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Lipoprotein(a), Cardiovascular Disease, and Contemporary Management

  • Terry A. Jacobson
    Correspondence
    Correspondence: Address to Terry A. Jacobson, MD, Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University, Faculty Office Building, 49 Jesse Hill Jr Dr SE, Atlanta, GA 30303.
    Affiliations
    Office of Health Promotion and Disease Prevention, Department of Medicine, Emory University School of Medicine, Atlanta, GA
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      Abstract

      Elevated lipoprotein(a) (Lp[a]) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in high-risk patients, an English-language search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening.

      Abbreviations and Acronyms:

      AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes), apo (apolipoprotein), CCHS (Copenhagen City Heart Study), CHD (coronary heart disease), CV (cardiovascular), CVD (CV disease), FH (familial hypercholesterolemia), HDL-C (high-density lipoprotein cholesterol), HPS2-THRIVE (Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events), HRT (hormone replacement therapy), KIV-2 (kringle IV type 2), LDL (low-density lipoprotein), LDL-C (LDL cholesterol), Lp(a) (lipoprotein(a)), Lp(a)-C (Lp(a) cholesterol), Lp(a)-P (Lp(a) particle), PN (pentanucleotide), RCT (randomized controlled trial), SNP (single-nucleotide polymorphism)
      Article Highlights
      • Lipoprotein(a) (Lp[a]) is an independent, causal risk factor for atherosclerosis that is highly heritable.
      • Each molecule of Lp(a) contains a single molecule of apolipoprotein (apo) B and a single apo(a) moiety secreted by the liver. Apo(a) moieties are biochemically heterogeneous, and a profile of predominantly smaller apo(a) isoforms is associated with higher cardiovascular (CV) risk.
      • Epidemiological evidence supports a continuous association between Lp(a) cholesterol levels and CV risk, with a steeper risk gradient when both Lp(a) and low-density lipoprotein cholesterol (LDL-C) are elevated (ie, “multiplier effect”).
      • Certain single-nucleotide polymorphisms of the LPA gene allele—rs10455872 and rs3798220 in whites and rs9457951 in blacks—may be associated with higher population CV risk levels.
      • Patients with both Lp(a) cholesterol levels above 30 mg/dL and Lp(a) particle levels (lipoprotein) above 72 nmol/L may be at particularly pronounced atherothrombotic risk and hence may warrant more intensive lipid-altering (and/or aspirin antiplatelet) therapy. However, even in the presence of elevated Lp(a), the first treatment target of lipid-altering therapy should be LDL-C, not Lp(a).
      Elevated lipoprotein(a) (Lp[a]) is an independent, causal risk factor for atherosclerotic cardiovascular disease (CVD).
      • Bennet A.
      • Di Angelantonio E.
      • Erqou S.
      • et al.
      Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.
      • Kamstrup P.R.
      • Tybjaerg-Hansen A.
      • Steffensen R.
      • Nordestgaard B.G.
      Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
      Discovered in 1963 by Kåre Berg's group, Lp(a) shares antigens with low-density lipoprotein (LDL)
      • Berg K.
      • Dahlén G.
      • Christophersen B.
      • Cook T.
      • Kjekshus J.
      • Pedersen T.
      Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study.
      • Berg K.
      A new serum type system in man–the Lp system.
      but is much denser, overlapping the band for high-density lipoprotein (HDL).
      • Krempler F.
      • Kostner G.M.
      • Bolzano K.
      • Sandhofer F.
      Turnover of lipoprotein (a) in man.
      This review (1) considers the biochemistry and potential pathophysiology of Lp(a), (2) surveys evidence linking LPA gene allelic variants and increased Lp(a) levels to increased cardiovascular (CV) risk, and (3) reviews potential screening and treatment strategies for the management of elevated Lp(a).
      An English-language search of PubMed and MEDLINE dating from January 1, 1975, through March 1, 2012, was conducted. The title terms lipoprotein(a) and Lp[a] were joined with terms including *apo*, atheroscl*, *cardiovasc*, *cholest*, *coronary*, heart disease, *lip*, myocardial infarction, risk factor, and stroke. MeSH key terms included human, drug therapy, and efficacy. For the clinical section, randomized controlled trials (RCTs) were eligible for inclusion, whereas the clinical algorithm section included data from RCTs, epidemiological studies, and consensus treatment guidelines.

      Overview of Biochemistry and Potential Pathophysiologic Effects

      Lipoprotein(a) includes a single molecule of apolipoprotein (apo) B100 covalently linked, in a 1:1 molar ratio, to apo(a). This unique glycoprotein-containing (hydrophilic) moiety is secreted by the liver.
      • Scanu A.M.
      Lp(a) lipoprotein—coping with heterogeneity.
      The 2 molecules are most likely complexed in the hepatocyte cellular membrane and are connected biochemically by a disulfide bridge through cysteine residues within apo(a) (Cys4057) and apo B100 (Cys4326).
      • Siekmeier R.
      • Scharnagl H.
      • Kostner G.M.
      • Grammer T.
      • Stojakovic T.
      • März W.
      Variation of Lp(a) plasma concentrations in health and disease.
      Although Lp(a) contains an LDL–receptor binding region, the hepatic LDL receptor likely plays a negligible role in Lp(a) catabolism. Rather, levels of Lp(a) are determined chiefly by the rate of de novo hepatic synthesis (∼5.0 mg/kg per day) (Figure 1). Catabolic pathways may include dissociation of apo(a) from apo B100, formation of differing molecular-weight fragments, and clearance largely by the kidney and spleen.
      • Frank S.
      • Hrzenjak A.
      • Blaschitz A.
      • Dohr G.
      • Kostner G.M.
      Role of various tissues in apo(a) fragmentation and excretion of fragments by the kidney.
      Figure thumbnail gr1
      Figure 1The “yin and yang” of lipoprotein(a) (Lp[a]) and low-density lipoprotein (LDL) cholesterol (LDL-C) levels. A, Although both lipoproteins contain apolipoprotein B (apo B100), their levels are influenced to differing extents by hepatic synthesis and fractional catabolic rate (FRC). B, Some patients with elevated Lp(a) can benefit from reductions in LDL-C (and vice versa). However, on the basis of extensive data relating elevated LDL-C to increased cardiovascular risk, Lp(a) should be targeted for reduction only after attaining maximal decreases in LDL-C. Approximately 45% of Lp(a) is composed of cholesterol. Hence, patients with marked Lp(a) elevations, such as those with nephrotic syndrome or those undergoing peritoneal dialysis, may be relatively resistant to LDL-C lowering by statins, which have minimal effects on Lp(a), including Lp(a)-trafficked cholesterol. FH = familial hypercholesterolemia.
      Within apo(a) is a unique region highly structurally homologous to plasminogen but devoid of protease activity. By competitively antagonizing plasminogen binding, Lp(a) may have played an ancestral role in hemostasis and wound healing at sites of arterial injury, attenuating fibrinolysis, promoting thrombosis/coagulation, and delivering cholesterol. Potential atherogenic effects may include arterial deposition of oxidized phospholipids by apo B100.
      • Tsimikas S.
      • Brilakis E.S.
      • Miller E.R.
      • et al.
      Oxidized phospholipids, Lp(a) lipoprotein, and coronary artery disease.

      Population-Based and Genetic Evidence

      Influence of Heredity on Lp(a) Structure, Levels, and CV Risk

      Lipoprotein(a) levels are codominantly inherited. The LPA gene is located on chromosome 6 (6q26-27). Although typically stable within individuals over time, Lp(a) levels are highly heterogeneous across individuals and populations, including members of different races: some black populations have up to 4-fold higher median Lp(a) levels than their white counterparts.
      • Marcovina S.M.
      • Albers J.J.
      • Wijsman E.
      • Zhang Z.
      • Chapman N.H.
      • Kennedy H.
      Differences in Lp[a] concentrations and apo[a] polymorphs between black and white Americans.
      • Sandholzer C.
      • Hallman D.M.
      • Saha N.
      • et al.
      Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups.
      Chief determinants of Lp(a) heterogeneity are the 30 different isoforms of apo(a), which are termed kringles because their biochemical structure resembles a Danish pastry. Each kringle contains approximately 80 amino acids and has a molecular weight of about 10 kDa.
      The key LPA gene sequence that influences Lp(a) levels and atherogenicity is the number of kringle IV type 2 (KIV-2) repeats. This number largely determines the size of apo(a) and levels of Lp(a). Smaller numbers of KIV-2 repeats (ie, <22) are associated with higher levels of Lp(a) and potentially more atherogenic apo(a). Small apo(a) Lp(a) may be associated with higher Lp(a) levels because the smaller molecules are more readily synthesized in the liver and less readily degraded by cellular organelles.
      In Europeans, a single-nucleotide polymorphism (SNP) in the LPA gene (rs3798220) was directly related to a small number of KIV-2 copies.
      • Luke M.M.
      • Kane J.P.
      • Liu D.M.
      • et al.
      A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
      In white adults, carriers of the rs3798220 allele were at more than a 3-fold increased risk of severe coronary heart disease (CHD) (adjusted odds ratio, 3.14; 95% CI, 1.51-6.56) and had more than a 5-fold increased median plasma Lp(a) level compared with noncarriers (P<.004).
      • Luke M.M.
      • Kane J.P.
      • Liu D.M.
      • et al.
      A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
      • Edelstein C.
      • Italia J.A.
      • Scanu A.M.
      Polymorphonuclear cells isolated from human peripheral blood cleave lipoprotein(a) and apolipoprotein(a) at multiple interkringle sites via the enzyme elastase: generation of mini-Lp(a) particles and apo(a) fragments.
      A second key gene sequence is the number of pentanucleotide (PN) repeats within the 5′ control region of the LPA gene. Allelic variants in the PN segment are in linkage disequilibrium with those in the KIV-2 sequence. In one study, the presence of KIV-2 allelic variants explained 9.7% of between-patient variance in Lp(a) levels, the PN allelic variant explained 3.5%, and the combination explained 19%.
      • Røsby O.
      • Berg K.
      LPA gene: interaction between the apolipoprotein(a) size ('kringle IV' repeat) polymorphism and a pentanucleotide repeat polymorphism influences Lp(a) lipoprotein level.

