有,460,万人死于糖尿病,4650,亿,$,：,每年用于糖尿病的医疗花费已经高达,4650,亿美元,糖尿病的认识不断加深,从“消渴症”到“八重奏 ”,黄帝内经,（公元前,500,年公元前,400,年）最早记载， 汉代,金匮要略,（公元前,206,年公元前,220,年）,:“,其人消渴，小便反多，一日饮水一斗，小便一斗。”,公元前,400,年，古印度医学文件记载“蜜糖味的尿”,罗马时代（公元,130,201,）的医学书籍中第一次使用“糖尿病”这个词,Mellitus,（拉丁语）“甘甜如蜜”,Diabetes,（希腊语）“排尿如虹吸管”,高血糖,肠促进胰素分泌减少,神经传导异常,肝糖产生增加,胰岛素分泌减少,葡萄糖摄取减少,脂解作用增加,肾脏葡萄糖,重吸收增加,糖尿病的认识不断加深,从“消渴症”到“八重奏 ”,Ralph DeFronzo, 2019 ADA Banting,Lecture,胰高糖素,生成增加,糖尿病分型与临床治疗,1,型糖尿病,2,型糖尿病,特殊类型糖尿病,其他,人之初性本“饿”,自然规律,治疗手段-药物,Buse,J. EASD OP, The ADA/EASD “Consensus” Algorithm 2009,10,01.,种类,常用药物,双胍类,二甲双胍,-,糖苷酶抑制剂,阿卡波糖，米格列醇,噻唑烷二酮类（,TZDs,）,罗格列酮，吡格列酮,GLP-1,受体激动剂,DPP-4,抑制剂,利拉鲁肽，艾塞那肽,西格列汀，沙格列汀,磺脲类,格列本脲，格列美脲，格列齐特,格列奈类,胰岛素,瑞格列奈，那格列奈,人胰岛素，胰岛素类似物,6,常用的降糖药,DPP,：,二肽基肽酶,TZDs,：,噻唑烷二酮类,6,糖尿病治疗药物及其作用部位,Hyperglycemia,2,肝糖输出,7,糖重吸收,8,神经传递功能紊乱,5,肠促胰素功能,4,脂肪分解,1,糖摄取,胰岛素分泌,胰高血糖素分泌,3,6,Source: DeFronzo RA. Banting Medal for Scientific Achievement Lecture. ADA 2019; San Francisco, CA. Diabetes. 2009;58(4):773-95,二甲双胍,胰岛素促泌剂,(SU/,非,SU),SGTL2,DPP-4I,GLP-1RA,TZD,DPP-4I,GLP-1RA,目前常用的降糖药物,针对胰岛素分泌不足：胰岛素及促胰岛素分泌剂,胰岛素,基础胰岛素,预混胰岛素,短效,/,速效胰岛素,中长效胰岛素,磺脲类,/,非磺脲类,针对胰岛素抵抗：胰岛素增敏剂及双胍,TZD,Met,针对肠促胰素缺陷：肠促胰素类药物,DPP-4I,GLP-1RA,Lepore M et al. Diabetes. 2000;49:2142-2148.,时间（小时）,相对胰岛素作用,短效胰岛素，,6-10 h,NPH,（中效低精蛋白锌胰岛素 ）, 10-20 h,门冬、赖脯、谷赖胰岛素（短效速效），,4-6 h,2,4,6,8,10,12,14,16,18,20,22,24,0,长效胰岛素，,16-20 h,各种胰岛素及其作用时间,胰岛素按,作用时间分类,超短效,速效,胰岛素类似物：,Aspart, Lispro,短效胰岛素,可溶性胰岛素:,Actrapid,（,Novolin R,Humulin R),中效,胰岛素,锌或鱼精蛋白悬浊液，,NPH,长效胰岛素,锌悬浊液:,PZI,长效,胰岛素类似物 :,Detemir,，,Glargin,药用,胰岛素种类,动物胰岛素,猪胰岛素,牛胰岛素,人胰岛素,半生物合成人胰岛素,基因重组,人胰,岛,素,预混人胰岛素,胰岛素类似物,速效胰岛素类似物,预混胰岛素类似物,长效胰岛素类似物,细胞生成胰岛素,并储存在分泌小体中,ATP,ADP,丙酮酸,电压门控钙通道,Ca,+,Ca,+,G,G,G,G,G,G,葡萄糖转运子,(Glut 2),G,G,G,G,G,G,G,G,G,G,G,K,+,通道,K,+,N,X,K,+,通道阻断细胞膜建立极性,S,R,K,+,胰岛素促泌剂,降糖机制：,胰岛素敏感性增加；,肝糖输出降低,副作用：,乳酸酸中毒；,消化道副反应,双胍类,寡糖,拜唐苹,小肠细胞,降糖机制：,竞争性抑制,-,糖苷酶,减慢葡萄糖吸收入血,使餐后血糖峰值降低,副作用：,主要为胃肠道作用,排气,-,糖苷酶抑制剂,-,细胞,胰岛素分泌？