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I K Wium-Andersen and Antidiabetic medications and 181:5 499–507 Clinical Study others dementia

Antidiabetic medication and risk of dementia in patients with type 2 : a nested case–control study

Ida Kim Wium-Andersen1, Merete Osler2,3, Martin Balslev Jørgensen1, Jørgen Rungby4 and Marie Kim Wium-Andersen2 Correspondence 1Psychiatric Center Copenhagen, Copenhagen Ø, Denmark, 2Center for Clinical Research and Prevention, should be addressed Frederiksberg Hospital, Frederiksberg, Denmark, 3Section of Epidemiology, Department of Public Health, University to I K Wium-Andersen of Copenhagen, Copenhagen K, Denmark, and 4Department of Endocrinology and Copenhagen Center for Email Translational Research, Bispebjerg Hospital, Copenhagen NV, Denmark Ida.kim.wiumandersen@ regionh.dk

Abstract

Objective: Diabetes is a risk factor for dementia, but whether antidiabetic medication decreases the risk is unclear. We examined the association between antidiabetic medication and dementia. Design: We performed a nested case–control study within a cohort of all 176 250 patients registered with in the Danish National Diabetes Register between 1995 and 2012. This population was followed for dementia diagnosis or anti-dementia medication use until May 2018. Using risk-set sampling, each dementia case (n = 11 619) was matched on follow-up time and calender year of dementia with four controls randomly selected among cohort members without dementia (n = 46 476). Ever use and mean daily defined dose of antidiabetic medication was categorized in types (, , and glinides combined, glitazone, dipeptidyl peptidase 4 (DPP4) inhibitors, glucagon- like peptide 1 (GLP1) analogs, -glucose transport protein 2 (SGLT2) inhibitors and ). Methods: Conditional logistic regression models were fitted to calculate odds ratios (ORs) for dementia associated with antidiabetic medication use, adjusting for potential confounders. European Journal of Endocrinology Results: Use of metformin, DPP4 inhibitors, GLP1 analogs, and SGLT2 inhibitors were associated with lower odds of dementia after multible adjustments (ORs of 0.94 (95% confidence interval (CI): 0.89–0.99), 0.80 (95% CI 0.74–0.88), 0.58 (95% CI: 0.50–0.67), and 0.58 (95% CI: 0.42–0.81), respectively), with a gradual decrease in odds of dementia for each increase in daily defined dose. Analyses of the most frequent treatment regimes did not show any synergistic effects of combined treatment. Conclusion: Use of metformin, DPP4 inhibitors, GLP1 analogs and SGLT2 inhibitors was associated with lower risk of dementia in patients with diabetes.

European Journal of Endocrinology (2019) 181, 499–507

Introduction

Dementia is a disease characterized by progressive (2). This risk may be caused by a shared pathophysiology irreversible cognitive damage. In 2015, 47 million people of diabetes and dementia involving hyperglycemia were living with dementia, and numbers are predicted to and hyperinsulinemia (3), which raises the question of triple by 2050 (1). Diabetes mellitus is a well-established whether use of antidiabetic medications can reduce risk risk factor for dementia, and particularly patients with of dementia in patients with diabetes. Only few studies type 2 diabetes seem to have increased risk of dementia have examined this with equivocal results and, although

