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28/8/2017 Metformin in the treatment of adults with type 2 diabetes mellitus - UpToDate

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Metformininthetreatmentofadultswithtype2diabetesmellitus

Author: DavidKMcCulloch,MD
SectionEditor: DavidMNathan,MD
DeputyEditor: JeanEMulder,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jul2017.|Thistopiclastupdated:Apr06,2017.

INTRODUCTIONTwoclassesoforalhypoglycemicdrugsdirectlyimproveinsulinaction:biguanides(only
metforminiscurrentlyavailable)andthiazolidinediones(TZDs).Intheabsenceofcontraindications,
metforminisconsideredthefirstchoicefororaltreatmentoftype2diabetes(table1).A2006consensus
statementfromtheAmericanDiabetesAssociation(ADA)andtheEuropeanAssociationfortheStudyof
Diabetes(EASD),updatedregularly,proposedthatmetformintherapy(intheabsenceofcontraindications)be
initiated,concurrentwithlifestyleintervention,atthetimeofdiabetesdiagnosis[13].

Thepharmacology,efficacy,andsideeffectsofmetforminforthetreatmentofdiabeteswillbereviewedhere.
Ageneraldiscussionofinitialtreatmentoftype2diabetesandtheroleofmetformininthepreventionof
diabetes,inthetreatmentofpolycysticovarysyndrome,andingestationaldiabetesarereviewedseparately.

(See"Initialmanagementofbloodglucoseinadultswithtype2diabetesmellitus".)
(See"Preventionoftype2diabetesmellitus",sectionon'Metformin'.)
(See"Metforminfortreatmentofthepolycysticovarysyndrome".)
(See"Gestationaldiabetesmellitus:Glycemiccontrolandmaternalprognosis",sectionon'Metformin'.)

MECHANISMOFACTIONMetformin'smajoreffectistodecreasehepaticglucoseoutputbyinhibiting
gluconeogenesis[47].Inaddition,metforminincreasesinsulinmediatedglucoseutilizationinperipheral
tissues(suchasmuscleandliver),particularlyaftermeals,andhasanantilipolyticeffectthatlowersserum
freefattyacidconcentrations,therebyreducingsubstrateavailabilityforgluconeogenesis[4,8,9].Asaresult
oftheimprovementinglycemiccontrol,seruminsulinconcentrationsdeclineslightly[10,11].Metforminhas
alsobeenshowntodecreasefoodintakeandbodyweight[12,13].

Metforminsuppressesgluconeogenesisbyinhibitingaspecificmitochondrialisoformofglycerophosphate
dehydrogenase(mGPD),anenzymeresponsibleforconvertingglycerophosphatetodihydroxyacetone
phosphate,therebypreventingglycerolfromcontributingtothegluconeogenicpathway[14,15].Inaddition,
inhibitionofmGPDleadstoaccumulationofcytoplasmicNADHandadecreaseintheconversionoflactateto
pyruvate,limitinglactatecontributionstohepaticgluconeogenesis.Excessglycerolandlactatearereleased
intotheplasma.

MetforminalsoactivatestheenzymeAMPactivatedproteinkinase(AMPK)inhepatocytes,whichappearsto
bethemechanismbywhichmetforminlowersserumlipidconcentrations[1618].AMPKdependentinhibitory
phosphorylationofacetylCoAcarboxylasesAcc1andAcc2suppresseslipogenesisandlowerscellularfatty
acidsynthesisinliverandmuscle[19,20].MetforminworksthroughthePeutzJeghersprotein,LKB1,to
regulateAMPK[21].LKB1isatumorsuppressor,andactivationofAMPKthroughLKB1mayplayarolein
inhibitingcellgrowth[22].(See'Cancerincidence'below.)

INDICATIONSInitialtreatmentofpatientswithtype2diabetesmellitusincludeseducation,withemphasis
onlifestylechangesincludingdiet,exercise,andweightreductionwhenappropriate(table1).Intheabsence
ofspecificcontraindications,metforminisconsideredinitialpharmacologictherapyformostpatientswithtype
2diabetesbecauseofglycemicefficacy,absenceofweightgainandhypoglycemia,generaltolerability,and

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favorablecost[2,3,2325].Itcanbeinitiatedatthetimeofdiabetesdiagnosis,alongwithconsultationfor
lifestyleintervention.Forhighlymotivatedpatientswithglycatedhemoglobin(A1C)neartarget(<7.5percent),
athreetosixmonthtrialoflifestylemodificationbeforeinitiatingmetforminisreasonable.Otheroptionsfor
initialtherapyarediscussedelsewhere.(See"Initialmanagementofbloodglucoseinadultswithtype2
diabetesmellitus",sectionon'Choiceofinitialtherapy'.)

