Continuous Glucose Monitoring:An Endocrine Society Clinical Practice Guideline

T h e E n d o c r i n e S o c i e t y ’ s

CliniCal Guidelines

Authors: david C. Klonoff (chair), Bruce Buckingham, Jens s. Christiansen, Victor M. Montori, William V.Tamborlane,Roberta.Vigersky,andHowardWolpert

Affiliations:Mills-PeninsulaHealthservices(d.C.K.),sanMateo,California94401;stanforduniversityschoolofMedicine(B.B.),stanford,California94305;aarhusuniversityHospital(J.s.C.),8000aarhusC,denmark;MayoClinic(V.M.M.),Rochester,Minnesota55905;YaleuniversityschoolofMedicine(W.V.T.),newHaven,Connecticut06510;WalterReednationalMilitaryMedicalCenter (R.a.V.),Bethesda,Maryland20889;andJoslindiabetesCenter(H.W.),Boston,Massachusetts02215

Co-Sponsoring Associations:diabetesTechnologysocietyandeuropeansocietyofendocrinology.

Disclaimer: ClinicalPracticeGuidelinesaredevelopedtobeofassistancetoendocrinologistsandotherhealthcareprofessionalsbyprovidingguidanceand recommendations forparticularareasofpractice.TheGuidelinesshouldnotbeconsideredinclusiveofallproperapproachesormethods,orexclusiveofothers.TheGuidelinescannotguaranteeanyspecificoutcome,nordotheyestablishastandardofcare.TheGuidelinesarenotintendedto dictate the treatment of a particular patient. Treatment decisions must be made based on the independentjudgmentofhealthcareprovidersandeachpatient’sindividualcircumstances.

Theendocrinesocietymakesnowarranty,expressorimplied,regardingtheGuidelinesandspecificallyexcludesanywarrantiesofmerchantabilityandfitnessforaparticularuseorpurpose.Thesocietyshallnotbeliablefordirect, indirect, special, incidental, or consequential damages related to the use of the information containedherein.

FirstpublishedinJournal of Clinical Endocrinology & Metabolism, October, 2011, 96 (10): 2968–2979.

©Theendocrinesociety,2011

Continuous Glucose Monitoring:An Endocrine Society Clinical Practice Guideline

T h e E n d o c r i n e S o c i e t y ’ s

CliniCal Guidelines

Table of Contents

abstract. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

summaryofRecommendations. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Methodofdevelopmentofevidence-BasedClinicalPracticeGuidelines. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

RT-CGMinadultHospitalsettings. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

RT-CGMinChildrenandadolescentOutpatients . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

RT-CGMinadultOutpatients. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

OrderForm. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Reprintinformation,Questions&Correspondences . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . insideBackCover

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Abstract

Objective:Theaimwastoformulatepracticeguide-linesfordeterminingsettingswherepatientsaremostlikely to benefit from the use of continuous glucosemonitoring(CGM).

Participants: The endocrine society appointed aTaskForceofexperts,amethodologist,andamedicalwriter.

Evidence: This evidence-based guideline wasdeveloped using the Grading of Recommendations,assessment,development,andevaluation(GRade)systemtodescribeboththestrengthofrecommenda-tionsandthequalityofevidence.

Consensus Process: One group meeting, severalconferencecalls,ande-mailcommunicationsenabledconsensus. Committees and members of The endo-crinesociety, thediabetesTechnologysociety,andtheeuropeansocietyofendocrinologyreviewedandcommentedonpreliminarydraftsoftheseguidelines.

Conclusions: TheTaskForceevaluatedthreepoten-tialusesofCGM:1)real-timeCGMinadulthospitalsettings; 2) real-time CGM in children and adoles-cent outpatients; and 3) real-time CGM in adultoutpatients. The Task Force used the best availabledata to develop evidence-based recommendationsaboutwhereCGMcanbebeneficial inmaintainingtarget levels of glycemia and limiting the risk ofhypoglycemia. Both strength of recommendationsand quality of evidence were accounted for in theguidelines.

J Clin Endocrinol Metab, October, 2011, 96 (10): 2968–2979.

Abbreviations: CGM, Continuous glucose monitoring; CIT, conventional insulin therapy; HbA1c, glycosylated hemoglobin; ICU, intensive care unit; IIT, intensive insulin therapy; ISF, interstitial fluid; MDI, multiple daily injections; MICU, medical ICU; POC, point-of-care; RT-CGM, real-time CGM; SMBG, self-monitoring of blood glucose; T1DM, type 1 diabetes mellitus.

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SuMMAry Of rECOMMEndATiOnS

1.0. real-time continuous glucose monitoring (rT-CGM) in adult hospital settings

1.1. We recommend against the use of RT-CGMalone for glucosemanagement in the intensivecareunit (iCu) or operating room until further studiesprovidesufficientevidenceforitsaccuracyandsafetyinthosesettings(1| ).

2.0. rT-CGM in children and adolescent outpatients

2.1. We recommend that RT-CGM with currentlyapproveddevicesbeusedbychildrenandadolescentswith type 1 diabetes mellitus (T1dM) who haveachieved glycosylated hemoglobin (Hba1c) levelsbelow7.0%becauseitwillassistinmaintainingtargetHba1clevelswhilelimitingtheriskofhypoglycemia(1| ).

2.2. WerecommendRT-CGMdevicesbeusedwithchildren and adolescents with T1dM who haveHba1clevels≥7.0%whoareabletousethesedevicesonanearlydailybasis(1| ).

