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RiskofDiabetesTreatedinEarlyAdulthoodAfterGrowthHormoneTreatmentof
ShortStatureinChildhood
AmliePoidvinAlainWeillEmmanuelEcosseJoelCosteJeanClaudeCarel

JClinEndocrinolMetab.2017102(4):12911298.

AbstractandIntroduction
Abstract

Context:Growthhormone(GH)isknowntobediabetogenic,buttheriskofdiabetesinindividualstreatedwithGHinchildhoodhasbeenlittle
evaluated,andconflictingresultshavebeenobtained.

Objective:ToinvestigatetheprevalenceofdiabetesandgestationaldiabetesinapopulationbasedcohortofpatientstreatedwithGHforshort
statureinchildhoodinFrance.

Design,Setting,andParticipants:Participantswereapopulationbasedcohortof5100childrenwithidiopathicisolatedGHdeficiency,idiopathic
shortstature,orshortstatureinchildrenbornshortforgestationalagewhostartedGHtreatmentbetween1985and1996.Dataonthedeliveryof
diabetesdrugsin2009and2010wereobtainedfromtheFrenchnationalhealthinsurancedatabase.Casesinpatientsandcontrolswereidentified
fromdiabetesdrugsdeliveries.

MainOutcomeMeasure:Theprevalenceofdiabeteswascalculatedandcomparedwiththatinthegeneralpopulation,determinedonthebasisof
datafromthesamesource,withthesamedefinition.

Results:Atameanageof30years,nodifferenceintheprevalenceoftreateddiabetes(oraldrugsorinsulin)wasfoundbetweensubjectstreated
withGHandthegeneralpopulationinFrance,regardlessofsex.Similarly,theriskofinsulintreatedgestationaldiabeteswassimilarinpatientsand
inthereferencepopulation.

Conclusions:NodifferenceintheriskofdiabeteswasfoundbetweenGHtreatedpatientsandthereferencepopulation.Theseresultsare
reassuring,butfurtherstudieswithalongerfollowuparerequiredtoevaluatetheriskofdiabeteswithageinthesepatients.

Introduction

Theeffectsofgrowthhormone(GH)oncarbohydratemetabolismhavebeenknownforalmostacentury,buttheunderlyingphysiological
mechanismsarecomplexandinvolveanumberofdifferentpathways.[1]Indeed,GHdirectlyinducesinsulinresistanceinmuscleandfat,while
exertingametaboliceffectontheadiposetissue,liver,skeletalmuscle,andproteinmetabolismthatisprobablymediatedbysubstratecompetition
betweenintermediatesofglucoseandfattyacids.Moreover,insulinlikegrowthfactor1(IGF1),whichhasinsulinlikeactivity,canactasaninsulin
antagonist,increasingthisdiabetogeniceffect.[24]Inpatientswithacromegaly,anincreaseinGHlevelsincreasestheriskofimpairedglucose
toleranceandovertdiabetesmellitus,withreportedprevalencevaluesof15to37%,dependingontheseriesconsidered.[5,6]

LittleisknownabouttheriskofdiabetesduringorafterGHtreatmentinchildhood,andtheavailabledataareconflicting.In2001,theGrowth
HormoneResearchSocietyconcludedthatGHtreatmentresultedinnoincreaseintheincidenceoftype1ortype2diabetesbutthatsome
subgroupsofpatientswithahigherinherentriskofdevelopingdiabetes[TurnerandPraderWillisyndromesandchildrenbornsmallforgestational
age(SGA)]shouldbemonitoredcarefully.[7]ThefindingsofarecentworkshoponGHsafetywerealsoreassuring.[8]In2010,theincidenceof
diabetesintheNationalCooperativeGrowthStudycohortwasreportedtobeabout14per100,000GHtreatmentyears,butnostandardized
incidenceratiowasassignedtotheseeventsduetotheabsenceofreferencedataforthepediatricpopulation.[9]Bycontrast,Cutfieldetal.[10]
showedthattheriskoftype2diabetesinchildrentreatedwithGHwassixtimeshigherthanexpectedfromdataforagematchedchildrenfromtwo
studies.InasmallgroupofyoungadultswhohadbeenbornSGAandwereevaluated6.5yearsafterthecessationofGHtreatment,insulin
resistancewasshowntobereversible,andnodetectableincreaseintheriskofdiabeteswasidentified.[11]Findingsconcerningtheincidenceof
diabetesafterGHreplacementtreatmentinadultsarealsodiscordant,withsomestudiesindicatinganincreaseindiabetesprevalenceandothers
indicatingnoeffect.[12]