      LPA Gene SNPs and Risks of CVD

      Supportive evidence for associations between SNPs of the LPA gene and increased Lp(a) levels (and/or elevated CHD risk) include data from Mendelian randomization studies and other investigations.
      • Clarke R.
      • Peden J.F.
      • Hopewell J.C.
      • et al.
      PROCARDIS Consortium
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      • Clarke R.
      • Xu P.
      • Bennett D.
      • et al.
      International Study of Infarct Survival (ISIS) Collaborators
      Lymphotoxin-alpha gene and risk of myocardial infarction in 6,928 cases and 2,712 controls in the ISIS case-control study.
      • Lamon-Fava S.
      • Marcovina S.M.
      • Albers J.J.
      • et al.
      Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study.
      • Hopewell J.C.
      • Clarke R.
      • Parish S.
      • et al.
      Heart Protection Study Collaborative Group
      Lipoprotein(a) genetic variants associated with coronary and peripheral vascular disease but not with stroke risk in the Heart Protection Study.
      • Deo R.C.
      • Wilson J.G.
      • Xing C.
      • et al.
      Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.
      Concurrence of 2 SNPs of the LPA gene—rs10455872 and rs3798220—accounted for 36% of the variance in Lp(a) concentrations among those of European descent within the Precocious Coronary Artery Disease Investigation (PROCARDIS).
      • Clarke R.
      • Peden J.F.
      • Hopewell J.C.
      • et al.
      PROCARDIS Consortium
      Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
      • Helgadottir A.
      • Gretarsdottir S.
      • Thorleifsson G.
      • et al.
      Apolipoprotein(a) genetic sequence variants associated with systemic atherosclerosis and coronary atherosclerotic burden but not with venous thromboembolism.
      Among African Americans, the LPA gene allelic variant most strongly associated with Lp(a) levels was rs9457951
      • Deo R.C.
      • Wilson J.G.
      • Xing C.
      • et al.
      Single-nucleotide polymorphisms in LPA explain most of the ancestry-specific variation in Lp(a) levels in African Americans.
      ; its presence explained about 5% of the variance in Lp(a) levels.

      Epidemiological Evidence Associating Elevated Lp(a) with Increased CV Risk

      Table 1 summarizes findings relating elevations in Lp(a) cholesterol (Lp[a]-C) to increased CV risk in diverse populations, including individuals of different sexes, ages, and races.
      • Bennet A.
      • Di Angelantonio E.
      • Erqou S.
      • et al.
      Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
      • Virani S.S.
      • Brautbar A.
      • Davis B.C.
      • et al.
      Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.
      • Erqou S.
      • Kaptoge S.
      • Perry P.L.
      • et al.
      Emerging Risk Factors Collaboration
      Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study.
      • Ariyo A.A.
      • Thach C.
      • Tracy R.
      Cardiovascular Health Study Investigators
      Lp(a) lipoprotein, vascular disease, and mortality in the elderly.
      • von Eckardstein A.
      • Schulte H.
      • Cullen P.
      • Assmann G.
      Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.
      • Danesh J.
      • Collins R.
      • Peto R.
      Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies.
      Potential conclusions from these epidemiological studies included the following:
      • There is an independent, continuous association between elevated Lp(a) and CV risk that is statistically significant, although of lower magnitude, compared with associations of elevated LDL cholesterol (LDL-C) with risk
      • Associations of Lp(a) with CV risk exhibit “multiplier effects”; the risk gradient per increment in Lp(a) is steeper in the presence of markedly elevated LDL-C
      • Lp(a) levels vary 500- to 1000-fold (vs 2- to 5-fold for LDL-C)
      • Distributions of Lp(a) levels are skewed; medians tend to be lower than means and more useful in characterizing population levels
      • Higher proportions of African Americans exhibit Lp(a) levels of at least 30 mg/dL (to convert to μmol/L, multiply by 0.0357) (68% vs 26% of whites
        • Paultre F.
        • Pearson T.A.
        • Wei H.F.
        • et al.
        High levels of Lp(a) with a small apo(a) isoform are associated with coronary artery disease in African American and white men.
        ). Although African Americans may not experience an equally elevated CHD risk per increase in Lp(a) compared with whites (possibly because of lower prevalences of small apo[a] isoforms, as well as lower LDL-C and higher HDL cholesterol [HDL-C] levels in African Americans), elevated Lp(a) confers significant increased CHD risk
        • Virani S.S.
        • Brautbar A.
        • Davis B.C.
        • et al.
        Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.
        • Tyroler H.A.
        • Heiss G.
        • Schonfeld G.
        • Cooper G.
        • Heyden S.
        • Hames C.G.
        Apolipoprotein A-I, A-II and C- II in black and white residents of Evans County.
        • Morrison J.A.
        • deGroot I.
        • Kelly K.A.
        • et al.
        Black-white differences in plasma lipoproteins in Cincinnati schoolchildren (one-to-one pair matched by total plasma cholesterol, sex, and age).
        • Srinivasan S.R.
        • Frerichs R.R.
        • Webber L.S.
        • Berenson G.S.
        Serum lipoprotein profile in children from a biracial community: the Bogalusa Heart Study.
      • Associations between elevated Lp(a) and CHD in women are less robust than in men, possibly because of the cardioprotective and vasoprotective effects of endogenous estrogen in premenopausal women. In women, elevated Lp(a) may function as a stronger risk factor when combined with elevated inflammatory or thrombotic markers: in the Nurses' Health Study, an Lp(a)-C level of at least 30 mg/dL, in combination with elevated fibrinogen (≥400 mg/dL [to convert to μmol/L, multiply by 0.0294]) or C-reactive protein (≥3 mg/L [to convert to nmol/L, multiply by 9.524]) levels, placed women at more than 3-fold increased relative CHD risk (vs lower values of each pair of factors/markers).
        • Lamon-Fava S.
        • Marcovina S.M.
        • Albers J.J.
        • et al.
        Lipoprotein(a) levels, apo(a) isoform size, and coronary heart disease risk in the Framingham Offspring Study.
        • Wild S.H.
        • Fortmann S.P.
        • Marcovina S.M.
        A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants.
        • Shai I.
        • Rimm E.B.
        • Hankinson S.E.
        • et al.
        Lipoprotein(a) and coronary heart disease among women: beyond a cholesterol carrier?.
      Table 1Summary of Lipoprotein(a) (Lp[a]) Levels and Cardiovascular Disease (CVD) Risk in Epidemiological Studies
      apo = apolipoprotein; BL = baseline; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol); HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; OR = odds ratio; PY = person-years; RR = relative risk.
      ,
      SI conversion factors: To convert HDL-C and LDL-C values to mmol/L, multiply by 0.0259; to convert Lp(a) values to μmol/L, multiply by 0.0357.
      Reference, yearPopulationLp(a)-C level (mg/dL)CVD riskOther risk relationshipsComment
      Virani et al,
      • Virani S.S.
      • Brautbar A.
      • Davis B.C.
      • et al.
      Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.
      2012
       CVD, prospective cohort13,318 Racially representative (26% African American) US adults aged 45-64 y initially without CVD followed up for 20 yAfrican Americans: Highest (>24) vs lowest (≤6.1) quintile

      Whites: Highest (>13.5) vs lowest (≤1.5) quintile
      African Americans (highest vs lowest): HR, 1.35; 95% CI, 1.06-1.74

      Whites (highest vs lowest): HR, 1.27; 95% CI, 1.10-1.47
      Per 1-SD increase in log-Lp(a) (0.90 mg/dL for African Americans and 1.15 mg/dL for whites): 13% increase in relative CVD risk in African Americans (HR, 1.13; 95% CI, 1.04-1.23); 9% increase in relative CVD risk in whites (HR, 1.09; 95% CI, 1.04-1.15)“[E]levated Lp(a) levels were associated with incident CVD in blacks…and this risk was comparable to that in whites. Elevated Lp(a) should therefore be considered a risk factor for CVD in blacks.”
      • Virani S.S.
      • Brautbar A.
      • Davis B.C.
      • et al.
      Associations between lipoprotein(a) levels and cardiovascular outcomes in black and white subjects: the Atherosclerosis Risk in Communities (ARIC) Study.


      Risk for incident CVD was graded but statistically significant only for the highest compared with the lowest Lp(a) quintile
       Ischemic stroke, as aboveAs above>30 vs ≤10African Americans: Adjusted HR for ischemic stroke, 2.12; 95% CI, 1.48-3.03

      Whites: Adjusted HR for ischemic stroke, 1.65; 95% CI, 1.04-2.61
      African Americans: Adjusted HR for ischemic stroke in upper (>24 mg/dL) vs lower (≤6.1 mg/dL) Lp(a) quintiles, 1.60; 95% CI, 1.10-2.34

      Whites: Adjusted HR for ischemic stroke in upper (>13.5 mg/dL) vs lower (≤1.5 mg/dL) Lp(a) quintiles, 1.27; 95% CI, 0.92-1.76

      Women: Adjusted HR in upper (18.6 mg/dL) vs lower (≤2.1 mg/dL) Lp(a) quintiles, 2.07; 95% CI, 1.41-3.03

      Men: Adjusted HR in upper (>15.2 mg/dL) vs lower (≤1.7 mg/dL) Lp(a) quintile, 1.50; 95% CI, 1.05-2.14
      Adjusted HR for incident ischemic stroke greater in African Americans, who also tended to have higher Lp(a)-C levels (upper quintile >24 mg/dL) vs whites (upper quintile >13.5 mg/dL). Women also tended to have higher Lp(a) levels: upper quintile, 18.7-81.7 mg/dL vs 15.3-80.3 mg/dL in men
      Emerging Risk Factors Collaboration,
      • Erqou S.
      • Kaptoge S.
      • Perry P.L.
      • et al.
      Emerging Risk Factors Collaboration
      Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
      2009; meta-analysis of 36 prospective cohort studies
      126,634 Participants with no BL history of CHD or stroke. Predominantly Europeans and North AmericansUpper tertile of BL Lp(a)

