www.rpped.com.br
REVISTA
PAULISTA
DE
PEDIATRIA
ORIGINAL
ARTICLE
Continuous
insulin
therapy
versus
multiple
insulin
injections
in
the
management
of
type
1
diabetes:
a
longitutinal
study
Maria
Estela
Bellini
Ribeiro,
Raphael
Del
Roio
Liberatore
Junior
∗,
Rodrigo
Custodio,
Carlos
Eduardo
Martinelli
Junior
UniversidadedeSãoPaulo(USP),RibeirãoPreto,SP,Brazil
Received12January2015;accepted9June2015 Availableonline2October2015
KEYWORDS
Type1diabetes mellitus; Insulin; Insulininfusion systems; Adolescents
Abstract
Objective: Tocompare multiple doses ofinsulin andcontinuous insulin infusion therapyas treatmentfortype1diabetesmellitus.
Methods: 40patientswithtype1diabetesmellitus(21female)withagesbetween10and20 years(mean=14.2)andmeandurationofdiabetesof7yearsusedmultipledosesofinsulinfor atleast6monthsandafterthat,continuousinsulininfusiontherapyforatleast6months.Each oneofthepatientshasusedmultipledosesofinsulinandcontinuousinsulininfusiontherapy. ForanalysisofHbA1c,meanglycatedhemoglobinlevels(mHbA1c)wereobtainedduringeach treatmentperiod(multipledosesofinsulinandcontinuousinsulininfusiontherapyperiod).
Results: AlthoughmHbA1c levels werelower duringcontinuous insulin infusiontherapythe differencewasnotstatisticallysignificant.Duringmultipledosesofinsulin,14.2%hadmHbA1c valuesbelow7.5%vs.35.71%whileoncontinuousinsulininfusiontherapy;demonstratingbetter glycemiccontrolwiththeuseofcontinuousinsulininfusiontherapy.Duringmultipledosesof insulin,15---40patientshaveseverehypoglycemiceventsversus5---40continuousinsulininfusion therapy.Noepisodesofketoacidosiseventswererecorded.
Conclusions: Thisisthefirst study withthisdesign comparingmultipledosesofinsulinand continuousinsulininfusiontherapyinBrazilshowingnosignificantdifferenceinHbA1c; hypo-glycemic events were less frequent during continuous insulin infusiontherapy than during multipledosesofinsulinandthepercentageofpatientswhoachievedaHbA1clessthan7.5% wasgreaterduringcontinuousinsulininfusiontherapythanmultipledosesofinsulintherapy. ©2015SociedadedePediatriadeSãoPaulo.PublishedbyElsevierEditoraLtda.Thisisanopen accessarticleundertheCCBYlicense(https://creativecommons.org/licenses/by/4.0/).
∗Correspondingauthor.
E-mail:[email protected](R.DelRoioLiberatoreJunior).
http://dx.doi.org/10.1016/j.rppede.2015.06.019
2359-3482/©2015SociedadedePediatriadeSãoPaulo.PublishedbyElsevierEditoraLtda.ThisisanopenaccessarticleundertheCCBY
PALAVRAS-CHAVE
Diabetesmelitotipo 1;
Insulina;
Sistemasdeinfusão deinsulina; Adolescentes
Insulinoterapiacontínuaversusmúltiplasinjec¸õesdeinsulinanotratamentoda diabetestipo1:umestudolongitudinal
Resumo
Objetivo: Compararterapiacommúltiplasdosesdeinsulinaeosistemadeinfusãocontinuade insulinanotratamentodadiabetesmelitotipo1.
Métodos: 40pacientescomdiabetesmelitotipo1(21mulheres)comidadesentre10e20anos (média=14,2)edurac¸ãomédiadodiabetesdeseteanosutilizarammúltiplasdosesdeinsulina durantepelomenosseismesese,depoisdisso,sistemadeinfusãocontinuadeinsulinaporpelo menosseismeses.Todosospacientesusarammúltiplasdosesdeinsulinaesistemadeinfusão continuadeinsulina.ParaaanálisedeHbA1c,níveismédiosdehemoglobinaglicada(mHbA1c) foramobtidosemcadaperíododetratamento(múltiplasdosesdeinsulinaesistemadeinfusão continuadeinsulina).
