Lipoprotein(a) / Lp(a) Measurement, Risk & Treatment an evolving story James A. Underberg, MS, MD, FACPM, FACP, FASH, FNLA Clinical Assistant Professor of Medicine NYU School of Medicine NYU Center for Prevention of Cardiovascular Disease Director, Bellevue Hospital Lipid Clinic, New York, NY Treasurer, National Lipid Association Slides Courtesy of Tom Daysping Disclosures Consultant: Aegerion Pharmaceuticals, Amarin, Amgen, AstraZeneca, Eli Lilly & Co., Genzyme, Sanofi, Alexion, Synageva, Recombine Contracted research: Aegerion, Genzyme, Pfizer Advisory board: Amgen, Aegerion, Sanofi, Regeneron, Genzyme,Akcea, Kowa Pharmaceuticals, Speakers bureau: Amgen, Genzyme, Aegerion, Regeneron, AstraZeneca, Merck & Co., Inc., Alexion/Synageva Lipoprotein (a) or Lp(a) Lipoprotein (a) is a lipid trafficking particle with structural similarity to low density lipoprotein (LDL) in that it has a core consisting of hydrophobic cholesteryl esters and triacylgycerols surrounded by a surface of amphipathic phospholipids and unesterified cholesterol Lp(a) like LDL has as its structural apolipoprotein a large peptide called apoprotein B 100 but differs as it also has bound on a 1:1 molar basis via a disulfide bond another protein called apoprotein (a) Scanu AM. N Engl J Med 2003;349;22:2089-2090 1
Lipoprotein (a) or Lp(a) The disulfide bridge links Cys4326 in apob- 100 with the only free Cys4057 in apo(a), located in kringle four (K-IV) type 9 Disulfide bond S S H 2N Apolipoprotein B 100 HO O C Apolipoprotein (a) Phospholipids Surface Free cholesterol Core lipids (cholesteryl ester and triglycerides Adapted from Kostner KM et al. European Heart Journal (2013) 34, 3268 3276 Lipoprotein (a) or Lp(a) There is significant heterogeneity (amino acid composition) of apoprotein(a) within and among persons with molecular weights ranging between 300 and 800 kd The amino acids are located in looped peptide chains called kringles Plasminogen and apoprotein (a) are both composed of chains of kringles Scanu AM. N Engl J Med 2003;349;22:2089-2090 Plasminogen Structure The characteristic glycoprotein component of plasminogen has a unique structure consisting of repetitive protein segments called kringles (I-V) III II IV V Active protease domain S S Kringle I Plasminogen S-S S-S Each kringle is stabilized by three internal disulfide bonds that produce the typical triple-loop structural motif referred to as a kringle The Kringle domains interact with plasminogen activators and plasmin binding sites on endothelial surfaces 2
Typical Extended Kringle S R 30 G T T G 20 Y S G T D P 80 T Y S S Q W M R W Y E 70 P Y N L T D P N R 40 P H Y 60 N L H G R 50 Y P N Kringles contain approximately 80 amino acids that are crosslinked by 3 internal disulfide bonds Having three cross links within such a small domain distorts it, creating the kringle shape Apo(a) can have from 17 to > 30 kringles 110 E 1 A E 10 V 90 E 100 C = cysteine O HS OH NH 2 Letters represent various amino acids Gotto & Pownall Manual of Lipid Disorders Lippincott 1999 Apoprotein (a) Apo(a) comprises three distinct structural domains, each of which shares a high degree of sequence identity with plasminogen: multiple copies of the plasminogen-like like kringle IV (4) domain, one copy of kringle V domain, and an inactive protease domain There are 10 different types of kringle IV (4) domains, numbered 1-10, 10, each present in a single copy except for the type 2 repeat Kringle IV subtypes are listed as KIV (n) or KIV-(n) or K4(n) where n = 1-1010 Kringle IV type 2 (KIV-2, KIV 2 or K4-2) varies from 3 to 40 repeats in the apo(a) alleles and is responsible for the intra- and interindividual size heterogeneity of apo(a) and Lp(a) mass Kringles are reported as type 1-5 or I - V Scanu AM. N Engl J Med 2003;349;22:2089-2090 Plasminogen and Apoprotein (a) Structure III II IV V Plasminogen Active protease domain The Kringle domains interact with plasminogen activators and plasmin binding sites on endothelial surfaces I Inactive protease domain IV 1 IV 2 On KIV 9 Disulfide bond links to apob S S V Apoprotein(a) IV 10 IV 3 IV 9 IV4 IV5 IV 6 IV7 IV 8 Variable size of K-IV 2 repeat domain (at least 30 alleles) results in over 500 phenotypically different forms of apo(a) Lysine binding domain on KIV 10 3
