Update on lipid Therapy and CVD Prevention. Disclosures

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1 Update on lipid Therapy and CVD Prevention Patrick M. Moriarty Professor of Medicine Director of Clinical Pharmacology and The Atherosclerosis / Lipoprotein-apheresis Center (University of Kansas) Aurora, CO May 4th 2018 Disclosures Regeneron, Sanofi, Amgen, Duke Clinical research, Espirion, Eliaz Therapeutics, Kaneka, RegenXBiio, Kastle Therapeutics, Ionis, Amarin, Gemphire Therapeutics, Aegerion, Stage II inovations, Pfizer, Novartis, Lilly, University of Penn, Zydus Discovery, Kowa, Akcea and FH Foundation Question #1: Which of the following is true 1. Statin therapy lowers Lp(a) levels by 30% and decreases oxidized phospholipids by a similar amount. 2. Niacin lowers Lp(a) levels and CVD events by at least 30%. 3. More than 10% of individuals have an elevated Lp(a) level (>30mg/dL). 4. Lp(a) makes up 30% of direct LDL-C.

2 Question #2: Which of the following is true 1. In children the majority of thrombotic stroke is associated with atherosclerosis. 2. In patients under 55 years, cryptogenic strokes account for almost 15% of all ischemic strokes. 3. Children with an elevated Lp(a) level have a four-fold increase risk of AIS and the risk of recurrent ischemic strokes is increased more than ten-times in patients with an elevated Lp(a). 4. There is a strong variability in Lp(a) values based on age and gender. Cholesterol and Triglyceride Metabolism, and Molecular Mechanisms of Lipid-Lowering Drugs Zodda D., et al. Pharmacy, 2018 Expected LDL Lowering by Treatment Treatment Diet 10-15% Statin (High Intensity/Medium Intensity) 35-55% Ezetimibe (Zetia) 18-25% Niacin 20-25% Bile Acid Sequestrant (Welchol) 18-25% PCSK9 inhibitor (Repatha, Praluent) 40-65% Lipoprotein Apheresis HoFH only - Lomitapide (Juxtapid) 35-50% HoFH only - Mipomersen (Kynamro) 30-45% % LDL Lowering Expected 60-70% acutely, 20-40% time averaged, 30% chronic

3 IMPROVE-IT Study Demonstrated That Aggressive LDL-C Lowering DOES NOT Eliminate Most CV Risk IMPROVE IT Study* (over 6 years) % 32.7% CV event (%) Significant residual risk remains due to untreated risk factors 0 a LDL-C - 70 mg/dl LDL-C - 53 mg/dl Simvastatin N=9077 Ezetimibe + Simvastatin N=9077 Cannon et al. (2015) NEJM. 372: Trial Design 27,564 stable patients with CV disease (prior MI, stroke or PAD) age 27, ,564 stable patients with CV disease (prior MI, stroke or PAD) years; additional CV risk factor(s) Screening, Placebo Run-in, & Lipid Stabilization Effective statin therapy (atorva 20 mg or statin dose ± ezetimibe) LDL-C 70mg/dL or NON-HDL-C 100mg/dL Evolocumab SC Randomized 140 mg Q2W or 420 mg QM Double Blinded Placebo SC Q2W or QM Follow-up Q 12 weeks Sabatine MS et al. Am Heart J 2016;173: Summary of FOURIER LDL-C by 59% (from 2.4 -> 0.8 [0.5, 1.2] mm) CV outcomes in patients already on statin therapy Evolocumab was safe and well-tolerated Placebo Evolocumab LDL-C (mm) 2.5 Placebo % mean decline P< Absolute 1.45 mm ( ) Evolocumab Median 0.78 mm (30mg/dL) IQR [ ] Weeks after randomization KM Rate (%) at 3 Years P< P< CV death, MI, stroke, CV death, MI, stroke UA, cor revasc Giugliano RP et al. N Engl J Med : Sabatine MS et al. Am Heart J 2016;173:94-101

