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ABetterTestthanHbA1c?DocOutlines
AlternativesforDiabetes

October19,2016
TheDiabetesControlandComplicationTrial(DCCT),firstpublishedmorethan20
yearsago,anditsfollow-on,theEpidemiologyofDiabetesInterventionsand
Complications(EDIC)study,establishedHbA1casagoldstandardintheclinical
diagnosisandmanagementofdiabetes.
AlexanderMCastellino,PhD

Indeed,ithasbeenthemarkerusedbytheUnitedStatesFoodandDrug
Administration(FDA)toevaluatethesafetyandefficacyofnewagentsthatclaimto
achieveglycemiccontrol.

ButnowthereisanemergingbodyofliteraturetosuggestthatHbA1conitsownshould
notbethecornerstoneusedindiagnosingandmanagingdiabetespatientsintheclinic.
OnerecentpublicationinScience Translational Medicinedetailingaproposednew
methodforbetterevaluationofbloodglucosegarneredmuchmediaattention.

Medscape Medical NewsaskedtheseniorauthorofthispaperJohnMHiggins,MD,

oftheCenterofSystemsBiologyatHarvardMedicalSchoolinBoston,Massachusetts
whatallthefussisabout.
What's Wrong With HbA1c?

HbA1cisameasureoftheglucosethathasbeenirreversiblylinkedwiththe
hemoglobininredbloodcells(RBCs)andassuchisanaverageoftheglucosein
RBCsovertime.

ThepopulationofRBCscomprisescellsofdifferentages,witholderRBCshavinghad
theopportunitytobecomemoreglycated.Giventhatthelife-spanofaRBCisabout
100days,HbA1cisthereforemostaccuratelyanestimateofaverageglucoselevelsin
theprior2to3monthsanddoesnotreflectanoverallglucoseprofile.

DrHigginssaidthenotionthatHbA1cisnotaperfectmeasurefirstsurfacedduringthe
DCCTtrialwhileHbA1cenabledmuchbettermanagementofdisease,therewasa
surprisingamountofvariationinHbA1cwithingroupsofpeoplewithsimilaraverage
glucosemeasuredbyothermethods,heexplained,addingthat"the[A1cDerived
AverageGlucose]ADAGstudyconfirmedthisnotion."
Inthenewpaper,DrHigginsandcolleaguesuseacomplexmathematicalmodelto
determinemoreaccurateglucoselevelsinpatientsusingexistingassays.

The Difference Between Being a Diabetic Patient or Not

IntheirreportpublishedonlineOctober5,DrHigginsandhiscolleaguessuggestthata
personalizedapproachmayhelpinreducingerrorsinaverageglucoseestimatesfrom
morethan15mg/dLtolessthan5mg/dLa66%reductionintheerror.

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Theyexplainthat15mg/dLcanbethedifferencebetweenanondiabeticandadiabetic
withsuboptimalcontrol.
Sucherrorscan"misleadcliniciansandpatientsandcompromisepatientcareand
optimalmanagementoflong-termriskofcomplications..Anerrorof28.7mg/dLis
equivalenttoanerrorof~1%pointinHbA1c,"theywrite.

Usingseparatecohortsoftype1diabetespatients(>300subjects),theyshowedthat
theirapproachcanreducetheerrorinestimatingaverageglucosevaluebyatleast
50%.

Theirmodelusesthreevariables:HbA1c,averageglucoselevel,andtheaverageage
ofapatient'sRBCs.

Theyfirstpairedmeasurementsofcontinuousglucosemonitoring(CGM)measured
glucoseandHbA1ctodeterminetheaverageageofapatient'sRBCs.Thismeasureis
thenusedgoingforwardtodeterminemoreaccurateglucoseestimatesfromanHbA1c
measurement.
"Inanygivenpatient,theaverageRBCageissufficientlystableforthismethodto
provideasignificantincreaseinaccuracy,"DrHigginsexplainedtoMedscape Medical
News.
"Themodelistheoreticallysensitivetochangesof2to3mg/dLinapatient'sactual
averageglucose;higher-resolutionHbA1cmeasurementswouldincreasethemodel's
sensitivityevenfurther,"headded.

Thepatient-specificmodeloptimizesglucosemanagementbetweenvisitsandcontrols
for"patient-specificvariationinnonglycemicfactorsinfluencingHbA1c,anditalsotakes
advantageofthevastlyricherglucosecharacterizationprovidedbyCGM,"DrHiggins
andhiscolleaguesoutline.
Butmanyendocrinologistsinsistthatdiabetespatientscanbeproperlymonitoredand
treatedwiththetoolsalreadyusedtheissueisthatpatientsdon'toftenmonitortheir
HbA1c.
Andexpectingprimary-careproviderstouseadifferentmetricwillbenighon
impossible.

