LIPOPROTEIN (a)D P Mikhailidis

BSc MSc MD FCPP FRSPH FFPM FRCP FRCPath

Dept. of Clinical Biochemistry Royal Free campus

University College London (UCL)

DECLARATION OF INTEREST

• Attended conferences and gave talks sponsored by MSD, AstraZeneca and Libytec

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

WHAT IS LIPOPROTEIN (a)

An LDL + apolipoprotein a

Different lengths of apo a (kringles)

More kringles = lower Lp(a) levels

Hepatic synthesis

Lp(a) levels about 90% inherited (repeat measurements?)

WHAT IS LIPOPROTEIN (a)

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 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

LIPOPROTEIN (a) MEASUREMENT

Commercially available assays that are completely insensitive tothe variability in particle mass, which arises not only from differences in apo(a) isoform mass but also from variations inlipid 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: 550 - 3

LIPOPROTEIN (a) levels

Lp(a) levels in 532 359 USA subjects from 2 data sets: 1] 531 144 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.

Varvel S, McConnell JP, Tsimikas S. Arterioscler Thromb Vasc Biol 2016; 36: 2239 - 45

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?

.

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 studiesHypothyroidism: corrected by achieving euthyroid statusRenal failure: GFR below 70 ml/min (causal/reverse causality?)FH?: not definitive, but may be relevant on a case by case basis

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 anOR 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 Jan 25. [Epub]

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 2016. Published by Oxford University Press on behalf of the European Society of Cardiology.

LIPOPROTEIN (a) LEVELS:clinical relevance

Aortic stenosis 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 AcademicEchocardiography Laboratory Setting. Angiology 2017 Jan [Epub]

LIPOPROTEIN (a) LEVELS:clinical relevance

Cerebrovascular events

Kostakou PM, et al. Lipoprotein (a) evolution: possible benefits and harm. Genetic and non-genetic factors influencing its plasma levels. Curr Med Chem 2017 Jan 20. [Epub]

LIPOPROTEIN (a) LEVELS:clinical relevance

Abdominal Aortic AneurysmSmall 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: 99 - 108

LIPOPROTEIN (a) LEVELS:clinical relevance

Peripheral graft stenosisSmall but significant increase

Cheshire NJ, Wolfe JH, Barradas MA, Chambler AW, Mikhailidis DP. Smoking andplasma fibrinogen, lipoprotein (a) and serotonin are markers for postoperativeinfrainguinal graft stenosis. Eur J Vasc Endovasc Surg 1996; 11: 479 - 86

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: anew treatment option for lowering elevated lipoprotein(a)? Curr Pharm Des 2017 Jan 25. [Epub]

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 lipoprotein-associated phospholipase A2 (Lp-PLA2) that catalyzesthe degradation of OxPL and is bound to plasma lipoproteins including Lp(a).

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 Jan 25. [Epub]

LIPOPROTEIN (a): treatment

Restoring euthyroid status

Hormonese.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: 87 - 96

Tibolone: synthetic molecule with estrogenic, progestogenic and weak androgenic actions

LIPOPROTEIN (a): future treatment

Anacetrapib (CETP inhibitor)

Mipomersen (apoB-100 inhibitor)

Lomitapide (microsomal triglyceride transfer protein inhibitor)

LIPOPROTEIN (a): future treatment

Antisense oligonucleotide against apo(a), IONIS-APO(a)Rx, hasbeen 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 Jan 25. [Epub]

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?

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)?