捷诺维-突破2型糖尿病治疗的新希望课件.ppt

1、捷诺维（西格列汀）捷诺维（西格列汀）突破突破2型糖尿病治疗的新希望型糖尿病治疗的新希望概概 述述n2型糖尿病治疗现状及挑战n以肠促胰岛激素为基础的治疗n捷诺维（西格列汀）的临床数据 临床疗效 安全性Adapted from Buse JB et al.In Williams Textbook of Endocrinology.10th ed.Philadelphia,Saunders,2003:14271483;Buchanan TA Clin Ther 2003;25(suppl B):B32B46;Powers AC.In:Harrisons Principles of Internal

2、Medicine.16th ed.New York:McGraw-Hill,2005:21522180;Rhodes CJ Science 2005;307:380384.2 2型糖尿病的病理生理包括三方面主要缺陷型糖尿病的病理生理包括三方面主要缺陷高血糖高血糖肝脏肝脏 胰胰岛岛素不足素不足糖输出过多糖输出过多胰岛素抵抗胰岛素抵抗(葡萄糖摄取减少葡萄糖摄取减少)胰腺胰腺肌肉和脂肪肌肉和脂肪过多胰高糖素胰岛胰岛胰岛素减少胰岛素减少胰岛素减少细胞细胞产生过多胰高糖素细胞细胞产生胰岛素减少不同降糖药的主要作用部位不同降糖药的主要作用部位Buse JB et al.In:Williams Textbo

3、ok of Endocrinology.10th ed.Philadelphia:WB Saunders;2003:14271483;DeFronzo RA.Ann Intern Med.1999;131:281303;Inzucchi SE.JAMA 2002;287:360-372;Porte D et al.Clin Invest Med.1995;18:247254.DPP-4=二肽基肽酶 4;TZDs=噻唑烷二酮类.胰腺血糖水平血糖水平肌肉和脂肪肝脏双胍类TZDs双胍类磺脲类格列奈类TZDs-糖苷酶 抑制剂胃肠道DPP-4 抑制剂抑制剂DPP-4抑制剂抑制剂双胍类胰岛素抵抗胰岛素抵抗

4、胰高糖素胰高糖素抑制不足抑制不足 细胞细胞功能失调功能失调胃肠道吸收胃肠道吸收葡萄糖葡萄糖慢性慢性细胞细胞功能衰竭功能衰竭胰岛素胰岛素分泌不足分泌不足细胞细胞功能异常功能异常2 2型糖尿病现有治疗选择型糖尿病现有治疗选择DeFronzo RA.Br J Diabetes Vasc Dis,2003;3(Suppl 1):S24-40未解决未解决未解决未解决二甲双胍二甲双胍格列酮类格列酮类磺脲类磺脲类格列奈类格列奈类-糖苷酶糖苷酶抑制剂抑制剂DPP-4抑制剂：抑制剂：2型糖尿病治疗新选择型糖尿病治疗新选择DPP 4抑制剂抑制剂DeFronzo RA.Br J Diabetes Vasc Dis,

5、2003;3(Suppl 1):S24-40胰岛素抵抗胰岛素抵抗胰高糖素胰高糖素抑制不足抑制不足 细胞细胞功能失调功能失调胃肠道吸收胃肠道吸收葡萄糖葡萄糖慢性慢性细胞细胞功能衰竭功能衰竭胰岛素胰岛素分泌不足分泌不足细胞细胞功能异常功能异常二甲双胍二甲双胍格列酮类格列酮类磺脲类磺脲类格列奈类格列奈类-糖苷酶糖苷酶抑制剂抑制剂成人成人2型糖尿病患者型糖尿病患者HbA1c 达标的比例不足达标的比例不足50%NHANES=美国人群的一项全国健康营养检查调查.Saydah SH et al.JAMA.2004;291:335342.HbA1c 水平7%血压 130/80 mmHg 总胆固醇 200 mg

