Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for ...

213 Pages·2016·2.01 MB·English

CochraneDatabaseofSystematicReviews
Insulin monotherapy compared with the addition of oral
glucose-lowering agents to insulin for people with type 2
diabetes already on insulin therapy and inadequate glycaemic
control (Review)
VosRC,vanAvendonkMJP,JansenH,GoudswaardAN,vandenDonkM,GorterK,KerssenA,
RuttenGEHM
VosRC,vanAvendonkMJP,JansenH,GoudswaardAN,vandenDonkM,GorterK,KerssenA,RuttenGEHM.
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyoninsulin
therapyandinadequateglycaemiccontrol.
CochraneDatabaseofSystematicReviews2016,Issue9.Art.No.:CD006992.
DOI:10.1002/14651858.CD006992.pub2.
www.cochranelibrary.com
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAINLANGUAGESUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARYOFFINDINGSFORTHEMAINCOMPARISON . . . . . . . . . . . . . . . . . . . 4
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
Figure3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
ADDITIONALSUMMARYOFFINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 25
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
AUTHORS’CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
CHARACTERISTICSOFSTUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
DATAANDANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127
Analysis1.1.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome1Weight(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
Analysis1.2.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome2Weight(changefrom
baseline)[kg]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 131
Analysis1.3.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome3HbA1c(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 132
Analysis1.4.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome4HbA1c(changefrom
baseline)GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 133
Analysis1.5.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome5Fastingglucose(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 134
Analysis1.6.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome6Fastingplasmaglucose
(changefrombaseline)[mmol/L]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . 135
Analysis1.7.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome7Totalcholesterol(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
Analysis1.8.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome8Totalcholesterol(change
frombaseline)[mmol/l]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 137
Analysis1.9.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome9HDL-cholesterol(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138
Analysis1.10.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome10HDL-Cholesterol
(changefrombaselinemmol/L)GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . 139
Analysis1.11.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome11Triglyceride(change
frombaseline)[mmol/L]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
Analysis1.12.Comparison1Insulinmonotherapyversusinsulinplussulphonylurea,Outcome12Triglycerides(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141
Analysis2.1.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome1Weight(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 142
Analysis2.2.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome2Weight(changefrombaseline)
[kg]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
Analysis2.3.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome3HbA1c(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
Analysis2.4.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome4HbA1c(changefrombaseline)
[%]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon i
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Analysis2.5.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome5Totalcholesterol(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
Analysis2.6.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome6Totalcholesterol(changefrom
baseline)[mmol/L]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
Analysis2.7.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome7HDL-cholesterol(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
Analysis2.8.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome8HDL-cholesterol(change
frombaseline)[mmol/L]. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 149
Analysis2.9.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome9Triglycerides(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
Analysis2.10.Comparison2Insulinmonotherapyversusinsulinplusmetformin,Outcome10Triglyceride(changefrom