,脂肪细胞,噻唑烷,二酮类,肝脏,肝糖产生,葡萄糖摄取,肌肉,血浆,FFA,胰岛素敏感性,=,葡萄糖转化、脂肪合成,脂肪分解和,FFA,排出,脂肪细胞数目,脂连素和,TNF-,分泌,(?),?,降糖机制：,激活,PPAR-,减轻外周组织对胰岛素的抵抗,减少肝内糖原异生,促进外周组织的葡萄糖摄取,副作用：,头痛、乏力、腹泻,部分患者体重增加，加重水肿,可引起贫血和红细胞减少,噻唑烷二酮类,GLP-1,相关药物的两种治疗机制,Drucker.,Expert Opin Invest Drugs,2019;12:87100; Ahrn.,Curr Diab Rep,2019;3:36572,GLP-1,释放,食物摄入,活性的,GLP-1(7-36),DPP-4,抑制剂,DPP-4,GLP-1,受体激动剂,无活性的,GLP-1 (9-36),GLP-1,受体激动剂,DPP-4,抑制剂,艾塞那肽,BID,利拉鲁肽,艾塞那肽,OW,Lixisenatide,Albiglutide,西格列汀,沙格列汀,维格列汀,利格列汀,阿格列汀,目前基于肠促胰素治疗的药物分类,Lixisenatide, Albiglutide:,未上市产品,中国上市的肠促胰素类药物的批准适应症,利拉鲁肽,(诺和力,),艾塞那肽,(百泌达,),西格列汀,(捷诺维,),沙格列汀,(安立泽,),维格列汀,(佳维乐,),上市时间,2019,2009,2019,2019,2019,SFDA批准适应症,单药治疗,联合二甲双胍,联合磺脲类,联合噻唑烷二酮类,联合,二甲双胍+磺脲类,利拉鲁肽，艾塞那肽、西格列汀、维格列汀、沙格列汀说明书。,主要内容,GLP-1,受体激动剂有差异吗？,1,DPP-4,抑制剂有差异吗？,2,GLP-1,受体激动剂与,DPP-4,抑制剂有差异吗？,3,利拉鲁肽,Albiglutide,GLP-1,受体激动剂的分子结构不同,天然人,GLP-1,Lixisenatide,艾塞那肽,BID&OW,97%,的氨基酸序列与人,GLP-1,同源,53%,的氨基酸序列与人,GLP-1,同源,分子结构的不同导致免疫原性的差异,Liraglutide SPC; Exenatide SPC;,DeFronzo,et al. Diabetes Care,2019;28:1092100,抗体增加的患者,(%),利拉鲁肽,艾塞那肽,BID,艾塞那肽,OW,44%,57%,9%,6%,患者产生高滴度抗体,12%,患者产生高滴度抗体,利拉鲁肽：抗体不影响其疗效,艾塞那肽,BID & OW,：,产生抗体的患者倾向于发生更多注射部位反应,未产生,GLP-1,或胰高糖素交叉反应,GLP-1,受体激动剂的药效学和药代动力学特征,利拉鲁肽,艾塞那肽,艾塞那肽,OW,人体治疗剂量,1.2/1.8 mg Qd,10 ug Bid,餐前,2 mg OW,活性,GLP-1,水平提升能力,(,给予治疗剂量,),5,倍,5,倍,5,倍,半衰期,13 h,2.4 h*,2 w,达峰时间,812 h,2.1 h,2.15.1 h,排泄途径,与大分子蛋白类似的方式代谢，在体内完全降解,主要通过肾小球滤过及随后的蛋白水解而消除,肾小球滤过和肾小管重吸收及蛋白水解而消除,肾脏排泄,无,有,有,利拉鲁肽，艾塞那肽产品说明书; Kim D, et al. Diabetes Care 2019, 30: 1487; Drucker et al. The Lancet 2019, Fineman Clin Pharmacokinet 2019,Qd,一天一次,; Bid,一天两次,; OW,一周一次 * 给药后约,10h,艾塞那肽浓度仍可测,主要内容,GLP-1,受体激动剂有差异吗？,1,DPP-4,抑制剂有差异吗？,2,GLP-1,受体激动剂与,DPP-4,抑制剂有差异吗？,3,沙格列汀,类似底物,共价作用,维格列汀,类似底物,共价作用,西格列汀,类似底物,非共价作用,利格列汀,非类似底物,非共价作用,阿格列汀,非类似底物,非共价作用,Roberta Baetta,Alberto Corsini.,Pharmacology of Dipeptidyl Peptidase-4 Inhibitors: Similarities and Differences. Drugs, 2019, 71(11): 1441-1467,DPP-4抑制剂的化学结构不同,西格列汀,维格列汀,沙格列汀,利格列汀,阿,格列汀,人体治疗剂量,100 mg Qd,50 mg Bid,5 mg Qd,5 mg Qd,25 mg