Insulin analogues in children with Type 1 diabetes: a 52-week randomized clinical trial.

0.3 MB·English

by  Thalange, N

DIABETICMedicine
DOI:10.1111/dme.12041
Research: Treatment
Insulin analogues in children with Type 1 diabetes:
a 52-week randomized clinical trial
N. Thalange1, A. Bereket2, J. Larsen3, L. C. Hiort4 and V. Peterkova5
1JennyLindChildren’sDepartment,NorfolkandNorwichUniversityHospital,Norwich,UK,2DivisionofPaediatricEndocrinologyandDiabetes,Marmara
UniversitySchoolofMedicine,Istanbul,Turkey,3InsulinMedicalandScience,NovoNordiskA/S,Bagsvaerd,Denmark,4Biostatistics,NovoNordiskA/S,Bagsvaerd,
Denmarkand5EndocrinologicalResearchCentre,InstituteofPaediatricEndocrinology,Moscow,Russia
Accepted11October2012
Abstract
Aims This 52-week, randomized, multinational, open-label, parallel-group, non-inferiority trial investigated the
efficacy and safety of basal–bolus treatment with insulin detemir vs. NPH (neutral protamine Hagedorn) insulin, in
combination with insulin aspart, in subjects aged 2–16 years with Type 1 diabetes mellitus.
Methods Of the 347 randomized and exposed subjects, 177 received insulin detemir and 170 NPH insulin, both
administered once or twice daily in combination with mealtime insulin aspart. Glycaemic measurements and weight
were followed over 52 weeks.
Results After 52 weeks, insulin detemir was shown to be non-inferior to NPH insulin with regard to HbA [mean
1c
difference insulin detemir–NPH: 1.30 mmol/mol, 95% CI –1.32 to 3.92 (0.12%, 95% CI –0.12 to 0.36) in the full
analysissetand1.41 mmol/mol,95% CI–1.26to4.08(0.13%,95% CI–0.12to0.37)intheperprotocolanalysisset].
Hypoglycaemiceventspersubject-yearofexposureof24-handnocturnalhypoglycaemiaweresignificantlylowerwith
insulin detemir than with NPH insulin (rate ratio 0.76, 95% CI 0.60–0.97, P = 0.028 and 0.62, 95% CI 0.47–0.84,
P = 0.002,respectively).Weightstandarddeviation(SD)scores(bodyweightstandardizedbyageandgender)decreased
with insulin detemir, but increased slightly with NPH insulin (change: –0.12 vs. 0.04, P < 0.001). At end of the trial,
median insulin doses were similar in both treatment groups.
Conclusions Insulin detemir was non-inferior to NPH insulin after 52 weeks’ treatment of children and adolescents
aged2–16 years,andwasassociatedwithasignificantlylowerriskofhypoglycaemia,togetherwithsignificantlylower
weight SD score when compared with NPH insulin.
Diabet. Med. 30, 216–225 (2013)
emiaareassociated withimpairedcognitiveandintellectual
Introduction
developmentinchildrenwithType 1diabetes[8,9].
EvidencefromtheDiabetesControlandComplicationsTrial Thechallengeofachievinggoodglycaemiccontrolismore
(DCCT) and other landmark studies [1–4] have shown that difficult in children and adolescents compared with adults
tightglycaemiccontrolinadultsandadolescentswithType 1 because of the characteristics of the paediatric population.
diabetes mellitus is of crucial importance in reducing the Growth, variable exercise and eating patterns, dependence
prematureonsetofmicro-andmacrovascularcomplications onparentsandothercaregiversforinjectionsandbloodtests,
[3,5,6]. However, in these studies, intensive insulin therapy difficultiesensuringoptimaldiabetescareinschoolsandthe
wasassociatedwithanincreasedriskofhypoglycaemiaand physiological and psychological burdens of adolescence all
increased body weight. These studies did not include pre- constitutechallengestoachievingoptimalglycaemiccontrol
adolescentchildren,butotherstudieshaveconfirmedthatpoor [10]. Consequently, an ideal insulin regimen would be
glycaemiccontrolintheyoungisnotharmless[7].Forexample, flexibleandpredictable,whilstprotectingagainsthypoglyca-
periodsofhyperglycaemiaandepisodesofseverehypoglyca- emia[11]andinappropriateweightgain.