6、/dl三项均达标心血管危险因素44.329.033.95.237.035.848.27.30102030405060成人（%）NHANES III(19881994)(n=1204)NHANES 19992000(n=370)美国人群美国人群中国中国2型糖尿病患者型糖尿病患者 HbA1c 达标率达标率中国糖尿病健康管理调查 2004华北、华南、华东、华西和东北5 个地区49 家市级中心医院参与分析的患者 2248 例中国糖尿病健康管理调查 2006中国18个城市60家医院登记治疗超过12个月的糖尿病患者参与分析的患者 2779 例DiabCare Study 2006,Data on file

7、潘长玉等中华内分泌代谢杂志20:420-424,2004达标率（%）25.9%29.5%44.6%010%20%30%40%50%6.5%7.5%达标率（%）25%35%010%20%30%40%50%6.5%7.5%40%平均平均HbA1c：7.6%平均平均HbA1c：7.7%副作用的增加和依从性的降低是治疗的副作用的增加和依从性的降低是治疗的两大潜在障碍两大潜在障碍美国社区单中心.N=128 2型糖尿病患者Grant RW et al.Diabetes Care.2003;26:14081412.大部分与不依从相关的常见因素United States study;Medi-Cal clai

8、ms data January 1996 through September 1998.Compliance was defined as total days of drug supply(measured by number of doses prescribed)during the follow-up period;compliance rate was calculated by dividing the number of compliance days by the number of days in the follow-up period.Dailey G et al.Cli

9、n Ther.2001;23:13111320.二甲双胍二甲双胍(n=2,996)磺脲类磺脲类(n=21,987)二甲双胍磺脲类二甲双胍磺脲类联合治疗联合治疗(n=1,354)多药治疗降低患者依从性58%23%8%11%58%23%8%11%不良反应不良反应 花费花费非特异非特异 记住药物记住药物 剂量困难剂量困难概概 述述n2型糖尿病治疗现状及挑战n以肠促胰岛激素为基础的治疗n捷诺维（西格列汀）的临床数据 临床疗效 安全性Time,minControl Subjects(n=8)Time,minIR Insulin,mU/L80604020018060120 0Oral glucose lo

10、adIntravenous(IV)glucose infusion正常的肠促胰岛激素效应正常的肠促胰岛激素效应IR=immunoreactiveAdapted with permission from Nauck M et al.Diabetologia 1986;29:4652.Copyright 1986 Springer-Verlag.Vilsbll T,Holst JJ.Diabetologia 2004;47:357366.正常个体的肠促胰岛激素效应正常个体的肠促胰岛激素效应肠促胰岛激素肠促胰岛激素GLP-1和和GIP的作用的作用由远端消化道由远端消化道L细胞分泌细胞分泌(回肠和结回

11、肠和结肠肠)以葡萄糖依赖的模式促进胰岛素释以葡萄糖依赖的模式促进胰岛素释放放以葡萄糖依赖的模式抑制胰高糖素以葡萄糖依赖的模式抑制胰高糖素分泌，从而抑制肝糖输出分泌，从而抑制肝糖输出在动物模型及离体人类胰岛中增强在动物模型及离体人类胰岛中增强beta细胞增殖和存活细胞增殖和存活由近端消化道由近端消化道K细胞分泌（十二指细胞分泌（十二指肠）肠）以葡萄糖依赖的模式促进胰岛素释以葡萄糖依赖的模式促进胰岛素释放放在胰岛细胞系中增强在胰岛细胞系中增强beta细胞增殖细胞增殖和存活和存活GLP-1GIPGLP-1=胰高糖素样肽胰高糖素样肽 1;GIP=葡萄糖依赖性促胰岛素多肽葡萄糖依赖性促胰岛素多肽Adap

12、ted from Drucker DJ Diabetes Care 2003;26:29292940;Ahrn B Curr Diab Rep 2003;3:365372;Drucker DJ Gastroenterology 2002;122:531544;Farilla L et al Endocrinology 2003;144:51495158;Trmper A et al Mol Endocrinol 2001;15:15591570;Trmper A et al J Endocrinol 2002;174:233246.Time,minIR Insulin,mU/L80604020

