捷諾維-突破2型糖尿病治療的新希望

捷諾維（西格列?。?/p>

突破2型糖尿病治療的新希望概述2型糖尿病治療現(xiàn)狀及挑戰(zhàn)以腸促胰島激素為基礎的治療捷諾維（西格列汀）的臨床數(shù)據(jù)臨床療效安全性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臟

胰島素不足糖輸出過多胰島素抵抗

(葡萄糖攝取減少)胰腺肌肉和脂肪過多胰高糖素胰島胰島素減少胰島素減少α細胞產(chǎn)生過多胰高糖素β細胞產(chǎn)生胰島素減少不同降糖藥的主要作用部位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=噻唑烷二酮類.葡萄糖吸收肝臟葡萄糖過度合成胰島素分泌受損胰島素抵抗胰腺↓血糖水平肌肉和脂肪肝臟雙胍類TZDs雙胍類磺脲類格列奈類TZDsα-糖苷酶

抑制劑胃腸道DPP-4抑制劑DPP-4抑制劑雙胍類胰島素抵抗胰高糖素抑制不足細胞功能失調(diào)胃腸道吸收葡萄糖慢性β細胞功能衰竭胰島素分泌不足β細胞功能異常2型糖尿病現(xiàn)有治療選擇DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40未解決未解決二甲雙胍格列酮類磺脲類格列奈類α-糖苷酶抑制劑DPP-4抑制劑：2型糖尿病治療新選擇DPP–4抑制劑DeFronzoRA.BrJDiabetesVascDis,2003;3(Suppl1):S24-40胰島素抵抗胰高糖素抑制不足細胞功能失調(diào)胃腸道吸收葡萄糖慢性β細胞功能衰竭胰島素分泌不足β細胞功能異常二甲雙胍格列酮類磺脲類格列奈類α-糖苷酶抑制劑成人2型糖尿病患者HbA1c達標的比例不足50%NHANES=美國人群的一項全國健康營養(yǎng)檢查調(diào)查.SaydahSHetal.JAMA.2004;291:335–342.HbA1c

水平

<7%血壓<130/80mmHg

總膽固醇

<200mg/dl三項均達標心血管危險因素44.329.033.95.237.035.848.27.30102030405060成人（%）NHANESIII(1988–1994)(n=1204)NHANES1999–2000(n=370)美國人群中國2型糖尿病患者HbA1c

達標率中國糖尿病健康管理調(diào)查2004華北、華南、華東、華西和東北5個地區(qū)49家市級中心醫(yī)院參與分析的患者2248例中國糖尿病健康管理調(diào)查2006中國18個城市60家醫(yī)院登記治療超過12個月的糖尿病患者參與分析的患者2779例DiabCareStudy2006,Dataonfile潘長玉等《中華內(nèi)分泌代謝雜志》20:420-424,2004達標率（%）25.9%29.5%44.6%010%20%30%40%50%<6.5%<7.5%>7.5%達標率（%）25%35%010%20%30%40%50%<6.5%<7.0%>7.5%40%平均HbA1c：7.6%平均HbA1c：7.7%副作用的增加和依從性的降低是治療的兩大潛在障礙美國社區(qū)單中心.N=1282型糖尿病患者GrantRWetal.DiabetesCare.2003;26:1408–1412.大部分與不依從相關的常見因素UnitedStatesstudy;Medi-CalclaimsdataJanuary1996throughSeptember1998.Compliancewasdefinedastotaldaysofdrugsupply(measuredbynumberofdosesprescribed)duringthefollow-upperiod;complianceratewascalculatedbydividingthenumberofcompliancedaysbythenumberofdaysinthefollow-upperiod.DaileyGetal.Clin

Ther.2001;23:1311–1320.二甲雙胍(n=2,996)磺脲類(n=21,987)二甲雙胍＋磺脲類聯(lián)合治療(n=1,354)多藥治療降低患者依從性58%23%8%11%

58%23%8%11%不良反應花費非特異

記住藥物劑量困難概述2型糖尿病治療現(xiàn)狀及挑戰(zhàn)以腸促胰島激素為基礎的治療捷諾維（西格列汀）的臨床數(shù)據(jù)臨床療效安全性Time,minControlSubjects