Afterasuccessfulinitialresponsetometformin,themajorityofpatientsfailtomaintainglycemictargetsand
requiretheadditionofasecondoraloraninjectableagent.Forpatientswhofailinitialtherapy,therearea
numberofagentsthatareavailableandcanbeusedincombinationwithmetformin.(See"Managementof
persistenthyperglycemiaintype2diabetesmellitus",sectionon'Treatmentoptions'.)

Althoughmetforminisbeingevaluatedasanadjuncttoinsulintherapyintype1diabetes,thereare
insufficientdatatorecommendmetforminforpatientswithtype1diabetes.Thistopicisreviewedseparately.
(See"Managementofbloodglucoseinadultswithtype1diabetesmellitus",sectionon'Adjunctivetherapy'.)

GLYCEMICEFFICACY

MonotherapyMetformintypicallylowersfastingbloodglucoseconcentrationsbyapproximately20percent
andA1Cby1.5percent,aresponsesimilartothatachievedwithasulfonylurea[10,11,2628].TheUnited
StatesMulticenterMetforminStudyGroup,forexample,randomlyassignedobesepatientswithtype2
diabeteswhowereinadequatelycontrolledondietalonetoeithermetforminorplacebo[29].After29weeks,
themeanA1Cconcentrationwas7.1percentinthemetformingroupascomparedwith8.6percentinthe
placebogroup.

CombinationtherapyCombinationsofdrugsareoftennecessarytoachieveoptimalglycemiccontrol.
Metformincanbegivenincombinationwithsulfonylureas,insulin,glinides,alphaglucosidaseinhibitors,
thiazolidinediones(TZDs),sodiumglucosecotransporter2(SGLT2)inhibitors,glucagonlikepeptide1(GLP
1)agonists,anddipeptidylpeptidase4(DPP4)inhibitors.Inmetaanalysesofplacebocontrolledtrials
evaluatingdifferentdrugs(sulfonylureas,TZDs,meglitinides,alphaglucosidaseinhibitors,GLP1agonists,
DPP4inhibitors)asaddontherapytometformin,reductionsinA1Cwithdifferentclassesofdrugsranged
from0.42to1.0percentagepoints[30,31].Combinationtherapyisdiscussedindetailinseparately.(See
"Managementofpersistenthyperglycemiaintype2diabetesmellitus",sectionon'Combinationwith
metformin'and"Sulfonylureasandmeglitinidesinthetreatmentofdiabetesmellitus"and"Thiazolidinediones
inthetreatmentofdiabetesmellitus",sectionon'Combinationtherapy'and"Alphaglucosidaseinhibitorsand
lipaseinhibitorsfortreatmentofdiabetesmellitus"and"Glucagonlikepeptide1receptoragonistsforthe
treatmentoftype2diabetesmellitus"and"Dipeptidylpeptidase4(DPP4)inhibitorsforthetreatmentoftype
2diabetesmellitus"and"Amylinanalogsforthetreatmentofdiabetesmellitus".)

WEIGHTLOSSInthosewhoareobese,metforminpromotesmodestweightreductionoratleastweight
stabilization(figure1)[10,32].Thisisincontrasttotheweightgainoftenassociatedwithinsulinor
sulfonylureatreatment[10,32].Inonelargestudy,forexample,patientstreatedwithglyburidegainedan
averageof1.6kg,whereasthosereceivingmetforminlost2.9kg[33].Inatrialcomparingmetforminwitha
longactingglucagonlikepeptide1(GLP1)receptoragonist,weightlossat52weekswassimilarinthetwo
groups(2.29and2.22kgfordulaglutide1.5mgandmetformin,respectively)[34].

CARDIOVASCULAREFFECTSMetformindoesnothaveadversecardiovasculareffects,anditappearsto
decreasecardiovasculareventsincertainpopulations[3538].Asexamples:

IntheUnitedKingdomProspectiveDiabetesStudy(UKPDS),obesepatientswhowereassignedinitially
toreceivemetforminratherthansulfonylureaorinsulintherapyhadadecreasedriskoftheaggregate
diabetesrelatedendpoint(endpointsincludedbothmacrovascularandmicrovascularcomplications)and
allcausemortality[38].DuringthepostinterventionalobservationperiodoftheUKPDS,reductionsinthe
riskofmacrovascularcomplicationsweremaintainedinthemetformingroup.(See"Glycemiccontroland
vascularcomplicationsintype2diabetesmellitus",sectionon'UKPDS'.)

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Inanothertrial,390patientstreatedwithinsulinwererandomlyassignedtometforminversusplacebo
[35].Afterfouryears,meanA1C(7.5versus7.9percent)andbodyweight(85versus90kg)were
significantlylowerinthemetformingroup.Inaddition,therewasadecreaseintheriskofthesecondary
macrovascularendpoint,whichwasacompositeof13vasculareventsincludingmyocardialinfarction
(MI),heartfailure,stroke,amputation,andsuddendeath(eventrates15versus18percent,adjusted
hazardratio[HR]0.6,95%CI0.40.9).