      Lower tertile of BL Lp(a)
      CHD (adjusted), 5.6/1000 PY

      CHD (adjusted), 4.4/1000 PY
      Adjusted HR for CHD, 1.13 (95% CI, 1.09-1.18) per 3.5-fold higher Lp(a)

      Adjusted HR for ischemic stroke, 1.10 (95% CI, 1.02-1.18) per 3.5-fold higher Lp(a)
      “Under a wide range of circumstances, there are continuous, independent, and modest associations of Lp(a) concentrations with risk of CHD and stroke. Further studies are needed in nonwhite racial groups, particularly blacks and South Asian populations, which have different Lp(a) concentrations.”
      • Erqou S.
      • Kaptoge S.
      • Perry P.L.
      • et al.
      Emerging Risk Factors Collaboration
      Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
      Bennet et al,
      • Bennet A.
      • Di Angelantonio E.
      • Erqou S.
      • et al.
      Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.
      2008; case-control study
      2047 Adults with incident MI or CHD death followed up for 19 y and 3921 controls>14.9 vs <4.2 (upper vs lower tertile)Adjusted OR for CHD, 1.61; 95% CI, 1.41-1.84Model adjusted for age, sex, and period of recruitment

      OR for CHD, 1.77 (95% CI, 1.57-1.99) for upper vs lower Lp(a) quintile

      OR for CHD, 1.23 (95% CI, 1.16-1.31) for log-Lp(a) >1 SD

      OR for CHD, 1.45 (95% CI, 1.32-1.58) for upper vs lower Lp(a) tertile in meta-analysis of 31 prospective studies
      ORs for CHD were smaller per increments in Lp(a) vs total cholesterol. Further research is needed to determine if the graph of relative CHD risk vs BL Lp(a) is linear or curvilinear

      “Levels of Lp(a) are highly stable within individuals across many years….”
      • Bennet A.
      • Di Angelantonio E.
      • Erqou S.
      • et al.
      Lipoprotein(a) levels and risk of future coronary heart disease: large-scale prospective data.
      Kamstrup et al,
      • Kamstrup P.R.
      • Benn M.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study.
      2008; prospective cohort study
      9330 Adults initially free of CHD followed up for 10 yvs <5:

      5-29

      30-84

      85-119

      ≥120

      vs <5:

      5-29

      30-84

      85-119

      ≥120
      Women (HR for MI):

      1.1 (95% CI, 0.6-1.9)

      1.7 (95% CI, 1.0-3.1)

      2.6 (95% CI, 1.2-5.9)

      3.6 (95% CI, 1.7-7.7)

      Men (HR for MI):

      1.5 (95% CI, 0.9-2.3)

      1.6 (95% CI, 1.0-2.6)

      2.6 (95% CI, 1.2-5.5)

      3.7 (95% CI, 1.7-8.0)
      For each 10-mg/dL increase in Lp(a), significant 6%-9% increase in relative risk of CHD

      For each log-SD increase, significant 12%-17% increase in relative risk of CHD
      “Multiplier effect”:

      Absolute 10-y CHD risk increases sharply when Lp(a) is extremely elevated and other risk factors are present

      Absolute 10-y MI risk in hypertensive female smokers aged >60 y with Lp(a) ≥120 vs <5 mg/dL: 20% vs 10%

      Corresponding data in men:

      35% vs 19%
      Suk Danik et al,
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
      2006
       CHD, prospective cohort study27,791 Initially healthy middle-aged (≥45 y) US women followed up for 10 yUpper quintile median (65.5) vs lower quintile median (1.9)Adjusted HR for CHD, 1.35; 95% CI, 1.07-1.71; P<.001 for trend

      Adjusted HR for ischemic stroke, 1.87; 95% CI, 1.29-2.71; P=.003 for trend
      Moderate but significant correlation between Lp(a) and apo B or LDL-C levels

      Multiplier effect: HR is increased most when LDL-C is >121 mg/dL (median) and Lp(a) is >90th percentile; HR, 1.81; 95% CI, 1.48-2.23
      Multiplier effects. “[E]xtremely high levels of Lp(a) (≥90th percentile)...were associated with increased cardiovascular risk, particularly in women with high levels of LDL-C….the threshold and interaction effects observed do not support routine measurement of Lp(a) for cardiovascular stratification in women.”
      • Suk Danik J.
      • Rifai N.
      • Buring J.E.
      • Ridker P.M.
      Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.
       Stroke, as aboveAs aboveAs aboveAdjusted HR for ischemic stroke,1.87; 95% CI, 1.29-2.71As aboveAs above
      Ariyo et al,
      • Ariyo A.A.
      • Thach C.
      • Tracy R.
      Cardiovascular Health Study Investigators
      Lp(a) lipoprotein, vascular disease, and mortality in the elderly.
      2003; prospective cohort study
      5888 Community-dwelling adults >65 y followed up for 7.4 y (median)Top quintile (8.2-47.5) vs bottom quintile (0.1-1.2); ie, Lp(a) levels varied nearly 500-fold despite use of a single isoform-sensitive assayUnadjusted risk of vascular death in men: RR, 2.54; 95% CI, 1.59-4.08

      Unadjusted risk of all-cause mortality in men: RR, 1.76; 95% CI, 1.31-2.36
      Risk relationships were similar after adjusting for conventional CVD risk factors

      No association was seen between Lp(a) and vascular risk in elderly women
      Among older US adults, elevated Lp(a) is an independent predictor of stroke, death from vascular disease, and death from any cause in men but not in women. These data support the use of Lp(a) in predicting the risk of these events in older men
      von Eckardstein et al,
      • von Eckardstein A.
      • Schulte H.
      • Cullen P.
      • Assmann G.
      Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.
      2001; prospective cohort study
      788 Men aged 35-65 initially free of CVD and followed up for 10 y≥17

      <17
      CHD: 118/1000

      42/1000
      In men with Lp(a) ≥20 mg/dL and:

      Absolute CVD risk in upper 2 quintiles: RR, 2.7; 95% CI, 1.3-5.7; P=.006

      LDL-C ≥160 mg/dL: RR, 2.6; 95% CI, 1.2-5.7; P=.018)

      HDL-C ≤35 mg/dL: RR, 8.3; 95% CI, 2.0-35.5; P=.001
      Potential multiplier effect: relative risk of CVD with elevated Lp(a) increases in the presence of other CVD risk factors (eg, low levels of HDL-C, hypertension, high absolute CVD risk)

      “The effect of elevated Lp(a) on coronary risk was modulated by other [conventional CVD risk] factors.”
      • von Eckardstein A.
      • Schulte H.
      • Cullen P.
      • Assmann G.
      Lipoprotein(a) further increases the risk of coronary events in men with high global cardiovascular risk.
      Danesh et al,
      • Danesh J.
      • Collins R.
      • Peto R.
      Lipoprotein(a) and coronary heart disease: meta-analysis of prospective studies.
      2000; meta-analysis of 27 prospective studies with ≥1-y follow-up, 1988-1999
      Mostly whites in population-based cohorts. Weighted mean BL age, 51 y. Weighted mean follow-up, 10 yUpper vs lower tertileCombined risk ratio, 1.6; 95% CI, 1.4-1.8; P<.0001Not applicableNot applicable
      a apo = apolipoprotein; BL = baseline; CHD = coronary heart disease; HDL-C = high-density lipoprotein cholesterol); HR = hazard ratio; LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; OR = odds ratio; PY = person-years; RR = relative risk.
      b SI conversion factors: To convert HDL-C and LDL-C values to mmol/L, multiply by 0.0259; to convert Lp(a) values to μmol/L, multiply by 0.0357.

      Lp(a) Levels and CV Risk in Major Clinical Outcomes Studies

      Most landmark RCTs reporting that lipid therapies decreased CV risk—including the influential Coronary Drug Project
      Coronary Drug Project Research Group
      Clofibrate and niacin in coronary heart disease.
      • Canner P.L.
      • Berge K.G.
      • Wenger N.K.
      • et al.
      Fifteen year mortality in Coronary Drug Project patients: long-term benefit with niacin.
      —did not report treatment effects on Lp(a) or reported that Lp(a) levels did not predict coronary events.
      • Jauhiainen M.
      • Koskinen P.
      • Ehnholm C.
      • et al.
      Lipoprotein (a) and coronary heart disease risk: a nested case-control study of the Helsinki Heart Study participants.

      Scandinavian Simvastatin Survival Study

      In the Scandinavian Simvastatin Survival Study (4S)
      • Berg K.
      • Dahlén G.
      • Christophersen B.
      • Cook T.
      • Kjekshus J.
      • Pedersen T.
      Lp(a) lipoprotein level predicts survival and major coronary events in the Scandinavian Simvastatin Survival Study.
      subgroup analysis in 4402 high-risk men with CHD, markedly elevated LDL-C, and data on Lp(a), results were compared in patients within the upper half of the Lp(a) distribution (Lp[a] >91.1 U/L) with those in the lower half of the distribution. Findings included the following:
      • Numbers of deaths were significantly lower in the bottom (192 deaths) vs the top (240 deaths) half of the Lp(a) distribution in the simvastatin and placebo groups combined (P<.05)
      • Numbers of coronary events were significantly lower in the bottom (487 patients with MCE events) vs the top (555 patients with MCE events) half of the Lp(a) distribution in both treatment groups combined (P<.03)
      • Baseline Lp(a) concentrations were significantly (directly) predictive of both (1) mortality in the simvastatin group (P=.013) and (2) coronary events in each treatment group (P≤.010) in adjusted logistic regression analyses.

