浅析GLP受体激动剂与DPP抑制剂

1、会计学1浅析浅析GLP受体激动剂与受体激动剂与DPP抑制剂抑制剂主要内容 葡萄糖-细胞数量减少-细胞肥大胰岛素缺乏高胰高糖素血症+ 葡萄糖摄取 肝葡萄糖输出+-细胞功能失调-细胞功能失调Unger RH. Metabolism. 1974;23:581.DeFronzo RA. Ann Intern Med. 1999;131:281303. Buse JB et al. In: Williams Textbook of Endocrinology. 10th ed. 2003:14271483.胰腺葡萄糖肌肉和脂肪组织 肝脏二甲双胍噻唑烷二酮类二甲双胍磺脲类格列奈类噻唑烷二酮类糖苷酶抑制剂胃

2、肠道二甲双胍胰岛素胰岛素胰岛素6.2% 正常值上限HbA1c 中位数(%)常规治疗*时间 (年)罗格列酮格列苯脲二甲双胍胰岛素UKPDS678924681007.58.56.5推荐治疗达标目标 15 mmol/L则加用磺脲类,胰岛素和/或二甲双胍 美国糖尿病学会临床实践指南. UKPDS, n=1704体重（kg）低血糖发生率*（%） 罗格列酮 二甲双胍 格列本脲p15 mmol/L则加用磺脲类,胰岛素和/或二甲双胍 胰岛素格列本脲二甲双胍12年中体重增加最高达8kg1. Drucker et al. Proc Natl Acad Sci U.S.A 1987;84:34348; 2. Dru

3、cker & Nauck. Lancet 2006;368:16961705胰腺胃心脏大脑肝Adapted from Baggio & Drucker. Gastroenterol 2007;132;213157肠心血管保护功能饱腹感学习能力和保护神经系统 (动物实验)胃排空葡萄糖生成葡萄糖依赖性胰岛素分泌胰岛素合成葡萄糖依赖性胰高糖素分泌GLP-1 L细胞分泌 GLP-1被 DPP-4 分解安慰剂 (PBO)人GLP-1Nauck et al. Diabetologia 1993;36:7414300 200 100 0 胰岛素 (pmol/L)时间 (分)-30 06012

4、0180240*输注胰高糖素 (pmol/L)-30 06012018024020100时间 (分)*输注血糖 (mmol/L)151050-30 060120180240 * * * * * *时间 (分)输注270180900血糖 (mg/dL)Mean (SE); n=10; *p0.05; type 2 diabetes patients (n=10)时间(分)胰岛素反应（胰岛素， mU/L）nmol/L0.60.50.40.30.20.10806040200180601200对照组(n=8)2型糖尿病患者(n=14)时间(分)胰岛素反应（胰岛素， mU/L）nmol / L0.60.

5、50.40.30.20.1080604020018060120 0口服葡萄糖静脉注射葡萄糖肠促胰素效应2型糖尿病患者肠促胰素效应降低Adapted with permission from Nauck M et al. Diabetologia. 1986;29:4652. Copyright 1986 Springer-Verlag.生理水平 GLP-11(15 mM 高糖钳夹)药理水平 GLP-12(15 mM 高糖钳夹)00306090120时间 (分)100020003000400050006000胰岛素 (pmol/L)GLP-1 输注时间(0.5 pmol/kg/min)01000

6、2000300040000306090120时间 (分)胰岛素 (pmol/L)50006000GLP-1 输注时间(1.0 pmol/kg/min)血浆 GLP-1:46 pM健康人血浆 GLP-1:41 pM2型糖尿病患者血浆 GLP-1:126 pM2型糖尿病患者Vilsbll et al. Diabetologia 2002;45:11119.9 Hjberg et al. Diabetologia 200810由于2型糖尿病患者GLP-1分泌量减少，需要体外补充药理浓度的GLP-1主要内容2型糖尿病患者(n=6)正常人(n=6)静脉推注GLP-1 (15 nmol/L)Intact

7、GLP-1 (pmol/L)时间 (分钟)551535450500100025被DPP-4降解失活7379LysHis AlaThrThr SerPheGlu GlyAspValSerSerTyrLeuGluGlyAlaAlaGlnLysPheGluIleAla Trp LeuGlyValGly Arg酶切高清除率(49 L/min)T=1.52.1 分钟 (IV bolus 2.525.0 nmol/L)Adapted from Bjerre Knudsen. J Med Chem 2004;47:412834; Vilsbll. J Clin Endocrinol Metab 2003;8

8、8:2204类似物类似物酰化位点酰化位点取代物取代物药性药性(pM)半衰期半衰期(小时小时), 猪猪GLP-1(7-37)55 191.2K18R26,34-GLP-1K18-Glu-C1635.2 6.2-K23R26,34-GLP-1K23-Glu-C1630.1 3.320 2R34-GLP-1liraglutideK26-Glu-C1661.0 7.114 2K27R26,34-GLP-1K27-Glu-C1636.3 0.3-R26-GLP-1K34-Glu-C16121 2613K36R26,34 -GLP-1K36-Glu-C1636.4 2.112 1K38R26,34-GLP

