screeningjapanese50m咸熟

ORIGINALARTICLESafetyandbenetsofatabletcombininglosartanandhydrochlorothiazideinJapanesediabeticpatientswithhypertensionKenichiroKinouchi1,AtsuhiroIchihara2,MariyoSakoda1,AsakoKurauchi-Mito1andHiroshiItoh1Thisstudywasconductedtodeterminetheeffectsofatabletcombininglosartan/hydrochlorothiazide(L/HCTZ)incomparisonwithlosartanaloneinJapanesediabeticpatientswithhypertension.
ThirtyconsecutiveJapanesediabeticpatientswithhypertensionwererandomlyassignedtogroupA,receivinglosartanalonefortherst3months,thenL/HCTZforthenext3months,orgroupB,receivingL/HCTZfortherst3months,thenlosartanaloneforthenext3months.
Clinicalandbiologicalparameterswereobtainedbefore,and3and6monthsafterthestartofthisstudy.
Thedecreasesinsystolicanddiastolicbloodpressure(BP)duringtreatmentwithL/HCTZweresignicantlygreaterthanintreatmentwithlosartanalone.
Bothtreatmentssignicantlyandsimilarlydecreasedurinaryalbuminexcretion,thecardio-anklevascularindex(CAVI)andaugmentationindex(AI).
Therewasnosignicantdifferenceinmetabolicchangeduringboththemono-andcombinationpharmacotherapies.
ThetabletcombiningL/HCTZsignicantlyreducedsystolicanddiastolicBPcomparedwiththelosartanmonotherapy,andofferedbenetssimilartolosartanmonotherapyforalbuminuria,arterialstiffnessassessedbytheCAVIandAI,andmetaboliceffects.
Thus,theL/HCTZtabletcouldbeausefuldrugforJapanesediabeticpatientswithhypertension.
HypertensionResearch(2009)32,1143–1147;doi:10.
1038/hr.
2009.
162;publishedonline18September2009Keywords:albuminuria;angiotensin;arterialstiffness;bloodpressure;diureticsINTRODUCTIONAchievementofthetargetbloodpressure(BP)isthemostcrucialobjectiveofantihypertensivetreatment.
Morethantwo-thirdsofhypertensivepatientswillrequiretwoormoreantihypertensiveagentsfromdifferentclassestocontroltheirBP.
1,2Patientswithdiabetesorrenaldiseasewillneedagreaterintensityofantihypertensivetreat-ment,onanaverageof2.
6to4.
3differentclassesofantihypertensiveagentstoattainaBPgoaloflowerthan130/80mmHg.
3TheangiotensinIItype1receptorblocker(ARB)iscurrentlyoneofthemostwidelyusedrst-lineantihypertensivedrugs,especiallyfordiabeticpatientswithhypertensionbasedontheevidencethatitslowstheprogressivedeteriorationofkidneyfunctioninpatientswithdiabeticnephropathy.
4However,itisoftendifculttoachievethetargetBPwithdosetitrationofARBalone,andotherantihypertensivemedicationsareoftenrequiredtoprovidesufcientBPcontrolinadditiontoanARB.
Hydrochlorothiazide(HCTZ)isadiureticthathasbeenastandardantihypertensivedrugprescribedworldwidebecauseofitscostandefcacyinloweringBPbasedontheavailableevidenceincludingtheALLHATtrial5andNICS-EHtrial.
6TheguidelinesoftheSeventhReportoftheJointNationalCommitteeonPrevention,Detection,Evaluation,andTreatmentofHighBloodPressure,7theEuropeanSocietyofHypertension8andJapaneseSocietyofHypertension9alsorecommendcombinationtherapycomprisingARBandthiazide-typediureticsforhypertensivepatients.
However,add-onHCTZmayhavesomeadverseeffectsonelectrolyte,glucose,lipidanduricacidmetabolism,especiallyinJapanesediabeticpatientswithhypertension.
TheaimofthiscrossoverstudywastoexaminetheeffectsofatabletcombininglosartanandHCTZ(L/HCTZ)onurinaryalbuminexcretion(UAE),arterialstiffness,andBPanditsadverseeffectsonthemetabolicchangesincomparisonwithlosartanaloneinJapanesediabeticpatientswithhypertension.
UAEwasevaluatedasasurrogatemarkerforcardiovascularmorbidityandmortality,10andarterialstiffnesswasassessedbythecardio-anklevascularindex(CAVI)andaugmentationindex(AI).
