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Role of Lipoprotein(a) in Coronary Disease: An Emerging Novel TargetRole of Lipoprotein(a) in Coronary

Disease: An Emerging Novel Target

Steven E. Nissen MD MACCChief Academic Officer, Heart and Vascular Institute

Cleveland Clinic

Steven E. Nissen MD MACCChief Academic Officer, Heart and Vascular Institute

Cleveland Clinic

Disclosure

Consulting: Many pharmaceutical companies

Clinical Trials: Abbvie, Amgen, AstraZeneca, Eli Lilly, Novartis, Novo Nordisk, The Medicines Company, Cerenis, Orexigen, Takeda and Pfizer. Companies are directed to pay any honoraria, speaking or consulting fees directly to charity so that neither income nor tax deduction is received.

Faculty Disclosure

Steven Nissen, MD

Dr. Nissen reports that the Cleveland Clinic Center for Clinical Research has received funding to perform clinical trials from Abbvie, AstraZeneca, Amgen, Cerenis, Eli Lilly, Esperion, Medtronic, MyoKardia, Novartis, Pfizer, The Medicines Company, Silence Therapeutics, Takeda, and Orexigen. Dr. Nissen is involved in these clinical trials, but receives no personal remuneration for his participation. Dr. Nissen consults for many pharmaceutical companies, but requires them to donate all honoraria or consulting fees directly to charity so that he receives neither income nor a tax deduction.

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A Case of Premature CADA Case of Premature CAD• A 42 year old man comes to see us in the clinic

with a history of recent myocardial infarction (STEMI).

• He was evaluated by his primary care physician 3 months prior to the ACS event with the following history/findings:

– Non-smoker, exercises regularly (runner). BMI 24.5 kg/m2

– Strong family history of premature coronary disease

– LDL-C 86 mg/dL, HDL 52 mg/dL, triglycerides 76 mg/dL

– BP 118/78 mm Hg

– Fasting blood glucose 81 mg/dL

Was This Patient Just Unluckyor Are We Missing Something?Was This Patient Just Unluckyor Are We Missing Something?

Lipoprotein(a) level = 189 mg/dL(normal <25 mg/dL)

Key Insight

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Jan 9, 2018

Lp(a)isoforms

Apo(a)

Apo(a)

Lipoprotein(a) and Plasminogen StructureLipoprotein(a) and Plasminogen Structure

Adapted from J Am Coll Cardiol 2017;69:692–711

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Distribution of Lp(a) in the General PopulationDistribution of Lp(a) in the General Population

Lipoprotein(a) (mg/dL)0 50 100 150 200

Lipoprotein(a) (mg/dL)0 50 100 150 200

Fra

ctio

n of

Pop

ulat

ion

20%20%

Men Women

Nordestgaard B G et al. Eur Heart J 2010;31:2844-2853

Dallas Heart Study: Lp(a) Levels by Race/EthnicityDallas Heart Study: Lp(a) Levels by Race/Ethnicity

Circulation. 2009;119:1711-1719

90%

75%

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Prevalence of Elevated Lp(a): US and GloballyPrevalence of Elevated Lp(a): US and Globally

Prevalence Top 20% Top 10% Top 5% Top 1%

Lp(a) Level 60 mg/dL 90 mg/dL 116 mg/dL 180 mg/dL

Number (USA) 64 million 30 million 16 million 3.2 million

Number (EU) 150 million 75 million 37.5 million 7.5 million

Number Globally 1.4 billion 700 million 350 million 7 million

Arterioscler Thromb Vasc Biol. 2016;36:2239-2245 and adapted from Tsimikas

LDL-C and Lp(a): A Key InsightLDL-C and Lp(a): A Key Insight

• Lipoprotein(a) is an ApoB containing particle that cross reacts with LDL-C in most assays.

• The LDL obtained in a standard lipid panel reflects BOTH Lp(a) and LDL.

• In patients whose LDL does not fall appropriatelywith statins/ezetimibe (so-called statin resistance), consider the possibility of a very high Lp(a).

• Formulae for adjusting LDL-C for Lp(a) mass are feasible, but not standardized.

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How Does Lipoprotein(a) Contribute to Atherosclerosis?

How Does Lipoprotein(a) Contribute to Atherosclerosis?

Lp(a) Components: Dual Mechanisms Of HarmLp(a) Components: Dual Mechanisms Of Harm

European Heart Journal (2017) 38, 1553–1560

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Lipoprotein(a) Levelsare Genetically Determined

Diet and Lifestyle Have No Effect

Lipoprotein(a) Levelsare Genetically Determined

Diet and Lifestyle Have No Effect

Odds Ratio: SNPs Associated with Elevated Lp(a)Odds Ratio: SNPs Associated with Elevated Lp(a)

New Engl J Med 2009; 361: 2518-28

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What are Abnormal (Risky)Levels of Lipoprotein(a)?

What are Abnormal (Risky)Levels of Lipoprotein(a)?

