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RESEARCHOpenAccessIshypoglycemiafearindependentlyassociatedwithhealth-relatedqualityoflifeLizhengShi1*,HuiShao1,YingnanZhao2andNinaAThomas3AbstractObjective:Patientsmayfearthesymptomsandconsequencesassociatedwithhypoglycemia.
Wetestedwhetherfearofhypoglycemiaisindependentlyassociatedwithpoorerhealth-relatedqualityoflife(HRQOL).
Researchdesignandmethods:Datawerecollectedusingdirect-mailsurveyandenrollmentinformationfromadultcommercialhealthplanenrolleeswithtype2diabetesduringa12-monthperiod(12/01/2008to11/30/2009).
HRQOLwasevaluatedbytheEuroQol(EQ)–5Dindexand12-itemShortFormHealthSurveyMentalComponentSummary(SF-12MCS)andPhysicalComponentSummary(SF-12PCS).
FearofhypoglycemiawasassessedusingtheHypoglycemiaFearSurvey(HFS).
Twoordinaryleast-squares(OLS)modelsofHRQOLcontrollingfordemographicsandillnesscharacteristicswerespecified,andOLSregressioncoefficientsandstatisticalinferenceswerecompared.
Model1included1variableofhypoglycemiasymptoms;Model2includedbothhypoglycemiasymptomsandHFSscore.
Results:Of3999patientscontacted,813respondedtothesurvey.
Model1:hypoglycemiasymptomsalonewereassociatedwithworseHRQOL(SF-12MCSandSF-12PCSscoresandEQ-5Dutilityscore;allP10pointsofHFStotalscore,P0.
05).
Model2showedthattheHFSscorewasstillsignificantlyassociatedwithscoresonall3HRQOLoutcomes(eachP0.
05).
Forsulfonylureausers(n=246),Model1showedthatthesymptomatichypoglycemiawasassociatedwithEQ-5DscoresandSF-12MCSscores(eachP1020(8.
6)69(12.
0)EthnicityWhiteNo52(22.
5)161(28.
3)0.
0961Yes179(77.
5)409(71.
8)BlackorAfricanAmericanNo196(84.
9)469(82.
3)0.
3806Yes35(15.
2)101(17.
7)HispanicorLatinoNo209(89.
7)525(92.
3)0.
2360Yes24(10.
3)44(7.
7)MaritalstatusSingle,nevermarried25(10.
7)68(11.
8)0.
6079Married167(71.
4)390(67.
7)Divorced32(13.
7)82(14.
2)Separated2(0.
9)14(2.
4)Widowed8(3.
4)22(3.
8)Annualhouseholdincome,$US100,00063(28.
4)142(25.
9)Shietal.
HealthandQualityofLifeOutcomes2014,12:167Page4of9http://www.
hqlo.
com/content/12/1/167Table1Populationcharacteristicsbetweenpatientswhoreportedversusthosewhodidnotreportsymptomsofhypoglycemia(Continued)EducationLessthansecondary9(3.
9)14(2.
5)0.
8425Somesecondary4(1.
7)14(2.
5)Secondaryorequivalent53(22.
8)131(22.
9)Tertiarybutnodegree60(25.
8)166(29.
0)2-yearundergraduatedegree28(12.
0)59(10.
3)>2-yearundergraduatedegree51(21.
9)199(20.
8)Graduateschool28(12.
0)69(12.
1)USRegionNortheast13(5.
5)33(5.
7)0.
2144Midwest29(12.
3)54(9.
3)South181(77.
0)440(76.
1)West12(5.
1)51(8.
8)MoriskyadherenceLow123(52.
8)265(46.
3)0.
3058Relativelylow71(30.
5)186(32.
5)Middle28(12.
0)77(13.
4)Relativelyhigh10(4.
3)36(6.
3)High1(0.
4)9(1.
6)OAD=oralantidiabeticmedication;SU=sulfonylurea.
*Chi-squaretest.
SF-12PCSNoHypoglycemiaHypoglycemia0102030405060HFSNoHypoglycemiaHypoglycemia010203040*NoHypoglycemiaHypoglycemia0.
00.
20.
40.
60.
81.
01.
2*EQ-5DSF-12MCSNoHypoglycemiaHypoglycemia0102030405060*Figure1Comparisonofhealth-relatedquality-of-lifescoresandfearofhypoglycemiabetweenpatientswhoreported(n=235)vsthosewhodidnotreport(n=578)symptomsofhypoglycemia.
EQ-5D=EuroQol-5Dscale;HFS=HypoglycemiaFearSurvey;MCS=MentalComponentSummary;PCS=PhysicalComponentSummary;SF-12=12-itemShortFormHealthSurvey.
*P<0.
0001,P=0.
0007byttest.
Shietal.
