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Biology of Omega-3Fatty Acids inCardiovascularDisease:What Do We KnowJorge Plutzky, MDDirector, Preventive CardiologyCardiovascular DivisionBrigham and Women’s HospitalHarvard Medical SchoolBoston, Massachusetts

GlycerolAliphatic, anhydrous carboxylic acids Highest energy yield Pack more tightly than glucose/glycogen Minimal water required for storageGlycogen: highly hydrate polymerTriglyceride: anhydrous Lighter, more portablePlutzy J, Nature Medicine 2009Tri - Acyl - Glycerol

Energy BalanceFatty Acids:TriglyceridesGlucose9 kcal/g4 kcal/gStorageCombustionMuscleFatSurvivalPlutzky, Nat Med 2009, Circ Res 2011

Fatty lammationHypertensionAtherosclerosisPlutzky, Nat Med 2009, Circ Res 2011Glucose

Energy BalanceFatty Acids:TriglyceridesPrimordial9 kcal/gGlucose4 tty acid handling: complex, highly regulated, carefully controlledFatty acids as biologic active signaling molecules

GlycerolVLDLFatty AcidFreefatty acid(Triglyceride rich)TriglycerideTri - Acyl - CHO

Diversity Among Fatty Acids: Structural and Beyond910CO2Heicosanoic acidC20:0CO2Hstearic acidC18:0oleic acidC18:0( 9)palmitic acidC16:0palmitoleic acidC16:0( 9)CO2Hmyristic acidC14:0CO2Hlauric acidC12:0CO2Hcapric acidC10:0CO2HCO2HLipoproteins:Lipoproteins:109 Chain length Saturation OxidationCO2HBiological chemical properties

Longstanding Clues: Dietary Intake of Different Fatty Acids May Impact CV Risk- Prospect swap of saturated fat forpolyunsaturated fat (or vice a versa) at2 psychiatric hospitals, 1222 patients;primary and secondary CHD.- 6 years follow-up.

2017

Triglycerides and Fatty AcidsSaturated fatty acidsOmega-3 vs Omega-6 Fatty AcidsNo double bondsOmega-n: the number carbon withfirst double bond from methyl endMonounsaturated fatty acidsPolyunsaturated fatty acids1 double bond 1 double bondhttps://www.eufic.org European Food Information Council

OMEGA-3 FATTY ACIDSDiet OnlyPlant O-3 FAAlpha-Linolenic Acid:ALAMozaffarian D, Lu J, JACC. 2011;58:2047-67.Marine O-3 FAEicosapentaenoicAcid: EPADocosapentaenoicAcid: DPADocosahexaenoicAcid: DHA

FDA-Approved Prescription Omega-3 FAsBrand NameGeneric available?EPA/DHA RatioEPA onlyEE3EPA DHAFFA4Lovaza, OmtrygVascepaEpanova55/45100/073/27YesNoNo2 BID w/ meals2 or 4 QD, mealindependentPopulationREDUCE-IT: CVD risk (30%)or CVD (70%):STRENGTH: CVD risk (50%)or CVD (50%):OutcomePositiveNegativeRegimen, capsulesClinical Trial1LovazaEPA DHAEE1,22 BID w/ meals or4 QD w/ meals2prescribing information, generics available. 2 Omtryg prescribing information 3Vascepa prescribing information.prescribing information. EE: Ethyl Ester; FFA: Free Fatty Acid4Epanova

Omega 3-Fatty Acids: Multiple Pleiotropic Mechanisms Underlying Clinical Effects?Decreased TG-Rich Lipoproteins:(Increased HDL)Anti-ArrhythmiaOmega 3-Fatty AcidsOther DirectAnti-Atherosclerotic EffectsPhysio-Chemical edProstaglandin Synthesis

Omega 3-Fatty Acids: Multiple Pleiotropic Mechanisms Underlying Clinical Effects?Decreased TG-Rich Lipoproteins:(Increased HDL)Anti-ArrhythmiaAnti-InflammatoryOmega 3-Fatty AcidsOther DirectAnti-Atherosclerotic EffectsMembrane BiologyPhysio-Chemical PropertiesEPAAnti-ThromboticAlteredProstaglandin Synthesis

