捷诺维-突破2型糖尿病治疗的新希望

捷诺维（西格列汀）

突破2型糖尿病治疗的新希望概述2型糖尿病治疗现状及挑战以肠促胰岛激素为基础的治疗捷诺维（西格列汀）的临床数据临床疗效安全性AdaptedfromBuseJBetal.InWilliamsTextbookofEndocrinology.10thed.Philadelphia,Saunders,2003:1427–1483;BuchananTAClin

Ther2003;25(supplB):B32–B46;PowersAC.In:Harrison’sPrinciplesofInternalMedicine.16thed.NewYork:McGraw-Hill,2005:2152–2180;

RhodesCJScience2005;307:380–384.2型糖尿病的病理生理包括三方面主要缺陷高血糖肝脏

胰岛素不足糖输出过多胰岛素抵抗

(葡萄糖摄取减少)胰腺肌肉和脂肪过多胰高糖素胰岛胰岛素减少胰岛素减少α细胞产生过多胰高糖素β细胞产生胰岛素减少不同降糖药的主要作用部位BuseJBetal.In:WilliamsTextbookofEndocrinology.10thed.Philadelphia:WBSaunders;2003:1427–1483;DeFronzoRA.AnnInternMed.1999;131:281–303;InzucchiSE.JAMA2002;287:360-372;PorteDetal.ClinInvestMed.1995;18:247–254.DPP-4=二肽基肽酶4;TZDs=噻唑烷二酮类.葡萄糖吸收肝脏葡萄糖过度合成胰岛素分泌受损胰岛素抵抗胰腺↓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TZDsα-糖苷酶

抑制剂胃肠道DPP-4抑制剂DPP-4抑制剂双胍类胰岛素抵抗胰高糖素抑制不足细胞功能失调胃肠道吸收葡萄糖慢性β细胞功能衰竭胰岛素分泌不足β细胞功能异常2型糖尿病现有治疗选择DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40未解决未解决二甲双胍格列酮类磺脲类格列奈类α-糖苷酶抑制剂DPP-4抑制剂：2型糖尿病治疗新选择DPP–4抑制剂DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40胰岛素抵抗胰高糖素抑制不足细胞功能失调胃肠道吸收葡萄糖慢性β细胞功能衰竭胰岛素分泌不足β细胞功能异常二甲双胍格列酮类磺脲类格列奈类α-糖苷酶抑制剂成人2型糖尿病患者HbA1c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.SaydahSHetal.JAMA.2004;291:335–342.HbA1c

水平

<7%血压<130/80mmHg

总胆固醇

<200mg/dl三项均达标心血管危险因素44.329.033.95.237.035.848.27.30102030405060成人（%）NHANESIII(1988–1994)(n=1204)NHANES1999–2000(n=370)美国人群中国2型糖尿病患者HbA1c

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DiabCareStudy2006,Dataonfile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%>7.5%达标率（%）25%35%010%20%30%40%50%<6.5%<7.0%>7.5%40%平均HbA1c：7.6%平均HbA1c：7.7%副作用的增加和依从性的降低是治疗的两大潜在障碍美国社区单中心.N=1282型糖尿病患者GrantRWetal.DiabetesCare.2003;26:1408–1412.大部分与不依从相关的常见因素UnitedStatesstudy;Medi-CalclaimsdataJanuary1996throughSeptember1998.Compliancewasdefinedastotaldaysofdrugsupply(measuredbynumberofdosesprescribed)duringthefollow-upperiod;complianceratewascalculatedbydividingthenumberofcompliancedaysbythenumberofdaysinthefollow-upperiod.DaileyGetal.Clin

Ther.2001;23:1311–1320.二甲双胍(n=2,996)磺脲类(n=21,987)二甲双胍＋磺脲类联合治疗(n=1,354)多药治疗降低患者依从性58%23%8%11%