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-19-0259 European Journal of Endocrinology https://eje.bioscientifica.com in theDanishPrescriptionRegister, andmeasuresof (NPR) after1990, prescriptions ofantidiabetic medication DH36.0, DO24)intheDanishNationalPatientsRegistry Classification ofDisease10(ICD10)codesDE10–14, ascertained byphysician’s diagnosis(International validated algorithmcombininginformationondiabetes ( 1, 1995 and December 31, 2012 (NDR) between January with type 2 diabetes in the National Diabetes Register The study was based on patients in Denmark registered Study populationandfollow-up Patients andmethods patients withtype2diabetes. associated withriskofdevelopingdementiainDanish regimens (combinationsofantidiabeticdrugs)were different typesofantidiabeticmedicationandtreatment combinations oftreatment. related tospecifictypesofantidiabeticmedicationor Moreover, itisimportanttoestablishifanyeffect diabetes could be reversedbyantidiabetic medication. the higherriskofdevelopingdementiainpatientswith suffer fromdiabetes( to improvecerebralmetabolisminAlzheimer’s disease( been showntoimprovecognitioninrodents( those, especiallyGLP1analogsareofinterestastheyhave sodium-glucose transportprotein2(SGLT2) inhibitors.Of inhibitors, glucagon-likepeptide1(GLP1)analogs,and medications such asdipeptidylpeptidase 4 (DPP4) combination therapyorincludedthenewestantidiabetic combination of treatment is common, none have studied n

Clinical Study = 178 403).Inclusioninthisregisterisbasedona Against thisbackground,weinvestigatedwhether As oneineleven(425millions)adultsworldwide 8 ), itisimportanttoknowwhether others I KWium-Andersenand 4 , 5 , 6 ) and 7 ). years, IQR:3.5–11.5years),weidentified11619casesof During amedianfollow-upof7.2years(range:0.0–22.8 Danish CivilRegistrationSystemoruntilMay2018. medication, emigration or death in the NPR and the until firstdementiadiagnosisorprescriptionof That leftastudypopulationof170417patientsfollowed (DPR)in1977and1995,respectively.Prescription Registry to theestablishmentofNPRandDanishNational diagnoses anddementiamedicationweretrackedback the NDR( of anti-dementiamedicationbeforeregistrationin age of35( patients withadiagnosisoftype2diabetesunderthe diabetes (DO24.4-9; validity ( toimprove the NPRandDanishAdultDiabetesRegistry from theNDRwerecomparedwithhistoricaldata Register( National HealthInsuranceService blood glucoseor referrals to feet therapists from the avoiding immortaltimebias. of antidiabeticmedicationusedinthestudyperiodwhile was thatthisdesignallowedustocalculate the amount case–control studyinsteadofaprospectivecohortdesign antidiabetic drugs. The rationale for choosing a nested time ensuringequalaccesstoforexamplethenewer cases andcontrolswerefollowedinthesamecalendar The matchingoncalendaryearwastoensurethatboth calendar yeartocasepatientsina1:4ratio( dementia freeandmatchedthemonfollow-uptime controls amongmembersinthecohortwhoremained the procedure with type2diabetesusingrisk-setsamplinggeneratedby control studywasnestedwithinthecohortofpatients medication: incident dementia(onlydiagnosis: dementia Antidiabetic medicationsand 10 n n ). Patients with diabetes due to gestational