TheSafetyandAppropriatenessofGrowthHormoneTreatmentsinEurope(SAGhE)projectisamultinationalEuropeanstudyaimingtoevaluate
longtermmortalityandcancermorbidityinsubjectstreatedwithGHinchildhood.WeusedtheFrenchSAGhEstudydatabase,whichincludes
extensivemorbiditydataobtainedwithpatientidentifiersfromtheFrenchnationalhealthinsuranceinformationdatabasetoevaluatetheprevalence
ofdiabetesincludinggestationaldiabetesinapopulationbasedcohortofpatientstreatedwithGHforshortstatureduringchildhoodandtocompare
thisprevalencewiththatforthegeneralpopulationinFranceoverthesameperiod.

Methods
Patients

Aspreviouslydescribed,[13,14]weusedthemandatoryregisterofallpatientstreatedwithGHinFranceuntil1996(AssociationFranceHypophyse)
weselectedthosepatientstreatedonlywithrecombinantGH,andnotwithpituitaryderivedGH,whowerebornbefore1January1990.Patients
wereassignedtothreeriskcategoriesforlongtermmorbidityandmortalityonthebasisoftheclinicalconditionleadingtotheinitiationofGH
treatment(Fig.1).Patientswereconsideredtobeathighriskiftheyhadbeentreatedforseriousconditions,suchascancerorchronicrenalfailure.
Patientswereassignedtotheintermediateriskgroupiftheyhadbeentreatedformultiplepituitaryhormonedeficiencyorpediatricsyndromes,such
astheTurner,PraderWilli,orFanconisyndromes.ThelowriskgroupincludedpatientstreatedforidiopathicisolatedGHdeficiency,idiopathic
shortstature,shortstatureinchildrenbornshortforgestationalage,orisolatedGHdeficiencyassociatedwithaminorcraniofacialmalformation,
suchascleftlip.Weincludedonlythelowriskpatientsinthisstudy,becausetheirbaselineriskoftheprincipalmorbidconditionsisthoughttobe
similartothatofthegeneralpopulation,withtheexceptionofthehigherfrequencyofmetabolicsyndromeinchildrenbornSGA.Therewere6874
eligiblepatients,asinourpreviousstudy.[14]

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Figure1.

FlowchartoftheSAGhEstudyinFrance,withriskgroupformortalityandmorbidity,andpopulationstudied.*PatientsnotfoundintheSNIIRAM
databasearethosecoveredbytheNationalHealthInsuranceFundforAgriculturalWorkersandFarmers(MutualitSocialeAgricole),theNational
HealthInsuranceFundfortheSelfused(RgimeSocialdesIndpendants),orothersminoradditionalinsurancesnotaffiliatedtonationalHealth
InsuranceFundforSalariedWorkers(CaisseNationaled'AssuranceMaladiedesTravailleursSalaries).Inaddition,somepatientsmighthavebeen
missedbythematchingschemeusedtoidentifypatientsfromtheFranceHypophysecohortintheSNIIRAMdatabase.

Asdescribedintheflowchart,patientsnotidentifiedbytheFrenchnationalhealthinsuranceinformationdatabase[SystmeNationald'Information
Interrgimesdel'AssuranceMaladie(SNIIRAM)]wereexcludedtofacilitatecomparisonbetweenourfindingsandreferencesratesforthesame
population(comparisonwithreferencevaluesfromSNIIRAMdata,coveringabout90%ofthegeneralpopulationinFrance).Asthiswasa
prevalencestudy,wealsoexcludedpatientswhodiedbefore31December2010(n=90),asdescribedbefore.[13]Thefinalanalysistherefore
included5100patients.