2.3. We make no recommendations for or againsttheuseofRT-CGMbychildrenwithT1dMwhoarelessthan8yrofage.

2.4. Wesuggestthattreatmentguidelinesbeprovidedtopatientstoallowthemtosafelyandeffectivelytakeadvantage of the information provided to them byRT-CGM(2| ).

2.5. WesuggesttheintermittentuseofCGMsystemsdesigned for short-term retrospective analysis inpediatric patients with diabetes in whom cliniciansworryaboutnocturnalhypoglycemia,dawnphenom-enon, and postprandial hyperglycemia; in patientswith hypoglycemic unawareness; and in patientsexperimenting with important changes to theirdiabetes regimen [such as instituting new insulin or

switching from multiple daily injections (Mdi) topumptherapy](2| ).

3.0. rT-CGM in adult outpatients

3.1. WerecommendthatRT-CGMdevicesbeusedbyadultpatientswithT1dMwhohaveHba1clevelsof at least 7.0% and who have demonstrated thatthey can use these devices on a nearly daily basis(1| ).

3.2. WerecommendthatRT-CGMdevicesbeusedbyadultpatientswithT1dMwhohaveHba1clevelsless than 7.0% and who have demonstrated thatthey can use these devices on a nearly daily basis(1| ).

3.3. WesuggestthatintermittentuseofCGMsystemsdesignedforshort-termretrospectiveanalysismaybeof benefit in adult patients with diabetes to detectnocturnal hypoglycemia, the dawn phenomenon,andpostprandialhyperglycemia,andtoassist in themanagementofhypoglycemicunawarenessandwhensignificantchangesaremadetotheirdiabetesregimen(such as instituting new insulins or switching fromMditopumptherapy)(2| ).

METhOd Of dEvElOPMEnT Of EvidEnCE- BASEd CliniCAl PrACTiCE GuidElinES

TheClinicalGuidelinessubcommitteeofTheendo-crinesocietydeemedcontinuousglucosemonitoring(CGM)apriorityareainneedofpracticeguidelinesand appointed a Task Force to formulate evidence-basedrecommendations.TheTaskForcefollowedtheapproach recommended by the Grading of Recom-mendations,assessment,development,andevalua-tion (GRade) workgroup, an international groupwithexpertiseindevelopmentandimplementationofevidence-basedguidelines(1).adetaileddescriptionofthegradingschemehasbeenpublishedelsewhere(2).TheTaskForceusedthebestavailableresearch

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evidencethatTaskForcemembersidentifiedandonecommissionedsystematicliteraturereviewofrandom-izedcontrolledtrialsofCGMuse(3)toinformsomeof the recommendations. The Task Force also usedconsistentlanguageandgraphicaldescriptionsofboththestrengthofarecommendationandthequalityofevidence.intermsofthestrengthoftherecommen-dation, strong recommendations use the phrase “werecommend”andthenumber1,andweakrecommen-dationsusethephrase“wesuggest”andthenumber2.Cross-filled circlesindicatethequalityoftheevidence,suchthat denotesverylowqualityevidence;

, lowquality; ,moderatequality;and,highquality.TheTaskForcehasconfidence

thatpersonswhoreceivecareaccordingtothestrongrecommendationswillderive,onaverage,moregoodthan harm. Weak recommendations require morecareful consideration of the person’s circumstances,values,andpreferencestodeterminethebestcourseofaction.linkedtoeachrecommendationisadescrip-tion of the evidence and the values that panelistsconsidered in making the recommendation. all ofour recommendations are expert opinions and areevidencebased.someoftheseopinionsarebasedonstrongerevidencethanothers.Forstrongrecommen-dationswithGRade1evidence,theTaskForcehasmaderecommendations,and forweakrecommenda-tions with GRade 2 evidence, the Task Force hasmadesuggestions.Forrecommendationsinthisguide-linethatarebasedonlow-qualitytoverylow-qualityevidence, the reader should note that our implicitrecommendationisformoreresearch.

ThetaskforcerecognizesthatCGMmayplaceeduca-tional and practical burdens on patients and theirfamiliesandondiabetescareproviderswhomustbeavailable to support, advise, and educate them. Wealsorecognizethattherearecostsassociatedwiththeuseofthistechnologyaccordingtoourrecommenda-tionsandthatultimately,theroutineuseofthistech-nology will depend on an evolving calculus of costvs. effectiveness.Wehaveconsideredthecost-benefitissues related to the use of CGM and feel that theclinical benefits justify the costs in a wide range ofpatients,butthatthesevaluesmaynotbeuniversallyshared in some healthcare settings (e.g. those withresource-constrained settings, clinics unable to

provide adequate support to patients and families).individuals orhealth systemsmaydisagreewithourrelativevaluation,andinthesecasesourrecommen-dations may not apply. it may then be necessary tomodifytheserecommendationsaccordingly.

inTrOduCTiOn

People who have diabetes mellitus face daily chal-lengesinmanagingglycemiclevels,aswellasavoidinghypoglycemic and hyperglycemic excursions. Bothsevere hypoglycemia and extreme hyperglycemiahave an immediate impact on mental and physicalfunctioning.Moreover,themaintenanceofglycemiccontrolwithinnear-normallimitshasbeenshowntosignificantly decrease the development of secondarymicro- and macrovascular complications to diabetes(4–6).

Capillarybloodglucosemeasurementsusingportabledeviceshavebeenusedtoassessbloodglucoseseveraltimesaday inaneffort toprovide thepatientwithreliable guidance for treatment (including dietary)measurestocorrecthypo-orhyperglycemia.However,even with frequent blood sampling for spot glucosemeasurements, some patients do not adequatelymanagetheirglycemiclevels.ithasbeenpostulatedthatsuchpatientsmaybenefitfromasystemprovidingthem with continuous real-time glucose readings.althoughthisargumentisintuitivelyeasytoaccept,thereremainanumberofcaveatstotakeintoaccountbefore accepting continuous monitoring of bloodglucoseasaroutine(orevenspecialized)measuretoimproveglycemiccontrolindiabetes.

