2019 Update to: Management ofHyperglycemia in Type 2 Diabetes,2018. A Consensus Report by theAmerican Diabetes Association(ADA) and the EuropeanAssociation for the Study ofDiabetes (EASD)Diabetes Care 2020;43:487–493 | https://doi.org/10.2337/dci19-0066

The American Diabetes Association and the European Association for the Study ofDiabetes have briefly updated their 2018 recommendations on management ofhyperglycemia, based on important research findings from large cardiovascularoutcomes trials published in 2019. Important changes include: 1) the decision totreat high-risk individuals with a glucagon-like peptide 1 (GLP-1) receptor agonist orsodium–glucose cotransporter 2 (SGLT2) inhibitor to reduce major adverse car-diovascular events (MACE), hospitalization for heart failure (hHF), cardiovasculardeath, or chronic kidney disease (CKD) progression should be consideredindependently of baseline HbA1c or individualized HbA1c target; 2) GLP-1 receptoragonists can also be considered in patientswith type 2diabeteswithout establishedcardiovascular disease (CVD)butwith thepresenceof specific indicators of high risk;and3) SGLT2 inhibitors are recommended inpatientswith type2diabetes andheartfailure, particularly those with heart failure with reduced ejection fraction, toreduce hHF, MACE, and CVD death, as well as in patients with type 2 diabetes withCKD (estimated glomerular filtration rate 30 to £60 mL min–1 [1.73 m]–2 or urinaryalbumin-to-creatinine ratio >30 mg/g, particularly >300 mg/g) to prevent theprogression of CKD, hHF, MACE, and cardiovascular death.

The American Diabetes Association (ADA) and the European Association for the Study ofDiabetes (EASD) requestedabrief updateof the2018 recommendationsonmanagementof hyperglycemia (1,2), based on the important research findings published in 2019, witha particular focus on new data from large cardiovascular outcomes trials (CVOTs). Theauthors began work on the brief update in July 2019 and submitted it for publication inDiabetes Care and Diabetologia in October 2019. Work was conducted over a series ofphone calls and by electronic interactions. This brief update provides a summary of theimplications of this new evidence on recommendations for the management ofhyperglycemia in type 2 diabetes (see text box), whichwill be addressedmore fully in theADA Standards of Medical Care in Diabetesd2020 (https://professional.diabetes.org/SOC). It should be considered in conjunction with the 2018 consensus report (1,2).The Researching Cardiovascular Events with a Weekly Incretin in Diabetes

(REWIND) trial of the glucagon-like peptide 1 (GLP-1) receptor agonist dulaglutide

1Department of Medicine, University of NorthCarolina School of Medicine, Chapel Hill, NC2Department of Medicine and Diabetes Unit,Massachusetts General Hospital, Boston, MA3Harvard Medical School, Boston, MA4Second Medical Department, Aristotle Univer-sity Thessaloniki, Thessaloniki, Greece5Steno Diabetes Center Copenhagen, Gentofte,Denmark6University of Copenhagen, Copenhagen, Den-mark7Fondazione Policlinico Universitario A. GemelliIRCCS, Rome, Italy8Universita Cattolica del Sacro Cuore, Rome,Italy9DiabetesandNutritional Sciences,King’sCollegeLondon, London, U.K.10Clinical and Experimental Endocrinology, UZGasthuisberg, KU Leuven, Leuven, Belgium11Department of Medicine, Duke UniversitySchool of Medicine, Durham, NC12Diabetes Research Centre, University of Leices-ter, Leicester General Hospital, Leicester, U.K.

Corresponding author: John B. Buse, jbuse@med.unc.edu

Received 15 October 2019 and accepted 15November 2019

M.J.D. and J.B.B. were co-chairs for the ConsensusStatement Writing Group. D.D’A. and D.J.W.were the writing group members for the ADA.C.M., G.M., P.R., and A.T. were the writing groupmembers for the EASD.

This article is being simultaneously published inDiabetologia (https://doi.org/10.1007/s00125-019-05039-w) and Diabetes Care (https://doi.org/10.2337/dci19-0066) by the European Association forthe Study of Diabetes and the American DiabetesAssociation.

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.

