Download - Insulin – Pharmacology, Types of Regimens, And Adjustments

25/06/2015 InsulinPharmacology,TypesofRegimens,andAdjustmentsEndotextNCBIBookshelf

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NCBIBookshelf.AserviceoftheNationalLibraryofMedicine,NationalInstitutesofHealth.

DeGrootLJ,BeckPeccozP,ChrousosG,etal.,editors.Endotext[Internet].SouthDartmouth(MA):MDText.com,Inc.2000.

InsulinPharmacology,TypesofRegimens,andAdjustmentsLisaKroon,PharmD,CDEProfessorandExecutiveViceChair,DepartmentofClinicalPharmacy,SchoolofPharmacy,UniversityofCaliforniaSanFrancisco,SanFrancisco,[email protected]

IraD.Goldfine,M.D.ProfessorofMedicine,DepartmentofMedicine,DiabetesandEndocrineResearch,UniversityofCaliforniaSanFrancisco/Mt.ZionMedicalCenter,SanFrancisco,[email protected]

SinanTanyolac,M.D.VisitingScientist,DepartmentofMedicine,UniversityofCaliforniaSanFrancisco,SanFrancisco,[email protected]

LastUpdate:October1,2010.

INTRODUCTION

Withtheintroductionofseveralnewinsulinssince1996,insulintherapyoptionsfortype1andtype2diabeticshaveexpanded.Insulintherapiesarenowabletomorecloselymimicphysiologicinsulinsecretionandthusachievebetterglycemiccontrolinpatientswithdiabetes.Thischapterreviewsthepharmacologyofinsulins(usingacomparativeapproach),typesofinsulinregimensandtherapeuticadjustmentofthem,andprovidesanoverviewofinsulinpumptherapy.

PHARMACOLOGY

In1922,Canadianresearcherswerethefirsttodemonstrateaphysiologicresponsetoinjectedanimalinsulininapatientwithtype1diabetes.In1955,insulinwasthefirstproteintobefullysequenced.Theinsulinmoleculeconsistsof51aminoacidsarrangedintwochains,anAchain(21aminoacids)andBchain(30aminoacids)thatarelinkedbytwodisulfidebonds (Figure1).ProinsulinistheinsulinprecursorthatistransportedtotheGolgiapparatusofthebetacellwhereitisprocessedandpackagedintogranules.Proinsulin,asinglechain86aminoacidpeptide,iscleavedintoinsulinandCpeptide(aconnectingpeptide)botharesecretedinequimolarportionsfromthebetacelluponstimulationfromglucoseandotherinsulinsecretagogues.WhileCpeptidehasnoknownphysiologicfunction,itcanbemeasuredandifpresent,indicatesapersonhasfunctioningbetacells.

Figure1 InsulinStructure

Insulinexertsitseffectonglucosemetabolismbybindingtoinsulinreceptorsthroughoutthebody.Uponbinding,insulinpromotesthecellularuptakeofglucoseintofatandskeletalmuscleandinhibitshepaticglucoseoutput,thusloweringthebloodglucose.(seeInsulinsignalingandaction:glucose,lipids,protein)

Commerciallyavailableinsulinsareusedforallpatientswithtype1diabetesinwhominsulinisrequiredforsurvival,andforpatientswithtype2diabeteswhendiet/exercise,oralagentsandotherinjectablehypoglycemicagents(i.e.,incretinemimeticagents/GLP1analogs)nolongerprovideadequateglucosecontrol.

SourcesofInsulin

WiththeavailabilityofhumaninsulinbyrecombinantDNAtechnologyinthe1980s,useofanimalinsulindeclined

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dramatically.Beefinsulin,beefporkandporkinsulinarenolongercommerciallyavailable.TheFDAmayallowforpersonalimportationofbeefinsulinfromaforeigncountryifapatientcannotbetreatedwithhumaninsulin .Beefinsulindiffersfromhumaninsulinby3aminoacidsandporkinsulindiffersbyoneaminoacid .

Currently,intheUSA,mostinsulinsusedareeitherhumaninsulinand/oranalogsofhumaninsulin.TherecombinantDNAtechniqueforhumaninsulininvolvesinsertionofthehumanproinsulingeneintoeitherSaccharomycescerevisiae(bakersyeast)oranonpathogeniclaboratorystrainofEscherichiacoli(Ecoli)whichserveastheproductionorganism.Humaninsulinisthenisolatedandpurified .

InsulinAnalogs

RecombinantDNAtechnologyhasallowedforthedevelopmentandproductionofanalogstohumaninsulin.Withanalogs,theinsulinmoleculestructureismodifiedslightlytoalterthepharmacokineticspropertiesoftheinsulin,primarilyaffectingtheabsorptionofthedrugfromthesubcutaneoustissue.TheB26B30regionoftheinsulinmoleculeisnotcriticalforinsulinreceptorrecognitionanditisinthisregionthataminoacidsaregenerallysubstituted .Thus,theinsulinanalogsarestillrecognizedbyandbindtotheinsulinreceptor.ThestructuresofthreeinsulinanalogsareshowninFigure2(insulinaspart,lisproandglulisine)andFigure3(insulinglargineanddetemir).

