A Case of Premature CAD• A 42 year old man comes to see you 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

Key Insight

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

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

Steven E. Nissen MD MACCChairman, Department of Cardiovascular Medicine

Cleveland Clinic

Disclosure

Consulting: Many pharmaceutical companiesClinical 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.

Acknowledgements

Some slides adapted from excellent reviewby Dr. Sam Tsimikas

(J Am Coll Cardiol 2017;69:692–711)

What is Lipoprotein(a)?• An LDL-like particle consisting of apo B covalently bound

to apo(a) via a disulfide bond.

• Likely evolved from the plasminogen gene. Plasminogen is a proenzyme converted to the fibrinolytic enzyme plasmin by activators such as tPA.

• Lp(a) has similarities to LDL, but is more atherogenicand also promotes both inflammation and thrombosis.

• Lp(a) has many isoforms (>40) based on Kringle repeats, but all isoforms appear to contribute to atherogenic risk.

Lp(a)isoforms

Apo(a)Apo(a)

Lipoprotein(a) and Plasminogen Structure

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

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

Distribution 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

Frac

tion

of P

opul

atio

n

20%20%

Men Women

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

How Does Lipoprotein(a) Contribute to Atherosclerosis?

J Am Coll Cardiol 2017;69:692–711

Lipoprotein(a) Levelsare Genetically Determined

Odds Ratio: SNPs Associated with Elevated Lp(a)

New Engl J Med 2009; 361: 2518-28

What Is The Relationship Between Lipoprotein(a) Level and Adverse

Cardiovascular Outcomes?

Risk of Elevated Lp(a) in General Population*

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

Lipoprotein(a) and Aortic Stenosis

Lipoprotein(a) Levels and Risk of Aortic Stenosis

J Am Coll Cardiol 2014;63:470–7

Lp(a) and Progression of Peak Velocity in AS

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

Survival without Aortic Valve ReplacementTertiles 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 Rosuvastatin on Lipoprotein(a) Levels

J Am Coll Cardiol 2017;69:692–711

Clinical Surveillance throughCleveland Clinic Prevention Clinic

• Database established by Dr. Leslie Cho, Section Head for Preventive Cardiology at the Cleveland Clinic

• Lipoprotein(a) measured on virtually every new patient as part of an initial prevention panel.

• Current database contains values for tens of thousands of patients

• Patient followed for outcomes, including mortality

Patient Characteristics in Cleveland Clinic Prevention Database by Lp(a) Quartile (n=11,644)

Variable1st Quartile

(0.6-7)2nd Quartile

(7.1-21.8)3rd Quartile

(22-57.5)4th Quartile

(58-496)N=2974 N=2822 N=2932 N=2916

Age, mean (SD) 52.7 (14.6) 53.3 (14.7) 53.9 (15.1) 53.9 (15.1)

Male, N (%) 1597 (53.7) 1406 (49.9) 1474 (50.3) 1257 (43.1)

BMI, mean (SD) 29.8 (15.7) 29.2 (6.5) 29.2 (6.4) 29.6 (7.1)

SBP, mean (SD) 125.4 (16.1) 123.8 (18.1) 125.3 (19.1) 124.4 (19.4)

DBP, mean (SD) 76.6 (10.4) 75.5 (9.9) 76.2 (10.5) 75.0 (10.2)

HTN, N (%) 1436 (48.3) 1302 (46.1) 1417 (48.3) 1517 (52.0)

DM, N (%) 456 (16.9) 342 (13.4) 385 (14.6) 397 (15.0)

Smoking, N (%) 1014 (34.1) 853 (30.2) 900 (30.7) 796 (27.3)

History of CAD, N (%) 944 (31.7) 874 (31.0) 1073 (36.6) 1167 (40.0)

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

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

Adjusted odds ratio = 1.28

Limited Current Treatmentsfor Elevated Lipoprotein(a)

Current Treatment for Increased Lipoprotein(a)• Lifestyle changes have minimal effect.

• Statins to lower LDL-C are reasonable.

• Estrogen replacement reported to lower Lp(a) 37%

• Niacin 1-3 g/day lowers Lp(a) by 30-40% but effectiveness in reducing events unknown.

• PCSK9 inhibitors modestly lower Lp(a) [~25%]

• Apheresis can significantly reduce levelsand may decrease events, but is cumbersome.

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

Apheresis: Effect on Major Cardiovascular Events

48

77

177

22

20

10

20

30

40

50

60

70

80

90

MI PCI CABG

Events in ApheresisTreatedPatients

2 Years Pre-Apheresis2 Years Post-Apheresis

Circulation. 2013;128:2567-2576

Can elevated Lp(a) be pharmacologically addressed?

Effect of Selected Interventions on Lipoprotein(a)

Therapy Mechanism Lp(a) Reduction

LDL Reduction

Statins Upregulation of LDL receptor 0-7% 30-50%

Niacin Reduced apo(a) transcription or Apo(B-secretion 20% 13%

CETP Inhibition Inhibition of Apo(B) lipidation 24-36% 20-35%

PCSK9 inhibition Upregulation of LDL receptor 25% 40-59%

Apheresis Removal of circulating Apo(B) containing lipoproteins ~70% up to 75%

Apo(a) antisense orSiRNA Decreased Apo(a) synthesis ~75-90% none

Adapted from J. Lipid Res. 2016. 57: 1612–1618

Lp(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

Anti-Sense Oligonuceotide

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

Phase 1 Trial: Anti-Sense Oligonucleotide Therapy

20 40 60 80 100 120Study DayLancet 2015; 386: 1472–83

Perc

ent c

hang

e in

fast

ing

(Lp(

a)

Study Day 1 78 120 162 19029 57

Initial Phase II Studies of Anti-sense Lp(a) Therapy

Lancet 2016; 388: 2239–53

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 Effect on Efficacy of Anti-Sense Therapy

Lancet 2016; 388: 2239–53

GalNAc-Enhanced Lp(a) Oligonucleotide Therapy

Lancet 2016; 388: 2239–53

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

Antisense Oligonucleotide Blocks Translationof Disease-Causing Protein by Targeting mRNA

A Case of Premature CAD• After his STEMI, the patient was placed on 80 mg

atorvastatin and now has an LDL-cholesterol of 39 mg/dL.

• He is taking dual antiplatelet therapy and carvedilol 25 mg B.I.D.

• Echocardiogram shows an anterior wall motion abnormality with an ejection fraction of 48%.

• Was this patient just unlucky or are we missing something?

• What additional imaging tests or laboratory studies should you order?