n = = 29 ol medication: only =3259; 2138) wereexcluded( 3695), oradiagnosisofdementiause sttocc Flowchart ofthestudydesign. Figure 1 inStata.Thus,werandomlyselected n 86, train (DE12; starvation =1806), Downloaded fromBioscientifica.com at09/23/202112:25:50PM n 7473; diagnosis and diagnosis =7473; 181 Fig. 1 :5 n 8) A case– A =887). ). Dementia 9 n ). Thedata 6 476). =46 n =347), 500 via freeaccess European Journal of Endocrinology education (morethanhigh schooldegree),orunknown medium (highschool degree/vocational), higher schooling), categorized asbasic(7–9grade ofobligatory Age wasincludedasa continuous variable. Education was Covariables and ‘othercombinationsnotincludingSGLT2’. combinations’ into‘othercombinationsincludingSGLT2’ included SGLT2 inhibitors,wefurthercategorized‘other However, as none of the most common combinations Tabletermed ‘othercombinations’(Supplementary 2). all othercombinationsusedformedonesinglecategory commonly used (which included used inourdiabetespopulationandextractedthe12most of the antidiabetic medication types mentioned above) treatment regimens(atotalof128differentcombinations added effectofcombinedtreatment.We firstgeneratedall one type of antidiabetic medication, we also evaluated any types ofmedication.Asmanypatientsusedmorethan sized groupsandconsequentlycutpointsdifferedacross antidiabetic medicationandclassifiedintosufficiently this article).MeanDDDwascalculatedforeachtypeof see section on SGLT2 Table inhibitorsandacarbose(Supplementary 1, combined, glitazones,DPP4inhibitors,GLP1analogs, types: insulin,metformin,sulfonylureasandglinides categorized antidiabeticmedicationintothefollowing study usedasameasurementofdosagepertime.We its mainindicationinadults’( average maintenancedoseperdayforadrugused define bythe World HealthOrganizationas‘theassumed number ofdailydefineddoses(DDD).TheDDDwas of thedispensedproduct,includingACTandtotal prescription, theDPRrecordsdateandafulldescription controls fromtheDPRusingATC codesA10.Foreach 1995 to the index date for both cases and from January We obtainedallprescriptions of antidiabetic medication Exposure: antidiabeticmedication therapeutic codes(ATCs) N06D. dementia medicationwasobtainedusingtheanatomic ( hospital contactsforbothin-andoutpatientsinDenmark diagnosis anddatesfromallsomaticpsychiatric and G30, registered in the NPR which holds data on of Diseases10threvision(ICD10)diagnosisF00-F04 Dementia wasdefinedasanInternationalClassification Outcome: dementia 11 Clinical Study ). FromtheDPR,informationonprescriptionsofanti- supplementary data supplementary others I KWium-Andersenand 12 > ) andisthusinour given at the end of 1000 patients) while complications, or diabetic angiopathy (Supplementary complications, ordiabeticangiopathy(Supplementary , eyecomplications,neurological , whilechroniccomplicationsincluded complications included occasions with or with complicationsafterdiabetesdiagnosis.Acute complications and the number of hospitalizations we includedinformationonacuteandchronicdiabetes depression andalcoholusedisorderwasincluded.Finally, disorder, disease,inflammatory obstructive pulmonary , hypercholesterolemia, infections, chronic heart disease,cerebrovascularhypertension, diagnosis). Comorbidityandco-medicationforischemic (i.e.diabetes diseases fiveyearsprecedingstudyentry hospitalization and medication for somaticorpsychiatric From theNPRandDPR,weincludedinformationon categorized as married,unmarried, divorced orwidowed. obtained from the Danish Civil Registration System and Market Research. Informationonmaritalstatuswas based ondatafromtheIntegratedDatabaseforLabor antidiabetic medications. finally ( number ofacuteandchronic diabetescomplications,and ( ( was usedtocalculateORsusingfourlevelsofadjustment: used forstatisticalanalyses.Conditionallogisticregression Stata version15(StataCorp,CollegeStation,TX,USA)was Statistical analysis Denmark andattheDanishClinicalRegistries. in thisstudyareanonymizeddatalocatedatStatistics informed consentwasnotrequiredofparticipants.Data All datawereretrievedfromadministrative registers, and The studywasapproved by the Danish Data Inspection. Data approval outpatients clinicsandhospitals( toreportdatatheregisterfrom has beenmandatory information ondiabetespatients,andsince2004it a databaseinitiatedin1999,whichincludesclinical (mmol/L), andsystolicbloodpressure.TheDADRis A1c (mmol/mol),low-densitylipoproteincholesterol (never, previous or currentsmoking), BMI, hemoglobin included informationonself-reportedsmokestatus (DADR),we from theDanishAdultDiabetesRegistry TableSupplementary 1.Finally, inasubgroupofpatients 10th revision(ICD10)codesandtheATCs areshownin Table 1).TheInternationalClassificationofDiseases dementia Antidiabetic medicationsand 3 1 ) addingmaritalstatus,comorbidity, co-medicationand ) unadjusted,( 4 ) addingmutuallyadjustment forothertypesof 2 ) adjustedforagegroups,sex, education, Downloaded fromBioscientifica.com at09/23/202112:25:50PM https://eje.bioscientifica.com 13 ). 181 :5 501 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com the combinationsincluding SGLT2 inhibitors odds ofdementiaafteradjustments withthelowestoddsof analogs, andSGLT2 inhibitorswereassociated withlower regimes, combinations with DPP4 inhibitors, GLP1 associated withdementiainadose-dependentmanner. of dementia( and GLP1analogsshowedagradualdecreaseinodds antidiabetic medications,metformin,DPP4inhibitors, dementia (OR:1.07(95%CI:1.02–1.13)). wereassociatedwithslightlyhigherodds of CI: 0.50–0.67) and 0.58 (95% CI: 0.42–0.81) respectively). for GLP1analogsandSGLT2 inhibitors(ORsof0.58(95% with lower odds of dementia with the strongest estimates GLP1 analogs, and SGLT2 inhibitors remained associated medications, useofinsulin,metformin,DPP4inhibitors, multiple adjustments, including use of other antidiabetic odds ofdementiaintheunadjustedmodels( sulfonylureas andacarbosewereassociatedwithlower 9, 10and11. Tablesusers areshowninSupplementary 3,4,5,6,7,8, Characteristics ofusersantidiabeticdrugsversusnon- 0.78), multipleadjustedOR:0.93(95%CI:0.87–0.99)). (CI):0.71– (unadjusted OR:0.75(95%confidenceinterval 572 (83%) of controls had used antidiabetic medication acarbose ( medication typeslessoftenexceptsulfonylureasand prevalence ofmostcomorbiditiesandusedallantidiabetic higher mean age, were less educated and showed higher and 46476controls.Casesweremoreoftenwomen,had Our studypopulationconsistedof11619dementiacases Results the clinicalvariablesfromDADR. subgroup, werepeatedanalyseswithfurtherinclusionof excluded andviceversa.Leftwith5449patientsinthis any patientlackingacorrespondingcontrolwasalso controls ( DADR afterthedementiadateorcorrespondingfor a registereddateforexaminationandbloodtestsinthe controls with data in the DADR ( complications, butresultsweresimilar(datanotshown). retinopathy, nephropathyetc.)insteadofnumber complication type(e.g.hypoglycemia, ketoacidosis, Clinical Study In the analyses of the most frequent treatment In theanalysesofmost frequenttreatment Further, increasing DDDofdifferenttypes Use ofanytypeantidiabeticmedicationexceptfor analysis,weidentifiedcasesand In asupplementary We repeatedallanalyseswithadjustmentfordiabetes n Table 1

