Efficacy and Safety ofDapagliflozin in the Elderly:Analysis From the DECLARE–TIMI 58 StudyDiabetes Care 2020;43:468–475 | https://doi.org/10.2337/dc19-1476

OBJECTIVE

Data regarding the effects of sodium–glucose cotransporter 2 inhibitors in theelderly (age ‡65 years) and very elderly (age ‡75 years) are limited.

RESEARCH DESIGN AND METHODS

The Dapagliflozin Effect on Cardiovascular Events (DECLARE)–TIMI 58 assessedcardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2diabetes. Efficacy and safety outcomes were studied within age subgroups fortreatment effect and age-based treatment interaction.

RESULTS

Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ‡65 to <75 years, and1,096 ‡75 years. Dapagliflozin reduced the composite of cardiovascular death orhospitalization for heart failure consistently, with a hazard ratio (HR) of 0.88 (95%CI0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ‡65 to <75,and ‡75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin didnot significantly decrease the rates ofmajor adverse cardiovascular events,withHR0.93 (95%CI 0.81,1.08), 0.97 (0.83,1.13), and0.84 (0.61, 1.15) inage-groups<65,‡65to <75, and ‡75 years, respectively (interaction P value 0.7352). The relative riskreduction for the secondary prespecified cardiorenal composite outcome rangedfrom 18% to 28% in the different age-groups with no heterogeneity. Majorhypoglycemiawas less frequent with dapagliflozin versus placebo, with HR 0.97 (95%CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ‡65 to <75,and ‡75 years, respectively (interaction P value 0.2107). Safety outcomes, includingfractures, volume depletion, cancer, urinary tract infections, and amputations werebalanced with dapagliflozin versus placebo, and acute kidney injury was reduced, allregardless of age. Genital infections that were serious or led to discontinuation of thestudy drug and diabetic ketoacidosis were uncommon, yet more frequent withdapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and0.8433, respectively).

CONCLUSIONS

The overall efficacy and safety of dapagliflozin are consistent regardless of age.

1Diabetes Unit, Department of Endocrinologyand Metabolism, Hadassah Medical Center, He-brew University of Jerusalem, The Faculty ofMedicine, Jerusalem, Israel2TIMI Study Group, Division of CardiovascularMedicine, Brigham and Women’s Hospital andHarvard Medical School, Boston, MA3Li Ka Shing Knowledge Institute, St. Michael’sHospital, University of Toronto, Toronto, Canada4University of Texas Southwestern Medical Cen-ter, Dallas, TX5Institute of Ageing and Chronic Disease, Uni-versity of Liverpool, Liverpool, U.K.6AstraZeneca, Molndal, Sweden

Corresponding author: Avivit Cahn, avivit@hadassah.org.il

Received26 July 2019andaccepted17November2019

Clinical trial reg. no. NCT01730534, clinicaltrials.gov.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc19-1476/-/DC1.

This article is featured in a podcast available athttp://www.diabetesjournals.org/content/diabetes-core-update-podcasts.

© 2019 by the American Diabetes Association.Readersmayuse this article as longas thework isproperly cited, the use is educational and not forprofit, and the work is not altered. More infor-mation is available at http://www.diabetesjournals.org/content/license.

Avivit Cahn,1 Ofri Mosenzon,1

Stephen D. Wiviott,2 Aliza Rozenberg,1

Ilan Yanuv,1 Erica L. Goodrich,2

Sabina A. Murphy,2 Deepak L. Bhatt,2

Lawrence A. Leiter,3 Darren K. McGuire,4

John P.H. Wilding,5

Ingrid A.M. Gause-Nilsson,6

Martin Fredriksson,6 Peter A. Johansson,6

Anna Maria Langkilde,6 Marc S. Sabatine,2

and Itamar Raz1

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Type 2 diabetes mellitus (T2DM) is aprevalent disorder in the elderly, withapproximately one-quarter of peopleage .65 years with diabetes and anexpected increase in rates of diabetesin the upcoming years (1). Diabetes carein the elderly is challenging due to highrates of concomitant comorbidities, func-tional disability, frailty, cognitive impair-ment, andpolypharmacy. The complexityof treatment, side effects, and drug inter-actionsare important considerationswhenchoosing the appropriate glucose-loweringpharmacotherapy for older patients withdiabetes (1,2). However, data regardingthe efficacy and safety of glucose-loweringagents are often lacking, particularly inthe very elderly, age $75 years. TheU.S. Food and Drug Administration aswell as the EuropeanMedicines Agencyrecommended collecting comprehen-sive data especially in very elderlypatients with diabetes to enable ap-propriate assessment of their drugresponses (2,3).Sodium–glucose cotransporter 2 (SGLT2)