Insulindetemirisalong-acting,solubleacylatedanalogue
ofhumaninsulin[LysB29(Netetradecanoyl)des(B30)human
insulin] with a protracted action profile attributable to
Correspondenceto:NanduThalange.E-mail:[email protected]
(ClinicalTrialsRegistryNo;NCT00435019) increased self-association at the injection site and buffering
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Researcharticle DIABETICMedicine
of insulin concentration via albumin binding in both the weektitration and treatmentperiod, including atotalof 10
subcutaneoustissueandtheblood[12].Incontrasttoneutral scheduled visits and eight telephone contacts during the
NPH human isophane insulin [13,14], insulin detemir does treatment period. Eligibility for the study was confirmed at
notrequirere-suspensionbeforeinjection. an initial screening visit. Eligible subjects were allocated to
Clinical trials in adults with Type 1 diabetes have shown treatmentwithinsulindetemirorNPH(1:1).Randomization
that insulin detemir is associated with comparable HbA , wascarriedoutusingacentralizedtelephoneandweb-based
1c
less variability in fasting plasma glucose, less nocturnal randomization system, the Interactive Voice Response Sys-
hypoglycaemiaandlessweightgaincomparedwithinterme- tem (IVRS)/Interactive Web Response System (IWRS), per-
diate-acting NPH [15–18]. In spite of the importance of formedwithin2 weeksofthescreeningvisit.Insulindetemir
optimizing diabetes care in children, few comparative ran- and NPH are visually distinguishable and, as the primary
domizedclinicaltrialshavebeenconductedinthisagegroup. endpoint HbA is not easily biased, an open-label study
1c
The aimof the current study was to establishthe efficacy designwaschosen.Stringentglycaemiccontrolinchildrenis
and safety of insulin detemir in children aged 2–16 years oftenavoidedinreal-lifeclinicalpracticebecauseofpotential
withType 1diabetesover52 weeksoftreatment.Resultsfor hypoglycaemiaanditsnegativeeffectsonyoungpatients.So
the youngest age strata (2–5 years) have already been that the diabetes treatment given during this trial could
published, and it was found that insulin detemir was closelyresembleareal-lifeenvironment,thisstudywasnota
associated with similar glycaemic control, but a greater treat-to-targetdesign.
reduction in fasting plasma glucose and a lower rate of
hypoglycaemia when compared with NPH insulin in these
Treatment
patientsafter52 weeks[19].
Childrenweretreatedwithinsulindetemir(Levemir®;Novo
Nordisk A/S, Bagsvaerd, Denmark; 100 U/ml) or NPH
Subjects and methods
(NPH, human isophane insulin®; Novo Nordisk A/S;
100 IU/ml)onceortwicedaily,accordingtopretrialinsulin
Subjects
regimen and dose. Both groups received insulin aspart
Children with Type 1 diabetes for at least 12 months (NovoRapid®/NovoLog®;Novo Nordisk A/S; 100 U/ml)2–
(n = 347), aged 2–16 years (~60% prepubertal and ~40% 4timesdaily,withmainmeals.
pubertal),atotaldailyinsulindose (cid:1) 2.0 U/kg,withHbA During the treatment period, the basal insulin dose was
1c
(cid:1) 97 mmol/mol (11.0%), insulin detemir-naı¨ve, non-obese adjusted according to plasma glucose measurements with a
(maximum BMI (cid:1) 27 kg/m2, depending on age) were preprandial plasma glucose goal of 4.0–7.0 mmol/l (72–
recruited from diabetes clinics at 35 sites in 11 European 126 mg/dl).Participantswereaskedtomeasuretheirplasma
countries (Bulgaria, the Czech Republic, Denmark, Finland, glucosebeforebreakfastanddinneronthelast3 daysprior
France, Hungary, Macedonia, Poland, Russia, Turkey and toeachcontactandtoadjustbasalinsulindosesaccordingto
the UK). Subjects with clinically significant concomitant asimpletitrationalgorithm(Table 1).
diseases (as judged by the investigator) were excluded. The Bolus insulin was to be taken 0–15 min prior to or
study was approved by local ethics committees and health immediatelyafterthemeal,aimingatapostprandialplasma
authorities, and carried out in accordance with Good glucoseof5.0–11.0 mmol/l(90–198 mg/dl)measured1–4 h
Clinical Practice [20] and the Declaration of Helsinki [21]. afterameal.Bolusinsulindoseswereadjustedaccordingto
Written informed consent was obtained from all children localpractice.
(whereappropriate)andtheirparentsorlegalrepresentative
beforeanystudy-relatedactivities.
