Glycaemic and haemoglobin A1c thresholds for detecting diabetic retinopathy: The fifth Korea National Health and Nutrition Examination Survey (2011)
Yong-Moon Park
a,b,1, Seung-Hyun Ko
c,1, Jung-Min Lee
c, Dae-Jung Kim
d, Dong-Joon Kim
e, Kyungdo Han
f, Julie K. Bower
g, Yu-Bae Ahn
c,*
Committee of Clinical Practice Guideline, Korean Diabetes Association
aDepartmentofPreventiveMedicine,TheCatholicUniversityofKorea,Seoul,RepublicofKorea
bDepartment of Epidemiology and Biostatistics, Arnold School of Public Health, University of South Carolina, Columbia,SC,USA
cDivisionofEndocrinologyandMetabolism,DepartmentofInternalMedicine,TheCatholicUniversityofKorea,Seoul, RepublicofKorea
dDepartmentofEndocrinologyandMetabolism,AjouUniversitySchoolofMedicine,Suwon,RepublicofKorea
eDepartmentofInternalMedicine,InjeUniversityCollegeofMedicine,Busan,RepublicofKorea
fDepartmentofBiostatistics,TheCatholicUniversityofKorea,Seoul,RepublicofKorea
gDivisionofEpidemiology,TheOhioStateUniversityCollegeofPublicHealth,Columbus,OH,USA
article info
Articlehistory:
Received13August2013 Receivedinrevisedform 25February2014 Accepted2April2014 Availableonline13April2014
Keywords:
Diabeticretinopathy(DR) Diagnosis
HaemoglobinA1c(HbA1c) Fastingplasmaglucose(FPG)
abstract
Aims:Few representative population-based data are availableregardingglycaemic and HbA1c thresholdsfordetecting diabetic retinopathy(DR) inAsia. We investigated the associationbetweenDRandfastingplasmaglucose(FPG)andHbA1clevelsamongKorean adults.
Methods:Using datafromtheKoreaNationalHealthandNutritionExaminationSurvey (2011),atotalof5212adults(19yearsold)wereanalysed.Whenparticipantshaddiabetes mellitusand/orasuspicionofDRintwo-fieldnonmydriaticfundusphotography,seven standardphotographswereobtainedafterpupildilatation(75.9%ofmen,75.0%ofwomen amongthesubjects).DRwasdefinedasthepresenceof1retinalmicroaneurysmsorblot haemorrhageswithorwithoutmoreseverelesions.Receiveroperatingcharacteristic(ROC) curveswereusedtodeterminetheoptimalcut-offvalueforHbA1corFPG.
Results: TheoverallglycaemicthresholdsforDRwere6.3mmol/lforFPGand6.2%(44mmol/
mol)forHbA1c.Theoptimalthresholdsdidnotdifferbyagegroup.Thesensitivitiesand specificitieswere82.6%and91.2%forFPGand93.9%and89.7%forHbA1c,respectively.The diagnosticdiscriminationwasbetterforHbA1cthanFPGforDR—areaundercurve:0.908for FPGand0.953forHbA1c(p=0.007).Afterbeingcontrolledforothercovariates,theoddsratio
*Correspondingauthorat:DivisionofEndocrinology&MetabolismDepartmentofInternalMedicine,TheCatholicUniversityofKorea St.Vincent’sHospital,93,Chi-Dong,Paldal-Gu,Suwon442-723,RepublicofKorea.Tel.:+82312498155;fax:+82312538898.
E-mailaddress:[email protected](Y.-B.Ahn).
1 Thesetwoauthorscontributedequally.
Abbreviations: KNHANES,KoreaNationalHealthandNutritionExaminationSurvey;DR,diabeticretinopathy;BP,bloodpressure;SBP, systolicbloodpressure;DBP,diastolicbloodpressure;FPG,fastingplasmaglucose;HbA1c,haemoglobinA1c.
ContentsavailableatScienceDirect
Diabetes Research and Clinical Practice
j o u r n a lh o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / d i a b r e s
http://dx.doi.org/10.1016/j.diabres.2014.04.003
0168-8227/#2014ElsevierIrelandLtd.Allrightsreserved.
1. Introduction
The prevalence of diabetes has steadily and dramatically increasedthroughouttheworld,includingKorea.Accordingto the Korean Diabetes Association (KDA), approximately 3.2 million Korean people aged at least 30 years (10.1%) had diabetesin2010,anddiabeteswillaffect6.0millionpeoplein Koreaby2050;thisprevalenceisestimatedtobetwicethatof 2010[1].Thedramaticincreaseinthediabeticpopulationwill inevitably beaccompanied byincreased diabetic complica- tionsandenormoushealthcosts.Therefore,earlydetection and screening of high-risk individuals for diabetes with appropriate intervention should be emphasised in clinical practice.
Thediagnosticcriteriaandcut-offvaluesforfastingplasma glucose(FPG)andhaemoglobinA1c(HbA1c)levelsfordiabetes havebeencontinuouslyupdatedandmodifiedduringthepast severaldecades.Before the late 1990s,diagnosing diabetes wasbasedonclinicalsymptomsandthemeanglucosevalue plustwostandarddeviationsofbloodglucoselevels[2].Since 1999,diagnosticcriteriaweredefinedusinglargeepidemio- logicstudiesassessingbimodaldistributionsandthresholds formicrovascularcomplications[3,4].