58%23%8%11%不良反应花费非特异

记住药物剂量困难概述2型糖尿病治疗现状及挑战以肠促胰岛激素为基础的治疗捷诺维（西格列汀）的临床数据临床疗效安全性Time,minControlSubjects

(n=8)Time,minIRInsulin,mU/L806040200180601200OralglucoseloadIntravenous(IV)glucoseinfusion正常的肠促胰岛激素效应IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:46–52.Copyright©1986Springer-Verlag.VilsbøllT,HolstJJ.Diabetologia2004;47:357–366.正常个体的肠促胰岛激素效应肠促胰岛激素GLP-1和GIP的作用由远端消化道L细胞分泌(回肠和结肠)以葡萄糖依赖的模式促进胰岛素释放以葡萄糖依赖的模式抑制胰高糖素分泌，从而抑制肝糖输出在动物模型及离体人类胰岛中增强beta细胞增殖和存活由近端消化道K细胞分泌（十二指肠）以葡萄糖依赖的模式促进胰岛素释放在胰岛细胞系中增强beta细胞增殖和存活GLP-1GIPGLP-1=胰高糖素样肽1;GIP=葡萄糖依赖性促胰岛素多肽AdaptedfromDruckerDJDiabetes

Care2003;26:2929–2940;AhrénBCurr

DiabRep2003;3:365–372;

DruckerDJGastroenterology2002;122:

531–544;FarillaLetalEndocrinology2003;144:5149–5158;TrümperAetalMolEndocrinol2001;15:1559–1570;TrümperAetalJEndocrinol2002;174:233–246.Time,minIRInsulin,mU/L806040200180601200ControlSubjects

(n=8)PatientsWithType2Diabetes

(n=14)Time,minIRInsulin,mU/L806040200180601200OralglucoseloadIntravenous(IV)glucoseinfusion正常的肠促胰岛激素效应减弱的肠促胰岛激素效应IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:46–52.Copyright©1986Springer-Verlag.VilsbøllT,HolstJJ.Diabetologia2004;47:357–366.2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GLP-1和GIP水平及活性*经过性别及BMI校正AdaptedfromToft-NielsenM-BetalJClinEndocrinolMetab2001;86:3717–3723;NauckMAetalJClinInvest1993;91:301–307.

2型糖尿病患者肠促胰岛激素水平肠促胰岛激素活性

GLP-1

(p<0.05vs.NGT)未受损

GIP未受损*

(p=0.047vs.NGT)以肠促胰岛激素为基础的治疗:作用机制DPP-IV=dipeptidylpeptidaseIVAdaptedfromDruckerDJExpertOpinInvestDrugs2003;12(1):87–100;AhrénBCurr

DiabRep2003;3:365–372.肠道GLP-1释放无活性GLP-1(9-36)进餐活性GLP-1(7-36)DPP-4

抑制剂DPP-4GLP-1类似物二肽基肽酶4(DPP-4)AdaptedfromEvansDMIDrugs2002;5:577–585;DruckerDJExpertOpin

InvestigDrugs2003;12:87–100;RasmussenHBetalNatStruct

Biol2003;10:19–25.DPP-4是一种prolyl

oligopeptidaseenzyme家族的丝氨酸蛋白酶，它有两种存在形式膜结合(广泛表达)溶解细胞膜细胞质NNCCDPP-4抑制剂捷诺维(西格列汀)的作用机制

活性肠促胰岛激素GLP-1和GIP释放餐前及餐后葡萄糖水平摄食胰高血糖素(GLP-1)

肝糖生成胃肠道DPP-4酶失活的GLP-1X捷诺维(DPP-4inhibitor)肠促胰岛激素GLP-1和GIP由肠道全天性释放，其水平在餐后升高胰岛素(GLP-1&GIP)

葡萄糖依赖性的

葡萄糖依赖性的胰腺失活的GIPGLP-1=glucagon-likepeptide-1;GIP=glucose-dependentinsulinotropicpolypeptide.西格列汀可升高活性肠促胰岛激素水平，从而增加和延长其活性作用BetacellsAlphacells

外周组织对葡萄的摄取DPP-4抑制剂与GLP-1类似物的差异DPP-4抑制剂GLP-1类似物促进胰岛素分泌++++++降低胰高血糖素++++++恶心/呕吐-+++体重减轻

++给药途径口服注射DPP-4抑制剂获批概况公司DPP-4抑制剂美国欧洲中国MSD捷诺维JANUVIA（Sitagliptin）

2006年10月

2007年4月

2009年9月JANUMETSita/MetFDC

2007年4月

2008年7月NovartisGalvus（Vildagliptin）X2007年9月,11月撤回,改100mgqd为50mgBidGalvusFDCX

2007年11月TakedaAlogliptin

Alogliptin

FDCBMS/AZSaxagliptin

Saxagliptin

FDC

2009年7月其他2008年ADA涉及十多种DPP-4抑制剂的研究报道捷诺维（西格列汀）是全球第一个上市的DPP-4抑制剂捷诺维(西格列汀)高度选择性阻断DPP-4酶西格列汀强效阻断DPP-4酶高亲和力对DPP-4的高选择性:>2500倍vs.DPP-8或9可逆性竞争性ThornberryNA，etal.CurrTopicsinMedChem,2007;7:557-568DPP酶IC50(nM)DPP-4 18DPP-8 48,000DPP-9>100,000DPP-2,DPP-7, >100,000口服西格列汀100mg和600mg的峰浓度是747nM和7000nM可有效抑制DPP-4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非选择性抑制剂