Qd,体外抑制活性,:,IC,50,nM*,19,62,50,1,24,体外选择性,(,与其它的,DPP-4,家族成员,a,比较,),高,中,中,中,高,对血浆,DPP-4,活性的影响,(,多次口服给药,),治疗剂量下,80%,抑制作用超过,24h,治疗剂量下,80%,抑制作用超过,24h,治疗剂量下,70%,抑制作用超过,24h,治疗剂量下,80%,抑制作用超过,24h,治疗剂量下,80%,抑制作用超过,24h,活性,GLP-1,水平提升能力,(,给予治疗剂量,),2,倍,3,倍,1.53,倍,4,倍,23倍,* Enzyme activity measured in Caco-2 cell extracts in one study in which the inhibitors were directly compared under identical experimental conditions,a,其它,DPP-4,家族成员包括,DPP-8, DPP-9, DPP-2, FAP,IC,50,= concentration at which there is 50% inhibition of measured activity,in vitro,Roberta Baetta,Alberto Corsini.,Pharmacology of Dipeptidyl Peptidase-4 Inhibitors: Similarities and Differences. Drugs, 2019, 71(11): 1441-1467,不同DPP-4抑制剂的药效学特征,西格列汀,维格列汀,沙格列汀,利格列汀,阿,格列汀,半衰期,(h),814,(,平均,:12.4),23,2.5,120,21.4,达峰时间,(h),14,1.72.5,2,13,12,排泄途径,尿液,:87%,粪便,:13%,尿液,:85%,粪便,:15%,尿液,:75%,粪便,:22%,尿液,:5%,粪便,:85%,尿液,:76%,粪便,:13%,肾脏排泄,主要,中度,主要,极少,主要,西格列汀、维格列汀、沙格列汀，利格列汀说明书,Roberta Baetta,Alberto Corsini.,Pharmacology of Dipeptidyl Peptidase-4 Inhibitors: Similarities and Differences. Drugs, 2019, 71(11): 1441-1467,不同DPP-4抑制剂的药代动力学特征,GLP-1,受体激动剂有差异吗？,1,DPP-4,抑制剂有差异吗？,2,GLP-1,受体激动剂与,DPP-4,抑制剂有差异吗？,3,主要内容,GLP-1,受体激动剂与,DPP-4,抑制剂有差异吗？,GLP-1,受体激动剂与,DPP-4,抑制剂头对头研究,1860,DURATION-2,GLP-1,受体激动剂之间头对头研究,LEAD-6,DURATION-6,利拉鲁肽与西格列汀1860及延长期研究设计,利拉鲁肽,1.8 mg,(n=221),西格列汀,100 m,g (n=219),主要研究,:,26,周,利拉鲁肽,1.2 mg (n=225),二甲双胍,1500 mg/,天,西格列汀,100 m,g,(n=166),利拉鲁肽,1.8 mg,(n=176),延长期研究,1:,26,周,利拉鲁肽,1.2 mg,(n=155),BMI,体重指数,; HbA,1c,糖化血红蛋白,; OD,每日一次,; T2D, 2,型糖尿病,利拉鲁肽,0.6 mg OD,1,周,利拉鲁肽,1.2 mg OD,1,周,延长期研究,2:26,周,1.8 mg OD,利拉鲁肽,1.8 mg,(n=218),利拉鲁肽,1.2 mg,(n=201),Pratley,et al,.,Lancet,2019;375:144756; Pratley,et al,.,Int J Clin Pract,2019;,65:397407,成人,1880,岁伴有,T2D,HbA,1c,:,7.510.0%,BMI: 45 kg/m,2,二甲双胍用药,1500mg 3,个月以上,在欧洲,11,个国家以及加拿大和美国进行的随机、开放,标签、活性对照研究,总人数,=665,治疗52周后，患者HbA,1c,降幅,HbA,1c,(%),0.0,1.51,1.29,0.88,两者均,p,0.0001,0,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,西格列汀,100 mg,时间,(,周,),均值,(1.96 SE);,数据来自完全分析集,(FAS);,末次观察推进法,(LOCF),Pratley,et al,.,Lancet,2019;375:144756; Pratley,et