DataCollected

ChildhoodData.Dataforpatientcharacteristics,GHandassociatedtreatments,andgrowthprogressionwereroutinelycollectedatbaselineandat
regularfollowupvisitsandwereobtainedfrompediatricendocrinologistsuntil1996,whenthenationalcompulsoryFranceHypophyseregisterwas
abolished.AdditionalfollowupdataforGHtreatmentwerecollectedfromclinicalcentersin2008to2010.Birthweightandbirthlengthare
expressedaszscoresforgestationalageaccordingtotheUsherandMcLeancharts,[15]andheightandweightareexpressedaszscoresforage.
ThemeanandmaximumdoseofGHwascalculatedinmicrogramsperkilogramperday.Bodymassindexwascalculatedfromthelatestheight
andweightknown(closetoorattheendoftreatment,oratadultageasavailable)andexpressedinstandarddeviationscoreforage.[16]

FollowupData.WeuseddatafromtheSNIIRAM,[17,18]whichrecordsalldrugsdeliveredtooutpatientsnationwide,toidentifyprevalentcasesof
diabetesinpatientswhohadreceivedatleastthreedeliveriesofanantidiabeticdrug(oralorinsulin)withintheyear2010(seetheSupplemental
Appendixforthelistofdrugsused).Patientswhohadreceivedatleastonedeliveryofinsulinwereconsideredtohavebeentreatedwithinsulin,
regardlessofwhethertheyalsoreceivedoralantidiabeticagents.Itwasnotpossibletodifferentiatebetweentype1andtype2diabetesonthe
basisoftheavailabledata,andnodataonfamilyhistoryofdiabeteswasavailable.

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Anancillarystudyongestationaldiabeteswasalsocarriedout.AllpregnanciesleadingtodeliveriesbetweenJanuary2008andDecember2010
wereidentifiedintheFrenchSAGhEcohortonthebasisoftheInternationalClassificationofDiseases10codescorrespondingtodelivery(060to
084).Casesofgestationaldiabetestreatedwithinsulinwereidentifiedbycrossreferencingwithinsulindeliverydata(insulindeliveredonlyonceor
twiceinthecourseofayearorduringaperiodstraddling2years,withthebirthoccurringlessthan3monthsafterthelastinsulindelivery).

StatisticalAnalyses

Weevaluatedtheriskofdiabetesbycalculatingstandardizedprevalenceratios(SPRs),withadjustmentforageandsex,usingreferenceratesof
theprevalenceofdiabetestreatmentinFrenchpatientsin2010fromSNIIRAM,includingseparatesubtypes(diabetestreatedwithinsulinand
diabetestreatedexclusivelywithoralantidiabeticdrugs).Thesereferencerateswerederivedfromthesamesourceofinformation(SNIIRAM)and
werebasedonthesamedefinitionsappliedtothegeneralpopulationduring2010inFrance.ThenumberofGHtreatedsubjectsatriskwas
calculatedforeach5yearageclass,separatelyformenandwomen,afterexcludingthosewhohaddiedbeforetheendof2010.Asimilar
calculationwasalsoperformedfor2009(observedprevalentcasesandreferencerates).Wethencalculatedtheexpectednumberofprevalent
casesforGHtreatedsubjects,bymultiplyingtheageandsexspecificprevalenceratesbythenumberofpeopleatrisk.SPRswereestimatedby
dividingthenumberofobservedprevalentcasesbythenumberofexpectedprevalentcases.Significancetestswereperformedand95%
confidenceintervals(CIs)fortheSPRwerecalculatedwithByar'sapproximationtotheexactPoissontestandexactPoissonlimits.

TheexpectedproportionofsubjectspresentinginsulintreatedgestationaldiabeteswascalculatedfromthereferenceratesfortheFrenchgeneral
populationin2011,by5yearageclass,withSNIIRAM.Thismadeitpossibletocomparetheproportionofsubjectsdisplayinginsulintreated
gestationaldiabetesinourcohortwiththeproportionexpectedonthebasisofreferencesrates.

StandardProtocolApprovals,Registrations,andPatientConsent

ThisstudywasapprovedbytheComitConsultatifsurleTraitementdel'InformationenMatiredeRecherchedansleDomainedelaSantand
theCommissionNationaledel'InformatiqueetdesLiberts(thenationaldataprotectionagency).TheuseoftheRegistreNationalInterrgimesde
l'AssuranceMaladiewasapprovedbyaspecificstatute.