HealthandQualityofLifeOutcomes2014,12:167Page5of9http://www.
hqlo.
com/content/12/1/167shownanassociationbetweenfearofhypoglycemiaandHRQOL[29,32].
Asignificantassociationwasobservedbetweensymp-tomatichypoglycemiaandEQ-5DandSF-12MCSscoresinModel1,whereasonlytheassociationwithSF-12MCSwassignificantafterincorporatingtheHFSintothemodel.
Incontrast,fearofhypoglycemiademon-stratedasignificantassociationwithall3HRQOLout-comes.
Thisfindingsuggeststhat,statistically,fearofhypoglycemiamaybeamoreimportantpredictorthanhypoglycemiaitselfofpatientwell-beingandhealthstatus.
Multiplefactorsassociatedwithfearofhypoglycemiawereidentified.
Consistentwithourstudy[16]andotherreports[29,31,33],symptomatichypoglycemiahadthestrongest(positive)associationwithfearofhypoglycemia.
Thus,itappearsthatinpatientswithtype2diabetes,ex-periencinganeventofhypoglycemiaincreasesratherthandiminishesfearofsuchanevent.
AnimportantclinicalpracticeimplicationofthisfindingistheneedforTable2InfluencingfactorsofhypoglycemiafearsurveytotalscoresVariable(reference)RegressioncoefficientStandarderrorPvalue95%CILowerUpperHypoglycemia10.
471.
28<0.
00017.
9512.
99Age(<65y)≥65y1.
231.
910.
524.
982.
51Sex(male)Female1.
761.
230.
154.
170.
66Bodymassindex0.
100.
080.
220.
250.
06Familyhistoryofdiabetes0.
581.
370.
673.
272.
10Treatment(SUwithoutinsulin)Non-SUOADwithoutinsulin2.
251.
440.
125.
090.
58AnyOADwithinsulin2.
091.
420.
140.
714.
89Durationofcurrentdiabetesmedication0.
700.
470.
141.
630.
23EthnicityWhite(notwhite)4.
561.
35<0.
00017.
221.
91HispanicorLatino(notHispanicorLatino)4.
742.
130.
030.
568.
92Married(currentlynotmarried)0.
041.
290.
972.
592.
50Householdincomelevel1.
940.
47<0.
00012.
861.
03Education(lessthansecondary)0.
753.
560.
836.
257.
75Region(Northeast)Midwest1.
242.
820.
664.
296.
77South1.
412.
330.
553.
175.
99West0.
213.
140.
955.
966.
37Diabetesduration(y)0.
360.
08<0.
00010.
200.
52Moriskyadherence1.
720.
60<0.
00010.
542.
91OAD=oralantidiabeticmedication;SU=sulfonylurea.
Table3Roleofhypoglycemiafearonhealth-relatedqualityoflifeusingalternativemodelsVariableEQ-5D(US)SF-12MCSSF-12PCSβPvalue95%CIforββPvalue95%CIforββPvalue95%CIforβModel1Hypo0.
0410.
0020.
067to0.
0153.
628<0.
00015.
259to1.
9980.
9740.
2472.
623to0.
675Model2Hypo0.
0140.
3030.
040to0.
0131.
9370.
0223.
591to0.
2830.
5790.
5001.
104to2.
262HFS0.
003<0.
00010.
003to0.
0020.
162<0.
00010.
210to0.
1150.
149<0.
00010.
197to0.
101β=regressioncoefficient;EQ=EuroQol;Hypo=symptomatichypoglycemia;HFS=HypoglycemiaFearSurvey;MCS=MentalComponentSummary;PCS=PhysicalComponentSummary;SF-12=12-itemShortFormHealthSurvey.
Shietal.
HealthandQualityofLifeOutcomes2014,12:167Page6of9http://www.
hqlo.
com/content/12/1/167healthcareprofessionalstobecognizantofthefearofhypoglycemiaandtakestepstoaddressthisfearandre-latedbehaviors.
Inthecurrentanalysis,Hispanic/Latinoethnicity,dur-ationofdiabetes,andself-reportedadherencealsoshowedapositiveassociationwithfearofhypoglycemia,whereashouseholdincomeandwhiteraceshowedanegativeassociation.
Thesedatasuggestthatdemo-graphicvariablesmightbehelpfulinpredictingthosepatientsmostlikelytoexperiencefearofhypoglycemia.
Thepositiveassociationbetweendurationofdiabetesandfearofhypoglycemiacouldreflectgreaterinsulinuseinpatientswithalongerdurationofdisease.
Alter-natively,anindependentassociationbetweenthesevari-ableswouldseemtofurtherindicatethatexperiencinghypoglycemiaincreasesfearoftheevent.
Asnocausalitycanbeinferredinthiscross-sectionalanalysis,thepositiverelationshipbetweenself-reportedadherenceandfearofhypoglycemiaisdifficulttointer-pret.
