《糖尿病新药》PPT课件.ppt

中国糖尿病患病发病率已达9.7%,N Engl J Med 2010; 362:1090 - 1101,20,30, 18.5,18.5-24.9,25.0- 9.9, 30,BMI (kg/m2),患病率(%),糖尿病合计,糖尿病前期,4.5,11.2,7.6,13.1,12.8,19.9,18.5,26.7,Yang et al: N Engl J Med 2010;362:1090-1101,0,10,中国糖尿病和糖尿病前期患者的患病率与体重指数的关系,降低体重将对2型糖尿病患者产生重要作用,*Intentional weight loss in overweight individuals Williamson DF, et al. Diabetes Care. 2000;23:1499-1504.,-20%,-30%,整体死亡率,肿瘤死亡率,糖尿病相关死亡率,-50%,空腹血糖,体重降低10%,2型糖尿病患者细胞功能进行性下降,Lebovitz. Diabetes Reviews 1999;7:13953 (data are from the UKPDS population: UKPDS 16. Diabetes 1995;44:124958),HOMA: homeostasis model assessment,6.2% 正常值上限,HbA1c 中位数(%),常规治疗*,时间 (年),罗格列酮,随着病程延长血糖控制逐渐恶化,UKPDS 34. Lancet 1998:352:85465; Kahn et al (ADOPT). NEJM 2006;355(23):242743,*最初采用饮食控制,如果空腹血糖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,随治疗强化低血糖风险逐渐增加,Patients reporting 1 hypoglycaemic event/year (%),0.8%,1.7%,7.9%,21.2%,32.6%,p0.0001,Wright et al. J Diabetes Complicat 2006;20:395401,MET, metformin; SU, sulphonylurea,基础胰岛素,基础+餐前胰岛素,饮食控制,二甲双胍,磺脲类,低血糖事件发生1次/年的患者（%）,2型糖尿病的现状与挑战小结,随着生活方式的改变，中国糖尿病发病率不断增加，总发病率已达9.7% 目前的治疗策略主要针对胰岛素抵抗、胰岛素分泌、抑制葡萄糖吸收 多数药物（胰岛素、磺脲类、格列酮类）治疗后导致体重进一步增加（UKPDS, ACCORD研究），治疗过程中低血糖的发生限制药物的应用和达标,八重奏,neurotransmitter dysfunction,Nauck MA, et al. J Clin Endocrinol Metab. 1986; 63: 492498.,口服糖耐量试验与静脉糖耐量试验,血糖 (mg/dL),时间 (分钟),C-肽 (nmol/L),时间 (分钟),希望的曙光“肠促胰素效应”的发现,N=6,50 g 葡萄糖,80年代通过检测C肽来反映胰岛素应答，确证了肠促胰素效应的存在,2型糖尿病中肠促胰素作用减弱,Strictly Confidential. Proprietary information of Novartis. For internal use ONLY. March 2010. GAL10.497. Novartis.,11,肠促胰素,Y,A,E,G,T,F,I,S,D,Y,S,I,A,M,D,K,I,H,Q,Q,D,F,V,N,W,L,L,A,Q,K,G,K,K,N,D,W,K,H,N,Q,T,I,GIP: 葡萄糖依赖性促胰岛素分泌多肽,H,A,E,G,T,F,T,S,D,V,S,S,Y,L,E,G,Q,A,A,K,E,F,I,A,W,L,V,K,G,R,G,GLP-1: 胰高糖素样肽-1,Amino acids shown in orange are homologous with the structure of glucagon.,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,体内GLP-1 被 DPP-4 降解及灭活,GLP-1作用小结,肠促胰素 增强葡萄糖依赖的胰岛素分泌 抑制胰高糖素分泌，减少肝糖输出 延缓胃排空 促进饱感，降低食欲 2型糖尿病患者肠促胰素效应降低，其中GLP-1水平降低 但作用正常 内源性GLP-1在体内被DPP-4酶降解,糖尿病治疗策略,依赖葡萄糖,GLP-1(艾塞那肽）,-葡糖苷酶抑制剂(阿卡波糖、米格列醇、伏格列波糖),DPP-4抑制剂(西格列汀),不依赖葡萄糖,外源性胰岛素,格列奈类,磺脲类,罗格列酮,二甲双胍,吡格列酮,抑制葡萄糖吸收,胰岛素抵抗,胰岛素分泌,治疗方案,目前治疗方案对体重的影响,体重,HbA1c 7%,1. Malone M. Ann Pharmacother. 2005;39:2046-2055. 2. Glucotrol PI. New York, NY: Pfizer Inc; 2010. 3. Actos PI. Deerfield, IL: Takeda Pharmaceuticals America Inc; 2009. 4. Avandia PI. Research Triangle Park, NC: GlaxoSmithKline; 2007. 5. Nathan DM, et al. Diabetes Care. 2008;31:173-175. 6. Holman RR. N Engl J Med. 2007;357:1716-1730. 7. Glucophage PI. Princeton, NJ: Bristol-Myers Squibb Company; 2009. 