First, maintaining direct access to the blood on acontinuous basis for an extended period has provedimpractical.Hence,anumberofdifferenttechniqueshave been evaluated, including invasive and non-invasive methods for indirectly estimating bloodglucose.second, the reliability in termsof accuracyandtheprecisionofthevarioussystemsneedproperdocumentationbeforebeingapplied inroutinecare.Third,financialconstraintsrequireanongoingevalu-ation of the socioeconomic consequences of these

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operatingroomuntilfurtherstudiesprovidesufficientevidenceforitsaccuracyandsafetyinthosesettings(1| ).

1.1. Evidence

The study of van den Berghe et al. (8) in surgicaliCupatientsshowingmarkedreductioninmortalityandmorbidityinthosetreatedwithintensiveinsulintherapy (iiT) comparedwith conventional insulintherapy(CiT)initiatedarapidlygrowingworldwidetrend to aggressively treat hyperglycemia in criti-cally ill patients. However, subsequent studies inmedical iCu(MiCu)patients, includingthosebyvandenBergheet al. (8),aswellasinsurgicalandMiCu/surgical iCupatients,havebeenunable toduplicateherresults(9–13).ameta-analysisbeforethe niCe-suGaR report, in fact, confirmed thattherewasnobenefittoiiT(14)intheiCupopula-tion. Furthermore, these prospective, randomizedcontrolled trials of iiT demonstrated that hypo-glycemia was significantly more common in thosereceiving iiT than in those treated with CiT.The niCe-suGaR study showed, in fact, anincreased mortality rate in those treated with iiT(12) (Table 1). although the reasons for thisincreasedrateareunclear,thefindingisconsistentwith a retrospective analysis showing that hypo-glycemiawasanindependentriskfactorformortality(15). in one series, however, this risk was limitedto patients with spontaneous hypoglycemia, but

new techniques, and therefore the eventual clinicalbenefits of their use need to be documented andbalancedagainsttheircosts.

The glucose concentration in the interstitial fluid(isF)hasprovenreasonablyassessable,evenforlong-term monitoring in an outpatient setting, andcurrently the vast majority of the available tech-nology, as well as technology under development,usestheisFformonitoringdirectlyorindirectly.inthis context, it is of particular interest that theglucoseconcentrationinthescisFhasbeenshowntoreflecttheconcentrationsanddynamicsofglucoseinthebrain(7).Thepresentsetofguidelinesisnotatechnicalreviewofavailabletechnologies.Rather,this document scrutinizes available evidence thatCGMintheisFisofclinicalvalue inthequesttoobtainandmaintainnearnormalglycemiccontrolinvarious clinical situations and subpopulations withdiabetesmellitus(3).

1.0. rT-CGM in AdulT hOSPiTAl SETTinGS

Recommendation

1.1. We recommend against the use of RT-CGMalone for glucose management in the iCu or

TABLE 1. rates of hypoglycemia in iCu patients receiving iiT vs. CiT

first author, year (ref.) hypoglycemia in iiT (%)

hypoglycemia in CiT (%) P value Glucose method Whole blood

source

Arabi, 2008 (9) 28.6 3.1 0.0001 Accu-Chek Inform Artery or capillary

Brunkhorst, 2008 (10) 17.0 4.1 0.001 HemoCue Artery or capillary

Devos, 2007 (11) 9.8 2.7 0.001 Not stated Not stated

Grey, 2004 (78) 32.0 7.4 0.001 Not stated Not stated

NICE-SUGAR, 2009 (12) 6.8 0.5 0.001 Blood gas analyzer Artery (mostly)

Van den Berghe, 2001 (8) 12.7 0.76 ? ABL700 Artery

Van den Berghe, 2006 (13) 3.1 18.7 0.001 HemoCue Capillary

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POCcapillarysamplesarethemostcommonlyusedmethod for obtaining blood glucose measurementsin the iCu.Furthermore, several studieshaveusedcapillary-derived samples to validate CGM in thissetting.

WithrespecttoiCuconditions,Kulkarniet al. (26)founda significantdiscrepancy in accuracy in thosetreated with iiT who had hypotension and/or weretreatedwithapressorascomparedwiththosewithouthypotension/pressortreatment(2sdvalues fromthemean difference between measurements in the lowrangewas–36.8mg/dl).Hauptet al. (29)foundthathypothermiacancausesignificantunderestimationofblood glucose, and Hoedemaekers et al. (24) foundthattheisOcriteriawerenotmetbythreedifferentmeters(accu-Chek,HemoCue,andPrecision)withallreadingshigherthanthereferencestandard,whichcan lead to potentially serious overtreatment withinsulin. Most recently, Vlasselaers et al. (30) foundsignificant clinical bias using both accu-Chek andHemoCuedevicesascomparedwithstandardlabora-torytestingandrecommendedcautioninusingsuchdevicestoregulateinsulininfusionrates.