EPA Incorporation Favorably Alters Membrane Properties Membrane stabilizingPhysiologic holesterol distributionDecreased lipid oxidationDecreased cholesterol crystal formationModulation of signal pathways- Inflammation- Vasoreactivity Increased membrane fluidityIncreased concentratio0n in brain, eyeAltered lipid domainsDecreased anti-oxidant propertiesDecreased cholesterol crystal formationMason, et al. ATVB. 40: 1135-1147

Anti-ArrhythmiaOmega 3-Fatty AcidsAtrial FibrillationVentricular Fib/TachycardiaEPAPhysio-Chemical PropertiesMembrane Biology and Stabilization

Anti-ArrhythmiaOmega 3-Fatty AcidsAtrial FibrillationVentricular Fib/TachycardiaEPAPhysio-Chemical PropertiesMembrane Biology and StabilizationAnti-ThromboticPlateletsPlatelet ReactivityCoagulant balance

Inflammation Resolution:Increased Resolvin Mediators:Anti-InflammatoryOmega 3-Fatty AcidsEPAAlteredProstaglandin Synthesis

Inflammation Resolution:Increased Resolvin Mediators:Anti-InflammatoryOmega 3-Fatty ndin Synthesis

PPARα Exerts Antiatherogenic Effects via Multiple Vascular TargetsPPARα Activation Limits AtherogenesisVia Multiple Vascular and Inflammatory Targets VSMC Monocytes/MP LymphocytesPlutzky et al JACC 2005, Circ 2007 Adhesion moleculesEndothelin 1CytokinesInflammationABCA1Tissue Factor

ogenous PPAR LigandPPAR gene regulation differs in response to distinct ligandsPNAS 2003JBC 2004ATVB 2006Circ Res 2006 VLDL hydrolysis by LPL releases specific fatty acids. PPARα activation by LPL/VLDL differs from fibrates. Mechanism for TG genetic athero-protection:LPL gain of function, ApoC3 loss of function. Mechanism for EPA vascular inflammatory effects?

ApoC3: Endogenous LPL InhibitorConsistent with:- Increased LPL action- Increased ENDOGENOUS PPARα ligand generation

Do CV Benefits of EPA Alone Derive from the Absence of DHA?DHA vs EPA: Differing Nuclear Receptor ActivationDHA is an RXR Ligand; Untoward Effects of RXR Activation?CytoplasmNucleusEPA?RXR Natural Ligands: DHA, Not EPARXRDHARXR: Partner for manynuclear receptors.Perlmann et al Science 2000

Decreased TG-Rich Lipoproteins:(Increased HDL)Omega 3-Fatty AcidsDirectAnti-Atherosclerotic EffectsEPA

Triglyceride-Rich Lipoproteins Increase Cholesterol Delivery to Macrophages and the Arterial WallMason, et al. ATVB. 40: 1135-1147, 2020

EPA: Potential Direct Effects On AtherosclerosisClinical Card 41, 2018, 13-19

Biology of Omega-3 Fatty Acids in Cardiovascular Disease:What We KnowDecreased TG-Rich Lipoproteins:(Increased HDL)Anti-ArrhythmiaInflammation Resolution:Increased Resolvin MediatorsOmega 3-Fatty AOther DirectAnti-Atherosclerotic EffectsAnti-ThromboticWhat We Need to Find OutPhysio-Chemical PropertiesAlteredProstaglandin SynthesisNew Era of Lipid Biology and CV Risk Reduction

ApoC-III and ApoA-V in Plasma Triglyceride MetabolismKhetarpal, Rader ATVB 2015;35:e3-e9