Diabeticretinopathy (DR) is aspecific and earlyclinical complicationrelatedtodiabetesandhasservedasthebasis fordeterminingdiagnosticcut-offpointsfordiabetesmellitus [5,6].Currently,somelargeepidemiologicstudiesareavailable abouttherelationshipbetweentheprevalenceofretinopathy andglycaemicmeasures,includingFPG,2-hplasmaglucose (2hPG), and HbA1c. The datasets from Pima Indians, an Egyptian study, the Third National Health and Nutritional ExaminationSurvey(NHANES),andtheDETECT-2collabora- tionGroupshowedthecut-offlevelsfordiagnosingdiabetes thatwerebasedontheassociationwithDR[6–9].Basedon theseresults,manyrecentlypublishedclinicalrecommenda- tions specify diagnostic criteria for diabetes as an FPG of 7.0mmol/l and an HbA1c of 6.5% (48mmol/mol) [10–12].
However,somestudiesshowsomewhatdifferentoptimalcut- offvaluesbasedonthepresenceofDR,thesubjectpopulation, ethnicity,agerangeofinclusion,oranalyticalmethods[13–
16]. Moreover, few published data have demonstrated the associationofFPGorHbA1cwithretinopathyprevalenceusing anationwidesurvey,particularlyinAsianpopulations.
Theaimsofthisstudyweretoinvestigatetheassociation betweenlevelsofFPGandHbA1cwithdiabeticretinopathy andtodeterminetheoptimalcut-offsofFPGandHbA1cfor detecting diabetic retinopathy in a representative Korean population.
2. Subjects and methods
2.1. StudypopulationThis study used data from the 5th KNHANES, which was conductedbytheKoreanMinistryofHealthandWelfarein2011.
This survey was a nationally representative study of non- institutionalisedciviliansusingastratified,multistageproba- bilitysamplingdesign.Samplingunitsweredefinedbasedon thedataregardinghouseholdregistries,includinggeographic area,sex,andagegroups.TheKNHANESwascomposedofa healthinterviewsurvey,ahealthexaminationsurvey,anda nutritionsurveyconductedbytrainedinvestigators.Additional details about the study design and methods are provided elsewhere [17,18]. Atotal of8055 of10,589 subjects (76.1%) participated in the health interview surveyand the health examinationsurvey.Fundusphotographswereavailable for 7654 subjects (72.3%). Participants aged 19 years and over, includingthosewithknowndiabetesandwithgradableretinal photographsandatleastonemeasureofglycemia(FPGand HbA1c), were included [18]. Pregnant women and subjects missingFPG,HbA1corfundusphotographywereexcluded.All of the participants provided written informed consent to participate in the study. This study was approved by the InstitutionalReviewBoardoftheCatholicUniversityofKorea.
The investigations were performed in accordancewith the principlesoftheDeclarationofHelsinkiasrevisedin2000.
2.2. Definitionofdiabetes
DiabeteswasdiagnosedonthebasisofanFPGof7.0mmol/l, HbA1c6.5%(53mmol/mol),self-reporteddiagnoseddiabe- tes,orcurrentuseoforalhypoglycaemicagentsand/orinsulin accordingtotheclinicalpracticeguidelinesfromtheKDA[12].
2.3. Diagnosisofdiabeticretinopathy(DR)
After 5min of dark adaptation, retinal photographs were taken using a digital nonmydriatic fundus camera (TRC- NW6S, TOPCON, Japan) with a Nikon D-80 digital camera (Nikon, Tokyo, Japan), and digital fundus images were obtained fromall participantsaged19 yearsand older.For eachparticipants,one458nonmydriaticdigitalretinalimage centredonthefoveawastakenpereye(2imagesperpersonin total)[19,20].
Inparticipantswhohadahistoryofdiabetesmellitusora randombloodglucoselevelof11mmol/land/orsuspicionof DR in nonmydriatic fundus photography, seven standard photographsfromtheEarlyTreatmentforDiabeticRetinopathy fortheriskofDRincreasedsignificantlyinaconsistentwayfrom6.2%(44mmol/mol)for HbA1cand6.3mmol/lforFPG.
Conclusions:Accordingtothesenationallyrepresentativedata,thecurrentdiabetesdiag- nosticvaluesforFPGandHbA1cbasedonDRmaybelowerfortheKoreanpopulation.
#2014ElsevierIrelandLtd.Allrightsreserved.
Study(ETDRS)wereobtainedfromeacheyeafterpharmaco- logicalpupildilatation.Amongthesubjects,photographswere takenin75.9%ofmen(n=278)and75.0%ofwomen(n=266) [19,20].Aretinopathyseverityscorewasassignedaccordingto theETDRSseverityscale.DRwasdefinedasthepresenceofone ormoreretinalmicroaneurysmsorblothaemorrhageswithor withoutmore severe lesions (hard exudates, soft exudates, intraretinalmicrovascularabnormalities,venousbleeding,new retinal vessels, and fibroproliferations) [19,20]. The final retinopathy grading for each participantwas basedon the diagnosisinthemoreseverelyaffectedeye.Twoophthalmol- ogistsreviewedallthefiles.Theintergraderandintragrader agreements were k>0.80. The primary outcome was any diabeticretinopathy.