2010 European Atherosclerosis Society Consensus Panel on Lp(a) Apolipoprotein(a) genotype, which determines both the synthetic rate and size of the apolipoprotein(a) moiety of Lp(a), alone accounts for 90% of plasma concentrations of Lp(a) Hepatic secretion rates are lower for large apolipoprotein(a) isoforms As most individuals are heterozygous for two different isoforms, the smallest isoform typically predominates in plasma Nordesgaard BG et al. Eur Heart J. 2010 Dec;31(23):2844-53 Lipoprotein (a) Assembly Upon maturation, intracellular apo(a) reaches the Golgi and is secreted in a mature form as a glycoprotein, most probably without being attached to LDL The genetically determined size of apo(a) reflecting the number of K-IV repeats correlates with the intracellular residence time and thus, small isoforms are secreted much faster when compared with large isoforms explaining the reason for the inverse correlation between apo(a) size and plasma Lp(a) Assembly of Lp(a) from apo(a) and LDL is a two-step process In the first step, specific K-IVs of apo(a), mostly K-IV types 3 6 non-covalently bind to lysine groups of apo B in LDL This binding is still reversible Kostner KM et al. Eur Heart J 2013;34:3268-3276 Oxidized Phospholipids on Lp(a) + NH 3 Lysine O H 3N Oxidized + phospholipid O Lysine binding domains Apolipoprotein(a) Lp(a) Kringle loops Modified Lp(a) lipoprotein, which accumulates in atherosclerotic lesions traffics oxidized phospholipids at its lysine binding domains Berliner JA et al. NEJM 2005;351:9-11 4
Lipoprotein (a) or Lp(a) Apolipoprotein (a) K IV 1 2n 3 4 5 6 7 8 9 10 V P N C The length of apolipoprotein (a) is genetically determined, indicated by the break in the line at K IV-2; its variability (3-40 copies) has an effect on the density of Lp(a) lipoprotein The more the number of KIV-2 repeats, the higher the molecular weight of Lp(a) or conversely the fewer the lower the MW will be Scanu AM. N Engl J Med 2003;349;22:2089-2090 Comparison of Plasminogen and Apo(a) cdnas A signal sequence, is a short (5-30 amino acids long) peptide present at the N-terminus of the majority of newly synthesized proteins Plasminogen Gene MW ~ 90 kda SS T 1 2 3 4 5 P 3 Complementary DNA (cdna) is doublestranded DNA synthesized from a messenger RNA (mrna) template Apoprotein (a) Gene MW ~ 300-800 kda 5 SS 4 4 4 4 4 4 4 4 4 4 4 4 5 P 3 % sequence identity 98 100 75-85 91 94 97 SS = signal sequence; T = tail region; 1-5 = kringle 1-5; P = protease domain GawA, Hobbs H. Chapter 6 in Lipoproteins in Health and Disease Arnold & Oxford University Press 1999 Lipoprotein (a) Based on genetic evidence provided by studies conducted over the last two decades, Lp(a), is now considered to be the strongest genetic risk factor for coronary heart disease (CHD) with > a 90% heritability in Europeans and Africans Alleles with a low kringle IV copy number that together have a population frequency of 25 35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes Lp(a) mass concentrations remain relatively stable over an individual's lifetime and are unaffected by age and gender 1000-fold intra-population range (from 0 to >200 mg dl1) and fourfold inter-population range with a skewed distribution in most populations (majority of Europeans have concentrations below 10 mg dl) Kronenburg F et al J Int Med 2013;273(1):6-30 5