Efficacymeasures
TheprimaryendpointofthistrialwasHbA measuredafter
Studydesign 1c
52 weeks. Blood samples for HbA and fasting plasma
1c
Inthis52-week,multinational,open-label,randomized(1:1, glucose were drawn at randomization and approximately
insulin detemir:NPH), two-armed parallel-group trial, eligi- every 3 months subsequently. Nine-point self-monitored
ble children were stratified according to age; 2–5 years plasma glucose profiles, including nocturnal plasma glucose
(n = 82, 23.6%) and 6–16 years (n = 265, 76.4%). In at 03.00 h, were assessed by the children on a normal
addition, in a post-hoc statistical analysis, the 6- to weekday4–7 dayspriortorandomization,andafter26and
16-year-old cohort was separated into 6- to 12-year-old 52 weeksoftreatment.
and13-to16-year-oldsubgroups.InsulindetemirandNPH Hypoglycaemic episodes were included as a secondary
wereadministeredonceortwicedaily(accordingtopretrial endpoint of this trial and were classified according to
regimen),andbothtreatmentgroupsreceivedinsulinaspart International Society for Pediatric and Adolescent Diabetes
asbolusinsulinwithmainmealsandlargersnacks.Thetrial (ISPAD)guidelines[22,23].Mildhypoglycaemiawasdefined
consisted of a 2-week screening period, followed by a 52- asepisodeswherethesubjectswereabletotreatthemselves.
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DIABETICMedicine Insulindetemiruseinchildren(cid:3)N.Thalangeetal.
Table1Algorithmfortitrationofbasalinsulindose
Currentdose <5U 5–15U >15U
Pre-breakfastor
pre-dinnerplasma
glucose Adjustment(U)
<4.0mmol/l <72mg/dl Reduce Reduce Reduce
according according according
tolocal tolocal tolocal
practice practice practice
4.0–7.0mmol/l 72–126mg/dl 0 0 0
7.1–10.0mmol/l 127–180mg/dl +0.5 +1 +2
10.1–15.0mmol/l 181–270mg/dl +1 +2 +4
>15.0mmol/l >270mg/dl +1.5 +3 +5
Moderatehypoglycaemiawascategorizedasepisodeswhere (Bio-Rad DiamatTM; Bio-Rad Laboratories, Hercules, CA,
subjectsrequiredassistance,butrespondedtooraltreatment. USA)andfastingplasmaglucosevalueswereassessedusinga
Severe hypoglycaemia was defined as episodes where the hexokinase method (Gluco-quant®; Roche Diagnostics
subjectsweresemi-conscious,unconsciousorinacoma,with GmbH, Mannheim, Germany). Self-monitored plasma glu-
or without convulsions. Episodes without signs/symptoms cose was measured using a glucose meter (Medisense
but with plasma glucose value < 3.6 mmol/l (< 65 mg/dl) Precision XtraTM or Optimum PlusTM; Abbott Diabetes
weredefinedasbiochemicalhypoglycaemia. Care,Delkenheim,Germany).Useofteststripscalibratedto
plasma glucose values ensured that capillary blood concen-
trations were displayed as plasma glucose values. All self-
Bodyweight
monitoredplasmaglucosevalues< 3.6 mmol/l(< 65 mg/dl),
Body weight was determined as a secondary endpoint and as well as signs and symptoms of hypoglycaemia, were
was measured at each visit and subsequently analysed by recordedinthepatients’diariesandincludedintheanalyses
standarddeviation(SD)scoresinordertocomparechildrenof of hypoglycaemia. All blood samples were obtained in the
differentageandgender,usingBritishgrowthstandards[24]. morningbeforeadministrationofinsulin.
ApositiveSDscoreindicatesahigherweightlevelcompared
withthepopulationmeanforagivenage.
Statisticalanalysis
Thetrialwasdesignedtoconfirmefficacyofinsulindetemir
Safetymeasures
in children in terms of glycaemic control. This was carried
Standardsafetyvariablesincludingadverseevents,laboratory outbyshowingthatinsulindetemirwasnon-inferiortoNPH
analyses(haematologyandbiochemistry),physicalexamina- both in combination with insulin aspart with respect to
tion findings and vital signs were evaluated as secondary HbA after 52 weeks of treatment using a non-inferiority
1c
outcomesofthetrial.Seriousadverseeventsweredefinedas, criterion of 0.4% [26]. Throughout the analyses, a signifi-
amongstothers,alife-threateningexperience,inpatient hos- cancelevelof5%wasused.
pitalization or prolongation of existing hospitalization, a Thepowercalculationwasanalysedonthisbasis:usinga
persistentorsignificantdisability/incapacityordeath. two-sided t-test with a one-sided significance level of 2.5%,
Fundoscopy/fundus photography, physical examination assuming SD of 1.1, a non-inferiority criterion of 0.4%, a
and vital signs were evaluated at randomization and after powerof85%andanexpecteddropoutrateof20%,atotal
52 weeksoftreatment.Heightmeasuredincentimetreswas of344childrenweretoberandomized.