Figure2 InsulinAspart,GlulisineandLisproStructures

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Figure3 InsulinGlargineandDetemirStructures

Becauseinsulinanalogsaremodifiedhumaninsulin,thesafetyandefficacyprofilesoftheseinsulinshavebeencomparedtohumaninsulin .InsulinandIGF1receptorbindingaffinities(IGFinsulinlikegrowthfactor),metabolicandmitogenicpotenciesofinsulinlispro,insulinaspart,insulinglargineandinsulindetemirrelativetohumaninsulinhasbeenassessed.Insulinlisproandaspartaresimilartohumaninsulinonalloftheaboveparameters,exceptinsulinlisprowasfoundtobe1.5foldmorepotentinbindingtotheIGF1receptorcomparedtohumaninsulin.Insulinglarginewasfoundtohavea6to8foldincreaseinmitogenicpotencyandIGF1receptoraffinitycomparedtohumaninsulin.Insulindetemirwasfoundtotobemorethan5foldlesspotentthanhumaninsulininbiningtoIGF1.Whiletheclinicalsignificanceofthesedifferencesisnotknown,theylikelydonotrepresentanysignificantconcern .

Immunogenicity

Becauseporkandbeefinsulindifferfromhumaninsulinby1and3aminoacidsrespectively,theyaremoreimmunogenicthanexogenoushumaninsulin.Olderformulationsofinsulinwerelesspure,containingisletcellpeptides,proinsulin,Cpeptide,pancreaticpolypeptides,glucagons,andsomastostatin,whichcontributedtoimmunogenicityofinsulin .Componentsofinsulinpreparations(e.g.,zinc,protamine)andsubcutaneousinsulinaggregatesarealsothoughttocontributetoantibodyformation .Commerciallyavailablehumaninsulinsarenowvirtuallyfreeofcontaminantsandcontain



Patientswhoexperienceatrueallergicreactiontoinsulinoftenhavereceivedinsulininthepast,andexperiencetheallergicreactionafterinsulinisrestarted.AnotherallergicreactionseenwithanimalinsulinswasadelayedlocalreactionthatwasIgGmediated .InsulintherapycanalsoresultintheproductionofinsulinantibodiesoftheIgGclass,whichneutralizeinsulin.AnimmunologicalinsulinresistancecanoccurinpatientswithveryhightitersofIgGantibodies.

Lipodystrophyseenwithinsulinreferstotwoconditions:lipoatrophyandlipohypertrophy.Lipoatrophyisanimmunemediatedconditioninwhichthereislossoffatattheinsulininjectionsites .Lipoatrophyoccursmuchlessfrequentlywithpurifiedhumaninsulins.Treatmentforpatientswhowereonananimalinsulinwasinjectionwithhumaninsulinattheatrophiedsite.Lipohypertrophyisanonimmunologicalsideeffectofinsulinresultingfromrepeatedadministrationofinsulinatthesameinjectionsite.

Concentration

IntheUnitedStates,allinsulinsareavailableintheconcentrationof100units/ml(denotedasU100).Insulinsyringesaredesignedtoaccommodatethisconcentrationofinsulin.Regularhumaninsulin(HumulinR,Lilly)isavailableinamoreconcentratedinsulin,U500(500units/ml),howeverthispreparationisusedprimarilyinaspecializedinstitutionalsettingorforrarecasesofextremeinsulinresistance,whereverylargedosesofinsulin(generally>200unitsperday)arerequired.SpecificsyringesforU500insulinarenotavailableandextremecautionmustbetakenaseachmarkedunitonaU100syringewillactuallydeliver5unitsofinsulin.

OutsidetheUnitedStates,alessconcentratedinsulinpreparation,U40,(40units/ml)isstillavailableandsometimesused.SpecificU40syringesareusedwiththisinsulin.Itisimportantthatpatientstravelingfromonecountrytothenext,beawareoftheconcentrationofinsulintheyuse,andthattheappropriatesyringeisused.

PhysicalandChemicalProperties

Regularhumaninsuliniscrystallinezincinsulindissolvedinaclearsolution.Itmaybeadministeredbyanyparenteralroute:subcutaneous,intramuscular,orintravenous.Insulinaspart,glulisineandlisproarealsosolublecrystallinezincinsulin,butareintendedforsubcutaneous(subQ)injection.NPH,orneutralprotamineHagedorn,isasuspensionofregularinsulincomplexedwithprotaminethatdelaysitsabsorption.Insulinsuspensionsshouldnotbeadministeredintravenously.Allinsulins,exceptinsulinglargine,areformulatedtoaneutralpH.

LongactingInsulinglargineisasoluble,clearinsulin,andhasapHof4.0.ItsacidicpHiscriticalforitssubQabsorptioncharacteristicsandwillbediscussedfurtherunderpharmacokinetics.Insulinglargineshouldnotbemixedwithotherinsulins,andshouldonlybeadministeredsubcutaneously .

InsulindetemirisalongactinginsulinanalogthathasafattyacidcoupledtoitsothatitbindstoalbumininthesubQtissueresultingindelayedabsorption,proloningitsdurationofaction.Likeinsulinglargine,insulindetemirshouldnotbemixedwithotherinsulins,andshouldbeinjectedsubcutaneously.