Inasubsequentmetaanalysisof170trialsand25observationalstudiesevaluatingtheeffectsoforalor
injectablediabetesmedicationsasmonotherapyandincombinationwithotheroralagentsorinsulinon
cardiovascularmortality,intermediateoutcomes(A1C,bodyweight,lipidprofiles),andadverseevents,
metforminwasassociatedwithlowerlongtermcardiovascularmortalitycomparedwithsulfonylurea
monotherapy(baseduponfindingsfromtworandomizedtrialsandthreeobservationalstudies)[37].Asan
example:

Inonetrial,304Chinesepatientswithestablishedcoronaryheartdiseaseandtype2diabeteswere
randomlyassignedtometforminversusglipizide[36].Lifestyleinterventionandothertreatmentfor
coronaryheartdiseaseweresimilarinbothgroups.Afterthreeyears,themeanachievedA1Clevelwas
similar(7.0and7.1percent)inthetwogroups.However,bodyweight,waistcircumference,andbody
massindex(BMI)weresignificantlylowerinthemetformingroup.Asimilarproportionofpatientsineach
groupreceivedinsulin(30and25patientsinmetforminandglipizidegroups,respectively).Aftera
medianfollowupoffiveyears,therewerefewercardiovascularevents(compositeofnonfatalMI[five
versussix],stroke[10versus15],arterialrevascularization[21versus25],ordeathfromcardiovascular
oranycause[7versus14])inthemetformingroup(totalevents43versus60HR0.54,95%CI0.30.9).
Themainlimitationofthistrialwasthesmallnumberofevents.Inaddition,itisnotpossibletodistinguish
thepotentialbeneficialeffectofmetforminfromtheputativeadverseeffectofsulfonylurea.However,the
resultssupporttheuseofmetformin,particularlyinpatientswithcoronaryheartdisease.

Metforminhaslipidloweringactivity,resultinginadecreaseinserumtriglycerideandfreefattyacid
concentrations,asmalldecreaseinserumlowdensitylipoprotein(LDL)cholesterolconcentrations,anda
verymodestincreaseinserumhighdensitylipoprotein(HDL)cholesterolconcentrations[11,26,27].

AnunexpectedfindinginaUKPDSsubstudywasthattheearlyadditionofmetformininpatientsalready
receivingasulfonylureawasassociatedwitha96percentincreaseintheriskofdiabetesrelateddeath
comparedwithcontinuationofthesulfonylureaalone(p=0.04)[38].Itisnotclearhowtointerpretthesedata
astheanalysesaresecondaryandnotinternallyconsistent.Ontheonehand,metforminappearstobe
beneficialasinitialmonotherapyinoverweightpatientswithtype2diabetes.However,theevidenceofan
adverseeffectwiththeearlyadditionofmetformintosulfonylureatherapyistroubling.

Theresultsoflargertrialsarereassuring,althoughtheywerenotspecificallydesignedtoaddressthisissue
[3941].IntheActioninDiabetesandVascularDisease:PreteraxandDiamicronMRControlledEvaluation
(ADVANCE)trial,themajorityofsubjectsweretakingmetformin,regardlessoftreatmentassignment(74and
67percentofthoseassignedtointensiveversusconventionaltherapy,respectively).However,asulfonylurea
(gliclazide)wasused,bydesign,byasignificantlygreaterproportionofsubjectsintheintensivegroup(90
versus16percent).Therewasnodifferenceinmortalitybetweenintensiveandconventionallytreated
subjectsintheADVANCEtrial.

CANCERINCIDENCEObservationaldatasuggestthatuseofmetformindecreasescancerincidence[42
44].Inmetaanalysesofpredominantlycasecontrolandcohortstudiesinpatientswithtype2diabetes,use
ofmetformincomparedwithnonuseorwithuseofotherdiabetestreatmentwasassociatedwithareduced
riskofallcancers(relativerisk[RR]0.61,95%CI0.540.70)[45,46],colorectalcancer(RR0.64,95%CI
0.540.76)[4547],andlowercancermortality(RR0.66,95%CI0.490.88)[45,48].Amongthemeta
analyses,thesummaryeffectestimatesweresimilar.Withtheexceptionofcolorectalcancer,therewas
significantheterogeneityamongtheindividualstudies.

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Incontrasttotheobservationaldata,ametaanalysisofrandomizedtrialscomparingmetforminwitha
comparator(thiazolidinedione[TZD],sulfonylurea,dipeptidylpeptidase4[DPP4]inhibitor,orplacebo)didnot
showareductionincancerincidence[49].Themajorityofthetrialswerenotdesignedtoexplorecancer
outcomes,whichwerenotuniformlycollectedoradjudicatedtherefore,malignancieswerenotedasserious
adverseevents.Inaddition,averagefollowupforcanceroutcomeswasonlyfouryears.Alongerintervalmay
berequiredtoadequatelyassesscanceroutcomes.Thus,prospectiveclinicaltrialdataarerequiredto
confirmorrefutethisprotectiveeffect.

