Current management of the patient with high lipoprotein(a)

Br J Cardiol 2022;29(suppl 1):S20–S23doi:10.5837/bjc.2022.s05 Leave a comment
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This sponsored supplement was initiated and funded by Novartis Pharmaceuticals UK Ltd. Editorial control was retained by the authors and editors, however, Novartis reviewed the supplement for technical accuracy and compliance with relevant regulatory requirements.

Job code: 196574
Date of preparation: March 2022

Lipoprotein(a) (Lp[a]), a low-density lipoprotein (LDL)-like particle with strong genetically predetermined concentration, is an independent risk factor for cardiovascular disease. Although evidence from previous clinical studies suggests that lowering Lp(a) level may reduce cardiovascular risk, there is no selective therapeutic management approved so far. Non-selective lipoprotein apheresis has limited use, only applying to extreme cases. Promising selective interventions in development, such as antisense oligonucleotides and siRNA therapies, need proper randomised-controlled trials for further assessment. The current management of raised Lp(a) is focused on optimising other risk factors, such as smoking, diet, hypertension, diabetes and high LDL-cholesterol level to reduce the overall cardiovascular risk.


Lipoprotein(a) (Lp[a]) is a LDL-like particle, with an apolipoprotein(a) (Apo[a]) moiety covalently bound to its apolipoprotein B (ApoB) component. The molecular mass of Apo(a) can vary between 275 and 800 kDa due to its genetic inheritance. Individuals producing the lower molecular mass Apo(a) have higher serum Lp(a) concentrations and vice versa.1 As an established causal risk factor for atherosclerotic cardiovascular disease (ASCVD), supported by mechanistic, epidemiologic and genetic evidence, Lp(a) is believed to contribute to ASCVD through the pro-atherogenic effects of the LDL-like structure, pro-inflammatory effects of the oxidised phospholipid content, and prothrombotic effects of its plasminogen-like protease domain on Apo(a).2 In addition, Lp(a) has more recently been found to be an independent risk factor for calcific aortic valve disease and its progression.

Serum Lp(a) levels are predominantly genetically determined and remain relatively stable over a lifetime. Consequently, Lp(a) need only be measured once, unless a secondary cause is suspected or therapeutic measures to lower levels have been introduced. The HEART UK consensus statement recommends the measurement of serum Lp(a) in those with:1

  • A personal or family history of premature atherosclerotic cardiovascular disease (<60 years of age).
  • First-degree relatives of patients with raised serum Lp(a) levels (>200 nmol/L).
  • Familial hypercholesterolaemia (FH) or other genetic dyslipidaemias.
  • Calcific aortic valve stenosis.
  • A borderline increased (but <15%) 10-year risk of a cardiovascular event.

The European Society of Cardiology/European Atherosclerosis Society guidelines, however, suggest that Lp(a) measurement should be considered at least once in each adult person’s lifetime.3 In contrast, the American Heart Association/American College of Cardiology guideline advises that a family history of premature ASCVD is the sole relative indication for Lp(a) measurement.4

HEART UK’s current recommendation for managing patients with high Lp(a), in both primary and secondary prevention of ASCVD, is at a threshold of >90 nmol/L.1 This represents the 80th percentile for Lp(a) concentration derived from the ongoing Copenhagen General Population Study. The threshold value advised by the US guideline4 is 125 nmol/L (which approximately corresponds with the 90th percentile1 of general population). The European guideline, on the other hand, focuses to identify those with very high Lp(a) value >430 nmol/L (>99th percentile1), who may have a lifetime cardiovascular risk equivalent to patients with heterozygous familial hypercholesterolaemia.3 Thus, it appears that cut-offs associated with increased cardiovascular risk are widely reported in guidelines, however, desirable or target levels are less clear. This is because there has been a lack of widely proven effective treatments to reduce Lp(a) and it is difficult to suggest a desirable target for Lp(a) in the absence of randomised-controlled trials demonstrating benefit of Lp(a) lowering. The guidelines consequently employ a pragmatic approach of not directly targeting Lp(a) levels but addressing other modifiable cardiovascular disease risk factors, such as dyslipidaemia, blood pressure, diabetes etc., with the aim of mitigating the risk conferred by high Lp(a).1,3,4

With regards to dyslipidaemia, current international guidelines have all suggested more intensive LDL-cholesterol or non-high-density lipoprotein (HDL)-cholesterol lowering therapy for patients exceeding their Lp(a) threshold. More specifically, HEART UK advises that in patients with raised Lp(a) levels >90 nmol/L, desirable non-HDL-cholesterol is <2.5 mmol/L (approximately equivalent to LDL-cholesterol <1.8 mmol/L). However, if patients with raised Lp(a) developed progressive cardiovascular disease and recurrent events, despite maximum tolerated lipid-lowering therapy, lipoprotein apheresis should be considered.1

The current management of patients with raised Lp(a) should focus on reducing cardiovascular risk and controlling dyslipidaemia. Below we summarise the principal therapeutic strategies for management of Lp(a) and divide these into those that lower Lp(a) and those intended to mitigate the risk of Lp(a) (table 1).