Pharmacokinetics

Absorption

InsulinadministeredviaSCinjectionisabsorbeddirectlyintothebloodstream,withthelymphaticsystemplayingaminorroleintransport .TheabsorptionofhumaninsulinaftersubQabsorptionistheratelimitingstepofinsulinactivity.ThisabsorptionisinconsistentwiththecoefficientsofvariationofT50%(timefor50%oftheinsulindosetobeabsorbed)varying~25%withinanindividualandupto50%betweenpatients .Mostofthisvariabilityofinsulinabsorptioniscorrelatedtobloodflowdifferencesatthevarioussitesofinjection(abdomen,deltoid,gluteus,andthigh) .Forregularinsulin,theimpactofthisisa~2timesfasterrateofabsorptionfromtheabdomenthanothersubcutaneoussites .Theclinicalsignificanceofthisisthatpatientsshouldavoidrandomuseofdifferentbody

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regionsfortheirinjections.Forexample,ifapatientpreferstousetheirthighforanoontimeinjection,thissiteshouldbeusedconsistentlyforthisinjection.Forsimplicity,however,theabdomenisoftenrecommendedasthepreferredsiteofinjectionbecauseitistheleastsusceptibletofactorsaffectinginsulinabsorption(seeTable1).Insulinaspart,glulisineandlisproappeartohavelessdaytodayvariationinabsorptionratesandalsolessabsorptionvariationfromthedifferentbodyregions .Insulinglarginespharmacokineticprofileissimilarafterabdominal,deltoidorthighSCadministration .

AgeneralprincipleforfactorsthatcanalterinsulinabsorptionisthatwhenlocalbloodflowinthesubQtissueischanged,theabsorptionrateofinsulinwillalsobeaffected.AfactorthatincreasessubQbloodflowwillincreasetheabsorptionrateandviceversa.SeeTable1forfactorsthataffectinsulinabsorption.

Table1 FactorsAffectingInsulinAbsorption( )

Factor Comment

Exerciseofinjectedarea Strenuousexerciseofalimbwithin1hourofinjection.Clinicallysignificantforregularhumaninsulin.

Localmassage WhileitisOKtopressontheinjectionsitetopreventseepage,thesiteshouldnotberubbedvigorouslyormassaged.

Temperature Heatcanincreaseabsorptionrate.Avoidthesauna,shower,hotbathsoonafterinjection.Coldhastheoppositeeffect.

Siteofinjection Insulinisabsorbedfasterfromtheabdomen.Lessclinicallyrelevantwithrapidactinginsulins,insulinglargineandinsulindetemir.

Lipohypertrophy Injectionintohypertrophiedareasdelaysinsulinabsorption.

Jetinjectors Increaseabsorptionrate.

Insulinmixtures Absorptionratesareunpredictablewhensuspensioninsulinsarenotmixedadequately(i.e.,theyneedtoberesuspended).

Insulindose Largerdoseshavedelayinactionandincreasedduration.

Physicalstatus(solublevs.suspension)

Suspensioninsulinsmustbesufficientlyresuspendedpriortoinjectiontoreducevariability.

Distribution

CirculatinginsulinisdistributedinequilibriumbetweenfreeinsulinandinsulinboundtoIgGantibodies .Thepresenceofinsulinantibodiescandelaytheonsetofinsulinactivity,reducethepeakconcentrationoffreeinsulin,andprolongthebiologichalflifeofinsulin .

Elimination

Thekidneysandliveraccountforthemajorityofinsulindegradation.Normally,theliverdegrades~60%ofinsulinreleasedbythepancreas(insulindeliveredthroughportalveinbloodflow)andthekidneys~3545% .Wheninsulinisinjectedexogenously,thedegradationprofileisalteredsinceinsulinisnolongerdelivereddirectlytotheportalvein.ThekidneyhasagreaterroleininsulindegradationwithsubQinsulin(~60%),withtheliverdegrading~3040%

.

Becausethekidneysareinvolvedinthedegradationofinsulin,renaldysfunctionwillreducetheclearanceofinsulinandprolongitseffect.Thisdecreasedclearanceisseenwithbothendogenousinsulinproduction(eithernormalproductionorthatstimulatedbyoralagents)andexogenousinsulinadministration.Renalfunctiongenerallyneedstobegreatlydiminishedbeforethisbecomesclinicallysignificant .

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Pharmacodynamics

Theonset,peak,anddurationofeffectarethemostclinicallysignificantdifferencesamongtheinsulins.Insulinpharmacodynamicsreferstothemetaboliceffectofinsulin.Commerciallyavailableinsulinscanbecategorizedasrapidacting,shortacting,intermediateacting,andlongacting.ThecurrentinsulinsavailableintheUnitedStatesarelistedinTable2.Insulinpharmacodynamics(i.e.,onset,peakandduration)ofthevariousinsulins)areshowninTable3.Itisimportanttonotethatrangesarelistedfortheonset,peakandduration,accountingforintra/interpatientvariability.Eachpatientwillhaveanindividualpatternofresponse.Byhavingthepatientselfmonitortheirbloodglucosefrequently,thepatientspecifictimeactionprofileofthespecificinsulincanbebetterappreciated.Figures4a4c

graphicallyshowthetimeactivityprofilesforthevariousinsulins.

