4/27/19

1

Back to the Future: What You Should Know About Prevention

of CVD

CarolH.Wysham,MDEndocrinologist

RockwoodClinic/MulticareHealthSystemClinicalProfessorofMedicineUniversityofWashington

WADEConferenceApril27,2019

Disclosures to Participants •  NoticeofRequirementsforSuccessfulCompletion:Forsuccessfulcompletion,participantsarerequiredtobein

attendanceinthefullactivityandcompletetheprogramevaluationattheconclusionoftheeducationalevent.•  PresenterConflictsofInterest/FinancialRelationshipsDisclosuresConsultant/AdvisoryPanel:Abbott,AstraZeneca,BoehringerIngelheim,Janssen,NovoNordisk,SanofiSpeaker’sBureau:AstraZeneca,BoehringerIngelheim,Insulet,Janssen,NovoNordisk,Sanofi

•  DisclosureofRelevantFinancialRelationshipsandMechanismtoIdentifyandResolveConflictsofInterest:NursePlannerfoundnoissuewithconflictofinterestorbias.Speakeragreestotheconstraintsofshowinganylogosorpreferencetoanyproductorcompany.Speakerstatesslideswillbefreeofanybias.

•  Non-EndorsementofProducts:AccreditedstatusdoesnotimplyendorsementbyAADE,ANCC,ACPEorCDRof

anycommercialproductsdisplayedinconjunctionwiththiseducationalactivity.•  Off-labelUse:Participantswillbenotifiedbyspeakerstoanyproductusedforapurposeotherthanthatforwhich

itwasapprovedbytheFoodandDrugAdministration.

Objectives

• DescribemanagementofCVDanddiabetestherapiespriortoCVDTrials

•  ExplorethehistoryandprocessofCardioVascularOutcomeTrials(CVOT)

• CompareandcontrastpublishedCVOTtrials•  Identifyupcomingtrials•  ExploretheroleofCDEinCV/DMmanagement• DiscussimplicationsofCVOTandroleofchangesmadeto2019ADAStandardsofCareguidelines

4/27/19

2

Diabetes Increases the Risk if Cardiovascular Disease

• 2foldincreaseinCoronaryHeartDisease1• 5foldincreaseinfirstMI2

• Poorerprognosis–increasedriskforCHF,CVA,death2,3• 2foldincreaseinsecondMI2• 2foldincreaseinischemicstroke1,4• 2–4foldincreaseinCVdeath5,6• 2to5foldincreaseinriskofheartfailure7-9

SawarNetal.Lancet2010;375:2215,2.HaffnerSMetal.NEnglJMed.1998:399:229.3.Malmbergketal.Circulation2000;102:1014.4.GoldsteinLBetal.Stroke.2011;42:517;5.TancrediMetalNEnglJMed2015;373:1720.6.GreggEWetal.DiabetesCare.2012;35:1252,7NicholsGAetal.DiabetesCare.2004:27:1879.8.BellDSHDiabetesCare2003;26:2433.9.NicholsGAetal.DiabetesCare2001;24:1614.

The Burden of Stroke in Patients with Diabetes

• Theage-adjustedprevalenceofstrokeinpatientswithdiabetesis9%1

• Fatalandnon-fatalischemicstrokeis2to6foldmorelikelyinpatientswithdiabetes1,2

• Inthose>65yearsoldwithdiabetes,16%ofCVmortalityisduetostroke3,4

• Strokeisalife-changingeventforpatients,theirfamiliesandcaregivers1,5

• Nonfatalstrokeisviewedasworsethandeathby45%ofthoseatrisk

1.GoldsteinLBetal.Stroke;42:517.2.SarkarNetalLancet2010;375:2215;BenjaminEJetal.Circulation2017;135:e145.4.http://heart.org/HEARTORG/Conditions/More/Diabetes/WhyDiabetesMatters.5.SmsaGPetal.AmHeartJ.1998;136:703.

The Burden of Heart Failure in Patients with Diabetes

• Thereissignificantoverlapbetweenheartfailureanddiabetescomorbidities1

• 35to45%ofpatientswithCHF(bothHF-refandHF-pef)havediabetes1

• 25%ofpatientswithdiabetesovertheageof65haveCHF2• Inadultswithdiabetesandheartfailure,mortalityoutcomesareworse,withmediansurvivalof4years2

1.PackerM.DiabetesCare2018;41:11.2.KannelWB,McGeeDL.JAMA1979;241:2035

4/27/19

3

ShahAD,LangenbergC,RapsomanikiE,etal.LancetDiabetesEndocrinol.2015;3(2):105-13.

