Lipoprotein (a): what is new?
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1 Lipoprotein (a): what is new? D P Mikhailidis BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath Dept. of Clinical Biochemistry Royal Free campus University College London (UCL)
2 DECLARATION OF INTEREST Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec
3 DECLARATION OF INTEREST Lead for Guidelines on the Management of Carotid Artery Stenosis (Eur Soc Vasc Surg) Chair European Expert Panel on Small Dense Low Density Lipoprotein Co-chair Expert Panel on Post-Prandial Lipaemia
4 WHAT IS LIPOPROTEIN (a) LDL + lipoprotein (a) linked to an apolipoprotein B (S-S bridge) Different lengths of lipoprotein (a) (kringles) More kringles = lower Lp(a) levels Hepatic synthesis Lp(a) levels about 90% inherited (repeat measurements?)
5 WHAT IS LIPOPROTEIN (a)
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7 IS LIPOPROTEIN (a) ESSENTIAL? Probably not; very low levels (or even absence?) do not seem to cause harm. Only humans and old world monkeys (e.g. baboons, macaques) have Lp(a). Also, European hedgehog. Transgenic animal models (e.g. rabbit and mouse) Wound healing and tissue repair? Infection control? Yeang C, Cotter B, Tsimikas S. Experimental Animal Models Evaluating the Causal Role of Lipoprotein(a) in Atherosclerosis and Aortic Stenosis. Cardiovasc Drugs Ther 2016; 30: 75-85
8 LIPOPROTEIN (a) MEASUREMENT Commercially available assays that are completely insensitive to the variability in particle mass, which arises not only from differences in apo(a) isoform mass but also from variations in lipid mass. Standardisation is necessary so that studies are comparable McConnell JP et al. Lipoprotein(a) mass: a massively misunderstood metric. J Clin Lipidol 2014; 8: However, some studies showed an increase in risk whatever the method used (4679 participants of the Multi-Ethnic Study of Atherosclerosis (MESA) study. Cao J, et al. Evaluation of Lipoprotein(a) Electrophoretic and Immunoassay Methods in Discriminating Risk of Calcific Aortic Valve Disease and Incident Coronary Heart Disease: The Multi-Ethnic Study of Atherosclerosis. Clin Chem 2017; 63:
9 LIPOPROTEIN (a) levels Lp(a) levels in USA subjects from 2 data sets: 1] subjects from a referral laboratory 2] 915 patients from a tertiary referral centre. Referral lab: Lp(a) levels >30 and >50 mg/dl present in 35.0% and 24.0% of subjects, respectively. Tertiary referral center: 39.5% and 29.2%, respectively. NOTE: smaller n in this group (i.e. 915 vs ). Varvel S, McConnell JP, Tsimikas S. Arterioscler Thromb Vasc Biol 2016; 36:
10 . LIPOPROTEIN (a): mechanisms of atherogenesis Homology with plasminogen (= impaired fibrinolysis) Binds to macrophages foam cell formation Binds to platelets (inhibition or stimulation?) Deposition of cholesterol into plaques?
11 LIPOPROTEIN (a) LEVELS: variability Ethnicity: African Americans, Indians have the highest levels Women higher levels than men: estrogens, progesterone, testosterone, and their equivalents reduce plasma Lp(a) levels by 40% Menopause: HRT 15-30% Lp(a) fall in some studies Hypothyroidism: corrected by achieving euthyroid status Renal failure: GFR below 70 ml/min (causal/reverse causality?) FH?: not definitive, but may be relevant on a case by case basis
12 LIPOPROTEIN (a) LEVELS: clinical relevance Ideally below 30 or 50 mg/dl (75 or 125 nmol/l) Plasma concentration of 60 mg/dl is associated with an OR for coronary heart disease of 1.5 after adjusting for other cardiovascular risk factors Schreml J, Gouni-Berthold I. Apolipoprotein(a) antisense oligonucleotides: a new treatment option for lowering elevated lipoprotein(a)? Curr Pharm Des 2017; 23:
13 Risk of ischaemic heart disease and myocardial infarction for highest vs. lowest quintile of random non-fasting lipids, lipoproteins, and apolipoproteins as part of standard and expanded lipid profiles in individuals in the general population. Børge G. Nordestgaard et al. Eur Heart J 2016;eurheartj.ehw152 The Author Published by Oxford University Press on behalf of the European Society of Cardiology.