METHODSStudypopulationanddesignThesubjectsofthisstudycomprised30consecutiveJapanesediabeticpatientswhohaduntreatedhypertensionoruncontrollablehypertensiontreatedwithmedicationsexceptforrenin–angiotensinsystem(RAS)inhibitors.
Hyperten-sionwasdenedasaclinicsystolicBPof4140mmHgatanytimeand/oraReceived28July2009;revised24August2009;accepted27August2009;publishedonline18September20091DivisionofEndocrinology,Metabolism,andNephrology,DepartmentofInternalMedicine,KeioUniversitySchoolofMedicine,Tokyo,Japanand2DepartmentsofEndocrinologyandAnti-AgingMedicineandInternalMedicine,KeioUniversitySchoolofMedicine,Tokyo,JapanCorrespondence:DrAIchihara,DepartmentsofEndocrinologyandAnti-AgingMedicineandInternalMedicine,KeioUniversitySchoolofMedicine,35Shinanomachi,Shinjuku-ku,Tokyo160-8582,Japan.
E-mail:atzichi@sc.
itc.
keio.
ac.
jpHypertensionResearch(2009)32,1143–1147&2009TheJapaneseSocietyofHypertensionAllrightsreserved0916-9636/09$32.
00www.
nature.
com/hrclinicdiastolicBPof490mmHgatanytime.
Patientswithseriousrefractoryhypertensiondenedasmorethan120mmHgindiastolicBP,historyofacutemyocardialinfarction,stroke,oranyothercardiovasculareventswithin6months,heartfailurewithNYHAgradeIII,orgradeIV,historyofgoutorhyperuricemiaatthebeginningofthisstudy,kidneydysfunctiondenedasaserumcreatinine(Cr)levelofmorethan2mgper100ml,liverdysfunctiondenedasaserumtransaminaselevelmorethan3timeshigherthannormal,bilateralrenalarterystenosis,secondary,ormalignanthypertension,polycystickidneydisease,congenitalkidneydeformities,solitarykidney,pregnancyorprobablepregnancy,historyofallergytothemedicationinthisstudy,orthoseconsideredinappropriatewereexcludedfromthestudy.
TheglomerularltrationratewasestimatedbytheMDRDequationmodiedbyaJapanesecoefcient,asfollows:eGFR0:741ifmalegenderor0:742iffemalegender175Age0:203Cr1:154(whereeGFRestimatedglomerularltrationrate,Ageage(yearsold);andCrserumCrlevelmgper100mlThisstudywasdesignedasacrossoverstudy.
AllpatientswererandomlyassignedeithertogroupA(receivinglosartanfortherst3months,thenL/HCTZforthenext3months)orgroupB(receivingL/HCTZfortherst3months,thenlosartanaloneforthenext3months).
Fivepatients(threepatientsingroupAandtwopatientsingroupB)weredroppedoutofthestudymainlyduetotheconcernaboutadverseeffectsofthemedicationsuchasdiabetesandhyperuricemia.
ThedosesoflosartanandL/HCTZwerexedthroughoutthestudyat50mgday1and50mgper12.
5mgday1,respectively,whicharetypicaldosesadministeredinJapanesepatients.
Clinicalandbiologicalparameterswereobtainedbeforethestartofthestudy,aswellas3and6monthsafter.
Duringthestudyperiod,previousmedicationsandtherapiesexceptRASblockersanddiureticswerecontinued.
ToachievethetargetBPofo130/80mmHg,amlodipinewasaddedatadoseof2.
5mgday1,andthedosewassubsequentlyincreasedby2.
5mgincrementsatintervalsof4weekstoamaximumdoseof10mgday1.
ThestudywasapprovedbythereviewboardofKeioUniversityMedicalSchoolHospital,andwritteninformedconsentwasobtainedfromeverysubject.
SerumlevelsofCr,cystatinC,potassium,uricacid,totalcholesterol,triglyceride,high-densitylipoproteincholesterol,low-densitylipoproteincho-lesterol,glucose,andglycoalbumin,andplasmalevelsofactivereninconcen-trations(ARC),andaldosteroneweremeasuredinvenousbloodsamplesdrawninthemorningafteranovernightfastonthesamedaysasthoseinwhichCAVI,AIandBPmeasurementsweretaken.