Fatty AcidTransportPPAR Res 2014:432647

Hypertriglyceridemiaand low HDLTGCentralAdiposity1VLDL-CFFA HDL-C, HDL-P, &Apo A-ICECETPVLDL VLDLSynthesisAtherogenic Dyslipidemia TG / VLDL-C SD LDL / LDL-P HDL-C & Apo A-I Free FAsHDLHepaticLipaseKidneyRapid Lossof Apo A-ISDHDLTGCEFatty liver & VLDL synthesis arekeyCETPto TG2TGLDLHepaticLipaseSDLDLLDL sizeApo B & LDL-PApo apolipoprotein; CETP CE transfer protein; FFA free fatty acid; HDL high-density lipoprotein; HDL-C HDL cholesterol; HDL-P HDLparticle; LDL low-density lipoprotein; LDL-P LDL particle; SD small dense; VLDL very-low-density lipoprotein; VLDL-C VLDL cholesterol.

Use of Omega-3 Fatty Acidsin Patients with DiabetesDeepak L. Bhatt, MD, MPHExecutive Director of Interventional Cardiovascular Programs,Brigham and Women’s Hospital Heart and Vascular CenterProfessor of Medicine, Harvard Medical School

DisclosuresDr. Deepak L. Bhatt discloses the following relationships - Advisory Board: Cardax, Cereno Scientific, Elsevier PracticeUpdate Cardiology, LevelEx, Medscape Cardiology, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: BostonVA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality OversightCommittee; Data Monitoring Committees: Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute,for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded byEdwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded byDaiichi Sankyo), Population Health Research Institute; Honoraria: American College of Cardiology (Senior Associate Editor,Clinical Trials and News, ACC.org; Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerlyHarvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-IIexecutive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke ClinicalResearch Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals),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), MJH Life Sciences, Population Health ResearchInstitute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader,funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of CardiovascularPatient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDRACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding:Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSLBehring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly,Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; Royalties:Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik,Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research:FlowCo, Merck, Novo Nordisk, Takeda.This presentation may include off-label and/or investigational uses of drugs. REDUCE-IT was sponsored byAmarin Pharma, Inc.

Low Dose Omega-3 Mixtures ShowNo Significant Cardiovascular BenefitNo. of Events (%)SourceTreatmentControlRate Ratios (CI)FavorsTreatmentFavorsControlCoronary heart diseaseNonfatal myocardial infarction1121 (2.9)1155 (3.0)0.97 (0.87–1.08)Coronary heart disease1301 (3.3)1394 (3.6)0.93 (0.83–1.03)Any3085 (7.9)3188 (8.2)0.96 (0.90–1.01)P .12StrokeIschemic574 (1.9)554 (1.8)1.03 (0.88–1.21)Hemorrhagic117 (0.4)109 (0.4)1.07 (0.76–1.51)Unclassified/other142 (0.4)135 (0.3)1.05 (0.77–1.43)Any870 (2.2)843 (2.2)1.03 (0.93–1.13)P .60RevascularizationCoronaryNoncoronaryAny3044 (9.3)3040 (9.3)1.00 (0.93–1.07)305 (2.7)330 (2.9)0.92 (0.75–1.13)3290 (10.0)3313 (10.2)0.99 (0.94–1.04)P .60Any major vascular event5930 (15.2)6071 (15.6)0.97 (0.93–1.01)P .100.51.02.0Rate RatioAdapted with permission* from Aung T, Halsey J, Kromhout D, et al. Associations of omega-3 fatty acid supplement use withcardiovascular disease risks: Meta-analysis of 10 trials involving 77917 individuals. JAMA Cardiol. 2018;3:225-234. .0/]

Contrasting Effects of EPA and DHAMason RP, Libby P, Bhatt DL. Arteriosclerosis, Thrombosis, and Vascular Biology 2020.