baseline)[mmol/L]GIV. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Analysis3.1.Comparison3Insulinmonotherapyversusinsulinpluspioglitazone,Outcome1HbA1c(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Analysis3.2.Comparison3Insulinmonotherapyversusinsulinpluspioglitazone,Outcome2Fastingglucose(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Analysis3.3.Comparison3Insulinmonotherapyversusinsulinpluspioglitazone,Outcome3Weight(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 153
Analysis4.1.Comparison4Insulinmonotherapyversusinsulinplusalpha-glucosidaseinhibitor,Outcome1Weight
(changefrombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 154
Analysis4.2.Comparison4Insulinmonotherapyversusinsulinplusalpha-glucosidaseinhibitor,Outcome2HbA1c
(changefrombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
Analysis4.3.Comparison4Insulinmonotherapyversusinsulinplusalpha-glucosidaseinhibitor,Outcome3Fasting
glucose(changefrombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
Analysis5.1.Comparison5InsulinmonotherapyversusinsulinplusDPP-4inhibitor,Outcome1Weight(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
Analysis5.2.Comparison5InsulinmonotherapyversusinsulinplusDPP-4inhibitor,Outcome2HbA1c(changefrom
baseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
Analysis5.3.Comparison5InsulinmonotherapyversusinsulinplusDPP-4inhibitor,Outcome3Fastingglucose(change
frombaseline). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
ADDITIONALTABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165
CONTRIBUTIONSOFAUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208
DECLARATIONSOFINTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
SOURCESOFSUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 209
DIFFERENCESBETWEENPROTOCOLANDREVIEW . . . . . . . . . . . . . . . . . . . . . 209
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 210
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon ii
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
[InterventionReview]
Insulin monotherapy compared with the addition of oral
glucose-lowering agents to insulin for people with type 2
diabetes already on insulin therapy and inadequate glycaemic
control
RimkeCVos1,MariëlleJPvanAvendonk2,HannekeJansen1,AlexanderNGoudswaard3,MaureenvandenDonk2,KeesGorter4,
AnneloesKerssen1,GuyEHMRutten1
1JuliusCenterforHealthSciencesandPrimaryCare,UniversityMedicalCenterUtrecht,Utrecht,Netherlands.2DutchCollegeof
GeneralPractitioners,GuidelineDevelopmentandResearch,Utrecht,Netherlands.3Houten,Netherlands.4Utrecht,Netherlands
Contact address: Rimke C Vos, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, PO Box
85500,Utrecht,3508AB,[email protected].
Editorialgroup:CochraneMetabolicandEndocrineDisordersGroup.
Publicationstatusanddate:New,publishedinIssue9,2016.
Reviewcontentassessedasup-to-date: 17November2015.
Citation: Vos RC, van Avendonk MJP, Jansen H, Goudswaard AN, van den Donk M, Gorter K, Kerssen A, Rutten GEHM.
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon
insulintherapyandinadequateglycaemiccontrol.CochraneDatabaseofSystematicReviews2016,Issue9.Art.No.:CD006992.DOI:
10.1002/14651858.CD006992.pub2.
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
ABSTRACT
Background
Itisunclearwhetherpeoplewithtype2diabetesmellitusoninsulin monotherapywhodonotachieveadequate glycaemiccontrol
shouldcontinueinsulinasmonotherapyorcanbenefitfromaddingoralglucose-loweringagentstotheinsulintherapy.
Objectives
Toassesstheeffectsofinsulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinmonotherapyfor
peoplewithtype2diabetesalreadyoninsulintherapyandinadequateglycaemiccontrol.
Searchmethods
We searchedthe Cochrane Central Register of ControlledTrials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, the World
HealthOrganization(WHO)InternationalClinicalTrialsRegistryPlatform(ICTRP)andreferencelistsofarticles.Thedateofthe
lastsearchwasNovember2015foralldatabases.
Selectioncriteria
Randomisedcontrolledclinicaltrialsofatleasttwomonths’durationcomparinginsulinmonotherapywithcombinationsofinsulin
withoneormoreoralglucose-loweringagentinpeoplewithtype2diabetes.
Datacollectionandanalysis
Tworeviewauthorsindependentlyselectedtrials,assessedriskofbias,extracteddataandevaluatedoverallqualityoftheevidenceusing
GRADE.Wesummariseddatastatisticallyiftheywereavailable,sufficientlysimilarandofsufficientquality.Weperformedstatistical
analysesaccordingtothestatisticalguidelinesintheCochraneHandbookforSystematicReviewsofInterventions.
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon 1
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
Mainresults
Weincluded37trialswith40treatmentcomparisonsinvolving3227participants.Thedurationoftheinterventionsrangedfrom2to
12monthsforparalleltrialsandtwotofourmonthsforcross-overtrials.