(n=8)Time,minIRInsulin,mU/L806040200180601200OralglucoseloadIntravenous(IV)glucoseinfusion正常的腸促胰島激素效應IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:46–52.Copyright?1986Springer-Verlag.Vilsb?llT,HolstJJ.Diabetologia2004;47:357–366.正常個體的腸促胰島激素效應腸促胰島激素GLP-1和GIP的作用由遠端消化道L細胞分泌(回腸和結(jié)腸)以葡萄糖依賴的模式促進胰島素釋放以葡萄糖依賴的模式抑制胰高糖素分泌，從而抑制肝糖輸出在動物模型及離體人類胰島中增強beta細胞增殖和存活由近端消化道K細胞分泌（十二指腸）以葡萄糖依賴的模式促進胰島素釋放在胰島細胞系中增強beta細胞增殖和存活GLP-1GIPGLP-1=胰高糖素樣肽1;GIP=葡萄糖依賴性促胰島素多肽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正常的腸促胰島激素效應減弱的腸促胰島激素效應IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:46–52.Copyright?1986Springer-Verlag.Vilsb?llT,HolstJJ.Diabetologia2004;47:357–366.2型糖尿病患者的腸促胰島激素效應減弱2型糖尿病患者的GLP-1和GIP水平及活性*經(jīng)過性別及BMI校正AdaptedfromToft-NielsenM-BetalJClinEndocrinolMetab2001;86:3717–3723;NauckMAetalJClinInvest1993;91:301–307.

2型糖尿病患者腸促胰島激素水平腸促胰島激素活性

GLP-1

(p<0.05vs.NGT)未受損

GIP未受損*

(p=0.047vs.NGT)以腸促胰島激素為基礎的治療:作用機制DPP-IV=dipeptidylpeptidaseIVAdaptedfromDruckerDJExpertOpinInvestDrugs2003;12(1):87–100;AhrénBCurr

DiabRep2003;3:365–372.腸道GLP-1釋放無活性GLP-1(9-36)進餐活性GLP-1(7-36)DPP-4

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

InvestigDrugs2003;12:87–100;RasmussenHBetalNatStruct

Biol2003;10:19–25.DPP-4是一種prolyl

oligopeptidaseenzyme家族的絲氨酸蛋白酶，它有兩種存在形式膜結(jié)合(廣泛表達)溶解細胞膜細胞質(zhì)NNCCDPP-4抑制劑捷諾維(西格列汀)的作用機制

活性腸促胰島激素GLP-1和GIP釋放餐前及餐后葡萄糖水平攝食胰高血糖素(GLP-1)

肝糖生成胃腸道DPP-4酶失活的GLP-1X捷諾維(DPP-4inhibitor)腸促胰島激素GLP-1和GIP由腸道全天性釋放，其水平在餐后升高胰島素(GLP-1&GIP)

葡萄糖依賴性的

葡萄糖依賴性的胰腺失活的GIPGLP-1=glucagon-likepeptide-1;GIP=glucose-dependentinsulinotropicpolypeptide.西格列汀可升高活性腸促胰島激素水平，從而增加和延長其活性作用BetacellsAlphacells

外周組織對葡萄的攝取DPP-4抑制劑與GLP-1類似物的差異DPP-4抑制劑GLP-1類似物促進胰島素分泌++++++降低胰高血糖素++++++惡心/嘔吐-+++體重減輕

++給藥途徑口服注射DPP-4抑制劑獲批概況公司DPP-4抑制劑美國歐洲中國MSD捷諾維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為50mgBidGalvusFDCX

2007年11月TakedaAlogliptin

Alogliptin

FDCBMS/AZSaxagliptin

Saxagliptin

FDC

2009年7月其他2008年ADA涉及十多種DPP-4抑制劑的研究報道捷諾維（西格列?。┦侨虻谝粋€上市的DPP-4抑制劑捷諾維(西格列汀)高度選擇性阻斷DPP-4酶西格列汀強效阻斷DPP-4酶高親和力對DPP-4的高選擇性:>2500倍vs.DPP-8或9可逆性競爭性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的峰濃度是747nM和7000nM可有效抑制DPP-4顯著低于抑制DPP-8和DPP-9所需濃度高度選擇性保證了捷諾維無動物毒性反應非選擇性抑制劑