14 Aortic stenosis LIPOPROTEIN (a) LEVELS: clinical relevance Of 124 patients with Calcific Aortic Valve Stenosis (CAVS) having Lp(a) measurements, 41 (33.1%) had an Lp(a) level 30 mg/dl Wilkinson MJ, et al. The Prevalence of Lipoprotein (a) Measurement and Degree of Elevation Among 2710 Patients With Calcific Aortic Valve Stenosis in an Academic Echocardiography Laboratory Setting. Angiology 2017; 68: Lp(a)-associated molecules (oxidized phospholipids (OxPL) and lysophosphatidic acid) in plasma and in aortic valve leaflets of patients with CAVS suggest that Lp(a) is a key etiological factor in CAVS. Torzewski M et al. Lipoprotein(a) Associated Molecules are Prominent Components in Plasma and Valve Leaflets in Calcific Aortic Valve Stenosis. JACC Basic Transl Sci 2017; 2:
15 Aortic stenosis LIPOPROTEIN (a) LEVELS: clinical relevance Copenhagen General Population Study (n=87 980), including 725 calcific aortic valve disease (CAVD) cases ( ) and 1413 controls free of cardiovascular disease. Procalcific oxidized phospholipids (OxPL) carried by apob or Lp(a) are novel genetic and potentially causal risk factors for CAVD and may explain the association of Lp(a) with CAVD. Kamstrup PR et al. Oxidized Phospholipids and Risk of Calcific Aortic Valve Disease: The Copenhagen General Population Study. Arterioscler Thromb Vasc Biol 2017; 37:
16 LIPOPROTEIN (a) LEVELS: Cerebrovascular events clinical relevance Kostakou PM, Hatzigeorgiou G, Kolovou V, Mavrogeni S, Kolovou GD. Lipoprotein (a) evolution: possible benefits and harm. Genetic and non-genetic factors influencing its plasma levels. Curr Med Chem 2017; 24:
17 LIPOPROTEIN (a) LEVELS: clinical relevance Abdominal Aortic Aneurysm Small but significant increase Kotani K, Sahebkar A, Serban MC, Ursoniu S, Mikhailidis DP, Mariscalco G, Jones SR, Martin S, Blaha MJ, Toth PP, Rizzo M, Kostner K, Rysz J, Banach M; Lipid and Blood Pressure Meta-analysis Collaboration (LBPMC) Group. Lipoprotein (a) Levels in Patients With Abdominal Aortic Aneurysm. Angiology 2017; 68:
18 LIPOPROTEIN (a) LEVELS: clinical relevance Peripheral graft stenosis Small but significant increase Cheshire NJ, Wolfe JH, Barradas MA, Chambler AW, Mikhailidis DP. Smoking and plasma fibrinogen, lipoprotein (a) and serotonin are markers for postoperative infrainguinal graft stenosis. Eur J Vasc Endovasc Surg 1996; 11:
19 LIPOPROTEIN (a) LEVELS: clinical relevance Recent epidemiologic and Mendelian randomization and genome-based studies evidence that Lp(a) may be causally related to the pathogenesis of atherosclerosis and CVD No trial assessed whether selectively lowering Lp(a) levels translates into clinical benefits Schreml J, Gouni-Berthold I. Apolipoprotein(a) antisense oligonucleotides: a new treatment option for lowering elevated lipoprotein(a)? Curr Pharm Des 2017; 23:
20 LIPOPROTEIN (a) LEVELS: clinical relevance Most of circulating oxidized phospholipids (OxPL) are associated with Lp(a). Hypothesis that the risk of Lp(a) is primarily driven by its OxPL content. An important role may be played by lipoproteinassociated phospholipase A2 (Lp-PLA2) that catalyses the degradation of OxPL and is bound to plasma lipoproteins including Lp(a).