Themajorityoftrialshadanunclearriskofbiasinseveralriskofbiasdomains. Fourteentrialsshowedahighriskofbias, mainly
for performance and detection bias. Insulin monotherapy, including once-daily long-acting, once-daily intermediate-acting, twice-
dailypremixedinsulin,andbasal-bolusregimens(multipleinjections),wascomparedtoinsulinincombinationwithsulphonylureas
(17 comparisons: glibenclamide =11, glipizide =2, tolazamide =2, gliclazide =1, glimepiride =1), metformin(11 comparisons),
pioglitazone (fourcomparisons), alpha-glucosidase inhibitors (fourcomparisons: acarbose =3,miglitol=1),dipeptidylpeptidase-4
inhibitors(DPP-4inhibitors)(threecomparisons:vildagliptin=1,sitagliptin=1,saxagliptin=1)andthecombinationofmetformin
andglimepiride(onecomparison). Notrialsassessedall-causemortality,diabetes-relatedmorbidity orhealth-relatedqualityoflife.
Onlyonetrialassessedpatients’treatmentsatisfactionandshowednosubstantialdifferencesbetweentheadditionofeitherglimepiride
ormetforminandglimepiridetoinsulincomparedwithinsulinmonotherapy.
Insulin-sulphonylureacombinationtherapy(CT)comparedwithinsulinmonotherapy(IM)showedaMDinglycosylatedhaemoglobin
A1c(HbA1c)of-1%(95%confidenceinterval(CI)-1.6to-0.5);P<0.01;316participants;9trials;low-qualityevidence.Insulin-
metforminCTcomparedwithIMshowedaMDinHbA1cof-0.9%(95%CI-1.2to-0.5);P<0.01;698participants;9trials;low-
qualityevidence.Wecouldnotpooltheresultsofaddingpioglitazonetoinsulin.Insulincombinedwithalpha-glucosidaseinhibitors
comparedwithIMshowedaMDinHbA1cof-0.4%(95%CI-0.5to-0.2);P<0.01;448participants;3trials;low-qualityevidence).
InsulincombinedwithDPP-4inhibitorscomparedwithIMshowedaMDinHbA1cof-0.4%(95%CI-0.5to-0.4);P<0.01;265
participants;2trials;lowqualityevidence.InmosttrialstheparticipantswithCTneededlessinsulin,whereasinsulinrequirements
increasedorremainedstableinparticipantswithIM.
Wedidnotperformameta-analysisforhypoglycaemiceventsbecausetheincludedstudiesuseddifferentdefinitions..Inmosttrialsthe
insulin-sulphonylureacombinationresultedinahighernumberofmildepisodesofhypoglycaemia,comparedtotheIMgroup(range:
2.2to6.1episodesperparticipant inCTversus2.0to2.6episodesperparticipantinIM;low-quality evidence).Pioglitazone CT
alsoresultedinmoremildtomoderatehypoglycaemicepisodescomparedwithIM(range15to90episodesversus9to75episodes,
respectively; low-quality evidence. The trials that reported hypoglycaemic episodes in the other combinations found comparable
numbersofmildtomoderatehypoglycaemicevents(low-qualityevidence).
Theadditionofsulphonylureasresultedinanadditionalweightgainof0.4kgto1.9kgversus-0.8kgto2.1kgintheIMgroup(220
participants;7trials;low-qualityevidence).PioglitazoneCTcausedmoreweightgaincomparedtoIM:MD3.8kg(95%CI3.0to
4.6);P<0.01;288participants;2trials;low-qualityevidence.MetforminCTwasassociatedwithweightloss:MD-2.1kg(95%CI
-3.2to-1.1),P<0.01;615participants;7trials;low-qualityevidence).DPP-4inhibitorsCTshowedweightgainof-0.7to1.3kg
versus0.6to1.1kgintheIMgroup(362participants;2trials;low-qualityevidence).Alpha-glucosidaseCTcomparedtoIMshowed
aMDof-0.5kg(95%CI-1.2to0.3);P=0.26;241participants;2trials;low-qualityevidence.
UsersofmetforminCT(range7%to67%versus5%to16%),andalpha-glucosidaseinhibitorsCT(14%to75%versus4%to35%)
experiencedmoregastro-intestinaladverseeffectscomparedtoparticipantsonIM.Twotrialsreportedahigherfrequencyofoedema
withtheuseofpioglitazoneCT(range:16%to18%versus4%to7%IM).