9、-1K38-Glu-C1653.0 2.83Bjerre Knudsen et al. J Med Chem 2000;43:16649Madsen et al. J Med Chem 2007;50(24):612632C11 脂肪酸C16脂肪酸 (利拉鲁肽)C12脂肪酸C18脂肪酸012243648607210100100010000时间 (小时)血药浓度(pM)Knudsen et al. J Med Chem 2000;43:16649; Degn et al. Diabetes 2004;53:118794天然人GLP-1被DPP-4降解利拉鲁肽C-16棕榈酰脂肪酸与人GLP-1氨基

10、酸同源性高达97%；通过酰化与白蛋白结合；七聚物构型皮下吸收缓慢不易被DPP-4降解半衰期达13小时血液中的单体与白蛋白结合 避免被肾脏快速清除 肽链 脂肪酸药物制剂和皮下组织中的七聚体Steensgaard et al. Diabetes 2008; 57 (suppl. 1):A164 (abstract 552-P)其机制为利拉鲁肽形成了七聚体的结构Agers et al. Diabetologia 2002;45:195202单变量模式：给药3次后达到稳态血浆利拉鲁肽(pmol/L)时间 (天)21268104600040002000800091173151330个基准点制成的曲线模型

11、安慰剂利拉鲁肽 (6 g/kg 每日一次，皮下注射) 血糖(mmol/L)注射 (08:00)注射后时间 (h)血糖(mg/dL)00481216202468101214100180220260140Degn et al. Diabetes 2004;53:118794Malm-Erjefalt M. Drug metabolism and disposition 2010; 38(1944-53).肾脏或肝脏受损患者体内利拉鲁肽药代动力学1. Jacobsen L et al. Diabetes 2007;56(Suppl. 1):A1372. Flint A et al. Diabetes

12、 2007;56(Suppl. 1):A145 70005000400030006000200000102030405060701000注射后时间 (小时)1000080006000400020000010203040506070注射后时间 (小时)终末期利拉鲁肽浓度 (pmol/L)正常轻度中度重度肾组肾脏受损 1正常轻度中度重度 肝脏组肝脏受损 2肝肾功能受损的患者利拉鲁肽药物暴露剂量未增加Early use of liraglutide饮食/运动开始一种口服药增加第二种口服药增加第三种口服药或开始胰岛素Liraglutide monotherapy vs. SULEAD-3Liraglu

13、tide + met vs. SU + met LEAD-2Liraglutide + SU vs. TZD + SU LEAD-1Liraglutide + met + TZDvs. met + TZDLEAD-4Liraglutide + met + SU vs. glargine + met + SULEAD-5Liraglutide + met and/or SU vs. exenatide + met and/or SULEAD-6Liraglutide + metvs. sitagliptin + metLira vs. DPP-4iMarre et al. Diabetic Me

14、dicine 2009;26;26878 (LEAD-1); Nauck et al. Diabetes Care 2009;32;8490 (LEAD-2); Garber et al. Lancet 2009;373:47381 (LEAD-3); Zinman et al. Diabetes Care 2009;32:122430 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:204655 (LEAD-5); Buse et al. Lancet 2009; 374:3947 (LEAD-6); Pratley et al. La

15、ncet 2010:375;144756 (Lira vs. DPP-4i); 1796 study, Novo Nordisk, data on file.LEAD, Liraglutide Effect and Action in Diabetes; TZD, thiazolidinedione; met, metformin Liraglutide + metvs. SU + met1796 (China)LEAD-1 联合SULEAD-2 联合METLEAD-4联合MET+TZDLEAD-5联合MET + SULEAD-3单药治疗*HbA1c下降(%)Change in HbA1c f

16、or overall population (LEAD-4,-5,-6, Lira vs Sita); add-on to diet and exercise failure (LEAD-3); or add-on to previous OAD monotherapy (LEAD-2,-1). *p0.01, *p0.0001 vs. active comparator. Data from core trials LEAD-6联合MET SU*Lira vs. sita联合MET*Liraglutide 1.8 mgLiraglutide 1.2 mgGlimepirideRosiglit

17、azoneGlarginePlaceboExenatideSitagliptin8.3 8.28.68.58.48.58.58.48.48.38.48.48.48.38.28.18.48.4 8.58.38.48.3基线HbA1c (%)LEAD: Liraglutide Effect and Action in Diabetes. Marre et al. Diabet Med 2009;26;26878 (LEAD-1); Nauck et al. Diabetes Care 2009;32;8490 (LEAD-2); Garber et al. Lancet 2009;373:4738

18、1 (LEAD-3); Zinman et al. Diabetes Care 2009;32:122430 (LEAD-4); Russell-Jones et al. Diabetologia 2009;52:204655 (LEAD-5); Buse et al. Lancet 2009;374:3947 (LEAD-6); Pratley et al. Lancet 2010;375:144756 (lira vs. sita) * *Gough et al. Diabetes 2010;59(Suppl. 1):A208 (764-P)低血糖事件/患者年26 周 HbA1c (LOC

