insulin – pharmacology, types of regimens, and adjustments
DESCRIPTION
With the introduction of several new insulins since 1996, insulin therapy options for type 1 and type 2 diabetics haveexpanded. Insulin therapies are now able to more closely mimic physiologic insulin secretion and thus achieve betterglycemic control in patients with diabetes. This chapter reviews the pharmacology of insulins (using a comparativeapproach), types of insulin regimens and therapeutic adjustment of them, and provides an overview of insulin pumptherapy.TRANSCRIPT
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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
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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%
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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.
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Figure4b PharmacodynamicProfilesofLongActingandIntermediateActing
BasalInsulins.
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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
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Preprandialplasmaglucose70130mg/dl
Postprandialplasmaglucose
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Figure5a.
Figure5b.
Figure5c.
TwicedailyInsulinRegimen(SplitMixedandPreMixedRegimens)
Twothirdsoftheinsulindoseisgiveninthemorningbeforebreakfastandonethirdisgivenbeforedinner.Premixedinsulinscanbeusedoramixtureofashortactinginsulin(e.g.,regular,insulinaspart/glulisine/lispro)andanintermediateactinginsulin(e.g.,NPH)(Figure6a) .[106]
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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).
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Figure7a.
Figure7b.
Figure8.
InsulinPumps
Insulinpumporcontinuoussubcutaneousinsulininfusion(CSII)therapyisanotheroptionforintensiveinsulintherapy.Whilepumptherapyusedtobereservedforprimarilytype1diabetes,patientswithtype2diabetesarenowusinginsulinpumps .Patientsinitiatedoninsulinpumptherapyneedtobeveryknowledgeableaboutdiabetesmanagementandbepracticingselfmanagement.Patientsalreadyknowhowtocountcarbohydratesandadjusttheir
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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
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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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