= 11 236)wereexcluded.Aftertheseexclusions Fig. 3 ). Overall,9122(79%)ofcasesand38 ). Insulinandsulfonylureaswerenot n others I KWium-Andersenand

= 24 182). Patients with Fig. 2 ). After

Clopidogrel, warfarin, Cerebrovascular disease, Ischemic heartdisease, Unknown Widow/widower Divorced Unmarried Married Marrital status, Unknown Long education Medium education Short education Education, Men, Age (years),mean(IQR) Number Diabetes Register. included patientswithtype2diabetesfromtheNational Table 1 like peptide1;SGLT2,sodium-glucose transportprotein2. DDD, dailydefineddose;DPP4,dipeptidyl peptidase4;GLP1,glucagon- Based on11619casesand46476controls. Acarbose SGLT2 inhibitors GLP1 analogs DPP4 inhibitors Glitazones Sulfonylureas Metformin Insulin Any type Antidiabetic medication 0 complications Acute diabetescomplications, 3 complications 2 complications 1 complication 0 complications Chronic diabetescomplications, Alcohol dependence, Depression, Inflammatory disorder, Chronic obstructive Infections, Hypercholesterolemia, Obesity, Hypertension, dementia Antidiabetic medicationsand ≥ ≥ n n users (%) use, no.ofever- n n pulmonary disease, n aspirin use, (%) (%) (%) (%) (%) 1 complications 4 complications n (%) n (%) Main demographicandclinicalcharacteristicsofthe n n (%) (%) n (%) n n (%) n (%) (%)

n

(%)