CGM may have an advantage over POC testing inthat ithas thepotential to reduce thepossibilityofunknown hypoglycemic events that may occurbetweenPOCmeasurements.Thesedevicesuse isFrather than blood to measure glucose, but the rela-tionshipof isF toblood incritically illpatientshasbeen investigated only to a limited degree. severalstudiesofCGMhaveevaluatedtheeffectsofcondi-tions that are common in the iCu, such as hypo-tension with or without inotrope use, hypothermia,edema, renal and hepatic failure, hyperinsulinemia,andacidosis,butthesestudiesweresmallandgener-ally not powered to assess each of those variables(Table2)(31–37).Forexample,deBlocket al. (31),inastudyof50adultiCupatients,notedworseaccu-racy inpatientson inotropesandbetteraccuracy inthoseinacuterenalfailureandsepticshockcomparedwith patients on no inotropes and without theseconditions. However, Holzinger et al. (33) foundthattherewasnosignificanteffectonaccuracyin27iCupatients treatedwithnorepinephrine for shockcompared with 23 without shock, and a lack of

iatrogenic hypoglycemia after insulin therapy wasnotassociatedwithahighermortalityrisk(16).

These trials used a variety of bedside point-of-care(POC) devices for testing glucose, which are listed(when specified) in Table 1. The listed devices useglucose dehydrogenase for glucose determination.Recently,theFoodanddrugadministration(Fda)haswarnedthatthismethodissubjecttofalseeleva-tion by maltose, icodextrine, galactose, and xylose,althoughtheFdahasnotproscribedtheiruseinthehospital(17).itisunlikely,althoughnotimpossible,thatpatients in intensivemanagement studiesweresubject to such errors. On the other hand, devicesthat use glucose oxidase are potentially subject tofalsely lower than actual values in settings wherethere is high oxygen tension produced by supple-mentaloxygen(18).Bothmethodsmaybeaffectedbyavarietyofmedications.importantly,therequire-mentsforaccuracyinacriticalcaresettinghavenotyetbeendetermined.Kostet al. (19)havesuggestedthatthemarginsoferrorforbloodglucosemeasure-ment should be within 15 mg/dl of the referencemeasurementforbloodsugarslessthan100mg/dlandwithin 15% if above 100 mg/dl in critical caresettings. it should be noted that the internationalOrganization for standardization (isO) (20)suggestedthat themarginoferror shouldbewithin15mg/dlforbloodsugarslessthan75mg/dl.inaddi-tiontotheissueofwhatstandardsshouldbeapplied,POC testing itself (rather than laboratory testing)in critically ill patients is controversial because ofunresolvedquestionsabouttheeffectsonaccuracyofcommon conditions, e.g. acidosis, hypothermia,and hypotension; or medications, e.g. dopamine,mannitol, acetaminophen, and pressor use. Thesecircumstances reduce tissue perfusion, which mayuncouple theusual relationshipbetweenthescandcirculatoryglucose.Thus,resultsmaydifferdependingnotonlyonthesourceofthesample—capillary,vein,or artery—but also on the concomitant cause andtreatmentofthepatient’siCustay.Ofseveralstudiesinvestigating the accuracy of POC testing in theiCu,somefoundadequateaccuracyifarterialsampleswereused(18,21),whereasothersgenerallyshowedmarginal or clinically unacceptable accuracy withcapillary samples (22–28). despite these findings,

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thelife-threateningzone.iniCupatientswithcontin-uousinsulininfusions,Rabieeet al. (41)comparedthedexComtothreedifferentmethodsofglucosedeter-mination—twowithcapillarybloodfromfingersticks(accu-Chek and OneTouch) and one from serum(Hitachi917),whichwasusedasthe“goldstandard”forclinicaldecisions.Therewere85pairedvalueswiththeHitachi917,and100%ofvaluesintheaandBzones.However,whentheseresultsandthepaireddatawith the accu-Chek (1065 paired values comparedwith dexcom) and OneTouch (232 paired valuescomparedwithdexcom)weremorecloselyexamined,the CGM generally overestimated the actual serumglucoseandmissed50%ofthe30actualhypoglycemicepisodes as determined by accu-Chek, leading theauthorstoconcludethatitwasnotsufficientlysafetobe used in an iCu setting. Blood glucose measure-ments on POC devices have been used as referencemethodsforCGMaccuracystudies,butthesedevicesprovidereadingswithuptoa20%bias(orgreaterinsome circumstances) compared to reference values.in hospitalized patients, anemia, abnormal oxygentension,andhypotensioncanalldegradeaccuracyofthesedevicesandmakeitdifficulttoassessthesimul-taneousperformanceofCGM.Tonyushkinaet al. (44)andMrazet al. (40),usingacomputer-basedpredictivemodel control algorithm in 10 post-cardiac surgerypatients, found that 97% of readings were clinicallyacceptable(aandBzones),andtherewerenoepisodesof hypoglycemia over 24 h, whereas there were fiveepisodes in 10 patients in the control group. in the

inotrope effect was noted in other studies (32, 37).CGMwasnotaffectedbymildketosiswithoutacidosisin a study of patients with T1dM in whom theirinsulinpumpwastemporarilystoppedinanon-iCusetting(35),buttheeffectofketo-orlacticacidosishasnotbeenevaluated.Otherstudieshavenotedthathypotension,hypothermia,andedemadidnotaffectCGM accuracy (32, 36). interestingly, hyperinsu-linemia itself reduced sensor glucose comparedwithvenousglucosereadingsabout20%inhumans(34).Thesefindingsdifferfromthoseinahyperinsulinemichyperglycemicdogmodel inwhich sensordynamicswereunchangedunderconditionsofdifferentinsulinconcentrations(38).