4 Odyssey Outcome Treatment Assignment Post-ACS patients (1 to 12 months) Run-in period of 2 16 weeks on high-intensity or maximum-tolerated dose of atorvastatin or rosuvastatin Randomization Alirocumab SC Q2W Placebo SC Q2W Schwartz GG, et al. Am Heart J2014;168: Odyssey Outcome LDL-C: ITT and On-TreatmentAnalyses Mean LDL-C (mg/dl) Placebo 96.4 ITT On-treatment* Alirocumab ITT 48.0 On-treatment* Months Since Randomization *Excludes LDL-C values after premature treatment discontinuation or blinded switch to placebo All LDL-C values, including those after premature treatment discontinuation, blinded down titration, or blinded switch to placebo ACC, Orlando 2018 Odyssey Outcome Primary Efficacy Endpoint: MACE ( CHD death, non-fatal MI, ischemic stroke, or UA requiring hospitalization ) ARR* 1.6% ACC, Orlando 2018

5 Historical Perspective of LDL-C Levels Achieved in Some of the Major Randomized Controlled trials with Lipid-Lowering Medications Masana et al. JCL , Exploratory Analysis of Patients with LDL-C <10 mg/dl vs >100mg/dL at 4 wks Cardiovascular Efficacy Safety >100mg/dL <10mg/dL P= mg/dL <10mg/dL 10 P= P= P= CVD, MI, Stroke, UA, Cor Revasc CVD, MI, Stroke Serious AE AE -> drug discontinued Giugliano RP, et al. Lancet 2017 Lipoprotein (a) [ Lp(a) ] Leibundgut et al JACC 2012 and JLR 2013, Rao ATVB 2015

6 Lp(a) Contains 10 Subtypes of KIV With Multiple Copies of KIV 2 The Author Sotirios Tsimikas JACC 2017;69: The Laboratory Measurement LDL-C is a Misnomer LDL-C = LDL-C + Lp(a)-C Yeang et al JCL 2016 Evidence Base for Lp(a) as an Independent, Causal, Genetic Risk Factor for CVD Epi/Meta-analyses Mendelian Randomization Genome-wide Association Risk ratio (95% CI) Adjustment for age and sex only Nonfatal MI and coronary death 1.8 (9318 cases) Usual Lp(a), Geometric Mean, mg/dl Lp(a) mg/dl > <5 Multivariable and KIV-2 adjusted P< Hazard Ratio (95% CI) Odds ratio for coronary disease 0 variant 1 variant 2 variant alleles allele alleles Geometric Mean Lp(a) Lipoprotein (mg/dl) Erqou et al JAMA 2009:302: Kamstrup et al JAMA 2009:301; Clarke et al NEJM 2009:361:

7 Prevalence of Elevated Lp(a) Levels in 629,858 Subjects from a Referral Laboratory Population in the US 21.8% of subjects had Lp(a) >50 mg/dl Subjects from the large referral dataset from Health Diagnostic Laboratory measured in years 2010 to 2014 Median age of the subjects was 56, and 53.7% were female Mean±SD levels were 31±38 mg/dl and median (IQR) levels were 15 (7-43) mg/dl, range mg/dl. Lp(a) percentile levels at 75% - >43 mg/dl 80% - >55 mg/dl 90% - >85 mg/dl 95% - >109 mg/dl 99% - >169 mg/dl Lp(a) levels >30 mg/dl and >50 mg/dl were present in 31.8% and 21.8% of subjects, respectively White et al AHA 2015 What are the mechanisms through which Lp(a) mediates CVD Tsimikas JACC 2017 Lp(a) and OxPL Induce Macrophage Apoptosis Koschinsky and Marcovina AJC 1998 Seimon Cell Metabolism 2010