REDUCE-IT DesignKey Inclusion Criteria Statin-treated menand women 45 yrs Established CVD( 70% of patients) orDM 1 risk factor TG 150 mg/dL and 500 mg/dL* LDL-C 40 mg/dLLead-in Statinstabilization Medicationwashout thcontinuation ofstable statintherapy(N 8179)4 g/day(n 4089)Placebo(n 4090)and 100 mg/dL4 months,12 months,annuallyEnd-of-studyfollow-upvisit4 months,12 tion-1 Month1ScreeningTime fromrandomization to thefirst occurrence ofcomposite of CV death,nonfatal MI, nonfatalstroke, coronaryrevascularization,unstable anginarequiring hospitalizationDouble-Blind Treatment/Follow-up PeriodScreening PeriodYearMonthsVisitLab valuesPrimary Endpoint002End of StudyUp to 6.2 years†43124Every 12 months56789Final VisitBaseline*Due to the variability of triglycerides, a 10% allowance existed in the initial protocol, which permitted patients to be enrolled with qualifying triglycerides 135 mg/dL.Protocol amendment 1 (May 2013) changed the lower limit of acceptable triglycerides from 150 mg/dL to 200 mg/dL, with no variability allowance.† Mediantrial follow-up duration was 4.9 years (minimum 0.0, maximum 6.2 years).Adapted with permissionǂ from Bhatt DL, Steg PG, Brinton EA, et al; on behalf of the REDUCE-IT Investigators. Rationale and design of REDUCE-IT: Reduction ofCardiovascular Events with Icosapent Ethyl–Intervention Trial. Clin Cardiol. 2017;40:138-148. REDUCE-IT ClinicalTrials.gov number, s/by-nc/4.0/]

Primary and Key Secondary CompositeEndpointsPrimary Composite Endpoint:CV Death, MI, Stroke, Coronary Revasc, Unstable Angina30Key Secondary Composite Endpoint:CV Death, MI, Stroke28.3%Hazard Ratio, 0.7530Hazard Ratio, 0.74(95% CI, 0.65–0.83)RRR 24.8%PlaceboARR 4.8%NNT 21 (95% CI, 15–33)P 0.0000000120Icosapent Ethyl10023.0%012345Patients with an Event (%)Patients with an Event (%)(95% CI, 0.68–0.83)RRR 26.5%ARR 3.6%NNT 28 (95% CI, 20–47)P 0.0000006Placebo2020.0%16.2%10Icosapent Ethyl001Years since RandomizationBhatt DL, Steg PG, Miller M, et al. N Engl J Med. 2019; 380:11-22. Bhatt DL. AHA 2018, Chicago.234Years since Randomization5

Number of Primary Composite Endpoint EventsFirst and Subsequent Events – Full DataRR 0.69P 0.00000000041,7241,500176 4 EventsRR 0.46(95% CI, 0.36-0.60)4633rd EventsHR 0.70(95% CI, 0.59-0.83)1841,000500031% Reduction in Total Events(95% CI, 0.61-0.77)2,000No. ofFewerCases2nd EventsHR 0.68(95% CI, 0.60-0.77)9011st EventsHR 0.75(95% CI, 0.68-0.83)P 0.00000002-5398596-99-80299-164705-196Icosapent Ethyl[N 4089]Placebo[N 4090]Full Dataset Event No.1,1851st2nd3rd 4Bhatt DL, Steg PG, Miller M, et al. J Am Coll Cardiol. 2019;73:2791-2802. Bhatt DL. ACC 2019, New Orleans.Note: WLW method for the 1st events,2nd events, and 3rd events categories;Negative binomial model for 4th eventsand overall treatment comparison.