Table2I nsulinsCommerciallyAvailableintheUS

Category/NameofInsulin

Source BrandName(manufacturer) Preparation(s)

RapidActingInsulinLisproInsulinAspartInsulinGlulisine

RecombinantDNARecombinantDNARecombinantDNA

Humalog(Lilly)Novolog(NovoNordisk)Apidra(sanofiaventis)

vial,cartridge,disposablepenvial,cartridge,disposablepenvial,disposablepen

ShortActingRegularHuman

RecombinantDNA HumulinR(Lilly)NovolinR(NovoNordisk)

vialvial

IntermediateActingNPHHuman

RecombinantDNA HumulinN(Lilly)NovolinN(NovoNordisk)

vial,disposablepenvial

LongActingInsulinDetemirInsulinGlargine

RecombinantDNARecombinantDNA

Levemir(NovoNordisk)Lantus(sanofiaventis)

vial,disposablepenvial,cartridge,disposablepen

InsulinMixturesNPH/Regular(70%/30%)HumanLisproProtamine/Lispro(50%/50%)LisproProtamine/Lispro(75%/25%)AspartProtamine/Aspart(70%/30%)

RecombinantDNARecombinantDNARecombinantDNARecombinantDNA

Humulin70/30(Lilly)Novolin70/30(NovoNordisk)HumalogMix50/50(Lilly)HumalogMix75/25(Lilly)NovologMix70/30(NovoNordisk

vial,disposablepenvialvial,disposablepenvial,disposablepenvial,disposablepen

Note:Allinsulinanalogsareavailablebyprescriptiononly.OnAugust17,2009,NovoNordiskannouncedtheNovolinInnoletR,N,and70/30devicesandtheNovolinR,Nand70/30PenFillcartridgeswouldnolongerbeavailableafterDecember31,2009.

Table3I nsulinPharmacodynamics( )

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Insulin Onset(hr) Peak(hr) Duration(hr) Appearance

InsulinLispro within15min 1 35 Clear

InsulinAspart within15min 13 35 Clear

InsulinGlulisine .25.5 .51 4 Clear

Regular 1 24 58 Clear

NPH 12 410 14+ Cloudy

InsulinDetemir 34 68(thoughrelativelyflat) upto2024 Clear

InsulinGlargine 1.5 flat 24 Clear

LisproMix50/50 .25.5 .53 1424 Cloudy

LisproMix75/25 .255 .52.5 1424 Cloudy

AspartMix70/30 .1.2 14 1824 Cloudy

Note:Patientspecificonset,peak,durationmayvaryfromtimeslistedintable,

Peakanddurationareoftenverydosedependentwithshorterdurationofactionswith

smallerdosesandviceversa.

Figure4a PharmacodynamicProfilesofaRapidInsulinAnalog(insulinlispro)andRegularInsulin.



Figure4b PharmacodynamicProfilesofLongActingandIntermediateActing

BasalInsulins.



Figure4c PharmacodynamicProfile:LisproNPLinComparisonwithNPH

DoseDependentEffect

ThepharmacodynamicsofregularandNPHareparticularlyaffectedbythesizeofthedose .Largerdosescancauseadelayinthepeakandincreasethedurationofaction.Forexample,injecting4unitsofNPHwillhaveasignificantlydifferenttimeactionprofilecomparedto30unitsofNPH.

RapidActingInsulins

InsulinLispro(Humalog)

Insulinlispro[Lys(B28),Pro(B29)]isaninsulinanalogthatwasapprovedin1996(Humalog).TheB28(proline),B29(lysine)aminoacidsequenceoftheinsulinmoleculeisreversedtobelysineprolineresultinginarapidabsorption,within15minutes.Becauseitisabsorbedmorerapidly,itsonsetandpeakaresooner(anddurationshorter)comparedtoregularinsulin.Insulinlisproisalsoapprovedforinjectionimmediatelyafterameal.Becauseinsulinlisprocanbeinjectedjustbefore(orafter)themealversuswaiting30minuteswithregularinsulin,patientsmayfinditprovidesthemwithmoreflexibilityandconveniencefortheirmealtimeinsulininjection.Insulinlisprocanbemoreeffectiveinloweringpostprandialbloodglucoselevelsandhasareducedriskofhypoglycemiacomparedtoregularinsulin

.Thereasoninsulinlisproisassociatedwithlesshypoglycemiaisduetobettermatchingofinsulineffectandfoodabsorption .Insulinlisprohasbeenstudiedforuseininsulinpumpsand,FDAapprovedforthisindicationin2004. .Intherarecaseofseverehumaninsulinallergy,insulinlisprohasbeenshowntobelessimmunogenic .

InsulinAspart(Novolog)

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InsulinaspartisahumaninsulinanalogapprovedJune7,2000(Novolog).TheB28aminoacidprolineissubstitutedwithasparticacidresultinginarapidonsetofactivity.Insulinaspartshouldbeinjected510minutesbeforethemeal.Advantageslistedaboveforinsulinlisproarethesameforinsulinaspart .TheinsulinaspartisFDAapprovedforuseininsulinpumps .

