01B.05 · Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran

Atherosclerosis V — lipid therapies, PCSK9 and inclisiran

Atherosclerosis series · 71 pages

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Atherosclerosis V — Lipid Therapies

1Atherosclerosis V — Lipid Therapies

LDL-C as Causal Driver

2Lipoprotein Characteristics 3Four Lines of Causal Evidence 4Time-Exposure Effect on CHD Risk 5PCSK9/HMGCR Genetic Evidence 6LDL-C Plus SBP Lowering — Mendelian Randomization 7Neonatal Lipid Levels 8Ideal LDL-C Level 9Anti-Cholesterol Misinformation

Pharmacological LDL-C Lowering

10Treatment Intensity Overview 11Guideline: High-Intensity Statin First

12Mechanism — HMG-CoA Reductase Inhibition

Clinical Evidence

134S Trial — Simvastatin Survival 14Early Statin Post-AMI — Swedish Registry 15Intensive vs Moderate — PROVE IT-TIMI 22 16CTT Meta-Analyses — Lower Is Better 17Cause-Specific Mortality — Collins et al.18Efficacy in Older Patients — CTT 2019 19PCSK9/HMGCR Genetic Evidence (Recap)

Safety and Adherence

20Consequences of Stopping Statins 21Benefit/Risk Ratio — EAS Consensus 22Nocebo Effect — ASCOT-LLA 23Discontinuation and Mortality

24Mechanism — ATP Citrate Lyase Inhibition 25CLEAR Outcomes Trial — Introduction 26CLEAR Outcomes — CV Event Reduction

Combination Therapy Strategy

27First-Line Combination in Very High Risk 28Guideline: Statin Then Add Ezetimibe

29Cholesterol Transport Overview 30Intestinal Cholesterol Absorption 31NPC1L1 Inactivating Mutations 32NPC1L1 Mutations — Lower LDL-C and CHD 33Counter-Regulation — Statin Plus Ezetimibe 34IMPROVE-IT — Ezetimibe Post-ACS

Treatment Evolution Summary

54LDL-C Reduction by Drug Combination 5525 Years — High to Lowest Is Best

01B.05Page 1Atherosclerosis V — Lipid Therapies

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 1

01B.05Page 2LDL-C as Causal DriverLipoprotein Characteristics

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 2

01B.05Page 3LDL-C as Causal DriverFour Lines of Causal Evidence

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01B.05Page 4LDL-C as Causal DriverTime-Exposure Effect on CHD Risk

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01B.05Page 5LDL-C as Causal DriverPCSK9/HMGCR Genetic Evidence

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01B.05Page 6LDL-C as Causal DriverLDL-C Plus SBP Lowering — Mendelian Randomization

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01B.05Page 7LDL-C as Causal DriverNeonatal Lipid Levels

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01B.05Page 8LDL-C as Causal DriverIdeal LDL-C Level

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01B.05Page 9LDL-C as Causal DriverAnti-Cholesterol Misinformation

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01B.05Page 10Pharmacological LDL-C LoweringTreatment Intensity Overview

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01B.05Page 11Pharmacological LDL-C LoweringGuideline: High-Intensity Statin First

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01B.05Page 12StatinsMechanism — HMG-CoA Reductase Inhibition

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01B.05Page 13StatinsClinical Evidence4S Trial — Simvastatin Survival

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01B.05Page 14StatinsClinical EvidenceEarly Statin Post-AMI — Swedish Registry

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01B.05Page 15StatinsClinical EvidenceIntensive vs Moderate — PROVE IT-TIMI 22

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01B.05Page 16StatinsClinical EvidenceCTT Meta-Analyses — Lower Is Better

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01B.05Page 17StatinsClinical EvidenceCause-Specific Mortality — Collins et al.

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01B.05Page 18StatinsClinical EvidenceEfficacy in Older Patients — CTT 2019

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01B.05Page 19StatinsClinical EvidencePCSK9/HMGCR Genetic Evidence (Recap)

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01B.05Page 20StatinsSafety and AdherenceConsequences of Stopping Statins

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01B.05Page 21StatinsSafety and AdherenceBenefit/Risk Ratio — EAS Consensus

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01B.05Page 22StatinsSafety and AdherenceNocebo Effect — ASCOT-LLA

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01B.05Page 23StatinsSafety and AdherenceDiscontinuation and Mortality

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01B.05Page 24Bempedoic AcidMechanism — ATP Citrate Lyase Inhibition

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01B.05Page 25Bempedoic AcidCLEAR Outcomes Trial — Introduction

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01B.05Page 26Bempedoic AcidCLEAR Outcomes — CV Event Reduction

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01B.05Page 27Combination Therapy StrategyFirst-Line Combination in Very High Risk

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01B.05Page 28Combination Therapy StrategyGuideline: Statin Then Add Ezetimibe

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 28

01B.05Page 29EzetimibeCholesterol Transport Overview

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01B.05Page 30EzetimibeIntestinal Cholesterol Absorption