inhibitors have been available for thetreatment of diabetes since 2012. Mul-tiple clinical benefits beyond glucoselowering have been established withthis drug class. These include reducedhospitalizations for heart failure, renalprotection, and improvements in weightand blood pressure (4–8). Furthermore,the drugs are taken orally and at any timeof the day and have no known significantdrug interactions (8). Considering theirmultiple favorable effects, minimal in-cremental risk for hypoglycemia, andsimplicity of administration, they appearto be an attractive therapeutic option forolder adults addressing themany comor-bidities more prevalent in this popula-tion. Nevertheless, there has been somehesitance in clinical practice prescribingthese agents to the elderly,mostly due toinsufficient long-term safety data (1).Older patients are more prone to thedevelopment of fractures and acute kid-ney injury (AKI), and safety alerts re-garding these potential risks with someSGLT2 inhibitors have been issued (9).Moreover, due to the limited therapeuticexperience in patients age 75 years andolder, initiation of SGLT2 inhibitor ther-apy at this age has so far not been rec-ommended by some authorities (10).The Dapagliflozin Effect on Cardiovas-

cular Events (DECLARE)–TIMI 58 studyis a cardiovascular (CV) outcome study

that ascertained the CV and renal effectsof dapagliflozin on a large patient pop-ulation both with and without establishedcardiovascular disease, including a largecohort of elderly and very elderly pa-tients (4). In the present analysis, westudied the efficacy and safety of dapa-gliflozin stratified by age.

RESEARCH DESIGN AND METHODS

Study OverviewIn the DECLARE–TIMI 58 trial, a total of17,160 patients, including 7,907 age$65years and1,096age$75years,with T2DMand established atherosclerotic cardiovas-cular disease or risk factors, 41% and 59%,respectively, were randomly assigned toreceive dapagliflozin or placebo in addi-tion tostandardof careand followed foramedian period of 4.2 years. The studyenrolled patients at least 40 years old,with HbA1c 6.5%212.0% and creatinineclearance $60 mL/min. Patients who re-mained eligible after a 4–8-week placeborun-in period were randomized in a 1:1double-blind fashiontodapagliflozin10mgdaily ormatchedplacebo.All patientsweretobe treatedaccording to regional stand-ards of care for CV risk factors: bloodpressure, lipids, antithrombotic treat-ment, and HbA1c. The design, baselinecharacteristics, and principal results ofthis study have been published (4,11,12).

Assessment of OutcomesThe dual primary composite efficacy endpoints were CV death or hospitalizationfor heart failure (CVD/HHF) and majoradverse cardiovascular events (MACE;the composite of CV death, MI, or ische-mic stroke). A secondary prespecifiedcardiorenal composite outcome was asustained decrease of 40% or more inestimated glomerularfiltration rate (eGFR)to,60 mL/min/1.73 m2, new end-stagerenal disease (ESRD), or death from renalor CV causes. A renal-specific compositeoutcome included a 40% decrease in eGFRto,60 mL/min/1.73 m2, ESRD, or deathfrom renal cause.

Safety end points were assessed in allpatients who received at least one dose ofstudy drug (the safety population). Foramputations, fractures, and malignancies,events ocurring from first dose until theend of trial were included in the analyses.The remaining safety outcomes were as-sessed on treatment, which included allevents that occurred after the first dose ofthe study drug to the earlier of 30 (for

serious adverse events [SAEs]) or 7 (fornonserious AEs) days after the last dose ofthe study drug or the closing visit. Majorhypoglycemiawasdefinedas symptomaticevents requiring external assistance due tothe severe impairment of consciousnesswith prompt recovery after glucose orglucagon administration. The urinarytract and genital infections collected wereonly those that were either serious or ledto the discontinuation of the study drug.