Thresholds for Increased Risk Reportedin the Literature Using 2 Different Units Thresholds for Increased Risk Reportedin the Literature Using 2 Different Units

• 100 nmol/L (~50 mg/dL)

• 140 nmol/L (~60 mg/dL)

• 165 nmol/L (~70 mg/dL)

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Risk of Elevated Lp(a) in General Population*Risk of Elevated Lp(a) in General Population*

JAMA. 2009;301(22):2331-2339 *Data from Copenhagen City Heart Study

Prevention Clinic: Mortality for Lp(a) for >58 mg/dL

Lp(a) >58 mg/dLLp(a) <58 mg/dL

Adjusted odds ratio = 1.28

N=11,614

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StudyPatients

> 30 mg/dLControls

>30 mg/dLOdds Ratio

95% CI)

The American Journal of Medicine (2007) 120, 728-733

Elevated Lp(a) and Venous Thrombosis RiskElevated Lp(a) and Venous Thrombosis Risk

Lipoprotein(a) and Aortic StenosisLipoprotein(a) and Aortic Stenosis

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Lipoprotein(a) Levels and Risk of Aortic StenosisLipoprotein(a) Levels and Risk of Aortic Stenosis

J Am Coll Cardiol 2014;63:470–7

Lp(a) and Progression of Peak Velocity in ASLp(a) and Progression of Peak Velocity in AS

J Am Coll Cardiol 2017;69:692–711J Am Coll Cardiol 2015;66:1236–46

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Survival without Aortic Valve ReplacementSurvival without Aortic Valve Replacement

Tertiles 1 & 2

Tertile 3

J Am Coll Cardiol 2017;69:692–711J Am Coll Cardiol 2015;66:1236–46

Effect of Statins on Lipoprotein(a) Levels

Effect of Statins on Lipoprotein(a) Levels

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Effect of Rosuvastatin on Lipoprotein(a) Levels

J Am Coll Cardiol 2017;69:692–711

Paradox: Statin Treatment and CV Risk of Lp(a)Paradox: Statin Treatment and CV Risk of Lp(a)Patient-level meta-analysis of placebo-controlled statin trials

Lancet 2018; 392: 1311–20

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Limited Current Treatmentsfor Elevated Lipoprotein(a) Limited Current Treatmentsfor Elevated Lipoprotein(a)

Aspirin in Patients with Elevated Lp(a)Aspirin in Patients with Elevated Lp(a)

• A Women’s Health Initiative substudy reported that patients with a genetically confirmed SNP for elevated lipoprotein(a):

– Had increased cardiovascular risk with a hazard ratio of 2.11 ( 95% CI 1.39-2.52)

– This risk was reduced by use of aspirin, HR 0.44, 95% CI 0.20-0.94) with a statistically significant interaction between genetic status and aspirin efficacy

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Apheresis: Effect on Major Cardiovascular EventsApheresis: Effect on Major Cardiovascular Events

48

77

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22

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30

40

50

60

70

80

90

MI PCI CABG

Events in ApheresisTreatedPatients

2 Years Pre-Apheresis

2 Years Post-Apheresis

Circulation. 2013;128:2567-2576

Can elevated Lp(a) be pharmacologically addressed?

Can elevated Lp(a) be pharmacologically addressed?

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Alternative Approaches to Gene SilencingAlternative Approaches to Gene Silencing

Lp(a) Anti-Sense Oligonucleotide TherapyLp(a) Anti-Sense Oligonucleotide Therapy

LPAGene

Anti-SenseOligonucleotide

(single stranded, DNA-like

RNase H1’Degrades

Apo(a) mRNA

No apo(a)produced

Lancet 2015; 386: 1472–83

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Anti-Sense Oligonuceotide

By blocking Apo(a) productionLp(a) is not synthesized

Phase 1 Trial: Anti-Sense Oligonucleotide TherapyPhase 1 Trial: Anti-Sense Oligonucleotide Therapy

20 40 60 80 100 120

Study DayLancet 2015; 386: 1472–83

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Advanced Anti-Sense Technology to EnhanceDrug Delivery and Improve Safety/Efficacy

Advanced Anti-Sense Technology to EnhanceDrug Delivery and Improve Safety/Efficacy

• Antisense therapy utilizes N-Acetyl-galactosamine(GalNAc), a highly efficient ligand for the hepatic asialoglycoprotein receptor.

• GalNAc, derived from gallactose, is a well-characterized pro-drug that is cleaved and cleared rapidly.

• Apo(a)-Lrx is roughly 30 times more potent than the parent antisense oligonucleotide, leading to a more than 10 times lower dose and improved tolerability

Prakash et al . Nucleic Acids Res. 2014

GalNAc-Enhanced Lp(a) Oligonucleotide TherapyGalNAc-Enhanced Lp(a) Oligonucleotide Therapy

Lancet 2016; 388: 2239–53

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Phase II: Effect of ASO on Lp(a) Levels (n=286)

Presented by Tsmikas et al (AHA 2018)

-6%

-35%

-56% -58%

-72.0%

-80.0%

-100%

-90%

-80%

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%Placebo 20mg/Q4W 40mg/Q4W 20mg/Q2W 60mg/Q4W 20mg/QW

LS M

ean

Per

cent

Cha

nge

(%)

Pivotal Phase 3 Trial: Lp(a)HORIZONPivotal Phase 3 Trial: Lp(a)HORIZON

• Approximately 8000 patients with established CAD in two strata (Lp(a) levels either >70 mg/dL or >90 mg/dL).

• Optimal background therapies including statins.

• Randomized to 80mg TQJ230 monthly or placebo for 4 years.

• Primary endpoint: 4 component MACE (CV death, nonfatal MI, stroke or hospitalization for urgent coronary revascularization

A trial with enormous public health implications, but we mustfind the patients and enroll them! We need your help!

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Whom to Screen for Elevated Lipoprotein(a)Whom to Screen for Elevated Lipoprotein(a)

• Premature CVD

• Familial hypercholesterolemia

• Family history premature CVD or Lp(a)

• Recurrent CVD despite statins

• ≥3% 10-year risk of fatal CVD

• ≥10% 10-year risk of fatal/nonfatal CHD

Nordestgaard et al. EAS Consensus Panel. Eur Heart J 2010;31:2844-2853

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