Results

Therewere6874patientsinthegroupofpatientsatlowriskofmortalityandmorbidity,5100ofwhomcouldbetracedviatheSNIIRAMdatabase.
Thedataforthese5100patientswereanalyzed().Thesepatientsdidnotdiffersignificantlyfromthe1774notidentifiedintheSNIIRAMdatabaseor
whodiedbeforetheendof2010.MostofthepatientshadisolatedGHdeficiency,asdeterminedbyGHstimulationtests(peak<10ng/mLn=
3440,67%).SomeofthesubjectswithapeakGH>10ng/mLwereconsideredtohaveneurosecretorydysfunctiononthebasisofnocturnalGH
profiles,whereastheotherswereconsideredtobetreatedforshortstatureassociatedwithbeingshortforgestationalage(n=250,3%)orfor
idiopathicshortstature(n=643,13%),althoughthisisnotanapprovedindicationinFrance.ThemeanintervalbetweenthebeginningofGH
treatmentandthefollowupevaluationwas19.2years,andthemeanchronologicalageofthepatientson31December2010was30.1years.The
meandurationoftreatmentwasfouryears,withmeandosesslightlybelowthecurrentrecommendationsforisolatedGHdeficiency.

Table1.MainCharacteristicsofPatientsandGHTreatmentintheLowRiskGroup

StudiedSample,N=5100 ExcludedPatients,N=1774
Malepatients,n(%) 3293(65) 1217(69)
IndicationforGHtreatment,n(%)
IsolatedGHdeficiency
MaximumpeakGH<3g/L 221(4) 74(4)
MaximumpeakGH3g/Land<7g/L 1175(23) 382(22)
MaximumpeakGH7g/Land<10g/L 2044(40) 704(40)
MissingvalueformaximumpeakGH 370(7) 146(8)
MaximumpeakGH10g/L
Neurosecretorydysfunction 397(8) 150(8)
Idiopathicshortstature 643(13) 225(13)
SGA 250(3) 93(5)
Yearoftreatmentinitiation,n(%)
1985to1987 347(6) 159(9)
1988to1990 1780(35) 690(38)
1991to1993 1761(35) 601(34)
1994to1997 1212(24) 324(18)
Birthlength(SDSforgestationalage) 1.21.2(n=3689) 1.21.3(n=1186)
Birthweight(SDSforgestationalage) 0.61.2(n=3865) 0.61.2(n=1205)
Birthweight(g) 3047(n=4301) 3033(n=1459)
ChildrenbornSGA,n(%)
(birthweightorlength2SDSforgestationalage)
Yes 969(20) 329(18)
No 2925(57) 939(53)
Missingdata 1206(23) 506(29)
Childrenwithabirthweightunder2500g(%) 527(10) 198(11)
Chronologicalageattreatmentinitiation(y) 10.93.4(n=5100) 11.33.3(n=1774)
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Heightatstartoftreatment(SDS) 2.70.8(n=4678) 2.70.8(n=1607)

Weightatstartoftreatment(SDS) 1.60.9(n=4656) 1.60.9(n=1586)
Meandose(g/kg/d) 24.712.2(n=4627) 23.812.6(n=1585)
Treatmentduration(y) 4.02.7(n=4712) 3.62.4(n=1665)
Chronologicalageatendoftreatment(y) 15.12.7(n=4712) 15.12.7(n=1665)
Chronologicalageat12/31/2010(y) 30.14.3
DurationoffollowupfromstartofGHtreatmentto12/31/2010(y) 19.22.7(n=5100)

ValuesareexpressedasthemeanSDorn(%).
Abbreviation:SDS,standarddeviationscore.

Weidentified26casesofdiabetesduringtheyear2010():17ofthesepatientsweretreatedwithinsulin,andtheothernineweretreatedwithoral
drugsonly.FourofthesubjectswerebornSGA,anddataforbirthcharacteristicsweremissingforfivepatients.Themean(SD)doseofGHfor
thesepatientswas27.9(17.7)g/kg/d,withtwopatientshavingmeandosesabove50g/kg/d.ThebodymassindexafterthestartofGHtreatment
wasavailablefor23patients,12ofwhomwereatadultage,andsixofwhomwereabove+2SD.