recorded pretreatment and after 26 and 52 weeks of treat- The primary endpoint HbA at the end of the trial was
1c
ment. Pubertal status was graded as prepubertal (Tanner tested for non-inferiority using a normal linear regression
grade 1)orpubertal(Tannergrade 2ormore)[25]pretreat- model with treatment, pubertal status at baseline, country
mentandafter52 weeks. and age stratification at randomization (only mentioned as
age in the remaining part of the section) as factors, and
baseline HbA as covariate. The primary efficacy analysis
Analyticalmethods 1c
was based on both the full analysis set and per protocol
HbA measurements and other laboratory analyses were population. The full analysissetwasdefined as allrandom-
1c
performed centrally by the Laboratorium fu¨r Klinische ized subjects exposed to at least one dose of trial product
Forschung (Germany). HbA was measured by ion- with a post-baseline observation, classified according to
1c
exchange high-performance liquid chromatography (HPLC) randomized treatment. The per protocol population was
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218 DiabeticMedicineª2012DiabetesUK
Researcharticle DIABETICMedicine
defined as all exposed subjects who took part in the trial
Glycaemiccontrol
withoutsignificantlyviolatingtheinclusion/exclusioncriteria
or other aspects of the protocol considered to potentially After52 weeks,non-inferiorityofinsulindetemirplusinsulin
affect the efficacy results, classified according to actual aspartvs.NPHplusinsulinaspartwasestablishedforHbA
1c
treatment. in the overall population [full analysis set: insulin detemir
Fastingplasmaglucoseattheendofthetrialwasanalysed 72.18 mmol/mol (8.75%), NPH 70.88 mmol/mol (8.64%),
using a similar model, replacing baseline HbA with mean difference insulin detemir–NPH 1.30 mmol/mol,
1c
baseline fasting plasma glucose. Last observation carried 95% CI –1.32 to 3.92 (0.12%, 95% CI –0.12 to 0.36%);
forwardwasappliedtoallHbA andfastingplasmaglucose andperprotocol:insulindetemir72.13 mmol/mol(8.75%),
1c
post-randomization values. All secondary efficacy analyses NPH 70.72 mmol/mol (8.62%), mean difference insulin
werebasedonthefullanalysisset. detemir–NPH 1.41 mmol/mol, 95% CI –1.26 to 4.08
Within-subjectvariationofself-monitoredplasmaglucose (0.13%, 95% CI –0.12 to 0.37%)]. HbA levels slightly
1c
was estimated using a variance-component model with and gradually increased over 52 weeks—both in patients
country, treatment and age as fixed factors and subject as giveninsulindetemirandthosereceivingNPH(Fig. 2a).The
randomeffect.Thetestwascarriedoutasalikelihoodratio highestHbA wasmeasuredatweek 38forbothtreatments
1c
test comparing the model with a separate residual variance {mean(SD)NPH:70.2(13.8)mmol/mol[8.6(1.3)%];insulin
component for each treatment group to a model with a detemir:71.1(16.0)mmol/mol[8.7(1.5)%]}.
commonresidualvariancecomponent. Given the physiological differences in children across the
Nine-point self-monitored plasma glucose profiles were 6-to16-yearagerange,wealsoanalysedthedataastwoage
analysed using a repeated-measurements model with treat- groups: 6–12 years (n = 167) and 13–16 years (n = 98).
ment, country, pubertal status at baseline, age, time point TherewasaslightincreaseinHbA withbothregimensfor
1c
andthetreatmentbytime-pointinteractionasfixedfactors. the6-to12-year-oldand13-to16-year-oldsubgroupsover
The covariance structure was modelled as unstructured for time(Fig. 2bandc).MeanHbA remainedstablewithboth
1c
each subject and independence between subjects was treatmentsinthe2-to5-year-oldcohort[19].
assumed. Both regimens appeared to cause a fairly rapid drop in
The number of hypoglycaemic episodes per subject was fasting plasma glucose at week 12, followed by a slight
analysed using a negative binomial regression model with increase measured at weeks 24 and 36 and a final decrease
treatment and age as factors and the logarithm of subject betweenweeks 36and52intheoverallpopulation(Fig. 2d).
exposure as offset, and from this model the rate ratio Althoughthemeanchangeinfastingplasmaglucosetended
between the two treatment groups was estimated. This was tobemorepronouncedwithinsulindetemir(–0.60 mmol/l)
performed for nocturnal, diurnal and 24-h hypoglycaemic thanwithNPH(0.02 mmol/l), nosignificantdifference was
episodes divided in the categories All, Severe, Moderate, observed after 52 weeks. Mean difference (insulin detemir–
Mild and Biochemical. Hypoglycaemic episodes were cate- NPH) was –0.63 mmol/l, 95% CI –1.56 to 0.31 (Fig. 2d).
gorized as nocturnal if they occurred between 22.00 and Meanfastingplasmaglucoselevels hada netdecrease from
07.00 h. baselinetoendoftrialinboththe6-to12-year-oldandthe
The weight SD score at the end of the trial was analysed 13- to 16-year-old cohorts for both treatments (Fig. 2e and
with a normal linear regression model with treatment, age f).Inthe6-to12-year-oldcohort,fastingplasmaglucosewas
and country as factors and baseline SD score as a covariate. consistently lower with insulin detemir than NPH through-
Last observation carried forward was applied to all post- out the trial (Fig. 2e), whereas fasting plasma glucose was
randomizationweightvalues. comparable between treatments in the 13- to 16-year-old
cohort over time (Fig. 2f). In the cohort of 2–5-year-old
children fasting plasma glucose was similar at baseline and
Results
decreasedwithboththerapiesduringthestudy[19].