(DPP-8/9&DPP-4)選擇性DPP-8/9抑制劑

西格列汀T-細胞

增殖研究1減少細胞增殖++–2周大鼠毒性研究2脫發(fā)++–血小板減少++–貧血癥++–脾腫大++–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.捷諾維(西格列汀)給藥24小時后

有效抑制血漿DPP-4活性達80%給藥后時間（小時）~80%~50%對DPP-4的抑制與基線相比對血漿DPP-4的抑制程度

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

Endocrinol

Metab2006;91:4612-4619GLP-1在體外保護人胰島細胞形態(tài)第1天GLP-1治療的細胞對照第3天第5天AdaptedfromFarillaLetalEndocrinology2003;144:5149–5158.加入GLP-1培養(yǎng)的胰島細胞能夠更長時間的保持其完整性.捷諾維(西格列汀)使細胞與細胞比例正常Mu,Jetal.Diabetes,2006;55:1695-1704HFD/STZmicetreatedwithDes-F-sitagliptinfor11-weeks.Green–insulinpositiveb-cellRed–glucagonpositivea-cell捷諾維(西格列汀)改善胰島功能(離體胰腺)Mu,Jetal.Diabetes,2006;55:1695-1704捷諾維(西格列汀)有效改善胰腺細胞功能動物實驗研究結(jié)果西格列汀增加

-細胞數(shù)量，使細胞與細胞比例正常增加胰島素陽性細胞數(shù)量增加胰腺內(nèi)胰島素含量改善葡萄糖刺激后胰島素分泌（離體胰腺）Mu,Jetal.Diabetes,2006;55:1695-1704概述2型糖尿病治療現(xiàn)狀及挑戰(zhàn)以腸促胰島激素為基礎的治療捷諾維（西格列?。┑呐R床數(shù)據(jù)臨床療效安全性捷諾維(西格列汀)

III期臨床研究評估主要臨床終點降糖療效:單藥治療與其他降糖藥物聯(lián)合

細胞功能HOMA-

胰島素原/胰島素比值安全性/耐受性臨床不良事件體重改變低血糖發(fā)生率實驗室不良事件HbA1c(所有研究主要終點)FPGPPGHbA1c（<7%或<6.5%)達標率捷諾維(西格列汀)

III期臨床研究匯總單藥治療18周安慰劑對照研究24周安慰劑對照研究12周日本人群安慰劑對照研究18周亞洲人群單藥研究（PN040）與其它降糖藥物聯(lián)用與二甲雙胍聯(lián)用24周與二甲雙胍聯(lián)合治療研究52周與二甲雙胍聯(lián)合治療活性對照研究24周與吡格列酮聯(lián)合治療研究起始聯(lián)合治療二甲雙胍和西格列汀對腸促胰島激素的作用二甲雙胍/西格列汀起始聯(lián)合治療三聯(lián)治療52周與磺脲或磺脲加二甲雙胍聯(lián)合治療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)=捷諾維一天一次單藥治療持續(xù)顯著降低HbA1CMonotherapyHbA1c(%±SE)HbA1c(%±SE)HbA1c(%±SE)7.28.27.47.06.66.47.88.2捷諾維在亞洲人群(中國、印度、韓國)降糖效果顯著

HbA1c從基線的改變(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周西格列汀聯(lián)合二甲雙胍vs格列吡嗪聯(lián)合二甲雙胍對照研究

研究設計2型糖尿病患者隨機，雙盲，平行，活性對照，非劣效性研究(N=1172)治療西格列汀100mg/day，二甲雙胍≥1500mg/day磺脲*最大劑量20mg/day，二甲雙胍≥1500mg/dayMetformin(stabledose≥1500mg/day)Add-on2HbA1c(%±