      Familial Atherosclerosis Treatment Study

      In the Familial Atherosclerosis Treatment Study (FATS),
      • Maher V.M.
      • Brown B.G.
      • Marcovina S.M.
      • Hillger L.A.
      • Zhao X.Q.
      • Albers J.J.
      Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).
      a post hoc analysis revealed a correlation between on-treatment Lp(a) levels and atherosclerotic progression, with an interaction between Lp(a) and LDL-C reductions. The baseline mean Lp(a) level of approximately 35 mg/dL and median Lp(a) level of 20 mg/dL were consistent with the expected skewed distribution for this lipoprotein. Among 120 participants completing the study, changes from baseline in Lp(a) included an 11.4% reduction in the conventional therapy group (placebo), a 9.9% decrease in a bile acid resin–lovastatin arm, and a 25.8% decline in the bile acid resin−niacin arm.
      • Brown G.
      • Albers J.J.
      • Fisher L.D.
      • et al.
      Regression of coronary artery disease as a result of intensive lipid-lowering therapy in men with high levels of apolipoprotein B.
      There was a sharp increase in CHD incidence over the serum Lp(a) range of 24 to 36 mg/dL (Figure 2). However, changes in Lp(a) were not independently predictive of atherosclerotic lesion regression. Lipoprotein(a) levels emerged as the best correlates to baseline CHD severity (r=0.30; multivariate adjusted P<.001). There was an interaction between changes in LDL-C and in Lp(a): when LDL-C decreased modestly, on-treatment Lp(a) levels were important CHD correlates. However, when LDL-C decreased markedly, “persistent elevations of Lp(a) were no longer atherogenic or clinically threatening.”
      • Maher V.M.
      • Brown B.G.
      • Marcovina S.M.
      • Hillger L.A.
      • Zhao X.Q.
      • Albers J.J.
      Effects of lowering elevated LDL cholesterol on the cardiovascular risk of lipoprotein(a).
      Figure thumbnail gr2
      Figure 2Effects of different pharmacotherapies on lipoprotein(a) cholesterol (Lp[a]-C) and the incidence of coronary heart disease (CHD). AIM-HIGH = Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health; FATS = Familial Atherosclerosis Treatment Study; HATS = HDL-Atherosclerosis Treatment Study; HERS = Heart and Estrogen/progestin Replacement Study (high-Lp[a] quartile subgroup); HRT = hormone replacement therapy.

      HDL-Atherosclerosis Treatment Study

      As in the FATS, the incidence of CHD in the HDL-Atherosclerosis Treatment Study (HATS)
      • Brown B.G.
      • Zhao X.Q.
      • Chait A.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      increased in the same direction as changes in Lp(a), albeit more sharply and over a narrower range of Lp(a) values (Figure 2). The baseline mean Lp(a) level ranged from 21 to 30 mg/dL in different treatment groups. Lipoprotein(a) decreased from baseline by 14.8% (from 27 to 23 mg/dL) in the niacin-statin group compared with 3.4% with placebo (from 30 to 29 mg/dL). The study did not report correlations between changes in Lp(a) and either percent stenosis or CV event incidence.
      • Brown B.G.
      • Zhao X.Q.
      • Chait A.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.

      Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes

      The Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH)
      • Investigators A.I.M.-H.I.G.H.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      RCT evaluated the hypothesis that increasing HDL-C (and improving other lipid/lipoprotein end points) would confer significantly enhanced cardioprotective effects compared with control of LDL-C alone. Although Lp(a) decreased by 24.9% with extended-release niacin (1.5-2.0 g) combined with simvastatin (40-80 mg) vs 6.4% with placebo at treatment year 1, incidences of CV events at year 3 were similar in the 2 treatment groups
      • Investigators A.I.M.-H.I.G.H.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      (Figure 2).
      Study limitations may have reduced the capacity to determine associations between changes in Lp(a) and coronary events on active treatment compared with placebo. Most patients in both treatment arms had LDL-C near or at goal (median, 72 mg/dL) on baseline statins, and significantly higher proportions of the control group received ezetimibe or maximum-dose simvastatin (vs the active treatment group). These interventions may have served to “delipidate” or otherwise stabilize plaque in both study arms, minimizing discernible on-treatment differences.

      The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events

      The Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE)

      MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, Medical Sciences Division, Oxford University. HPS2-THRIVE: Preliminary results. January 2013. University of Oxford CTSU website. http://www.ctsu.ox.ac.uk/hps2-thrive/index.htm. Updated May 2, 2013. Accessed September 15, 2013.

      involved over 25,000 individuals with preexisting vascular disease who were initially treated with simvastatin (40 mg) and ezetimibe (if needed). Patients were then randomized to either niacin in combination with laropiprant or to placebo. Laropiprant was added to attenuate niacin-induced, receptor-mediated, prostaglandin-driven vasodilation with subsequent subcutaneous flushing. In the HPS2-THRIVE, treatment with niacin-laropiprant together with statins and/or ezetimibe conferred no cardioprotective benefit compared with background statin-ezetimibe therapy alone in reducing CVD events.
      Similar to the findings in the AIM-HIGH trial,
      • Investigators A.I.M.-H.I.G.H.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      in the HPS2-THRIVE there was no incremental benefit of niacin when added to a statin in patients whose LDL-C levels were near or at LDL-C goal at baseline: 63 mg/dL in the HPS2-THRIVE and 72 mg/dL in the AIM-HIGH study.
      • Investigators A.I.M.-H.I.G.H.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • et al.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.

      MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, Medical Sciences Division, Oxford University. HPS2-THRIVE: Preliminary results. January 2013. University of Oxford CTSU website. http://www.ctsu.ox.ac.uk/hps2-thrive/index.htm. Updated May 2, 2013. Accessed September 15, 2013.

      However, in the HPS2-THRIVE, laropiprant treatment may have complicated associations between lipid-altering treatment and CVD rates.

      Overview of Currently Approved Treatments that Lower Lp(a)

      Lipid Therapies

      Niacin monotherapy and niacin-containing regimens are the only lipid pharmacological treatments that consistently, markedly, and dose-dependently lower Lp(a) and have been recognized as such by consensus clinical guideline panels.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • et al.
      European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status.
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      • Marcovina S.M.
      • Koschinsky M.L.
      • Albers J.J.
      • Skarlatos S.
      Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions.
      Percent lowering tends to be greater at higher baseline Lp(a) values. In clinical trials, niacin-containing regimens (with minimum daily niacin doses of ≥1.0 g) reduced Lp(a) by approximately 7% to 40%.
      • Ballantyne C.M.
      • Davidson M.H.
      • McKenney J.
      • Keller L.H.
      • Bajorunas D.R.
      • Karas R.H.
      Comparison of the safety and efficacy of a combination tablet of niacin extended release and simvastatin vs simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I study).
      • Chen F.
      • Maccubbin D.
      • Yan L.
      • et al.
      Lipid-altering efficacy and safety profile of co-administered extended release niacin/laropiprant and simvastatin versus atorvastatin in patients with mixed hyperlipidemia.
      • Ballantyne C.M.
      • Davidson M.H.
      • McKenney J.M.
      • Keller L.H.
      • Bajorunas D.R.
      • Karas R.H.
      Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study.
      • Insull Jr., W.
      • Basile J.N.
      • Vo A.N.
      • Jiang P.
      • Thakkar R.
      • Padley R.J.
      Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: the SUPREME Study.
      • Maccubbin D.
      • Bays H.E.
      • Olsson A.G.
      • et al.
      Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.
      • Karas R.H.
      • Kashyap M.L.
      • Knopp R.H.
      • Keller L.H.
      • Bajorunas D.R.
      • Davidson M.H.
      Long-term safety and efficacy of a combination of niacin extended release and simvastatin in patients with dyslipidemia: the OCEANS study.
      • Capuzzi D.M.
      • Morgan J.M.
      • Weiss R.J.
      • Chitra R.R.
      • Hutchinson H.G.
      • Cressman M.D.
      Beneficial effects of rosuvastatin alone and in combination with extended-release niacin in patients with a combined hyperlipidemia and low high-density lipoprotein cholesterol levels.
      • Kashyap M.L.
      • McGovern M.E.
      • Berra K.
      • et al.
      Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia.
      • Guyton J.R.
      • Blazing M.A.
      • Hagar J.
      • et al.
      Niaspan-Gemfibrozil Study Group
      Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol.
      • Goldberg A.
      • Alagona Jr., P.
      • Capuzzi D.M.
      • et al.
      Multiple-dose efficacy and safety of an extended-release form of niacin in the management of hyperlipidemia.
      • Morgan J.M.
      • Capuzzi D.M.
      • Guyton J.R.
      A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients.
      • Morgan J.M.
      • Capuzzi D.M.
      • Guyton J.R.
      • et al.
      Treatment effect of Niaspan, a controlled-release niacin, in patients with hypercholesterolemia: a placebo-controlled trial.
      • Capuzzi D.M.
      • Guyton J.R.
      • Morgan J.M.
      • et al.
      Efficacy and safety of an extended-release niacin (Niaspan): a long-term study.
      • Seed M.
      • O'Connor B.
      • Perombelon N.
      • O'Donnell M.
      • Reaveley D.
      • Knight B.L.
      The effect of nicotinic acid and acipimox on lipoprotein(a) concentration and turnover.
      • Carlson L.A.
      • Hamsten A.
      • Asplund A.
      Pronounced lowering of serum levels of lipoprotein Lp(a) in hyperlipidaemic subjects treated with nicotinic acid.
      • Goldberg A.C.
      Clinical trial experience with extended-release niacin (Niaspan): dose-escalation study.
      • McKenney J.M.
      • Jones P.H.
      • Bays H.E.
      • et al.
      Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study).
      At daily doses of 1.0 g of niacin (among studies in which specific niacin dosing data are available), niacin-containing regimens reduced Lp(a) by approximately 5% to 17%.
      • Ballantyne C.M.
      • Davidson M.H.
      • McKenney J.
      • Keller L.H.
      • Bajorunas D.R.
      • Karas R.H.
      Comparison of the safety and efficacy of a combination tablet of niacin extended release and simvastatin vs simvastatin monotherapy in patients with increased non-HDL cholesterol (from the SEACOAST I study).
      • Chen F.
      • Maccubbin D.
      • Yan L.
      • et al.
      Lipid-altering efficacy and safety profile of co-administered extended release niacin/laropiprant and simvastatin versus atorvastatin in patients with mixed hyperlipidemia.
      • Ballantyne C.M.
      • Davidson M.H.
      • McKenney J.M.
      • Keller L.H.
      • Bajorunas D.R.
      • Karas R.H.
      Comparison of the efficacy and safety of a combination tablet of niacin extended-release and simvastatin with simvastatin 80 mg monotherapy: the SEACOAST II (high-dose) study.
      • Insull Jr., W.
      • Basile J.N.
      • Vo A.N.
      • Jiang P.
      • Thakkar R.
      • Padley R.J.
      Efficacy and safety of combination therapy with niacin extended-release and simvastatin versus atorvastatin in patients with dyslipidemia: the SUPREME Study.
      • Maccubbin D.
      • Bays H.E.
      • Olsson A.G.
      • et al.
      Lipid-modifying efficacy and tolerability of extended-release niacin/laropiprant in patients with primary hypercholesterolaemia or mixed dyslipidaemia.
      • Kashyap M.L.
      • McGovern M.E.
      • Berra K.
      • et al.
      Long-term safety and efficacy of a once-daily niacin/lovastatin formulation for patients with dyslipidemia.
      • Morgan J.M.
      • Capuzzi D.M.
      • Guyton J.R.
      A new extended-release niacin (Niaspan): efficacy, tolerability, and safety in hypercholesterolemic patients.
      • McKenney J.M.
      • Jones P.H.
      • Bays H.E.
      • et al.
      Comparative effects on lipid levels of combination therapy with a statin and extended-release niacin or ezetimibe versus a statin alone (the COMPELL study).
      Niacin therapy likely reduces Lp(a) by decreasing mobilization of free fatty acids from adipose tissues. Reduced trafficking of unesterified fatty acids to the liver may lower Lp(a) by attenuating hepatic synthesis of apo B. Niacin stimulates degradation of apo B−containing lipoproteins and decreases triglyceride synthesis by inhibiting diacylglycerol acyltransferase 2.
      • Ganji S.H.
      • Kamanna V.S.
      • Kashyap M.L.
      Niacin and cholesterol: role in cardiovascular disease (review).
      Possibly because hepatic complexation of apo(a) to apo B100 is facilitated by intracellular triglyceride synthesis, niacin-dependent decreases in Lp(a) may be especially marked in patients with hypertriglyceridemia. It is also possible that niacin inhibits hepatocyte linkage of oxidized lipids to apo(a), generating a relatively benign species of apo(a).