8 Lp(a) is Present in Humans, Apes and Monkeys Chimp, Human, Bonobo, Gorilla, Orangutan - KIV and KV European hedgehog - KIII Baboon, Cynomolgus, Rhesus - KIV Leibundgut et al JLR 2013 Determinants of Binding of Oxidized Phospholipids on Apolipoprotein (a) and Lp(a) Leibundgut et al JLR 2013 Determinants of Binding of Oxidized Phospholipids on Apolipoprotein (a) and Lp(a) Leibundgut et al JLR 2013

9 LPA snp rs Thanassoulis G et al. NEJM 2013;368(6): ASTRONOMER Trial (Aortic Stenosis progression Observation: measuring Effects of Rosuvastatin) by Kwan Leung Chan, Koon Teo, Jean G. Dumesnil, Andy Ni, and James Tam Circulation Volume 121(2): January 19, 2010 ASTROMOMER Results: Changes in Peak AS gradient (A) and aortic valve area (B) Kwan Leung Chan et al. Circulation. 2010;121:

10 Relationship of Lp(a) and OxPL-apoB and OxPL-apo(a) Levels With The Development and Progression of Calcific Aortic Stenosis Capoulade et al JACC 2015 Relationship of Lp(a) and OxPL-apoB Levels With The Development and Progression of Calcific Aortic Stenosis (A&B), AV Replacement (C&D) and Rosuvastatin effects on Lp(a) and OxPL-apoB (E&F) Tsimikas JACC 2017 A: Is a cholesterol-rich lipoprotein in which apob is covalently linked to apo(a). B: Carries OxPLs in plasma. Proposed model of Lp(a)-mediated Calcific Aortic Valve Disease C: Binds avidly to areas of endothelial injury. D: Leads to delivery of OxPLs, a known promoter of steoblastic differentiation and calcification. George Thanassoulis J. Lipid Res. 2015;57:

11 Acute Ischemic Strokes (AIS) in Young Adults In adults the majority of thrombotic stroke is associated to atherosclerosis compared to only 2% for the pediatric patient. In patients under 55 years, cryptogenic strokes account for almost 40% of all ischemic strokes. Children with an elevated Lp(a) level have a fourfold increase risk of AIS and the risk of recurrent ischemic strokes (nl: 5-15%) is increased more than ten-times in patients with an elevated Lp(a) (>90 th percentile). Sultan S.M., et al. Int. J. of Stroke. 2014, Nave A.H., et al. Atherosclerosis Goldenberg N. A., et al. Haematologica. 2013;98(5). Oxidized Phospholipids on APOB-100 and Recurrent Ischemic Events Following Stroke or Transient Ischemic Attack Young Sup Byun, Xiaohong Yang, Weihang Bao, David DeMicco, Rachel Laskey, Joseph L. Witztum, Sotirios Tsimikas, for the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) Trial Investigators SPARCL Trial: Association Between OxPL-apoB Levels and CVD Events Byun Y.S., et al. JACC 2017

12 Available Therapies That Affect Lp(a) Levels Statins Diet Exercise Niacin Estrogen Aspirin PCSK9 antibodies Mipomersen Lipoprotein Apheresis Do statins increase Lp(a) levels? Tsimikas JACC 2017 JUPITER Trial Cumulative Incidence mg/dl Baseline Follow-up LDL-C 108 (94-119) 55 (44-70) HR 0.56, 95% CI P < Follow-up (years) Placebo 251 / % Rosuvastatin 142 / 8901 Ridker PM, et al. N Engl J Med 2008;359:

13 Efficacy of rosuvastatin* according to Baseline Lp(a) *On-statin Lp(a) concentrations were associated with residual risk of CVD (adjusted hazard ratio, 1.27; 95% CI, ; P=0.04), which was independent of LDL-c and other factors. Khera A V et al. Circulation. 2014;129: Effects of Diet, Exercise, Niacin and Aspirin on Lp(a) and CVD Risk -Low-fat with low or high-vegetable diet raises Lp(a) levels. Silaste M-L, et al. ATVB, Physical activity has little effect on Lp(a) levels. Mackinnon L.T., et al. Medicine & Science in Sports & Exercise Niacin therapy reduces Lp(a) and oxidized phospholipid levels but has not demonstrated, in clinical trials, its ability to lower CVD events. Albers J.J., et al. JACC Hormone replacement therapy lowers Lp(a) levels and CVD events. Danik J. S., et al. JACC Aspirin lowers Lp(a) levels and CVD events. Singh Ranga G. et al. J. of Stroke and CVD. 2007, Chasman D.I., et al. Atherosclerosis 2009 Distribution of Lp(a) % Change From Baseline With Mipomersen

14 R-square: Lp(a) change from baseline (%) vs. LDL-C change from baseline in alirocumab treatment group Lp(a) % change from baseline Spearman s correlation coefficient: p= LDL-C % change from baseline Individual measurements Fit 95% confidence limits 95% prediction limits Gaudet D., et al. AJC 2014;114: Apheresis Preparative Plasmapheresis Therapeutic Plasmapheresis Conserved Plasma Plasma Fractions Blood cells non-selective semi-selective selective Plasma Protein Concentrates Fresh-frozen- Plasma Coagulation Factors Human Albumin Leukocyte Erythrocyte Thrombocyte Concentrates Therapeutic Plasma Exchange Activated Charcoal Adsorption Cascade Filtration Cryofiltration Enzyme Adsorption (Bioreaction) Immuno- adsorption Ion Exchange Adsorption Immunoadsorption Phenylalanin Protein A Lipid-Apheresis Tryptophan Heparin Precipitation Collection of blood components Removal of blood components Dextransulfate Adsorption Immunoadsorption hemopheresis Lipid Levels Pre and Post Lipid-apheresis Total Cholesterol Triglycerides HDL LDL Lp(a) 611 mg/dl 128 mg/dl 78 mg/dl 507 mg/dl 105 mg/dl Total Cholesterol Triglycerides HDL LDL Lp(a) 216 mg/dl 49 mg/dl 72 mg/dl 134 mg/dl 28mg/dL

15 Indications For Lipid-apheresis U.S.A. Japan Germany LDL-C > 160 mg/dl (with CHD) - or - LDL-C > 300 mg/dl (without CHD) TC > 250 mg/dl (LDL-C >140 mg/dl) (with CHD) LDL-C > 130 mg/dl (with CHD) or Lp (a) > 60mg/dL (with symptomatic CHD) Lipid-apheresis Therapy for Elevated Lp(a) Levels and CVD Jaeger Rosada Leebmann Apheresis Pre- Post- (% reduction) Pre- Post- (% reduction) Pre- Post- (% reduction) Patients Duration (years) LDL-C mg/dl (-65%) (-60%) (-60%) Lp(a) mg/dl (-72%) (-68%) (-70%) MACE* (total) (-81%) (-70%) (-78%) MACE* (per year) (-86%) (-97%) (-78%) *MACE= Major Coronary Event percentages are mean percent change Moriarty PM, Hamphill L. Cardiol Clin 33 (2015) Lipid-apheresis Therapy for Elevated Lp(a) Levels and CVD from German Apheresis Centers Jaeger Rosada Leebmann Apheresis Pre- Post- (% reduction) Pre- Post- (% reduction) Pre- Post- (% reduction) Patients Duration (years) LDL-C mg/dl (-65%) (-60%) (-60%) Corrected LDL-C 30% vs 45% of Lp(a) Lp(a) mg/dl (-72%) (-68%) (-70%) MACE* (total) (-81%) (-70%) (-78%) *MACE= Major Coronary Event percentages are mean percent change Moriarty PM, Hamphill L. Cardiol Clin 33 (2015)