SE)LSMchangefrombaseline

(forbothgroups):–0.67%達到首要假設：療效非劣效于磺脲

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

Metab.2007;9:194–205.52周西格列汀聯(lián)合二甲雙胍vs格列吡嗪聯(lián)合二甲雙胍對照研究

與二甲雙胍聯(lián)用時，

捷諾維一天一次降糖效果不低于磺脲類(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周西格列汀聯(lián)合二甲雙胍vs格列吡嗪聯(lián)合二甲雙胍對照研究

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周西格列汀聯(lián)合二甲雙胍vs格列吡嗪聯(lián)合二甲雙胍對照研究

捷諾維聯(lián)合二甲雙胍組更多的患者達到血糖控制目標Add-on252周西格列汀聯(lián)合二甲雙胍vs格列吡嗪聯(lián)合二甲雙胍對照研究

捷諾維組體重下降且低血糖發(fā)生率顯著低于對照組Sulfonylurea+metformin(n=584)Sitagliptin100mg/day+metformin(n=588)HypoglycemiabP<0.00132%5%01020304050Week52低血糖發(fā)生率(%)LSMchangeinbodyweightovertimeb體重(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研究設計Week54Metformin1,000mgbidSitagliptin100mgqdMetformin500mgbidMetformin1000mgbidSitagliptin50mg/metformin500mgbidSitagliptin50mg/metformin1000mgbid24-Week(PhaseA)30-WeekContinuationPhaseInitialCombination西格列汀與二甲雙胍起始聯(lián)合治療

HbA1c24周時自基線的改變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西格列汀與二甲雙胍起始聯(lián)合治療

54周時改善β細胞功能指標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西格列汀與二甲雙胍起始聯(lián)合治療

54周內(nèi)持續(xù)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西格列汀與二甲雙胍起始聯(lián)合治療

持續(xù)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捷諾維聯(lián)合格列吡嗪或格列吡嗪/二甲雙胍*=Pioglitazone30mgQDScreeningPeriodPatientswithtreatedoruntreatedT2DM,ages18to78years

PlaceboSitagliptin100mgQDSingle-blindPlacebo

Week24Continue/startregimenof

glimepiride±m(xù)etforminSingle-blind

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

medicationin24-weekphase

couldcontinuethrough54weeks.ActiveTreatment*Week0入選病例：441例隨機化病例，平均56歲，

~53%男性

糖尿病平均病程為8.8年，平均基線

A1C=8.34%Add-ontoSUTripleCombination

各組A1c自基線的改變

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.三聯(lián)治療中捷諾維改善細胞功能指標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聯(lián)合治療中捷諾維改善細胞功能指標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周與二甲雙胍聯(lián)用研究24周與吡格列酮聯(lián)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%).單藥治療中捷諾維顯著改善細胞功能指標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捷諾維(西格列汀)治療組與非西格列汀治療組間

總體不良事件相似SitagliptinN=3145

n(%)Nonexposed

N=2724

n(%)Between-GroupsDifference,%(95%CI)a1次或多次臨床不良事件2150(63.0)1711(62.8)0.1(–2.3,2.6)藥物相關臨床不良事件b440(12.9)483(17.7)–4.8(–6.7,–3.0)嚴重臨床不良事件230(6.7)184(6.8)–0.0(–1.3,1.2)藥物相關臨床不良事件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)中止治療,n(%)

臨床不良事件

藥物相關臨床不良事件

嚴重臨床不良事件

藥物相關嚴重臨床不良事件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任一組發(fā)生的≥3%的臨床不良事件SitagliptinN=3415

n(%)NonexposedN=2724

n(%)Between-GroupsDifference,%(95%CI)a任一組中≥3%的臨床不良事件腹瀉170(5.0)144(5.3)–0.3(–1.4,0.8)支氣管炎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)關節(jié)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)頭痛169(4.9)129(4.7)0.2(–0.9,1.3)高血壓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安全性薈萃分析：

可能與免疫功能相關的臨床不良事件SitagliptinN=3415

n(%)NonexposedN=2724

n(%)Between-Gr