Apoprotein (a) With codominant inheritance almost everyone and their progeny has the LPA gene but only ~ one third of patients will have an at-risk plasma mass concentration of the protein apo(a) Previous assumption was that more than 90% of the variance of LP(a) mass was under genetic control but newer data suggest ~ one third of the variation is due to heterogeneity of the Lp(a) locus, meaning the KIV-2 makeup of LPA is not the only determinant of Lp(a) mass concentration Single nucleotide polymorphisms (SNPs) are also at play and as has been the case with other lipids it is likely that additional apo(a) modifying genes or even epigenetic factors yet to be discovered have an effect Kronenberg F & Utermann G. J Intern Med 2013;273:6-30 LDL and Lp(a) Peak Density 18 16 14 12 10 8 6 4 2 LDL Lp(a) Plasma from 75 subjects, obtained at the time of entry into the study, was subjected to density gradient ultracentrifugation, and the densities of the LDL & Lp(a) peak fractions were measured for each subject 0 1.03 1.03 1.04 1.04 1.05 1.06 1.07 1.08 1.09 Peak density gm/ml Nakjima K et al. ATVB 2001;21:1248-1253 Chromosome 6 Lipoprotein (a) Genetics The specific genetics of Lp(a) are significantly more complex than classic lipid monogenic disorders like autosomal dominant or recessive familial hypercholesterolemia (FH) Codominant Inheritance: two alleles of a gene pair in a heterozygote both have full phenotypic expression: Heterozygotes for Kringle IV Type 2 (KIV-2) repeats have 2 different Lp(a) particles in their plasma (which can be physically separated) Lp(a) mass is largely controlled by a size polymorphism of the LPA gene on chromosome 6q26-q27 q27 and of the apo(a) protein (>30 alleles and isoforms) which control the Copy Number Variation (CNV) of KIV-2 in LPA (apoprotein a) 6q26-27 27 Kronenburg F et al J Int Med 2013;273(1):6-30 6
Lipoprotein (a) Genetics Chromosome 6 The incidence of at-risk Lp(a) mass concentration depends on what level is defined as high risk: If 30 mg/dl is used then ~30 % (1 in 3) of Caucasians (100 million in the US) As many as 50% of African Americans (~12 million) have an at-risk Lp(a) concentration > 30 mg/dl Two LPA variants or single nucleotide polymorphisms (SNPs), namely rs10455872, which is a noncoding intronic SNP, and rs3798220 which is a missense variant are the SNPs that are most consistently associated with both plasma Lp(a) levels and CHD risk 6q26-27 27 Kronenburg F et al J Int Med 2013;273(1):6-30. Clark R et al. N Engl J Med 2009;361:2518-28 2010 European Atherosclerosis Society Consensus Panel on Lp(a) Fraction of population Men 30% (levels > 30 mg/dl) 20% (levels > 50 mg/dl) Women 30% (levels > 30 mg/dl) 20% (levels > 50 mg/dl) Green color indicates levels below the 80th percentile, whereas red color indicates levels above the 80th percentile 0 50 100 150 200 0 50 100 150 200 Lp(a) mg/dl Lp(a) mg/dl Typical distributions of lipoprotein(a) levels in the general population. These graphs are based on non-fasting fresh serum samples from 3000 men and 3000 women from the Copenhagen General Population Study collected from 2003 through 2004 adapted from NordesgaardBG et al. Eur Heart J. 2010 Dec;31(23):2844-53 Multi-Ethnic thnic Study of Atherosclerosis (MESA) Histograms of Lp(a) Mass Distribution 25 th %ile Mean 75 th %ile Blacks Caucasians 0 40 40 60 80 120 160 200 240 280 320 0 40 40 60 80 120 160 200 240 280 320 Lp(a) (mg/dl) Lp(a) (mg/dl) 50 Histograms mg/dl cut point of identifies Lp(a) distribution CHD risk in frequency 3 of 4 races/ethnicities, and quartile box but the plots lower of 30 mg/dl Lp(a) cut point levels may in be the more Black appropriate and Caucasian for detecting groups CHD risk for black individuals The left and right box edges correspond to 25% and 75% percentiles, and the vertical line within the box indicates the median level Guan W, et al. ATVB 2015;35:996-1001 7