Downloaded fromBioscientifica.com at09/23/202112:25:50PM n Dementia cases 11 243(97) (%) 11 619 n 4232 (36) 1011 (9) 1502 (13) 6704 (58) 6279 (54) 2425 (21) 9122 (79) 1236 (11) 2880 (25) 6579 (57) 2458 (21) 1718 (15) 2363 (20) 2190 (19) 1054 (9) 7229 (62) 3176 (27) 1538 (13) 6027 (52) 1992 (17) 3187 (27) 5522 (48) 5566 (48) (%) 70.8 (51–67) 197 (2) 246 (2) 902 (8) 271 (2) 376 (3) 362 (3) 562 (5) 536 (5) 543 (5) 820 (7) 918 (8) 58 (0.5) 44 (0.4) 181 :5 10 655(23) 26 276(57) 30 894(66) 12 267(26) 35 078(82) 45 268(97) 11 195(24) 26 793(58) 24 325(52) 28 720(62) 17 566(38) 20 112(43) 25 900(56) 46 476 59.0 (64–78) 1881 (4) 4589 (10) 3922 (8) 6121 (13) 2015 (4) 1208 (3) 1512 (3) 2082 (4) 4894 (11) 1655 (4) 6980 (15) 1880 (4) 6060 (13) 7322 (16) 9044 (19) 7231 (16) 5106 (11) 6682 (14) 5696 (12) 3693 (8) 5105 (11) Controls 833 (2) 868 (2) 272 (1) 502 via freeaccess European Journal of Endocrinology depression, alcoholusedisorder, andnumberofacutechronicdiabetescomplications. hypertension, obesity,hypercholesterolemia, infections,chronicobstructivepulmonarydisease, inflammatorydisorder, status, yearofdementiadiagnosis, ischemicheartdisease,cerebrovascularclopidogrel/warfarin/aspirin use, National DiabetesRegister,based on11,619casesand46,476controls.Multipleadjustments includeage,sex,education,marital Use ofantidiabeticmedication intype2diabeticpatientswith(cases)orwithout(controls)dementia duringfollow-upinthe Figure 2 demonstrated thatpatientswithdiabeteswhoused In thisnationwidenestedcase–controlstudy, we Discussion Fig.2). variables (Supplementary analogs stayedsignificantafteradjustmentforclinical change theORs.InanalysesofDDD,bothgroupsGLP1 adjustment forclinicalvariablesincludingHbA1cdidnot Fig.1).Further 0.43 (95%CI:0.22–0.83)(Supplementary significantly lowerORsof0.59(95%CI:0.45–0.77)and analogs and SGLT2 inhibitors were associatedwith including otherantidiabeticmedications,onlyGLP1 Tablein Supplementary 12.Aftermultipleadjustments and clinicalcharacteristicsofthissubgroupareshown 4003 controlshadclinicaldataavailable.Demographic patients includedintheDADR,atotalof1446casesand medications providedin multiplicative modelsfortherespectivetypesof were nearlyidenticaltotheexpectedoddsfrom oddsduetomorethanonetypeoftreatment observed (OR of0.39(95%CI:0.29–0.55))( Clinical Study In the supplementary analysisofthesubgroup In thesupplementary Fig. 2 . others I KWium-Andersenand Fig. 4 ). However, the comparison is difficult since previous studies included comparison isdifficultsincepreviousstudiesincluded risk ofdementia,aresupportedbyotherstudies,butdirect types of antidiabeticmedication are associated with lower could notbereplicatedinthelateranalyses. the analysisofeveruseinsulin( Insulin seemedassociatedwithlowerriskofdiabetesin drugs inthecombinationwithnosynergisticeffect. effect ofcombinedusedependsonlyontheindividual for therespectivetypesofmedicationssuggestingthat identical to theexpected odds from amultiplicative model with thelowestoddsofdementia.Thewerenearly DPP4 inhibitors, and SGLT2 inhibitors were associated the combinedanalysis,combinationswithGLP1analogs, seemed dependentondoseanddurationoftreatment.In other typesofantidiabetic medication. The association after adjustment for potential confounders and for useof inhibitors hadloweroddsofdevelopingdementiaeven metformin, DPP4inhibitors,GLP1analogs,orSGLT2 dementia compared to patients not using antidiabetic and metforminwereassociatedwithadecreasedriskof showed thatinpatientswithdiabetes,useofsulfonylureas National HealthInsuranceResearch DatabasefromTaiwan older antidiabeticmedicationsonly. Two studiesbasedon dementia