8. Januvia PI. Whitehorse Station, NJ: Merck and Company Inc; 2010. 9. Drucker DJ. J Clin Invest. 2007;117:24-32. 10. Golay A. Int J Obes (Lond). 2008;32:61-72.,P,P,P,P,P,P,*Approximately half of the studies in drug-nave T2D patients have shown significant weight loss with MET compared with baseline or comparator drugs; however, pooled analyses have suggested no significant effect vs placebo10 See accompanying Prescribing Information and safety information included in this presentation,*,GLP-1 9,胰岛素5,6,DPP-4 8,噻唑烷二酮3,4,磺脲1,2,二甲双胍7,艾塞那肽 (Exendin-4) 人工合成的希拉巨蜥唾液中的一种蛋白质 与人GLP-1约有53的同源性 体外试验中与人 细胞表面GLP-1受体结合,对GLP-1受体的激活作用至少和GLP-1相近 能抵抗DPP-4降解灭活作用,艾塞那肽: 一种GLP1受体激动剂,Adapted from Nielsen LL, et al. Regulatory Peptides. 2004;117:77-88. Reprinted from Regulatory Peptides, 117, Nielsen LL, et al, Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycaemic control of type 2 diabetes, 77-88, 2004, with permission from Elsevier for English use only.,DPP-4灭活位点,H G E G T F T S D L S K Q M E E E A V R L F I E W L K N G G P S S G A P P P S NH2,H A E G T F T S D V S S Y L E G Q A A K E F I A W L V K G R NH2,艾塞那肽,人GLP-1,艾塞那肽不被DPP-4降解,GLP-1 葡萄糖依赖性的促进胰岛素分泌,N=10; Mean SEM; *p.05. Nauck MA, et al. Diabetologia. 1993;36:741-744.,2型糖尿病患者Beta细胞功能进行性降低 艾塞那肽可以促进Beta细胞增殖与新生,生理盐水,Exendin-4,艾塞那肽每日一次治疗2周后增加糖尿病小鼠胰岛体积,Mean (SE); N=25. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. Copyright 2005, The Endocrine Society.,2型糖尿病患者中短时间输注艾塞那肽可恢复1相胰岛素分泌,艾塞那肽 vs 安慰剂,p=.0002,p=.0002,时间(min),胰岛素分泌 (pmolkg-1min-1),艾塞那肽使胰岛素和C肽的AUC0-10 min和AUC10-120 min增加约180%310%,艾塞那肽作用机制总结,调节摄食中枢*,延缓胃排空,抑制胰高糖素分泌 减少肝糖输出,血糖依赖性的控制胰岛素分泌 恢复第一时相胰岛素,When BYETTA is used with an SFU, there is an increased risk of hypoglycaemia 1. Kolterman OG, et al. J Clin Endocrinol Metab. 2003;88:3082-3089. 2. Nielsen LL, et al. Regul Pept. 2004; 117:77-88. 3. Fehse F, et al. J Clin Endocrinol Metab. 2005;90:5991-5997. 4. Blonde L, et al. Diabetes Obes Metab. 2006;8:436-447. See accompanying Prescribing Information and safety information included in this presentation,艾塞那肽临床研究历程,9年以上 临床使用经验,1300万 患者处方经验,发表了超过723篇论著，其中125篇经同行审阅,百泌达现已被包括ADA/EASD列入2型糖尿病治疗药物，并被列入AACE/ACE，NICE以及中国2010糖尿病防治指南,See accompanying Prescribing Information and safety information included in this presentation,和胰岛素治疗 相比,单个口服药 失效,多个口服药 失效,百泌达 + 二甲双胍 + 磺脲类 (N=733),百泌达 + 二甲双胍 (N=336),百泌达 + 磺脲类 (N=377),百泌达 + 二甲双胍 + 磺脲类 vs 甘精胰岛素 + 二甲双胍 + 磺脲类 (N=551),百泌达 + 二甲双胍 + 磺脲类 vs 双相门冬胰岛素 + 二甲双胍 + 磺脲类 (N=501),百泌达 + 二甲双胍 或 磺脲类 vs 甘精胰岛素 + 二甲双胍 或 磺脲类 (N=138),百泌达 + 二甲双胍 vs 甘精胰岛素 + 二甲双胍 (N=69),百泌达 + 二甲双胍 vs 西格列汀 + 二甲双胍 (N=61),艾塞那肽的临床研究覆盖了2型糖尿病的不同治疗阶段,ITT 30-week data; N = 1446; Mean (SE); *p0.005; Weight was a secondary endpoint. Data on file, Amylin Pharmaceuticals, Inc.,HbA1c变化(%),体重变化 (kg),AMIGO研究（合并结果）： 艾塞那肽降低 HbA1c 及体重,Mean (SE); N = 138; Evaluable meal tolerance cohort. p.0001 for change in PPG from baseline to week 30, exenatide vs placebo group. Data on file, Amylin Pharmaceuticals, Inc.,多个3期临床试验的合并结果,基线,血糖 (mmol/L),30周,进餐,安慰剂,进餐,艾塞那肽,-30,0,30,60,90,120,150,180,5,8,11,13,16,15,14,12,10,9,7,6,5,-30,0,30,60,90,120,150,180,16,6,7,8,9,10,11,12,13,14,15,AMIGO研究（合并结果）： 30周时艾塞那肽降低餐后血糖,AMIGO研究（合并结果）：恶心随时间延长而减少，而体重持续减轻,ITT 30-week data; N=1446. Data on file, Amylin Pharmaceuticals, Inc.,时间 (周),恶心发生率 (%),12-16,24-28,100,0-4,16-20,20-24,28,4-8,8-12,0,15,30,45,60,75,0,-2,-4,体重减轻(Kg),第4周时剂量从5 g 增加至10 g 的患者,开放性延长期研究: 艾塞那肽治疗82周仍保持降低HbA1c的作用,时间 (周),HbA1c平均变化(%),0,10,20,30,40,50,60,70,80,90,-2.0,-1.5,-1.0,-0.5,0.0,0.5,安慰剂对照试验,均数 (SE); N = 393; 完成研究的受试者; 82周的数据; 3个组的基线HbA1c平均为8.3%。 Data on file, Amylin Pharmaceuticals, Inc.,开放性延长期研究 (所有受试者用10 g BID),安慰剂 ,10 g 艾塞那肽 BID,10 g 艾塞那肽 BID,5 g BID ,10 g 艾塞那肽BID,开放性延长期研究: 艾塞那肽治疗82周进行性降低体重,与基线相比体重的平均变化 (kg SEM),时间 (周),安慰剂对照试验,0,10,20,30,40,50,60,70,80,90,-5,-4,-3,-2,-1,0,开放性延长期研究 (所有受试者用10 g BID),均数(SE); N = 393; 完成研究的患者; 82周的数据; 体重变化是次要终点。基线体重: 安慰剂组 = 98 kg, 5 g = 98 kg, 10 g = 100 kg. Data on file, Amylin Pharmaceuticals, Inc.,安慰剂 ,10 g 艾塞那肽 BID,10 g 艾塞那肽 BID,10 g BID ,5 g BID ,10 g 艾塞那肽 BID,艾塞那肽治疗3年降低HbA1c及体重,N=217; Mean Adapted from Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286.,156,基线 99.3 1.2 kg,0,26,52,78,104,130,-6,-4,-2,0,156 周 -5.3 kg (95% CI: -6.0 to -4.5 kg; p0.0001),治疗 (周),Weight Change from Baseline (kg),HbA,0,26,52,78,104,130,156,4,5,6,7,8,9,10,156 周 -1.0% (95% CI: -1.1 to -0.8%; p0.0001),治疗 (周),1c,(%),-5,-4,-3,-2,-1,0,1,2,3,4,5,-65,-55,-45,-35,-25,-15,-5,5,15,25,35,10%,68%,6%,16%,和基线相比 HbA1c (%) 变化,和基线相比体重变化 (lbs),N=217 Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.,See accompanying Prescribing Information and safety information included in this presentation,68% 的患者HbA1c和体重均下降,基线 HbA1c 9% 的患者艾塞那肽治疗后HbA1c降低更显著,2.5-year completers; n=241 at weeks 30 and 130; mean SE Klonoff DC, et al. Curr Med Res Opin 2008;24:275-286,开放标签延伸期研究,基线 HbA1c (%) 基线 HbA1c 9% (n=59) 9.7 基线 HbA1c 9% (n=182) 7.8,安慰剂对照开放延伸试验(合并): 3.5年时脂代谢改变,TG = triglycerides; SBP = systolic BP; DBP = diastolic BP Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.,安慰剂对照研究/开放标签延伸期研究 (合并),平均变化 (%),N=151; *p.001 *p.05,TG,LDL,TC,*,*,*,+24%,-5%,-6%,-12%,-20,-15,-10,-5,0,5,10,15,20,25,30,SBP,DBP,- 4%,*,-2%,HDL,*,*,安慰剂对照开放延伸试验(合并): 基线时ALT升高组3.5年时ALT显著降低,Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286,Week 156 Between Group Difference:-1.7kg(95%Cl:-3.2 to -0.2kg;p=0.0266),艾塞那肽显著降低亚洲人群的HbA1c与体重,HbA1c改变（%）,体重改变（Kg）,Diabetes Research And Clinical Practice 83(2009):69-79,艾塞那肽用于亚洲人群66%的患者HbA1c与体重都降低,Diabetes Research And Clinical Practice 83(2009):69-79,AMIGO研究及开放延伸试验小结,Klonoff DC, et al. Curr Med Res Opin. 2008;24:275-286.,在用二甲双胍和/或磺脲类药物治疗的2型糖尿病患者中加用艾塞那肽治疗3 年： 显著持续改善血糖控制 进行性降低体重 改善血脂、血压及ALT 恶心随时间延长而减少，而体重持续减轻 在亚洲患者中艾塞那肽同样能显著降低HbA1c与体重,艾塞那肽/甘精胰岛素对比试验: 终点时 2组HbA1c 降低相似,Intent-to-treat sample, N=138; LS mean SEM. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.,艾塞那肽/甘精胰岛素对比试验: 终点时 HbA1c 达标患者百分比,Intent-to-treat sample, N=138 Barnett AH, et al. Clin Ther. 2007;29:2333-2348.,40,38,14,22,Intent-to-treat sample, N=138; LS mean SEM; *p.001, exenatide versus insulin glargine; *p=.016, exenatide versus insulin glargine. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.,艾塞那肽/甘精胰岛素对比试验: 餐后2小时血糖波动,-0.5,0,0.5,1.0,1.5,2.0,2.5,3.0,早晨,中午,晚上,*,*,*,餐后血糖波动 (mmol/L),艾塞那肽 (n=136),甘精胰岛素 (n=127),艾塞那肽/甘精胰岛素对比试验: 治疗期间的体重变化,甘精胰岛素,艾塞那肽,时间 (周),0,2,4,6,8,12,16,18,20,22,24,28,32,体重变化 (kg),-,3,-,2,-,1,0,1,2,N=138; Intent-to-treat sample, LS mean SEM. Barnett AH, et al. Clin Ther. 2007;29:2333-2348.,n=70,n=68,艾塞那肽和甘精胰岛素相比：HbA1c及体重变化,Data on file, Amylin Pharmaceuticals, Inc. and Lilly USA, LLC.,-5,-4,-3,-2,-1,0,1,2,3,11%,3%,24%,63%,百泌达 (n=231),甘精胰岛素 (n=245),5%,10%,63%,23%,和基线相比体重变化 (磅),和基线相比 HbA1c (%) 变化,See accompanying Prescribing Information and safety information included in this presentation,艾塞那肽/甘精胰岛素对比试验: 低血糖发生率,艾塞那肽 (n=136),甘精胰岛素 (n=127),低血糖发生率 (%),0,5,10,15,20,25,30,35,40,所有患者,用二甲双胍 治疗的患者,用磺脲类药物 治疗的患者,*,Intent-to-treat sample, N=138; LS mean (SEM); *p=0.010 Barnett AH, et al. Clin Ther. 2007;29:2333-2348.,25.2,14.7,2.6,17.4,34.5,30.0,HbA1c 7%,治疗达标患者 (%),*,32%,24%,0,5,10,15,20,25,30,35,艾塞那肽 预混胰岛素,HbA1c变化 (%),-1.04%,-0.89%,-2.0,-1.5,-1.0,-0.5,0.0,ITT sample; left panel; ITT sample, mean change SE shown; NSD=nonsignificant differences; Right panel: between-group difference *p=.038 Nauck MA, et al. Diabetologia. 2007;50:259-267.,-0.15% (95% CI, -0.32 to 0.01, p=.067),艾塞那肽/ 双相门冬胰岛素对比试验: 终点时 HbA1c 变化,血糖 (mmol/L),*,*,*,早餐前,早餐后,午餐前,午餐后,晚餐前,晚餐后,03:00,7,8,9,10,11,12,13,艾塞那肽, 0周,艾塞那肽, 52周,7,8,9,10,11,12,13,预混胰岛素, 0周,预混胰岛素, 52周,早餐前,早餐后,午餐前,午餐后,晚餐前,晚餐后,03:00,ITT sample, mean (SE) shown; significantly lower mean glucose level observed for exenatide *p.001, premixed insulin *p=.0370; p=.0040; p=.002. Nauck MA, et al. Diabetologia. 