Number of Baseline Anti-DiabetesMedications: Diabetes SubgroupTypeof n atTakenat Baseline,n(%)Baseline,n (%)MetforminNo Anti-Diabetes MedicationsSulfonylureasAnti-Diabetes MedicationsMeglitinidesOne Anti-Diabetes MedicationThiazolidinedionesDPP-4InhibitorsTwo nti-DiabetesMedicationSGLT2 inhibitorsFour or more Anti-Diabetes MedicationsInsulinIcosapent Ethyl(N 2394)Placebo(N 2393)Overall(N 4787)1764(73.7)221 (10.5)806(33.7)105((14.5)4.4)34714( 0.6)69 (2.9)568(23.7)1779(74.3)208 8(10.4)792(33.1)112((12.0)4.7)2889( 0.4)67 (2.8)555(23.2)3543(74.0)429 500(10.4)1598(33.4)217((13.3)4.5)63523( 0.5)136 (2.8)1123(23.5)Note: Percentages were based on the number of patients randomized to each treatment group in the ITT population with diabetes at baseline (N).Abbreviations: GLP-1 Glucagon-Like Peptide 1; DPP-4 Dipeptidyl Peptidase 4 ; SGLT2 Sodium/Glucose cotransporter 2; ITT Intention-toTreat.Note: Percentages were based on the number of patients randomized to each treatment group in the ITT population with diabetes at baseline(N).Bhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointCumulative Events per Patient0.60.50.40.30.20.10.001234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).Placebo: First EventsIcosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointCumulative Events per Patient0.60.50.40.3HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.001234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).Placebo: First EventsIcosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointCumulative Events per Patient0.651.6%0.50.40.3HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.001234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).Placebo: First EventsIcosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointCumulative Events per Patient0.651.6%0.5RR, 0.77(95% CI, 0.66–0.88)38.9%0.40.3P 0.0003HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.001234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).Placebo: First EventsIcosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointKey Secondary Composite Endpoint0.651.6%0.5RR, 0.77(95% CI, 0.66–0.88)38.9%0.40.3P 0.0003HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.0Cumulative Events per PatientCumulative Events per Patient0.60.50.40.30.20.10.001234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).01234Years Since RandomizationPlacebo: First Events5Icosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointKey Secondary Composite Endpoint0.651.6%0.5RR, 0.77(95% CI, 0.66–0.88)38.9%0.40.3P 0.0003HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.0Cumulative Events per PatientCumulative Events per Patient0.60.50.40.31234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).(95% CI, 0.60–0.81)P 0.0000030.10.00HR, 0.700.201234Years Since RandomizationPlacebo: First Events5Icosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointKey Secondary Composite Endpoint0.651.6%0.5RR, 0.77(95% CI, 0.66–0.88)38.9%0.40.3P 0.0003HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.0Cumulative Events per PatientCumulative Events per Patient0.60.50.41234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).HR, 0.700.2(95% CI, 0.60–0.81)P 0.0000030.10.0030.1%0.301234Years Since RandomizationPlacebo: First Events5Icosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Time to First and Total Primary andKey Secondary Endpoint Events:Diabetes Subgroup: N 4787Primary Composite EndpointKey Secondary Composite Endpoint0.651.6%0.5RR, 0.77(95% CI, 0.66–0.88)38.9%0.40.3P 0.0003HR, 0.77(95% CI, 0.68–0.87)P 0.000050.20.10.0Cumulative Events per PatientCumulative Events per Patient0.60.50.40.31234Years Since RandomizationPlacebo: Total Events5Icosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).RR, 0.71(95% CI, 0.60–0.84)P 0.000050.221.2%HR, 0.70(95% CI, 0.60–0.81)P 0.0000030.10.0030.1%01234Years Since RandomizationPlacebo: First Events5Icosapent Ethyl: First EventsTotal events analyses are based on reduced dataset accounting for statistical handlingof multiple endpoints occurring in a single calendar day by counting as a single event.

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReduction433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23%Hazard Ratio(95% CI)EndpointPrimary Composite Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value 0.0001