16 Lipid-apheresis for Refractory Angina with Elevated Lp(a): Dr Tina Khan Cardiology SpR and PhD Fellow Royal Brompton and Harefield NHS Foundation Trust, Imperial College London Dr Li-Yueh Hsu, Dr Andrew E Arai, Samantha Rhodes, Alison Pottle, Ricardo Wage, Winston Banya, Dr Peter D Gatehouse, Dr Shivraman Giri, Prof. Peter Collins, Prof. Dudley J Pennell, Dr Mahmoud Barbir Khan T., et al. EHJ 2017 Khan T., et al. EHJ 2017 Results: Net changes in primary endpoint PRIMARY OUTCOME Apheresis: mean (95% CI) Sham: mean (95% CI) P-Value (between groups) MPR 0.47 (0.31, 0.63) (-0.33, 0.02) Stress myocardial perfusion (ml/min/g) 0.44 [0.18, 0.67] [-0.14, 0.09] Rest myocardial perfusion (ml/min/g) (-0.09, 0.10) 0.06 (-0.05, 0.17) 0.42 MPR = Myocardial Perfusion Reserve Mean (lower 95% CI, upper 95% CI) or median [lower quartile, upper quartile] Khan T., et al. EHJ 2017

17 70m (41.5, 100.5) Composite graphs showing impact of Apheresis vs. Sham on Exercise and Symptoms 3.5m (-51.1, 30.8) Khan T., et al. EHJ 2017 Lipid-apheresis (LA) Patients Treated at KUMC Total patients (n=72) Gender M 28 (38.9 %) F 44 (61.1%) Age (years) ± (range 13-83) Indication for LA FH FH and Lp(a) Isolated Lp(a) 28 (38.9%) 35 (48.6%) 9 (12.5%) Cardiovascular Disease # (mean age) Coronary Artery Disease 55 (52 ± 11.88) Myocardial infarction 24 (48.82 ± 9.86) Stroke 11 (51.6 ± 17.34) Trans Ischemic Attack 7 (48.82 ± 3.03) Interventions # (mean age) Carotid artery revascularization 4 (56.25 ± 3.9) Coronary Angioplasty 40 (53.23 ± 9.23) CABG 31 (53.7 ± ) CVD Patients with an Elevated Lp(a)Treated with Lipid-apheresis (Kansas University Atherosclerosis Prevention Center (n=15) Patient Characteristics Male 9 Mean Age (range) Mean LA treatment Duration (range) CVD Risk Factors 56±16 (13-82) 3.54 (8 mo- 7.5 years) Total Patients Family History of CVD 10 Hypertension 9 Diabetes 4 LMT Statin 8 Ezetimibe 6 O-3-FA 11 PCSK9 Inhibitor 4 ACC 2018

18 Summary of Results Pre vs. Post LA Therapy Initiation Apheresis Pre- Post- (% reduction) Patients N=15 N=15 Mean Duration to MACE event (years) LDL-C mg/dl ± ± 3.08 (- 71%) Lp(a) mg/dl ± ± 3.77 (- 64%) MACE (total) N=32 N=2 (- 94%) Stroke N=5 N=0 Myocardial Infarction N=10 N=0 CABG N=8 N=0 Stent N=9 N=2 ACC 2018 Potential Future Treatments to Lower Lp(a) levels RNA-targeted Antisense RNA Interference Hepatic Thyroid Receptor Agonists RNA-targeted Antisense Drugs Block the Translation of a Specific Protein DNA Transcription mrna Translation Disease-associated Protein Traditional Drug Transcription Antisense Drug (Single stranded, DNA-like) (Oligonucleotide) RNase H1 Degrades mrna=no Translation No Disease-associated Proteins Produced Crooke ST, ed. Antisense Drug Technology: Principles, Strategies and Applications. 2007: X X

19 Dose-Dependent Effect of Optimized ASO to Apo(a) in Reducing Plasma Lp(a) Viney NJ, et al. Lancet Gene Silencing via RNA Interference Effects of Eprotirome, a Hepatic Thyroid Receptor Agonist, on LDL and Lp(a) Levels in FH Subjects Sjouke B, et al. Lancet Endocrinol Diab