Inapreviousstudy,patientsreportinghypoglycemiasymptomsweremorelikelytoreportbarrierstoadher-ence(eg,botheredbymedicationsideeffects,unabletofollowplans)[4].
Inaddition,datasuggestthatpatientswhohaveexperiencedahypoglycemicepisodearelikelytoinitiatepreventivebehaviorsthatmayincludemodifica-tionoftheirdosingregimen[14,16].
Althoughthesefind-ingsmayseematoddswithoneanother,itisreasonabletoexpectthatpatientsadherenttostrictglycemiccontrolregimenswouldhavemorereasontobefearfulofhypoglycemia.
Additionalstudieswithlongitudinaldatacollectionareneededtofullyunderstandthevariablesthatpredictfearofhypoglycemia.
Predictorsofhypoglycemiainpatientswithtype2dia-betesarebetterunderstood.
Inthecurrentanalysis,morewomenversusmenandmorepatientstreatedwithOADplusinsulinversussulfonylureawithoutinsulinornonsul-fonylureaOADwithoutinsulinreportedhypoglycemia.
Thedifferenceinhypoglycemiawithrespecttodiabetestherapyistobeexpected,giventhatinsulinandinsulinse-cretagoguesarethemostcommoncauseofhypoglycemiainpatientswithtype2diabetes[15].
Theobservationthatmorewomenthanmenreportedhypoglycemicsymptomswasunexpectedbuthasbeenobservedinanotherstudy[29]andcouldpossiblyreflectsex-relateddifferencesinself-reportingofhypoglycemicsymptoms.
Thisanalysishassomelimitations.
Becausethestudywascross-sectional,nocausalrelationshipscanbein-ferredfromthefindings.
Dataonthefrequencyandse-verityofhypoglycemicepisodeswerenotcollectedsotheircontributiontofearofhypoglycemiacouldnotbeassessed.
Also,becausethesurveydesignusedacon-veniencesampleofpatientsthatincludedonlythosewhoweremembersofspecifichealthplans,withvolun-taryparticipation,surveyparticipantsmaynotberepre-sentativeofallpatientswithtype2diabetes.
Thestudyalsoreliedonpatientself-report,andthesurveyhadapatientrecallperiodof6months.
LongitudinalcohortstudiesarewarrantedtofurtherunderstandtheimpactofhypoglycemiaandtotestpotentialinterventionstoaddresstheissueofhypoglycemiafeartoimprovehealthTable4Roleofhypoglycemiafearonhealth-relatedqualityoflifeusingalternativemodels(InsulinSubgroup)VariableEQ-5D(US)SF-12MCSSF-12PCSβPvalue95%CIforββPvalue95%CIforββPvalue95%CIforβModel1Hypo0.
0010.
960.
058to0.
0552.
5060.
1375.
813to0.
8011.
6680.
3595.
244to1.
908Model2Hypo0.
0290.
3110.
027to0.
0860.
2850.
8633.
534to2.
9650.
3580.
8474.
011to3.
296HFS0.
003<0.
0010.
004to0.
0010.
188<0.
00010.
259to0.
1160.
111<0.
0070.
191to0.
031β=regressioncoefficient;EQ=EuroQol;Hypo=symptomatichypoglycemia;HFS=HypoglycemiaFearSurvey;MCS=MentalComponentSummary;PCS=PhysicalComponentSummary;SF-12=12-itemShortFormHealthSurvey.
Table5Roleofhypoglycemiafearonhealth-relatedqualityoflifeusingalternativemodels(SulfonylureaSubgroup)VariableEQ-5D(US)SF-12MCSSF-12PCSβPvalue95%CIforββPvalue95%CIforββPvalue95%CIforβModel1Hypo0.
0770.
0010.
123to0.
0316.
531<0.
0019.
606to3.
4561.
8150.
2414.
857to1.
226Model2Hypo0.
0600.
0140.
107to-0.
0135.
3000.
0018.
453to2.
1470.
0560.
9712.
973to3.
084HFS0.
0020.
0140.
004to0.
0000.
1400.
0080.
243to0.
0380.
213<0.
0010.
311to0.
114β=regressioncoefficient;EQ=EuroQol;Hypo=symptomatichypoglycemia;HFS=HypoglycemiaFearSurvey;MCS=MentalComponentSummary;PCS=PhysicalComponentSummary;SF-12=12-itemShortFormHealthSurvey.
Shietal.
HealthandQualityofLifeOutcomes2014,12:167Page7of9http://www.
hqlo.
com/content/12/1/167forpatientswithdiabetes.
Inconclusion,inadditiontosymptomatichypoglycemiaitself,fearofhypoglycemiawasindependentlyassociatedwithlowerHRQOL(over-allhealthstatus,mentalhealth,andphysicalhealth)inpatientswithtype2diabetes.