TherehavebeenninestudiesthathaveevaluatedtheaccuracyofisF-basedCGMintheiCu(23,32,33,36,37,39–42)(Table3);ofthem,onlyoneinvolveduse of CGM to control iiT (40). The other studiesused retrospective comparisons of a reference POCvaluewithsimultaneousCGMdata.eachstudyhadasmall number of patients (17 to 50, for a combinedtotal of 256), and few data were obtained duringhypoglycemia.Goldberget al. (32)foundthat98.7%of resultswere in theClarkeet al. (43)error gridaand B zones, although they used capillary samplesas the reference method. Only four of 546 pairingsfound blood glucose less than 60 mg/dl. Corstjenset al. (23)foundthat100%ofthereadingsofMiCupatientswere in theaandB zones.Holzingeret al. (33) also found excellent clinical agreement with98.6%intheacceptabletreatmentzoneandnonein

TABLE 2. Effects of different conditions and treatments on CGM accuracy in the iCu

first author, year (ref.) Condition/treatment no. of patients no. of paired samples

Accuracy interference

De Block, 2006 (31) Inotropes ? ? Yes

Goldberg, 2004 (32) Inotrope/edema/hypotension 21 546 No

Holzinger, 2009 (33) Inotropes 50 736 No

Monsod, 2002 (34) Hyperinsulinemia 11 88 Yes

Pfützner, 2006 (35) Ketosis 12 159 No

Price, 2008 (37) Inotropes 17 371 No

Piper, 2006 (36) Edema, hypothermia, inotropes 20 246 No

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beforeitcanberecommendedforusewithiiTproto-cols.Finally,intheonlyrandomizedstudy,Mrazet al. (40)foundthatCGMprovidedbetterglycemiccontrolwithout hypoglycemia in comparison with standardmonitoring to manage glycemia (using an enhancedmodelpredictivecontrolalgorithm)inaniiTprotocol.Thisstudyisaharbingerofan“artificialpancreas”andrepresents a valuable and rapidly progressing area ofresearchtodeterminewhetherornottheapplicationofsophisticatedmodelpredictivecontrolleralgorithmswillbesufficienttoovercometheinherentinaccura-ciesofCGMtechnology.

1.1. Values and preferences

TheTaskForce recommends against usingCGM iniCusettingswherepatientsarelikelytobeunabletoprovidefeedbackabouthypoglycemicsymptoms.Thisrecommendation is based on the limited availabledata related toaccuracyandourconcerns regardingpotential danger in their use in guiding insulin

onlystudyinapediatricpopulation,Piperet al. (36)foundexcellentclinicalaccuracy,with98.8%inzonesaandBin20patientsaftercardiacsurgery.However,onlytwoof246pairedvalueswerelessthan75mg/dl.Finally,Yamashitaet al.(42),usinganivCGM,found100%inzonesaandB.Thesepromisingresultsaremitigated by other studies. Price et al. (37) found apoorcorrelationbetweenCGMandbothcapillaryandarterial samples when the blood sugar was less than81 mg/dl. CGM overestimated capillary or arterialglucoseby18mg/dlormore in23%of readings lessthan80mg/dl,althoughtherewereonly36compari-sonsinthatrange.logtenberget al. (39),incomparingcapillary, arterial, and venous reference standards iniCu patients after cardiac surgery, found that 96.0,92.1,and84.6%,respectively,werewithintheClarkeerror grid a and B zones; and 3.3, 7.4, and 14.7%,respectively,wereinthedzone.Bloodsugarslessthan60mg/dlwererareintheirstudy,aswell.insummary,whereas theuse ofCGMappears promising, itmustundergolargerandrigoroustestingintheiCusetting

TABLE 3. Accuracy of iSf-based CGM systems compared with POC glucometry in iCu patients

first author, year (ref.) device Comparison no. of

patients Siteno. of paired

samples

Clarke A, B (%)

Clarke C, d, E

(%)

Corstjens, 2006 (23) CGM Arterial ABL715/ Precision PCx 19 MICU 165 100 0

Goldberg, 2004 (32) CGM Capillary 21 MICU 546 98.7 1.3

Holzinger, 2009 (33) CGM Arterial ABL700 50 MICU 736 98.6 1.4

Logtenberg, 2009 (39) RT-CGM Capillary

(Accu-Chek)/arterial 30 Post-op SICU 275/216 96/92.1 4.1/7.9

Mraz, 2009 (40) CGM/eMPC Arterial 10 SICU 24 97 3

Piper, 2006 (36) CGM Lab 20 Post-op ICU 246 98.8a 1.2

Price, 2008 (37) RT-CGM Accu-Chek, capillary/arterial 17 MICU? 366 Not done Not done

Rabiee, 2009 (41) CGM

Arterial: Hitachi 917 19 SICU/ burn ICU 84 100 0

Capillary: Accu-Chek 19 1065 99.25 0.75

OneTouch 19 232 97.41 2.59

Yamashita, 2008 (42) STG-22 Arterial ABL 800FLEX 50 SICU 200 100 0

SICU, Surgical ICU; eMPC, enhanced model predictive control algorithm.

a Insulin titration grid analysis.

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Recommendation

2.1. We recommend that RT-CGM with currentlyapproveddevicesbeusedbychildrenandadolescentswithT1dMwhohaveachievedHba1clevelsbelow7.0% because it will assist in maintaining targetHba1clevelswhilelimitingtheriskofhypoglycemia(1| ).