Statistical AnalysisPrespecified age-groups were,65,$65and ,75, and $75 years. The data pre-sented in the main article are for threeage-groups (,65,$65 to,75, and$75years) to enable the description of datafromallagesubgroups, including65to,75years, which comprised 39.7% of thestudy population. Efficacy and safetydata limited to the prespecified age-groups are included in the SupplementaryMaterial.

Baseline characteristics are reportedas frequencies and percentages for cat-egorical variables and as median and in-terquartile range (IQR) for continuousvariables. Incidence rates and log-rank testfor trendPvalues in efficacyand safety endpoints are reported for the three age-groups.

Analyseswere performed on an intention-to-treat basis. Hazard ratios (HRs) and 95%CIs were determined from Cox regressionmodels with stratification factor (athero-sclerotic cardiovascular disease ormultipleCV risk factors and hematuria status) asstrata in models comparing treatment inage-groups.

Mixedmodels for repeatedmeasures inHbA1c, weight, systolic blood pressure, anddiastolic blood pressure were analyzed toproduce least squaresmean estimates and95% CIs in each treatment and age-group.Attainment of glycemic andweight targetswas compared between groups usinglogistic regression models. P values forthe covariate of interest were adjustedfor baseline HbA1c or weight accordingly.

Therewasno statistical adjustment formultiple comparisons. All analyses wereperformed using SAS software, version9.4 (SAS Institute Inc., Cary, NC) and Stataversion 14.2 (College Station, TX).

RESULTS

Baseline CharacteristicsThe study included9,253patients age,65years, 6,811 patients age $65 to ,75

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years, and 1,096 patients age$75 years.Their baseline characteristics are showninSupplementaryTable1.Chronic kidneydisease and history of heart failure weremore prevalent with increasing age aswas use of ACE inhibitors or angiotensinreceptor blockers (ARBs), diuretics, loopdiuretics, and antiplatelet therapy.

EfficacyOverall incidence rates of the dual pri-mary composite efficacy end points andof their individual components werehigher with increasing age. Incidencerates of CVD/HHF were 10.9, 14.8, and26.7 (P , 0.0001) and those of MACEwere 20.9, 24.7, and 37.4 cases per 1,000person-years in age-groups ,65, $65to,75, and$75 years, respectively (P,0.0001).Dapagliflozin reduced the composite

CVD/HHFconsistently,withHR0.88 (95%CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94(0.65, 1.36) in age-groups ,65, $65to ,75, and $75 years, respectively(interaction P value 0.5277). The HR for

dapagliflozin for MACE was 0.93 (95% CI0.81, 1.08), 0.97 (0.83, 1.13), and 0.84(0.61, 1.15) in age-groups ,65, $65to ,75, and $75 years, respectively(interaction P value 0.7352). Rates ofHHF were reduced with dapagliflozin,with HR 0.88 (95% CI 0.68, 1.15), 0.60(0.46, 0.79), and 0.81 (0.50, 1.30), re-spectively, inage-groups,65,$65 to,75,and$75years (interactionPvalue0.1402).The other components of the primary endpoints as well as all-cause mortality wereunchanged, with effects consistent acrossall age-groups (Fig. 1).

The cardiorenal secondary compositeoutcome (sustained decrease of 40% ormore in eGFR to ,60 mL/min/1.73 m2,new ESRD, or death from renal or CVcauses) was reduced with dapagliflozinversus placebo, with HR 0.72 (95% CI0.59, 0.88), 0.80 (0.65, 0.98), and 0.82(0.52,1.29) inage-groups,65,$65to,75,and$75 years, respectively (interaction Pvalue 0.7299). Similar results were ob-served for the renal-specific compositeoutcome (Fig. 1). Efficacy end points by

dichotomous age-groups showed similarresults with no age-based treatmentinteractions (Supplementary Fig. 1).