20 When to Measure Plasma Level of Lp(a) ulp(a) should be measured once in all subjects at intermediate or high risk of CVD/CHD who present with: Premature CVD, FH A family history of premature CVD and/or elevated Lp(a) Recurrent CVD despite statin treatment 3% 10-year risk of fatal CVD according to the ESC/EAS 10% 10-year risk of fatal and/or non-fatal CHD according to the AHA/ACC guidelines urepeat measurement is only necessary if treatment for high Lp(a) levels is initiated in order to evaluate response. Nordesgaard BG et al. Eur Heart J Dec;31(23): When to Measure Plasma Level of Lp(a) -When a patient is a poor responder to LMT (statins, ezetimibe, PCSK9i). Newer Therapies for Dyslipidemia Under Investigation 1) Bempedoic Acid: Inhibits adenosine triphosphate-citrate lyase and enzyme upstream from HMGCoAR. 2) Gemcabene calcium: Inhibits acetyl coa carboxylase. 3) Gene Replacement Therapy: AAV8-mediated LDLR gene replacement for HoFH patients. 4) IONIS-ANGPTL-3-Lrx: An antisense inhibitor to angiopoietin-like protein 3. 5) IONIS-APOCIII: An antisense inhibitor to apociii.

21 Bempedoic Acid Properties and Mechanism of Action ETC-1002 (Bempedoic Acid ) O O HO OH An oral, once-daily small molecule Inhibits ATP citrate lyase OH Half-life: hr (ETC- 1002) T max: <4 hours Target organ: Liver Elimination: Urinary excretion Apolipoprotein C-III Key Regulator of Serum Triglyceride Levels ApoC-III is a 79 amino acid glycoprotein synthesized principally in the liver Multiple apoc-iii proteins on VLDL and HDL particles Plays a key role in determining serum triglyceride (TG) levels Potent inhibitor of lipoprotein lipase Inhibits hepatic uptake of triglyceride rich lipoproteins

22 ApoC-III: A Genetically Validated Target ApoC-III in a complex with an SDS micelle as derived by NMR Individuals with loss of function mutations in apoc-iii exhibit a favorable lipid profile, reduced CHD and increased longevity Old World Amish 1 Ashkenazi Jews 2 Exome Sequencing Project 3 Copenhagen City cohorts 4 1) Pollin, et al., Science 2008: 322, ) Atzmon et al., PLoS Bio : e113. 3) National Heart, Lung, and Blood Institute, Exome Sequencing Project, N Engl J Med, published on line June ) Jorgensen AB et al. N Engl J Med, published on line June ApoC-III as a Target for CHD Risk Reduction 40% Reduction in apoc-iii 40% Reduction in TG 40% Reduction in CHD Risk 65 AKCEA-APOCIII-L Rx Selective delivery to hepatocytes Triantennary N-acetyl Galactosamine (GalNAc 3 ) represents a new class of ligand-conjugated antisense (LICA) modifications for selectively targeting hepatocytes. Prakash TP et al Nucleic Acids Research 2014

23 Mean % Reductions in Serum ApoC-III Following 4 Monthly Doses of AKCEA-APOCIII-L Rx Mean % reduction apoc-iii: Day 43-80%, Day 92-83% Mean % Reductions in Serum TG Following 4 Monthly Doses of AKCEA-APOCIII-L Rx Mean % reduction TG: Day 43-61%, Day 92-65% Mean % Reductions in Serum ApoB Following 4 Monthly Doses of AKCEA-APOCIII-L Rx Mean % reduction apob: Day 43-22%, Day 92-30%