(DPP-8/9&DPP-4)选择性DPP-8/9抑制剂

西格列汀T-细胞

增殖研究1减少细胞增殖++–2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2血痢++–1. LeitingBetal.Presentedat64thScientificSessionsoftheAmericanDiabetesAssociation;2004.Abstract6-OR.2. LankasGKetal.Diabetes.2005;54:2988–2994.捷诺维(西格列汀)给药24小时后

有效抑制血浆DPP-4活性达80%给药后时间（小时）~80%~50%对DPP-4的抑制与基线相比对血浆DPP-4的抑制程度

(%)0124812162024–10040506080100907030201061014182226OGTT西格列汀25mg(n=56)西格列汀200mg(n=56)安慰剂(n=56)HermanGA,etal.JClin

Endocrinol

Metab2006;91:4612-4619GLP-1在体外保护人胰岛细胞形态第1天GLP-1治疗的细胞对照第3天第5天AdaptedfromFarillaLetalEndocrinology2003;144:5149–5158.加入GLP-1培养的胰岛细胞能够更长时间的保持其完整性.捷诺维(西格列汀)使细胞与细胞比例正常Mu,Jetal.Diabetes,2006;55:1695-1704HFD/STZmicetreatedwithDes-F-sitagliptinfor11-weeks.Green–insulinpositiveb-cellRed–glucagonpositivea-cell捷诺维(西格列汀)改善胰岛功能(离体胰腺)Mu,Jetal.Diabetes,2006;55:1695-1704捷诺维(西格列汀)有效改善胰腺细胞功能动物实验研究结果西格列汀增加

-细胞数量，使细胞与细胞比例正常增加胰岛素阳性细胞数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）Mu,Jetal.Diabetes,2006;55:1695-1704概述2型糖尿病治疗现状及挑战以肠促胰岛激素为基础的治疗捷诺维（西格列汀）的临床数据临床疗效安全性捷诺维(西格列汀)

III期临床研究评估主要临床终点降糖疗效:单药治疗与其他降糖药物联合

细胞功能HOMA-

胰岛素原/胰岛素比值安全性/耐受性临床不良事件体重改变低血糖发生率实验室不良事件HbA1c(所有研究主要终点)FPGPPGHbA1c（<7%或<6.5%)达标率捷诺维(西格列汀)

III期临床研究汇总单药治疗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（PN040）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三联治疗52周与磺脲或磺脲加二甲双胍联合治疗AdaptedfromRazetal.Diabetologia.2006;49:2564–2571AdaptedfromAmericanDiabetesAssociation.FromDiabetesCare®,Vol.29,2006;2632–2637AdaptedfromNonakaetal.Posterpresentedatthe66thScientificSessions,AmericanDiabetesAssociation,Washington,DC,June9–13,2006.7.47.68.08.4Placebo(n=244)Sitagliptin100mg(n=229)24-weekStudyTime(weeks)06121824-0.79%(p<0.001)Japanese12-weekStudy-1.05%(p<0.001)Placebo(n=75)Sitagliptin100mg(n=75)Time(weeks)048127.68.08.47.26.8changevs.placebo*18-weekStudyPlacebo(n=74)Sitagliptin100mg(n=168)Time(weeks)0612187.27.68.08.4-0.6%(p<0.001)=捷诺维一天一次单药治疗持续显著降低HbA1CMonotherapyHbA1c(%±SE)HbA1c(%±SE)HbA1c(%±SE)7.28.27.47.06.66.47.88.2捷诺维在亚洲人群(中国、印度、韩国)降糖效果显著

HbA1c从基线的改变(FASPopulation)9.29.08.88.68.48.28.07.8061218Time,weeksMean±SEChangeinHbA1c,%FAS=fullanalysisset;qd=onceaday;SE=standarderror.MohanVetal.DiabetesResClin