ApossiblemechanismbywhichmetforminmaydecreasecancerincidenceisregulationofAMPactivated
proteinkinase(AMPK)throughLKB1[21].LKB1isatumorsuppressor,andactivationofAMPKthroughLKB1
mayplayaroleininhibitingcellgrowth.StudiesinC.eleganshavesuggestedthatinactivationofmTORC1
withsubsequentinhibitionofgrowththroughinductionofACAD10mayexplaintheanticancereffectsof
metformin[50].(See'Mechanismofaction'above.)

SIDEEFFECTS

GastrointestinalThemostcommonsideeffectsofmetforminaregastrointestinal,includingametallic
tasteinthemouth,mildanorexia,nausea,abdominaldiscomfort,andsoftbowelmovementsordiarrhea[27].
Thesesymptomsareusuallymild,transient,andreversibleafterdosereductionordiscontinuationofthe
drug.Inclinicaltrials,only5percentofstudysubjectsdiscontinuemetforminbecauseofthegastrointestinal
sideeffects.

VitaminB12deficiencyMetforminreducesintestinalabsorptionofvitaminB12inupto30percentof
patientsandlowersserumvitaminB12concentrationsin5to10percentbutonlyrarelycausesmegaloblastic
anemia[51,52].InsomepatientswithvitaminB12deficiency,peripheralneuropathymayprecedethe
developmentofmegaloblasticanemia[53].Thedoseanddurationofuseofmetformincorrelateswiththerisk
ofvitaminB12deficiency[52,54].Inonestudy,thisreductionappearedtobeduetopoorabsorptionofB12in
theileumandwascorrectedbyadministrationoforalcalciumcarbonate(1.2gdaily)[55].Inanotherstudy,
supplementationwithadailymultivitaminwasassociatedwithalowerprevalenceofB12deficiency[56].(See
'Dosingandmonitoring'belowand"TreatmentofvitaminB12andfolatedeficiencies".)

LacticacidosisBiguanidetherapyintype2diabeteswithphenformininthepastorcurrentlywith
metformincanleadtolacticacidosis[57,58].Symptomsoflacticacidosisarenonspecificandmayinclude
anorexia,nausea,vomiting,abdominalpain,lethargy,hyperventilation,andhypotension.Serumlactate
concentrationsareusuallylessthan2mmol/Linpatientstakingmetformin,valuesthatarenotclinically
important.Moreseriouslacticacidaccumulationoccurswithsuperimposedshockorinthepresenceof
predisposingconditionstometformintoxicityasdescribedbelow[59].(See'Predisposingfactors'below.)

Metformininducedlacticacidosiscanoccurinpatientswithnormalrenalandhepaticfunction.Onesuch
settingisapurposefulmetforminoverdose[60,61].Inaddition,patientswiththegeneticdiabetessyndrome,
maternallyinheriteddiabetesanddeafness(MIDD),areatincreasedriskofdevelopinglacticacidosiswith
metformintherapy.(See"Classificationofdiabetesmellitusandgeneticdiabeticsyndromes",sectionon
'GeneticdefectsinmitochondrialDNA'and"Causesoflacticacidosis".)

IncidenceTheincidenceoflacticacidosisinmetforminusersappearstobeverylow[58,6264].Ina
reviewof11,800patientstreatedwithmetforminforameanofapproximatelytwoyears,onlytwopatients
developedlacticacidosis(incidenceninecasesper100,000personyearsofexposure)[58].Thiscompares
witharateof40to64per100,000patientyearsinthosetakingphenformin,apreviouslyapprovedbiguanide
thatwasremovedfromthemarketbecauseofthissideeffect.

Theverylowincidenceoflacticacidosiswithmetforminwasconfirmedbyasystematicreviewof347
randomizedtrialsandprospectivecohortstudiesrepresenting70,490patientyearsofmetforminuseand
55,451patientyearsinthecomparatorgroup[63].Therewerenocasesoflacticacidosis.Almostonehalfof
thestudiesallowedinclusionofpatientswithaserumcreatinineabove1.5mg/dL(133micromol/L),and
almostallallowedinclusionofpatientswithatleastonestandardcontraindicationtometformintherapy.
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However,thenumberofpatientswhoactuallyhadthesecontraindicationswasnotpresentedand,therefore,
thesafetyofmetformininthepresenceofstandardcontraindicationscouldnotbeassessed.(See
'Contraindications'below.)