2.4. Measurements
Byspeciallytrainedexaminers,thebloodpressureofsubjects, whowereseatedforat least5min,was measuredusing a mercurysphygmomanometer(Baumanometer;Baum,Copia- gue,NY). Themean valueofthreeseparateblood pressure readings wasused. Hypertension was definedasasystolic bloodpressure(SBP)140mmHg,adiastolicbloodpressure (DBP)90mmHg,orself-reportedcurrentuseofantihyper- tensive medications [21]. Waist circumference (WC) was measuredtothenearest0.1cminahorizontalplaneatthe midpointbetweentheiliaccrestandthecostalmarginatthe endofanormalexpiration.Thebodymassindex(BMI)was calculatedastheindividual’sweightinkilogramsdividedby thesquareoftheindividual’sheightinmeters.
Thebloodsampleswereobtainedafteraminimumfasting time of 8h. HbA1c values were measured using high- performance liquid chromatography (HLC-723G7, Tosoh, Japan).RegardingtheHbA1c,periodiccheckingandcompar- isonsofthe test resultswiththe reference materials from reference institutes such as ‘‘National Glycohemoglobin StandardizationProgram(NGSP)’’wereperformedthreetimes during the 2011 KNHANES survey and the results were acceptable.Theserumlevelsoffastingglucose,totalcholes- terol(TC),high-densitylipoprotein(HDL)cholesterol,triglyc- erides, and creatinine were measured enzymatically in a centrallaboratoryusinga HitachiAutomaticAnalyzer7600 (Hitachi,Tokyo,Japan).Thedetailedmethodsforcomparing andverifyingthe validityandreliabilityineachsurveyare described elsewhere [18,22]. Lifestyle-relatedor other char- acteristics, including diabetic duration, diabetestreatment, andsubjects’co-morbiditieswereascertainedusingastruc- turedquestionnaire.
2.5. Statisticalanalysis
Thedatawereanalysedusingtheappropriatesampleweights provided by the Korea Centers for Disease Control and Prevention.Alldatawerepresentedasthemeanstandard error (SE) for continuous variables and as a frequency percentage(SE)forcategorical variables.Statisticalanalyses were performed using the SAS (Version 9.2; SAS Institute, Cary, NC) survey procedure to account for the complex samplingdesign and toprovideanationally representative prevalence estimate. Age-adjustment was also used to
compareothercharacteristicsbetweenthesubjectswithDR andwithoutDR.
Receiveroperatingcharacteristic(ROC)curveanalysiswas applied to determinethe optimal cut-off value ofFPG and HbA1c foridentifyingDR.Youden’sindexwas alsousedto evaluate the discriminative power of FPG and HbA1c for predicting DR with the following formula:
(sensitivity+specificity) 1. The associations of FPG and HbA1c were analysed using multiple logistic regression analysisafteradjustingforage,sex,smoking,waistcircum- ference, and hypertension. Sensitivity analyses were per- formedusingthesamplesafterexcludingtheindividualswho werereceivinganti-hyperglycaemic treatment.Apvalueof lessthan0.05wasconsideredtobestatisticallysignificant.
3. Results
3.1. Clinicalcharacteristicsoftheparticipants
Afterexclusionofthenon-eligiblesubjects,5212patients(2213 menand2999women)participatedintheanalysis.Themean ageofthesubjectswas44.30.4years,and49.4%weremale (Table1).Theprevalenceofdiabeteswas10%,andthemean durationofdiabetesforindividualswithdiagnoseddiabetes was8.0years.
ThesubjectswithDRweresignificantlyolderandhigher FPG, HbA1c, SBP, WC, creatinine, and lipid profile levels comparedwithsubjectswithoutDR.Men,ever-smokers,and hypertensive subjects had a higher prevalence of DR. In addition,amongthesubjectswithdiabetes,thosewithDRhad a longer durationof diabetesand weremore likelyto use insulinororalmedicationthanthosewithoutDR.
3.2. Prevalenceofdiabeticretinopathy(DR)
The overall prevalence of DR was 1.6% (95% confidence interval(CI):1.2–2.0%).TheprevalenceofDRincreasedwith age(pfortrend<0.0001).NoDRwasfoundinsubjects<30 yearsold(SupplementaryFig.1),regardlessoftheFPGlevel range. Whenconfinedtopatientswithdiabetes,thepreva- lenceofDRwas18.6%(95%CI:14.1–23.2%),including24.1%
(18.5–29.8)inthosewithknowndiabetes,19.1%(14.5–23.7%)in subjectswithHbA1c6.5%(48mmol/mol),and0.02%(0.0–0.1) insubjectswithnormalFPGandnormalHbA1c.
Fig. 1 shows the prevalence of DR by deciles of the distributionoftheFPGandHbA1clevels.Theprevalenceof DR showed a curvilinear relationship. The prevalence in- creasedsignificantlybetweentheninthandthetenthdeciles ofeachvariable,correspondingtoanFPGof6.4mmol/land HbA1cof6.4%(46mmol/mol).TheprevalenceofDRforFPG andHbA1cinthetenthdecileswas16.6%withbothmeasures, whilethoseintheninthdecileswere0.6%forFPGand1.6%for HbA1c.
3.3. Optimalglycaemicthresholdsfordetectingdiabetic retinopathy(DR)
Theoverallappropriateglycaemicthresholdsforidentifying DR by maximising the sensitivity and specificity were
6.3mmol/l in FPG and 6.2% (44mmol/mol) in HbA1c. The sensitivityandspecificitywere82.6%and91.2%inFPGand 93.9%and89.7%inHbA1c,respectively(Fig.2).Theoptimal thresholds did not differ by age group in the sensitivity analyses(6.3mmol/linFPGand6.2%(44mmol/mol)inHbA1c forthepopulation30yearsold;6.3mmol/linFPGand6.5%
(48mmol/mol) in HbA1c for the subjects 40 years old, SupplementaryTable1).