Cardio-anklevascularindexTheCAVIwasmeasuredusingaVaSeraVS-1000vascularscreeningsystem(FukudaDenshi,Tokyo,Japan)asdescribedpreviously.
11.
Cuffsareappliedtothebilateralupperarmsandankles,withthesubjectlyingsupineandtheheadheldinthemidlineposition.
ECGelectrodesareplacedonbothwrists,andamicrophonefordetectingheartsoundsisplacedonthesternum.
Patientsrestedinthesupinepositionforatleast10minbeforethestartofmonitoring.
TheCAVIwascalculatedwiththefollowingformula:CAVIaf2r=DPlnPs=PdPWV2g+bwherePsissystolicBP,PdisdiastolicBP,DPisPsPd,risblooddensityandaandbareconstants.
Thenumberofpatientsinthisstudywasassumedtobestatisticallysufcientbecausetheestimatedrequiredsamplesizeforpulsewavevelocity(PWV)is15.
6ineachgroupwithana-errorof0.
05andapowerof0.
8.
AugmentationindexTheAIwasmeasuredusinganautomatedtonometricdevice(HEM-9000AI;OmronHealthcare,Kyoto,Japan)asdescribedpreviously.
12Peripheralpressurewaveformswererecordedover30sfromtheradialarteryatthewristwiththesubjectsinasittingpositionafteratleast5minrest.
TheAIwascalculatedwiththefollowingformula:AIlatesystolicBPdiastolicBPDBP=systolicBPDBP100%UrinaryalbuminexcretionUrinaryalbuminexcretionwasevaluatedonthebasisofthemeanalbumin-to-creatinineratiointhreenonconsecutiveovernighturinesamples.
UrinaryconcentrationsofalbuminandCrweredeterminedusingaturbidimetricimmunoassaywithaSuperior-Microalbuminkit(DPC,Tokyo,Japan)andwiththeJaffereactionusinganautoanalyzer.
StatisticalanalysesAnalyseswereperformedwithStatView5.
0.
software(SASInstitute,Cary,NC,USA).
Thew2-testandFisher'sexacttestwereusedtoanalyzetheproportionofpatientswhoachievedtargetBP.
Thechangesinbiologicalparameterswereanalyzedwithaone-wayanalysisofvarianceforrepeatedmeasurescombinedwiththeDunnettandTukey–Kramerposthoctests.
AP-valueo0.
05wasconsideredsignicant.
Dataarereportedasmeans±s.
d.
RESULTSAllpatientsinthisstudyhaduntreatedhypertensionorhypertension,whichhadbeeninadequatelytreatedformorethanamonthwithmedicationsotherthanRASinhibitors.
Patientcharacteristicsinbaselinevalueswereasfollows:age,53±11years;thenumberofmalegender,20;bodymassindex,25.
2±4.
5kgm2;waistcircum-ference,88±13cm;serumCr,0.
82±0.
16mgper100ml;eGFR,75.
2±14.
1mlmin1per1.
73m2;cystatinC,0.
74±0.
09mgl1;serumpotassium,4.
31±0.
24mEql1;serumuricacid,5.
9±1.
4mgper100ml;serumtotalcholesterol,211±34mgper100ml;serumtriglyceride,161±153mgper100ml;serumhigh-densitylipoproteincholesterol,54±13mgper100ml;serumlow-densitylipoproteincholesterol,125±34mgper100ml;bloodsugar,109±24mgper100ml;glycoalbumin,15±2.
9%;plasmaARC,9.
4±8.
5pgml1;plasmaaldosteroneconcentration,147±59pgml1;UAE,25.
7±42.
4mggCr1;CAVI,8.
7±1.
1;AI,87.
2±11.
6%;systolicBP,156±16mmHg;diastolicBP,98±16mmHg.
ToachievethetargetBPofo130/80mmHg,amlodipinewasaddedduringthelosartantreatmentintwopatientsatadoseof5and10mgday1,respectively.
Figure1illustratedthechangesinthemetaboliceffectswithbothdrugs.
Therewasnosignicantchangeinmetabolicparameterswitheithertreatment.
Figure2illustratedthechangesinclinicalparameterswithbothdrugs.
TheplasmaARCsignicantlyincreasedfrom9.
4±8.
5to70.
5±72.
2pgml1duringtheL/HCTZtreatment.