N=1,921,260 in England; ≥30 years and free of CVD at entry

Within 5 years of availability of

insulin, death from

atherosclerosis increased 3 fold in patients with

diabetes

“Ibelievethechiefcauseofprematuredevelopmentofatherosclerosisindiabetes,saveforadvancedage,isanexcessoffat,anexcessoffatinthebody,anexcessoffatinthedietandanexcessoffatintheblood.Withanexcessoffat,diabetesbegins,andwithanexcessoffatdiabeticsdie.”

Ø EliottPJoslin,MD1927

First ADA Standards of Medical Care

DiabetesCare1989,365-368

4pages10references

Now126pages100’sofreferences

4/27/19

4

RF Atherosclerosis

• Obesity• Hypertension• Dyslipidemia•  Smoking•  FHprematurecoronarydisease• Chronickidneydisease

Diabetes-Specific Risk Enhancers That Are Independent of Other Risk Factors in Diabetes Mellitus

RiskEnhancers•  Longduration(≥10yearsfortype2diabetesmellitus(S.4.3-20)or≥20yearsfortype1diabetesmellitus)

•  Albuminuria≥30mcgofalbumin/mgcreatinine•  eGFR<60mL/min/1.73m2•  Retinopathy•  Neuropathy•  ABI<0.9

Tonellietal(2012)Lancet

4/27/19

5

http://tools.acc.org/ASCVD-Risk-Estimator-Plus/#!/calculate/estimate/

AHA/ACC Management of Hyperlipidemia in Diabetes Endorsed by the ADA

https://www.ahajournals.org/doi/10.1161/CIR.0000000000000625

3.   Inveryhigh-riskASCVD,useaLDL-Cthresholdof70mg/dL(1.8mmol/L)toconsideradditionofnonstatinstostatintherapy.

•Veryhigh-riskincludesahistoryofmultiplemajorASCVDeventsor1majorASCVDeventandmultiplehigh-riskconditions.

•Inveryhigh-riskASCVDpatients,itisreasonabletoaddezetimibetomaximallytoleratedstatintherapywhentheLDL-Clevelremains≥70mg/dL(≥1.8mmol/L).

•InpatientsatveryhighriskwhoseLDL-Clevelremains≥70mg/dL(≥1.8mmol/L)onmaximallytoleratedstatinandezetimibetherapy,addingaPCSK9inhibitorisreasonable,althoughthelong-termsafety(>3years)isuncertainandcost-effectivenessislowatmid-2018listprices.

Top 10 Take Home Messages

4/27/19

6

3.   Inveryhigh-riskASCVD,useaLDL-Cthresholdof70mg/dL(1.8mmol/L)toconsideradditionofnonstatinstostatintherapy.

•Veryhigh-riskincludesahistoryofmultiplemajorASCVDeventsor1majorASCVDeventandmultiplehigh-riskconditions.

•Inveryhigh-riskASCVDpatients,itisreasonabletoaddezetimibetomaximallytoleratedstatintherapywhentheLDL-Clevelremains≥70mg/dL(≥1.8mmol/L).

•InpatientsatveryhighriskwhoseLDL-Clevelremains≥70mg/dL(≥1.8mmol/L)onmaximallytoleratedstatinandezetimibetherapy,addingaPCSK9inhibitorisreasonable,althoughthelong-termsafety(>3years)isuncertainandcost-effectivenessislowatmid-2018listprices.

Top 10 Take Home Messages

List of Statins by Intensity of LDL Lowering

When Statins Are Not Enough: The Role of Ezetimibe

1. Cannon CP, et al. N Engl J Med. 2015;372:2387-2397; 2. Garber A, et al. Endocr Pract. 2016;22:84-113; 3. ADA. Diabetes Care. 2016;39(suppl 1):S1-S112; 4. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/

Scripts/cder/DrugsatFDA.