Metabolic OutcomesChanges in HbA1c, weight, and bloodpressure by age subgroups and treat-ment allocation are shown in Fig. 2.Baseline HbA1c in the elderly and veryelderly was lower compared with theyounger population (median levels 8.2[IQR 7.5, 9.3], 7.9 [7.3, 8.7], and 7.8 [7.2,8.5] in age-groups ,65, $65 to ,75,and $75 years, respectively; P-trend,0.0001). Nevertheless, significant andsimilar declines in HbA1c with dapagli-flozin versus placebo were observed forall age-groups (Fig. 2). At 1 year, leastsquares mean difference between thetreatmentgroupswas20.58 (95%CI20.63,20.53),20.46 (20.51,20.41), and20.51(20.63, 20.40) in age-groups ,65, $65to ,75, and $75 years, respectively (allP, 0.0001). At 1, 2, and 3 years, patientsallocated to dapagliflozin versus placebo,at all age subgroups, were statistically

Figure 1—Efficacy outcomes by age-groups. CVD, cardiovascular death.

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more likely to attain an HbA1c of ,7.0%(excluding age $75 years at year 3)or,8.0%ortoreducetheirHbA1cby$0.5%(Fig. 3). The effect was somewhat atten-uated at year 4, particularly in the veryelderly.Dapagliflozin yielded a greater reduc-

tion in weight versus placebo, and thiswas maintained in all age-groups duringthe entire study period (all P , 0.0001)(Fig. 2). Patients allocated to dapagliflo-zin versus placebo were more likely toattain a 5% weight loss at all age-groups,which was sustained throughout thestudy (Fig. 3). In the 4th year, a 5%weight reduction was observed in 37.0%vs. 23.2%, 40.5% vs. 24.6%, and 52.9% vs.31.2% with dapagliflozin versus placeboin age-groups,65,$65 to,75, and$75years, respectively (all P , 0.0001).

SafetySAEs in the overall safety populationwere more common in the elderly andvery elderly compared with the youngerpatients, with incidence rates of 107.3,131.2, and 191.1 cases per 1,000 person-years in age-groups ,65, $65 to ,75,and$75 years, respectively (P, 0.0001).The incidence of SAEs was lower withdapagliflozin versus placebo overall inthe trial, and this pattern was consistent

regardless of age, with HR 0.93 (95% CI0.86, 1.00), 0.88 (0.81, 0.95), and 1.02(0.85, 1.21) in age-groups ,65, $65to ,75, and $75 years, respectively,with no age-based treatment interac-tion (interaction P value 0.2667) (Fig.4). Moreover, no heterogeneity acrossage-groups was observed for any of theoutcomes assessed, although the num-ber of events in the very elderly wasoften quite small, yielding wide CIs inthis age category.

Major hypoglycemia events increasedwith increasing age in the overall safetypopulation, with incidence rates of 1.7,2.6, and 6.5 cases per 1,000 person-yearsin age-groups,65,$65 to,75, and$75years, respectively (P , 0.0001). Majorhypoglycemia was less frequent with da-pagliflozin versus placebo, with the effectmore predominantly observed in the age-group $65 vs. ,65 years (HR 0.53 [95%CI 0.34, 0.83] vs. 0.97 [0.58, 1.64], re-spectively; interaction P value 0.0896)(Supplementary Fig. 2). Overall fractureswere more common in the elderly andvery elderly, with incidence rates of 11.2,15.8, and 17.4 cases per 1,000 person-years in age-groups ,65, $65 to ,75,and$75 years, respectively (P, 0.0001),yet events were balanced between thedapagliflozin and placebo groups at all

age subgroups studied, with no hetero-geneity. Events of volume depletion inthe overall safety study population in-creased with increasing age, with inci-dence rates of 5.6, 7.8, and 14.9 cases per1,000 person-years in age-groups ,65,$65 to,75, and$75 years, respectively(P, 0.0001). Similarly, AKI was reportedoverall at higher rateswith increasing age,with incidence rates of 4.2, 5.4, and 9.3cases per 1,000 person-years in age-groups ,65, $65 to ,75, and $75years, respectively (P 5 0.0001). Vol-ume depletion events were balancedbetween the dapagliflozin and placebogroups, and AKI events were overallfewer with dapagliflozin versus placebo,withnoage-based treatment interaction.The amputation rate did not differ by age(P 5 0.3201) and was balanced betweendapagliflozin and placebo, with no age-based treatment interaction. Diabetic ke-toacidosiswas rare, butmore eventswereobserved with dapagliflozin versus pla-cebo, consistently across age-groups.Genital infections that led to the discon-tinuation of the study drug were morecommonwithdapagliflozinversusplacebo,and there were two SAE genital infectionsin each treatment arm, with no heteroge-neity. There was no statistically significantincrease in urinary tract infections (serious

Figure 2—Changes inmetabolic parameters over time. Change inHbA1c (A),weight (B), systolic bloodpressure (C), anddiastolic bloodpressure (D)withdapagliflozin vs. placebo according to age-group. Dapa, dapagliflozin.