2007;50:259-267. Copyright 2007 Springer-Verlag. Reprinted with permission from Springer-Verlag.,艾塞那肽/ 双相门冬胰岛素对比试验: 7点自我血糖监测谱,时间 (周),体重变化 (kg),5.4 kg,*,*,0,2,4,8,12,16,28,40,52,-3,-2,-1,0,1,2,3,*,*,*,*,*,*,艾塞那肽 预混胰岛素,ITT sample, mean (SE) shown. p.001, exenatide versus premixed insulin at postbaseline time points. Nauck MA, et al. Diabetologia. 2007;50:259-267. Copyright 2007 Springer-Verlag. Reprinted with permission from Springer-Verlag.,+2.9 kg,-2.5 kg,艾塞那肽/ 双相门冬胰岛素对比试验: 体重变化,比较研究总结： 艾塞那肽和胰岛素血糖改善作用相似,与甘精胰岛素头对头对照试验：艾塞那肽能达到相似的血糖控制 艾塞那肽减轻体重 甘精胰岛素增加体重 艾塞那肽能提供更严格的餐后血糖控制，甘精胰岛素降低更多空腹血糖 与门冬胰岛素头对头对照试验：艾塞那肽能达到相似的血糖控制 艾塞那肽减轻体重 预混胰岛素增加体重 对于空腹血糖作用相似 艾塞那肽更好地控制餐后血糖，更多患者达到HbA1c 7.0%,2-hr PPG (mg/dL),阶段1 终点,阶段2 终点,After Period 1, patients were switched to the other therapy; Patients with T2D; Evaluable population: exenatide-sitagliptin, n = 29; sitagliptin-exenatide, n = 32; Mean SE Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.; Data on file, Amylin Pharmaceuticals, Inc.,基线,110,130,150,170,190,210,230,250,270,艾塞那肽降低餐后2小时血糖的程度较西格列汀更大,胰岛素分泌指数 1,艾塞那肽,西格列汀,Patients with T2D; Evaluable population, n = 61 for both treatment groups; Geometric LS mean SE Standard meals administered at t = 0 min 1. Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.; 2. Data on file, Amylin Pharmaceuticals, Inc.,基线时胰岛素分泌指数 几何平均数2: 0.4,0.55,P = 0.02,0.82,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0.55,0.82,艾塞那肽较西格列汀更大程度地改善胰岛素分泌指数,Patients with T2D; Evaluable population, n = 61 for all treatment groups; Mean SD; Acetaminophen was administered immediately before the standard meal Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.,时间 (分),标准餐,Baseline Exenatide Sitagliptin,-30,0,30,60,90,120,150,180,210,240,0.0,2.5,5.0,7.5,10.0,12.5,15.0,17.5,20.0,血浆乙酰氨基酚 (ug/ml),艾塞那肽延缓胃排空，西格列汀无此作用,和基线相比热量摄入变化(kcal)1,Patients with T2D; Evaluable ad lib cohort, n = 25 for both treatment groups; LS mean SE Standard meals administered at t = 0 min 1. Adapted from DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.; 2. Data on file, Amylin Pharmaceuticals, Inc.,基线平均热量摄入 2: 1071 kcal,艾塞那肽,西格列汀,P = 0.0227,- 134,+130,-200,-100,0,100,200,300,- 134,+130,-300,艾塞那肽降低平均热量摄入,艾塞那肽对西格列汀作用机制研究: 总结,DeFronzo RA, et al. Curr Med Res Opin. 2008;24(10)2943-2952.,艾塞那肽较西格列汀显著降低餐后2小时血糖 和西格列汀相比，艾塞那肽能引起 更大幅度的降低： 整个餐后时间段的血糖 餐后血糖波动 餐后胰高糖素水平 胰岛素分泌指数的改善 延缓胃排空 减少热量摄入 空腹血