2.1. Evidence

TheJuvenilediabetesResearchFoundationContin-uous Glucose Monitoring (JdRF CGM) (59) studyGrouphasdemonstratedthatinpatientswithT1dMwho have achieved Hba1c levels less than 7.0%,RT-CGMusecanreducethe frequencyofbiochem-ical hypoglycemia (which they defined as a bloodglucose level below 70 mg/dl) and help maintainHba1clevelslessthan7.0%comparedwithstandardblood glucose monitoring over a 6-month studyperiod.Ofthe129enrolledsubjects,62(or48%)wereyoungerthan25,and67(or52%)wereatleast25yrofage.Themediantimeperdaywithaglucoselevelof70mg/dlorlessasmeasuredwithCGMwaslessintheCGMgroupthaninthecontrolgroup;however,thedifferencewasnotstatisticallysignificant.inthisstudy, almost all the other analyses (including thetime per day≤ 60 mg/dl, time per day between 71and 180 mg/dl, and combined outcomes involvingHba1c coupled with hypoglycemia) favored theCGMgroupcomparedwiththecontrolgroup.Treat-menteffectsweregenerallysimilaracrossagegroups.

Recommendation

2.2. WerecommendRT-CGMdevicesbeusedwithchildren and adolescents with T1dM who haveHba1clevels7.0%whoareabletousethesedevicesonanearlydailybasis(1| ).

2.2. Evidence

ThedirecnetGlucoWatch2Biographer(52),GuardControl(60),sTaR-1(55),andtheJdRFrandom-ized clinical trials [JdRF CGM RCT (61)] have alldemonstrated a usage-dependent effect of loweringHba1c in youth with T1dM. For example, thedirecnetGluco-Watchstudyobservednobenefitof

administration in an acute-care setting, whichoutweighsthepossibleconvenienceandtrendaware-nessthatthetechnologyprovides.

2.0. rT-CGM in ChildrEn And AdOlESCEnT OuTPATiEnTS

CGM use with either blinded or unblinded sensorsprovidesclinicalinvestigatorswithapowerfultooltoassessnewoutcomesindiabetesresearchsuchastheeffects of new treatments on glucose variability andexposuretobiochemicalhypoglycemia.

self-monitoring of blood glucose (sMBG) is animportant component of therapy for children andadolescents with T1dM for optimizing glycemiccontrolaswellasreducingtheriskforhypoglycemia.However, standardmethods forsMBGonlyprovidepatientswithintermittent,singlepoint-in-timesnap-shotsofglucoselevels.Thereadingsoftenmissmarkedand sustained hyper- and hypoglycemic excursions(45),especiallyduringthenightwhencheckingbloodglucoseisinconvenient(46,47).

CGMsystemshavebeendevelopedthatallowmorecomplete blood glucose profiles to be obtained(48–50). However, the first generation of Fda-approved devices either provided data only forshort-term retrospective analysis (the MiniMedCGMs)orweretoodifficultanduncomfortabletouse(the GlucoWatch 2 Biographer) (51, 52). newerRT-CGM systems provide improved accuracy andfunctionalityandbetterpatienttolerance(48,53–57).FutureCGMsystemsmightcontainsoftwarethatcananalyzeinputtedclinicalfactorsandglycemictrendsto predict future glucose levels (58). However,evidenceisstillbeinggatheredregardingtheefficacy,safety, tolerability, and subjective benefits of thesedevices in different populations of patients withdiabetes.

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CGMuse,primarilybecausefewifanyofthesubjectsusedthisdeviceregularly.inthe6-monthJdRFCGMRCT in patients with T1dM and Hba1c of 7.0%or greater, 83% of adults wore their CGM devices6–7 d/wk and lowered Hba1c levels by 0.53%compared with controls. CGM was less effective inHba1c reduction inyoungerpatients inassociationwith much less frequent use of the devices (61).subjects in that study aged 8–17 yr who wore theCGM device 6–7 d/wk lowered Hba1c levels by0.8%withoutincreasingthefrequencyoflowsensorglucoseconcentrations(62).Moreover,theimprove-ment in glycemic control was maintained for a full12 months in those subjects (21% of the pediatriccohort)whowereabletocontinuethefrequentuseofthesedevices.itisalsonoteworthythattheincidenceofseverehypoglycemiaintheentirepediatriccohortwasonly11.2eventsper100patient-yearsover the12monthsofstudy.Forcomparison,therateofseverehypoglycemia in intensively treated adolescents inthediabetesControlandComplicationsTrialwas86events per 100 patient years (63). Thus, CGM usemayimprovethesafetyofintensivetreatmentofchil-dren and adolescents with T1dM even when wornlessthan6–7d/wk.

Post hoc analysesoftheJdRFCGMRCTdataindi-catethattherearefewstrongpredictorsthatcanbeusedtoidentifywhichyoungpatientswithT1dMwillusethesensoronanearlydailybasis.Theonlybase-linecharacteristicotherthanolderagethatpredictednear-dailyCGMusewasfrequentdailybloodglucosemetertestingbeforeenteringthetrial(64).

additionaldatafromtheJdRFCGMRCTindicatethat patients’ perception of the inconvenience ofusingcurrentCGMdevices is themajorobstacle tomoreconsistentuseofthesesystems(65).

in a randomized, controlled, multicenter european/israeli study of both children (ages 10–17 yr) andadultswithT1dMwhoseHba1clevelswerelessthan7.5%, a post hoc per protocol analysis demonstratedthattimespentinhypoglycemiabelow63mg/dlwasreducedby64%(P<0.001)inthechildren(66).

Recommendation

2.3. We make no recommendations for or againstthe use of RT-CGM by children with T1dM whoare less than8yrofage.More research in thisfieldisneeded.

2.3. Evidence

Randomized trials in younger age groups have beeninitiated, but no results have been reported yet.limited data from nonrandomized studies indicatethatthesedevicescanbeusedsuccessfullyinpatientslessthan8yrofage(47,67).Thequalityofevidenceis insufficient to support recommendations for oragainstitsuseinthispatientpopulationatthistime.