24 Mean % Increase in Serum HDL-C Following 4 Monthly Doses of AKCEA-APOCIII-L Rx Mean Percent Change in Lipids From Baseline 1 Week After Last Dose of AKCEA-APOCIII-L Rx 15 mg/week Day mg/week Day mg/mo Day mg/mo Day 92 ApoC-III -65%** -84%** -80%* -83%* TG -61%** -71%** -61%* -65%* LDL-C -3% -17% -10% -22% ApoB -15%* -26%** -22% -30%* Non-HDL-C -22%* -30%** -27%* -31%* HDL-C +50%** +56%* +64% +76%* Lp(a) -0.1% -11% -7% -27% 1. Monthly dosing Day 43, 2 weeks after second dose, shown for comparison to weekly dosing cohorts *p 0.05 **p 0.01 Associations of Omega-3 Fatty Acid Supplement Use With Cardiovascular Disease Risks Meta-analysis of 10 Trials Involving Individuals The Omega-3 Treatment Trialists Collaboration. JAMA. 2018

25 Ongoing CV Outcomes Trials of Omega-3 Fatty Acids STatin Residual risk reduction with EpaNova in high CV risk patients with Hypertriglyceridemia [STRENGTH], n = 13, 000. Reduction of Cardiovascular Events With EPA Intervention Trial [REDUCE-IT], n = 8,000. The STRENGTH and REDUCE-IT trials will test the effects on major vascular events of much higher doses of omega-3 FAs (3-4 g/d) in patients with high plasma levels of triglycerides Conclusion ApoB lipoprotein is a toxin and lowering levels is safe an effective in reducing CVD risk. Lp(a) is an independent CVD risk factor. Present therapy is limited but aggressive treatment of other treatable CVD risk factors should be employed. Future therapy, antisense AB and RNA interference, may offer appropriate treatment for an elevated Lp(a). Newer therapies are under investigation for further reduction of apob lipoproteins. Question #1: Which of the following is true 1. Statin therapy lowers Lp(a) levels by 30% and decreases oxidized phospholipids by a similar amount. 2. Niacin lowers Lp(a) levels and CVD events by at least 30%. 3. More than 10% of individuals have an elevated Lp(a) level (>30mg/dL). 4. Lp(a) makes up 30% of direct LDL-C.

26 Answer #1: 1. False: Statin therapy may raise Lp(a) and oxidized phospholipids. Sotirios Tsimikas. JACC. Vol. 69, NO. 6, 2017; False: Niacin does lower Lp(a) levels by at least 30% but CVD benefit has not been demonstrated. O'Donoghue M., et al. JACC, Vol.63, 2014, False: More than 30% of individuals have an elevated Lp(a) level (>30mg/dL). Nordestgaard BG, et al. EHJ 2010; 31: True: Lp(a) contains 30% free and esterified cholesterol which represents 30% of LDL-C. Yeang C, et al. JCL (2016) 10, Question #2: Which of the following is true 1. In children the majority of thrombotic stroke is associated with atherosclerosis. 2. In patients under 55 years, cryptogenic strokes account for almost 15% of all ischemic strokes. 3. Children with an elevated Lp(a) level have a four-fold increase risk of AIS and the risk of recurrent ischemic strokes is increased more than ten-times in patients with an elevated Lp(a). 4. There is a strong variability in Lp(a) values based on age and gender. Answer #2: 1. False: Only 2% of thrombotic strokes are associated with atherosclerosis in children. Sultan S.M., et al. Int. J. of Stroke. 2014, False: Cryptogenic strokes account for almost 40% of all ischemic strokes in young adults. Nave A.H., et al. Atherosclerosis True: Children with an elevated Lp(a) level have a four-fold increase risk of AIS and the risk of recurrent ischemic strokes (nl: 5-15%) is increased more than ten-times in patients with an elevated Lp(a) (>90 th percentile). Goldenberg N. A., et al. Haematologica. 2013;98(5). 4. False: There is no variability in Lp(a) values based on age and gender. Chunsheng L, et al. Chin Med Sci J 1999;14:232.