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22 LIPOPROTEIN (a): treatment NICOTINIC ACID: Extended-release niacin decreases elevated Lp(a) levels by 20-30%. Nicotinic acid is no longer available in many countries LIPOPROTEIN APHERESIS: for very high levels; 70% decrease with optimal lipid therapy (statins with ezetimibe, nicotinic acid, fibrates, colestyramine or omega-3 fatty acids) PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 (PCSK9) INHIBITORS: decrease by 20-30% Schreml J, Gouni-Berthold I. Apolipoprotein(a) antisense oligonucleotides: a new treatment option for lowering elevated lipoprotein(a)? Curr Pharm Des 2017; 23:
23 Restore euthyroid status LIPOPROTEIN (a): treatment Hormones e.g. tibolone (25% fall in Lp(a) levels): Kotani K, et al. Tibolone decreases lipoprotein(a) levels in postmenopausal women: A systematic review and meta-analysis of 12 studies with 1009 patients. Atherosclerosis 2015; 242: Tibolone: synthetic molecule with estrogenic, progestogenic and weak androgenic actions Anagnostis P, et al. The effect of hormone replacement therapy and tibolone on lipoprotein (a) concentrations in postmenopausal women: A systematic review and meta-analysis. Maturitas 2017; 99: HRT significantly decreases Lp(a) concentrations (approx. 20%), with oral being more effective than transdermal estradiol. Type of HRT, dose of estrogen and addition of progestogen do not seem to modify the Lp(a)- lowering.
24 LIPOPROTEIN (a): treatment In rheumatoid arthritis (biological therapy (BT) with anti-interleukin-6 receptor tocilizumab): García-Gómez C et al. Lipoprotein(a) concentrations in rheumatoid arthritis on biologic therapy: Results from the CARdiovascular in rheumatology study project. J Clin Lipidol 2017; 11: e3
25 LIPOPROTEIN (a): future treatment Anacetrapib (CETP inhibitor) this drug will not be developed further Mipomersen (apob-100 inhibitor) Lomitapide (microsomal triglyceride transfer protein inhibitor)
26 LIPOPROTEIN (a): future treatment Antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, has been shown to selectively decrease Lp(a) by 80% Schreml J, Gouni-Berthold I. Apolipoprotein (a) antisense oligonucleotides: a new treatment option for lowering elevated lipoprotein(a)? Curr Pharm Des 2017; 23:
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28 LIPOPROTEIN (a): comment Lp(a) levels are skewed towards low levels. What is the value of lowering Lp(a) levels when LDL-C is lowered to 1.8 mmol/l (70 mg/dl) or perhaps even lower as in the most recent guidelines ( mmol/l; mg/dl)? PCSK 9 inhibitors lower Lp(a) levels by 20-30%. Cost of any new treatment option (especially if used with a PCSK 9 inhibitor)? Safety (especially long-term)? This will need big trials over a period of several years.
29 Garcia-Rios A, Leon-Acuna A, Lopez-Miranda J, Perez-Martinez P. Lipoprotein Management: Lifestyle and Hormones. Curr Med Chem 2017; 24: Kostakou PM, Hatzigeorgiou G, Kolovou V, Mavrogeni S, Kolovou GD. Lipoprotein Evolution: Possible Benefits and Harm. Genetic and Non-Genetic Factors Influencing its Plasma Levels. Curr Med Chem 2017; 24: Hanssen R, Gouni-Berthold I. Lipoprotein(a) Management: Pharmacological and Apheretic Treatment. Curr Med Chem 2017;24: Katsiki N, Al-Rasadi K, Mikhailidis DP. Lipoprotein (a) and Cardiovascular Risk: The Show Must go on. Curr Med Chem 2017; 24: Kolovou GD, Katsiki N, Mikhailidis DP. Editorial: Lipoprotein (a), More than Just Cholesterol? Curr Med Chem 2017; 24: 952-6
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