Table2presentstheprevalenceofDRbelowandabovethe various cut-off points of FPG and HbA1c as well as the sensitivity,specificity, and positive and negativepredictive values.Belowourthresholdvaluesof6.3mmol/lforFPGand 6.2%(44mmol/mol)forHbA1c,theprevalenceofDRwas0.19%
(0.08–0.31)forthethresholdofFPG,0.10%(0.01–0.18)forthe thresholdofHbA1c,and0.07%(0.01–0.14)forthethresholdof bothFPGandHbA1c.Thepre-existingthresholdsof7.0mmol/l in FPG and 6.5% (48mmol/mol) in HbA1c for diagnosing diabetesshowed73.9%and89.6%sensitivity,respectively.In addition, when we used the pre-existing thresholds, the specificityandthepositivepredictivevaluewereimproved, but the sensitivity and the negative predictive valuewere reduced compared with the optimal glycaemic thresholds suggestedfromthisstudy.
Table3showstheassociationofFPGandHbA1cwithDR.
Aftercontrollingforage,sex,smoking,waistcircumference, andhypertension,theassociationwasstatisticallysignificant
Fig.1–TheprevalenceofdiabeticretinopathybydecilesofthedistributionofFPGandHbA1clevels.
Table1–Clinicalcharacteristicsofpopulationaccordingtothepresenceofdiabeticretinopathy.
Total Noretinopathy Retinopathy pValue Age-adjustedpvalue
N 5212 5097 115
Age(years) 44.30.4 44.10.4 61.41.2 <0.0001
Men(%) 49.4(0.7) 49.3(0.7) 58.5(6.1) 0.150 0.034
BMI(kg/m2) 23.70.1 23.70.1 24.20.3 0.084 0.665
Waistcircumference(cm) 81.20.2 81.10.2 86.80.9 <0.0001 0.005
Income(lowestquartile) 14(0.8) 13.7(0.8) 32.4(5.3) <0.0001 0.965
currentsmoker(%) 24.1(0.9) 24.1(0.9) 27.3(5.0) 0.510 0.035
Ever-smoker(%) 31.4(1.0) 31.2(1.0) 42.4(6.3) 0.068 0.002
SBP(mmHg) 116.70.4 116.50.4 132.32.4 <0.0001 0.001
DBP(mmHg) 76.10.2 76.00.2 76.51.4 0.764 0.507
Hypertension(%) 24.3(0.8) 23.7(0.8) 63.6(5.2) <0.0001 0.0004
Diabetes 9.9(0.5) 0.02(0.0) 15.7(2.0) <0.0001 <0.0001
Diabeticduration(years) 8.00.4 6.80.4 11.80.8 <0.0001 <0.0001
Diabetestreatment
Insulintreatment(%) 0.7(0.1) 0.5(0.1) 14.4(4.5) <0.0001 <0.0001
Oralmedication(%) 5.2(0.4) 3.9(0.3) 87.8(3.9) <0.0001 <0.0001
Insulinororalmed(%) 5.4(0.4) 4.0(0.4) 92.4(2.9) <0.0001 <0.0001
FPG(mmol/l) 5.30.0 5.30.0 8.60.2 <0.0001 <0.0001
HbA1c(mmol/mol) 49.00.1 48.00.1 73.01.5 <0.0001 <0.0001
HbA1c(%) 5.70.0 5.60.0 8.00.2 <0.0001 <0.0001
Totalcholesterol(mmol/l) 4.90.0 4.90.0 4.80.1 0.372 0.010
Triglyceride(mmol/l) 1.50.0 1.50.0 2.00.2 0.0003 0.066
Creatinine(mmol/l) 0.080.0 0.070.0 0.080.0 0.004 0.007
BMI,bodymassindex;SBP,systolicbloodpressure;DBP,diastolicbloodpressure.
inthe categoryof6.3–6.5mmol/l forFPGand 6.2–6.4%(44–
47mmol/mol)forHbA1cwhenthecriteriaof<6.3mmol/lof
FPG and <6.2% (44mmol/mol) for HbA1c were used as a
reference.Furthermore,withincreasingcategoriesofFPGand HbA1c,theoddsratiosincreasedmarkedlyforbothFPGand HbA1c. In addition, when the criteria of HbA1c<5.7%
(39mmol/mol) and FPG<5.5mmol/l were used as the references, significantassociationswerefoundintherange of6.2to6.6%(44–49mmol/mol)forHbA1cand5.5–6.2mmol/l forFPG.WithincreasingvaluesforHbA1c,theoddsratioswere sharplyincreased.Anabruptincreaseintheoddsratiowas observed in the range of 6.3 to 7.0mmol/l for the FPG (SupplementalTable1).
TheareaundertheROCcurveforHbA1cwas0.953(95%CI:
0.947–0.959)andwassignificantlylargerthanthatofFPG(0.908 (95%CI:0.900–0.915);pfordifference=0.007)(Fig.2).Whenwe excludedindividualswhowerereceivinganti-hyperglycaemic treatment,thethresholdsofdetectingDRwere6.8mmol/lin FPGand6.0%(42mmol/mol)inHbA1c.Inthiscase,theAUCfor HbA1c was 0.911 (95% CI: 0.903–0.919), and it was not significantly different from that for FPG (0.893; 95% CI:
0.884–0.902;pfordifference=0.755).Inthesubgroupanalysis, theoptimalcut-offvaluesforFPGandHbA1crangedfrom6.8 to6.9mmol/land6.4%(46mmol/mol)to6.5%(48mmol/mol), respectively,inwomen,elderlysubjects65yearsold,obese participantswithabodymassindex25kg/m2,andhyper- tensivesubjects(SupplementaryTable2).