Authors’conclusions
Theadditionofalloralglucose-loweringagentsinpeoplewithtype2diabetesandinadequateglycaemiccontrolwhoareoninsulin
therapyhaspositiveeffectsonglycaemiccontrolandinsulinrequirements.Theadditionofsulphonylureasresultsinmorehypoglycaemic
events.Additionalweightgaincanonlybeavoidedbyaddingmetformintoinsulin.Otherwell-knownadverseeffectsoforalglucose-
loweringagentshavetobetakenintoaccountwhenprescribingoralglucose-loweringagentsinadditiontoinsulintherapy.
PLAIN LANGUAGE SUMMARY
Combinationsofinsulinandoralglucose-loweringdrugsforpeoplewithtype2diabetesoninsulintreatment
Introduction
Manyguidelinesontype2diabetesrecommendaglycosylatedhaemoglobinA1c(HbA1c)levelbelow7%.HbA1clevelsintheblood
expressglucoseorglycaemiccontroloveralongertimeperiod(twotothreemonths).Duringthecourseoftype2diabetesitwillget
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon 2
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
moredifficulttoreachtheselevelswith’lifestyle’modification(diet,exerciseorboth)andoralglucose-loweringagentsalone.Finally,
asubstantialnumberofpeoplewillneedinsulintherapyforbetterglycaemiccontrol.Insulintherapycanbeinitiatedasinsulinalone,
calledmonotherapy(whichmeansthatoralglucose-loweringmedicationwillbestopped)orincombinationwithoralglucose-lowering
agents.Intheformercase,oralbloodglucose-loweringagentscanbeaddedatalaterstage,ifinsulinmonotherapyfailstoachievea
goodHbA1clevel.Hypoglycaemiaandweightgainarethemostcommonandwellknownsideeffectsofinsulintherapy.Addingoral
agentstoinsulincouldreducetherequiredinsulindoseandthusdecreasetheseinsulin-relatedsideeffects.However,therecouldbe
othersideeffectsspecifictothevariousoralbloodglucose-loweringdrugs.
Reviewquestion
Toassesstheeffectsofinsulinmonotherapyandtheadditionofanoralantidiabeticdruginpeoplewithtype2diabetesalreadytreated
withinsulinbutnothavinggoodglycaemiccontrol.
Background
Itisunclearwhetherpeoplewithtype2diabetesmellitusoninsulinalonewhodonotachievegoodglucoselevelsshouldcontinue
withinsulinaloneorcanbenefitfromaddinganoralantidiabeticdrugtotheirinsulintherapy.
Studycharacteristics
All37includedstudieswererandomisedcontrolledtrials(clinical studieswherepeopleare randomlyputintoone oftwoor more
treatmentgroups).Theirdurationrangedfrom2to12months.Thetotalnumberofparticipantswas3227.Severaltypesofinsulin
monotherapy (once-daily long- or intermediate-acting insulin, twice-daily premixedinsulin, multipleinjection therapywith short-
actinginsulin)werecomparedwithdifferenttypesofadditionalantidiabetictablets:sulphonylureas(suchasglibenclamide/glyburide),
metformin,alpha-glucosidaseinhibitors(suchasacarbose),pioglitazoneandDPP-4inhibitors(suchassaxagliptin).