Table2.ClinicalCharacteristicsandCharacteristicsofGHTreatmentofthe26CasesofDiabetes

BMI
Ageat SDS
Birth Birth
Birth Birth GHPeak Startof Treatment Mean Dose (Adult Typeof Ageat
Length Weight
Sex Length Weight SGA Maximum GH Duration Dose Maximum Age Diabetes Diabetes
SDS SDS
(cm) (g) (g/L) Treatment (y) (g/kg/d) (g/kg/d) or Treatment Diagnosis
Usher Usher
(y) Latest
Visit)
1 F 49.0 2500 1.2 2.1 Yes 2.8 17.0 0.8 18.1 24.5 +3.6 Insulin U
2 M 51.5 3500 0.2 0.0 No 7.5 8.7 8.2 27.8 32.5 +1.3 Insulin 21.4
3 F 48.0 3600 0.3 2.9 No 9.6 13.4 1.9 27.5 32.4 +1.4 Insulin 4.2a
4 F 51.0 3370 0.1 0.2 No 5.1 15.4 1.4 19.8 21.7 +1.5 Insulin 12.6a
5 M U 15.1 1.3 Insulin 13.9a
6 F 49.0 3000 1.2 1.0 No 11.1 12.4 31.8 33.1 +1 Insulin 23.3
7 M 47.0 2620 1.5 1.3 No 3.6 12.8 24.2 26 1.2 Insulin 25.5
8 F U 13.9 1.0 Insulin 20.7
9 M 50.0 3630 0.6 0.3 No 21.7 6.4 5.5 23.1 27 +0.8 Insulin 19.4
10 F 51.0 3500 0.4 0.1 No 10.7 12.5 3.0 23.1 28.2 2.2 Insulin 30.4
11 F 48.0 3650 1.5 0.7 No 5.1 6.5 3.8 21.5 20.4 +3 Insulin 17.0
12 M 48.5 3500 1.7 0.1 No 9.8 9.3 2.6 21.7 23.2 +0.3 Insulin 25.6
13 M 50.0 3500 0.9 0.1 No 14.0 6.1 6.8 20.5 24.2 0.1 Insulin 23.4
14 M 47.0 2450 2.0 2.1 Yes 8.4 13.8 1.0 24.6 24.6 1.8 Insulin 5.6a
15 M 47.5 3300 1.9 0.4 No 4.0 10.7 7.3 30.8 36.1 0.3 Insulin 11.8
16 M 48.0 3260 1.9 0.6 No 4.2 8.8 3.8 22.2 23 0.7 Insulin 25.4
17 F 42.0 2200 3.0 1.1 Yes 6.2 8.7 . 33.8 44.3 +1.5 Insulin 22.7
Oral
18 M U 6.6 2.9 63.6 72.5 0.2 U
antidiabetic
Oral
19 M U 14.9 3.0 95.2 95.2 +3.3 U
antidiabetic
Oral
20 M 47.0 3050 1.5 0.2 No 8.1 13.5 1.8 17.3 18 +3.5 U
antidiabetic
Oral
21 F U 6.7 5.0 U
antidiabetic
Oral
22 M 56.0 3080 2.5 0.9 No 3.6 11.7 5.5 27.4 33.3 0.3 U
antidiabetic
Oral
23 F 47.0 2500 1.5 1.6 No 2.8 8.5 2.1 21.9 23.8 +2.3 U
antidiabetic
Oral
24 F 50.0 3250 0.4 0.3 No 2.1 12.6 2.1 13.6 13.2 +3.7 U
antidiabetic
Oral
25 M 47.0 3530 2.2 0.1 Yes 4.3 11.4 2.7 20.0 21.2 0.5 U
antidiabetic
Oral
26 F 50.0 3850 0.9 0.6 No 2.3 1.5 0.2 12.7 13.1 0.2 U
antidiabetic

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Abbreviations:,notavailableinthedatabaseBMI,bodymassindexF,femaleM,maleSDS,standarddeviationscoreU,unknown.
aPatientswhowerealreadyoninsulinbeforethestartofGHtreatment.