Table2–Percentageofcases,sensitivity,specificity,positiveandnegativepredictivevaluesatdifferentcutoffsofFPGand HbA1cfordetectingdiabeticretinopathy.
Cutoff Belowthecutoff Abovethecutoff Sensitivity Specificity Youden’sindex PPV NPV FPG(mmol/l)
>5.5 0.1(0) 6.4(0.8) 91.3 74.5 0.658 7.5 99.7
>6.0 0.2(0.1) 12.1(1.5) 85.2 87.6 0.728 13.4 99.6
>6.1 0.2(0.1) 12.8(1.6) 83.5 88.5 0.72 14.1 99.6
>6.2 0.2(0.1) 14.3(1.8) 82.6 89.9 0.725 15.6 99.6
>6.3 0.2(0.1) 15.4(1.9) 82.6 90.8 0.734 16.8 99.6
>6.4 0.2(0.1) 16.6(2.1) 80.9 91.6 0.725 17.9 99.5
>6.5 0.2(0.1) 17.5(2.3) 80 92.3 0.723 19 99.5
>6.6 0.3(0.1) 17.4(2.2) 78.3 92.7 0.710 19.4 99.5
>6.7 0.3(0.1) 19(2.4) 78.3 93.6 0.719 21.5 99.5
>6.8 0.3(0.1) 20.2(2.5) 77.4 94.2 0.716 23.1 99.5
>6.9 0.4(0.1) 21(2.7) 75.7 94.6 0.703 24 99.4
>7.0 0.4(0.1) 21.3(2.8) 73.9 95 0.689 24.9 99.4
>7.5 0.6(0.1) 24(3) 65.2 96.4 0.616 29.1 99.2
HbA1c(%)
>5.5 0.1(0.1) 3.4(0.4) 97.4 48.4 0.458 4.1 99.9
>6.0 0.1(0) 11.5(1.4) 96.5 84.7 0.812 12.5 99.9
>6.1 0.1(0) 13.3(1.6) 93.9 87.6 0.815 14.6 99.8
>6.2 0.1(0) 15.5(1.9) 93.9 89.7 0.836 17.1 99.8
>6.3 0.2(0.1) 16.6(2) 91.3 91.2 0.825 19 99.8
>6.4 0.2(0.1) 19.1(2.3) 90.4 92.5 0.829 21.4 99.8
>6.5 0.3(0.1) 19.7(2.2) 89.6 93.2 0.828 22.9 99.7
>6.6 0.3(0.1) 21.2(2.4) 86.1 93.9 0.8 24.3 99.7
>6.7 0.3(0.1) 22.7(2.6) 82.6 94.6 0.772 25.7 99.6
>6.8 0.4(0.1) 23.2(2.8) 79.1 95.1 0.742 26.5 99.5
>6.9 0.4(0.1) 24.3(3) 78.3 95.4 0.737 27.8 99.5
>7.0 0.5(0.1) 26.3(3.3) 74.8 96 0.708 29.5 99.4
>7.5 0.8(0.2) 27.9(3.7) 58.3 97.4 0.557 33.5 99
FPG,fastingplasmaglucose;PPV,positivepredictivevalue;NPV,negativepredictivevalue.
Fig.2–ThresholdsofFPGandHbA1cfordiabetes-specific retinopathyfromreceiver-operatingcharacteristic(ROC) curveanalyses.
4. Discussion
Inthisnationwidestudyconductedusingdatafromthe2011 KNHANES,weexaminedtheassociationsofFPGandHbA1c withDRinaKoreanpopulationaged19years.Tothebestof ourknowledge,thisisthefirstpopulation-basednationwide studyinAsia.Wefoundthatthe prevalenceofDRsharply increasedbetweenthe9thand10thdecilesforbothFPGand HbA1c.Inourpopulation,theoptimalglycaemicandHbA1c cut-offlevels fordetectingDRwere6.3mmol/lforFPGand 6.2%(44mmol/mol)forHbA1c;thesevaluesweredefinedby theROCcurvesthatmaximisedthesensitivityandspecificity fordetectingdiabeticretinopathy.Thecut-offvaluesbetween the9thand10thdecilesforFPGandHbA1c(FPGof6.4mmol/l andHbA1cof6.4%(46mmol/mol))weresimilartothosebased ontheROCcurve.Ourcut-offpointsforHbA1candFPGwere lowerthanthoseofthecurrentlyuseddiagnosticcriteriafor diabetes.
Optimalcut-offthresholdsforFPGandHbA1cfordefining DRvaryacrosspopulations.BasedonROCcurveanalysis,the optimal FPG threshold levels were demonstrated to be 6.8mmol/l inthePima Indianpopulation[7], 6.7mmol/lin the US population (NHANES III) [9], and 7.1mmol/l in the AusDiabstudy[4].AccordingtotheDETECT-2Collaboration WritingGroup,whichincludedapproximately45,000partici- pants,theglycaemicthresholdsfordiabetes-specificretinop- athy(definedasmoderateormoresevereDR)were6.6mmol/l forFPG, 13.0mmol/lfor2hPG,and6.4%(47mmol/mol)for HbA1c[8].