al,.,Diabetes,2019;59(Suppl.1):LB-16;,Pratley et al. IJCP 2019; 65: 397-407,患者在,52,周转换为利拉鲁肽,西格列汀,西格列汀,利拉鲁肽,1.2 m,利拉鲁肽,1.8 mg,0,4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,0.0,9.0,8.0,7.5,7.0,6.5,6.0,HbA,1c,(%),8.5,时间,(,周,),西格列汀转为利拉鲁肽后，患者,HbA,1c,的变化,均值,(1.96 SE);,采用配对,t,检验评价延长期研究,2,治疗,52,周至,78,周的,HbA,1c,变化完全分析集,末次观察转结法,(LOCF),Pratley,et al. Diabetes Care,2019;DOI:10.2337/dc11-2113,HbA,1c,达到ADA和AACE控制目标的患者比例,Pratley,et al. Int J Clin Pract,2019;65:397407,AACE: HbA,1c,6.5%,Patients reaching target (%),0,10,20,30,40,50,60,70,NS,p,=0.0012,p,0.0001,24.3,40.4,16.8,ADA: HbA,1c,7.0%,Patients reaching target (%),50.3,p,0.0001,p,=0.0119,p,0.0001,63.3,27.1,0,10,20,30,40,50,60,70,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,西格列汀,100 mg,患者达标比例,(%),患者达标比例,(%),西格列汀转为利拉鲁肽后，患者HbA,1c,达标率,Estimates are from a logistic regression model with treatment as fixed effect and baseline HbA,1c,as covariate. Comparisons between Weeks 52 and 78 were performed,using McNemars test for matched pairs,. FAS, LOCF.*,p,=0.01, *,p,0.005, *,p,=0.0005,Pratley,et al. Diabetes Care,2019;DOI:10.2337/dc11-2113,HbA,1c,7.0%,HbA,1c,6.5%,52,周,29.5,52,周,29.5,52,周,21.8,52,周,12.7,78,周,49.2,78,周,50.0,78,周,28.7,78,周,24.5,西格列汀转换为,利拉鲁肽,1.2mg,*,*,*,治疗转换组患者达标率,(%),西格列汀转换为,利拉鲁肽,1.8mg,西格列汀转换为,利拉鲁肽,1.2mg,西格列汀转换为,利拉鲁肽,1.8mg,治疗52周后，患者体重自基线水平的变化,3.68,2.78,1.16,两者均,p,0.0001,0,Pratley,et al,.,Lancet,2019;375:144756;,Pratley,et al. Int J Clin Pract,2019;65:397407,均值,(1.96 SE);,数据来自,FAS LOCF.,体重的变化（,kg,）,利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,时间,(,周,),3.68,2.78,1.16,Both,p,0.0001,0,Pratley,et al,.,Lancet,2019;375:144756; Pratley,et al,.,Diabetes,2019;59(Suppl.1):LB-16;,Pratley et al. IJCP 2019; 65: 397-407 ; Pratley,et al,. ADA 2019 (poster 1119),利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,体重的变化（,kg,）,estimates are from a paired t-test of change in body weight from weeks 52 to 78 from the ext. 2 