13、0180601200Control Subjects(n=8)Patients With Type 2 Diabetes (n=14)Time,minIR Insulin,mU/L80604020018060120 0Oral glucose loadIntravenous(IV)glucose infusion正常的肠促胰岛激素效应正常的肠促胰岛激素效应减弱的肠促胰岛激素效应减弱的肠促胰岛激素效应IR=immunoreactiveAdapted with permission from Nauck M et al.Diabetologia 1986;29:4652.Copyright 198

14、6 Springer-Verlag.Vilsbll T,Holst JJ.Diabetologia 2004;47:357366.2 2型糖尿病患者的肠促胰岛激素效应减弱型糖尿病患者的肠促胰岛激素效应减弱2型糖尿病患者的型糖尿病患者的GLP-1和和GIP水平及活性水平及活性*经过性别及经过性别及BMI校正校正Adapted from Toft-Nielsen M-B et al J Clin Endocrinol Metab 2001;86:37173723;Nauck MA et al J Clin Invest 1993;91:301307.2型糖尿病患者肠促胰岛激素水平肠促胰岛激素活性

15、GLP-1(p2500倍 vs.DPP-8或9 可逆性竞争性NONH2NNCF3FFFNThornberryNA，et al.Curr Topics in Med Chem,2007;7:557-568DPP酶酶IC50(nM)DPP-418DPP-848,000DPP-9 100,000DPP-2,DPP-7,100,000l 口服西格列汀100mg和600mg的峰浓度是747nM和7000nMl 可有效抑制DPP-4l 显著低于抑制DPP-8和DPP-9所需浓度 高度选择性保证了捷诺维无动物毒性反应高度选择性保证了捷诺维无动物毒性反应非选择性抑制剂非选择性抑制剂 (DPP-8/9&DPP-

16、4)选择性选择性DPP-8/9抑制剂抑制剂 西格列汀西格列汀T-细胞细胞 增殖研究增殖研究1减少细胞增殖+2周大鼠毒性研究周大鼠毒性研究2脱发+血小板减少+贫血症+脾肿大+死亡+急性狗毒性研究急性狗毒性研究2血痢+1.Leiting B et al.Presented at 64th Scientific Sessions of the American Diabetes Association;2004.Abstract 6-OR.2.Lankas GK et al.Diabetes.2005;54:29882994.捷诺维捷诺维(西格列汀西格列汀)给药给药24小时后小时后有效抑制血浆有效抑

17、制血浆DPP-4活性达活性达80%给药后时间（小时）给药后时间（小时）80%50%对对DPP-4的抑制的抑制与基线相比对血浆与基线相比对血浆DPP-4的抑制程度的抑制程度(%)012481216202410040506080100907030201061014182226OGTT西格列汀 25 mg(n=56)西格列汀 200 mg(n=56)安慰剂(n=56)Herman GA,et al.J Clin Endocrinol Metab 2006;91:4612-4619GLP-1 在体外保护人胰岛细胞形态在体外保护人胰岛细胞形态第第1天天GLP-1治疗的细胞治疗的细胞对照对照第第3天天第第

18、5天天Adapted from Farilla L et al Endocrinology 2003;144:51495158.加入加入GLP-1培养的胰培养的胰岛细胞能够更长时间的岛细胞能够更长时间的保持其完整性保持其完整性.捷诺维捷诺维(西格列汀西格列汀)使使 细胞与细胞与 细胞比例正常细胞比例正常Mu,J et al.Diabetes,2006;55:1695-1704HFD/STZ mice treated with Des-F-sitagliptin for 11-weeks.Green insulin positive-cellRed glucagon positive-cell捷