John B. Buse,1 Deborah J. Wexler,2,3

Apostolos Tsapas,4 Peter Rossing,5,6

GeltrudeMingrone,7,8,9 ChantalMathieu,10

David A. D’Alessio,11 and

Melanie J. Davies12

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included a greater proportion of individ-uals with type 2 diabetes with high car-diovascular riskbutwithoutpriorestablishedcardiovascular disease (CVD) (68.5%) andwith longer follow-up (median 5.4 years)than prior CVOTs (3). The primary majoradverse cardiovascular event (MACE) out-comeoccurred in2.7 per 100patient-yearswith a hazard ratio (HR) of 0.88 (95% CI0.79, 0.99) in favor of dulaglutide. Therewasnodifference in theMACEeffect in thesubpopulations with and without a historyof CVD, although the treatment effect ofdulaglutide did not reach statistical signif-icance when the groups were consideredseparately. Most other CVOTs with GLP-1receptor agonists have included aminorityof patients with risk factors only but with-out evidence of benefit onMACE outcomesin the lower-risk subgroups. Whether thedifferences in outcomes in trial subgroupswithout established CVD are related tostudy details or to the assigned therapy isuncertain. In REWIND, prior CVD was de-fined as a history of myocardial infarction,ischemic stroke, unstable anginawith elec-trocardiogram (ECG) changes, myocardialischemia on imaging or stress test, orcoronary, carotid, or peripheral revascu-larization. We previously recommendedthat established CVD was a compellingindication for treatment with a GLP-1receptor agonist or sodium–glucose co-transporter 2 (SGLT2) inhibitor. We nowalso suggest that to reduce risk ofMACE,GLP-1 receptor agonists can also be con-sidered in patients with type 2 diabeteswithout established CVD with indicatorsof high risk, specifically, patients aged

55 years or olderwith coronary, carotid,or lower extremity artery stenosis >50%,left ventricular hypertrophy, an estimatedglomerularfiltration rate (eGFR)<60mLmin–1 [1.73m]–2, or albuminuria. To date,the levelofevidence tosupport theuseofGLP-1 receptor agonists for primary pre-vention is strongest for dulaglutide butlacking forotherGLP-1 receptor agonists.

The Dapagliflozin Effect on Cardiovas-cular Events–Thrombolysis inMyocardialInfarction 58 (DECLARE–TIMI 58) trialcompared the SGLT2 inhibitor dapagli-flozin with placebo and also enrolled agreater proportion of participants withtype 2 diabeteswithout prior establishedCVDbutwithmultiple risk factors (59.4%)and with longer follow-up (median 4.2years) than other SGLT2 inhibitor trials(4). Dapagliflozin demonstrated cardio-vascular (CV) safety but not a benefit forthe MACE end point (HR 0.93; 95% CI0.84, 1.03). Dapagliflozin was associatedwith benefit for the coprimary efficacyend point of CV death or hospitalizationfor heart failure (hHF) with HR 0.83 (95%CI 0.73, 0.95) as well as renal end points.For MACE, the HR in the multiple riskfactor group without established athero-sclerotic vascular disease was 1.01, butthis group had strong evidence for ben-efit for the composite of CVdeath or hHF.Meta-analysis of the SGLT2 inhibitorCVOTs suggests a class effect to reducehHF and chronic kidney disease (CKD)progression across high and lower CVDrisk subgroups with no effect on MACEin the absence of established athero-sclerotic vascular disease (5).

Analysis of two SGLT2 inhibitor CVOTs,DECLARE–TIMI 58 (6) and the Canagli-flozin Cardiovascular Assessment Study(CANVAS) Program (7), suggests that thebenefits of SGLT2 inhibitors for hHF,MACE, and CV death are greatest forthose individuals with preexisting heartfailure with reduced ejection fraction(HFrEF) compared with those withoutHFrEF. It is important to note that hHFwas a secondary outcome, relatively lownumbers of patients had HF at baseline,and data on ejection fraction (EF) wereonly available for a proportion of pa-tients. In DECLARE–TIMI 58, individualswith HF but no reduction of EF as well asthosewithout HF did not seem to benefitfrom dapagliflozin treatment to lowerMACE and CV death outcomes. The ben-efit for hHF was strongest for those whoat baseline had an EF ,30%, strong forthose with an EF,45%, andmarginal forthose with an EF$45% or those withoutHF. The Dapagliflozin and Prevention ofAdverse Outcomes in Heart Failure (DAPA-HF) trial of dapagliflozin was the first heartfailure outcome trial of a diabetes med-ication (8). Recruitment included pa-tients with and without type 2 diabeteswith heart failure and an EF #40% anddemonstrated benefits for reduction ofthe primary composite end point of CVdeath, hHF, and urgent HF visits, as wellas for HF events and mortality (CV andtotal) considered separately. We nowsuggest that SGLT2 inhibitors are recom-mended in patients with type 2 diabetesand HF, particularly those with HFrEF, toreduce hHF, MACE, and CV death.