WhenconfinedtoAsian populations,includingJapanese andChinesepopulations,theoptimalcut-offvaluesofFPGfor retinopathyrangedfrom5.6to7.2mmol/linthesensitivity andspecificityanalysisforDR[14,16,23].Wesuggestthatthe FPGthresholdsfordiagnosingdiabetesbasedonthepreva- lenceofretinopathy,includingourvalueof6.3mmol/l,are somewhat lower in Asian populations than in western populations[16,23].
InadditiontoFPG,HbA1ccut-offvaluesalsovaryacross populations.InPimaIndians,theoptimalHbA1ccut-offpoint of 7.0% (53mmol/mol) had 78.1% sensitivity and 84.7%
specificityfordetectinganyretinopathy[7].IntheHisayama study,theoptimalHbA1ccut-offpointof5.7%(39mmol/mol) wasreportedtohaveasensitivityof86.5%withaspecificityof 90.1%[16].OurHbA1ccut-off valuewas similartothoseof otherpopulations,suchastheEgyptianstudy(6.3%;45mmol/
mol)and NHANESIII(6.0%;42mmol/mol)[7,24],but higher than those of a previous Japanese study (5.3–5.7%;
34–39mmol/mol), the AusDiab study (6.1%; 43mmol/mol), andNHANES2005–2006(5.5%)[4,13,16].
According to the DiabetesPrevention Program [25] and NHANES[13],8%ofpeoplewithanFPGbelowdiabeticlevels haveretinopathy.Theprevalenceofretinopathyinsubjects whoseFPGvaluewaslowerthannormalrangewasverylowin thepresentstudyincontrasttopreviousreportsfromwestern countries.Only0.1%ofthepopulationwithanormalFPGlevel (lessthan7.0mmol/l)hadretinopathy.
TheKDAindicatedthatFPGandHbA1ctestsareequally reliablemethodsfordetectingindividualswithdiabetesora high risk of diabetes [12]. Various reasons, such as the independencefromfasting,lowerbiologic variability,lower pre-analytical instability, and lower day-to-day variation compared withFPG, indicate that HbA1cwould beamore convenientandreliablemethodfordiagnosingdiabetes[26].
Previous studies, including the Pima Indian study and the Japanesestudy,triedtodemonstratetheusefulnessofHbA1c asdiagnosticcriteriaofdiabetes[7,16,26].Ouranalysisshowed thesuperiorityofHbA1ctoFPGwithalargerareaunderthe ROC curve. This finding suggests the possibility of better discrimination for DR by HbA1c than by the FPG value.
Therefore,HbA1cwouldbeamoreusefulglycaemicmeasure thanFPGforadiagnosticcriterionbasedonDR.
DifferencesintheprevalenceofDRbetweenethnicgroups have been reported [15,27]. The Diabetic Retinopathy In VariousEthnic groupsinUK(DRIVEUK)studyshowedthat the prevalence of any retinopathy in type 2 diabetes was highest in people of African/Afro-Caribbean descent com- paredwithSouthAsiansorwhiteEuropeans[15].Moredata areneededtoaddresstheethnicdifferencesintheprevalence ofdiabeticretinopathybetweenAsianandCaucasianpopula- tionsbecausethesedifferenceswouldinfluencethedetermi- nationofadiagnosticcut-offvalueforHbA1corFPGbasedon thepresenceofdiabeticretinopathy.However,alackofethnic differences in the association of HbA1c with prevalent retinopathyinU.S.adultsaged40yearsand olderhasalso been reported [28]. According to their results, the current guidelineforthediagnosisofdiabetesbasedonHbA1cand glycaemiccut-offvaluescouldbeappliedequallytowhites, blacks,andHispanics.
Themainstrengthsofthisstudyincludethefollowing:the largepopulation-basednationwidehomogenoussample,our preciseestimation ofanyDRfrom19years andolder, and measurementofHbA1caccordingtointernationallyaccepted standards using standard national quality-assurance protocols.
Table3–Oddsratios(ORs)ofdiabeticretinopathyaccordingtothecategoriesofHbA1candFPG.
HbA1c FPG
Categories(%) CrudeOR(95%CI) AdjustedORa(95%CI) Categories(mmol/l) CrudeOR(95%CI) AdjustedORa(95%CI)
<6.2 1 1 <6.3 1 1
6.2–6.4 16.84(3.21,88.25) 24.78(4.81,127.67) 6.3–6.5 20.53(4.72,89.32) 32.30(7.78,134.14) 6.5–6.7 60.00(13.54,265.90) 84.46(22.40,318.49) 6.6–6.9 25.34(7.34,87.45) 39.35(11.84,130.77) 6.8–7.0 76.53(18.92,309.53) 119.58(34.66,412.55) 7.0–7.3 55.11(18.08,168.01) 85.89(29.73,248.16) 7.1 249.32(84.99,731.42) 357.45(140.98,906.27) 7.4 104.44(49.49,220.42) 155.46(80.31,300.91)
a Adjustedbyage,sex,smokingstatus,waistcircumference,andhypertension.
Severallimitationsofthisstudyshouldbeacknowledged.