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Cardiovascular Death123/2394 (5.1%)151/2393 (6.3%)0.79 (0.62–1.00)21%0.05Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Cardiovascular Death123/2394 (5.1%)151/2393 (6.3%)0.79 (0.62–1.00)21%0.0572/2394 (3.0%)74/2393 (3.1%)0.96 (0.69–1.33)4%0.81Hazard Ratio(95% CI)EndpointHospitalization for Unstable Angina0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Cardiovascular Death123/2394 (5.1%)151/2393 (6.3%)0.79 (0.62–1.00)21%0.05Hospitalization for Unstable Angina72/2394 (3.0%)74/2393 (3.1%)0.96 (0.69–1.33)4%0.81Fatal or Non-Fatal Stroke62/2394 (2.6%)92/2393 (3.8%)0.65 (0.47–0.90)35%0.009Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Cardiovascular Death123/2394 (5.1%)151/2393 (6.3%)0.79 (0.62–1.00)21%0.05Hospitalization for Unstable Angina72/2394 (3.0%)74/2393 (3.1%)0.96 (0.69–1.33)4%0.81Fatal or Non-Fatal Stroke62/2394 (2.6%)92/2393 (3.8%)0.65 (0.47–0.90)35%0.009335/2394 (14.0%)435/2393 (18.2%)0.73 (0.64–0.84)27% 0.0001Hazard Ratio(95% CI)EndpointTotal Mortality/Nonfatal Myocardial Infarction,or Nonfatal Stroke0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Prespecified Hierarchical Testing:Diabetes SubgroupIcosapent Ethyln/N (%)Placebon/N (%)Hazard Ratio (95% CI)RelativeRiskReductionPrimary Composite Endpoint433/2394 (18.1%)536/2393 (22.4%)0.77 (0.68–0.87)23% 0.0001Key Secondary Composite Endpoint286/2394 (11.9%)391/2393 (16.3%)0.70 (0.60–0.81)30% 0.0001Cardiovascular Death orNonfatal Myocardial Infarction243/2394 (10.2%)324/2393 (13.5%)0.72 (0.61–0.85)28% 0.0001Fatal or Nonfatal Myocardial Infarction147/2394 (6.1%)212/2393 (8.9%)0.67 (0.54–0.83)33%0.0002Urgent or Emergent Revascularization136/2394 (5.7%)173/2393 (7.2%)0.76 (0.61–0.95)24%0.02Cardiovascular Death123/2394 (5.1%)151/2393 (6.3%)0.79 (0.62–1.00)21%0.05Hospitalization for Unstable Angina72/2394 (3.0%)74/2393 (3.1%)0.96 (0.69–1.33)4%0.81Fatal or Non-Fatal Stroke62/2394 (2.6%)92/2393 (3.8%)0.65 (0.47–0.90)35%0.009Total Mortality/Nonfatal Myocardial Infarction,or Nonfatal Stroke335/2394 (14.0%)435/2393 (18.2%)0.73 (0.64–0.84)27% 0.0001Total Mortality180/2394 (7.5%)202/2393 (8.4%)0.86 (0.71–1.06)14%0.15Hazard Ratio(95% CI)Endpoint0.40.6Icosapent Ethyl Better12Placebo BetterBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).P-value

Time to First and Total Primary EndpointEvents by CV Risk Category and DiabetesStatus at BaselineCumulative Events per Patient0.50Patients without Established CVDWith Diabetes and Other Risk Factors0.400.3025.4%22.1%0.20RR, 0.88(95% CI, 0.68–1.15)P 0.35HR, 0.88(95% CI, 0.70–1.10)P 0.240.100.00012345Years Since RandomizationPlacebo: Total EventsIcosapent Ethyl: Total EventsBhatt DL, Brinton EA, Miller M, et al. ADA 2020, Chicago (virtual).Placebo: First EventsIcosapent Ethyl: First Events

Time to First and Total Primary EndpointEvents by CV Risk Category and DiabetesStatus at Baseline0.50Patients without Established CVDWith Diabetes and Other Risk Factors0.9Patients with Established CVDWith Diabetes82.0%0.400.300.20RR, 0.8825.4%(95% CI, 0.68–1.15)22.1%P 0.35HR, 0.88(95% CI, 0.70–1.10)P 0.240.10Cumulative Events per PatientCumulative Events per Patient0.8RR, 0.70(95% CI, 0.59–0.84)P 0.000090.70.658.0%0.5HR, 0.720.4(95% CI, 0.62–0.84)P 0.000030.30.20.10.00012340.

Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, - funded by Bayer), Slack Publications (Chief Medical Editor, Ca