Within-subject variation in fasting plasma glucose mea-
Demographics
surements assessed by self-monitored plasma glucose at
Atotalof381childrenwerescreened,ofwhom33failedto 52 weekswaslowerwithinsulindetemirthanwithNPHin
meetalltheselectioncriteria,themajoritybecauseofHbA1c thetotalcohort(SD3.01vs.3.68 mmol/l,P < 0.001).
> 97 mmol/mol(> 11%)(Fig. 1).Threehundredandforty- The analysis of nocturnal plasma glucose (03.00 h) after
eight children entered the trial, of whom 347 were exposed 52 weeksshowednosignificantdifferencebetweentreatments
to trial products. One subject allocated to NPH withdrew intheoverallpopulation.Thetotalmediandailyinsulindose
consent prior to treatment. The treatment groups were perkgbodyweightwassimilarinthetwotreatmentgroups
similar withrespect to withdrawalandbaseline characteris- after52 weeksforallsubgroupsandthetotalcohort(Table 3)
tics (Table 2). The median daily dose of basal, bolus and [19]. The ratios (insulin detemir:NPH) of the median daily
premixedinsulinperkgbodyweightwassimilarinthetwo insulindosesattheendofthetrialwere1.04(0.57:0.55 U/kg)
groups. forbasalinsulinand1.09(0.47:0.43 U/kg)forbolusinsulin.
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DIABETICMedicine Insulindetemiruseinchildren(cid:3)N.Thalangeetal.
FIGURE1Subjectdisposition.Perprotocolanalysissetwasdefinedaschildrennotsignificantlyviolatingtheinclusion/exclusioncriteriaorother
aspectsoftheprotocolconsideredtopotentiallyaffecttheefficacyresultswithanexposureofatleast6months.‘Other’includedunspecified
unwillingnesstocontinue(14subjects)andhighlevelofHbA (onesubject).NPH,neutralprotamineHagedorn.
1c
Hypoglycaemicepisodes Adverseevents
Inthetotalcohort,childrentreatedwithinsulindetemirhada For the total cohort, the number of events/1000 exposure-
lowerrateofepisodesthanthosetreatedwithNPH(Table 4). years of all adverse events and non-serious adverse events
Noseverenocturnalhypoglycaemicepisodeswerereportedin were similar in the two treatment groups, while the rate of
theinsulindetemirgroup,whilefiveepisodestookplaceinthe serious adverse events was lower with insulin detemir (95)
NPHgroup(Table 4).Therateofall24-hepisodes,mild24-h than with NPH (147) (see also Supporting Information,
episodes,anynocturnalepisodesandmildnocturnalepisodes TableS1).
waslowerwithinsulindetemirthanwithNPHinsulininthe
overallpopulation(Table 4,Fig. 3).Thiswasalsoobserved
Discussion
in the separate 6- to 12-year-old and 13- to 16-year-old
subgroups (Fig. 3), and frequency of hypoglycaemia was To our knowledge, this study is the largest and longest
numericallylowerinthe13-to16-year-oldscomparedwith randomized clinical trial ever performed in children and
the 6- to 12-year-old subgroup (Fig. 3). In the 2- to 5-year- adolescentswithType 1diabetes.