TheplasmaARCafterthetreatmentwithL/HCTZwassignicantlygreaterthanthatafterlosartanalone.
UAEsignicantlydecreasedfrom25.
7±42.
4to11.
5±17.
0mggCr1duringthelosartantreatment,whereasUAEsignicantlydecreasedfrom25.
7±42.
4to6.
1±13.
6mggCr1duringtheL/HCTZtreatment,althoughtherewasnosignicantdifferenceinUAEvaluesbetweenbothtreatmentperiods.
TheCAVIsignicantlydecreasedfrom8.
7±1.
1to8.
0±1.
3duringthelosartantreatment,andsignicantlydecreasedfrom8.
7±1.
1to7.
7±1.
3duringtheL/HCTZtreatment.
TherewasnosignicantdifferenceintheCAVIbetweenbothtreatments.
TheAIsignicantlydecreasedfrom87.
2±11.
6to77.
2±13.
9duringthelosartantreatment,andsigni-cantlydecreasedfrom87.
2±11.
6to77.
5±9.
6duringtheL/HCTZtreatment.
TherewasnosignicantdifferenceintheAIvaluesbetweenbothtreatmentperiods.
ThesystolicBPsignicantlydecreasedfrom156±16to137±14mmHgduringthelosartantreatment,whereasthesystolicBPsignicantlydecreasedfrom156±16to130±10mmHgduringtheL/HCTZtreatment.
ThesystolicBPCombinationtabletofLosartanandhydrochlorothiazideKKinouchietal1144HypertensionResearchafterthetreatmentwithL/HCTZwassignicantlylowerthanthatafterthetreatmentwithlosartanalone.
ThediastolicBPsignicantlydecreasedfrom98±16to87±6mmHgduringthelosartantreatment,whereasthediastolicBPdecreasedfrom98±16to81±8mmHgduringtheL/HCTZtreatment.
ThediastolicBPduringthetreatmentwithL/HCTZwassignicantlylowerthanthatduringthetreatmentwithlosartanalone.
ThepercentageofpatientshavingachievedtargetBPofo130/80mmHgduringthetreatmentwithlosartanaloneandL/HCTZwas12and32%,respectively,andwerenotstatisticallydifferentbetweenbothtreatmentperiods.
Therewerenosignicantchangesinotherparametersduringeithertreatmentperiod.
DISCUSSIONThisstudydemonstratedthatthetreatmentwiththeL/HCTZtabletprovidedasignicantlygreatreductioninBPcomparedwithlosartanalone,consistentwiththepreviousstudiesinwhichARB+HCTZcombinationtherapyproducedmoresignicantBPreductionthanmonotherapywithARBordiuretics.
13ThismighthavederivedfromtheenhancedsuppressionofRAS,asweobservedthesignicantlygreaterincreaseofARCwithL/HCTZtreatmentthanlosartanalone.
Ontheotherhand,diureticshavebeenreportedtohavesomeadverseeffectsonthemetabolism,suchasinsulinresistance,hyperuricemiaandelectrolytedisturbances.
14Inthisstudy,however,theelevationinserumlevelsofglucoseanduricacidandthereductioninserumpotassiumlevelduringthetreatmentwithL/HCTZweresimilartothoseduringthetreatmentwithlosartanalone.
AsitwasexpectedthattheuseoflosartanandHCTZincombinationwouldcounteracteachother'spotentialadverseeffects,whichoccurwhentheyaregivenasamonotherapy,mostoftheundesirablemetabolicsideeffectsofthiazidewereminimizedbythecombinationwithlosartan.
Figure1Serumcreatinine(Cr),estimatedglomerularltrationrate(eGFR),serumcystatinC,serumpotassium,bloodsugar(BS),glycoalbumin(GA),serumuricacid(UA),serumlow-densitylipoproteincholesterol(LDL-C),atbaseline,after3monthsoftreatmentwithlosartanalone(opencircles,n25)andwithL/HCTZ(closedcircles,n25).
CombinationtabletofLosartanandhydrochlorothiazideKKinouchietal1145HypertensionResearchAlbuminuriaisanimportantpredictorofcardiovasculareventsandofprogressiontoend-stagerenaldiseaseindiabeticpatientswithhypertension.
15,16Inthisstudy,thereductioninUAEwiththe3-monthcombinationtherapywith50mgoflosartanand12.
5mgofHCTZwassimilartothatwiththelosartanalone.