PredisposingfactorsDespiteitsrarity,lacticacidosisrelatedtometforminremainsaconcernbecause
ofthehighcasefatalityrate.Mostcaseshaveoccurredinpatientswithconditionsthatpredisposeto
hypoperfusionandhypoxemia(acuteorprogressiverenalimpairment,acuteorprogressiveheartfailure,
acutepulmonarydecompensation,sepsis,dehydration)[27,57,65].Thisfindinghasresultedinthe
developmentofstandardcontraindicationstometformin,includingimpairedrenalfunction,heartfailure,liver
disease,andexcessivealcoholintake.(See'Contraindications'below.)

Anumberofpatientstreatedwithmetforminhaveoneormoreofthesecontraindications(mostoftenrenal
impairmentorheartfailure).Thefrequencywithwhichthisoccurshasvariedindifferentseries,witharange
of14to27percentinmostreports[6671].

Despitetheappreciabledisregardofcontraindications,theincidenceofmetformininducedlacticacidosisis
notincreasing.Thisfindinghasledtoareevaluationofthestandardcontraindicationstometformintherapy,
particularlyinpatientswithanestimatedglomerularfiltrationrate(eGFR)above30mL/min[72].(See
'Contraindications'below.)

TreatmentTheroleofbicarbonatetherapyinpatientswithlacticacidosisandshockortissuehypoxiais
notwellestablished,exceptinseveremetabolicacidosis,becauseofconcernaboutpossibleworseningof
intracellularacidosis.(See"Bicarbonatetherapyinlacticacidosis".)

However,thismaynotapplytometforminassociatedlacticacidosissince,inpatientswithconcurrentrenal
failure,bicarbonatehemodialysiscanbothcorrecttheacidosisandremovemetformin[73,74].Treatmentof
metformininducedlacticacidosisisdiscussedelsewhere.(See"Metforminpoisoning".)

CONTRAINDICATIONSMetforminiscontraindicatedinpatientswithfactorspredisposingtolactic
acidosis.

Thesepredisposingfactors/contraindicationsare:

Impairedrenalfunction(estimatedglomerularfiltrationrate[eGFR]<30mL/min)
Concurrentactiveorprogressiveliverdisease
Activealcoholabuse
Unstableoracuteheartfailureatriskofhypoperfusionandhypoxemia
Pasthistoryoflacticacidosisduringmetformintherapy
Decreasedtissueperfusionorhemodynamicinstabilityduetoinfectionorothercauses

ThepreciseeGFRthresholdsforthesafeuseofmetforminremainuncertain.Improvedclinicaloutcomeswith
metforminhavebeenreportedinobservationalstudiesofpatientswithdiabetesandheartfailure[7577],
renalimpairment(eGFR45to60mL/min)[7779],orchronicliverdiseasewithhepaticimpairment[77].In
onesystematicreviewof17observationalstudiescomparingregimenswithandwithoutmetformin,metformin
usewasassociatedwithlowerallcausemortalityamongpatientswithheartfailure,renalimpairment,or
chronicliverdiseasewithhepaticimpairment[77].Inaddition,metforminuseinpatientswithrenalimpairment
orheartfailurewasassociatedwithfewerheartfailurereadmissions.

Onthebasisoftheseandotherstudies,theUSFoodandDrugAdministration(FDA)reviseditslabelingof
metformin,whichpreviouslyhadidentifiedmetforminascontraindicatedinwomenandmenwithserum
creatininelevels1.4mg/dL(124micromol/L)and1.5mg/dL(133micromol/L),respectively[72].Theuseof
metforminiscontraindicatedinpatientswithaneGFR<30mL/min,andtheinitiationofmetforminisnot
recommendedinpatientswithaneGFRbetween30and45mL/min.Forpatientstakingmetforminwhose
eGFRfallsbelow45mL/min,thebenefitsandriskofcontinuingtreatmentshouldbeassessed,whereas
metforminshouldbediscontinuediftheeGFRfallsbelow30mL/min.
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Thefollowingisourapproachtotheadministrationofmetformin:

ForpatientswithaneGFR<30mL/min,wedonotprescribemetformin.

ForpatientswithaneGFR45mL/min,weprescribefulldose.

ForpatientswithaneGFRof30to44mL/minandintheabsenceofactivekidneydisease(eg,a
glomerulonephritis),someUpToDateauthorsandeditorswouldnotinitiatemetformin,whereasothers
wouldreducethemetformindosebyhalf(nomorethan1000mgperday)andincreasethefrequencyof
kidneyfunctionmonitoring,althoughtherearelittleornodatatosupporttheglycemicefficacy[71,80]
andsafetyofthelatterapproach.Lowerdosesofmetforminmaynotproducethedesiredloweringof
glycemiaandmaynotbesafer.

ForpatientstakingmetforminwhoseeGFRfallsbelow45mL/min,wereducethemetformindosebyhalf
(nomorethan1000mgperday)withmorefrequenttestingofeGFR,althoughtherearefewdatato
supporttheefficacyandsafetyofthisapproach.

