基于肠促胰素治疗的药物概览修改后

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,Click to edit Master title style,Click to edit Master text styles,Second level,Third level,Fourth level,Fifth level,*,基于肠促胰素治疗的药物概览,利拉鲁肽，用于治疗,2,型糖尿病的人,GLP-1,类似物,每日注射一次,LIRA-2012-41,肠促胰素在正常胰岛素应答反应中至关重要,Nauck et al. Diabetologia 1986;29:4652,健康志愿者,(n=8),口服葡萄糖负荷,静脉输注葡萄糖,血浆葡萄糖,(mmol/L),10,5,60,120,180,10,时间,(,分,),5,0,15,血浆葡萄糖,尽管血浆葡萄糖浓度相似，口服葡萄糖后的胰岛素应答反应要强于静脉输注葡萄糖,胰岛素应答反应,胰岛素,(mU/L),80,60,40,20,10,5,60,120,180,0,时间,(,分,),肠促胰素,效应,2,型糖尿病患者肠促胰素效应减弱,0,20,40,60,80,胰岛素,(mU/L),0,30,60,90,120,150,180,时间,(min),*,*,*,*,*,*,*,0,20,40,60,80,0,30,60,90,120,150,180,时间,(min),*,*,*,2,型糖尿病患者,n=14,正常人,n=8,静脉注射葡萄糖,口服葡萄糖,*,与口服后的相应值相比,p.05,Nauck MA, et al.,Diabetologia,. 1986;29:46-52.,胰岛素,(mU/L),肠促胰素,胃肠道 L 细胞产生的,胰高血糖素样肽1,（GLP-1）和由 K细胞生成的,葡萄糖依赖性促胰岛素多肽,（GIP）,都具有葡萄糖浓度依赖性刺激胰岛素分泌的作用，但 GLP-1作用明显强于GIP,GLP-1还能发挥延迟胃排空、增加饱食感，从而减轻体重的作用，而GIP均不具备,目前所有的药物研发均针对,GLP-1,进行的,GLP-1,在人体中的作用,促进饱感,降低食欲,细胞,:,增强葡萄糖依赖的胰岛素分泌,肝脏,:,胰高糖素水平下降,减少肝糖输出,细胞,:,减少餐后胰高糖素分泌,胃,:,帮助调节胃排空,Adapted from Flint A, et al.,J Clin Invest,. 1998;101:515-520; Adapted from Larsson H, et al.,Acta Physiol Scand,. 1997;160:413-422;,Adapted from Nauck MA, et al.,Diabetologia,. 1996;39:1546-1553; Adapted from Drucker DJ.,Diabetes.,1998;47:159-169.,进食促进,GLP-1,分泌,降低,细胞负荷,增加,细胞反应,*,*,*,*,*,*,*,2,型糖尿病患者餐后,GLP-1,水平下降,20,15,10,5,0,0,60,120,180,240,时间,(min),进餐,GLP-1 (pmol/L),正常糖耐量,n=33,糖耐量受损,n=15,Mean SE; N=54; * T2DM,和,NGT,组的差别,p.05,。,Toft-Nielsen M, et al.,J Clin Endocrinol Metab.,2001;86:3717-3723.,2,型糖尿病,n=54,GLP-1,被,DPP-4,降解及灭活,GLP-1,相关药物的两种治疗机制,Drucker.,Expert Opin Invest Drugs,2003;12:87100; Ahrn.,Curr Diab Rep,2003;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,G,LP-1 (9-36),已在中国上市的基于肠促胰素治疗代表性药物,GLP-1,受体,激动剂,DPP-IV,抑制剂,如：西格列汀,维格列汀,沙格列汀,基于肠促胰素的治疗,人,GLP-1,类似物,利拉鲁肽,（每日一次注射）,基于,Exendin-4,的治疗,艾塞那肽,（每日两次注射）,GLP-1受体激动剂与DPP-4抑制剂的比较,目前上市的肠促胰素产品中仅有的头对头,GLP-1,和,DPP-4i,比较的试验：,LIRA-DPP-4i,随机、开放研究,在欧洲、加拿大、美国等,11,个国家进行,总人数,=665,1880,岁成年,T2D,患者,HbA,1c,:,7.510.0%,BMI: 45 kg/m,2,使用二甲双胍,1500mg,3,个月以上,利拉鲁肽,1.8 mg sc +MET,0.6mg OD 1,周,1.2mg OD 1,周,西格列汀,100 m,g OD + MET,主体研究,26,周,26,周,利拉鲁肽,1.2 mg sc +MET,0.6mg OD 1,周,26,周,延长期研究,0.6 mg OD 1,周,1.2 mg OD 1,周,Pratley,et al,.,Lancet,2010;375:144756,1.2 mg OD,1.8 mg OD,与西格列汀相比，利拉鲁肽更持久显著降低,HbA,1c,HbA,1c,(%),0.0,both,p,0.0001,Pratley et al. Lancet 2010,375:1447-56; Pratley et al. Int J Clin Pract 2011;65(4):,397-407,7.7%,7.2%,7.0%,both,p,0.0001,7.6%,7.2%,7.0%,利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,时间,(,周,),不同基线,HbA,1c,水平，利拉鲁肽较西格列汀更有效降低,HbA,1c,Analysis includes data from the Lira vs. DPP-4i study; *,p,0.05 vs. sitagliptin;,p,0.01 vs. sitagliptin,Davies et,al,. ADA 2011:Abstract 2314-PO,7.5,7.58,88.5,8.59,糖尿病的严重程度,基线,HbA,1c,(%),Change in HbA,1c,(%),Liraglutide 