19、诺维捷诺维(西格列汀西格列汀)改善胰岛功能改善胰岛功能(离体胰腺离体胰腺)Mu,J et al.Diabetes,2006;55:1695-1704捷诺维捷诺维(西格列汀西格列汀)有效改善胰腺有效改善胰腺 细胞功能细胞功能动物实验研究结果西格列汀动物实验研究结果西格列汀 增加增加-细胞数量，使细胞数量，使 细胞与细胞与 细胞比例正常细胞比例正常 增加胰岛素阳性增加胰岛素阳性 细胞数量细胞数量 增加胰腺内胰岛素含量增加胰腺内胰岛素含量 改善葡萄糖刺激后胰岛素分泌（离体胰腺）改善葡萄糖刺激后胰岛素分泌（离体胰腺）Mu,J et al.Diabetes,2006;55:1695-1704概概 述述n

20、2型糖尿病治疗现状及挑战n以肠促胰岛激素为基础的治疗n捷诺维（西格列汀）的临床数据 临床疗效 安全性捷诺维捷诺维(西格列汀西格列汀)III期临床研究评估主要临床终点期临床研究评估主要临床终点 单药治疗 与其他降糖药物联合u HOMA-胰岛素原/胰岛素比值 临床不良事件 体重改变 低血糖发生率 实验室不良事件 HbA1c(所有研究主要所有研究主要终终点点)FPG PPG HbA1c（7%或或6.5%)达达标标率率29捷诺维捷诺维(西格列汀西格列汀)III期临床研究汇总期临床研究汇总l单药治疗 18周安慰剂对照研究 24周安慰剂对照研究 12周日本人群安慰剂对照研究 18周亚洲人群单药研究（PN

21、040）l与其它降糖药物联用 与二甲双胍联用 24周与二甲双胍联合治疗研究 52周与二甲双胍联合治疗活性对照研究 24周与吡格列酮联合治疗研究l起始联合治疗 二甲双胍和西格列汀对肠促胰岛激素的作用 二甲双胍/西格列汀起始联合治疗l三联治疗 52周与磺脲或磺脲加二甲双胍联合治疗30Adapted from Raz et al.Diabetologia.2006;49:25642571Adapted from American Diabetes Association.From Diabetes Care,Vol.29,2006;26322637Adapted from Nonaka et al.

22、Poster presented at the 66th Scientific Sessions,American Diabetes Association,Washington,DC,June 913,2006.7.47.68.08.4Placebo(n=244)Sitagliptin 100 mg(n=229)24-week StudyTime(weeks)06121824-0.79%(p0.001)Japanese 12-week Study-1.05%(p0.001)Placebo(n=75)Sitagliptin 100 mg(n=75)Time(weeks)048127.68.08

23、.47.26.8Dchange vs.placebo*18-week StudyPlacebo(n=74)Sitagliptin 100 mg(n=168)Time(weeks)0612187.27.68.08.4-0.6%(p0.001)=捷诺维一天一次单药治疗持续显著降低捷诺维一天一次单药治疗持续显著降低HbA1CMonotherapyHbA1c(%SE)HbA1c(%SE)HbA1c(%SE)7.28.27.47.06.66.47.88.231捷诺维在亚洲人群捷诺维在亚洲人群(中国、印度、韩国中国、印度、韩国)降糖效果显著降糖效果显著HbA1c 从基线的改变(FAS Population

24、)9.29.08.88.68.48.28.07.8061218Time,weeksMean SE Change in HbA1c,%FAS=full analysis set;qd=once a day;SE=standard error.Mohan V et al.Diabetes Res Clin Pract.2009;83:106116.Sitagliptin 100 mg qd(n=339)Placebo(n=169)Monotherapy-1.03%32Screening Single-blindplacebo Double-blind treatment period:Sulfon

25、ylurea or sitagliptin 100 mg/dayMetformin monotherapyWeek 2:Eligible if HbA1c6.5%to 10%If on an OHA,D/CContinue/startmetforminDay 1RandomizationWeek 52D/C=discontinued;OHA=oral antihyperglycemic agent;T2DM=type 2 diabetes.*Specifically,glipizide 5 mg/day increased to 20 mg/day(dose not uptitrated if