Antidiabetic medicationsand The resultsofourstudy, suggestingthatuseofspecific Downloaded fromBioscientifica.com at09/23/202112:25:50PM https://eje.bioscientifica.com Fig. 2 181 :5 ); however, this 503 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com pro-cognitive effects( have suggestedthatespecially insulinandglitazoneshave even thoughpreviousrandomized controlledstudies of insulin,sulfonylureas,or glitazoneswithdementia In ourstudy, we didnotfindanyconsistentassociations were notascomparedtonon-userswithoutdiabetes( odds ofAD,whileinsulin,sulfonylureas,andglitazones long-term useofmetforminwasassociatedwithincreased from general practice in the United Kingdom found that with Alzheimer’s dementia (AD) recruited among patients potential toxiceffectsonneurons( which areproducedduringhyperglycemiaandhave damaging effectsofadvancedglycosylationendproducts inflammation, andapoptosisbysuppressingthe may reducedementiariskbyreducingoxidativestress, use wasassociatedwithloweroddsofdementia.Metformin years ( compared to sulfonylureas in US veterans younger than 75 that metformindecreasedtheriskofdementiawhen glitazone users( lower ratesofdementiacomparedtosulfonylureaand medications ( depression, alcoholusedisorder,andnumberofacutechronicdiabetescomplications. hypertension, obesity,hypercholesterolemia,infections,chronicobstructivepulmonarydisease,inflammatorydisorder, marital status,yearofdementiadiagnosis,ischemicheartdisease,cerebrovascularclopidogrel/warfarin/aspirinuse, the NationalDiabetesRegisterbasedon11,619casesand46,476controls.Multifactorialisadjustedforage,sex,education, Previous useofantidiabeticmedicationintype2diabeticpatientswith(cases)orwithout(controls)dementiaduringfollow-up in Figure 3 Clinical Study By contrast,acase–controlstudyincluding7086cases 16 ). This is in line with our finding that metformin ). Thisisinlinewithourfindingthatmetformin 14 15 ), while metformin users seemed to have ), whilemetforminusersseemedtohave ). Similarly, Orkaby 20 ). Itmaybethattheantidiabetic others I KWium-Andersenand 17 , et al 18 ). . recently found . recentlyfound 19 ). than forGLP1analogusebut withthesametendency. where theassociationsforDPP4 inhibitorusewereweaker This is in accordance with the results seen in our study, glycemic effects (e.g. body weight and ) ( resulting inlowerimpacton bothglycemicandextra- inhibitors increaseactiveGLP1levelsconsiderablyless of activeGLP1( degradation ofGLP1herebydoublingtheconcentration improve cerebralglucosemetabolism( prevent amyloid plaque formation in the brain ( against apoptosis, inflammation and oxidativestressand cognitive effectsbyimprovingneurogenesis,protect GLP1 maycrosstheblood–brainbarrierandexhibitpro- GLP-1 analogs improve cognition( dementia andseveralrodentstudieshavesuggestedthat protective roleoncognitive symptoms ( risk. However, manystudieshavedescribedGLP1’s possible influence ofnewerantidiabeticmedicationsondementia in diabetespatients. diabetes arenotthesamedrugsthatmaypreventdementia medications whichbenefitdementiapatientswithout dementia Antidiabetic medicationsand DPP4 inhibitors inhibit the enzyme responsible for No population-basedstudysofarhasexaminedthe 24 ). Compared to GLP1 analogs, DPP4 ). ComparedtoGLP1analogs,DPP4 Downloaded fromBioscientifica.com at09/23/202112:25:50PM 5 , 181 6 7 ). Mechanistically, , :5 7 23 , 21 ). ) andriskof 22 504 ) and 25 via freeaccess ). ). European Journal of Endocrinology Registry, whichprovideddetailedlong-termdrug use antidiabetic medication from a nationwide Prescription did notchangetheresults. of hypoglycemic episodes registered at a hospital, and this type 