oldcohort,alowerrateofhypoglycaemiawasobservedwith The efficacy results from the trial showed that glycaemic
insulindetemircomparedwithNPH[19]. control with insulin detemir plus insulin aspart was non-
inferior to treatment with NPH plus insulin aspart, as
measuredbytheprimaryendpointHbA after52 weeksof
MeanSDscoreofbodyweight 1c
treatment. The slight increase in HbA seen with insulin
1c
Thedifferencebetweenthetwotreatmentgroupsinestimated detemirandNPHreflectsthedifficultiesintreatingchildren
weightSDscoreattheendofthetrialwassignificantforthe forwhommanyfactors,includingsocialstatus,diabetescare
overall population (insulin detemir 0.18, NPH 0.33, mean in school or day care, highly variable lifestyle and (fear of)
difference–0.15,95% CI–0.23to–0.07,P < 0.001)(Fig. 4). hypoglycaemia,influenceglycaemiccontrol[8].Additionally,
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Table2Baselinecharacteristics
Subjectsexposedto Insulindetemir NPH All
treatment,n(%) 177(100.0%) 170(99.4%) 347(99.7%)
Gender
Female 94(53.1%) 73(42.9%) 167(48.1%)
Male 83(46.9%) 97(57.1%) 180(51.9%)
Age(years) 10.0(4.09) 9.8(3.90) 9.9(3.99)
Pubertalstatus
Tannergrade1 104(58.8%) 104(61.2%) 208(59.9%)
Tannergrade2 73(41.2%) 66(38.8%) 139(40.1%)
Stratificationbyage
2–5years 42(23.7%) 40(23.5%) 82(23.6%)
6–16years 135(76.3%) 130(76.5%) 265(76.4%)
Diabetesduration(years) 3.70(2.66) 3.68(2.51) 3.69(2.58)
BodyweightSDscore 0.24(0.92) 0.32(0.99) 0.28(0.96)
HbA (mmol/mol)* 68.42(12.1) 68.29(12.0) 68.36(12.1)
1c
(%)* 8.41(1.11) 8.40(1.10) 8.40(1.10)
Fastingplasmaglucose(mmol/l)* 8.36(4.38) 8.70(4.59) 8.52(4.48)
Pretrialinsulinregimens
1basal+3bolusinjectionsdaily 40% 34%
2basal+3bolusinjectionsdaily 25% 31%
Premixalonedaily 8% 9%
Premix+basaland/orbolusdaily 14% 15%
Pretrialdailyinsulindose
Basalinsulin(IU/kg) 0.43(0.09–1.22) 0.47(0.03–2.82) 0.45(0.03–2.82)
Mealtimeinsulin(U/kg) 0.46(0.07–1.00) 0.44(0.02–1.00) 0.45(0.02–1.00)
Premix 0.80(0.05–5.75) 0.62(0.01–1.17) 0.70(0.01–5.75)
Numbersaren(%),mean(standarddeviation)ormedian(range).
*HbA ,fastingplasmaglucoserecordedatorbeforerandomization.
1c
NPH,neutralprotamineHagedorn.
physiciansandfamiliesareoftenreluctanttotitrateinsulinin detemir vs. NPH without an increase in HbA and,
1c
children as aggressively as in adults, because of the risk of reassuringly,thiswasseenacrossallagegroupsstudied[19].
severehypoglycaemiaanditsconsequences[27]. Weight gain was also lower for insulin detemir when
Another finding similar to previously reported results in compared with NPH for all age strata. The decrease in
both children and adults was that of a lower within-subject weightSDscorefrombaselinetoendoftrialinthosechildren
variation in self-monitored plasma glucose before breakfast treated with insulin detemir indicated that their weight
with insulin detemir than with NPH [28–30]. The low decreasedtowardsthatforthenormalreferencepopulation.
glucose-lowering variability of an insulin is desirable, as Accurate and detailed growth standards were not available
fluctuationsinglucoselevelshavebeenshowntoincreasethe for all 11 participating countries; accordingly, British stan-
risk of retinopathy and neuropathy in patients with Type 1 dards [23] were used. These standards allow very accurate
diabetesandmayinducehigherratesofhypoglycaemia[31]. calculationofSDscoreasdataareavailableformonthlytime
Insulin detemir was associated with a significantly lower intervals and gender. This was not the case for other
riskof24-handnocturnalhypoglycaemia.Thelowerrateof available population data. Although the derivation of the
hypoglycaemia with insulin detemir may in part be attrib- SDscoreforallcountrieswasbasedonBritishgrowthcurves,
utable to its lower within-subject variability compared with thedifferencebetweentreatmentarmswasnotinfluencedby
NPH.Theseresultssupportfindingsfromasimilarstudyalso this.
examining insulin detemir with insulin aspart with children The weight-sparing property of insulin detemir is a
with Type 1 diabetes [30]. Severe hypoglycaemia is associ- phenomenon observed in several other studies in both
ated with impaired cognitive capabilities in children [8,9] Type 1 [28] and Type 2 diabetes [33], but the reasons for
andparents’fearofhypoglycaemiaepisodeshasbeenshown thisremainunclear.Theimportanceofkeepingweightgain
toimpactnegativelyonadherencetodiabetestreatmentand associated with diabetes therapy low, especially in adoles-
thus glycaemic control [32]. Hence, attempting to minimize cents, is highlighted by the observation that young people
theoccurrenceofhypoglycaemiainchildrenisessential,and withType 1diabetesoftenuseinsulinomissionasastrategy
it is therefore noteworthy that there were fewer severe tomanagetheirweight[34,35],withadetrimentaleffecton
hypoglycaemiceventswithinsulindetemirthanwithNPH. glycaemiccontrol,andcomplicationrisk.