26、 finger stick 110 mg/dL or hypoglycemia).Adapted from Nauck et al.Diabetes Obes Metab.2007;9:194205.52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究研究设计研究设计 2型糖尿病患者随机，双盲，平行，活性对照，非劣效性研究(N=1172)治疗西格列汀100 mg/day，二甲双胍1500 mg/day磺脲*最大剂量20 mg/day，二甲双胍 1500 mg/dayMetformin(stable dose 1500 mg/day)Add-on 233HbA1c(%SE)LSM chan

27、ge from baseline(for both groups):0.67%达到首要假设：达到首要假设：疗效非劣效于磺脲疗效非劣效于磺脲 LSM=least-squares mean.aSpecifically,glipizide;bsitagliptin(100 mg/day)with metformin(1500 mg/day);per-protocol population.Adapted from Nauck et al.Diabetes Obes Metab.2007;9:194205.52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究与二甲双胍联用时，与二甲双胍联用时，捷

28、诺维一天一次降糖效果不低于磺脲类捷诺维一天一次降糖效果不低于磺脲类(52周周)Weeks5.86.06.26.46.66.87.07.27.47.67.80612182430384652SulfonylureaSulfonylureaa a+metforminmetformin(n=411)(n=411)SitagliptinSitagliptinb b+metforminmetformin(n=382)(n=382)Add-on 234aSpecifically,glipizide;bsitagliptin(100 mg/day)with metformin(1500 mg/day);per

29、-protocol population.Adapted from Nauck et al.Diabetes Obes Metab.2007;9:194205.Sulfonylurea+metforminBaseline HbA1C CategoryChange from baseline in HbA1c(%)n=117n=117112179167828233217%7 to 8%8 to 9%9%-0.14-0.59-1.11-1.76-0.26-0.53-1.13-1.68-2.0-1.8-1.6-1.4-1.2-1.0-0.8-0.6-0.4-0.20.0Sitagliptinb+me

30、tformin52周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究基值越高，基值越高，HbA1c 降幅越大降幅越大Add-on 235Patients at HbA1c goal(%)HbA1c7%at week 52*Specifically,glipizide.Per-protocol population.Mean baseline HbA1c levels:sitagliptin 100 mg,7.48%;glipizide,7.52%.Adapted from Nauck et al.Diabetes Obes Metab.2007;9:194205.n=240n=24252周

31、西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究捷诺维联合二甲双胍组更多的患者达到血糖控制目标Add-on 23652周西格列汀联合二甲双胍vs格列吡嗪联合二甲双胍对照研究捷诺维组体重下降且低血糖发生率显著低于对照组捷诺维组体重下降且低血糖发生率显著低于对照组Sulfonylurea+metformin(n=584)Sitagliptin 100 mg/day+metformin(n=588)HypoglycemiabP0.00132%5%01020304050Week 52低血糖发生率(%)LSM change in body weight over timeb体重(kg SE)LSM=

32、least-squares mean.aSpecifically,glipizide;ball-patients-treated population.LSM between-group difference at week 52(95%CI):D in body weight=2.5 kg 3.1,2.0(P0.001);LSM change from baseline at week 52:glipizide:+1.1 kg;sitagliptin:1.5 kg(P0.001).Adapted from Nauck et al.Diabetes Obes Metab.2007;9:1942

33、05.Sulfonylurea+metformin(n=416)Sitagliptin 100 mg/day+metformin(n=389)Add-on 237bid=twice daily;qd=daily;R=randomization.Williams-Herman D et al.Curr Med Res Opin.2009;25(3):569583.Week 2Day 1Single-Blind PlaceboRun-In PeriodEligible if HbA1c 7.5%11%Week 24PlaceboSitagliptin 100 mg qdMetformin 500