Changes to consensus recommendationsWe previously recommended that, in the setting of type 2 diabetes, established CVD was a compelling indication for treatment with a GLP-1receptor agonist or SGLT2 inhibitor. We now further suggest the following:

General considerationc In appropriate high-risk individuals with established type 2 diabetes, the decision to treat with a GLP-1 receptor agonist or SGLT2 inhibitor toreduce MACE, hHF, CV death, or CKD progression should be considered independently of baseline HbA1c or individualized HbA1c target.

c Providers should engage in shared decision making around initial combination therapy in new-onset cases of type 2 diabetes.GLP-1 receptor agonist recommendationsc For patients with type 2 diabetes and established atherosclerotic CV disease (such as those with prior myocardial infarction, ischemic stroke,unstable anginawith ECG changes,myocardial ischemia on imaging or stress test, or revascularization of coronary, carotid, or peripheral arteries)where MACE is the gravest threat, the level of evidence for MACE benefit is greatest for GLP-1 receptor agonists.

c To reduce riskofMACE,GLP-1 receptor agonists canalsobe considered inpatientswith type2diabeteswithoutestablishedCVDwith indicatorsofhigh risk, specifically, patientsaged55yearsorolderwith coronary, carotid,or lowerextremity artery stenosis.50%, left ventricularhypertrophy,eGFR ,60 mL min–1 [1.73 m]–2, or albuminuria.

SGLT2 inhibitor recommendationsc For patients with or without established atherosclerotic CVD, but with HFrEF (EF ,45%) or CKD (eGFR 30 to #60 mL min–1 [1.73 m]–2 orUACR .30 mg/g, particularly UACR .300 mg/g), the level of evidence for benefit is greatest for SGLT2 inhibitors.

c SGLT2 inhibitors are recommended in patients with type 2 diabetes and HF, particularly those with HFrEF, to reduce hHF, MACE, and CV death.c SGLT2 inhibitors are recommended to prevent the progression of CKD, hHF, MACE, and CV death in patients with type 2 diabetes with CKD.c Patients with foot ulcers or at high risk for amputation should only be treated with SGLT2 inhibitors after careful shared decisionmaking aroundrisks and benefits with comprehensive education on foot care and amputation prevention.

488 2019 Update to ADA-EASD Consensus Report, 2018 Diabetes Care Volume 43, February 2020

Figure

1—Glucose-loweringmed

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Figure 2—Glucose-lowering medication in type 2 diabetes: overall approach. ASCVD, atherosclerotic cardiovascular disease; RA receptor agonist; SU,sulfonylureas; TZD, thiazolidinediones. Adapted from Davies et al. (1). © American Diabetes Association and European Association for the Study ofDiabetes, 2018.

490 2019 Update to ADA-EASD Consensus Report, 2018 Diabetes Care Volume 43, February 2020

The REWIND trial of the GLP-1 recep-tor agonist dulaglutide had no lower limitto HbA1c for eligibility and demonstratedequivalent efficacy for reduction of MACEabove and below the median HbA1c of55 mmol/mol (7.2%) (3). None of theCVOTs of SGLT2 inhibitors with primaryMACE end points have recruited patientswith an HbA1c ,48 mmol/mol (,6.5%),and there is little data to inform clinicaldecision making for patients with anHbA1c ,53 mmol/mol (,7%) (9). How-ever, the outcome benefits observed inthe CVOTs do not appear restricted topatients with an elevated HbA1c. Thatsaid, the DAPA-HF trial recruited patientswithHFrEFwith andwithoutdiabetes (8).The benefit for reduction of mortalityrate andHF eventswith dapagliflozinwassignificant in both subgroups, suggestingthat the effects of dapagliflozin on theseend points is independent of HbA1c (8).Wenow recommend that in appropriatehigh-risk individuals with establishedtype 2 diabetes, the decision to treatwith a GLP-1 receptor agonist or SGLT2inhibitor to reduce MACE, hHF, cardio-vascular death, or CKD progressionshould be considered independently ofbaseline HbA1c or individualized HbA1c