Atherosclerosis Risk in Communities (ARIC) Study Lipoprotein (a), Ethnicity & Cardiovascular Risk CVD Caucasian CHD Stroke African American African American Caucasian African American Caucasian 0.8 0.9 1.0 1.1 1.2 1.3 1.4 Hazard Ratio per standard deviation increase in log-transformed Lp(a) mass values Lp(a) levels in ARIC were significantly higher among the black group than the white group, and in both populations, increasing Lp(a) levels tended to correlate positively with low-density lipoprotein cholesterol and negatively with triglycerides Increasing quintiles of Lp(a) were just as predictive of future cardiovascular disease in the black population as in the white population Paul Ridker Circulation 2012, 125:207-209 Relationship Between Apo(a) Isoform Size & Lp(a) Mass in a Caucasian Population Lp(a) mass (mg/dl) 80 70 80 50 40 30 20 10 0 Isoform MW: kda Frequency B S1 S2 S3 S4 460 520 580 640 700 3% 12% 28% 26% 31% The larger isoforms (S1-4) are associated with lower plasma Lp(a) mass concentrations are most common in Caucasian populations The smaller (F & B) isoforms are associated with higher plasma concentrations of Lp(a) mass MW = molecular weight, B = Smaller isoforms, S = Larger isoforms Utermann Science 1989;246(4932):904-10 Lipoprotein (a) Particles Apo(a) Isoforms: Kringle IV-2 Copy Variation Lp(a) mass is the cumulative mass of apo(a), apo(b), other LDL proteins, phospholipids, free cholesterol, cholesteryl ester, triglycerides and other lipid moieties K IV, Type 1 Protease domain Disulfide bond K V K IV, Types 3-10 Apo B 100 K IV, Type 2 K IV, Type 1 12 Kringles K IV, Type 2 35 Kringles K IV, Types 3-10 Apo B 100 Disulfide bond Low MW apo(a) K V Protease domain High MW apo(a) 8
Lipoprotein (a) Lipoprotein (a) Heterogeneity Small Dense LDL Buoyant LDL? Highest atherogenic potential Large apo (a) isoform Small apo (a) isoform Both apo(a) and the particles of LDL that are found in Lp(a) lipoprotein also vary in size Scanu AM. N Engl J Med 2003;349;22:2089-2090 K IV, Type 1 Apo B100 K IV, Type 2 B A Understand that apoprotein (a) size has nothing to do with LDL particle size D Disulfide bond K IV, Types 3-10 KV Protease domain C Lp(a) Testing Apo(a) mass Lp(a)-C Variable: High & low molecular weight Variable: particle cholesterol mass Cholesterol Cholesteryl ester Phospholipids Lp(a) mass Lp(a)-P Multiple variables No variables Triglyceride 9
Lipoprotein(a)-P versus Lp(a) mass Concentrations Lp(a)-P (nmol/l) 900 800 700 600 500 400 300 200 100 0 0 MW = 700-800 HIGH MW = 600-700 MW = 300-600 LOW Lp(a) isoform sizes determined by Western blot analysis 50 100 150 200 Lp(a) mass (mg/dl) 250 Comparison of Lipo- IFE Lp(a)-P concentrations with Lp(a) mass for samples of large (blue, n=51), intermediate (green, n=25)) and small (red, n=38) isoforms Because the Lipo- IFE concentration assay is not influenced by isoform size, the difference in slopes observed here indicates that the mass assay is influenced by isoform size Guadagno PA et al Clin Chim Acta 2015;439:215-224 Bruneck Study Lp(a) & Risk of Advanced Atherogenesis n = 50 6.4 0.8 1.0 Adjusted OR n = 73 1.8 n = 14 n = 189 High Low Lp(a) concentration: Cutoff 32 mg/dl Risk of advanced atherogenesis (incident stenosis >40%) according to 4 categories built by Low and high Lp(a) mass (cutoff, 32 mg/dl) HMW and LMW apo(a) phenotypes (cutoff, 22 K-IV repeats) ORs adjusted for age, ferritin, factor V Leiden, fibrinogen, diabetes, LDL, HTN, smoking & alcohol, antithrombin III Kronenberg F, et al. Circulation. 1999;100;1154-1160. OR of incident stenosis OR of incident stenosis 1.0 0-8 n = 156 0.8 8-16 Lp(a) mg/dl 1.3 0.5 16-24 24-32 32-40 > 40 Kringle IV Repeats 3.5 (1.2-10.1) p<0.05 5.8 (2.0-16.9) p<0.01 >31 29-31 26-28 23-25 20-22 11-19 n = 32 HMW LMW HMW LMW 55 47 27 24 26 38 4.7 5.7 (2.0-15.9) p<0.01 (1.4-16.4) p<0.05 78 46 89 34 Bruneck Study Lp(a) & Risk of Advanced Atherogenesis Risk of advanced atherogenesis (incident stenosis > 40%) according to categories of Lp(a) concentrations apo(a) phenotypes Graph demonstrates a binary type of association with a clear cutoff at 32 mg/dl of Lp(a) concentration and 22 K-IV repeats (the low MW isoforms) ORs adjusted for age, ferritin, factor V Leden, fibrinogen, diabetes, LDL, HTN, smoking & alcohol, antithrombin III Kronenberg F, et al. Circulation. 1999;100;1154-1160. 10