SPRs,calculatedwiththenationalreferencevaluesderivedfromtheSNIIRAMdatabaseforthesameyear,arereportedin.Weobservednooverall
differenceintheriskofdiabetesbetweentheGHtreatedandgeneralpopulation(SPR=1.0,95%CI,0.7to1.5).Wealsofoundnodifference
betweenthesetwopopulationsinanalysesconsideringinsulintreatedpatientsandpatientstreatedexclusivelywithoraldrugsseparately.The
prevalenceofinsulintreatedcasesofdiabeteswassignificantlyhigherinpatientsagedbetween25and29yearsthanintheotheragegroups
considered(SPR=2.3,95%CI,1.1to4.0).WedidnotexcludepatientstreatedwithantidiabeticdrugsbeforeGHtreatmentfromthisprevalence
study,butwedidevaluatethepossibleinfluenceofincludingthesepatientsonourresults.Whenweexcludedthefourpatientsconcerned(all
treatedwithinsulin,nonewithoralantidiabeticdrugs),theexcessofriskofinsulintreateddiabetesinthisageclassdisappeared(SPR=1.8,95%
CI,0.8to3.5).Asimilaranalysisonthedataextractedfor2009yieldedsimilarresults(SupplementalTable1).

Table3.SPRforDiabetesfortheYear2010,CalculatedWithReferenceRatesFromtheSNIIRAMDatabasefortheSameYear

OralAntidiabetic Insulin All

Prevalence Prevalence Prevalence
Cases Cases SPR Cases Cases SPR Cases Cases SPR
Rates Rates Rates
Observed, Expected, (95% Observed, Expected, (95% Observed, Expected, (95%
SNIIRAM SNIIRAM SNIIRAM
n n CI) n n CI) n n CI)
(%) (%) (%)
1.0 1.1 1.0
All (0.4 (0.6 (0.7
9 9.5 17 16.1 26 25.6
patients to to to
1.8) 1.7) 1.5)
Sex
0.8 0.8 0.8
(0.3 (0.4 (0.5
Male 5 6 9 10.8 14 16.9
to to to
1.9) 1.6) 1.4)
1.2 1.5 1.4
(0.3 (0.7 (0.7
Female 4 3.4 8 5.3 12 8.7
to to to
3.0) 3.0) 2.4)
Age

class(y)
7.2 0.6 1.4
20to
(0.8 (0.01 (0.3
24,n= 2 0.09 0.3 1 0.50 1.8 3 0.58 2.1
to to to
720
25.9) 3.1) 4.2)
0.6 2.3 1.8
25to
(0.01 (1.1 (0.9
29,n= 1 0.21 1.7 11 0.57 4.9 12 0.78 6.6
to to to
1701
3.4) 4.0)a 3.2)
1.2 0.3 0.7
30to
(0.4 (0.04 (0.3
34,n= 5 0.43 4.0 2 0.66 6.4 7 1.09 10.4
to to to
1944
2.9) 1.1) 1.4)
1.0 0.6
35to 0.3
(0.2 (0.2
39,n= 1 0.91 3.3 (0to 3 0.78 2.9 4 1.70 6.2
to to
721 1.7)
3.0) 1.6)
40to
44,n= 0 2.06 0.2 0.0 0 1.00 0.1 0.00 0 3.06 0.2 0.00
14

aSignificantdifferencewithP<0.05.

Wealsocomparedthenumberofobservedcasesofinsulintreatedgestationaldiabeteswiththenumberofcasesexpectedforthispopulation.We
foundnosignificantdifferencebetweenwomentreatedwithGHduringchildhoodandthegeneralpopulation(fourcasesforthe256deliveriesinour
cohort,vsthe3.47expectedonthebasisoftheprevalenceofgestationaldiabetesindeliveriesinthegeneralpopulation,notsignificant).

Discussion

UsingalargeregisterofpatientstreatedwithGHduringchildhoodanddataextractedfromSNIIRAMwefoundnodifferenceinthelongtermriskof
prevalenttreateddiabetes(oraldrugsorinsulin)insubjectstreatedwithGHforidiopathicisolatedGHdeficiency,idiopathicshortstature,orshort
statureinchildrenbornshortforgestationalage,regardlessofsex.Theprevalenceofinsulintreateddiabeteswasslightlyhigherinsubjectsaged
25to29yearsinclusive,inboth2009and2010.Therewasnosignificantdifferenceinthefrequencyofinsulintreatedgestationaldiabetesbetween
womentreatedwithGHduringchildhoodandthegeneralpopulation.TheseresultsarereassuringastheysuggestthatGHtreatmentdoesnot
increasetheriskofdiabetes,butfurtherstudiesarerequiredtoconfirmtheirvalidity.