Recommendation

2.4. Wesuggestthattreatmentguidelinesbeprovidedtopatientstoallowthemtosafelyandeffectivelytakeadvantage of the information provided to them byRT-CGM(2| ).

2.4. Evidence

The direcnet study group (68) has developed andimplementedusefulguidelinesforinitiatingtheuseofRT-CGM. Proper training is necessary for patientsand healthcare professionals to use CGM properly(69). additional studies are needed to evaluate theeffectiveness of current and future guidelines, withregardtothetimingofapremealinsulinbolus,usingglucose trends during exercise, and using RT-CGMwheninitiatingpramlintidetherapy.

Recommendation

2.5. WesuggesttheintermittentuseofCGMsystemsdesignedforshort-termretrospectiveanalysisinpedi-atricpatientswithdiabetesforwhomcliniciansworryabout nocturnal hypoglycemia, dawn phenomenon,and postprandial hyperglycemia; in patients withhypoglycemic unawareness and in patients experi-menting with important changes to their diabetesregimen(suchasinstitutingnewinsulinorswitchingfrom Mdi to pump therapy) (2| ). Thesedevices represent an alternative for patients who

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3.0. rT-CGM in AdulT OuTPATiEnTS

Recommendation

3.1. WerecommendthatRT-CGMdevicesbeusedbyadultpatientswithT1dMwhohaveHba1clevelsofatleast7.0%andwhohavedemonstratedtheycanusethesedevicesonanearlydailybasis(1| ).

3.1. Evidence

TheJdRFCGMRCT(59),theGuardControlstudy(60), and O’Connell et al. (75) demonstrated thatadults with Hba1c of at least 7.0% had a greaterreduction inHba1cwith theuseofRT-CGMthanwith intermittent sMBG. Furthermore, unlike find-ingswithsMBG, the improvement inHba1cwithCGMisnotaccompaniedbyanincreaseinbiochem-ical hypoglycemia (54, 60). The improvement inHba1c in theCGMsubjects in the6-month JdRFtrialwassustainedduringthe6-monthobservationalperiodthatfollowedcompletionofthetrial(76).Thisongoing benefit occurred despite reduction in officevisit frequency during this observational period tolevels (2.7 ± 1.2 visits over 6 months) similar toroutinecare.Furthermore,theincidencerateofseverehypoglycemia declined from 20.5 events per 100patient-yearsduring the initial6-monthrandomizedtrial to12.1eventsper100patient-yearsduringthe6-month observational follow up. in a randomized,controlled,multicentereuropean/israelistudyofbothchildren (ages 10–17 yr) and adults with T1dMwhoseHba1clevelswerelessthan7.5%,apost hoc perprotocolanalysisdemonstratedthattimespentinhypoglycemia below 63 mg/dl was reduced by 50%(P=0.02)intheadults(66).

Recommendation

3.2. WerecommendthatRT-CGMdevicesbeusedbyadultpatientswithT1dMwhohaveHba1clevelsless than 7.0% and who have demonstrated thatthey can use these devices on a nearly daily basis(1| ).

cannot safely and effectively take advantage of theinformationprovidedtothembyRT-CGM.

2.5. Evidence

WhentheMiniMedCGMswasfirst introduced for3-d retrospective analysis of plasma glucose profiles,investigators quickly showed that this method ofglucose monitoring revealed patterns of post-mealhyperglycemiaandnocturnalhypoglycemiathatwerenot evident during standard sMBG testing in chil-drenwithT1dM(45,47).severalsmallclinicaltrialssuggested that even one or two uses of the CGMsdevicecouldleadtotreatmentadjustmentsthathadlong-lasting improvements in metabolic control ofT1dM (70–73). The validity of these findings hasbeencastindoubtbytheresultsofRT-CGMstudiesthat indicate the need for nearly daily use of thedevices to obtain and maintain lowering in Hba1clevels (61). nevertheless, in the judgment of manydiabetescareproviders,retrospectiveanalysisofshort-term CGM profiles can be of benefit in individualpatientsinwhomthecausesofpersistentelevationsinHba1careunclear.

Sensor-augmented pump therapy vs. insulin pump and SMBG at onset in youth with T1D

use of CGM in combination with insulin pumptherapy during the first year of diabetes does notappeartoimprovemetaboliccontrolincomparisontoinsulin pump therapy with standard sMBG wheninitiatedinyouthwithT1dattheonsetofthedisease.

in the OnseT study that involved 160 youth(aged 1–16 yr) (74), no significant difference inHba1c levels was observed after 12 months insubjects randomized to sensor-augmented pumptherapy(i.e. pumpandCGM)incomparisonwiththeuse of insulin pumps and standard blood glucosemetermonitoring.

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detect nocturnal hypoglycemia, the dawn phenom-enon,andpostprandialhyperglycemia,andtoassistinthe management of hypoglycemic unawareness andwhen significantchangesaremade to theirdiabetesregimen(suchasinstitutingnewinsulinorswitchingfrom Mdi to pump therapy) (2| ). Thesedevices represent an alternative for patients whocannot safely and effectively take advantage of theinformationprovidedtothembyRT-CGM.

3.3. Evidence

Thestudiesandconclusionsdiscussedinrecommen-dation2.6pertaintoadultpatientsaswellaspediatricpatients. There is also evidence that intermittentprofilescanprovideadditionalinsightsinadultswithtype2diabetesmellitusregardingglucoselevelsandthetimeintargetrange(77).