34、mg bidMetformin 1000 mg bidSitagliptin 50 mg/metformin 500 mg bidSitagliptin 50 mg/metformin 1000 mg bidR研究设计研究设计Week 54Metformin 1,000 mg bidSitagliptin 100 mg qdMetformin 500 mg bidMetformin 1000 mg bidSitagliptin 50 mg/metformin 500 mg bidSitagliptin 50 mg/metformin 1000 mg bid24-Week(Phase A)30-

35、Week Continuation PhaseInitial Combination38西格列汀与二甲双胍起始联合治疗HbA1c 24周时自基线的改变周时自基线的改变aLeast squares mean change from baseline with adjustment for placebo.bWithin-group mean change from baseline.bid=twice daily;qd=daily.Goldstein B et al.Diabetes Care.2007;30:19791987.Please note:Dr.Goldstein is curren

36、tly a Merck employee but was not at the time this study was conducted or when the publication was written.1172.9bMetformin 1000 mg bid Sitagliptin 100 mg qd Sitagliptin 50 mg+metformin 500 mg bid Metformin 500 mg bid Sitagliptin 50 mg+metformin 1000 mg bidHbA1c Change From Baseline,%3.53.02.52.01.51

37、.00.50.00.5 178177183178175n=0.8a1.0a1.3a1.6a2.1a24-Week Placebo-Adjusted ResultsMean HbA1c=8.8%Open-LabelMean Change From Baseline Mean HbA1c=11.2%All-Patients-Treated PopulationHbA1c change from baseline at week 24 for placebo group(n=165)=0.17%Initial Combination39西格列汀与二甲双胍起始联合治疗西格列汀与二甲双胍起始联合治疗54

38、周时改善周时改善细胞功能指标细胞功能指标Sita 50 mg+met 1000 mg bidSita 50 mg+met 500 mg bidMet 1000 mg bidMet 500 mg bidSita 100 mg qdn=88n=102n=126n=133n=143n=61n=75n=114n=100n=130Proinsulin-to-Insulin Ration=88n=102n=126n=133n=143HOMA-Changebid=twice daily;HOMA=homeostasis model assessment;LSM=least-squares mean;met=

39、metformin;qd=daily;Sita=sitagliptin.Williams-Herman D et al.Curr Med Res Opin.2009;25(3):569583.Continuation All-Patients-Treated PopulationInitial Combination40西格列汀与二甲双胍起始联合治疗西格列汀与二甲双胍起始联合治疗54周内持续降低周内持续降低HbA1cSita 50 mg+met 1000 mg bid(n=153)Met 1000 mg bid(n=134)Sita 100 mg qd(n=106)Sita 50 mg+met

40、 500 mg bid(n=147)Met 500 mg bid(n=117)APT=all-patients-treated;bid=twice daily;LSM=least-squares mean;Met=metformin;qd=daily;Sita=sitagliptin.Reproduced with permission from Williams-Herman D et al.Curr Med Res Opin.2009;25(3):569583.24-Week(Phase A)30-Week Continuation Phase Mean SE Change in HbA1

41、c,%6.06.57.07.58.08.59.00612182430384654WeeksContinuation All-Patients-Treated PopulationInitial Combination410 6 12 18 24 30 38 46 54 62 70 78 91 10466.577.588.59*Completers populationSita=sitagliptin;Met=metformin西格列汀与二甲双胍起始联合治疗持续持续2年降低年降低HbA1cTime(weeks)24-Week PhaseContinuation Phase Extension P

42、hase HbA1c(LS mean change%)Sita 100 mg q.d.(n=22)Met 500 mg b.i.d.(n=26)Met 1000 mg b.i.d.(n=53)Sita 50 mg b.i.d.+Met 500 mg b.i.d.(n=64)Sita 50 mg b.i.d.+Met 1000 mg b.i.d.(n=77)2008 EASDInitial Combination42捷诺维联合格列吡嗪或格列吡嗪捷诺维联合格列吡嗪或格列吡嗪/二甲双胍二甲双胍*=Pioglitazone 30 mg QDScreeningPeriodPatients with tr