Wefoundaslightlyhigherriskofinsulintreateddiabetesinpatientsaged25to29yearsin2010thanintheotheragegroups.Thissmall,
apparentlyrandomeffectisunlikelytobereal.Itresultedmostlyfromtheinclusionoffourpatientsalreadyoninsulintreatmentbeforetheinitiation
ofGHtreatment.Indeed,adolescentswithpoorlycontrolledtype1diabetesfrequentlydisplaygrowthretardationanddelayedpuberty,typicallywith
highGHandlowIGF1levels.[19,20]Wehavenoinformationaboutdiabetescontrolinourcohortofpatients,butitseemslikelythatthesediabetic
childrenweretreatedwithGHinthiscontext,accountingfortheapparentlyhigherprevalenceinourstudypopulation.Noexcessriskwasfoundin
ananalysisexcludingthesefourpatients,demonstratingthatthiseffectwasnotduetoGHtreatment.

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Otherwise,wedetectednoincreaseintheriskofdiabeteswithGHtreatment,despitethepresenceofseveralpotentialriskfactorsinour
population.Indeed,diabetesriskishigherinindividualsbornSGA,[21,22]whichwasthecaseforatleast20%ofourpatients.Moreover,excessGH
isknowntoincreasetheriskofimpairedglucosetoleranceandtype2diabetesinpatientswithacromegaly.Birthweightisassociatedwiththerisk
ofdiabetes,[2325]withanapproximate25%decreaseinriskforeachadditionalkilogramatbirth,anda30%to60%increaseinriskforindividuals
withbirthweightsbelow2500g.Ourpopulation,withameanbirthweightof3050gabout500gbelowthemeanfortheFrenchpopulation,in
whichatleast10%ofindividualshadabirthweightbelow2500gwouldbeexpectedtohaveahigherriskofdiabetesthanthegeneralpopulation.
However,ourstudypopulationhadameanageof30.1yearsandtheoldestpatientwasundertheageof43years,whereasmostofthestudies
identifyinganincreaseindiabetesriskreportedthisincreaseinmucholderpatients.IntheUSNurses'HealthStudy2,on81,732womenwitha
meanageof35years,anincreaseinriskwasidentified,withrelativerisksof1.67forbirthweightsbelow2500gand1.27forbirthweightsbetween
2500and3150g.[25]InFrance,theprevalenceratesofdiabetesshowasharpincreaseaftertheageof45years.[26]Furthermore,noexcessriskof
type2diabeteswasdetectedinastudyofindividualswithameanageof29.5yearswhohadbeenbornSGA,confirmingthatthisriskoccurslater
inlife.[27]Thesizeandlowmeanageofourcohortmayaccountforthelackofdetectionofanincreaseintheriskofdiabetesduetobirth
characteristicsinthispopulation,butourresultssuggest,atleast,thatGHtreatmenthasnotamplifiedtheriskatthisage.

TheeffectofGHoninsulinsensitivityanddiabetesriskiswellestablished.[1]Theriskofdiabetesismarkedlyincreasedinpatientswithacromegaly,
withaprevalenceof15%to37%,[5,6]independentlyofGHorIGF1levels,butwithaneffectofageanddiseaseduration.Theremissionof
acromegalyleadstoanimprovementininsulinsensitivity.[28]ThemetaboliceffectsofGHtreatmenthavemostlybeenevaluatedinchildrenborn
SGA,whodisplayanincreaseininsulinsecretionandadecreaseininsulinsensitivityduringtreatment.[22]Fewerdataareavailableforpatients
afterthecompletionofGHtreatment,butthereseemstobeatrendtowardthenormalizationofinsulinsensitivityandinsulinsecretion,atboth6
monthsand6yearsafterthecessationoftreatment.[29,30]Theseobservationssuggestthat,incasesinwhichGHexcessleadstodiabetes,a
remissionofdiabetesisobservedinonlyafewcases.Bycontrast,ifGHtreatmentaltersonlyinsulinandglucosemetabolismparameters,these
effectsaremostlyreversible,consistentwithourfindingsforthisstudy,inwhichnoincreaseintheriskofdiabeteswasobserved.Ouranalysisof
gestationaldiabetessuggeststhat,eveninthediabetogenicsituationofpregnancy,ourpopulationwasatnohigherriskthanthegeneral
population.However,cautionisrequiredintheinterpretationofourresults,becausethisanalysiswasclearlyunderpowered.