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01B.05Page 31EzetimibeNPC1L1 Inactivating Mutations

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01B.05Page 32EzetimibeNPC1L1 Mutations — Lower LDL-C and CHD

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01B.05Page 33EzetimibeCounter-Regulation — Statin Plus Ezetimibe

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01B.05Page 34EzetimibeIMPROVE-IT — Ezetimibe Post-ACS

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01B.05Page 35PCSK9 InhibitorsGuideline: Add PCSK9 Inhibitor

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 35

01B.05Page 36PCSK9 InhibitorsPCSK9 Biology and GeneticsBench to Clinic Timeline

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01B.05Page 37PCSK9 InhibitorsPCSK9 Biology and GeneticsGain-of-Function Mutations

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01B.05Page 38PCSK9 InhibitorsPCSK9 Biology and GeneticsLoss-of-Function Mutations

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01B.05Page 39PCSK9 InhibitorsPCSK9 Biology and GeneticsKnockout Mice — Increased LDLR

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01B.05Page 40PCSK9 InhibitorsPCSK9 Biology and GeneticsVery Low Lifelong LDL-C — Case Reports

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 40

01B.05Page 41PCSK9 InhibitorsPCSK9 Biology and GeneticsLOF Mutations — 60% Lower MI Risk

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 41

01B.05Page 42PCSK9 InhibitorsMonoclonal AntibodiesEvolocumab Mechanism — LDLR Recycling

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01B.05Page 43PCSK9 InhibitorsMonoclonal AntibodiesFOURIER and ODYSSEY OUTCOMES

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01B.05Page 44PCSK9 InhibitorsMonoclonal AntibodiesFOURIER — Achieved LDL-C and Outcomes

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01B.05Page 45PCSK9 InhibitorsCoronary Imaging StudiesHUYGENS Trial Design

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01B.05Page 46PCSK9 InhibitorsCoronary Imaging StudiesHUYGENS — FCT and Lipid Arc Results

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 46

01B.05Page 47PCSK9 InhibitorsCoronary Imaging StudiesHUYGENS — OCT and IVUS Plaque Regression

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01B.05Page 48PCSK9 InhibitorsCoronary Imaging StudiesHUYGENS — Published Summary

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01B.05Page 49PCSK9 InhibitorsCoronary Imaging StudiesPACMAN-AMI — Alirocumab Plaque Imaging

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01B.05Page 50PCSK9 InhibitorsCoronary Imaging StudiesPlaque Regression vs On-Treatment LDL-C

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01B.05Page 51PCSK9 InhibitorsAntibody Design and LimitationsEvolution of Therapeutic mAbs

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01B.05Page 52PCSK9 InhibitorsAntibody Design and LimitationsBococizumab — SPIRE Trials (Negative)

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01B.05Page 53PCSK9 InhibitorsAntibody Design and LimitationsBococizumab — Immunogenicity Problem

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01B.05Page 54Treatment Evolution SummaryLDL-C Reduction by Drug Combination

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01B.05Page 55Treatment Evolution Summary25 Years — High to Lowest Is Best

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01B.05Page 56Inclisiran — siRNA TherapyLDL-C Lowering Approaches Overview

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01B.05Page 57Inclisiran — siRNA TherapyRNA Interference BiologyNon-Coding RNAs and siRNA

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01B.05Page 58Inclisiran — siRNA TherapyRNA Interference BiologyRNA Interference Mechanism

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01B.05Page 59Inclisiran — siRNA TherapyInclisiran Drug DesignsiRNA Structure and Chemical Modifications

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01B.05Page 60Inclisiran — siRNA TherapyInclisiran Drug DesignHepatocyte Uptake and RISC-Mediated Silencing

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01B.05Page 61Inclisiran — siRNA TherapyInclisiran Drug DesignDosing Regimen — Twice-Yearly SC Injection

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01B.05Page 62Inclisiran — siRNA TherapyClinical EvidenceORION-1 — ~50% LDL-C Reduction

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01B.05Page 63Inclisiran — siRNA TherapyClinical EvidenceORION-11 — 18-Month Durability

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01B.05Page 64Inclisiran — siRNA TherapyClinical EvidenceORION Development Program Overview

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01B.05Page 65Inclisiran — siRNA TherapyClinical EvidenceORION-4 Design — CV Outcomes Trial

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01B.05Page 66Future DirectionsRNA-Based Therapy in Cardiology

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01B.05Page 67Future DirectionsGene Editing for Dyslipidemias

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01B.05Page 68ConclusionsLDL-C — Causal and Cumulative Effect

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01B.05Page 69ConclusionsStatins Lower Synthesis and LDL

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01B.05Page 70ConclusionsEzetimibe Enhances Statin Effect

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01B.05Page 71ConclusionsPCSK9 Antibodies — Additional LDL and CV Benefit

Athérosclérose V — traitements lipidiques, PCSK9 et inclisiran page 71