Whileonamolarbasisinsulinaspartandlisprohaveidenticalinvivopotencycomparedtoregularhumaninsulin,higherpeakconcentrationsareachievedwiththerapidactinginsulins .Thus,whilea1:1conversionisoftenusedfortheinitialswitchfromregularinsulintoinsulinaspart,glulisineorlispro,overtime,apatientsrapidactinginsulindosemayneedtobeadjusted,oftenreduced.Thisdosingchangeisalsoduetothebettermatchingofthepeakoftheinsulinwiththemeal,thusachievingbetterpostprandialcontrol.

InsulinGlulisine(Apidra)

InsulinglulisineisarapidactinginsulinanaloguethatdiffersfromhumaninsulininthattheaminoacidasparagineatpositionB3isreplacedbylysineandthelysineinpositionB29isreplacedbyglutamicacid.Chemically,itis3Blysine29Bglutamicacidhumaninsulin.Wheninjectedsubcutaneously,itsonsetofactionismorerapidandachieveshigherconcentrationscomparedtohumaninsulinonaunitperunitbasis.Whenusedasamealtimeinsulin,thedoseshouldbegivenwithin15minutesbeforeamealorwithin20minutesafterstartingameal.Insulinglulisinealsoisbeingusedininsulinpumps .InsulinglulisinehasbeenavailableinUSAsince2007andFDAapprovedin2004.

ShortActingInsulin(Regular)

Regularinsulinhasanonsetofactionof3060minutes.Itshouldbeinjectedapproximately30minutesbeforethemeal.Adherencetothisschedulecanbeinconvenientanddifficultforsomepatients.

IntermediateActingInsulins(NPH)

NPH,whichstandsforNeutralProtamineHagedorn,wascreatedin1936byHansChristianHagedornandB.NormanJensen.Thesescientistsdiscoveredthattheeffectsofsubcutaneouslyinjectedinsulincouldbeprolongedbytheadditionofprotamine,aproteinthattheyobtainedfromthe"milt"orsemenofrivertrout.NPHinsuliniscategorizedasanintermediateactinginsulin,whoseonsetofactionisapproximately2hours,peakeffectat614hours,anddurationofactionupto24hours(dependingonthesizeofthedose).Intermediateactinginsulinscanserveabasalinsulinand/orprandialinsulindependingontimeofadministration.NPHinsulinisavailableinvariouscombinationswitheitherregularinsulinorshortactinginsulins(Table2).

LongActingInsulins

Longactinginsulinsservetoprovideabasal(orbaseline)levelofinsulin.

InsulinGlargine(Lantus)

Insulinglargine(21AGly30BaLArg30BbLArghumaninsulin)isaninsulinanalogapprovedApril20,2000(Lantus).Itconsistsoftwomodificationstohumaninsulin.TwoargininesareaddedtotheCterminusoftheBchainshiftingtheisoelectricpointoftheinsulinfromapHor5.4to6.7 .ThischangemakestheinsulinmoresolubleatanacidicpHandinsulinglargineisformulatedatapHof4.0 .ThesecondmodificationisattheA21position,whereasparagineisreplacedbyglycine.Thissubstitutionpreventsdeamidationanddimerisationthatwouldoccurwithacidsensitiveasparagine.Wheninsulinglargineisinjectedintosubcutaneoustissue,whichisatphysiologicpH,theacidicsolutionisneutralized.Microprecipitatesofinsulinglargineareformed,fromwhichsmallamountsofinsulinarereleasedthroughouta24hourperiod,resultinginalowlevelofinsulinthroughouttheday .Thebiologicalactivityofinsulinglargineisduetoitsabsorptionkineticsandnotadifferentpharmacodynamicactivity(e.g.,stimulationofperipheralglucoseuptake) .

Itiscriticalthatinsulinglarginenotbemixedinthesamesyringewithanyanotherinsulinorsolutionbecausethiswill

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alteritspHandthusaffectitsabsorptionprofile.Lantusmaybegivenatanytimeofday.InsulinglarginehasbeenshowntohavelessnocturnalhypoglycemiawhenusedatbedtimecomparedwithNPHinsulin .

InsulinDetemir(Levemir)

InsulindetemirisalongactinghumaninsulinanalogformaintainingthebasallevelofinsulinitstradenameisLevemir.ItisaninsulinanaloginwhichtheB30aminoacidisomittedandaC14fattyacidchain(myristicacid)isboundtotheB29lysineaminoacid.InsulindetemirisslowlyabsorbedduetoitsstrongassociationwithalbumininthesubQtissueandwhenitreachesthebloodstreamitagainbindstoalbumindelayingitsdistributiontotheperipheraltissues.