ForpatientstakingmetforminwhoseeGFRfallsbelow30mL/min,wediscontinuemetformin.

Wedonotviewstablecompensatedheartfailureasacontraindicationtometforminuse.

WeadvisepatientswithaneGFRbetween30and60mL/minorstableheartfailuretostoptaking
metforminiftheydevelophypoxemiaoranyconditionassociatedwithhypoxemia,dehydration,orsepsis
(eg,influenza,urinarytractinfection)untiltheconditionhasresolved.(See"Heartfailureindiabetes
mellitus",sectionon'Metformin'.)

Wedonotviewfattyliverdiseasegenerallyasacontraindicationunlesstherearemajormanifestations,
suchasreducedsyntheticfunctionorcirrhosis.

Weprefertoholdmetformininpatientswhoareabouttoreceiveintravenousiodinatedcontrastmaterial
(withpotentialforcontrastinducedrenalfailure)iftheyareatincreasedriskforlacticacidosis
independentofmetformin.Suchpatientsincludethosewithvascularinstability,hypotension,and
potentialhypoperfusion.Inaddition,owingtothepotentialformetforminaccumulationinthesettingof
renalinsufficiencyandthecurrentcontraindicationtousingmetformininpatientswitheGFR<30mL/min,
metforminshouldbediscontinuedinsuchpatientspriortoanyradiologicprocedureswithintravenousor
intraarterialcontrast.Metforminshouldnotberestartedinsuchpatientsuntiltheyarenolongeratrisk
forlacticacidosisanddemonstratedtohaveeGFR>30mL/min.Serumcreatinineistypicallyassessed
twotothreedaysaftercontrastadministration.

Therelationshipamongmetforminuse,intravenouscontrastadministration,andtheoccurrenceoflactic
acidosisisnotwellstudied.Therationaleforstoppingmetforminpriortointravenousiodinatedcontrastisto
avoidthepotentialforhighplasmametforminconcentrations(andlacticacidosis)ifthepatientdevelops
contrastinducedacuterenalfailure.Patientmortalityinreportedcasesofmetformininducedlacticacidosis
maybeashighas50percent[81].

Inasystematicreviewofstudiesandevidencebasedguidelinesontheuseofintravenouscontrastin
patientstakingmetformin,theonlyavailabledatawerefromcasereportsandcaseseries[82].Themajorityof
casesofmetforminrelatedlacticacidosisoccurredinpatientswithabnormalrenalfunctionwhoreceived
intravenouscontrastmedium.Theriskofmetformininducedlacticacidosisinpatientswithnormalrenal
functionwhoreceiveintravenouscontrastisunknownbutappearstoberare.

TheAmericanCollegeofRadiologysuggeststhereisnoneedtodiscontinuemetforminpriortoorfollowing
theintravenousadministrationofiodinatedcontrastmediainpatientswithnoevidenceofacutekidneyinjury
andwitheGFR30mL/min[83].Thisrecommendationwaspresumablypredicatedontheincreasing
uncertaintyregardingtheroleofcontrastdyeproceduresinacutekidneyinjury[84]andtheoverallrarityof
lacticacidosisinmetformintreatedpatients(see'Incidence'above).Untilmoredataareavailable,however,

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andtakingintoaccountthemorbidityandmortalityofmetforminassociatedlacticacidosis,weprefertohold
metformininpatientsatincreasedriskforlacticacidosis(eg,vascularinstability,hypotension,
potentialhypoperfusion)independentofmetformin,asdescribedinthebulletabove.(See"Pathogenesis,
clinicalfeatures,anddiagnosisofcontrastinducednephropathy".)

DOSINGANDMONITORINGMetforminisabsorbedrapidlyfromthesmallintestine,withpeakplasma
concentrationsattainedintwohours.Itisnotboundtoplasmaproteins,isnotmetabolized,andisrapidly
excretedintheurine[27,85].

Metforminisavailableas500,850,or1000mgtablets,andshouldbetakenwithmeals.Webeginwith500
mgoncedailywiththeeveningmealand,iftolerated,addasecond500mgdosewithbreakfast.Thedose
canbeincreasedslowly(onetableteveryonetotwoweeks)asnecessary[27].Theusualeffectivedoseis
1500to2000mg/daythemaximumrecommendeddoseof2550mg/day(850mgthreetimesdaily)provides
onlymarginallybetterglycemiccontrolandisoftennottoleratedduetogastrointestinalsideeffects[1].For
patientswithestimatedglomerularfiltrationrate(eGFR)between30and45mL/min,wetypicallyincreasethe
frequencyofkidneyfunctionmonitoringandpotentiallyreducethemetformindosebyhalf(nomorethan1000
mgperday),althoughtherearelittleornodatatosupporttheglycemicefficacyandsafetyofthelatter
approach.MetforminshouldnotbeusedinpatientswitheGFR<30mL/min.(See'Contraindications'above.)