Resultados: EmboraosníveisdemHbA1ctenhamsidomenorescomousodesistemadeinfusão continuadeinsulinaadiferenc¸anãofoiestatisticamentesignificante.Duranteousodemúltiplas dosesdeinsulina,14,2%tiveramvaloresdemHbA1c<7,5%vs.35,71%quandousandosistema deinfusãocontinuadeinsulina;demonstrandomelhorcontroleglicêmicocomousodesistema deinfusãocontinuadeinsulina.Duranteousodemúltiplasdosesdeinsulina,15-40pacientes tiverameventoshipoglicêmicosgravescontra5-40comsistemadeinfusãocontinuadeinsulina. Nãoforamregistradosepisódiosdecetoacidose.
Conclusões: Esse é o primeiro estudo cujodesenho comparou ouso de múltiplasdoses de insulina e sistema de infusão continua de insulina no Brasil, não demonstrando nenhuma diferenc¸a significativanosníveis deHbA1c. Eventoshipoglicêmicosforammenos frequentes comousodesistemadeinfusãocontinuadeinsulinadoquecommúltiplasdosesdeinsulina eaporcentagemdepacientesqueobteveumHbA1c<7,5%foimaiorcomsistemadeinfusão continuadeinsulinadoquecommúltiplasdosesdeinsulina.
©2015SociedadedePediatriadeSãoPaulo.PublicadoporElsevierEditoraLtda.Esteéumartigo OpenAccesssobalicençaCCBY(https://creativecommons.org/licenses/by/4.0/deed.pt).
Introduction
Diabetesmellitus(DM)isachronicmetabolicsyndrome char-acterizedby intense catabolism.Type 1diabetes mellitus (T1DM)isdue todeficient insulinsecretion,inmost cases after autoimmune destruction of pancreatic beta cells. It is a very frequent chronic disease affecting children,1 withincidenceincreasingallover theworld.2 Inthis way, diabetic ketoacidosis (DKA) and hypoglycemia are acute complications of T1DM associated with variety adverse effects andboth can havefatal effects ifnot reversedin time.3
TheDCCTstudy(TheDiabetesControlandComplications TrialResearchGroup)4 demonstratedthatintensive insulin therapy with multiple doses of insulin (MDI) or with a continuous insulin infusion therapy (CIIT) would be the besttreatmentforT1DM.Inspite oftheknowledgeabout both, MDI5---7 and CIIT,7 the comparison between these therapeuticschemes,particularlyamongchildrenand ado-lescents,is incipient. Severalstudies have suggested that CIIT may provide better glycemic control,8---11 with lower risk of severe hypoglycemia and a smaller weight gain8 comparedtothe MDItherapy.Among these analyses,few of these studies have been conducted on children and adolescents.9,10
The aim of thepresent study wasto assess,in a com-parative manner, the MDI therapy and the use of CIIT regarding metabolic control and the occurrence of acute complications of the disease in a sample of children and
adolescentswithT1DMfollowedupat apublichospitalin SãoPaulostate,Brazil.
Method
Thiswasalongitudinalstudybasedondataobtained retro-spectivelyfromthemedicalrecordsofpatientsofbothsexes aged5---20yearswithadiagnosisofT1DMaccordingtothe InternationalSocietyforPediatricandAdolescentDiabetes criteria(ISPAD,1995).
Thepatients hadbeen usingMDIfor atleast6months, andlaterCIIT,usingbothbrandsavailableinBrazil,alsofor atleast6months.Thedurationofdiabeteswasrequiredto bemorethan2years.
All patients were trained to count carbohydrates, to modify insulin dosage and to measure capillary glucose levels 7---9 times daily. They all have a telephone num-ber to make contact if they need, and the consultations were made every 3 months by a multi professional team.
Thefollowingdatawereobtained:sex,age,timeofMDI use, time of CIIT use, mean glycated hemoglobin levels (mHbA1c),number of severe hypoglycemic events requir-inghelpforrecovery,andnumberofDKAepisodes.HbA1c levelsweremeasuredbyHPLCanditwasthesamemethod duringallthestudy.
Table1 Meanglycated hemoglobin(mHbA1c)values(%) for the total sample (T), Mean glycated hemoglobin for patients who were submitted to at least 1 year of each treatment(1y)and2yearsofeachtreatment(2y).
mHbA1c(n=40) Mean±SD Median p-valuea
MDI(T) 9.1±2.0 8.6 0.55b
CIIT(T) 8.9±2.5 8.2
MDI(1y) 9.3±2.3 8.6 0.095c
CIIT(1y) 8.4±1.9 7.8
MDI(2y) 8.4±0.9 8.4 0.67d
CIIT(2y) 8.4±2.3 7.7
SD,standarddeviation;MDI,multipledosesofinsulin;CIIT, con-tinuousinsulininfusiontherapy.
aSingle-samplenonparametricWilcoxontest. b ComparisonbetweenMDIandCIIT.
c ComparisonbetweenMDIandCIIT(1y). d ComparisonbetweenMDIandCIIT(2y).