DrHigginsadmitsthatitwillbeanuphillbattletoaffectthecurrentmind-set
entrenchedinpatientmanagementfromthefamilypractitionertothediabetologist:
"It'schallenging,giventhefloodofinformationandsuggestionsthatcliniciansare
facedwith."
"StudiesliketheDCCTandEDICdefinitivelyshowthebenefitsoftighterglucose
control,"hestressed,"butthecurrenterror-proneinterpretationofHbA1cmakesthat
levelofcontroldifficultformanypatientstoachieve."
Personalized Diabetes Monitoring Using a Mechanistic Model

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"Thepersonalizedestimatesofaverageglucoseprovidedbythisnewmethodwill
makeitmucheasierforpatientstoreachtheirgoalsoftighterglucosecontrol,andI
thinkthispossibilityofusingexistingroutinelyavailableclinicalassaystoreduceriskof
bothshortandlong-termdiseasecomplicationswillcapturetheattentionofmany
patientsandclinicians,"DrHigginsexplained.
Yetheadmitsthattheapproachisnotyetreadyforprimetime.

Whenaskedwhetherhisinstitutionisusingit,heindicatedthatalthoughthereisgreat
interestlocally,therearestillsomeissuestobeironedout.
"TherearemultipleCGMdeviceswithdifferentdataformatsandstoragestrategies,
andthoselargesetsofresultsneedtobeimportedandanalyzed,"henoted.

"Wealsodonothaveaneasywaytostoreanduseeachpatient'saverageRBCage.
Weareintheprocessofdevelopinganintuitivegraphicaltoolthatwouldintegratewith
ourownmedicalrecordsystem,butthereisstillmoreworktodo,"headmitted.
Andtoboot,manydiabeticpatientsdon'tuseCGMs.

"InsurancedoesnotcoverCGMsforthevastmajorityofdiabetics.Ihopethatthis
studywillpersuadeinsurancecompaniestocoveratleastthebaselineCGMto
estimateapatient'saverageRBCage,"hecommented.

And"forpatientsusingCGMindefinitely,thismethodwillprovideamoreaccuraterealtimeestimateofHbA1c,andpatientsmayprefertotracktheirdiseasemanagementin
thosefamiliarterms,"headded.

Lookingforwardtorollingoutthismodeintotheclinicalsetting,DrHigginssaid:"Ithink
therecouldbeanapporawebsite,or[themodel]couldbeintegratedintoCGMs,
electronicmedicalrecords,andmore."
Heisalsokeentoworkwithindustrytomakethisaseasilyaccessibleaspossible.

ItisimportanttonotethatthereportbyDrHigginsandcolleagueswasrestrictedto
studysubjectswhoweregenerallyhealthyapartfromhavingtype1diabetesandwho
werereceivingroutinemedicalcare.
Futurestudieswillbeneededtodeterminetheaccuracyofthemodelinthesettingof
diabetespatientswithacuteconditionsand/orseriouscomorbidities,whichmayaffect
RBCturnover.
Other Important Metrics in Glycemic Control
BeyondthemodelingstudyofDrHigginsandcolleagues,therehasbeenanongoing
discussionofsupplementingHbA1cmeasurementswithothermetricsthatmaymore
accuratelydefineapatient'sglycemicstatus.

SubsequenttotheDCCTpublicationandwiththeavailabilityofinsulinanalogs,
glycemicvariabilityhasbeenrecognizedasanimportantfactoraffectingglycemic
control,withreferencetotheoscillationsinbloodglucoselevelsthatoccurthroughout
theday,includinghypoglycemicperiods,postprandialspikes,andbloodglucose
fluctuations.

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Inapoint-counterpointdebateontheissuepublishedlastyear,IrlBHirsch,MD,
diabetestreatmentandteachingchairattheUniversityofWashingtonSchoolof
Medicine,StLouis,Missouri,arguedthatglycemicvariabilityaffectsboth
macrovascularandmicrovascularendpointsandmayexplainsomeoftheoutcomes
seenwithdifferentglycemic-controlstrategiesinclinicaltrialsthatwerenotexplained
byHbA1c(Diabetes Care.2015;38:1610-1614).
GlycemicvariationscanbemeasuredusingCGMorbymeasuringbloodlevelsof
glycatedalbumin,1,5-anhydroglucitol,orglycatedalbumin/glycatedhemoglobinratio.
"HbA1c,ourfirstrealbiomarkerofdiabetesmanagement,hasmajorlimitationsand
eveninthebestofcircumstancesprovidesonlyasimplifiedsnapshotofglycemic
control,"DrHirschwrote.