Thiswasinconsistentwitharecentstudyshowingthatadd-on6-monthtreatmentwithalowsodiumdietor25mgofHCTZfurtherdecreasedproteinuriainpatientstreatedwith100mgoflosartan.
17AsourstudydemonstratedthattheBPreductionduringtheL/HCTZtabletwassignicantlygreaterthanthelosartanalone,moreextendedobservationperiodmighthaveprovidedthesignicantdifferenceinproteinuriabetweenbothtreatments.
BothtreatmentswithlosartanandL/HCTZsignicantlyandsimilarlyimprovedtheCAVI,whichreectsarterialstiffnesswithlessdependencyonBPcomparedwithPWV,11andAI,whichisamarkerforthemagnitudeofarterialwavereections.
PreviousstudieshavedemonstratedthatARBimprovesarterialstiffnessassessedbyPWVindependentlyofloweringBPindiabeticpatients18andinhypertensivepatients,19andthatthiazidediureticshavealimitedeffectonarterialstiffness.
20,21Inaddition,angiotensin-convertingenzymeinhibitorsandARBshavebeenreportedtoreduceAIinhypertensivepatients,22andmonotherapywithHCTZhasbeenreportednottodecreaseAIevenifitreducedBPtoanextentsimilartoARB.
23Onthebasisoftheseevidences,ARBhasaBP-independentbenetonvascularwallproperties.
Thus,theimprovementoftheCAVIandAImightresultfromtheRASblockadebutnotfromthereductioninBPorHCTZtreatment.
Asarterialstiffnessisapowerfulandindependentriskfactorformortalityincardiovascularevents,24L/HCTZcouldbeoneoftheusefulantihypertensivedrugswithcardiovascularprotectiveproperties.
Althoughpreviousstudieshavedemonstratedthebenetsofaxed-doseangiotensin-convertingenzymeinhibitor–diureticcombinationforAIcomparedwithdiureticmonotherapy,25therehavenotbeenanystudieswhichexaminedtheeffectsofaxed-doseARB–diureticcombinationonCAVIorAIincomparisonwithdiureticalone.
Furtherstudieswillbeneededtoelucidatethedifferencebetweenthetwotreatments.
Thereweresomeotherlimitationsininterpretingtheresultsofthisstudy.
First,thetrialpopulationwascomparativelysmallinnumber.
Second,wedidnotcomparetheL/HCTZtabletwithdose-titratedARBs.
Thus,thisstudydidnotprovideadenitiveconclusionregardingthesuperiorityoftheL/HCTZtabletvs.
losartanaloneinreducingBP.
However,asnodifferenceinadverseeffectswasobservedduringthetreatmentperiods,theL/HCTZtabletisasafeandusefulantihypertensivedrugindiabeticpatientswithhypertension.
Finally,prognosticeventswerenotexamined.
FurtherstudieswillbeneededtoconrmthebenetsoftheL/HCTZtherapy.
Inconclusion,thetreatmentwiththetabletcombiningL/HCTZexertedagreaterreductioninBPthanlosartanmonotherapy,anddecreasedalbuminuriaandarterialstiffnessassessedbyCAVIandAItothelevelssimilartolosartanmonotherapy.
AsmetabolicadverseeffectsweresimilarintheL/HCTZtreatmentandlosartantreatment,theL/HCTZtabletcouldbeasafeandpotentantihypertensivedruginJapanesediabeticpatientswithhypertension.
Figure2Plasmaactivereninconcentration(ARC)andplasmaaldosteroneconcentration(PAC)serumbrainnatriuricpeptide(BNP),urinaryalbuminexcretion(UAE),thecardio-anklevascularindex(CAVI),augmentationindex(AI)andbloodpressure(BP)atbaseline,after3monthsoftreatmentwithlosartanalone(opencircles,n25)andwithL/HCTZ(closedcircles,n25).
*Po0.
05vs.
thebaseline.
zPo0.
05vs.
thelosartanalone.
CombinationtabletofLosartanandhydrochlorothiazideKKinouchietal1146HypertensionResearchCONFLICTOFINTERESTTheauthorsdeclarenoconictofinterest.
ACKNOWLEDGEMENTSThisworkwassupportedinpartbygrantsfromtheMinistryofEducation,ScienceandCultureofJapan(16790474and17390249).
WealsoappreciatetheskillfulsecretarialworkofMsChikaMiki.
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