      Estrogen or Hormone Replacement Therapy

      Elevated Lp(a) is associated with increased coronary risk in both premenopausal and postmenopausal women.
      • Wild S.H.
      • Fortmann S.P.
      • Marcovina S.M.
      A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants.
      • Orth-Gomér K.
      • Mittleman M.A.
      • Schenck-Gustafsson K.
      • et al.
      Lipoprotein(a) as a determinant of coronary heart disease in young women.
      However, as with the case for pharmacologically reducing Lp(a) in order to decrease CV risk in overall populations, the argument as related to postmenopausal women is controversial. A US Preventive Services Task Force recently issued a recommendation against routine use of hormone replacement therapy (HRT) to prevent chronic conditions, including unopposed estrogen to prevent CHD.

      US Preventive Services Task Force. Menopausal Hormone Therapy for the Primary Prevention of Chronic Conditions: Clinical Summary of US Preventive Services Task Force Recommendation. AHRQ Publication No. 12-05168-EF-4. http://www.uspreventiveservicestaskforce.org/uspstf12/menohrt/menohrtsum.htm. Published October 2012. Accessed September 15, 2013.

      Clinical and observational studies in women with or without a history of CHD have shown potential increases in the risks of thromboembolic stroke, venous thromboembolism, and cholecystitis among women receiving HRT; these and other studies have largely excluded a role for long-term HRT to prevent chronic diseases, including CHD, in postmenopausal women.
      • Hulley S.
      • Grady D.
      • Bush T.
      • et al.
      Heart and Estrogen/progestin Replacement Study (HERS) Research Group
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
      • Furberg C.D.
      • Vittinghoff E.
      • Davidson M.
      • et al.
      Subgroup interactions in the Heart and Estrogen/Progestin Replacement Study: lessons learned.
      • Anderson G.L.
      • Limacher M.
      • Assaf A.R.
      • et al.
      Women's Health Initiative Steering Committee
      Effects of conjugated equine estrogen in postmenopausal women with hysterectomy: the Women's Health Initiative randomized controlled trial.
      • Nelson H.D.
      • Humphrey L.L.
      • Nygren P.
      • Teutsch S.M.
      • Allan J.D.
      Postmenopausal hormone replacement therapy: scientific review.
      The Heart and Estrogen/progestin Replacement Study (HERS), a major study of HRT for secondary prevention in postmenopausal women, did not find any decrease in overall CV risk with HRT despite lowering of Lp(a) vs placebo
      • Hulley S.
      • Grady D.
      • Bush T.
      • et al.
      Heart and Estrogen/progestin Replacement Study (HERS) Research Group
      Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.
      (Figure 2).
      Multivariate adjusted relative hazards of primary CHD events and coronary revascularization in the placebo group tended to be significantly higher among postmenopausal women with greater baseline Lp(a)-C levels (eg, in the fourth quartile [55.0-236.0 mg/dL] compared with the first quartile [0-7.0 mg/dL]; P≤.04 for trends).
      • Shlipak M.G.
      • Simon J.A.
      • Vittinghoff E.
      • et al.
      Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.
      Women with elevated Lp(a)—either above the median or in higher quartiles of the distribution—derived greater potential cardioprotective effects from HRT than their counterparts with lower Lp(a) values; there was a significant interaction of baseline Lp(a), HRT treatment, and CHD risk.
      • Shlipak M.G.
      • Simon J.A.
      • Vittinghoff E.
      • et al.
      Estrogen and progestin, lipoprotein(a), and the risk of recurrent coronary heart disease events after menopause.

      Other Nonpharmacological Intervention: LDL Apheresis

      Low-density lipoprotein apheresis is typically reserved for patients with profoundly elevated lipoprotein levels.
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      Low-density lipoprotein apheresis techniques available in North America include dextran sulfate cellulose adsorption and heparin-induced extracorporeal LDL-C precipitation. Most LDL apheresis procedures are well tolerated, with maximum 5% incidences of most adverse events (including bradykinin-driven anaphylactoid responses and reductions in HDL-C).
      • Thompson G.R.
      HEART-UK LDL Apheresis Working Group
      Recommendations for the use of LDL apheresis.
      In the Low-Density Lipoprotein Apheresis Angioplasty Restenosis Trial, the rate of restenosis after percutaneous coronary intervention was 21% in 42 patients with at least 50% reductions in Lp(a), compared to 50% among 24 patients with lower percent reductions in Lp(a), using LDL apheresis via dextran sulfate cellulose adsorption (P<.05).
      • Daida H.
      • Lee Y.J.
      • Yokoi H.
      • et al.
      Low-Density Lipoprotein Apheresis Angioplasty Restenosis Trial (L-ART) Group
      Prevention of restenosis after percutaneous transluminal coronary angioplasty by reducing lipoprotein (a) levels with low-density lipoprotein apheresis.
      • Daida H.
      • Yamaguchi H.
      Clinical application and effectiveness of low-density lipoprotein apheresis in the treatment of coronary artery disease.
      After percutaneous coronary intervention, a restenosis rate of 12.5% was observed after LDL apheresis with adjunctive niacin-pravastatin that reduced Lp(a) by at least 50% compared to 53% with lower percent Lp(a) reductions.

      Suggested Treatment Algorithm

      A new clinical algorithm to inform lipid-altering treatment decision making in patients with elevated Lp(a) focuses largely on consensus guidelines and synthesis of findings from recent studies (Figure 3). While noting that niacin can lower Lp(a) by up to 30%, the National Cholesterol Education Program Adult Treatment Panel III stated that it was unclear whether such Lp(a) reductions induced by niacin decrease CHD risk: “the quantitative contribution of elevated Lp(a) to CHD risk beyond the major risk factors is uncertain. This uncertainty extends both to individuals and populations; in the latter, the frequency of elevated Lp(a) is not as high as for the major risk factors.”
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      Figure thumbnail gr3
      Figure 3Suggested clinical algorithm for assessment and treatment of elevated low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a) cholesterol (Lp[a]-C) using major lipid-altering therapies to reduce cardiovascular risk. Elevated LDL-C should be the primary target of therapy. Because Lp(a) may mediate thrombogenic as well as atherogenic effects, some patients with elevated Lp(a) may be candidates for antiplatelet therapies (eg, aspirin). *The optional category includes a 10-year Framingham risk score of 5% to 19% or a CHD risk equivalent. BAR = bile acid resin (sequestrant); CAI = cholesterol absorption inhibitor; CHD = coronary heart disease; CVD = cardiovascular disease; LDL = low-density lipoprotein; NCEP = National Cholesterol Education Program.
      As mentioned previously, no RCT involving lipid pharmacotherapy has explicitly ascribed reduced CV risk specifically to the lowering of Lp(a) with either niacin or other pharmacotherapies. Given the strong evidence base supporting the cardioprotective benefits of lowering LDL-C with statins, and the multiplier effects on CV risk of elevated Lp(a) when in the presence of increased LDL-C levels, the first lipid treatment target should be to reduce LDL-C. A prospective cohort study at the Cleveland Clinic (a GeneBank study) revealed that the attributable risk of CV events associated with elevated Lp(a) is markedly attenuated in patients with LDL-C levels below 70 mg/dL after aggressive pharmacotherapy.
      • Nicholls S.J.
      • Tang W.H.
      • Scoffone H.
      • et al.
      Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy.
      Lipoprotein(a) screening can also improve discrimination and stratification of CV risk. Such testing should be conducted in patients with elevated LDL-C together with a personal or family history of premature CVD, familial hypercholesterolemia (FH), recurrent cardiovascular events despite maximum statin therapy, or insufficient LDL-C responses to statins (Figure 3). If the Lp(a)-C level is at or above 30 mg/dL (>75th percentile in most population distributions), clinicians should institute maximum-potency statins or statin combinations (with sequestrants or ezetimibe) to decrease LDL-C levels to below 70 mg/dL or achieve a minimum 50% reduction in LDL-C. (However, further LDL-C reductions on treatment with either ezetimibe monotherapy or bile acid resins apart from cholestyramine have not been associated with significant incremental reductions in incidences of CVD.)
      If the LDL-C level remains at or above 70 to 100 mg/dL, adding niacin, up to 2 g daily, is a rational approach to further reduce apo B100, which is a component of both LDL-C and Lp(a). Of note, niacin treatment is not recommended if patients are using high-potency statins and their LDL-C levels are already at goal (<70 mg/dL). Confirming the multiplier effect of elevated Lp(a) in the presence of elevated LDL-C were findings from the recent large angiographic study from the GeneBank program.
      • Nicholls S.J.
      • Tang W.H.
      • Scoffone H.
      • et al.
      Lipoprotein(a) levels and long-term cardiovascular risk in the contemporary era of statin therapy.
      Baseline Lp(a)-C levels of 30 mg/dL or above were significantly associated with 3-vessel/obstructive disease or major adverse coronary events (death, myocardial infarction, stroke, revascularization) in patients with LDL-C levels ranging from 70 to 100 mg/dL (P=.049) and above 100 mg/dL (P=.02) but not below 70 mg/dL (P=.77).
      In addition, in a recent subgroup analysis of the AIM-HIGH trial, baseline and on-treatment levels of Lp(a) significantly predicted CV events in each treatment group; however, extended-release niacin treatment reduced Lp(a) by 21% but did not significantly affect CV risk.