Extendedreleasetabletsarealsoavailable[86,87],althoughpatientswhoaredoingwellonimmediate
releasemetforminshouldprobablycontinuewiththispreparation,asthereislittle,ifany,additionalbenefit
documentedwiththelongactingpreparation.Combinationtabletsofmetforminandsulfonylureas,
thiazolidinediones(TZDs),ordipeptidylpeptidase4(DPP4)inhibitorsarealsoavailable.

Forpatientstakingmetformin,wemeasureA1Ceverythreetosixmonthsserumcreatinineannuallyand
hemoglobin,hematocrit,andredcellindicesatdiagnosisandatothertimesifthepatientdevelopssymptoms
suggestiveofanemia,neuropathy,ordeterioratingrenalfunction.Ifanemiaispresent,vitaminB12andfolate
shouldbemeasuredandtreatedaccordingly.Becausedatasuggestthatanemiaisnotasensitiveindicatorof
B12deficiency,andwithaprevalenceofB12deficiencythatmayapproach10percentovertimein
metformintreatedpatients[52],routineB12monitoringmaybeconsidered.(See"Clinicalmanifestationsand
diagnosisofvitaminB12andfolatedeficiency".)

SOCIETYGUIDELINELINKSLinkstosocietyandgovernmentsponsoredguidelinesfromselected
countriesandregionsaroundtheworldareprovidedseparately.(See"Societyguidelinelinks:Diabetes
mellitusinadults".)

SUMMARYANDRECOMMENDATIONS

Metformintypicallylowersglycatedhemoglobin(A1C)concentrationsbyapproximately1.5percent,is
notassociatedwithweightgain,andislesslikelytocausehypoglycemiathansulfonylureasandinsulin.
(See'Introduction'aboveand'Glycemicefficacy'above.)

Intheabsenceofspecificcontraindications,wesuggestmetforminasinitialtherapyinmostpatientswith
type2diabetes(Grade2B)(table1).Insulincanalsobeconsideredafirstlinetherapyforallpatients
withtype2diabetes,particularlypatientspresentingwithA1C>10percent,fastingplasmaglucose>250
mg/dL(13.9mmol/L),randomglucoseconsistently>300mg/dL(16.7mmol/L),orketonuria.(See"Initial
managementofbloodglucoseinadultswithtype2diabetesmellitus"and"Insulintherapyintype2
diabetesmellitus".)

Wesuggestinitiatingmetforminatthetimeofdiabetesdiagnosis,alongwithconsultationforlifestyle
intervention(Grade2C).Thedoseofmetforminshouldbetitratedtoitsmaximallyeffectivedose(usually
1700to2550mgperdayindivideddoses)overonetotwomonths,astolerated.

Alternativeinitialtreatmentforpatientswithcontraindicationsorintolerancetometforminisreviewed
separately.(See'Contraindications'aboveand"Initialmanagementofbloodglucoseinadultswithtype2

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diabetesmellitus",sectionon'Initialpharmacologictherapy'.)

Themostcommonsideeffectsofmetforminaregastrointestinal,includingametallictasteinthemouth,
mildanorexia,nausea,abdominaldiscomfort,andsoftbowelmovementsordiarrhea.(See'Sideeffects'
above.)

Lacticacidosisisanextremelyuncommonsideeffect.However,itremainsaconcernbecauseofthehigh
casefatalityrate.Mostcaseshaveoccurredinpatientswithconditionsthatpredisposetohypoperfusion
andhypoxemia(acuteorprogressiverenalimpairment,acuteorprogressiveheartfailure,acute
pulmonarydecompensation,sepsis,dehydration).(See'Predisposingfactors'above.)

Thepreciseserumcreatininelimitsandestimatedglomerularfiltrationrate(eGFR)thresholdsforthesafe
useofmetforminremainuncertain.Inclinicalpractice,someexpertsuseaneGFRof30mL/minasa
thresholdforthesafeuseofmetformin.ForapatientwithaneGFRbetween30and45mL/min,we
typicallyreducethemetformindosebyhalf.(See'Contraindications'above.)

Wedonotviewstablecompensatedheartfailureasacontraindicationtometforminuse.(See
'Contraindications'above.)

Weadvisesuchpatientstostoptakingmetforminiftheyhaveanyillnesslikelytoadverselyaffect
hydrationstatusorkidneyfunctionorcausehypoxemia,suchasinfluenzaorurinarytractinfection,until
theconditionhasresolved.