target. That said, there are no specificanalyses addressing HbA1c ,48 mmol/mol (,6.5%). We continue to recom-mend that substituting a drug withknownCVD, CKD, andhHFbenefit for onewithout known benefit in high-risk pa-tients is reasonable when patients are atindividualized glycemic targets.The Canagliflozin and Renal Events in

Diabetes with Established NephropathyClinical Evaluation (CREDENCE) trial ofthe SGLT2 inhibitor canagliflozin was thefirst renal outcome trial of a diabetesmedication (10) with a primary compos-ite end point of end-stage kidney disease(dialysis, transplantation, or a sustainedeGFR of ,15 mL min–1 [1.73 m]–2), adoubling of the serum creatinine level, ordeath from renal or cardiovascular causes.The trial recruited patients with type 2diabetes and CKD on the maximally tol-erated dose of ACE inhibitors or angio-tensin receptor blockers with a urinaryalbumin-to-creatinine ratio (UACR) of300–5,000 mg/g and an eGFR of 30to ,90 mL min–1 [1.73 m]–2. This trialdemonstrated a clear benefit of canagli-flozin (100 mg) on multiple renal endpoints, including progression to end-stage kidney disease, and on cardiovascular

mortality, MACE, and hHF. Furthermore,the CREDENCE results demonstrated thatthe benefits conferred by canagliflozin interms of reducing MACE, hHF, cardio-vascular mortality, and renal end pointswere similar regardless of baseline statusfor cardiovascular or CKD grade 2–3 (11).We now recommend that SGLT2 inhib-itors should be used to prevent hHF,MACE, and CV death and the progres-sion of CKD in patients with type 2diabeteswithCKD. The benefits are clear-cut for those with UACR.300 mg/g andeGFR 30–90 mL min–1 [1.73 m]–2 and lesswell established for lesser grades of CKDbased on secondary end point analyses ofthe CVOT.

A concern in the CANVAS Programwasthe increased risk of amputation withcanagliflozin compared with placebo (7).In CREDENCE (10), although the risk ofamputation was higher overall than inother SGLT2 inhibitor trials, no significantincrease in risk was observed with can-agliflozin 100 mg versus placebo (HR1.11; 95% CI 0.79, 1.56). This may bedue to the risk mitigation strategiesemployed: exclusion of patients with ahistory of a traumatic amputation within12months of screening, or an active footulcer, osteomyelitis, gangrene, or criticalischemia of the lower extremity within6 months of screening; and interruptionof therapy for emergence of any of theabove with careful consideration of theindividual risks and benefits prior torestarting canagliflozin after resolutionof the event. We now recommend thatpatients with foot ulcers or at high riskfor amputation should only be treatedwith SGLT2 inhibitors after carefulshared decision making around risksand benefits with comprehensive ed-ucation on foot care and amputationprevention.

Based on the studies published thusfar, we believe that for patients withtype 2 diabetes and established athero-sclerotic CVD (such as those with priormyocardial infarction, ischemic stroke,unstable anginawith ECGchanges,myo-cardial ischemia on imaging or stresstest, or revascularization of coronary,carotid, or peripheral arteries) whereMACE is thegravest threat, that the levelof evidence forMACE benefit is greatestfor GLP-1 receptor agonists.

The Peptide Innovation for Early Di-abetes Treatment 6 (PIONEER 6) cardio-vascular safety trial of oral semaglutide, a

GLP-1 receptor agonist, involved 3,183patients with type 2 diabetes followedfor only a median of 16 months, but itprovided adequate demonstration ofcardiovascular safety (HR 0.79; 95% CI0.57, 1.11) and a strong signal for re-duction of CV mortality rate (HR 0.49;95% CI 0.27, 0.92) (12). This formulationof semaglutide has been approved formarketing in theU.S. andadecision in theEuropean Union is expected soon.