"The"HbA1cmessage"isimportantbutincompletebecauseHbA1cbyitselfdoesnot
explainalltheriskforthosewhodevelopdevastatingcomplicationsofdiabetes,he
added.

DrHirschadmitsthatonlyaformalclinicaltrialthatexaminestherelationshipbetween
glycemicvariabilityandhardendpointssuchasretinopathy,nephropathy,ora
cardiovascularoutcomewillsettlethisdebate.

"Althoughitwilltakealargestudyofmanyyearstoprovethis(similartotheDCCT),
currentevidencesupportsthatfluctuationsinbloodglucosearedangerousandshould
beaprimarytreatmenttarget,"heconcluded.

However,incountering,RichardMBergenstal,MD,aresearchclinicianatInternational
DiabetesCenter,StLouisPark,Minnesota,arguedthattherearebetterglycemic
markersthanglycemicvariability(Diabetes Care.2015;38:1615-1621).
HeindicatedthatADAGreviewedstudiesthatcorrelatedglucoselevels(throughselfmonitoringorCGM)withknowncardiovascularriskfactors.Theresearchconcluded
thatinsubjectswithdiabetes,riskfactorssuchasHbA1candmeanglucoseshow
strongerassociationswithcardiovascularriskthandoespostprandialglycemiaor
glycemicvariability.

AndtheHEART2Dstudyfailedtoshowthatreducingglycemicvariabilitywas
associatedwithreducingriskforcomplications,DrBergenstalsaid,althoughheagrees
that"itmakessensetominimize[glycemicvariability]."
Andhealsoacknowledgedthatitisimportanttolookatglycemicmetricsbeyond
HbA1c.

"IthinkitmakessensetoexploretheuseofmarkerstosupplementtheuseofHbA1c,"
hewrote.Hesuggestedhypoglycemiaastheobviousglucosemetric."[It]cangreatly
enhancetheclinicalinterpretationofHbA1c,iscriticalforeffectiveclinicaldecision
making,andisclearlylinkedtodiabetescomplications,"headded.
DrBergenstalcallsfortheuseofCGMstodocumentandquantifyhypoglycemia.

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"Wewillneedtoderiveawell-validated,clinicallymeaningful,andstandardized
measureofCGM-detectedhypoglycemia,firstintheclinical-researchsettingandthen
inpractice,"heasserts.

HecontendsthatassessmentofglucosecontrolwouldbebasedonHbA1c,percent
timespentinthreecategoriesofhypoglycemia(low,verylow,anddangerouslylow),
andepisodesofseverehypoglycemia,whichrequiretheassistanceofanotherperson
torecover.

"Onlywheneachindividualwithdiabeteshasaclearlydefinedandagreed-onglycemic
targetcanwetheneffectivelyusecareteams,newtherapies,andadvanced
technologyasneededtosafelyreachtheglucosetarget,"heopined.
"Itistimetouseglucosedatatoaddressbothpopulationhealthandpersonalizedcare
indiabetesmanagement,"heconcluded.
Yet22yearsafterthefirstpublicationofDCCT,HbA1cisstillconsideredthegold
standardindiabetesmanagement,withlittleindicationthatthisisabouttochangeany
timesoon.
Dr Higgins reported no relevant financial relationships. Dr Hirsch reported research
grants from Sanofi, Novo Nordisk, and Halozyme and consulting with Roche
Diagnostics, Abbott Diabetes Care, and Valeritas. Dr Bergenstal reported has served
on a scientific advisory board, consulted, or performed clinical research with Abbott
Diabetes Care, Bayer, Becton Dickinson, Boehringer Ingelheim, AstraZeneca,
Dexcom, Eli Lilly, Halozyme Therapeutics, Hygieia, Johnson & Johnson, Medtronic,
Merck, Novo Nordisk, Roche, Sanofi, and Takeda. His employer contracts for his
services, and no personal income goes to him. He has inherited Merck stock. He is a
volunteer for the American Diabetes Association and JDRF.
For more diabetes and endocrinology news, follow us on Twitter and on Facebook.
Sci Transl Med. PublishedonlineOctober5,2016.Abstract
MedscapeMedicalNews2016WebMD,LLC

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