Taken together, the outcomes discussed above suggest a In consequence of the findings of this trial, regulatory
reduction in hypoglycaemia was achieved with insulin approval has been granted by the European Medicines
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DIABETICMedicine Insulindetemiruseinchildren(cid:3)N.Thalangeetal.
(a) (d)
(b) (e)
(c) (f)
FIGURE2Observedmeanglycatedhaemoglobin(HbA1c)(±SEM)overtimeforfullanalysissetlastobservationcarriedforwardfortheoverall
cohort(a),the6-to12-year-oldsubgroup(b)andthe13-to16-year-oldcohort(c),andfastingplasmaglucose(±SEM)overtimeforfullanalysisset
lastobservationcarriedforwardfortheoverallcohort(d),the6-to12-year-oldsubgroup(e)andthe13-to16-year-oldcohort(f).NPH,neutral
protamineHagedorn.
Table3Dailyinsulindose
Agency for use of insulin detemir within the European
13–16years Union,forchildrenaged2–5 years.
6–12yearsold old Totalcohort In conclusion, this study confirmed efficacy of insulin
Insulin Insulin Insulin Insulin detemir by demonstrating non-inferiority of insulin detemir
dose detemir NPH detemir NPH detemir NPH compared with NPH with respect to HbA , with an
1c
improved safety profile including significantly fewer hypo-
Basalinsulin
Baseline 0.48 0.44 0.41 0.44 0.42 0.42 glycaemic episodes and less undesirable weight gain in
Endof 0.64 0.63 0.53 0.54 0.57 0.55 children and adolescents aged 2–16 years with Type 1
trial diabetes. An ideal insulin regimen—particularly for chil-
Bolusinsulin
Baseline 0.42 0.46 0.52 0.47 0.46 0.46 dren—should be physiological, flexible and predictable,
Endof 0.44 0.40 0.48 0.47 0.47 0.43 whilst protecting against hypoglycaemia and inappropriate
trial
weight gain. Although here the efficacy and tolerability of
insulin detemir was compared with NPH, which is not
Dataaremedian,inU/kg.
NPH,neutralprotamineHagedorn. always used as part of a basal–bolus regimen in the young
ª2012TheAuthors.
222 DiabeticMedicineª2012DiabetesUK
Researcharticle DIABETICMedicine
FIGURE3Themeanrateofhypoglycaemicepisodes(perpatient-year)
in6-to12-year-oldsubgroup,13-to16-year-oldsubgroupandthe FIGURE4ObservedmeanweightSDscoreovertimeforsafetyanalysis
totalcohort.Nocturnalhypoglycaemia:22.00–07.00h,inclusive. setlastobservationcarriedforward.NPH,neutralprotamine
Hagedorn.
NPH,neutralprotamineHagedorn.
Competinginterests
in clinical practice, the most suitable comparator, insulin Thisstudy wassupportedfinancially byNovoNordiskA/S,
glargine, has not yet been approved for use in children Denmark,whowerealsoresponsibleforthedesign,conduct,
under the age of 6 years, and therefore the choice of NPH analysis and reporting of the study, with input from the
as a comparator does not detract from the positive authors. All authors were involved in the preparation and
outcomes seen with insulin detemir. This study therefore approval of the manuscript in collaboration with Novo
confirmsthatinsulindetemir,coupledwithinsulinaspartin Nordisk. NT has received fees for speaking and consulting
a basal–bolus insulinregimen, hasthe key characteristics of fromNovoNordiskA/S.LCHandJLareemployedby,and
an ideal insulin regimen, and that these benefits extend to hold stock in, Novo Nordisk A/S. AB and VP have no
the very young. competingintereststodeclare.
Fundingsources Acknowledgements
Thisstudy wassupportedfinancially byNovoNordiskA/S, WewouldliketothankWatermeadowMedicalforeditorial
Denmark. assistance in preparing this manuscript, supported by Novo
Table4Summaryofallhypoglycaemicepisodes
Insulindetemir NPH
n (%) Episodes Rate* n (%) Episodes Rate* Rateratio† 95%CI P-value
All24-hepisodes 168 95 9448 56.3 166 98 11576 71.0 0.76 0.60–0.97 0.028
Severe24h 3 2 3 0.0 12 7 15 0.1 — — —
Moderate24h 30 17 370 2.2 28 16 947 5.8 0.38 0.14–1.03 0.057
Mild24h 148 84 5956 35.5 151 89 7189 44.1 0.71 0.52–0.96 0.027
Biochemical24h 135 76 3119 18.6 128 75 3425 21.0 0.90 0.63–1.29 0.565
Allnocturnal 131 74 1379 8.2 141 83 2141 13.1 0.62 0.47–0.84 0.002
Severenocturnal 0 0 0 0.0 5 3 6 0.0 — — —
Moderatenocturnal 15 8 59 0.4 14 8 112 0.7 0.44 0.14–1.42 0.169
Mildnocturnal 100 56 712 4.2 111 65 1139 7.0 0.54 0.38–0.78 0.001
Biochemicalnocturnal 83 47 608 3.6 85 50 884 5.4 0.74 0.47–1.17 0.194
Alldiurnal 167 94 8069 48.1 166 98 9435 57.9 0.79 0.62–1.01 0.061
Severediurnal 3 2 3 0.0 8 5 9 0.1 — — —
Moderatediurnal 27 15 311 1.9 27 16 835 5.1 0.37 0.13–1.03 0.058
Milddiurnal 146 82 5244 31.2 150 88 6050 37.1 0.74 0.55–1.01 0.060
Biochemicaldiurnal 128 72 2511 15.0 123 72 2541 15.6 0.95 0.66–1.37 0.783
*Numberofepisodespersubject-yearofexposure.