Dataarereportedasmean(±SD)andmedian.The non-parametricWilcoxontestwasusedforthepairedvaluesof thevariables,withthelevelofsignificancesetatp<0.05.
Results
Weanalyzed themedicalrecordsof 40patients, 46.4%of them males,who firstused MDIand laterCIIT during the periodfrom2011 to2012.At thetimeof datacollection, patient’s age ranged from 10 years and eight months to 20yearsand2months(mean±standarddeviation:14±2.35 years).Timesincethediagnosisofthediseaserangedfrom 2yearsand2monthsto15yearsand3months(mean7.0 years).
Time of MDI ranged from8 months to 14 years and 9 months(mean±standarddeviation:5.1±3.6months).Time ofCIITuserangedfrom6monthsto4yearsand5months (mean±standarddeviation:1.4±3.6years)(Table1).
Thedatadidnotshowvariationaccordingtosex. ForanalysisofHbA1clevels,theresultsobtainedduring each treatment period(MDI andCIIT) were retrievedand themHbA1cvaluewascalculatedforeachpatientandeach period.ThemeanandthemedianmHbA1cvalueswerethen calculatedforthesampleandfortheperiodofeach treat-ment.Table2showsthemHbA1cresultsobtainedinthetwo periods.Thedatashowthat,althoughmHbA1clevelswere lowerduringtheuseofCIITthanduringtheuseofMDI,no significantdifferencewasobserved.
Analysisofthedatafor patientswhohadusedatleast one year of each treatment revealed that mHbA1c lev-elswere9.3(±2.3)%duringtheMDIperiod(median:8.6), and8.4 (±1.9)% duringthe CIIT period,withamedian of 7.8%(p=0.095),showingthattherewasnosignificant differ-enceinmHbA1clevelsobtainedduringthetwotreatments (Table1).
Analysisofthedatafor patientswhohadusedatleast twoyearsof eachtreatment revealedthatmHbA1c levels were8.4(±0.9%)duringtheMDIperiod,withamedianof 8.4,and8.4(±2.3%)withamedianof7.7%duringtheperiod ofuseofCIIT.Again,theWilcoxontestshowednosignificant differencebetweenperiods(p=0.67)(Table1).
Table2 Meanglycated hemoglobin (mHbA1c)values(%) forpatientswithlevelsoflessthan7.5%duringonlyoneof thetreatments.
Patient mHbA1cduringMDI mHbA1cduringCIIT
1 7.85 7.1
2 7.96 7.33
3 7.9 6.87
4 9.45 7.26
5 8.33 7.26
6 8.4 5.35
7 8.61 7.5
8 9.3 7.05
9 7.1 7.5
10 7.06 7.7
11 7.1 7.8
12 7.1 7.5
mHba1c,meanglycatedhemoglobinforeachpatients;MDI, mul-tiple dailyinsulin injections; CIIT, continuousinsulin infusion therapy.
During the use of MDI, 14.2% had mHbA1c values below7.5%,thevaluerecommendedbyISPADastargetto metabolic control, andduring the use of CIIT 35.71% had mHbA1cvaluesbelow7.5%,demonstratingbetterglycemic controlwiththeuseofaninfusionpumpfortreatment.
Analysisofcaseswithlessthan7.5%ofmHbA1clevelsin onlyoneofthetreatments(MDIorCIIT)revealedthateight of the 12 patients (66.6%) showed reduced mHbA1c lev-elswhentheyswitchedtoCIIT,whilefourpatients(33.3%) showed lower mHbA1c levels during treatment with MDI (Table2).
Regarding acute complications, the number of hos-pitalizations and visits to emergency services due to hypoglycemic and diabetic ketoacidosis events were recordedduringthetwotreatmentperiods.
During MDI, 15---40 patients have hypoglycemic events needinghelpfromotherperson.Fromthose15patients,3 hadtwoevents,1treeeventsandone,4events.No ketoaci-dosiseventswererecorded.
During CIIT, 5---40 patients have hypoglycemic events needing help from other person. From those 5, only one event by each one was recorded. Again, no ketoacidosis eventswererecorded.