FAS, LOCF,西格列汀转为利拉鲁肽后，体重的变化,时间,(,周,),患者轻度低血糖发生率低,n,患者数量,; %,患者比例,.,数据来自,0-52,周安全分析集,Pratley,et al. Int J Clin Pract,2019;65:397407,n=18,(8.1%),n=18,(8.3%),n=14,(6.4%),轻度低血糖,事件,/,患者,-,年,利拉鲁肽,利拉鲁肽,西格列汀,胃肠道不良反应,恶心事件发生率,利拉鲁肽的恶心发生率起始时较高，但为,一过性,在2752周用药期间，恶心发生率相似,利拉鲁肽1.2mg、1.8mg和西格列汀100mg的恶心发生率分别为1.9、1.1和1.8%,Pratley,et al,.,Lancet,2019;375:144756; Pratley,et al,.,Diabetes,2019;59(Suppl.1):LB-16;,Pratley et al. IJCP 2019; 65: 397-407,数据来自安全分析集,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,西格列汀,100 mg,患者恶心发生率,(%),时间,(,周）,0,2,4,6,8,10,12,14,16,0,4,8,12,16,20,24,28,32,36,40,44,48,2,50,6,10,14,18,22,30,34,38,42,46,26,52,艾塞那肽,OW,与西格列汀,DURATION-2研究设计,T2D,患者，二甲双胍使用稳定,随机、双盲、双模拟研究,基线均值：,HbA,1c,8.51.1%,FPG 9.12.6 mmol/L,体重,88.020.1 kg,艾塞那肽,OW 2 mg (n=160),Bergenstal,et al,.,Lancet,2019;376:4319,吡格列酮,45 mg (n=165),西格列汀,100 mg (n=166),周,: 0,26,OW,一周一次,*,p,0.05,艾塞那肽,vs.,吡格列酮,;,p,0.0001,艾塞那肽,vs.,吡格列酮,;,p,0.05,艾塞那肽,vs.,西格列汀,;,p,0.0001,艾塞那肽,vs.,西格列汀,;,p,0.001,艾塞那肽,vs.,吡格列酮,Bergenstal,et al,.,Lancet,2019;376:4319,2.0,艾塞那肽,OW (n=160),西格列汀,(n=166),吡格列酮,(n=165),HbA,1c,变化,时间,(,周,),0,2,4,6,8,10,12,14,16,18,20,22,24,26,*, ,*,*,0,0.5,1,1.5,患者,HbA,1c,降幅,1. Nathan,et al,.,Diabetes Care,2009;32:193203; 2. Rodbard,et al,.,Endocr Pract,2009;15:54059,Bergenstal,et al. Lancet,2019;376:4319,AACE,美国临床内分泌医师协会,; ACE,美国内分泌学学会,; ADA,美国糖尿病协会,; EASD,欧洲糖尿病研究协会,AACE/ACE,2,ADA/EASD,1,70,60,50,40,30,20,10,0,Proportion of patients (%),p,0.0001,p,=0.0015,p,=0.0120,p,0.0001,7.0%,6.5%,HbA,1c,艾塞那肽,OW,西格列汀,吡格列酮,患者达标率,(%),HbA,1c,达到,ADA,和,AACE,控制目标的患者比例,*,p,0.05,艾塞那肽,vs.,吡格列酮,;,p,0.0001,艾塞那肽,vs.,吡格列酮,;,p,0.05,艾塞那肽,vs.,西格列汀,;,p,0.0001,艾塞那肽,vs.,西格列汀,;,p,0.001,艾塞那肽,vs.,吡格列酮,Bergenstal,et al,.,Lancet,2019;376:4319,患者体重自基线水平的变化,时间,(,周,),4,3,2,1,Change in body weight (kg),4,1,0,3,2,0,2,4,6,8,10,12,14,16,18,20,22,24,26,*,艾塞那肽,OW (n=160),吡格列酮,(n=165),西格列汀,(n=166),体重的变化,1.,Bergenstal,et al. Lancet,2019;376;4319;,2. Bydureon. EMA: Summary of Product Characteristics. 