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or leading to drug discontinuation) withdapagliflozin versus placebo in the over-all populationor in anyof theage-groups.Overall malignancies were balanced be-tween treatment arms across all age-groups (Fig. 4).Safety endpoints bydichotomous age-

groups revealed consistent results withno age-based treatment interaction foranyof theoutcomes(SupplementaryFig.2).

CONCLUSIONS

In this manuscript, we present analysesof data from the DECLARE–TIMI 58 studythat establish the beneficial CV and renaleffects of dapagliflozin in a robust num-ber of elderly and very elderly partici-pants. The overall pattern of efficacy andsafety of dapagliflozin was consistentregardless of age.Care of older patients with diabetes

represents an ongoing challenge. Ratesof HHF, CV disease, andMI are increasedin those age$65 years and aremarkedlyincreased in patientswith age$75 years.The robust reduction in HHF observedwith dapagliflozin is thus of great clinicalsignificance, particularly when viewedin light of the fact that many of thesepatients were already treated with stan-dard of care, including ACE inhibitors,

ARBs,b-blockers, anddiuretics. Althoughfewer events of MACE were observed inpatients treated with dapagliflozin, it didnot result in a significant reduction in theincidence of MACE. The study met itsprimary safety noninferiority end pointfor MACE across all studied age-groups.

SAEs, though generally more frequentin older versus younger individuals, werenot increased in the elderly or the veryelderlywith dapagliflozin versus placebo,and there was no age-based treatmentinteraction for any of the safety outcomesassessed. Several adverse outcomes areof particular concern in older patientswith diabetes. Events of volume deple-tion increase with increasing age, andthere is greater concern related to pos-sible adverse consequences of volumedepletion in older patients, including fallsand kidney injury. In that respect, theobserved reduction in HHF and renal ben-efitwithdapagliflozinwithnoexcess riskofvolume depletion and fewer events ofAKI is reassuring. Older adults are athigher risk of hypoglycemia from bothinsulin and sulfonylurea treatment as aresult of insulin deficiency, progressiverenal insufficiency, and higher rates ofcognitive deficits, which may cause diffi-culty in disease management, i.e., glucose

monitoring and adjustment of insulin dos-ing (1). Hypoglycemia should be particu-larly avoided in older patients due to theirgreater risk of other major adverse out-comes secondary to hypoglycemia, suchas falls or fractures (1). Patients ran-domized to dapagliflozin versus placeboin addition to standard of care attainedsuperior glycemic control with lower ratesof hypoglycemia, irrespective of age, high-lighting the benefit of the drug.

The greater morbidity of the elderlyand very elderly population in our study,as reflectedbyhigher ratesof baselineHFand chronic kidney disease, strengthensthe clinical impact of our results, whichdemonstrate consistent efficacy and safetyof dapagliflozin extending across all age-groups.

The paradigm of diabetes treatmenthas shifted from a glucose-focused ap-proach to the pursuit of a therapeuticregimen that will yield a reduction inmorbidity and mortality. This is particu-larly true in the elderly, whose life ex-pectancy is shorter and for whom eventrates are higher (13). Treatment goals forT2DM in the elderly should be individ-ualized; thus, in healthy patients withgood functional status, few comorbid-ities, and intact cognitive function, goals

Figure 3—Attainment of HbA1c and weight targets. Percentage of patients attaining HbA1c ,8 (A), HbA1c ,7 (B), reducing HbA1c by .0.5% (C), orreducing weight by .5% (D) with dapagliflozin vs. placebo by age-group. Black bars, dapagliflozin; white bars, placebo. *P , 0.0001; 1P , 0.05.