Storage

Allinsulinshaveanexpirationdatewhichislabeledondirectlyontheproduct(vials,cartridges,disposablepensandotherdeliverydevices)applieswhentheyareunopenedandrefrigerated.Unopened(i.e.,insulinnotcurrentlyinuse)insulinshouldbestoredintherefrigeratorat36F46F(2C8C).Insulinshouldneverbefrozenorstoredinanambienttemperaturegreaterthan86F(30C).Aninsulinvialinusemaybekeptatroomtemperature,below86F,or30C(insulinglulisineandNovoNordiskhumaninsulins,N,Rand70/30,shouldbestoredupto77Fonly),for28days,orabout1month(exceptforinsulindetemirandNovoNordiskhumaninsulins,whichcanbekeptforupto42days).Insulincartridges,disposablepensandotherdeliverydevicescanhavedifferentstoragerecommendationsforroomtemperature.Onceopened,insulincartridgesandpensshouldnotberefrigerated.

AdverseEffects

Themostsignificantadverseeffectofinsulinishypoglycemia.IntheDCCT(DiabetesControlandComplicationsTrial),intensiveinsulintherapywasassociatedwitha23foldincreaseinseverehypoglycemia(i.e.,apersonrequiringassistance) .Likewise,intheUKPDS(UnitedKingdomProspectiveDiabetesStudy),insulintherapyintheintensivelytreatedgroupresultedin1.8%rateofmajorhypoglycemicepisodescomparedto0.7%intheconventionalgroup .Allpatientsreceivinginsulinshouldbeawareofthesymptomsofhypoglycemiaandhowtotreatit.

Weightgainisanothersignificantsideeffectofinsulintherapy.Inpart,theweightgaincanbearesultoffrequenthypoglycemicepisodesinwhichpatientsoftenovertreat/overeatinresponsetohunger.Insulin,beingananabolichormone,alsopromotestheuptakeoffattyacidsintoadiposetissue.TheamountofweightgainintheDCCTandUKPDSassociatedwithinsulintherapywas4.6kgand4.0kgrespectively .However,lessweightgainisencounteredwithlongactinginsulinanalogs .

Trueallergicreactionsandcutaneousreactionsarerare(seeImmunogenicity).Toavoidlipohypertrophy,patientsshouldbeinstructedtorotatetheirinsulininjectionsites,preferablyrotatingwithinonearea(e.g.,abdomenavoid2inchradiusaroundnavel)andnotreusingforoneweek .

InJune2009,4retrospective,epidemiologicstudiesassessingtheriskofcancerfrominsulinuse,glargineinparticular,werepublishedonlineattheEuropeanAssociationfortheStudyofDiabetes'journalwebsite3oftheseEuropeanstudiesreportedanincreasedriskofcancerwithinsulinglargine.IntheGermanystudy,acorrelationbetweeninsulindoseandcancerriskwasfoundforallinsulintypes(humaninsulin,aspart,lisproorglargine)howeverafteradjustingfordose,insulinglarginewasfoundtohaveadosedependentincreasedriskofcancercomparedtohumaninsulin(e.g.,HR1.09,1.19and1.31foratotaldailydosesof10units,30unitsand50unitsrespectively). Themedianfollowuptimewasonly1.63years(1.31yearsforinsulinglargine)andbodymassindexwasnotaccountedfor.TheSwedishstudyfoundastatisticallysignificantincreasedriskofbreastcanceronlyinwomenwhousedinsulinglarginealone(RR1.99),butnotinthoseoninsulinglargineplusotherinsulins. TheScotlandstudydemonstratedaincreasedriskofcancer(HR1.55)forpatientsoninsulinglarginealone,whilethoseoninsulinglargineplusotherinsulinshadaslightlylowerincidenceofcancer(HR0.81)comparedtohumaninsulinonlyuserswhichwasnotstatisticallysignificant.

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Finally,intheUKstudy,nolinkbetweeninsulinglargineandcancerwasfound. Theseobservationalstudiesassessedlargepatientdatabasesandhavesignificant,inherentlimitationstogeneralizetheirconclusions,suchasthepotentialfordifferentpretreatmentcharacteristicsofthegroups,selectionbias,thesmallnumbersofcancercasesfound,andshortdurationoffollowup.Also,type2diabetesitselfisassociatedwithanincreasedriskofcolon,pancreasandbreastcancer.Furthermore,inarandomised,5year,openlabeltrialcomparingtheprogressionofretinopathyofNPHandinsulinglargineusers,noincreasedriskofcancerwasfoundinthe1017patientsample. Lastly,inananalysisof31randomizedcontrolledtrialsfromthesanofiaventissafetydatabase(phase2,3,and4studies),insulinglarginewasnotassociatedwithanincreasedriskofcancer,includingbreastcancer. Ofnote,themainstudyaffectingthesefindingsistheRosenstocketalstudycomparingglarginetoNPHthathadanapproximate5yearduration,whereas19ofthestudiesincludedhadveryshortdurations(approximately6months).OnJuly1,2009,theFDAissuedanearlycommunicationaboutthesafetyofLantusandisworkingwiththemanufacturertoreviewthecollectivedataanddeterminewhetheradditionalstudiesneedtobeperformed.Atthistime,thesedatadonotprovideconclusiveevidenceofanincreasedriskofcancerassociatedwithinsulinglargine.