COnCluSiOnS

CGMcanbebeneficial inmaintaining target levelsof glycemia and limiting the risk of hypoglycemia.The Task Force used best available data to makerecommendations about the use of CGM in threeclinical settings: 1) RT-CGM in adult hospitalsettings; 2) RT-CGM in children and adolescentoutpatients; and 3) RT-CGM in adult outpatients.With varying degrees of strength of evidence andquality of evidence, the Task Force recommendedthe use of CGM in the second and third settings.The routineuseof this technologywill alsodependinpartonfuturedeterminationsofitscostrelativetoits benefits. The Task Force recommended againstusingCGMinadulthospitalsettingsatthistimeandcanmakenorecommendationsabouttheuseofCGMinchildrenlessthan8yrofagebecauseofthepaucityofdata.

3.2. Evidence

TheJdRFCGMstudyGrouphasdemonstratedthatinpatientswithT1dMwhohaveachievedHba1clevels less than7.0%,RT-CGMusecan reduce thefrequencyofbiochemicalhypoglycemia(whichtheydefinedasabloodglucose levelofbelow70mg/dl)and help maintain Hba1c levels less than 7.0%compared with standard blood glucose monitoringover a 6-month study period. Of the 129 enrolledsubjects,62(or48%)wereyoungerthan25,and67(or52%)weremorethan25yrofage.Themediantimeperdaywithaglucoselevelof70mg/dlorlessasmeasuredwithCGMwaslessintheCGMgroupthaninthecontrolgroup;however,thedifferencewasnotstatistically significant. in this study, almost all theotheranalyses(includingthetimeperday≤60mg/dl,timeperdaybetween71and180mg/dl,andcombinedoutcomes involving Hba1c coupled with hypo-glycemia) favored the CGM group compared withthe control group.Treatment effectswere generallysimilar across age groups (59). For the CGM userswhowere25yrandolder,theincidencerateofseverehypoglycemia was 21.8 events per 100 person-yearsduringthe6-monthrandomizedcontrolledtrialand7.1eventsper100person-yearsduringthe6monthsof continued CGM use after the conclusion of therandomized clinical trial (the observational periodthatfollowedthetrial).FortheseCGMuserswhoseHba1c levels were below 7.0%, these incidenceswere 23.6 events per 100 person-years during the6-month randomizedcontrolled trial and0per100patient-yearsduringthe6monthsofcontinuedCGMuse after the conclusion of the randomized clinicaltrial(76).Thisevidenceofanongoinglearningcurveandimprovementinglycemiccontroloverthelongterm points to the user dependence of CGM tech-nology, and this may partly account for the failureof other randomized trials enrolling individualswithpoorerglycemiccontrol(55)todemonstrateareductioninseverehypoglycemia.

Recommendation

3.3. We suggest that the intermittent use of CGMsystemsdesignedforshort-termretrospectiveanalysismay be of benefit in adult patients with diabetes to

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59. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group, Beck RW, Hirsch IB, Laffel L, Tamborlane WV, Bode BW, Buckingham B, Chase P, Clemons R, Fiallo-Scharer R, Fox LA, Gilliam LK, Huang ES, Kollman C, Kowalski AJ, Lawrence JM, Lee J, Mauras N, O’Grady M, Ruedy KJ, Tansey M, Tsalikian E, Weinzimer SA, Wilson DM, Wolpert H, Wysocki T, Xing D 2009 The effect of continuous glucose monitoring in well-controlledtype1diabetes.diabetesCare32:1378–1383

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AcknowledgmentsThemembersoftheTaskForcethankTheendocrinesociety’sClinicalGuidelinessubcommittee,ClinicalaffairsCoreCommittee, andCouncil for their careful, critical reviewof earlierversionsof thismanuscript and theirhelpful comments and suggestions. We also thank the leadership of the diabetes Technology society and theeuropeansocietyofendocrinologyfortheirreviewandcomments.FinallywethankthemanymembersofTheendocrinesocietywhoreviewedthedraftversionofthismanuscriptwhenitwaspostedonthesociety’swebsiteandwhosentagreatnumberofadditionalcommentsandsuggestions,mostofwhichwereincorporatedintothefinalversionoftheguideline.

financial disclosures of the Task forceDavid C. Klonoff, M.D., F.A.C.P. (chair)—FinancialorBusiness/Organizationalinterests:Bayer,C8Medisen-sors,insuline,lifescan,Medtronicdiabetes,Roche;significantFinancialinterestorleadershipPosition:diabetesTechnology society. Bruce Buckingham, M.D.—Financial or Business/Organizational interests: MedTronicMiniMed,lifescan,novonordisk,JdRF,unoMedical;significantFinancialinterestorleadershipPosition:nonedeclared.Jens S. Christiansen, M.D., F.R.C.P.I., Dr.Med.Sci.—FinancialorBusiness/Organizationalinterests:novonordisk,Roche;significantFinancialinterestorleadershipPosition:europeansocietyofendocrinology.Victor M. Montori, M.D.*—FinancialorBusiness/Organizationalinterests:KeRunit(MayoClinic);significantFinancialinterestorleadershipPosition:nonedeclared.William V. Tamborlane, M.D.—FinancialorBusiness/Organizationalinterests:Medtronicdiabetes,abbottdiabetes,novonordisk,elililly,Macrogenics;significantFinancialinterestorleadershipPosition:novonordisk,elililly,Medtronic,Macrogenics.Robert A. Vigersky, M.D.—Financial or Business/Organizational interests: dexcom; significant Financial interest or leadershipPosition:Theendocrinesociety.Howard Wolpert, M.D.—FinancialorBusiness/Organizationalinterests:insulet,novonordisk,Roche;significantFinancialinterestorleadershipPosition:insulet.

*evidence-basedreviewsforthisguidelinewerepreparedundercontractwithTheendocrinesociety.

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