StudiesonlargepharmaceuticalcompanysponsoreddatabaseshaveaddressedtheriskofdiabetesduringGHtreatmentinchildren,buthave
beenlimitedbythedurationoffollowupandthelackofanappropriatecontrolgroup.Cutfieldetal.[10]reportedasixtimeshigherriskoftype2
diabetesintheKabiInternationalGrowthStudydatabasethaninpublisheddataforhighlyselectedpatientpopulations.However,thesefindings
werelimitedbythehighlyheterogeneousnatureofthepopulation,andthestudydidnotexcludesyndromesassociatedwithahigherriskof
diabetes,suchastheTurnerandPraderWillisyndromes.IntheNationalCooperativeGrowthStudycohort,diabetescaseswererecorded,butno
comparisonwiththeexpectednumberoftype2diabetescaseswasperformed.[9]Ourstudyis,thus,thefirsttocomparetheprevalenceofdiabetes
inthegeneralpopulationwiththatinalargeandrelativelyhomogeneousgroupofGHtreatedpatientswithlongtermfollowup.

Ourstudyhasseverallimitations.Firstly,thedeliveryofdiabetesdrugs,asrecordedintheSNIIRAMdatabase,wasusedtoidentifycases.Latent
casesandcasesmanagedbylifestylechangeswere,therefore,notincluded.Inindividualsbetweentheagesof30and54yearslivinginmainland
Francein2006,theprevalenceofundiagnosedcaseswasestimatedat30%ofthetotalnumberofcasesofdiabetes.[31]We,therefore,cannotrule
outthepossibilitythatlatentdiabetesorotherpreclinicalmetabolicalterationsaremoreprevalentinourpatientsthaninthegeneralpopulation.
Secondly,duetothepopulationcoverageoftheSNIIRAMdatabase,wewereunabletoascertaincasesinasubstantialproportion(1774/6874,
26%)ofourpopulation.[26]However,thecharacteristicsoftheexcludedpatientswereverysimilartothoseofthepatientsincluded.Moreover,we
usedtheSNIIRAMdatabaseasacomparator,toeliminateanyconfoundersreflectingdifferencesininsuranceaffiliationcoverage.Inaddition,the
algorithmusedtoidentifycasesofdiabetesonthebasisofdrugdeliveryhasbeenvalidatedbyvariousstudiesoftheSNIIRAMdatabase.[32,33]

Inconclusion,wefoundnoincreaseintheriskoftreateddiabetesinsubjectsreceivingGHtreatmentduringchildhood,withameanfollowupof19
years,despitetheinclusionofsubjectsbornSGAinthecohort.Furtherstudiesarerequired,ongroupsathigherriskofdiabetesandgroupswitha
longerfollowup.Thisstudydemonstratesthevalueofthelongtermfollowupofselectedgroupsofpatientsthroughepidemiologicalstudieson
medicaladministrativedatabases.

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Acknowledgments
WethankFabienneLandierfordatacollectionandorganizationofthestudy,PhilippeRicordeauforassistancewiththedatafromtheFrench
nationalhealthinsuranceinformationdatabase[SystmeNationald'InformationInterrgimesdel'AssuranceMaladie(SNIIRAM)],andCcile
Billionnetforthereferencedataforgestationaldiabetes.
ThisstudywassupportedbyAgenceFranaisedeScuritSanitairedesProduitsdeSant(theFrenchdrugsafetyagency),DirectionGnralede
laSant(FrenchMinistryofHealth),InstitutNationalduCancer,andaCommissionofEuropeanCommunitiesGrant(HEALTHF22009223497).
Thefundingsourceshadnoroleinstudydesign,datacollection,datainterpretation,dataanalysis,orthewritingofthereport.

Abbreviations
CI,confidenceintervalGH,growthhormoneIGF1,insulinlikegrowthfactor1SAGhE,SafetyandAppropriatenessofGrowthHormone

http://www.medscape.com/viewarticle/879115_print 7/8
6/19/2017 www.medscape.com/viewarticle/879115_print
TreatmentsinEuropeSGA,smallforgestationalageSNIIRAM,Syste`meNationald'InformationInterrgimesdel'AssuranceMaladie(French
nationalhealthinsuranceinformationdatabase)SPR,standardizedprevalenceratio.

JClinEndocrinolMetab.2017102(4):12911298.2017EndocrineSociety

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