TYPESOFREGIMENS

GeneralPrinciples

Type1Diabetes

Withdecreasingbetacellfunctionresultingindecreasedinsulinproduction,peoplewithtype1diabetesmayrequireinsulinforsurvival.Ingeneral,insulinopenictype1diabeticsgenerallyrequire0.51.0unitsperkgofbodyweightperdayofinsulin .Insulintherapyisofteninitiatedat0.50.75units/kg/day .Duringtheearlystagesoftype1diabetes,patientswillrequirelessinsulinbecausethebetacellsarestillproducingsomeinsulininsulinrequirementscanbeintherangeof0.10.6unitsperkgperday .Intensiveinsulintherapy(definedas3insulininjectionsdaily)isindicatedforpeoplewithtype1diabetesasthishasbeenshowntoprovidebetterglycemiccontrolthan1or2dailyinjectionsandreducethedevelopmentandprogressionofmicrovascularcomplications .

Type2Diabetes

Manypatientswithtype2diabeteswilleventuallyrequireinsulintherapy.Sincetype2diabetesisassociatedwithinsulinresistance,insulinrequirementscanexceed1unit/kg/day.IntheUKPDS,by9yearslessthan25%ofpatientstreatedwithasulfonylureaasmonotherapywereabletomaintainA1Clevels



Preprandialplasmaglucose70130mg/dl

Postprandialplasmaglucose



Figure5a.

Figure5b.

Figure5c.

TwicedailyInsulinRegimen(SplitMixedandPreMixedRegimens)

Twothirdsoftheinsulindoseisgiveninthemorningbeforebreakfastandonethirdisgivenbeforedinner.Premixedinsulinscanbeusedoramixtureofashortactinginsulin(e.g.,regular,insulinaspart/glulisine/lispro)andanintermediateactinginsulin(e.g.,NPH)(Figure6a) .[106]



Figure6a.

2/3totaldailydoseatbreakfast:givenas2/3NPHand1/3Regular(orinsulinaspart/glulisine/lispro)

1/3totaldailydoseatdinner:dividedinequalamountsofNPHandRegular(orinsulinaspart/glulisine/lispro)

ForpatientswhoexperiencenocturnalhypoglycemiawhenNPHisadministeredatdinnerwithashortactinginsulin,movingtheNPHdosetobedtimehelpsreducetheriskfornocturnalhypoglycemia .Conversely,NPHatdinnercanresultinfastinghyperglycemiaduetodissipationofinsulinactivityandthedawnphenomenon.MovingtheNPHdosetobedtimecanhelpresolvethisproblem (Figure6b).Anobviouslimitationtousingpremixedinsulinisreducedflexibilityindosingifthedoseisadjusted,bothtypesofinsulininthemixtureareadjusted.

Figure6b.

MultipleDailyInsulinInjectionRegimen:BasalplusPrandialInsulin

Manydifferenttypesofregimensarepossiblewithmultipledailyinjections.Regular,insulinaspart,glulisineandlisproareusedtoprovideprandialinsulin.NPH,insulinglargine,andinsulindetemirareusedtoprovidebasalinsulin.

Regular,insulinaspart/glulisine/lisprobeforemealsandNPH,insulinglargineorinsulindetemiratbedtime(Figure7a,7b).

Insulinaspart/glulisine/lisprobeforemealsandNPHtwicedaily(breakfastandbedtime)(Figure8).

[107]

[108]



Figure7a.

Figure7b.

Figure8.

InsulinPumps

Insulinpumporcontinuoussubcutaneousinsulininfusion(CSII)therapyisanotheroptionforintensiveinsulintherapy.Whilepumptherapyusedtobereservedforprimarilytype1diabetes,patientswithtype2diabetesarenowusinginsulinpumps .Patientsinitiatedoninsulinpumptherapyneedtobeveryknowledgeableaboutdiabetesmanagementandbepracticingselfmanagement.Patientsalreadyknowhowtocountcarbohydratesandadjusttheir

[109]



insulindoses.Potentialadvantagesofinsulinpumpsincludelessweightgain,lesshypoglycemia,andbettercontroloffastinghyperglycemiaduetothedawnphenomenoncomparedtomultipledailyinjections .

TimingofPrandialInsulinInjection

Thelagtimefrominjectingregularinsulinandeatingisapproximately30minuteswhileinsulinaspart/glulisine/lisprocanbeinjectedwithin15minutesofeating.Dependingonthelevelofhyperglycemiabeforemeals,thelagtimecanbeincreased.Rapidactinginsulinsallowpatientstoadjustinsulintomatchtheirlifestyleratherthanhavingtoadaptthetimingofmealstoamorefixedinsulinregimen .

Adjustments

Insulindosesshouldbeadjustedtoachieveglycemictargets.Itisalwaysbesttoerrontheconservativesidewhendosinginsulinatinitiationorwhenadjustingcurrentinsulintherapy.Typicallya1020%increaseordecreaseinaninsulindoseisappropriate.Ifapatientisexperiencinghypoglycemia,adjustmentoftheinsulindosecausingthehypoglycemiashouldbeaddressedpreferentiallyoverotherinsulindoseadjustments.Hyperglycemiaisadominoeffect:ifapatientishyperglycemicinthemorning,chancesaretheyremainhyperglycemicthroughouttheday.Therefore,adjusttheearliesttimeofhyperglycemiafirst .