For patients with or without estab-lished atherosclerotic CVD, but withHFrEF or CKD (eGFR 30 to £60 mL min–1

[1.73 m]–2 or UACR >30 mg/g, partic-ularly UACR >300 mg/g), the level ofevidence for benefit is greatest for SGLT2inhibitors. For patients with type 2 di-abetes at low cardiovascular risk andwithout CKD, there have been no studiesto examine the cardiovascular or renalbenefit of GLP-1 receptor agonists orSGLT2 inhibitors.

Somemeta-analyses (5,13,14) suggestthe presence of heterogeneity in esti-mates forMACE andCVdeathwithGLP-1receptor agonists, although this ismostlydue to the results of a single trial withlixisenatide. Likewise, there is some het-erogeneity in the estimate for CV deathwith SGLT2 inhibitors. Whether differ-ences in point estimates of benefits andharms are the result of differences in theeffects of the medications, the designand conduct of the trials, or chanceeffects is uncertain. Attention to pa-tient-specific factors and preferences,product labeling, meta-analyses, andthe primary research reports should driveindividualized clinical decisionmakingwithregard to prescribing particular medica-tions within a class. For many patients,treatment with a GLP-1 receptor agonistor SGLT2 inhibitor in some health care set-tings involves considerable direct cost tothem, and the impact of this on their overallwell-being needs to be factored into de-cision making.

The Cardiovascular Outcome Study ofLinagliptin Versus Glimepiride in Type 2Diabetes (CAROLINA) trial randomizedadults at high cardiovascular risk to re-ceive the dipeptidyl peptidase 4 (DPP-4)inhibitor linagliptin or to receive the sulfo-nylurea glimepiride to evaluate a primaryMACE end point. No between-group dif-ference in the primary end point wasdemonstrated (HR 0.98; 95% CI 0.84,1.14). At trial end, for linagliptin as com-pared with glimepiride, there was a 1.5-kg

care.diabetesjournals.org Buse and Associates 491

weight loss benefit, no difference in HbA1cor introductionof glucose-loweringmed-ications postbaseline, and substantialbenefits in terms of reductions in hy-poglycemia, though serious hypoglyce-mic events were rare with glimepiride(0.45/100 patient-years) (15). Pairedwith other DPP-4 inhibitor CVOTs, includ-ing Cardiovascular and Renal Microvas-cular Outcome Study with Linagliptin(CARMELINA) (16), which demonstratedthe CV safety of linagliptin, this is areassuring safety signal for glimepiride,an inexpensive and effective sulfonylurea.It is unclear whether these findings extendto other sulfonylureas.Whereas we previously stated that there

was limited evidence for initial combina-tion therapy, the Vildagliptin Efficacy inCombination with Metformin for EarlyTreatment of Type 2 Diabetes (VERIFY)trial provides additional information. Theinitial combination of the DPP-4 inhibitorvildagliptin andmetformin was shown toprovide for a lower rate of secondaryfailure of glycemic control to HbA1c $53mmol/mol ($7%) versus metformin aloneor the sequential addition of metforminand vildagliptin (17). We now suggestthat providers should engage in shareddecision making around initial combina-tion therapy in new-onset cases of type 2diabetes.There are several major questions re-

garding the optimal application of newdiabetes drugs. One obvious question aris-ing from recent trial results is whethercombined use of GLP-1 receptor agonistsand SGLT2 inhibitors provides additionalbenefit for the prevention of MACE, CVdeath, hHF, and CKD progression. Threetrials have demonstrated the HbA1c-low-ering and weight-reduction efficacy ofthe combination (18–20), but none ad-dresses the impact of the combination ofthe two on cardiorenal end points.A second question that arises from therecent secondary analyses of SGLT2inhibitor studies is whether there aresubsets of patients who benefit dispro-portionately, or very little, from treat-mentwith the newer diabetes drugs. Theemerging evidence that SGLT2 inhibitorsmay be particularly useful in preventingadverse outcomes in patients with di-abeteswithHFrEF raises the possibility ofmore targeted use of these agents. Fi-nally, the mechanism(s) of action bywhichGLP-1 receptor agonists and SGLT2inhibitors confer cardiorenal benefit in

diabetes are not understood. Researchin this area will be very useful in opti-mizing the now clear potential of drugsfor diabetes to mitigate the cardiovas-cular and renal complications of thedisease.