First, the survey was based on cross-sectional data and includedallpatientswithdiabetesregardlessofthesubtypeof theirdiabetes.Second,2-hPGvalueswerenotincludedinthis analysis. Practically, an oral glucose tolerance test (OGTT) couldnotbeperformedinallofthegeneralpopulationinthis nationalsurvey.Moreover,anOGTTisnotrecommendedfor subjectswithoutanyriskfactorsfortype2diabetes.Third,we included people with previous or current hypoglycaemic treatment and people with hypertension, which might influencethedistributionofHbA1corFPGlevels.However, wefoundthathypoglycaemictreatmenthadnoeffectonthe HbA1ccut-offvalueinasensitivityanalysis.Fourth, differ- encesinthresholdsmightarisewhentheanalysiswasbased onanyDRasopposedtodiabetes-specificDR.Inotherwords,a microaneurysm could be caused from other causes than diabetes.Lastly,differentstatisticalapproachesmightleadto different diagnostic thresholds. It might be difficult to determine clear cut-offs if changes in the prevalence of diabetic retinopathy tend to be linear, especially for the changepointanalysis.Inthepresentstudy,thecut-offsfrom the ROC analysis were similar to those observed in the continuousdecileplot;thesevalueswerealsosupportedby thechangesoftheORinthelogisticregressionanalysis.
Insummary,ourstudyshowedtheassociationofHbA1c and FPG with the prevalence of retinopathy and provided additionalevidencefordiagnosingdiabetesinAsianpopula- tions. Using the HbA1c and FPG cut-off values of 6.2%
(44mmol/mol)and 6.3mmol/l,respectively, the prevalence of retinopathy increased. HbA1c had better discrimination thanFPGfordetectingthepresenceofretinopathy.Afollow- upstudytodeterminetherelationshipofFPGandHbA1ctothe incidenceofDRisneeded.
Conflict of interest statement
Theauthorsdeclarethattherearenoconflictsofinterests.
Acknowledgements
We thank all participants and members of Committee of Clinical practice Guideline of Korean Diabetes Association.
ThemembersoftheCommitteeare:N.H.Kim(Departmentof InternalMedicine,KoreaUniversityCollegeofMedicine),D.H.
Kim(SanggyePaikHospital),S.Y.Kim(DepartmentofInternal Medicine,Chosun University School ofMedicine), S.R.Kim (DepartmentofInternalMedicine,TheCatholicUniversityof Korea), S.K. Kim (Department of Internal Medicine, CHA University School of Medicine), C.H. Kim (Department of Internal Medicine, Soonchunhyang University College of Medicine), K.H.Shim(Samsung MedicalCenter), M.H. Woo (KyungHeeUniversityMedicalCenter),J.H.Lee(Departmentof Internal Medicine, Daegu Catholic University), H.J. Lee (DepartmentofInternalMedicine,EwhaWoman’sUniversity School of Medicine), E.K. Hong (Department of Internal Medicine,Hallym University CollegeofMedicine), and Y.C.
Hwang(DepartmentofInternalMedicine,KyungHeeUniver- sitySchoolofMedicine).
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the online version, at http://dx.doi.org/10.1016/
j.diabres.2014.04.003.
references
[1] JeonJY,KoSH,KwonHS,KimNH,KimJH,KimCS,etal.
TaskforceTeamofDiabetesFactSheetoftheKorean DiabetesAssociation,prevalenceofdiabetesand prediabetesaccordingtofastingplasmaglucoseand HbA1c.DiabetesMetabJ2013;37:349–57.
[2] NationalDiabetesDataGroup.Classificationanddiagnosis ofdiabetesmellitusandothercategoriesofglucose intolerance.Diabetes1979;28:1039–57.
[3] AlbertiKG,ZimmetPZ,Definition.Diagnosisand classificationofdiabetesmellitusanditscomplications, Part1:Diagnosisandclassificationofdiabetesmellitus.
provisionalreportofaWHOconsultation.DiabeticMed 1998;15:539–53.
[4] TappRJ,ZimmetPZ,HarperCA,deCourtenMP,McCartyDJ, BalkauB,etal.AusDiabStudyGroup,diagnosticthresholds fordiabetes:theassociationofretinopathyand
albuminuriawithglycaemia.DiabetesResClinPract 2006;73(3):315–21.
[5] CheungN,MitchellP,WongTY.Diabeticretinopathy.
Lancet2010;376(9735):124–36.
[6] WongTY,LiewG,TappRJ,SchmidtMI,WangJJ,MitchellP, etal.Relationbetweenfastingglucoseandretinopathyfor diagnosisofdiabetes:threepopulation-basedcross- sectionalstudies.Lancet2008;371(9614):736–43.
[7] McCanceDR,HansonRL,CharlesMA,JacobssonLT,Pettitt DJ,BennettPH,etal.Comparisonoftestsforglycated haemoglobinandfastingandtwohourplasmaglucose concentrationsasdiagnosticmethodsfordiabetes.BMJ 1994;308(6940):1323–8.
[8] ColagiuriS,LeeCM,WongTY,BalkauB,ShawJE,Borch- JohnsenK.DETECT-2CollaborationWritingGroup, glycemicthresholdsfordiabetes-specificretinopathy:
implicationsfordiagnosticcriteriafordiabetes.Diabetes Care2011;34(1):145–50.
[9] TheExpertCommitteeontheDiagnosisandClassification ofDiabetesMellitus.Reportoftheexpertcommitteeonthe diagnosisandclassificationofdiabetesmellitus.Diabetes Care1997;20:1183–97.
[10] InzucchiSE,BergenstalRM,BuseJB,DiamantM,Ferrannini E,NauckM,etal.,AmericanDiabetesAssociation(ADA);
EuropeanAssociationfortheStudyofDiabetes(EASD).