Keyresults
TheadditionoforalagentstoinsulinmonotherapyreducedHbA1cby0.4%to1%.Mostcombinationsoforalantidiabeticagentswith
insulinresultedinareductioninthenecessaryinsulindoseperdaywhereastheinsulindoseperdayhadtobeincreasedorremainedstable
inparticipantswithinsulinmonotherapy.Instudiesreportinghypoglycaemicepisodessevereeventswererareandmildtomoderate
hypoglycaemiawasobservedinsimilarnumberswhencomparinginsulinmonotherapytotheadditionoforalantidiabeticagentsto
insulin. However,moststudiesadding sulphonylureastoinsulinreportedmore hypoglycaemicepisodes. Moreover,theaddition of
sulphonylureastoinsulin resultedinanadditional weightgainof 0.4kgto1.9kgcomparedwith -0.8kgto2.1kgintheinsulin
monotherapygroups.Pioglitazoneinsulincombinationtherapycausedonaverageanincreaseinweightof3.8kgcomparedwithinsulin
monotherapy.Thedifferenceinaverageweightgainwithmetformininsulincombinationtherapycomparedwithinsulinmonotherapy
was2.1kglessinfavourofthecombinationtherapy.Gastro-intestinalsideeffectssuchasflatulenceanddiarrhoeaweremostlyreported
withmetforminandalpha-glucosidaseinhibitors.Additionofpioglitazonetoinsulincomparedwithinsulinmonotherapyresultedin
morecasesofoedema(fluidretentioninthebody)andheartfailure.Onlyonestudyassessedparticipants’treatmentsatisfactionand
showednosubstantialdifferencesbetweentheadditionofglimepirideormetforminandglimepiridetoinsulincomparedwithinsulin
monotherapy.Nostudyassessedall-causemortality,diabetes-relatedmorbidityorhealth-relatedqualityoflife.
ThisevidenceisuptodateasofNovember2015.
Qualityoftheevidence
Almostathirdofthestudieshad30orfewerparticipants.Alotofstudiesseemedtobeunderpoweredandthuswereprobablynot
abletoanswertheirownresearchquestion.Thiscouldmeanthatpotentiallyimportantdifferencesbetweeninterventionandcontrol
groupswerenotdetected.Onlyfivestudieshadafollow-upof12months.
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon 3
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
CopinsuInsu SUMMARY OF FINDINGS FOR THE MAIN COMPARISON [Explanation]
yrighlinthlinm
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BACKGROUND Experimentalandobservationaltrialshaveshownthatexogenous
insulinmayleadtoincreasedatherosclerosis(Muis2005;Ruige
1998;Stout1990).Weightgainisanotherfrequentlyreportedad-
Descriptionofthecondition verseeffectofinsulin,withweightgainrangesfrom0.3kgto3.8
kg.SeveralDutchtrialsreportednoeffectornonegativeeffectson
Diabetesmellitusisametabolicdisorderresultingfromadefectin
health-relatedquality oflifeafterstartinginsulin treatment(De
insulinsecretion,insulinaction,orboth.Aconsequenceofthese
Grauw 2001;De Sonnaville 1998; Goddijn 1999;Goudswaard
defects is chronic hyperglycaemia and disturbances of carbohy-
2004a). On the other hand, many people with type 2 diabetes
drate, fat and protein metabolism. Long-term complications of
(and healthcare providers) are reluctant to initiate insulin ther-
diabetesmellitusincluderetinopathy,nephropathyandneuropa-
apy.Peoplewithtype2diabetesmaybeafraidofhypoglycaemia
thy.Theriskofcardiovasculardiseaseisincreased.
andweightgain,theymaybeuncomfortablewithdailyinjections,
TheUnitedKingdomProspectiveDiabetesStudy(UKPDS)and
theymightexperiencerestrictionsinlifestyleandfeelingsofguilt
its 10-year follow-up afterwards showed that tight glycaemic
andfailure(Brunton2005;Hunt1997;Korytkowski2002;Snoek
control can significantly reduce the development and progres-
2002).Inaddition,primarycarepatientstreatedwithinsulinre-
sionofmicrovascularcomplications(Holman2008;UKPDS33;
portedhigherdiabetes-relateddistresscomparedwithoral-ordiet-
UKPDS34).Thereissomeinconsistencyintheevidenceofthe
treatedpatients,whichisstableovertimeandmightbedifficult
effects of intensive treatment on macrovascular outcomes and
toalter(Delahanty2007;Karlsen2014).