Lipoprotein (a) Mass Concentrations Lp(a) mg/dl 70 60 50 40 30 20 10 0 60 11-16 Low (LMW) 49 52 17-19 20-22 Molecular Weight of Apo(a) 19 23-25 26-28 High (HMW) 15 14 29-31 12 32-34 Number of KIV Repeats There is a clear inverse correlation between the number of KIV repeats and Lp(a) concentration 7 35-37 5 > 37 Mean Lp(a) concentration in various groups of subjects stratified by the number of kringle (K) IV (KIV) repeats; 11 22 KIV repeats are considered as low molecular weight (LMW) or small isoforms and those with >22 KIV repeats are considered as high molecular weight (HMW) or large apolipoprotein(a) [apo(a)] isoforms Kronenberg F et al. J Int Med 2013 LDL-cholesterol (LDL-C) Direct Calculated LDL-cholesterol LDL-cholesterol is the cholesterol is the cholesterol trafficked within trafficked all of the within low all density of the lipoproteins low and intermediate and Lp(a) in density lipoproteins a deciliter in of a plasma deciliter of plasma IDL apoe LDL Apo(a) Lp(a) apob apob apob IDL-C + LDL-C + Lp(a) (a)-c Calculated Direct LDL-Cholesterol Lipoprotein (a) Metabolism 11
In two different cell lines (HEK293 & HeLA) Lp(a) is a ligand for the SR- BI receptor Both cell lines when transfected with SR-BI showed increased association with Lp(a) SR-BI can promote the selective lipid uptake of CEs from Lp(a), as it does from other lipoproteins although SR-BI appears to preferentially promote the uptake of CE, a neutral core lipid Lp(a) and not LDL has also been shown to be the principal carrier of negatively charged oxidized lipids in plasma and enrichment of anionic charged lipids has been shown to enhance the uptake of lipoproteins by SR-BI Thus, negatively charged oxidized lipids could potentially explain the affinity of Lp(a) for SR-BI J Lipid Res 2013;54:2450-2457 Overexpression of the low-density lipoprotein (LDL) receptor (LDLr) in HepG2 cells dramatically increased the internalization of Lp(a) Internalization of Lp(a) was markedly reduced following treatment of HepG2 cells with a function-blocking monoclonal antibody against the LDLr or the use of primary human fibroblasts from an individual with familial hypercholesterolemia; in both cases, Lp(a) internalization was not affected by PCSK9 Lp(a) internalization by hepatic HepG2 cells and primary human fibroblasts was effectively reduced by PCSK9 Optimal Lp(a) internalization in both hepatic and primary human fibroblasts was dependent on the LDL rather than the apolipoprotein(a) component of Lp(a) Romagnuolo R et al. J Biol Chem 2015;290:11649-1166211662 Adapted from J Biol Chem 2015;290:11649-11662 K IV, Type 1 Apo B 100 K IV, Type 2 Apo B 100 Apo(a) Lp(a) LDL K IV Types 3-10 K V Protease domain Plasminogen receptors LDL receptors Romagluono J Biolog Chem 2015 12
Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin ( JUPITER) Study: Lp(a) Median overall value = 23, 60 mg/dl (Caucasians, Blacks) Primary Endpoint Lp(a) <Median Lp(a) > Median Lp(a) <Median Lp(a) > Median 0.25 0.5 1.0 2.0 Primary Endpoint + Total Mortality 0.25 0.5 1.0 2.0 Khera A et al. Circulation. 