Pract.2009;83:106–116.Sitagliptin100mgqd

(n=339)Placebo(n=169)Monotherapy-1.03%ScreeningSingle-blindplaceboDouble-blindtreatmentperiod:Sulfonylureaorsitagliptin100mg/dayMetformin

monotherapyWeek2:EligibleifHbA1c≥6.5%to≤10%IfonanOHA,D/CContinue/startmetforminDay1RandomizationWeek52

D/C=discontinued;OHA=oralantihyperglycemicagent;T2DM=type2diabetes.*Specifically,glipizide5mg/dayincreasedto20mg/day(dosenotuptitratediffingerstick<110mg/dLorhypoglycemia). AdaptedfromNaucketal.DiabetesObes

Metab.2007;9:194–205.52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100mg/day，二甲双胍≥1500mg/day磺脲*最大剂量20mg/day，二甲双胍≥1500mg/dayMetformin(stabledose≥1500mg/day)Add-on2HbA1c(%±

SE)LSMchangefrombaseline

(forbothgroups):–0.67%达到首要假设：疗效非劣效于磺脲

LSM=least-squaresmean.aSpecifically,glipizide;bsitagliptin(100mg/day)withmetformin(≥1500mg/day);per-protocolpopulation.AdaptedfromNaucketal.DiabetesObes

Metab.2007;9:194–205.52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，

捷诺维一天一次降糖效果不低于磺脲类(52周)Weeks5.86.06.26.46.66.87.07.27.47.67.80612182430384652Sulfonylureaa+metformin(n=411)Sitagliptinb+metformin(n=382)Add-on2aSpecifically,glipizide;

bsitagliptin(100mg/day)withmetformin(≥1500mg/day);per-protocolpopulation.AdaptedfromNaucketal.DiabetesObes

Metab.2007;9:194–205.Sulfonylurea+metforminBaselineHbA1CCategoryChangefrombaselineinHbA1c(%)n=117n=11711217916782823321<7%≥7to<8%≥8to<9%³9%-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+metformin52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，HbA1c降幅越大Add-on2PatientsatHbA1cgoal(%)HbA1c<7%atweek52*Specifically,glipizide.Per-protocolpopulation.MeanbaselineHbA1clevels:sitagliptin100mg,7.48%;glipizide,7.52%.AdaptedfromNaucketal.DiabetesObes

Metab.2007;9:194–205.n=240n=24252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

捷诺维联合二甲双胍组更多的患者达到血糖控制目标Add-on252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Sulfonylurea+metformin(n=584)Sitagliptin100mg/day+metformin(n=588)HypoglycemiabP<0.00132%5%01020304050Week52低血糖发生率(%)LSMchangeinbodyweightovertimeb体重(kg±SE)LSM=least-squaresmean.aSpecifically,glipizide;ball-patients-treatedpopulation.

LSMbetween-groupdifferenceatweek52(95%CI):inbodyweight=–2.5kg[–3.1,–2.0](P<0.001);

LSMchangefrombaselineatweek52:glipizide:+1.1kg;sitagliptin:–1.5kg(P<0.001).

AdaptedfromNaucketal.DiabetesObesMetab.2007;9:194–205.Sulfonylurea+metformin(n=416)Sitagliptin100mg/day+metformin(n=389)Add-on2bid=twicedaily;qd=daily;R=randomization.Williams-HermanDetal.CurrMedResOpin.2009;25(3):569–583.Week–2Day1Single-BlindPlaceboRun-InPeriodEligibleifHbA1c7.5%–11%Week24PlaceboSitagliptin100mgqdMetformin500mgbidMetformin1000mgbidSitagliptin50mg/metformin500mgbidSitagliptin50mg/metformin1000mgbidR研究设计Week54Metformin1,000mgbidSitagliptin100mgqdMetformin500mgbidMetformin1000mgbidSitagliptin50mg/metformin500mgbidSitagliptin50mg/metformin1000mgbid24-Week(PhaseA)30-WeekContinuationPhaseInitialCombination西格列汀与二甲双胍起始联合治疗

HbA1c24周时自基线的改变aLeastsquaresmeanchangefrombaselinewithadjustmentforplacebo.bWithin-groupmeanchangefrombaseline.bid=twicedaily;qd=daily.