Modifications to the main figures ofthe prior publication are suggested asshown in Figs. 1 and 2.

Acknowledgments. The authors would like tothank William T. Cefalu (Director of the Divisionof Diabetes, Endocrinology, and Metabolic Dis-eases at the National Institute of Diabetes andDigestive and Kidney Diseases, National Insti-tutesofHealth) for his review. Theauthorswouldlike to acknowledge M. Saraco (Managing Di-rector, Scientific & Medical Affairs) from ADA,as well as M. Hata (Executive Assistant) andP. Niemann (Executive Assistant) from EASD fortheir assistance. The authors would also like toacknowledge M. Bonar (Creative Director) andC. Franklin (Design Assistant) from the LeicesterDiabetes Centre, Leicester, U.K., who providedconsiderable support in drafting and amendingthe figures. The authors also acknowledge thecareful review and helpful suggestions of themembers of the ADA Professional Practice Com-mittee and the EASD Committee on ClinicalAffairs.Funding. This activity was funded by the Amer-ican Diabetes Association and the EuropeanAssociation for the Study of Diabetes.Duality of Interest. J.B.B. has provided con-sultation to Adocia, AstraZeneca, Eli Lilly,MannKind, NovaTarg, Novo Nordisk, Senseonics,and vTv Therapeutics with fees paid to theUniversity of North Carolina. He has receivedgrant support from Novo Nordisk, Sanofi, andvTv Therapeutics. He is a consultant to CiriusTherapeutics Inc., CSL Behring, and Neurim-mune AG. He holds stock options in MellitusHealth, PhaseBio, Stability Health, and Pen-dulum Therapeutics. He is supported by agrant from the National Institutes of Health(UL1TR002489). D.J.W. reports serving on a DataMonitoring Committee for Novo Nordisk. A.T.reports nonfinancial support from EASD duringthe conduct of the study, grants and other fromBoehringer Ingelheim, grants and other fromNovo Nordisk, other from Novartis, grants andother from Sanofi, grants and other fromAstraZeneca, grants from GlaxoSmithKline, andgrants and other from the European Founda-tion for the Study of Diabetes (EFSD) outside thesubmitted work. P.R. reports grants, nonfinan-cial support, and other from Novo Nordisk,grants and other from AstraZeneca, other fromBayer, other from Boehringer Ingelheim, otherfromMerck Sharp & Dohme, and other from EliLillyduring theconductof the study.G.M. reportsgrants and personal fees from Novo Nordisk,personal fees from Johnson & Johnson, andpersonal fees fromFractyl Inc.during theconductof the study. C.M. reports grants and fees fromNovoNordisk, grants and fees fromSanofi, grantsand fees fromMerck Sharp &Dohme, grants andfees from Eli Lilly and Company, grants and feesfromNovartis, fees fromAstraZeneca, grants and

fees fromBoehringer Ingelheim, fees fromRocheDiagnostics, grants and fees fromMedtronic, andgrants and fees from ActoBio Therapeutics out-side the submittedwork, with all fees paid to heruniversity.D.A.D’A. reportspersonal fees fromEliLilly, Merck, Novo Nordisk, and Intarcia andgrants from Merck and Ligand during theconduct of the study, personal fees from Lilly,Merck, Novo Nordisk, and Intarcia, and grantsfrom Merck and Ligand outside the submittedwork. M.J.D. reports personal fees and grantsfrom Boehringer Ingelheim, Janssen, Novo Nor-disk, and Sanofi and personal fees from Astra-Zeneca, Eli Lilly, Gilead Sciences Ltd., Intarcia/Servier, Merck Sharp & Dohme, MitsubishiTanabe Pharma Corporation, and Takeda Phar-maceuticals International Inc. No other potentialconflicts of interest relevant to this article werereported.Author Contributions. All authors were re-sponsible for drafting the article and revising itcritically for important intellectual content. Allauthors approved the version as published.

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