2014;129:635-642 Efficacy of rosuvastatin according to baseline lipoprotein(a) concentration Hazard ratios and 95% confidence intervals according to intention-to-treat analysis for the primary endpoint (top) and the expanded endpoint (bottom) by baseline lipoprotein(a) mass concentrations For the primary endpoint, hazard ratio with rosuvastatin therapy was 0.47 (95%CI 0.30 0.72) for participants with baseline Lp(a) mass concentration below the median and 0.62 (95%CI 0.43 0.90) in those above the median (p-interaction = 0.33) Similarly, for the expanded endpoint, hazard ratios were 0.46 (95%CI 0.32 0.69) and 0.72 (95%CI 0.52 0.97) for those below and above the median respectively (p-interaction = 0.10) Although the median change in Lp(a) mass with rosuvastatin and placebo was zero, rosuvastatin nonetheless resulted in a small but statistically significant positive shift in the overall Lp(a) distribution (P<0.0001) Effect of Statins on LDL-receptor and PCSK9 Statin Lysosomal Degradation oxysterols SREBP-2 LDLr PCSK9 SREBP-2 Sterol regulatory element binding protein - 2 Konrad RJ et al. Lipids Health Dis. 2011;10:38 Atherothrombosis Intervention in Metabolic Syndrome with Low HDL-C/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) The principal findings of our study were at 1 year, compared to the placebo group, those randomized to ERN had significantly higher apoa-i levels, a lower apob/apoa-i ratio, and lower levels of Lp(a) Despite these favorable changes with ERN, apoa-1, apob, and Lp(a) variables did not identify any subgroup of participants who benefited from ERN therapy Baseline and on-study Lp(a) predicted CV events in both the control LDL-lowering therapy plus placebo and LDL lowering therapy plus ERN arms, suggesting that Lp(a) still contributes to residual CV risk in patients achieving target LDL-C levels with statin therapy Albers JJ et al. Am Coll Cardiol 2013;62:1575 9 13
Current therapeutic options to reduce Lp(a) are limited Evolocumab treatment for 12 weeks resulted in significant (p < 0.001) mean (95% confidence interval) dose-related reductions in Lp(a) compared to control: 29.5% (23.3% to 35.7%) and 24.5% (20.4% to 28.7%) with 140 mg and 420 mg, dosed every 2 and 4 weeks, respectively, with no plateau of effect Lp(a) reductions were significantly correlated with percentages of reductions in LDL-C and apolipoprotein B Mean percentage reductions did not differ based on age or sex but the trend was greater in those patients taking statins Raal FJ et al. JACC 2014;63:1278-8888 Evolocumab-induced Lp(a) Percentage Change from Baseline to 12 weeks Lipoprotein (a) mass Percentage Change from Baseline 0-10 -20-30 -40 Evolocumab Q 2 wks Evolocumab Q 4 wks 70 mg 105 mg 140 mg 280 mg 350 mg 420 mg -13.8* -18.7* -21.3* -24.5* -25.2* -29.5* Current therapeutic options to Statistically significant mean reductions in Lp(a) mass were observed with all doses of evolocumab compared with those of control. Leastsquares mean differences (95% CI) from ANCOVA model are shown with last observation carried forward (LOCF) imputation Treatment difference within each dose frequency group used control in the same frequency group as the reference *p < 0.001. Raal FJ et al. JACC 2014;63:1278-8888 Model for receptor-mediated catabolism of apo(a) and Lp(a). Koschinsky ML, Biol Chem 2015;290:11649-11662 14
Sotirios Tsimikas, Lancet 2015; 386: 1472 83 Mean percent change in Lp(a) and OxPL-apoB with time by treatment group in the multi-dose cohorts Sotirios Tsimikas, Lancet 2015; 386: 1472 83 15
Effect of mipomersen and ISIS 144367 on Lp(a) and apo(a) plasma levels. Sotirios Tsimikas, JLR Accessed online Feb 12016 Summary Lp(a) is a risk factor for ASCVD, Aortic Stenosis and Thrombotic disease Family screening is important when index patients identified The measurement of Lp(a) is a complex issue Lp(a) levels can be used to guide lipid lowering therapy and ASCVD risk reduction paradigms Investigational agents in development lower Lp(a) and may offer additonal options for treating patients. 16
Additional Information / Resources The Lipoprotein (a) Foundation www.lipoproteinafoundation.org 17