Whatdoesitdo?1

• Cholesterolabsorptioninhibitor• GreaterLDL-Creductionthanwithmoderate-intensitystatinalone

Newrecommendations2,3

Considerezetimibewithmoderate-intensitystatinforpatients:• Whocannottoleratehigh-intensitystatintherapy

• WithrecentACSandLDL-C≥50mg/dLwhocannottoleratehigh-intensitystatintherapy

Newrecommendations:evidence

• IMPROVE-IT:ezetimibevsPBOaddedtomoderate-intensitystatin1

• Participants:aged≥50years;ACSinprevious10days;LDL-C≥50mg/dL1

• SignificantreductionsvsPBO1,2•  LDL-C:to53vs70mg/dL• MACE:6%infullstudypopulation;14%inpatientswithdiabetes

Safetyconsiderations4

• Contraindications:liverdisease,highALT;usewithstrongCYP3A4inhibitors,gemfibrozil,cyclosporine,danazol

• Myopathymorecommonathigherdoses

• Nodifferenceinmyopathy,prespecifiedsafetyendpointsvsPBOinIMPROVE-IT1

4/27/19

7

When Statins Are Not Enough: The Role of PCSK9 Inhibitors

1. US FDA. Drugs@FDA. http://www.accessdata.fda.gov/Scripts/cder/DrugsatFDA; 2. ADA. Diabetes Care. 2016;39(suppl 1):S1-S112; 3. Garber A, et al. Endocr Pract. 2016;22:84-113; 4. Zimmerman MP. Am Health Drug Benefits. 2015;8:436-442; 5. Gidding SS, et al.

Circulation. 2015;132:2167-2192; 6. Zhang XL, et al. BMC Med. 2015;13:123; 7. Banach M, et al. Lipids Health Dis. 2015;14:167.

Whatdotheydo?1-3

• AntibodyinhibitorsofproteinthatregulateLDLreceptorrecycling(PCSK9serineprotease)

• ReduceLDL-Cby≈50%whenusedwithmaximalstatintherapy

• Preliminarydatasuggest≈50%reductioninCVevents

Whenwouldyouusethem?1

• ASCVD:adjuncttomaximalstatintofurtherreduceLDL-C

• Familialhypercholesterolemia(FH)• WithmaximalstatininHeFH:alirocumab,evolocumab

• WithotherLDLtherapiesinHoFH:evolocumab

RecognizingHeFHorHoFH?4,5

• LCL-C>190mg/dLorrelativeswithprematureASCVD

• LDL-C>400mg/dLandbothparentswithHeFH

• Geneticscreeningusuallynotneeded• FHisassociatedwithahighriskofprematureCVDanddeath

Safetyconsiderations1,6,7

• SCinjectionevery2weeks(bothagents)oroncemonthly(evolocumab)

• Generallywelltolerated• Caution:hypersensitivityreactions• NeurocognitiveAEsrequirefurtherinvestigation

Treatment of Hypertension: ADA • Bloodpressureshouldbemeasuredateveryroutineclinicalvisit.IfBP≥140/90mmHg,itshouldbeconfirmedonaseparatedaytodiagnosehypertension1

• Allhypertensivepatientswithdiabetesshouldmonitortheirbloodpressureathome1

•  Target<140/90inallpatients1•  <130/80maybeappropriateforhighCVDrisk(>15%),historyofCVA,retinopathy,albuminuria1

•  <130/80isendorsedbytheAHA/ACCandAACE2,3

American Diabetes Association Dia Care 2019;42:S103-S123, 2019. 2.GarberAJ,etal.EndocrPract.2018;24:91-120.3.AHA/ACCguidelines

American Diabetes Association Dia Care 2019;42:S103-S123

©2019 by American Diabetes Association

**Thiazide-like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. **Dihydropyridine calcium channel blocker (CCB).

4/27/19

8

Effects of Diabetes on ASCVD

LowWangCC,HessCN,HiattWR,GoldfineAB.Circulation.2016;133(24):2459-502.

Akt,proteinkinaseB;ERK,extracellularsignal-regulatedkinase;GlcNAc,N-Acetylglucosamine;IL,interleukin;JNK,c-JunN-terminalkinase;MAPK,mitogen-activatedproteinkinase;NF-κβ,nuclearfactor–kappabeta;NOS,nitricoxidesynthase;PI3K,phosphoinositide3-kinase;RNS,reactivenitrogenspecies;ROS,reactiveoxygenspecies.