2diabetes.Inouranalyses,weadjustedfornumber relationship, but severe hypoglycemia remains rare in control (HbA1c).Also,hypoglycemiamaymediatethe treated. Inasubanalysis,wefoundnoimpactofglycaemic example thenewerantidiabeticdrugsweremorewell and wehavenoevidence that patientstreatedwithfor reduced riskforallmedicationgroupsbutonlysome antidiabetic medicationsisunclear. We donotseea target forcurrentAlzheimer’s therapy( may inhibittheenzyme acetylcholinesterase, the primary Furthermore, ithasbeensuggestedthatSGLT2 inhibitors is particularlyaffectedbytype2diabetes( function andplasticityinthehippocampuswhich stress andinflammation,improvedbrainmitochondrial may preventcognitivedeclineduetoreducedoxidative rodent studieshaveindicatedthatSGLT2 inhibitors plasma glucosebyincreasedrenalexcretion( calculated usingtheriskestimatesinFigure 1. disorder, andnumberofacutechronicdiabetescomplications.*Theexpectedpointestimatesforcombinedusewas obesity, hypercholesterolemia,infections,chronicobstructivepulmonarydisease,inflammatorydisorder,depression,alcohol use year ofdementiadiagnosis,ischemicheartdisease,cerebrovascularclopidogrel/warfarin/aspirinuse,hypertension, the NationalDiabetesRegister.Basedon11,619casesand46,476controls.Adjustmentforage,sex,education,maritalstatus, Combinations ofantidiabeticmedicationintype2diabeticpatientswith(cases)orwithout(controls)dementiaduringfollow-up in Figure 4 Clinical Study The roleoftheglucose-loweringeffect SGLT2 inhibitorsare a newdrugclasswhichreduces Our studyhas several strengths. We assessed use of others I KWium-Andersenand 29 , 30 ). 26 27 ). Two , 28 ). consequently, wecannot excludethattheoddscouldbe use andtobaccosmoking or onsocialrelationsand, information onlifestylesuch asphysicalactivity, alcohol time ofthediabetes diagnosis. However, we had no though, unfortunately, theywerenotmeasured atthe cholesterol, systolicbloodpressureandsofortheven for clinicalvariableslikeHbA1c,low-densitylipoprotein prescription choice.Inasubgroupwecouldfurtheradjust were alsomutuallyadjustedforlimitingconfoundingby complications. Thedifferentantidiabeticmedications on anumberofrelevantcovariablesincludingdiabetes was thatwewereabletoincluderegister-basedinformation associated withdementia.Anotherstrengthofourstudy that we could also test whether a higher exposure was of purchases ofeachdrug foreachpatientwhichmeant case–control study, wecouldcalculatetheexactamount without risk of immortal time bias ( exposure This designallowedustohandlethetime-varying diabetes patientsdiagnosedwithdementiainDenmark. data to performa nested case–control study including all outcomes minimizedselectionbiasandprovideduswith updates ondemographics, hospital contacts and dementia registries with nearly complete coverage and continuous histories andeliminatedrecallbias.Theuseofnationwide dementia Antidiabetic medicationsand Downloaded fromBioscientifica.com at09/23/202112:25:50PM https://eje.bioscientifica.com 181 31 :5 ). In our nested 505 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com EJE-19-0259 at paper the of version online the to linked is This Supplementary data diabetes inotherpopulations andclinicaltrails. medications mayinfluencetheriskofdementiarelated to hypothesis thatsomeespeciallynewerantidiabetic in patientswithtype2diabetes.We propose totestthe were associatedwithsignificantlyloweroddsofdementia GLP1 analogs,DPP4inhibitors,andSGLT2 inhibitors decline anddementiadiagnosis. but mayindicatethatthesedrugspostponecognitive these groupswasshorterwhichcouldquestioncausality relatively newdrugsandconsequentlyfollow-uptime in analogs, DPP4inhibitors,andSGLT2 inhibitorsareall again lead