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may be similar to those of younger adults.However, inpatientswith an intermediateremaining life expectancy, targets shouldbe less stringent as part of individualizedcare and a target HbA1c ,8.0% may beacceptable (13). Dapagliflozin enabledmore patients to attain a clinically sig-nificant HbA1c reduction, whether strivingfor the standard or less stringent target.Weight loss is generally not a treat-

ment goal in the very elderly population;nevertheless, in our analysis, we observedsustained weight loss across all age-groups. This did not appear to lead to anyuntoward effects in the elderly duringthe time frame of the study, althoughnotably, median BMI was 31.1 and30.2 kg/m2 at baseline in the elderly andvery elderly patients in the study, re-spectively. SGLT2 inhibitors have beenshown to reduce adipose tissue masswhile maintaining lean body mass (14),

changes which are probably beneficial atall ages.

Few studies have been published todate on the use of SGLT2 inhibitors in theelderly.A randomized, double-blind, age-stratified trial of dapagliflozin versus pla-cebo demonstrated a beneficial effect ofdapagliflozinonglucose,weight, andbloodpressure across all age-groups studied,with no outstanding safety issues in theelderly or very elderly, although notmany very elderly patientswere included(15). Postmarketing reports from Japanreported no age-related safety issueswith tofogliflozin, ipragliflozin, and can-agliflozin, yet these studies are limited bythe lack of comparator and dependenceupon physician reporting of AEs (16–18).

Theefficacyandsafetyofotherglucose-lowering agents in the elderly havebeen studied. Dipeptidyl peptidase 4 (DPP-4) inhibitors showed no CV benefit in any

age-group studied, and safety outcomesof DPP-4 inhibitors were shown to besimilar in older versus younger patients(19,20). GLP-1 receptor agonists havealso shown efficacy and safety in theelderly that are comparable to that ofyounger patients, and post hoc analysisof the Liraglutide Effect and Action inDiabetes: Evaluation of CardiovascularOutcome Results (LEADER) trial pro-posed greater benefit in the elderly (21).Our study is the first to substantiate theefficacy and safety of an SGLT2 inhibitorin the elderly and very elderly and maypave the way for relaxing the warningplaced on this drug in the geriatric pop-ulation, although individualization oftherapy is pivotal, particularly in thisvulnerable population.

Some limitations of our study shouldbe noted. Creatinine clearance,60 mL/min was an exclusion criterion in the

Figure 4—Safety outcomes by age-groups. DKA, diabetic ketoacidosis.

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study, and this may have led to exclusionof the frailer elderly patients, which aremore prone to volume depletion, AKI,fractures, and other adverse outcomes.Moreover, there were no assessments ofcognitive function, functional capacity,or frailty at baseline or at any time duringthe study; however, as a randomizedtrial, one would expect that these un-measured features would be balancedbetween groups. Additionally, the veryelderly subgroup consisted of a smallsubset (6.4%) of the total population of17,160, and the number of events wassmall, yet it still accounted for 1,096participants. Finally, the analyses of met-abolic outcomes were post hoc and shouldbe considered exploratory.In conclusion, our study establishes

the CV and renal benefits of dapagliflozinin theelderly andveryelderly. Theoverallefficacy and safety of dapagliflozin wereconsistent regardless of age; thus, thisdrugmaybe considered a valuable glucose-lowering agent regardless of age.

Funding. The DECLARE–TIMI 58 trial was acollaboration between AstraZeneca and twoacademic research organizations (TIMI StudyGroup and Hadassah Medical Organization).Data analyses were performed by the academicTIMI Study Group, which has access to thecomplete study database, allowing independentanalyses of the results; any discrepancies wereresolved by discussion. The DECLARE–TIMI 58 pub-lication committee made the decision to submitfor publication.Dualityof Interest.ThesponsorsoftheDECLARE–TIMI 58 study were initially AstraZeneca andBristol-Myers Squibb, and AstraZeneca laterbecame the sole sponsor of the study. A.C.reports grants and personal fees from Astra-Zeneca andNovoNordiskandpersonal fees fromAbbott, Eli Lilly, Sanofi, Boehringer Ingelheim,Merck Sharp & Dohme, Medial Early-Sign, andGlucoMe. O.M. reports grants and personal feesfrom AstraZeneca, Bristol-Myers Squibb, andNovo Nordisk and personal fees from Eli Lilly,Sanofi, Merck Sharp & Dohme, Boehringer In-gelheim, Johnson & Johnson, and Novartis.S.D.W. reports grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, and Amgen, grants andpersonal fees from Arena, Daiichi Sankyo, Eisai,Eli Lilly, and Janssen, grants and consulting feesfrom Merck Sharp & Dohme (additionally hisspouse is employed by Merck Sharp & Dohme),and personal fees from Aegerion, Allergan, An-gelMed, Boehringer Ingelheim, Boston ClinicalResearch Institute, Icon Clinical, Lexicon, St. JudeMedical, Xoma, Servier, AstraZeneca, andBristol-Myers Squibb. E.L.G. and S.A.M. report researchgrant support through Brigham and Women’s Hos-pital from Abbott, Amgen, Aralez, AstraZeneca,Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen,The Medicines Company, MedImmune, Merck,