GoldsteinBetal.DiabetesCare.2007;30:1979–1987.Pleasenote:Dr.GoldsteiniscurrentlyaMerckemployeebutwasnotatthetimethisstudywasconductedorwhenthepublicationwaswritten.117–2.9bMetformin1000mgbidSitagliptin100mgqd

Sitagliptin50mg+

metformin500mgbidMetformin500mgbidSitagliptin50mg+

metformin1000mgbidHbA1cChangeFromBaseline,%–3.5–3.0–2.5–2.0–1.5–1.0–0.50.00.5

178177183178175n=–0.8a–1.0a–1.3a–1.6a–2.1a24-WeekPlacebo-AdjustedResultsMeanHbA1c=8.8%Open-Label

MeanChangeFromBaseline

MeanHbA1c=11.2%All-Patients-TreatedPopulationHbA1cchangefrombaselineatweek24forplacebogroup(n=165)=0.17%InitialCombination西格列汀与二甲双胍起始联合治疗

54周时改善β细胞功能指标Sita50mg+met1000mgbidSita50mg+met500mgbidMet1000mgbidMet500mgbidSita100mgqdn=88n=102n=126n=133n=143n=61n=75n=114n=100n=130Proinsulin-to-InsulinRation=88n=102n=126n=133n=143HOMA-βChangebid=twicedaily;HOMA=homeostasismodelassessment;LSM=least-squaresmean;met=metformin;qd=daily;Sita=sitagliptin.Williams-HermanDetal.CurrMedResOpin.2009;25(3):569–583.ContinuationAll-Patients-TreatedPopulationInitialCombination西格列汀与二甲双胍起始联合治疗

54周内持续降低HbA1cSita50mg+met1000mgbid(n=153)Met1000mgbid(n=134)Sita100mgqd(n=106)Sita50mg+met500mgbid(n=147)Met500mgbid(n=117)APT=all-patients-treated;bid=twicedaily;LSM=least-squaresmean;

Met=metformin;qd=daily;Sita=sitagliptin.ReproducedwithpermissionfromWilliams-HermanDetal.CurrMedResOpin.2009;25(3):569–583.24-Week(PhaseA)30-WeekContinuationPhaseMean±SEChangeinHbA1c,%6.06.57.07.58.08.59.00612182430384654WeeksContinuationAll-Patients-TreatedPopulationInitialCombination06121824303846546270789110466.577.588.59*CompleterspopulationSita=sitagliptin;Met=metformin西格列汀与二甲双胍起始联合治疗

持续2年降低HbA1cTime(weeks)24-WeekPhaseContinuationPhaseExtensionPhaseHbA1c(LSmeanchange%)Sita100mgq.d.(n=22)Met500mgb.i.d.(n=26)Met1000mgb.i.d.(n=53)Sita50mgb.i.d.+Met500mgb.i.d.(n=64)Sita50mgb.i.d.+Met1000mgb.i.d.(n=77)2008EASDInitialCombination捷诺维联合格列吡嗪或格列吡嗪/二甲双胍*=Pioglitazone30mgQDScreeningPeriodPatientswithtreatedoruntreatedT2DM,ages18to78years

PlaceboSitagliptin100mgQDSingle-blindPlacebo

Week24Continue/startregimenof

glimepiride±metforminSingle-blind

eligibleifA1C7.5%to10.5%24-WeekPhaseRStratum1:Glimepiride(≥4mg/d)Stratum2:Glimepiride+Metformin(≥1500mg/d)ContinuationPhaseWeek54Patientsnotrequiringrescue

medicationin24-weekphase

couldcontinuethrough54weeks.ActiveTreatment*Week0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-ontoSUTripleCombination

各组A1c自基线的改变

Placebo-controlledAdd-ontoGlimepiride(+/-metformin)Study

*DifferenceinLSMeanchangefrombaseline-0.9%*-0.6%*Add-ontoglimepiride+metforminWeeks06121824A1C(%)7.27.68.08.48.8Sitagliptin+Glim+MFPlacebo+Glim+MFSitagliptin+GlimPlacebo+Glim

AdaptedfromHermansenetal.DiabetesObes

Metab2007;9:733-745MeandurationofT2DM:8.8yearsTripleCombinationBaseline(pmol/L/pmol/L):Sitagliptin=0.517;

Placebo=0.491p=n.s.三联治疗中捷诺维改善细胞功能指标Sitagliptin

Placebo

Proinsulin/InsulinRatioBaseline:Sitagliptin=50.7;