43、eated or untreated T2DM,ages 18 to 78 years PlaceboSitagliptin 100 mg QDSingle-blindPlacebo Week 24Continue/startregimen of glimepiride metforminSingle-blind eligible ifA1C 7.5%to 10.5%24-Week PhaseRStratum 1:Glimepiride(4 mg/d)Stratum 2:Glimepiride+Metformin(1500 mg/d)Continuation PhaseWeek 54Patie

44、nts not requiring rescue medication in 24-week phase could continue through 54 weeks.Active Treatment*Week 0入选病例：441例随机化病例，平均56岁，53%男性 糖尿病平均病程为8.8年，平均基线 A1C=8.34%Add-on to SUTriple Combination43各组各组A1c自基线的改变自基线的改变Placebo-controlled Add-on to Glimepiride(+/-metformin)Study*Difference in LS Mean chang

45、e from baseline -0.9%*-0.6%*Add-on to glimepiride+metforminWeeks06121824A1C(%)7.27.68.08.48.8Sitagliptin+Glim+MFPlacebo+Glim+MFSitagliptin+GlimPlacebo+Glim Adapted from Hermansen et al.Diabetes Obes Metab 2007;9:733-745Mean duration of T2DM:8.8 yearsTriple Combination44 Change from Baseline-5051015B

46、aseline(pmol/L/pmol/L):Sitagliptin=0.517;Placebo =0.491p=n.s.三联治疗中捷诺维改善三联治疗中捷诺维改善 细胞功能指标细胞功能指标Sitagliptin Placebo Proinsulin/Insulin RatioBaseline:Sitagliptin=50.7;Placebo =47.4*p=0.021HOMA-*Adapted from Hermansen et al.Diabetes Obes Metab 2007;9:733-745-0.08-0.06-0.04-0.020.000.02Triple Combination

47、45联合治疗中捷诺维改善联合治疗中捷诺维改善 细胞功能指标细胞功能指标Baseline:proinsulin-to-insulin ratio(sitagliptin+pioglitazone=0.41 pmol/L/pmol/L;placebo+pioglitazone=0.40 pmol/L/pmol/L);HOMA-(sitagliptin=36.2%,placebo=39.6%).Add-onHOMA-=homeostasis model assessment-;LSM=least-squares mean.All-patients-treated population.Adapted

48、 from Charbonnel et al.Diabetes Care.2006;29:26382643;Adapted from Rosenstock et al.Clin Ther.2006;28:15561568.24周与二甲双胍联用研究周与二甲双胍联用研究24周与吡格列酮联用研究周与吡格列酮联用研究Baseline:Proinsulin-to-insulin ratio(sitagliptin=0.357 pmol/L/pmol/L,placebo=0.369 pmol/L/pmol/L),HOMA-(sitagliptin=46.4%,placebo=45.1%).单药治疗中捷诺维

49、显著改善单药治疗中捷诺维显著改善 细胞功能指标细胞功能指标All-patients-treated population.HOMA-=homeostasis model assessment-.Adapted from Raz et al.Diabetologia.2006;49:25642571.Adapted from Aschner et al.Diabetes Care.2006;29:26322637.At Week 18(18-Week,Monotherapy,Placebo-Controlled Study)At Week 24(24-Week,Monotherapy,Place

50、bo-Controlled Study)Monotherapy捷诺维捷诺维(西格列汀西格列汀)治疗组与非西格列汀治疗组间治疗组与非西格列汀治疗组间总体不良事件相似总体不良事件相似SitagliptinN=3145n(%)NonexposedN=2724 n(%)Between-Groups Difference,%(95%CI)a1次或多次临床不良事件2150(63.0)1711(62.8)0.1(2.3,2.6)药物相关临床不良事件b440(12.9)483(17.7)4.8(6.7,3.0)严重临床不良事件230(6.7)184(6.8)0.0(1.3,1.2)药物相关临床不良事件b8(0