Novartis, Pfizer, Poxel, Quark Pharmaceut-icals, Roche, Takeda, and Zora Biosciences.D.L.B. is affiliated with the following: (advisoryboard) Cardax, Cereno Scientific, Elsevier Prac-tice Update Cardiology, Medscape Cardiology,PhaseBio, and Regado Biosciences; (board ofdirectors) Boston VA Research Institute, Societyof Cardiovascular Patient Care, and TobeSoft;(chair) American Heart Association Quality Over-sight Committee; (data monitoring committee)Baim Institute for Clinical Research (formerlyHarvard Clinical Research Institute, for thePORTICO trial, funded by St. Jude Medical,now Abbott), Cleveland Clinic (including forthe ExCEED trial, funded by Edwards), DukeClinical Research Institute, Mayo Clinic, MountSinai School of Medicine (for the ENVISAGE trial,fundedbyDaiichi Sankyo), andPopulationHealthResearch Institute; (honoraria) American Collegeof Cardiology (Senior Associate Editor, ClinicalTrials and News, ACC.org, Vice-Chair, ACC Ac-creditation Committee), Baim Institute for Clin-ical Research (formerly Harvard Clinical ResearchInstitute, RE-DUAL PCI clinical trial steering com-mittee funded by Boehringer Ingelheim, AEGIS-IIexecutive committee funded by CSL Behring),Belvoir Publications (Editor in Chief, HarvardHeart Letter), Duke Clinical Research Institute(clinical trial steering committees), HMP Global(Editor in Chief, Journal of Invasive Cardiology),Journal of the American College of Cardiology(Guest Editor, Associate Editor), Medtelligence/ReachMD (CME steering committees), Popula-tion Health Research Institute (for the COMPASSoperations committee, publications commit-tee, steering committee, and U.S. national co-leader, funded by Bayer), Slack Publications(Chief Medical Editor, Cardiology Today’s Inter-vention), Society of Cardiovascular Patient Care(Secretary/Treasurer), andWebMD (CME steer-ing committees); (other) Clinical Cardiology(Deputy Editor), NCDR-ACTION Registry Steer-ing Committee (Chair), and VA CART Researchand Publications Committee (Chair); (researchfunding) Abbott, Amarin, Amgen, AstraZeneca,Bayer, Boehringer Ingelheim, Bristol-MyersSquibb,Chiesi, CSLBehring,Eisai, Ethicon,FerringPharmaceuticals, Forest Laboratories, Idorsia,Ironwood, Ischemix, Lilly, Medtronic, PhaseBio,Pfizer, Regeneron, Roche, Sanofi, Synaptic, andThe Medicines Company; (royalties) Elsevier(Editor,Cardiovascular Intervention: A Compan-ion to Braunwald’s Heart Disease); (site coinves-tigator) Biotronik, Boston Scientific, St. JudeMedical (now Abbott), and Svelte; (trustee)American College of Cardiology; and (un-funded research) FlowCo, Fractyl, Merck Sharp& Dohme, Novo Nordisk, PLx Pharma, andTakeda. L.A.L. reports grants and personal feesfromAstraZeneca, Boehringer Ingelheim, Eli Lilly,Janssen, Novo Nordisk, and Sanofi; personal feesfrom Merck Sharp & Dohme and Servier; andgrants from GlaxoSmithKline. D.K.M. reportspersonal fees for clinical trial leadership fromGlaxoSmithKline, Janssen, Lexicon AstraZeneca,Sanofi, Boehringer Ingelheim, Merck Sharp &Dohme, Pfizer, NovoNordisk, Eisai, Esperion, andLilly and personal fees for consultancy fromAstraZeneca, Lilly, Boehringer Ingelheim, MerckSharp & Dohme, Novo Nordisk, Metavant, Ap-plied Therapeutics, Sanofi, and Afimmune.J.P.H.W., outside the submittedwork, has grants,