      Albers JJ, Slee A, O'Brien K, et al. Relationship of apolipoproteins A-1 and B, and lipoprotein (a) to cardiovascular outcomes in the AIM-HIGH trial [published online ahead of print August 7, 2013]. J Am Coll Cardiol. http://dx.doi.org/10.1016/j.jacc.2013.06.051.

      Data from a larger subgroup analysis of the HPS2-THRIVE in patients with different levels of Lp(a) are eagerly awaited.
      A recent systematic review and meta-regression analysis of 11 RCTs including nearly 10,000 patients revealed that niacin treatment was associated with a significant decline in any CHD (P=.02) or any CVD (P=.007) event.
      • Lavigne P.M.
      • Karas R.H.
      The current state of niacin in cardiovascular disease prevention: a systematic review and meta-regression.
      However, the analysis included the AIM-HIGH study but not the HPS2-THRIVE. Subgroup analyses, potentially including patient segments with elevated Lp(a), may show incremental benefits of niacin when administered in combination regimens.
      • Lavie C.J.
      • DiNicolantonio J.J.
      • Milani R.V.
      • O'Keefe J.H.
      Niacin therapy lives for another day—maybe? [letter].
      The Lp(a)-lowering effects of niacin must be weighed against potential adverse effects, many of which are time-limited/reversible in individual patients: flushing, gastrointestinal disorders (eg, peptic ulcer), reduced insulin sensitivity, increased uric acid, and atrial fibrillation.
      Returning to the algorithm, if the LDL-C level remains at 160 to 200 mg/dL or higher, or the patient has progressive CHD on maximal therapy, LDL apheresis should be considered. However, this use of LDL apheresis and its use to specifically lower Lp(a) have not been approved by the US Food and Drug Administration and are hence considered off-label. A repeated Lp(a) measurement is generally not recommended in consensus guidelines but may be useful in evaluating responses to therapy.
      A position statement by the National Lipid Association for patients with FH recommended that physicians consider LDL apheresis for patients using maximal drug therapy (1) whose LDL-C level is at least 200 mg/dL in the presence of 2 risk factors or a high Lp(a)-C level (≥50 mg/dL) and (2) who have LDL-C levels at or above 160 mg/dL and very high-risk characteristics, including established CHD, other CVD, or diabetes.
      • Ito M.K.
      • McGowan M.P.
      • Moriarty P.M.
      National Lipid Association Expert Panel on Familial Hypercholesterolemia
      Management of familial hypercholesterolemias in adult patients: recommendations from the National Lipid Association Expert Panel on Familial Hypercholesterolemia.
      At this writing, LDL apheresis is not a widely available treatment.
      The clinical algorithm identifies an Lp(a)-C level above 30 mg/dL as a threshold to institute high-potency statins to reduce LDL-C levels to below 70 mg/dL (or to attain at least a 50% LDL-C reduction) in order to minimize CVD risk. If high-intensity statin therapy is inadequate to achieve this goal, then other evidence-based LDL–lowering therapies should be considered in combination with statins. If LDL-C values remain above 70 to 100 mg/dL despite high-intensity statin therapy with or without other LDL–lowering therapies, then niacin therapy should be contemplated as a further means to reduce all apo B−containing lipoproteins, including LDL and Lp(a). The algorithm thus represents a stepped-care approach to minimize the residual risk conferred by an elevated Lp(a) level. The role of Lp(a) screening is not specifically part of a strategy to reduce CVD risk by lowering Lp(a) but rather a way to identify patients who warrant more aggressive overall lipid-lowering therapy to reduce all apo B−containing lipoproteins.
      According to the European Atherosclerosis Society, Lp(a)-C should be lowered to below the 80th percentile, or less than 50 mg/dL, using niacin in patients with the characteristics noted previously, including FH and recurrent CVD
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • et al.
      European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status.
      (Figure 3). However, desirable Lp(a)-C levels may be closer to below 30 or 40 mg/dL. When the Lp(a)-C level is above 30 mg/dL and the Lp(a) particle (Lp[a]-P) level is above 72 nmol/L (mean conversion factor of 2.4:1
      • Brown W.V.
      • Ballantyne C.M.
      • Jones P.H.
      • Marcovina S.
      Management of Lp(a).
      ), the patient should be considered at elevated atherosclerotic and thrombogenic risk and may be a candidate for antiplatelet (aspirin), as well as lipid-altering, therapy. (See the “Lp(a) Measurement Issues” section for further information about assaying different Lp[a] subfractions.)
      In a meta-analysis, a US Preventive Services Task Force panel also identified an Lp(a)-C level of 30 mg/dL as a potential decision limit, noting that the relative risk of CHD increased by nearly 60% in those with levels above (vs below) this threshold.

      Helfand M, Buckley D, Fleming C, et al. Screening for Intermediate Risk Factors for Coronary Heart Disease: Systematic Evidence Synthesis. Evidence Syntheses, No. 73, 2009. AHQR Publication No. 10-05141-EF-1. http://www.ncbi.nlm.nih.gov/books/NBK35208. Accessed September 15, 2013.

      US Preventive Services Task Force
      Using nontraditional risk factors in coronary heart disease risk assessment: US Preventive Services Task Force recommendation statement.
      Some clinical laboratories use 30 mg/dL as a cut point to define elevated Lp(a)-C. A single Lp(a)-C measure below 25 mg/dL largely rules out elevated Lp(a) as a contributor to advanced CV risk in an individual. Recent guidelines from the Canadian Cardiovascular Society also noted that Lp(a)-C levels above 30 mg/dL are associated with increased CV risk.
      • Anderson T.J.
      • Grégoire J.
      • Hegele R.A.
      • et al.
      2012 Update of the Canadian Cardiovascular Society Guidelines for the Diagnosis and Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult.
      Recently reported data from the Copenhagen City Heart Study (CCHS) indicated that the presence of extremely elevated Lp(a)-C—above the 80th percentile (>47 mg/dL)— significantly enhanced prediction of coronary events compared with existing conventional CHD risk factors alone.
      • Kamstrup P.R.
      • Tybjærg-Hansen A.
      • Nordestgaard B.G.
      Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.
      As shown in the algorithm, Lp(a) can be measured in order to further stratify selected individuals with intermediate-risk profiles, including a 10-year Framingham risk score of 5% to 19% or a CHD risk equivalent. Given the findings from the CCHS, it is plausible that the presence of an Lp(a)-C level above the 80th percentile (>50 mg/dL) could move such an intermediate-risk patient into the secondary prevention category, warranting more aggressive apo B−lowering therapy via statins and/or niacin. The CCHS data could also potentially support the use of a higher Lp(a)-C cut point (ie, >80th percentile; ≥50 mg/dL) to predict CHD and inform clinical decisions.
      LPA genotyping may assist in determining the presence of allelic gene variants (eg, rs3798220, rs10455872, rs9457951, rs41272110) that may be associated with increased Lp(a) levels and/or elevated CV risk. The presence of these SNPs could, in theory, signal a potential benefit from more intensive treatment of Lp(a) and LDL-C, either to lower levels or to higher absolute decreases (mg/dL) from baseline. Patients with these gene variants (including carriers) may also benefit from addition of aspirin or other antiplatelet therapies to reduce coronary events; a precedent for this strategy was established in both the Women's Health Study and the Atherosclerosis in Communities (ARIC) trial. In these studies, carriers of the rs3798220 allele experienced a significant decrease in coronary events while receiving aspirin therapy, whereas noncarriers did not.
      • Chasman D.I.
      • Shiffman D.
      • Zee R.Y.
      • et al.
      Polymorphism in the apolipoprotein(a) gene, plasma lipoprotein(a), cardiovascular disease, and low-dose aspirin therapy.
      • Li Y.
      • Luke M.M.
      • Shiffman D.
      • Devlin J.J.
      Genetic variants in the apolipoprotein(a) gene and coronary heart disease.
      • Shiffman D.
      • Chasman D.I.
      • Ballantyne C.M.
      • Nambi V.
      • Devlin J.J.
      • Boerwinkle E.
      Coronary heart disease risk, aspirin use, and apolipoprotein(a) 4399Met allele in the Atherosclerosis Risk in Communities (ARIC) study.
      • Ridker P.M.
      • Cook N.R.
      • Lee I.M.
      • et al.
      A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women.
      In summary, the clinical algorithm presented in this article is consistent with the National Cholesterol Education Program Adult Treatment Panel III view that measuring Lp(a) is an option that may help to further risk stratify patients with a “strong family history of premature CHD or...with...familial hypercholesterolemia.”
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      Among such patients, “an elevated Lp(a)...presents the option to raise a person's risk to a higher level…The finding of a high Lp(a) could count as a second risk factor”
      National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)
      Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report.
      to warrant treatment of LDL-C to a lower target.