Thereisanunmetneedforpatienteducationprogramsthataddresspatientfearofhypoglycemiaanduseofmedicationswithalowerriskofhypoglycemia.
AdditionalfileAdditionalfile1:TableS1.
1FullySpecifiedHypoglycemiaModel1:EQ-5D(US).
TableS1.
2FullySpecifiedHypoglycemiaModel1:SF-12MCS.
TableS1.
3FullySpecifiedHypoglycemiaModel1:SF-12PCS.
TableS1.
4FullySpecifiedHypoglycemiaModel2:EQ-5D(US).
TableS1.
5FullySpecifiedHypoglycemiaModel2:SF-12MCS.
TableS1.
6FullySpecifiedHypoglycemiaModel2:SF-12PCS.
TableS2.
0HypoglycemiaModel1:InsulinSubgroupMeasuredbyEQ-5D(US).
TableS2.
1HypoglycemiaModel1:InsulinSubgroupMeasuredbySF-12MCS.
TableS2.
2HypoglycemiaModel1:InsulinSubgroupMeasuredbySF-12PCS.
TableS2.
3HypoglycemiaModel2:InsulinSubgroupMeasuredbyEQ-5D(US).
TableS2.
4HypoglycemiaModel2:InsulinSubgroupMeasuredbySF-12MCS.
TableS2.
5HypoglycemiaModel2:InsulinSubgroupMeasuredbySF-12PCS.
TableS3.
0HypoglycemiaModel1:SulfonylureaSubgroupMeasuredbyEQ-5D(US).
TableS3.
1HypoglycemiaModel1:SulfonylureaSubgroupMeasuredbySF-12MCS.
TableS3.
2HypoglycemiaModel1:SulfonylureaSubgroupMeasuredbySF-12PCS.
TableS3.
3HypoglycemiaModel2:SulfonylureaSubgroupMeasuredbyEQ-5D(US).
TableS3.
4HypoglycemiaModel2:SulfonylureaSubgroupMeasuredbySF-12MCS.
TableS3.
5HypoglycemiaModel2:SulfonylureaSubgroupMeasuredbySF-12PCS.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsLSistheguarantorofthisarticle.
HSperformeddataanalysis.
YZreviewedtheresultsandimprovedmodelspecifications.
LS,HS,YZ,andNATreviewed,edited,andapprovedthemanuscript.
AcknowledgmentsTheauthorsthankVivianFonseca,MD,forhishelpfuldiscussionsduringthedevelopmentofthisstudy.
Allauthorscontributedtotheconceptanddesignofthestudy;theacquisition,analysis,andinterpretationofdata;developmentofthestatisticalanalysisplan;andreview/editingofthemanuscriptforcontent.
Allauthorshadfullaccesstothedataincludedinthemanuscriptandapprovedthefinalversion.
L.
S.
hasreceivedgrants(toTulane)fromNovartis,Takeda,andGenentechandhasreceivedhonorariaforconsultingfromAstraZeneca.
N.
A.
TisanemployeeofBristol-MyersSquibb.
Y.
Z.
andH.
S.
reportnopotentialconflicts.
ThestudywassponsoredbyAstraZeneca(Wilmington,DE).
MedicalwritingsupportforthepreparationofthismanuscriptwasprovidedbyDeborahM.
Campoli-Richards,BSPharm,RPh,NicoleStrangman,PhD,andJanetE.
Matsuura,PhD,ofCompleteHealthcareCommunications,Inc.
(ChaddsFord,PA),withfundingfromBristol-MeyersSquibbandAstraZeneca.
DatafromthisstudywerepresentedattheInternationalSocietyforPharmacoeconomicsandOutcomesResearch18thAnnualInternationalMeeting,May18–22,2013,NewOrleans,LA.
Authordetails1DepartmentofGlobalHealthSystemsandDevelopment,TulaneUniversitySchoolofPublicHealthandTropicalMedicine,NewOrleans,LA,USA.
2CollegeofPharmacy,XavierUniversityofLouisiana,NewOrleans,LA,USA.
3USHealthServicesResearch,Bristol-MyersSquibb,Princeton,NJ,USA.
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:Ishypoglycemiafearindependentlyassociatedwithhealth-relatedqualityoflifeHealthandQualityofLifeOutcomes201412:167.
SubmityournextmanuscripttoBioMedCentralandtakefulladvantageof:ConvenientonlinesubmissionThoroughpeerreviewNospaceconstraintsorcolorgurechargesImmediatepublicationonacceptanceInclusioninPubMed,CAS,ScopusandGoogleScholarResearchwhichisfreelyavailableforredistributionSubmityourmanuscriptatwww.
biomedcentral.
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