to an underestimation of risks. Fourth, GLP1 affecting cognitiveskills.However, anysuchbiaswould influence adherencetomedicationuse,forexample,by is conceivablethat,priortodiagnosis,dementiacould may haveledtoattenuation of riskestimates. Third, it non-use. Suchassumednon-differentialmisclassification 1995 orduringhospitalstaywouldbemisclassifiedas hospitalization, antidiabeticmedicationusepriorto in 1995and does not include drugs received during Secondly, wasestablished sincethePrescriptionRegistry in order to eliminate any confounding by indication. a largenumberofcomorbiditiesandclinicalvariables to thosetreatedwitholderdrugs.We alsoadjustedfor newer antidiabetic medications were relatively similar lowering drugs ( channeling biasdoesnotseemtobepresentforglucose- received a diagnosis of dementia. However, such potential patients withearlycognitivedeclinewhohavenotyet drugs (SGLT2, GLP1)mightlessoftenbeprescribedto prescribed antidiabetic medications, especially the newer an earlystageofcognitivedeclinemightlessoftenbe could be explained by reverse causation: patients with estimates wouldbeevenstronger. Further, theassociation a dementiadiagnosis,butthiswouldimplicatethatour users ofantidiabeticmedicationweremorelikelytoget potential limitations.First,ourresultscouldbebiasedif the youngestpopulation( patients admitted in 2008. The lowest validity was seen in assessor ( 2003, 83%ofthediagnosiswereconfirmedbyanexternal ( has previously been evaluated in two independent studies validity ofthedementiadiagnosesinDanishregisters explained byresidualconfoundingfromotherfactors.The 32 Clinical Study , In conclusion,wefoundthatuseofmetformin, 33 ). Thesestudiesfoundthatforpatientsadmittedin . 32 ). Thecorrespondingnumberwas70%for 34 ) and we found that patients with 33 ). Ourstudyalsohasseveral others I KWium-Andersenand https://doi.org/10.1530/ and approved the final version of the article. The corresponding author Thecorresponding the article. of version final the approved and read have and results, the of interpretation design, in part took authors All J. B M and O, M A, W M from help with study the of collection data and the data with help from I W A and M O. I W A is responsible for the funding I W A made the first draft of the article. M W A was responsible for analyzing Author contributionstatement approval ofthemanuscript. or review, preparation, the in or data; the of interpretation and analysis, role in the design no and conduct of the study; had in the collection, management, sponsors The Association. Diabetes Danish the and Foundation, Foundation, the Holger Rabitz and Nielsen wife Doris Mary, born Phillip’s Memorial Hede Family the Foundation, Nordisk Novo the and Foundation for Clinical Research Infrastructure (PROCRIN) established by the Lundbeck Program the Grant, Linds Gerhard M.D. the HBN), 22017-1064/26 number Foundation (Grant Lundbeck Association Medical Danish the The R249-2017-1074), Jaschafonden, number (Grant by supported was work The Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisstudy. no is there that declare authors The Declaration ofinterest References helped establishourdiabetesandreferencepopulationfromtheNDR. who PROCRIN, from Jacobsen Kart Rikke thank to want they Also, study. this make to us inspired has who McIntyre S Roger Dr thank authors The Acknowledgements meeting thecriteriahavebeenomitted. others no that and criteria authorship meet authors listed all that attests dementia Antidiabetic medicationsand 7 6 5 4 3 2 1 Gejl M, Gjedde A,Egefjord L,Moller A, Hansen SB,Vang K, Rodell A, Holscher C. 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