Lipoprotein(a) Excess

Lipoprotein(a) excess is a genetically determined elevation of lipoprotein(a), an LDL-like particle with an attached apolipoprotein(a). It causes independent, causal risk of atherosclerotic cardiovascular disease, calcific aortic valve stenosis and ischaemic stroke.

About 20% of people have Lp(a) of 50 mg/dL (125 nmol/L) or more. Levels are higher in people of African and South Asian ancestry.

Levels are over 90% genetically determined by the LPA gene (kringle IV type 2 repeat number, with smaller isoforms giving higher levels). They are set by age 2 to 5 years and change little through life.

Lp(a) rises modestly with menopause, hypothyroidism, nephrotic syndrome and chronic kidney disease, and falls with severe liver disease and growth hormone excess.

Pathophysiology.

Lp(a) promotes atherothrombosis through its LDL-like cholesterol content, its proinflammatory oxidised phospholipid cargo, and a structural resemblance to plasminogen that may impair fibrinolysis.

It also promotes valve calcification through oxidised phospholipids and autotaxin activity, which explains its link with aortic stenosis.

Risk categories (isoform insensitive assay, expressed as nmol/L): under 75 nmol/L (30 mg/dL) low; 75 to 125 nmol/L (30 to 50 mg/dL) borderline; 125 nmol/L or more (50 mg/dL or more) elevated; 430 nmol/L or more (180 mg/dL or more) very high, with lifetime risk comparable with heterozygous familial hypercholesterolaemia. Conversion between mg/dL and nmol/L is only approximate.

Excess is asymptomatic. It is identified by testing in people with premature or recurrent vascular events, unexplained aortic stenosis, family history of premature disease or raised Lp(a), or familial hypercholesterolaemia.

Measure Lp(a) once in a lifetime using an isoform insensitive assay reported in nmol/L. Repeat only for secondary causes (kidney disease, thyroid disease, hormonal change) or after major changes.

Offer testing to:

• People with premature atherosclerotic disease, recurrent events despite treatment, or unexplained aortic stenosis.
• First degree relatives of those with high Lp(a).
• People with familial hypercholesterolaemia or borderline intermediate risk where it would change management.

Add a full lipid profile with LDL-C and apoB, correcting LDL-C for the Lp(a) cholesterol content where possible. Assess global risk, and consider coronary calcium scoring in those with high Lp(a).

Differential diagnosis.

• Raised Lp(a) secondary to kidney disease, nephrotic syndrome or hypothyroidism.
• Other causes of premature atherosclerosis (familial hypercholesterolaemia, familial combined hyperlipidaemia, diabetes, smoking).

No Lp(a)-lowering drug is yet licensed for cardiovascular risk reduction. The aim is to reduce global risk and LDL-C intensively.

Targets. Regard patients with Lp(a) of 125 nmol/L or more plus other risk factors as high risk, and those with established disease as very high risk. LDL-C under 1.8 mmol/L (70 mg/dL) in high risk patients and under 1.4 mmol/L (55 mg/dL) in very high risk patients. Control blood pressure, glucose, smoking and weight.

Drug therapy.

• Atorvastatin 40 to 80 mg orally once daily (maximum 80 mg) or rosuvastatin 20 to 40 mg once daily (maximum 40 mg; start 5 mg and limit to 10 mg when eGFR is under 30 mL/min/1.73 m2); statins do not lower Lp(a) and may raise it by 10 to 20%, but the LDL-C reduction is still beneficial.
• Ezetimibe 10 mg orally once daily as add on.
• Evolocumab 140 mg subcutaneously every 2 weeks or 420 mg monthly, or alirocumab 75 to 150 mg every 2 weeks: lower Lp(a) by about 20 to 30% and reduce events, with greater benefit at high Lp(a); long term; lipids at 4 to 12 weeks.
• Inclisiran 284 mg subcutaneously at day 0, 3 months, then every 6 months: lowers Lp(a) by about 20 to 25%.
• Niacin is not advised: it lowers Lp(a) modestly without proven benefit and with adverse effects.
• Low dose aspirin 75 to 100 mg daily may be considered in selected primary prevention with low bleeding risk. Evidence is limited and this is not routine.
• Lipoprotein apheresis (weekly or every 2 weeks; lowers Lp(a) by 60 to 70% for each session) is reserved for progressive vascular disease despite optimised therapy with LDL-C controlled and Lp(a) over 60 mg/dL (about 120 to 150 nmol/L).
• RNA-targeted agents (pelacarsen, olpasiran, lepodisiran, zerlasiran) and oral inhibitors (muvalaplin) are investigational in late stage studies.

Monitoring. LDL-C and apoB 4 to 12 weeks after change, then annually. Reassess global risk and blood pressure annually. Aortic valve surveillance by echocardiography when stenosis is present or suspected.

Referral and escalation. Refer very high Lp(a) (430 nmol/L or more), or any progressive vascular disease, to a lipid specialist. Cascade test first degree relatives.

Special groups.

• Pregnancy: Lp(a) rises; statins are stopped; no specific therapy.
• Children: test children with a family history of premature vascular disease or very high Lp(a), or with stroke.
• Kidney disease: levels rise, and statins alone do not lower them.