AdjustmentofIntermediatetoLongActingInsulin

Whenadoseofintermediateorlongactinginsulinisadjusted,itisrecommendedtowaitatleast25daysbeforefurtherchangesinthedosetoassesstheresponse .

AdjustmentofOnceDailyEveningInsulin

TheFPGisusedtoadjusttheintermediatetolongactinginsulingivenintheevening.Acommonweeklytitrationscheduleusedis :

IftheFPGis>140mg/dl:Increaseby4units

IftheFPGis120140mg/dl:Increaseby2units

Forinsulinglargine,thefollowingtitrationschedulehasbeenstudiedandshowntocauselessnocturnalhypoglycemiacomparedtobedtimeNPHinsulin.Inthisstudy,insulinwastitrated,usingaforcedtitrationschedule,totargetaFPGof100mg/dl .

ForcedTitrationScheduleStartwith10unitsbedtimebasalinsulindoseadjustweekly

FPG(mg/dL) Increaseinsulindose

100120 2

120140 4

140180 6

180 8

Decreaseinsulindose(e.g.,24units/day)ifhypoglycemiaoccurs.(modifiedrecommendationfromreference112)

SupplementalInsulinforCorrectionofHyperglycemia

Regularinsulin,insulinaspart/glulisine/lisprocanbeusedtocorrectforhyperglycemia .Ingeneral,12unitsofinsulinwilllowerthebloodglucoseby3050mg/dl.Often1unitforevery50mg/dlabovetheglucosetargetisastartingsupplementaldose,adjustingforinsulinsensitivity .Anexampleofasupplementalinsulinregimenisasfollows:Forevery50mg/dlabovethepremealglucosetarget(e.g.,150mg/dl),add1unitofinsulin .So,ifa

[110] [111] [112] [113]

[114]

[115]

[116]

[117]

[118]

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1.

2.

3.

4.

personspremealglucosewas250mg/dl,2unitsofinsulinwouldbeaddedtotheusualdoseofpremealinsulin.Supplementalinsulincanalsobeusedforsnacks .

CarbohydrateCounting

Amoresophisticatedtypeofinsulinregimenisoneinwhichapatientdosestheirprandialinsulinbasedonthenumberofcarbohydrateseatenatthemeal.Bylearninghowtocounttheircarbohydrates,anddosingtheirinsulinaccordingly,patientsareaffordedflexibilityintheirmeals.Astartinginsulintocarbohydraterationoftenusedis1unitofinsulinforevery15gramsofcarbohydrate .Thisratioisadjustedbasedoninsulinsensitivityandmaybedifferentforeachmeal.Carbohydratecountingistoodifficultforsomepatients.Inthesepatients,mealportionsizesandestimatesofcarbohydrateservings(15grams)areconceptsthatcanbelearned.Medicalnutritiontherapyisacriticalcomponentoftherapyforpatientsoninsulin.

Acomprehensivediabeteseducationclass,thatteachesselfmanagementskills,suchashowtodoseprandialinsulinbymatchingittotheamountofcarbohydrateintakeareanexcellentresourcetofacilitatepatientsinadoptinganintensiveinsulintherapyregimen .

AdjustmentsforExercise

Exerciseimprovesinsulinsensitivity.Thus,whenapatientexercises,itisoftennecessarytodecreasetheinsulindose(andincreasecaloricintake).Formorningexercise,theprebreakfastinsulindoseshouldbereduced(~25%dependingonthedurationandintensityoftheexercise).Forlatemorning/earlyafternoonandeveningexercise,theprelunchandpredinnerinsulindoseshouldbereducedrespectively .Theeffectofexerciseoninsulinsensitivitycanlastformanyhourssoseveralinsulindosesmayneedtobeadjusted.

SelfMonitoringofBloodGlucose

Patientswhowerenotselfmonitoringtheirbloodglucose(SMBG)levelspriortoinsulinneedtobeeducatedhowtodothis,howtointerprettheirglucosereadings,andhowtotreathypoglycemiaifitoccurs.Involvementofdiabeteseducatorisextremelyusefulwheninitiatingpatientsoninsulintoprovidecomprehensiveselfmanagementtraining.TheADAcurrentlyrecommendthatpeoplewithtype1diabetesSMBGatleast3timesdailyandthosewithtype2diabetesatleastdaily .Mostglucosemetersarenowplasmareferenced,correlatingbettertotheADAsglycemicgoals.Plasmaglucoseconcentrationsareapproximately1015%higherthanwholebloodglucoseconcentrations .

SICKDAYGUIDELINES

Acommonmisconceptionamongpatientsisthatiftheyaresickenoughthattheydonteatorevenvomit,theyshouldnottaketheirdiabetesmedications,insulinincluded.Patientsshouldbeinstructedtocontinuetheirinsulintherapy,maintainfluidintake,eatsmallermealsastolerated,andtesttheirglucoselevelsevery14hours(ketonesaswellforpeoplewithtype1diabetes).Insulintherapyshouldbeadjustedbasedontheglucoselevels.Iftheglucoseis>240mg/dlwithmoderatetolargeketonuria,patientsshouldcontacttheirproviderimmediately .

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