19、F)654321066.577.58磺脲类 (格列美脲) 利拉鲁肽 1.2 mg 利拉鲁肽 1.8 mg*p0.0001 和 *p0.05 vs.利拉鲁肽 1.8 mg; p0.0001 和p0.001 vs. 利拉鲁肽 1.2 mg BID, 每日两次; HOMA-B, -细胞功能评价稳态模型； OD, 每日一次; P/IR, 胰岛素原：胰岛素比值: -细胞压力测定Matthews et al. Diabetes 2010;59 (Suppl 1): A401 (1513-P)早期使用利拉鲁肽可以显著改善2型糖尿病的细胞功能治疗利拉鲁肽利拉鲁肽罗格列酮格列美脲艾塞那肽安慰剂LEAD-1 联合

20、SULEAD-2 联合METLEAD-4联合MET + TZD LEAD-5联合MET + SU LEAD-3单药治疗*体重的变化 (kg)LEAD-6联合MET SU *Lira vs. Sita联合MET*p0.01, *p0.0001 vs. active comparator; p0.01, p0.0001 vs. placebo. Active comparators vs. placebo not shown. Data from core trials Liraglutide 1.8 mgLiraglutide 1.2 mgGlimepirideRosiglitazoneGlar

21、ginePlaceboExenatideSitagliptinLEAD: Liraglutide Effect and Action in Diabetes. Marre et al. Diabet Med 2009;26;26878 (LEAD-1); Nauck et al. Diabetes Care 2009;32;8490 (LEAD-2); Garber et al. Lancet 2009;373:47381 (LEAD-3); Zinman et al. Diabetes Care 2009;32:122430 (LEAD-4); Russell-Jones et al. Di

22、abetologia 2009;52:204655 (LEAD-5); Buse et al. Lancet 2009;374:3947 (LEAD-6); Pratley et al. Lancet 2010;375:144756 (lira vs. sita) Marre et al. Diabetic Medicine 2009;26;26878 (LEAD-1); Nauck et al. Diabetes Care 2009;32;8490 (LEAD-2); Garber et al. Lancet 2009;373:47381 (LEAD-3); Zinman et al. Di

23、abetes Care 2009;32:122430 (LEAD-4); Buse et al. Lancet 2009;374 (9683):3947 (LEAD-6); Colagiuri et al. Diabetes 2008;57(Suppl. 1):A16 (LEAD-1-5) SBP 变化(mmHg)与SU合用 LEAD-1 与Met合用 LEAD-2 与Met+TZD合用 LEAD-4 与Met+SU合用 LEAD-5 单药治疗LEAD-31567432102.82.62.86.7利拉鲁肽 1.8 mg利拉鲁肽 1.2 mg5.64.02.32.13.6*与MetSU合用 LE

24、AD-6 2.52.00.70.40.50.91.1* vs. 对照药有显著差异格列美脲格列美脲艾塞那肽甘精胰岛素安慰剂罗格列酮051015202530354045达标比率 (%)利拉鲁肽 1.8 mg(n=1363)利拉鲁肽 1.2 mg(n=896)8%*, 格列美脲(n=490)6%*, 罗格列酮(n=231)15%*甘精胰岛素(n=232)艾塞那肽(n=231)8%*, 安慰剂(n=524)利拉鲁肽 1.8 mg(n=214)利拉鲁肽1.2 mg(n=210)14%*,西格列汀(n=210)LEAD 研究利拉鲁肽 vs. 西格列汀Liraglutide 1.8 mg is superi

25、or (*p0.01; * p0.0001); Liraglutide 1.2 mg is superior ( p0.0001)Percentages are from logistic regression model adjusted for trial, previous treatment and with baseline HbA1c and weightZinman et al, Diabetologia 2009;52(Suppl 1):S292; Pratley et al. Lancet 2010;375:1447-565039%32%*24%*46%35%*主要内容Dru

26、cker. Expert Opin Invest Drugs 2003;12:87100; Ahrn. Curr Diab Rep 2003;3:36572GLP-1释放 食物摄入活性的GLP-1(7-36)DPP-4抑制剂DPP-4GLP-1受体激动剂无活性的GLP-1 (9-36)Slide No 31人GLP-1类似物如：利拉鲁肽基于exendin-4治疗如：艾塞那肽GLP-1受体激动剂DPP-IV抑制剂如：西格列汀等基于肠促胰素的治疗利拉鲁肽利拉鲁肽艾塞那肽艾塞那肽用法QDBID同源性高高(97%)低低(53%)抗体是否影响降糖疗效无影响无影响高滴度影响降糖高滴度影响降糖恶心持续时间短

27、短长长HbA1C降幅大大较小较小Buse JB et al. Lancet 2009;374:39-47利拉鲁肽利拉鲁肽西格列汀西格列汀用法注射注射口服口服HbA1C降幅大大较小较小降低体重幅度大大中性中性恶心持续时间稍长稍长短短低血糖发生率低低低低Pratley R, et al. The International Journal of Clinical Practice 2011,6,4,397-407主要内容根据诺和力(利拉鲁肽)中文说明书利拉鲁肽注射液储存条件胰腺胃心脏大脑肝Adapted from Baggio & Drucker. Gastroenterol 2007;132;2