Analysisofthemeannumberofeventsshowedthatmore complications occurred during MDItreatment than during CIIT(p=0.021,single-samplenonparametricWilcoxontest).
Discussion
TheDCCTstudydemonstratedthat,whenHbA1cexceeds 7.5%, therisk of complications increasessignificantly.12---14 TheISPAD15recommendsavalueofHbA1coflessthat7.5%. The present study showed that 14.2% of the patients hadlowerthan7.5%mHbA1cduringtheuseof MDI,while 35.71%showedan mHbA1cvaluelowerthan7.5%withthe useofCIIT,demonstratingbetterglycemiccontrolwiththe use of infusion pump therapy. The same conclusion was observed when individual analysis cases of patients with mHbA1clowerthan7.6%inatleastoneofthetreatments (Table2).
Comparison of the periods of use of MDI and CIIT revealed a reductionof both the mean(9.1---8.9) and the median (8.6---8.2) values of HbA1c levels; although these valuesnosignificantdifferencewasobserved.Several stud-ies,especiallythoseconductedonyoungindividuals,have demonstrated that CIIT and MDI induce similar results of glycemiccontrol.16---19Inarecentmeta-analysis,Yehetal.16 analyzed 33randomizedandcontrolledstudies comparing the two therapies in children and adults with T1DM and concludedthatmoststudiesshowedsimilareffectsonthe controlofglycemia inchildren,withafavorableeffectof theuseofCIITonthereductionofHbA1clevelsinadults. However,otherstudieshaveshownthattheuseofCIIT pro-motesareductionofHbA1clevelsbothinchildren20---24and inadults.21,22,24
Inviewthatthetimeofuseofoneofthetherapiesmight influence theevaluationof HbA1clevels,thesame analy-sis of meanand median HbA1c valueswere performed in patients with at least 1 year of each treatment. Another analysiswasperformedinpatientswithatleast2yearsof eachtreatment(Table1).However,nosignificantdifference wasdetectedfavoringoneofthetreatments.
Regardingadverseeffects,asystematicreviewbyPickup etal.25 showedthatthefrequencyofseverehypoglycemia episodes was reduced 4.2 times with the use of CIIT, compared to MDI, although other studies did not detect a significant difference in the number of adverse events betweenthetwotreatments.20---22,26 Inthepresentpatient series, therewas a reduction of the frequency of severe hyperglycemic episodes.Similarly to ourdata, a previous Brazilian studyhasalsoshowed reductionofsevere hypo-glycemia episodes.In spite of fewer subjects andshorter periodofobservation,thisanalysisshowedalittle improve-mentofmetabolic control;furthermore,theauthorshave notcomparedMDIandCITT.27Arecentpapershowedin345 patientsa0.6%reductionofHbA1clevelsfrominjectionsto insulinpumptherapy.Theauthorsalsoshowedareduction ofseverehypoglycemiceventsandDKAepisodes.28
In the design of the present study, the fact that each patientactedashisowncontroleliminatedinterindividual differences(suchaseatinghabits,patternsofphysical activ-ities, motivationand attitude toward the disease, among others)thatmightinterferewiththeanalysissincetwo sam-ples,evenwhenmatched,mayshowdifferences.However, a limitation of the study is the fact that it was not con-trolled,witharetrospectiveandwithsmallsample.Other importantissueistheperiodofobservation;probablylonger periodsoftimecouldhaveshownasignificantdifferencein themetaboliccontrol.Despitetheselimitations,tothebest ofourknowledge,thisisthefirststudywiththisdesign com-paringtheuseoftwoformsofbasal-bolustherapyfor the
metaboliccontrolofdiabetesandoftheoccurrenceofacute complicationsofthedisease,inBrazil.
In conclusion, intensive insulin therapy (MDI or CIIT) representsthe bestform of treatment in orderto obtain adequatemetaboliccontrolforT1DMpatients.Analysisof severalstudiesshowedthatthereisnoconsensusaboutthe choicebetween MDI andCIIT for thetreatment of T1DM, regardingglycemiccontrolandtheratesofadverseevents. ThepresentstudyisthefirstinBraziltocomparethetwo formsof therapy witha design of patientas self-control, showingimprovementinmetaboliccontrolwiththeuseof CIIT,withareducedoccurrenceof acutecomplicationsof diabetesinthissample.
Funding
Thestudyreceivednofunding.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
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