mortality.Severallargelong-termclinical trialscomparing stan-
dard with intensive therapy did not show a significant reduc-
tionofcardiovascularoutcomesandmortality(ACCORD2008;
ADVANCE2008;Duckworth2009;Kooy2009).Intensivegly- Howtheinterventionmightwork
caemic control reduced the risk of microvascular complications
In the 1990s three reviews were executed comparing insulin
butincreasedtheriskofhypoglycaemia.Manyguidelinesontype
monotherapywithinsulin-oralglucose-loweringagentscombina-
2diabetesrecommendaglycosylatedhaemoglobinA1c(HbA1c)
tiontherapy(Johnson1996;Peters1991;Pugh1992).Thereviews
below7%forthemajorityofpeoplewithtype2diabetes,however,
didnotdistinguishbetweeninsulin-treatedandinsulin-naivepar-
apatient-centredapproachismoreandmoreadvocated,withthe
ticipants. Besides,theyonlyfocusedonsulphonylureasincom-
intenttoencourage anappreciationofthevariableandprogres-
binationwithinsulintherapyandexcludedtrialswithotheroral
sivenatureoftype2diabetes,thespecificroleofeachdrug,the
agents. Their conclusions differed. Peters 1991 concluded that
patientanddiseasefactorsthatdriveclinicaldecisionmakingand
combination therapyhasnoadditional value forinsulin-treated
theconstraintsimposedbyageandcomorbidity(Inzucchi2012).
peoplewithtype2diabetes,sinceitimprovedglycaemiccontrol
Duringthecourseoftype2diabetesitwillgetmoredifficultto
onlyslightlyanditdidnotproducenormalbloodglucoseconcen-
reach theHbA1c targetlevelswith ’lifestyle’modification (diet,
trations.ButPugh1992andJohnson1996concludedthatinsulin
exerciseorboth)andoralglucose-loweringagentsalone.Finally,
combination therapywithsulphonylureaswasmoreappropriate
asubstantialnumberofindividualswillneedinsulintherapyfor
thaninsulinmonotherapybecauseitwasmoreefficaciousandmay
betterglycaemiccontrol(Turner1999;Wright2002).
bemorecost-effective.Amorecomprehensivereviewonthecom-
bination of insulin and oral glucose-lowering agents in insulin-
naiveandinsulin-treatedpatientsdidnotmeetCochranecriteria
Descriptionoftheintervention
(Yki-Jarvinen2001).Itshowedthatinmosttrialsglycaemiccon-
Sincethenaturalcourseoftype2diabetescausesprogressivede- trolwasbetterandlessinsulinwasrequiredwiththecombination
clineofthepancreaticß-cellfunction,finallyoralglucose-lowering ofinsulinandoralglucose-loweringagentscomparedwithinsulin
agentsmaynotsufficeandexogenousinsulinwillberequiredina alone.Notably,thedifferenceintherequiredinsulindosebetween
substantialnumberofpeople.Atthatstageinsulintherapycanbe insulinmonotherapyandthecombinationtherapywassmallerin
initiatedasinsulinalone,thatismonotherapy(whichmeansthat participantswhowerealreadybeingtreatedwithinsulinthanin
oralglucose-loweringmedicationwillbestopped)orincombina- insulin-naiveparticipants.
tionwithoralglucose-loweringagents.Intheformercategoryof
people,oralbloodglucose-loweringagentscanbeaddedatalater
stage,ifmonotherapyfailstoachieveasufficientHbA1clevel.The Whyitisimportanttodothisreview
latterinterventionistheinterventionunderstudyinthisreview.
In 2004 a Cochrane Review was published on the comparison
ofinsulinmonotherapy versuscombinations ofinsulinandoral
Adverseeffectsoftheintervention glucose-loweringagentsininsulin-naive peoplewithtype2dia-
Hypoglycaemia, injection site reactions and weightgain are the beteswithpoorglycaemiccontroldespitemaximaldosagesoforal
mostcommonandwellknownadverseeffectsofinsulintherapy. glucose-loweringagents(Goudswaard2004b).Theauthorscon-
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon 6
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.
cludedthatbedtimeNeutralProtamineHagedorn(NPH)insulin Combinationsofinsulinwithoneormoreoralglucose-lowering
combinedwithoralglucose-loweringagentsprovidescomparable agent(s).
glycaemic control to insulin monotherapy, but with less weight
gainifmetforminwasused.