      Lp(a) Measurement Issues

      For decades, issues surrounding Lp(a) measurement and standardization have complicated interpretations of Lp(a) levels in the context of CVD risk. In addition, most clinical laboratories have used various methods of reporting Lp(a) levels that have been confusing to clinicians. Some clinical laboratories are still reporting Lp(a) mass, whereas others report Lp(a)-C, Lp(a) protein, or Lp(a)-P. This variability has created confusion for clinicians who are not knowledgeable about how clinical laboratories measure and report Lp(a) values. Over the years, several efforts have been undertaken to enhance standardization of the measurement and reporting of Lp(a) levels.
      A National Heart, Lung, and Blood Institute panel advocated expression of Lp(a) levels in nmol/L of protein, in order to capture the total number of Lp(a)-Ps (by analogy to apo B signifying the total number of atherogenic lipoprotein particles). According to the National Heart, Lung, and Blood Institute, Lp(a) levels above the 75th percentile are associated with increased CV risk; in whites (in the Framingham Heart Study), this percentile translates to above 75 nmol/L of Lp(a) protein.
      • Marcovina S.M.
      • Koschinsky M.L.
      • Albers J.J.
      • Skarlatos S.
      Report of the National Heart, Lung, and Blood Institute Workshop on Lipoprotein(a) and Cardiovascular Disease: recent advances and future directions.
      If an apo(a) isoform−sensitive assay is used, Lp(a) protein values above 50 nmol/L should be retested, according to validated methods, by a referral laboratory.
      Most available assays to evaluate Lp(a) levels include an immune/antibody component (eg, immunonephelometry, immunoturbidimetry, latex immunoassays). The recent European Atherosclerosis Society guidelines recommended the use of assays with coefficients of variation below 10% that are also economically priced and accurate.
      • Nordestgaard B.G.
      • Chapman M.J.
      • Ray K.
      • et al.
      European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status.
      Immunoassays, other methods of quantifying Lp(a) (eg, vertical auto profile, β-lipoprotein cholesterol quantitation with polycations
      • Marcovina S.M.
      • Koschinsky M.L.
      Lipoprotein (a): structure, measurement and clinical significance.
      • Kulkarni K.R.
      • Garber D.W.
      • Marcovina S.M.
      • Segrest J.P.
      Quantification of cholesterol in all lipoprotein classes by the VAP-II method.
      • Heuck C.C.
      • Schlierf G.
      Beta-lipoprotein cholesterol quantitation with polycations.
      ), and protocols for phlebotomy and plasma storage should be standardized for quality control, including the use of an Lp(a) preparation approved as a secondary reference by international agencies (World Health Organization, International Federation of Clinical Chemistry). The current International Federation of Clinical Chemistry reference material, with an assigned value of 107 nmol/L for Lp(a) protein, should be used to calibrate assays. Manufacturers of assays for Lp(a) should seek to minimize the effects of apo(a) size on Lp(a) levels.
      • Marcovina S.M.
      • Albers J.J.
      • Gabel B.
      • Koschinsky M.L.
      • Gaur V.P.
      Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).
      An early assay (Northwest Lipid Research Laboratories) with accuracy not influenced by the heterogeneity of apo(a) isoform size utilized a monoclonal antibody targeted against a unique apo(a) epitope (within KIV-9 and not within the variable part of the protein sequence); the monoclonal antibody was then used to generate an enzyme-linked immunosorbent assay. This assay specifically and size-independently measures Lp(a)-P number in SI units (mol/L or similar units such as nmol/L).
      • Marcovina S.M.
      • Albers J.J.
      • Scanu A.M.
      • et al.
      Use of a reference material proposed by the International Federation of Clinical Chemistry and Laboratory Medicine to evaluate analytical methods for the determination of plasma lipoprotein(a).
      Total Lp(a) mass can also be measured. One validated, high-quality assay is the Denka-Seiken immunoturbidimetric assay (Atherotech Diagnostics Lab; Berkeley Extended-Range Lp[a] Test). Results are expressed in mg/dL, and the coefficient of variation is less than 3%. Lipoprotein(a)-C can be measured with density-gradient tests such as vertical auto profile or β-lipoprotein cholesterol quantitation with polycations.
      • Kulkarni K.R.
      • Garber D.W.
      • Marcovina S.M.
      • Segrest J.P.
      Quantification of cholesterol in all lipoprotein classes by the VAP-II method.
      • Heuck C.C.
      • Schlierf G.
      Beta-lipoprotein cholesterol quantitation with polycations.
      A lipoprotein quantitative immunofixation electrophoresis assay developed by Health Diagnostic Laboratory, Inc measured Lp(a)-P number in a manner that correlated strongly with a research methodology but not with the Denka-Seiken Lp(a) mass assay, most likely because the mass assay is sensitive to size variations in apo(a) isoforms. Electrophoresis is highly specific (∼93%) but not sensitive (60%) for Lp(a) mass exceeding 30 mg/dL.
      • Nguyen T.T.
      • Ellefson R.D.
      • Hodge D.O.
      • Bailey K.R.
      • Kottke T.E.
      • Abu-Lebdeh H.S.
      Predictive value of electrophoretically detected lipoprotein(a) for coronary heart disease and cerebrovascular disease in a community-based cohort of 9936 men and women.
      One way to help discriminate CV risk associated with elevated Lp(a) is to obtain measures of both Lp(a)-P and Lp(a)-C. Evidence suggests that Lp(a)-P and Lp(a)-C are complementary subfractions in terms of conferring CV risk. In one study, the ratio of Lp(a)-C to Lp(a)-P was 0.46 in healthy individuals, 1.40 in those with Lp(a)-C above the upper limit of normal (10 mg/dL), 0.06 in those with Lp(a)-P above the upper limit of normal (70 nmol/L), and 0.08 in those with elevations in both fractions.
      • Konerman M.
      • Kulkarni K.
      • Toth P.P.
      • Jones S.R.
      Lipoprotein(a) particle concentration and lipoprotein(a) cholesterol assays yield discordant classification of patients into four physiologically discrete groups.
      Assays of Lp(a) fractions were developed by Joseph P. McConnell, PhD, of the Mayo Clinic and Mayo Foundation for Medical Education and Research. Two patients may have identical levels of Lp(a) mass, but in the patient with smaller Lp(a) containing lower-molecular-weight apo(a) isoforms (the liver secretes smaller apo[a] particles more readily than larger ones), greater amounts of cholesterol are trafficked by Lp(a), and hence Lp(a) elevations may be potentially more atherosclerotic and thrombogenic. The patient with an Lp(a)-C level of at least 30 mg/dL (75th percentile population risk cut point) and elevated Lp(a) mass may be at particularly elevated CV risk. On the other hand, in the presence of predominantly large apo(a) isoforms, an Lp(a)-C level of 30 mg/dL places a patient at only the 50th percentile of CV risk. Protocols for quantification of different apo(a) isoforms (including heterogeneous kringle architectures) have been developed by Drs Marlys Koschinsky and Santica Marcovina.
      • Kulkarni K.R.
      • Garber D.W.
      • Marcovina S.M.
      • Segrest J.P.
      Quantification of cholesterol in all lipoprotein classes by the VAP-II method.
      • Marcovina S.M.
      • Albers J.J.
      • Gabel B.
      • Koschinsky M.L.
      • Gaur V.P.
      Effect of the number of apolipoprotein(a) kringle 4 domains on immunochemical measurements of lipoprotein(a).
      However, the relative prognostic utility of assaying Lp(a) by particle number (Lp[a]-P), cholesterol (Lp[a]-C), or mass remains controversial at this writing. In one clinical trial reported by McConnell et al,
      • McConnell J.P.
      • Baudhuin L.M.
      • Berger P.B.
      • et al.
      Lipoprotein(a) cholesterol, but not Lp(a) mass, is an independent predictor of angiographic coronary artery disease and subsequent cardiovascular events in patients referred for coronary angiography.
      Lp(a)-C was an independent predictor of angiographic CHD and CVD events, whereas Lp(a) mass was not an independent risk factor for these outcomes.

      The Way Forward

      To inform controversies surrounding Lp(a), prospective RCTs are being conducted to determine whether pharmacotherapies that lower Lp(a) also decrease CV risk
      • Akdim F.
      • Visser M.E.
      • Tribble D.L.
      • et al.
      Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.
      • Merki E.
      • Graham M.J.
      • Mullick A.E.
      • et al.
      Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice.
      • Bloomfield D.
      • Carlson G.L.
      • Sapre A.
      • et al.
      Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.
      • Gutstein D.E.
      • Krishna R.
      • Johns D.
      • et al.
      Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.
      • Krauss R.M.
      • Wojnooski K.
      • Orr J.
      • et al.
      Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib.
      • Krishna R.
      • Anderson M.S.
      • Bergman A.J.
      • et al.
      Effect of the cholesteryl ester transfer protein inhibitor, anacetrapib, on lipoproteins in patients with dyslipidaemia and on 24-h ambulatory blood pressure in healthy individuals: two double-blind, randomised placebo-controlled phase I studies.
      • Cannon C.P.
      • Shah S.
      • Dansky H.M.
      • et al.
      DEFINE Investigators
      Safety of anacetrapib in patients with or at high risk for coronary heart disease.
      • Cannon C.P.
      • Dansky H.M.
      • Davidson M.
      • et al.
      DEFINE investigators
      Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib.
      • Stein E.A.
      • Mellis S.
      • Yancopoulos G.D.
      • et al.
      Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.
      (Table 2). As mentioned previously, the HPS2-THRIVE reported that treatment with niacin-laropiprant together with statins and/or ezetimibe conferred no cardioprotective benefit compared with background statin-ezetimibe therapy alone in reducing CV events.

      MRC/Cancer Research UK/BHF Clinical Trial Service Unit & Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, Medical Sciences Division, Oxford University. HPS2-THRIVE: Preliminary results. January 2013. University of Oxford CTSU website. http://www.ctsu.ox.ac.uk/hps2-thrive/index.htm. Updated May 2, 2013. Accessed September 15, 2013.