2019; Available from: medicines.org.uk/emc/medicine/24665/SPC/ (accessed 2 November 2019),安全性和耐受性良好,艾塞那肽,OW,轻度低血糖发生率低，与西格列汀相当,(13%),恶心主要为轻微症状,1,2,不良事件发生率,(%),艾塞那肽,西格列汀,吡格列酮,恶心,腹泻,呕吐,头痛,乏力,便秘,注射部位皮炎,URTI,窦炎,外周水肿,GLP-1受体激动剂与DPP-4抑制剂的临床特点,GLP-1,受体激动剂,临床疗效,DPP-4,抑制剂,+,增强,GLP-1,活性,1,+,+,增加胰岛素合成和分泌,1,+,+,增强,细胞功能,1-3,+,+,减少胰高糖素生成,1,+,+,降低,A,1c,2,3,+,+,降低,FPG,1-3,b,+,+,降低,PPG,1,+,+,胃肠道不良反应,1-3,+,+,减缓胃排空,1,a,-,+,减少热量摄入,1,-,+,体重降低,1-3,-,a,Nausea and vomiting generally transient and mild to moderate in intensity with GLP-1 RAs.,b,Significantly greater effect with liraglutide or exenatide QW vs sitagliptin, but similar for exenatide BID and sitagliptin.,1. DeFronzo RA, et al.,Curr Med Res Opin,. 2019;24:2943-2952.,2. Pratley R, et al.,Lancet,. 2019;375:1447-1465.,3. Russell-Jones D, et al.,Diabetes Care,. 2019;35:252-258.,GLP-1,受体激动剂与,DPP-4,抑制剂有差异吗？,GLP-1,受体激动剂与,DPP-4,抑制剂头对头研究,1860,DURATION-2,GLP-1,受体激动剂之间头对头研究,LEAD-6,DURATION-6,利拉鲁肽与艾塞那肽LEAD-6及延长期研究设计,1. Buse,et al,.,Lancet,2009;374:3947; 2. Buse,et al,.,Diabetes Care,2019;33:13003,成人,1880,岁患有,2,型糖尿病,HbA,1c,: 7.011.0%,BMI 45 kg/m,2,随机、开放标签、平行分组、国际多中心研究,利拉鲁肽,(n=233),0.6,mg OD,1,周,1.2 mg OD,1,周,1.8 mg OD,24,周,二甲双胍 和,/,或,磺脲类 继续使用试验前剂量,艾塞那肽,(n=231),5,g BID,4,周,10 g BID,22,周,筛查,26,周,1,延长期,14,周,2,利拉鲁肽,(n=187),1.8 mg OD,12,周,1.2 mg OD,1,周,0.6 mg OD,1,周,利拉鲁肽,(n=202),1.8 mg OD,14,周,利拉鲁肽,艾塞那肽,艾塞那肽组转换至利拉鲁肽治疗,(,第,26,周,),利拉鲁肽,利拉鲁肽,艾塞那肽,利拉鲁肽,0,HbA,1c,目标值,7.21%,6.95%,p,0.0001,治疗时间,(,周,),HbA,1c,的变化,(%),患者HbA,1c,降幅,均值,(2,标准误,),，其中所用,026,周数据仅包括参加,LEAD-6,扩展研究的患者数据,Buse,et al. Lancet,2009;,374(9683):3947,(LEAD-6); Buse,et al.,Diabetes Care,2019;33:1300-03,26-40,周,HbA,1c,水平变化,(%),艾塞那肽,利拉鲁肽,利拉鲁肽,利拉鲁肽,-0.32,-0.06,p,0.0001,所用,026,周数据仅包括参加,LEAD-6,扩展研究的患者数据,HbA,1c,7.0%,HbA,1c,6.5%,利拉鲁肽,利拉鲁肽,艾塞那肽,利拉鲁肽,艾塞那肽,利拉鲁肽,利拉鲁肽,利拉鲁肽,26,周,26,周,26,周,26,周,Subjects (%),40,周,40,周,40,周,40,周,患者达标率,(%),Buse,et al Diabetes Care,2019;33:130003 (LEAD-6 ext.),HbA,1c,达到,ADA,和,AACE,控制目标的患者比例,Buse,et al. Lancet,2009;374:3947 (LEAD-6); Buse,et