Control
Uptonow,nodefinitiveanswerhasbeenavailablewithregardto
Insulinmonotherapy.
thecomparison of insulin monotherapy versus combinations of
insulinandoralglucose-loweringagentsinpeoplewithtype2di-
abetesalreadyoninsulintherapy.Inotherwords:istheaddingof Typesofoutcomemeasures
anoralglucose-loweringagenttoinsulinbeneficialwithregardto
outcomessuchasglycaemiccontrol,weightgain,hypoglycaemia,
insulin dosage, health-relatedquality of life and other outcome Primaryoutcomes
parameters?Thissystematicreviewwilltrytoclarifythebenefitsof • All-causemortality
addinganoralbloodglucose-loweringagenttoinsulinmonother- • Diabetes-relatedmorbidity
apyinpeoplealreadyoninsulintherapy. • Adverseevents
Secondaryoutcomes
• Health-relatedqualityoflife
OBJECTIVES
• Patientsatisfaction
Toassesstheeffectsofinsulinmonotherapy comparedwith the • GlycosylatedhaemoglobinA1c(HbA1c)
additionoforalglucose-loweringagentstoinsulinmonotherapy • Fastingglucose
for people with type 2 diabetes already on insulin therapy and • Lipids
inadequateglycaemiccontrol. • Insulindose
Methodandtimingofoutcomemeasurement
METHODS
• Mortality:definedasall-causeanddiabetes-related
(cardiovascularmortality,mortalityduetoend-stagerenaldisease
orduetoamputation)andmeasuredatbaselineandfollow-up
Criteriaforconsideringstudiesforthisreview
withaminimumdurationoftwomonths.
• Diabetes-relatedmorbidity:definedasmyocardial
infarction,angina,heartfailure,stroke,renalfailure,amputation
Typesofstudies
(ofatleastonedigit),vitreoushaemorrhage,retinal
Weincludedrandomisedcontrolledtrials(RCTs)withaminimal photocoagulation,blindnessinatleastoneeye,orcataract
follow-upperiodoftwomonths. extractionandmeasuredatbaselineandfollow-upwitha
minimumdurationoftwomonths.
• Adverseeventssuchashypoglycaemicepisodes,weightgain,
Typesofparticipants
gastrointestinalsymptoms,heartfailureandmeasuredatbaseline
Participantswithtype2diabetesmellitus(accordingtotheappro-
andfollow-upwithaminimumdurationoftwomonths.
priate diagnostic criteriaatthetime)already oninsulin therapy
• Health-relatedqualityoflife:evaluatedbyavalidated
andinadequateglycaemiccontrol.Tobeconsistentwithchanges
instrumentandmeasuredatbaselineandfollow-upwitha
inclassificationanddiagnosticcriteriaoftype2diabetesmellitus
minimumdurationoftwomonths.
throughtheyears,thediagnosisshouldhavebeenestablishedus-
• Patientsatisfaction:evaluatedbyavalidatedinstrumentand
ingthestandardcriteriavalidatthetimeofthebeginningofthe
measuredatbaselineandfollow-upwithaminimumdurationof
trial(for exampleADA1997; ADA1999;WHO 1980;WHO
twomonths.
1985;WHO1998).Ideally,diagnosticcriteriashouldhavebeen
• HbA1c:measuredatbaselineandfollow-upwitha
described. If necessary, we used thestudy authors’ definition of
minimumdurationoftwomonths.
diabetesmellitus.
• Fastingglucose:definedasafteraperiodofeighthoursof
noteatingordrinkingwiththeexceptionofwaterandmeasured
Typesofinterventions atbaselineandfollow-upwithaminimumdurationoftwo
months.
• Lipids:definedastotalcholesterol,high-densitylipoprotein
Intervention (HDL)-cholesterol,low-densitylipoprotein(LDL)-cholesterol,
Insulinmonotherapycomparedwiththeadditionoforalglucose-loweringagentstoinsulinforpeoplewithtype2diabetesalreadyon 7
insulintherapyandinadequateglycaemiccontrol(Review)
Copyright©2016TheCochraneCollaboration.PublishedbyJohnWiley&Sons,Ltd.