Managementofhyperglycemiaintype2diabetes:a patient-centeredapproach:positionstatementofthe AmericanDiabetesAssociation(ADA)andtheEuropean AssociationfortheStudyofDiabetes(EASD).DiabetesCare 2012;35(6):1364–79.
[11] SeinoY,NanjoK,TajimaN,KadowakiT,KashiwagiA, ArakiE,etal.CommitteeoftheJapanDiabetesSocietyon thediagnosticcriteriaofdiabetesmellitus,reportofthe Committeeontheclassificationanddiagnosticcriteriaof diabetesmellitus.DiabetolInt2010;1:2–20.
[12] KoSH,KimSR,KimDJ,OhSJ,LeeHJ,ShimKH,etal.
CommitteeofClinicalPracticeGuidelines,KoreanDiabetes Association.2011clinicalpracticeguidelinesfortype2 diabetesinKorea.DiabetesMetabJ2011;35(5):431–6.
[13] ChengYJ,GreggEW,GeissLS,ImperatoreG,WilliamsDE, ZhangX,etal.AssociationofA1Candfastingplasma glucoselevelswithdiabeticretinopathyprevalenceinthe U.S.population:implicationsfordiabetesdiagnostic thresholds.DiabetesCare2009;32(11):2027–32.
[14] XinZ,YuanMX,LiHX,HuaL,FengJP,ShiJ,etal.Evaluation forfastingand2-hourglucoseandHbA1cfordiagnosing diabetesbasedonprevalenceofretinopathyinaChinese population.PLoSOne2012;7(7):e40610.
[15] SivaprasadS,GuptaB,GullifordMC,DodhiaH,Mohamed M,NagiD,etal.Ethnicvariationsintheprevalenceof diabeticretinopathyinpeoplewithdiabetesattending screeningintheUnitedKingdom(DRIVEUK).PLoSOne 2012;7(3):e32182.
[16] MiyazakiM,KuboM,KiyoharaY,OkuboK,NakamuraH, FujisawaK,etal.Hisayamastudy,Comparisonof diagnosticmethodsfordiabetesmellitusbasedon prevalenceofretinopathyinaJapanesepopulation:the HisayamaStudy.Diabetologia2004;47(8):1411–5.
[17] KoSH,KwonHS,SongKH,AhnYB,YoonKH,YimHW, etal.Long-termchangesoftheprevalenceandcontrolrate ofhypertensionamongKoreanadultswithdiagnosed diabetes:1998–2008KoreanNationalHealthandNutrition ExaminationSurvey.DiabetesResClinPract2012;97(1):
151–7.
[18] KoreaCentersforDiseaseControlandPrevention(KCDC).
KoreaNationalHealthandNutritionExaminationSurvey, Availablefromhttps://knhanes.cdc.go.kr(accessed17April 2014).
[19] KleinR,KleinBE,MossSE,DavisMD,DeMetsDL.The Wisconsinepidemiologicstudyofdiabeticretinopathy,III.
Prevalenceandriskofdiabeticretinopathywhenageat diagnosisis30ormoreyears.ArchOphthalmol 1984;102:527–32.
[20] YoonKC,MunGH,KimSD,KimSH,KimCY,ParkKH,etal.
PrevalenceofeyediseasesinSouthKorea:datafromthe KoreaNationalHealthandNutritionExaminationSurvey 2008–2009.KoreanJOphthalmol2011;25(6):421–33.
[21] GeissLS,RolkaDB,EngelgauMM.Elevatedbloodpressure amongU.S.adultswithdiabetes,1988–1994.AmJPrevMed 2002;22:42–8.
[22] LimS,ShinH,SongJH,KwakSH,KangSM,WonYJ,etal.
IncreasingprevalenceofmetabolicsyndromeinKorea:the KoreanNationalHealthandNutritionExaminationSurvey for1998–2007.DiabetesCare2011;34:1323–8.
[23] SabanayagamC,LiewG,TaiES,ShankarA,LimSC, SubramaniamT,etal.Relationshipbetweenglycated haemoglobinandmicrovascularcomplications:istherea naturalcut-offpointforthediagnosisofdiabetes?
Diabetologia2009;52(7):1279–89.
[24] EngelgauMM,ThompsonTJ,HermanWH,BoyleJP,Aubert RE,KennySJ,etal.Comparisonoffastingand2-hour glucoseandHbA1clevelsfordiagnosingdiabetes.
Diagnosticcriteriaandperformancerevisited.Diabetes Care1997;20(5):785–91.
[25] DiabetesPreventionProgramResearchGroup.The prevalenceofretinopathyinimpairedglucosetolerance andrecentonsetdiabetesinthediabetesprevention program.DiabeticMed2007;24:137–44.
[26] BonoraE,TuomilehtoJ.Theprosandconsofdiagnosing diabeteswithA1C.DiabetesCare2011;34(Suppl2):S184–90.
[27] BowerJK,BrancatiFL,SelvinE.Noethnicdifferencesinthe associationofglycatedhemoglobinwithretinopathy:the nationalhealthandnutritionexaminationsurvey2005–
2008.DiabetesCare2013;36(3):569–73.
[28] WongTY,KleinR,IslamFM,CotchMF,FolsomAR,KleinBE, etal.Diabeticretinopathyinamulti-ethniccohortinthe UnitedStates.AmJOphthalmol2006;141(3):446–55.