Impact of Intensive Therapy in Diabetes in Major Clinical Trials

AdaptedfromBergenstalRM,etal.AmJMed2010;123:374e9-e18

Study A1c Microvascular CVD Mortality

DCCT/EDIC 9 → 9 & 7 ↓ ↓ ↔ ↓ ↔ ↔

UKPDS 9 → 7.9 & 7 ↓ ↓ ↔ ↓ ↔ ↓

ACCORD 8.3 → 7.5 & 6.4 ↓ ↔ ↑ ?

ADVANCE 7.5 → 7.0 & 6.4 ↓ ↔ ↔

VADT 9.4 → 8.5 & 6.9 ↓ ↔ ↔

Baseline StudyEndStdIntensive

LongTermFollow-upInitialTrial

↓ ↓

23

Legacy Effects: New T2DM UKPDS F/U NEJM 2008;359:1-13

MyocardialInfarctionHR0.85(0.74-0.97)

TotalMortalityHR0.87(0.79-0.96)

YearsSinceRandomization YearsSinceRandomization

4/27/19

9

Intensive Glycemic Control and Cardiac Outcomes DCCT/EDIC (1441 patients with T1DM)

•  ~42%reductioninriskofafirstCVeventwithintensivetherapy

•  Long-termbenefit

•  20%reductioninCVriskwitha10%reductioninA1C

NathanDM,ClearyPA,BacklundJY,etal..NEnglJMed2005;353:2643-53.

A1CLevels

Baseline EndofStudyTreatment EndofFollowUp

Conventional

Intensive

9.1±1.6%

9.1±1.6%

9.1±1.5%

7.4±1.1%

7.9±1.3%

7.8±1.3%

42% risk reduction

DCCT

Treatment

Mean 6.5 years

EDIC

Follow-up

Mean 17 years

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

0.12

0.10

0.08

0.06

0.04

0.05

0.00

Years since Entry

No. at Risk

Intensive

Treatment 705 683 629 113

Conventional

Treatment 714 688 618 92

Intensive

Treatment

Conventional

Treatment

Cum

ula

tive Incid

ence o

f A

ny P

redefined

CV

Outc

om

e

26

Concern for adverse CV events led the FDA to require demonstration of CV safety for new glucose-lowering drugs

•  1.Nissen.AnnInternMed2012;157:671–2.2.Nissenetal.JAMA2005;294:2581–6.3.Nissenetal.NEnglJMed2007;356:2457–71.4.ACCORDStudyGroup.NEnglJMed2008;358:2545–59.5.http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/%20guidances/ucm071627.pdf6.http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf7.http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm376683.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery

UGDP trial: tolbutamide discontinued due to increased CV mortality vs other treatment groups1

•  Sponsorwithdrewapplication1

•  WithdrawnintheEU1•  UserestrictedinUS1**In2013,FDApanelvotedtoreducesafetyrestrictionsonrosiglitazone7

1961

2005

2007

2008

20082012

Muraglitazar found to potentially increase CV risk during FDA assessment2

Rosiglitazone associated with increased risk for MI and CV-related death3

ACCORD trial: intensive glucose lowering was associated with increased all-cause mortality4 HR1.22(95%CI1.01‒1.46);p=0.04

New FDA requirements5 New EMA requirements6 New diabetes drugs should demonstrate CV safety with meta-analysis and a CV outcome trial (CVOT)

UGDP: Tolbutamide vs insulin vs placebo

UGDP,Diabetes,1970

4/27/19

10

William T. Cefalu et al. Dia Care 2018;41:14-31 ©2018 by American Diabetes Association

Completed and Ongoing CVOTs

• CVOT are designed and powered to assess non-inferiority versus placebo in addition to standard of care in a high risk CVD patient population (prior CVD ± high risk patients without proven CVD). • Major endpoint composite of Major Adverse Cardiovascular Events: - Usual is 3 point MACE – new nonfatal MI, new stroke, CV death based on careful adjudication to confirm accuracy of the events*

• Key understandings: - Powered for safety. - Studied populations provide data on SECONDARY PROTECTION. - Original studies not powered for subgroup analysis - Different design does not consistently enable direct comparison of results of one study to another.

Cardiovascular Outcome Trials (CVOT)

Usualcare–glucoselowering,BPlowering,lipidloweringetc.