personal fees for lectures, and consultancy fees(paid to his institution) from AstraZeneca andNovo Nordisk; personal fees for lectures andconsultancy fees (paid to his institution) fromBoehringer Ingelheim, Janssen, Lilly,Mundipharma,Napp, Sanofi, and Takeda; and consultancyfees (paid to his institution) from WilmingtonHealthcare. I.A.M.G.-N., M.F., P.A.J. and A.M.L.are employees of AstraZeneca. M.S.S. reportsresearch grant support through Brigham andWomen’s Hospital from Amgen, AstraZeneca,Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline,Intarcia, Janssen Research and Development,The Medicines Company, MedImmune, MerckSharp & Dohme, Novartis, Poxel, Pfizer, Quark,and Takeda and consulting fees from Alnylam,Anthos Therapeutics, Amgen, AstraZeneca,Bristol-Myers Squibb, CVS Caremark, Dyrnamix,Esperion, IFM Therapeutics, Intarcia, Ionis, Jans-sen Research and Development, The MedicinesCompany, MedImmune, Merck Sharp & Dohme,and Novartis; M.S.S. is a member of the TIMIStudy Group, which has also received institu-tional research grant support through Brighamand Women’s Hospital from Abbott, Aralez,Roche, and Zora Biosciences. I.R. reports per-sonal fees from AstraZeneca, Bristol-MyersSquibb, Boehringer Ingelheim, Concenter Bio-Pharma and Silkim, Eli Lilly, Merck Sharp &Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi,SmartZyme Innovation, Panaxia, FuturRx, InsulineMedical, Medial EarlySign, CameraEyes, Exscopia,Dermal Biomics, Johnson & Johnson, Novartis,Teva, GlucoMe, and DarioHealth. No other po-tential conflicts of interest relevant to this ar-ticle were reported.AstraZeneca was involved in the study design,

data collection, data analysis, interpretation, andwriting of the manuscript.AuthorContributions.A.C., O.M., S.D.W., A.R.,I.Y., E.L.G., S.A.M., D.L.B., L.A.L., D.K.M., J.P.H.W.,I.A.M.G.-N., M.F., P.A.J., A.M.L., M.S.S., and I.R.contributed to data analysis. A.C., O.M., S.D.W.,A.R., I.Y., E.L.G., S.A.M., D.L.B., L.A.L., D.K.M.,J.P.H.W., I.A.M.G.-N., M.F., P.A.J., A.M.L., M.S.S.,and I.R. contributed to the writing of the man-uscript andapproved thefinal submittedversion.A.C., O.M., S.D.W., A.R., I.Y., D.L.B., L.A.L.,D.K.M., J.P.H.W., I.A.M.G.-N., M.F., A.M.L.,M.S.S., and I.R. contributed to data interpreta-tion. A.C., S.D.W., A.R., I.Y., E.L.G., S.A.M.,I.A.M.G.-N., A.M.L., M.S.S., and I.R. designed thefigures. A.C., S.D.W., I.A.M.G.-N., M.F., A.M.L.,M.S.S., and I.R. contributed to the study design.A.C., S.D.W., I.A.M.G.-N., M.F., A.M.L., M.S.S.,and I.R. contributed to data collection. A.C.,S.D.W., I.A.M.G.-N., A.M.L., M.S.S., and I.R. per-formed the literature search. A.C., S.D.W., E.L.G.,and S.A.M., and I.R. are the guarantors of thiswork and, as such, had full access to all the data inthe study and take responsibility for the integrityof the data and the accuracy of the data analysis.Prior Presentation. These data were presentedas a poster and at a symposium at the 55thAnnual Meeting of the European Association forthe Study of Diabetes, Barcelona, Spain, 16–20September 2019.

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