Weprefertoholdmetformininpatientswhoareabouttoreceiveintravenousiodinatedcontrastmaterial
(withpotentialforcontrastinducedrenalfailure)orundergoasurgicalprocedure(withpotential
compromiseofcirculation),iftheyareatincreasedriskforlacticacidosisindependentofmetformin.Such
patientsincludethosewithvascularinstability,hypotension,andpotentialhypoperfusion.Metformin
shouldalsobediscontinuedinpatientswitheGFR<30mL/minpriortoanyradiologicprocedureswith
intravenousorintraarterialcontrast.(See'Contraindications'above.)

Forpatientstakingmetformin,wemeasureA1Ceverythreetosixmonths,serumcreatinineannually,
andhemoglobin,hematocrit,andredcellindicesatdiagnosisandatothertimesifthepatientdevelops
symptomssuggestiveofanemia,neuropathy,ordeterioratingrenalfunction.(See'Dosingand
monitoring'above.)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS

Summaryofglucoseloweringinterventions

Expected
decreaseinA1C
Intervention Advantages Disadvantages
with
monotherapy,%

Tier1:Wellvalidatedcore

Step1:Initialtherapy

Lifestyleto 1.0to2.0 Broadbenefits Insufficientformostwithinfirstyear


decrease
weightand
increase
activity

Metformin 1.0to2.0 Weightneutral GIsideeffects,contraindicatedwith


renalinsufficiency

Step2:Additionaltherapy

Insulin 1.5to3.5 Nodoselimit,rapidly Onetofourinjectionsdaily,


effective,improvedlipid monitoring,weightgain,
profile hypoglycemia,analoguesare
expensive

Sulfonylurea 1.0to2.0 Rapidlyeffective Weightgain,hypoglycemia


(especiallywithglibenclamideor
chlorpropamide)

Tier2:Lesswellvalidated

Thiazolidinedione 0.5to1.4 Improvedlipidprofile Fluidretention,HF,weightgain,


(pioglitazone),potential bonefractures,expensive,potential
decreaseinMI increaseinMI(rosiglitazone)
(pioglitazone)

GLP1agonist 0.5to1.0 Weightloss Requiresinjection,frequentGIside


effects,longtermsafetynot
established,expensive

Othertherapy

Alpha 0.5to0.8 Weightneutral FrequentGIsideeffects,three


glucosidase times/daydosing,expensive
inhibitor

Glinide 0.5to1.5* Rapidlyeffective Weightgain,threetimes/daydosing,


hypoglycemia,expensive

Pramlintide 0.5to1.0 Weightloss Threeinjectionsdaily,frequentGI


sideeffects,longtermsafetynot
established,expensive

DPP4inhibitor 0.5to0.8 Weightneutral Longtermsafetynotestablished,


expensive,possibleincreasedrisk
ofHFwithsaxagliptin

SGLT2inhibitor 0.5to0.7 Weightloss,reductionin Vulvovaginalcandidiasis,urinary


systolicbloodpressure tractinfections,longtermsafetynot
established

A1C:glycatedhemoglobinGI:gastrointestinalMI:myocardialinfarctionHF:heartfailureGLP1:glucagonlikeprotein
1DPP4:dipeptidylpeptidase4SGLT2:sodiumglucosecotransporter2.
*RepaglinidemoreeffectiveinloweringA1Cthannateglinide.

Modifiedwithpermissionfrom:NathanDM,BuseJB,DavidsonMB,etal.MedicalManagementofHyperglycemiainType2
Diabetes:AConsensusAlgorithmfortheInitiationandAdjustmentofTherapy:AconsensusstatementoftheAmerican
DiabetesAssociationandtheEuropeanAssociationfortheStudyofDiabetes.DiabetesCare200932:193203.Copyright
2009AmericanDiabetes.
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Graphic56876Version9.0

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Metaboliceffectsofdrugtherapyintype2diabetes

Meanchangesinbodyweight(top)andfastingplasmainsulinconcentrations
(bottom)oversixyearsinpatientswithtype2diabetesmellitusintheprimarydiet
failuregroupwhowereallocatedtotherapywithinsulin(red),sulfonylurea(blue),
or,onlyinobesesubjects,metformin(green).Leftpanelsshowdatafromnonobese
patients,rightpanelsshowdatafromobesepatients.Metformindidnotincrease
weightorraiseplasmainsulin.ToconvertplasmainsulinvaluestoU/mLdivideby
6.

Datafrom:UnitedKingdomProspectiveDiabetesStudy24:a6year,randomized,
controlledtrialcomparingsulfonylurea,insulin,andmetformintherapyinpatientswith
newlydiagnosedtype2diabetesthatcouldnotbecontrolledwithdiettherapy.United
KingdomProspectiveDiabetesStudyGroup.AnnInternMed1998128:165.

Graphic55968Version2.0

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Contributor Disclosures
David K McCulloch, MD Nothing to disclose David M Nathan, MD Nothing to disclose Jean E Mulder,
MD Nothing to disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conict of interest policy

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