Placebo=47.4*p=0.021HOMA-b*AdaptedfromHermansenetal.DiabetesObes

Metab2007;9:733-745-0.08-0.06-0.04-0.020.000.02TripleCombination联合治疗中捷诺维改善细胞功能指标Baseline:proinsulin-to-insulinratio(sitagliptin+pioglitazone=0.41pmol/L/pmol/L;placebo+pioglitazone=0.40pmol/L/pmol/L);HOMA-β(sitagliptin=36.2%,placebo=39.6%).Add-onHOMA-β=homeostasismodelassessment-β;LSM=least-squaresmean.All-patients-treatedpopulation.AdaptedfromCharbonneletal.DiabetesCare.2006;29:2638–2643;AdaptedfromRosenstocketal.Clin

Ther.2006;28:1556–1568.24周与二甲双胍联用研究24周与吡格列酮联用研究Baseline:Proinsulin-to-insulinratio(sitagliptin=0.357pmol/L/pmol/L,placebo=0.369pmol/L/pmol/L),

HOMA-β(sitagliptin=46.4%,placebo=45.1%).单药治疗中捷诺维显著改善细胞功能指标All-patients-treatedpopulation.HOMA-β=homeostasismodelassessment-β.AdaptedfromRazetal.Diabetologia.2006;49:2564–2571.AdaptedfromAschneretal.DiabetesCare.2006;29:2632–2637.AtWeek18(18-Week,Monotherapy,Placebo-ControlledStudy)AtWeek24(24-Week,Monotherapy,Placebo-ControlledStudy)Monotherapy捷诺维(西格列汀)治疗组与非西格列汀治疗组间

总体不良事件相似SitagliptinN=3145

n(%)Nonexposed

N=2724

n(%)Between-GroupsDifference,%(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(0.2)8(0.3)–0.1(–0.4,0.2)死亡，n(%)11(0.3)16(0.6)–0.3(–0.7,0.1)中止治疗,n(%)

临床不良事件

药物相关临床不良事件

严重临床不良事件

药物相关严重临床不良事件106(3.1)30(0.9)51(1.5)4(0.1)101(3.7)40(1.5)47(1.7)4(0.1)–0.6(–1.5,0.3)–0.6(–1.2,–0.1)–0.2(–0.9,0.4)–0.0(–0.3,0.2)AE=adverseexperience;CI=confidenceinterval.aPositivedifferencesindicatethattheproportionforthesitagliptingroupishigherthantheproportionforthenonexposedgroup.

“–0.0”representsroundingforvaluesthatareslightlylessthanzero.

bDeterminedbytheinvestigatortobepossibly,probably,ordefinitelydrugrelated.Williams-HermanDetal.BMCEndocr

Disord.2008;8:14.CopyrightBioMedCentral.

Pooledsafetyandtolerabilityanalysis任一组发生的≥3%的临床不良事件SitagliptinN=3415

n(%)NonexposedN=2724

n(%)Between-GroupsDifference,%(95%CI)a任一组中≥3%的临床不良事件腹泻170(5.0)144(5.3)–0.3(–1.4,0.8)支气管炎135(4.0)83(3.0)0.9(–0.0,1.8)流感145(4.2)127(4.7)–0.4(–1.5,0.6)鼻咽炎244(7.1)162(5.9)1.2(–0.1,2.4)上呼吸道感染265(7.8)228(8.4)–0.6(–2.0,0.8)尿道感染134(3.9)100(3.7)0.3(–0.7,1.2)低血糖b117(3.4)296(10.9)–7.4(–8.8,–6.1)关节痛113(3.3)92(3.4)–0.1(–1.0,0.8)背痛142(4.2)108(4.0)0.2(–0.8,1.2)头痛169(4.9)129(4.7)0.2(–0.9,1.3)高血压110(3.2)89(3.3)–0.0(–1.0,0.8)aPositivedifferencesindicatethattheproportionforthesitagliptingroupishigherthantheproportionforthenonexposedgroup.

“–0.0”representsroundingforvaluesthatareslightlygreaterandslightlylessthanzero,respectively.bIncludesstudiesinwhichasulfonylureawasanactivecomparatororabackgroundagent.

Williams-HermanDetal.BMCEndocr

Disord.2008;8:14.CopyrightBioMedCentral.

Pooledsafetyandtolerabilityanalysis安全性荟萃分析：

可能与免疫功能相关的临床不良事件SitagliptinN=3415

n(%)NonexposedN=2724

n(%)Between-Gr