      However, it is possible that patients with elevated Lp(a) at baseline experienced special benefits of the combination niacin regimen, but the number of such individuals may be insufficient to draw statistically valid conclusions. Published results of this clinical trial are eagerly awaited. Trials evaluating investigational agents that also lower Lp(a) (Table 2) may be useful in future efforts to determine the role of on-treatment changes in Lp(a) compared with other lipids in preventing CVD.
      Table 2Ongoing Clinical Trials With Niacin and Other Investigational Agents That Lower Lipoprotein(a)
      ANA = anacetrapib; apo = apolipoprotein; ASO = antisense oligonucleotide; BL = baseline; CBVD = cerebrovascular disease; CETP = cholesteryl ester transfer protein; CHD = coronary heart disease; CVD = cardiovascular disease; DM = diabetes mellitus; ERN = extended-release niacin; FOCUS FH = Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; HR-QOL = health-related quality of life; KIV-2 = kringle IV type 2; LDL-C = low-density lipoprotein cholesterol; LMT = lipid-modifying (drug) therapy; Lp(a) = lipoprotein(a); LRPT = laropiprant; mAb = human monoclonal antibody; MI = myocardial infarction; MPMN = mipomersen; NICOLa = Evaluation of the Effect of NICOtinic Acid (Niacin) on Elevated Lipoprotein(a) Levels; ODYSSEY FH I = Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy; ODYSSEY Outcomes = Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727); Pbo = placebo; PCSK9 = proprotein convertase subtilisin/kexin type 9; PVD = peripheral vascular disease; RCT = randomized placebo-controlled trial; REVEAL = Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification; SC = subcutaneous; TG = triglycerides.
      ,
      SI conversion factors: To convert Lp(a) values to μmol/L, multiply by 0.0357; to convert triglyceride values to mmol/L, multiple by 1.8; to convert LDL-C values to mmol/L, multiply by 0.0259.
      Agent; study (clinicaltrials.gov identifier)Study setting/design (status)PatientsTreatmentsMain outcome measuresComment
      Approved
       Niacin regimens; NICOLa (NCT00633698)German phase 3 RCT (recruitment status unknown)Lp(a)-C >30 mg/dL, TG <400 mg/dL with or without CVDERN 0.5-2.0 g + ongoing statin vs Pbo + ongoing statin (at stable doses) for 20 wkPrimary: Percent change in Lp(a)

      Secondary: Percent change in LDL-C, HDL-C, TG, blood glucose
      Other: adverse clinical events, HR-QOL, disease-related costs
       Niacin regimens; Effect of Niacin in the Lipoprotein(a) Concentration (NCT01321034)Spanish phase 4 open-label trial (completed)LDL-C 70-190 mg/dL + Lp(a) <30 (“normal”), 30-60 (“high”), or >60 (“very high”) mg/dLERN/LRPT 1-2 g/20-40 mg for 12 wkPrimary: Absolute and relative change in Lp(a) stratified by BL Lp(a)

      Secondary: Percent change in Lp(a) stratified by number of KIV-2 repeats in apo(a) gene
      None
      Investigational
       ASO (MPMN [ISIS 301012]); FOCUS FH
      • Akdim F.
      • Visser M.E.
      • Tribble D.L.
      • et al.
      Effect of mipomersen, an apolipoprotein B synthesis inhibitor, on low-density lipoprotein cholesterol in patients with familial hypercholesterolemia.
      • Merki E.
      • Graham M.J.
      • Mullick A.E.
      • et al.
      Antisense oligonucleotide directed to human apolipoprotein B-100 reduces lipoprotein(a) levels and oxidized phospholipids on human apolipoprotein B-100 particles in lipoprotein(a) transgenic mice.
      (NCT01475825)
      North American phase 3 RCT (recruiting)Severe HeFH (LDL-C ≥200 mg/dL [with CHD] or ≥300 mg/dL)Weekly SC:

      MPMN 200 mg 1×/wk or MPMN 70 mg 3×/wk vs Pbo for each (each for 60 wk)
      Primary: Percent change in LDL-C

      Secondary: Percent change in Lp(a)
      Other: Percent change in apo B

      Frequencies of adverse events and injection-site reactions
       CETP inhibitor (ANA); REVEAL
      • Bloomfield D.
      • Carlson G.L.
      • Sapre A.
      • et al.
      Efficacy and safety of the cholesteryl ester transfer protein inhibitor anacetrapib as monotherapy and coadministered with atorvastatin in dyslipidemic patients.
      • Gutstein D.E.
      • Krishna R.
      • Johns D.
      • et al.
      Anacetrapib, a novel CETP inhibitor: pursuing a new approach to cardiovascular risk reduction.
      • Krauss R.M.
      • Wojnooski K.
      • Orr J.
      • et al.
      Changes in lipoprotein subfraction concentration and composition in healthy individuals treated with the CETP inhibitor anacetrapib.
      • Krishna R.
      • Anderson M.S.
      • Bergman A.J.
      • et al.
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      • Cannon C.P.
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      Design of the DEFINE trial: Determining the EFficacy and tolerability of CETP INhibition with AnacEtrapib.
      (NCT01252953)
      International (Europe, UK, Scandinavia, Asia, North America)

      Phase 3 RCT (recruiting)
      ≥50 y + MI history, CBVD, PVD, or DM + symptomatic CHDANA 100 mg/d (or Pbo) + statins for 4 yPrimary: Major coronary events (coronary death, MI, coronary revascularization)Other: Percent change in lipids/lipoproteins
       PCSK9 mAb (REGN727/ SAR236553);

      ODYSSEY FH I
      • Stein E.A.
      • Mellis S.
      • Yancopoulos G.D.
      • et al.
      Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.


      (NCT01623115)
      US and South African phase 3 RCT (recruiting)HeFH not adequately controlled on LMT: LDL-C ≥70 mg/dL with CVD or LDL-C ≥100 mg/dL without CVDPCSK9 mAb (vs Pbo) SC + ongoing LMT for up to 24-88 wkPrimary: Percent change in LDL-C up to 24 wk

      Secondary: Percent change in other lipids/lipoproteins up to 78 wk
      None
       PCSK9 mAb (REGN727/ SAR236553); ODYSSEY Outcomes
      • Stein E.A.
      • Mellis S.
      • Yancopoulos G.D.
      • et al.
      Effect of a monoclonal antibody to PCSK9 on LDL cholesterol.


      (NCT01663402)
      US phase 3 RCT (recruiting)≥40 y + hospitalized for acute coronary syndrome within prior 16 wkPCSK9 mAb (vs Pbo) SC + ongoing LMT for up to 280 wkPrimary: Time to first major CVD eventOther: Percent change in lipids/lipoproteins
      a ANA = anacetrapib; apo = apolipoprotein; ASO = antisense oligonucleotide; BL = baseline; CBVD = cerebrovascular disease; CETP = cholesteryl ester transfer protein; CHD = coronary heart disease; CVD = cardiovascular disease; DM = diabetes mellitus; ERN = extended-release niacin; FOCUS FH = Study of the Safety and Efficacy of Two Different Regimens of Mipomersen in Patients With Familial Hypercholesterolemia and Inadequately Controlled Low-Density Lipoprotein Cholesterol; HDL-C = high-density lipoprotein cholesterol; HeFH = heterozygous familial hypercholesterolemia; HR-QOL = health-related quality of life; KIV-2 = kringle IV type 2; LDL-C = low-density lipoprotein cholesterol; LMT = lipid-modifying (drug) therapy; Lp(a) = lipoprotein(a); LRPT = laropiprant; mAb = human monoclonal antibody; MI = myocardial infarction; MPMN = mipomersen; NICOLa = Evaluation of the Effect of NICOtinic Acid (Niacin) on Elevated Lipoprotein(a) Levels; ODYSSEY FH I = Efficacy and Safety of Alirocumab SAR236553 (REGN727) Versus Placebo on Top of Lipid-Modifying Therapy in Patients With Heterozygous Familial Hypercholesterolemia Not Adequately Controlled With Their Lipid-Modifying Therapy; ODYSSEY Outcomes = Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab SAR236553 (REGN727); Pbo = placebo; PCSK9 = proprotein convertase subtilisin/kexin type 9; PVD = peripheral vascular disease; RCT = randomized placebo-controlled trial; REVEAL = Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification; SC = subcutaneous; TG = triglycerides.
      b SI conversion factors: To convert Lp(a) values to μmol/L, multiply by 0.0357; to convert triglyceride values to mmol/L, multiple by 1.8; to convert LDL-C values to mmol/L, multiply by 0.0259.

      Conclusion

      Lipoprotein(a) is a genetic, causal risk factor for CVD. Population-based studies have determined that there is a continuous, graded association between Lp(a) levels and CV risk that is somewhat less marked compared with the association of elevated LDL-C and such risk. Partly because both Lp(a) and LDL-C contain the atherogenic moiety apo B100, there is a multiplier effect such that CV risk is synergistically increased when both lipoproteins are elevated; conversely, elevated Lp(a) becomes more clinically innocuous when accompanied by lower levels of LDL-C (<70 mg/dL after maximum statins). Elevated LDL-C (or apo B) should always be targeted for lipid-modifying therapy before treating elevated Lp(a).
      Niacin reduces Lp(a) by up to 40% and has been identified by consensus treatment panels as the only medication that consistently lowers Lp(a). Because niacin treatment can reduce the apo B100 component of both LDL and Lp(a), such therapy is a rational alternative in the presence of refractorily elevated LDL-C despite maximum-dose statins or statin combination therapy. Further clinical trials are needed to determine if reductions in CV risk can be specifically ascribed to on-treatment changes in Lp(a).

      Acknowledgments

      Assistance in research and manuscript preparation was provided by Stephen W. Gutkin, BA, of Rete Biomedical Communications Corp. and funded by AbbVie. AbbVie was given the opportunity to review the final draft. Dr Jacobson had complete autonomy over decisions concerning manuscript content and did not receive compensation from AbbVie.

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      • Correction
        Mayo Clinic ProceedingsVol. 89Issue 7
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          In the article “Lipoprotein(a), Cardiovascular Disease, and Contemporary Management,” published in the November 2013 issue of Mayo Clinic Proceedings (2013;88(11):1294-1311), Lp(a) cholesterol and Lp(a)-C should read as Lp(a) throughout the article.
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