1.8 mg,Liraglutide 1.2 mg,Sitagliptin 100 mg,利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,利拉鲁肽改善,细胞功能较西格列汀明显,p,0.0001,p,0.0001,NS,平均值,;,数据来自,FAS, LOCF,于,52,周治疗后,Pratley et al.,Int J Clin Pract,2011;65:397,407,；,52,周数据,利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,深色柱体,=,基线值,浅色柱体,=,从基线值变化,24.2%,26.0%,2.8%,利拉鲁肽降低体重显著优于西格列汀,both,p,0.0001,-1.20 kg,-2.80 kg,-3.70 kg,西格列汀,100 mg,利拉鲁肽,1.8 mg,利拉鲁肽,1.2 mg,Both,p,0.0001,-0.96 kg,-2.86 kg,-3.38 kg,Pratley et al.,Int J Clin Pract,2011;65:397,407,；,利拉鲁肽低血糖发生风险与西格列汀相当,p,=NS,Prately R, et al . Int J Clin Pract, April 2011, 65, 4, 397407;,Pratley,et al. Lancet,2010,375:1447-56,轻度低血糖发生率,（事件,/,患者,/,年）,利拉鲁肽,1.2mg,利拉鲁肽,1.8mg,西格列汀,100mg,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,西格列汀,100 mg,患者,(%),时间,(,周,),0,2,4,6,8,10,12,14,16,0,4,8,12,16,20,24,28,32,36,40,44,48,52,2,50,6,10,14,18,22,30,34,38,42,46,26,利拉鲁肽引起的恶心为一过性,利拉鲁肽恶心的发生在初始阶段较高，但是短暂。,Pratley et al.,Int J Clin Pract,2011;65:397,407,；,52,周后利拉鲁肽治疗满意度高于西格列汀,(DTSQs),Mean2SE; data are from the PRO analysis set. Estimated treatment differences are from an ANCOVA model with treatment and country as fixed effects and baseline value as a covariate,Prately R, et al . Int J Clin Pract, April 2011, 65, 4, 397407,利拉鲁肽,1.2mg,西格列汀,100mg,利拉鲁肽,1.8mg,3.3,4.3,3.0,P,=NS,总体治疗满意度评分变化,（,DTSQs,）,LIRA-DPP-4i,延长期研究,1880,岁成年,T2D,患者,HbA,1c,:,7.510.0%,BMI: 45 kg/m,2,使用二甲双胍,1500mg,3,个月以上,随机、开放研究,在欧洲、加拿大、美国等,11,个国家进行,总人数,=665,利拉鲁肽,1.8 mg sc +MET,0.6mg OD 1,周,1.2mg OD 1,周,西格列汀,100 m,g OD + MET,主体研究,26,周,26,周（,52-78,周）,利拉鲁肽,1.2 mg sc +MET,0.6mg OD 1,周,26,周,延长期研究,0.6 mg OD 1,周,1.2 mg OD 1,周,Pratley,et al,.,Lancet,2010;375:144756,1.2 mg OD,1.8 mg OD,西格列汀转为利拉鲁肽治疗后,HbA,1c,进一步降低,52,周时转为使用利拉鲁肽的患者,西格列汀,西格列汀,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,0.0,0,4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,时间（周）,HbA,1c,(%):,基线,52,周,8.4,7.2,8.4,7.6,p,=0.006,p,=0.0001,Pratley,et al. Diabetes Care,2012;DOI:10.2337/dc11-2113,西格列汀转为利拉鲁肽治疗后体重显著下降,52,周时转为使用利拉鲁肽的患者,西格列汀,西格列汀,利拉鲁肽,1.2 mg,利拉鲁肽,1.8 mg,94.3 kg,93.0 kg,基线体重,0,4,8,12,16,20,24,28,32,36,40,44,48,52,56,60,64,68,72,76,80,时间（周）,体重变化（,Kg,）,西格列汀,利拉鲁肽,1.8mg,平均体重变化,(kg),体重,(kg):,基线,52,周,94.3,92.8,93.0,91.6,P,0.0001,p,0.0001,西格列汀,利拉鲁肽,1.2mg,西格列汀,利拉鲁肽,1.8mg,Pratley,et al. Diabetes Care,2012;DOI:10.2337/dc11-2113,转为利拉鲁肽治疗后引起的恶心为一过性,Ext. 2 FAS, LOCF,转换到利拉鲁肽,（,52,周,),西格列汀转换为利拉鲁肽,1.2 mg,西格列汀转换为利拉鲁肽,1.8 mg,Pratley,et al. Diabetes Care,2012;DOI:10.2337/dc11-2113,利拉鲁肽,1.8 mg,利拉鲁肽,1.2 mg,西格列汀,100 mg,40%,32%,11%,和西格列汀相比，利拉鲁肽治疗复合终点达标率高,*,p,0.0001 vs. sitagliptin,Zinman,et al. Diabetes Obes Metab,2011;14:7782,HbA,1c,7.0% +,无体重增加,+,无低血糖,*,*,复合终点,：,胃肠道副反应多为一过性,利拉鲁肽和西格列汀疗效和安全性对比总结,降糖效果更强,体重减轻,低血糖发生风险低,利拉鲁肽,中等降糖效果,体重变化不大,耐受性好,低血糖发生风险低,西格列汀,患者总体满意度更高,患者总体满意度高,谢谢！,