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(chǔ)的治療捷諾維（西格列?。┑呐R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(guò)多胰島素抵抗

(葡萄糖攝取減少)胰腺肌肉和脂肪過(guò)多胰高糖素胰島胰島素減少胰島素減少α細(xì)胞產(chǎn)生過(guò)多胰高糖素β細(xì)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(lèi).葡萄糖吸收肝臟葡萄糖過(guò)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(lèi)TZDs雙胍類(lèi)磺脲類(lèi)格列奈類(lèi)TZDsα-糖苷酶

抑制劑胃腸道DPP-4抑制劑DPP-4抑制劑雙胍類(lèi)胰島素抵抗胰高糖素抑制不足細(xì)胞功能失調(diào)胃腸道吸收葡萄糖慢性β細(xì)胞功能衰竭胰島素分泌不足β細(xì)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(lèi)磺脲類(lèi)格列奈類(lèi)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(xì)胞功能失調(diào)胃腸道吸收葡萄糖慢性β細(xì)胞功能衰竭胰島素分泌不足β細(xì)胞功能異常二甲雙胍格列酮類(lèi)磺脲類(lèi)格列奈類(lèi)α-糖苷酶抑制劑成人2型糖尿病患者HbA1c達(dá)標(biāo)的比例不足50%NHANES=美國(guó)人群的一項(xiàng)全國(guó)健康營(yíng)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(xiàng)均達(dá)標(biāo)心血管危險(xiǎn)因素44.329.033.95.237.035.848.27.30102030405060成人（%）NHANESIII(1988–1994)(n=1204)NHANES1999–2000(n=370)美國(guó)人群中國(guó)2型糖尿病患者HbA1c

達(dá)標(biāo)率中國(guó)糖尿病健康管理調(diào)查2004華北、華南、華東、華西和東北5個(gè)地區(qū)49家市級(jí)中心醫(yī)院參與分析的患者2248例中國(guó)糖尿病健康管理調(diào)查2006中國(guó)18個(gè)城市60家醫(yī)院登記治療超過(guò)12個(gè)月的糖尿病患者參與分析的患者2779例DiabCareStudy2006,Dataonfile潘長(zhǎng)玉等《中華內(nèi)分泌代謝雜志》20:420-424,2004達(dá)標(biāo)率（%）25.9%29.5%44.6%010%20%30%40%50%<6.5%<7.5%>7.5%達(dá)標(biāo)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(guó)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(guān)的常見(jiàn)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(lèi)(n=21,987)二甲雙胍＋磺脲類(lèi)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(yīng)花費(fèi)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(chǔ)的治療捷諾維（西格列?。┑呐R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(yīng)IR=immunoreactiveAdaptedwithpermissionfromNauckMetal.Diabetologia1986;29:46–52.Copyright?1986Springer-Verlag.Vilsb?llT,HolstJJ.Diabetologia2004;47:357–366.正常個(gè)體的腸促胰島激素效應(yīng)腸促胰島激素GLP-1和GIP的作用由遠(yuǎn)端消化道L細(xì)胞分泌(回腸和結(jié)腸)以葡萄糖依賴的模式促進(jìn)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(dòng)物模型及離體人類(lèi)胰島中增強(qiáng)beta細(xì)胞增殖和存活由近端消化道K細(xì)胞分泌（十二指腸）以葡萄糖依賴的模式促進(jìn)胰島素釋放在胰島細(xì)胞系中增強(qiáng)beta細(xì)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(yīng)減弱的腸促胰島激素效應(yīng)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(yīng)減弱2型糖尿病患者的GLP-1和GIP水平及活性*經(jīng)過(guò)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(chǔ)的治療:作用機(jī)制DPP-IV=dipeptidylpeptidaseIVAdaptedfromDruckerDJExpertOpinInvestDrugs2003;12(1):87–100;AhrénBCurr

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

抑制劑DPP-4GLP-1類(lèi)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(dá))溶解細(xì)胞膜細(xì)胞質(zhì)NNCCDPP-4抑制劑捷諾維(西格列汀)的作用機(jī)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(zhǎng)其活性作用BetacellsAlphacells

外周組織對(duì)葡萄的攝取DPP-4抑制劑與GLP-1類(lèi)似物的差異DPP-4抑制劑GLP-1類(lèi)似物促進(jìn)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(guó)歐洲中國(guó)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(bào)道捷諾維（西格列?。┦侨虻谝粋€(gè)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(qiáng)效阻斷DPP-4酶高親和力對(duì)DPP-4的高選擇性:>2500倍vs.DPP-8或9可逆性競(jìng)爭(zhēng)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(wú)動(dòng)物毒性反應(yīng)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(xì)胞

增殖研究1減少細(xì)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(shí)后

有效抑制血漿DPP-4活性達(dá)80%給藥后時(shí)間（小時(shí)）~80%~50%對(duì)DPP-4的抑制與基線相比對(duì)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(hù)人胰島細(xì)胞形態(tài)第1天GLP-1治療的細(xì)胞對(duì)照第3天第5天AdaptedfromFarillaLetalEndocrinology2003;144:5149–5158.加入GLP-1培養(yǎng)的胰島細(xì)胞能夠更長(zhǎng)時(shí)間的保持其完整性.捷諾維(西格列汀)使細(xì)胞與細(xì)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(xì)胞功能動(dòng)物實(shí)驗(yàn)研究結(jié)果西格列汀增加

-細(xì)胞數(shù)量，使細(xì)胞與細(xì)胞比例正常增加胰島素陽(yáng)性細(xì)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(chǔ)的治療捷諾維（西格列汀）的臨床數(shù)據(jù)臨床療效安全性捷諾維(西格列汀)

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

細(xì)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(shí)驗(yàn)室不良事件HbA1c(所有研究主要終點(diǎn))FPGPPGHbA1c（<7%或<6.5%)達(dá)標(biāo)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(duì)照研究24周安慰劑對(duì)照研究12周日本人群安慰劑對(duì)照研究18周亞洲人群?jiǎn)嗡幯芯浚≒N040）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(duì)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(duì)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(guó)、印度、韓國(guó))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(duì)照研究

研究設(shè)計(jì)2型糖尿病患者隨機(jī)，雙盲，平行，活性對(duì)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(dá)到首要假設(shè)：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(duì)照研究

與二甲雙胍聯(lián)用時(shí)，

捷諾維一天一次降糖效果不低于磺脲類(lèi)(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(duì)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(duì)照研究

捷諾維聯(lián)合二甲雙胍組更多的患者達(dá)到血糖控制目標(biāo)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(duì)照研究

捷諾維組體重下降且低血糖發(fā)生率顯著低于對(duì)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(shè)計(jì)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(shí)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(shí)改善β細(xì)胞功能指標(biāo)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(jī)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(xì)胞功能指標(biāo)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(xì)胞功能指標(biāo)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(xì)胞功能指標(biāo)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(guān)臨床不良事件b440(12.9)483(17.7)–4.8(–6.7,–3.0)嚴(yán)重臨床不良事件230(6.7)184(6.8)–0.0(–1.3,1.2)藥物相關(guān)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(guān)臨床不良事件

嚴(yán)重臨床不良事件

藥物相關(guān)嚴(yán)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(guān)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(guān)的臨床不良事件SitagliptinN=3415

n(%)NonexposedN=2724

n(%)Between-Gr