30

Contemporary Cardiovascular Outcome Trial Design for Type 2 Diabetes

•  AdaptedfromGeigeretal.TherInnovationRegScience2014;1–15.

•  1.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

AimDetermineeffectofDrugXcomparedwithplacebo/comparatoronCVoutcomes,ontopofglucose-loweringandCVtherapiesadjustedaccordingtolocalguidelines,inpatientswithT2D

PlaceboHighCVriskpatients

Compositeprimaryendpoint

Statistics RRun-in

Events

DrugX

FDAmandatesthatCVsafetybedemonstratedinhighCVriskpopulation1Run-inhelpstoestablishpatientadherencetolong-termtreatmentandFUAllpatientsareonausualcarebackground(tocontroldiabetesandCVriskfactors);investigatorsencouragedtoadjusttherapyfollowinglocalguidelinesAsadjustmentofbackgroundtherapyisencouraged,CVOTsnotdesignedtoassessimpactofadifferenceinHbA1cbetweenstudyarmsFDArecommends3P-MACEasprimaryCVendpointorexpanded4P-MACE(e.g.,includinghospitalisationforunstableanginapectoris)1

4/27/19

11

Considerations for Interpretation of Contemporary CVOTs

Designfeatures

1.Hirshberg&Katz.DiabetesCare2013;36(suppl2):S253–8.

2.http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf.

• MostCVOTsemployhierarchicaltestingtotestforsuperiorityfollowingestablishmentofnon-inferiority

• CVOTsaretypicallyevent-driven;studydurationcanonlybeestimated1

Powerandduration

• Primaryandsecondaryoutcomesvaryacrosstrials(3P-MACEand4P-MACEarecommonprimaryoutcomes)2Outcomes

• Inclusioncharacteristicsvaryacrosstrials(e.g.,degreeofpre-existingCVriskorpriorCVD,durationofT2D)

• Thisnecessitatescautionincomparingresultsacrosstrials1Population

Backgroundtherapy

• Trialsperformedonausualcarebackground(e.g.,highantihypertensiveandstatinuse)soCVriskfactors(e.g.BP,LDL-C)aregenerallywellcontrolled

• Investigatorsshouldadjustbackgroundtherapyaccordingtolocalguidelines1

DemonstrationofCVsafetyisrequiredbyregulatorsforneweranti-hyperglycemicdrugsas‘classeffects’cannotbeassumedbasedondrug-specifictrials

Study SAVOR EXAMINE TECOS CAROLINA CARMELINA

DPP4-i saxagliptin alogliptin sitagliptin linagliptin linagliptin

Comparator placebo placebo placebo sulfonylurea placebo

N 16,500 5,400 14,000 6,000 8,300

Results 2013 2013 2015 2017 2017

Study LEADER ELIXA SUSTAIN6 EXSCEL REWIND

GLP1-RA liraglutide lixisenatide semaglutide exenatideLR dulaglutide

Comparator placebo placebo placebo placebo placebo

N 16,500 14,000 6,000 5,400 9901

Results 2016 2015 2016 2018 2019

Study EMPA-REG CANVAS/-R DECLARE VERTIS-CV

SGLT-2-i empaglifozin canagliflozin dapagliflozin ertugliflozin

Comparator placebo placebo placebo placebo

N 7034 10,142 17,160 8238

Results 2015 2017 2019 2020

Large CV Outcomes Trials in Diabetes (Non-Insulin)

+ + +

+ + +

NEUTRAL

NEUTRAL

NEUTRAL

NEUTRAL

NEUTRAL NEUTRAL

NEUTRAL

Summary of CVD Trials – GLP-1 RA

MACE MI CVA CVdeath HHF AllDeathLiraglutide 0.87 0.88 0.89 0.78 0.87 0.85Semaglutide 0.74 0.74 0.61 0.98 1.11 NGExenatideQW 0.91 0.97 0.85 0.88 0.94 0.86Albiglutide 0.78 0.75 0.86 0.93 NG 0.93

HighlevelresultsofREWINDshowedsuperiorityin3-pointMACEoverplacebo.

1.MarsoSP,etal.NEnglJMed.2016;375:311-3222.MarsoSP,etal.NEnglJMed.2016;375:1834-18443.HolmanRRetalNEnglJMed2017;377(13):1228–12394.HernandezAFetalLancet.2018392(10157):1519–1529..