†Adjustedratefromnegativebinomialregressionmodelincludinglog-transformedexposuretimeasanoffsetvariable,stratificationand
treatment.
NPH,neutralprotamineHagedorn.
ª2012TheAuthors.
DiabeticMedicineª2012DiabetesUK 223
DIABETICMedicine Insulindetemiruseinchildren(cid:3)N.Thalangeetal.
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their co-workers for their participation in this study— 10 SilversteinJ,KlingensmithG,CopelandK,PlotnickL,KaufmanF,
Laffel L et al. Care of children and adolescents with type1
Bulgaria:AssociateProfessorKalinkaKopriavarova,Profes- diabetes.DiabetesCare2005;28:186–212.
sorValentinaTzaneva,AssociateProfessorChaykaPetrova; 11 Ludvigsson J, Bolli GB. Intensive insulin treatment in diabetic
CzechRepublic:ProfessorJanLeblMD,JitrenkaVenhacova children.DiabetesNutrMetab2001;14:292–304.
MD,BarboraCervickovaMD;Denmark:BirtheOlsenMD, 12 HavelundS,PlumA,RibelU,JonassenI,VolundA,MarkussenJ
et al. The mechanism of protraction of insulin detemir, a long-
ThomasHertelMD,ElisabethLundMD;Finland:DrRiitta
acting, acylated analog of human insulin. Pharm Res 2004; 21:
Veijola, Dr Timo Talvitie, Dr Paula Piekkala, Dr Marja- 1498–1504.
TerttuSaha,DrTuulaHa¨rko¨nen,DrPekkaAhonen;France: 13 HeiseT,NosekL,RønnBB,EndahlL,HeinemannL,KapitzaC
ProfessorJean-JaquesRobert,DrNicoleSer,ProfessorRe´gis et al. Lower within-subject variability of insulin detemir in
Coutant,DrFabienneDalla-Vale;Hungary:La´szloMada´csy comparison to NPH insulin and insulin glargine in people with
type1diabetes.Diabetes2004;53:1614–1620.
MD, La´szlo Barkai MD; Macedonia: Professor Dr Zoran
14 JehlePM,MichelerC,JehleDR,BreitigD,BoehmBO.Inadequate
Gucev; Poland: Ewa Pankowska MD PhD, Izabela Rog-
suspensionofneutralprotamineHagendorn(NPH)insulininpens.
ozinska MD PhD, Mieczyslaw Szalecki MD PhD, Malgorz- Lancet1999;354:1604–1607.
ataMysliwiecMDPhD,StanislawPawelczakMD,Professor 15 DeLeeuwI,VagueP,SelamJL,SkeieS,LangH,DraegerEetal.
Elzbieta Piontek; Russia: Dr E. Petraikina, Professor E Insulindetemirusedinbasal–bolustherapyinpeoplewithtype1
diabetesisassociatedwithalowerriskofnocturnalhypoglycaemia
Kasatkina,DrBashina;Turkey:ProfessorDrHulyaGunoz,
andlessweightgainover12monthsincomparisontoNPHinsulin.
Professor Dr Ece Bober, Professor Dr Iffet Bircan; UK: DiabetesObesMetab2005;7:73–82.
Professor David Dunger, Dr Stephen Greene, Professor 16 HermansenK,FontaineP,KukoljaKK,PeterkovaV,LethG,Gall
TimothyBarrett,DrAmaliaMayo-Garcia.Finally,wethank MA.Insulinanalogues(insulindetemirandinsulinaspart)versus
Irene Vejgaard Sørensen (Novo Nordisk A/S) for assistance traditional human insulins (NPH insulin and regular human
insulin) in basal–bolus therapy for patients with type1 diabetes.
inpreparingthispaper.
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