al,.,Diabetes Care,2019;33:1300-1303 (LEAD-6 ext; change in body weight from baseline to week 40),体重变化（,kg,）,时间,(,周,),均值,(2,标准误,);,所用,026,周数据仅包括参加,LEAD-6,扩展研究的患者数据,艾塞那肽转换为利拉鲁肽,(26,周,),艾塞那肽,艾塞那肽,利拉鲁肽,利拉鲁肽,利拉鲁肽,利拉鲁肽,患者体重自基线水平的变化,胃肠道不良反应,恶心事件发生率,Buse,et al,.,Lancet,2009;374:39-47,时间（周）,Proportion of subjects experiencing nausea (%),0,2,4,6,8,10,12,14,16,18,20,22,24,26,10,8,6,4,2,0,12,14,18,20,16,艾塞那肽,10,g BID,利拉鲁肽,1.8 mg OD,p,0.0001,受试者发生恶心的比例,(%),利拉鲁肽较艾塞那肽恶心持续时间更短,图中数据是指暴露治疗的患者数量,(%) (,安全性人群,);,第,26,周全人群变化值的估计治疗间差异,利拉鲁肽与艾塞那肽OW DURATION-6研究设计,随机、开放标签、为期26周、国际多中心、非劣效性、头对头临床试验,主要终点: HbA,1c,从基线水平的变化,艾塞那肽,OW 2 mg (n=461),利拉鲁肽,1.8 mg (n=450),饮食和运动治疗失败后加用,:,二甲双胍,磺脲类,二甲双胍,+,磺脲类,或者,二甲双胍,+,吡格列酮,周,: 0,26,Buse,et al.,Diabetologia,2019;54(Suppl. 1):S38(Abstract 75),治疗26周后，HbA,1c,降幅,艾塞那肽,OW 2 mg,利拉鲁肽,1.8 mg,(n=461),(n=450),Buse,et al.,Diabetologia,2019;54(Suppl. 1):S38(Abstract 75),HbA,1c,的变化,HbA,1c,7.0%,的患者达标率,Buse,et al.,Diabetologia,2019;54(Suppl. 1):S38(Abstract 75),52.3,Patients (%),0,10,20,30,40,50,60,70,利拉鲁肽,1.8 mg,(n=450),2 mg,(n=461),60.2,艾塞那肽,OW,p,=0.008,患者达标率,(%),体重自基线水平的变化,Buse,et al.,Diabetologia,2019;54(Suppl. 1):S38(Abstract 75),3.58,2.68,Mean weight change (kg),3.6,2.7,1.8,0.8,0.0,(n=450),(n=461),艾塞那肽,OW 2mg,利拉鲁肽,1.8mg,平均体重的变化（,kg,）,安全性与耐受性良好,无重度低血糖事件报告,轻度低血糖发生率：艾塞那肽,OW,为,10.8%,利拉鲁肽为,8.9%,Buse,et al.,Diabetologia,2019;54(Suppl. 1):S38(Abstract 75);,DURATION-6 top-line study results available at: https:/investor.lilly/releasedetail2.cfm?ReleaseID=554248.,注射部位节结,恶心,腹泻,呕吐,不良反应,(%),艾塞那肽,OW (100mg),利拉鲁肽,(1.8mg),不同GLP-1受体激动剂之间的临床特点,临床疗效,利拉鲁肽 QD,艾塞那肽 BID,空腹血糖降低,1,+,+,餐后血糖降低,1,+,+,HbA,1c,降低 (%),1,+,+,体重降低,2,+,+,常见不良反应,1,恶心/呕吐,恶心/呕吐,1. Shyangdan DS, et al. Cochrane Database Syst Rev. 2019, 10:1-232.,2. Vilsbell T, et al. BMJ. 2019, 344:d7771.,总结,基于肠促胰素治疗的药物包括GLP-1受体激动剂和DPP-4抑制剂,在分子结构、药效学及药代动力学等方面，不同的GLP-1受体激动剂及DPP-4抑制剂之间各有差异,与DPP-4抑制剂相比，在临床疗效上， GLP-1受体激动剂降低血糖和体重的能力更强；在安全性方面，GLP-1受体激动剂的低血糖风险低，恶心时有发生，但呈一过性,谢谢！,