Table 1. Summary of therapeutic strategies to manage high lipoprotein(a)

Drug/intervention In current clinical use for high Lp(a) Lp(a) reduction Cardiovascular risk reduction
Mitigating the cardiovascular risk of Lp(a)
Statins Yes Yes
Aspirin Yes Yes
Lifestyle modification Yes Yes
Lp(a)-lowering strategies
Lipoprotein apheresis Yes >50% Yes
Monoclonal antibodies to PCSK9 No 20–30% Yes
siRNA to PCSK9 No 18–25% No
Niacin No 30–40% No
Mipomersen No 25–40% No
Antisense oligonucleotides No up to 90% No
Roux-en-Y gastric bypass No ~30% Yes
Hormonal drugs No 15–20% No
Anacetrapib No ~35% No
Key: Lp(a) = lipoprotein(a); PCSK9 = proprotein convertase subtilisin/kexin type 9; siRNA = small-interfering ribonucleic acid

Mitigating the risk of Lp(a)


Statins have an established critical role in both the primary and secondary prevention of cardiovascular risk in patients with raised LDL-cholesterol. However, they only have a marginal effect on Lp(a) concentration. Data from previous studies suggest that statins, either have no effect on, or can increase Lp(a) concentration by 10–20%.5 The underlying mechanism might be that statins increase expression of LPA mRNA and Apo(a) protein via downregulation of the farnesoid X receptor, however, this needs further investigation.6 Nevertheless, more intensive statin therapy is recommended in individuals with raised Lp(a) to maximally reduce the LDL-cholesterol-related cardiovascular risk. The risk:benefit ratio of the modest Lp(a) increase versus the potent LDL-cholesterol decrease favours this approach and is supported by Mendelian-randomisation studies that seek to quantitate cardiovascular risk based on LDL-cholesterol and Lp(a) concentration.5 Of interest, ezetimibe and fibrates, as monotherapy or in combination with statins, have no clear effect on Lp(a) concentration.5


Considering the prothrombotic properties of Lp(a), aspirin has been prescribed to individuals with elevated Lp(a) levels for its antiplatelet effect. A retrospective analysis further suggests that carriers of an Lp(a)-raising SNP (single nucleotide polymorphism) benefit from the use of aspirin therapy and their risk of cardiovascular disease is attenuated to that of non-carriers.7 There are also small studies suggesting that aspirin can marginally lower Lp(a) level by reducing LPA gene transcription, however, these studies are small and require further confirmation.8

Lifestyle modification

Although lifestyle modifications to optimise body mass index (BMI), diet, physical activity, smoking status, blood pressure, diabetes and high LDL level have little effect on lowering Lp(a) level, they are recommended to help reduce general cardiovascular risk.9

Current management of the patient with high lipoprotein(a)

Lp(a)-lowering strategies

Lipoprotein apheresis

Lipoprotein apheresis (LA) is currently the most effective therapy available for reducing Lp(a) concentration. This method was first introduced for the treatment of homozygous familial hypercholesterolaemia 50 years ago.5 LA is based on the selective or non-selective removal of plasma/whole blood constituents. Several different apheresis approaches can be used, including heparin-mediated extracorporeal LDL precipitation (HELP) and double filtration, to reduce both LDL-cholesterol and Lp(a) by more than 50% in one session.1 

Several multi-centre studies have demonstrated a reduction in cardiovascular disease event rate on commencing LA in high-risk patients with raised Lp(a).5 It is a pity that the studies so far are mainly observational and did not include a proper control group. Currently, there is an ongoing randomised multi-centre study (MultiSELECt trial) investigating the cardiovascular effects of LA in patients with elevated Lp(a) levels in secondary prevention.10 However, the effect of LA in these studies may be confounded by the removal of other atherogenic lipoproteins, including LDL, and other procoagulant and pro-inflammatory molecules.8

LA is usually reserved for the most severe and refractory cases of cardiovascular disease, and can only be offered in a limited number of tertiary centres. In the US, LA is approved for homozygous familial hypercholesterolaemia if LDL-cholesterol is persistently >12.9 mmol/L and heterozygote familial hypercholesterolaemia for primary prevention if LDL-cholesterol >7.8 mmol/L and secondary prevention if LDL-cholesterol >5.2 mmol/L. In the latter group, if Lp(a) level >120 nmol/L, the threshold for LDL-cholesterol is lowered to 3.1 mmol/L.5 In the UK and Germany, the guidelines both recommend that LA should be considered if Lp(a) is greater than 150 nmol/L with progressive cardiovascular disease. The HEART UK guideline also specifies that the LDL-cholesterol should be more than 3.2 mmol/L despite maximal lipid-lowering therapy.11 In contrast, the German reimbursement criteria require LDL-cholesterol to be within the normal range before considering apheresis for raised Lp(a).3 In summary, although there is an absence of randomised-controlled trial data to definitively assess the utility of apheresis in patients with high Lp(a), current data suggest that it may reduce cardiovascular disease progression in this cohort.

Inhibitors of PCSK9 function/production

Monoclonal antibodies to PCSK9

PCSK9 (proprotein convertase subtilisin/kexin type 9) monoclonal antibodies, such as evolocumab and alirocumab, can specifically bind to PCSK9 to upregulate LDL-receptor recycling, leading to a 60–70% decrease in LDL-cholesterol. Interestingly, recent studies have also demonstrated that PCSK9 inhibitors are able to reduce Lp(a) by around 20–30%. This is thought to be mediated by enhanced clearance and reduced production of Lp(a).12-13 The randomised-controlled trial, FOURIER, showed a significant Lp(a) reduction with evolocumab and found that those with higher baseline Lp(a) had greater absolute cardiovascular disease risk reduction compared with their counterparts with lower Lp(a) levels.12-13 The ODYSSEY OUTCOMES trial also demonstrated alirocumab was able to reduce both the Lp(a) concentration and cardiovascular events.14 However, a caveat here is the difficulty in defining whether the PCSK9 inhibition-induced cardiovascular event reduction is related to the decrease of LDL-cholesterol or Lp(a). Thus, these agents are not currently licensed for lowering Lp(a).

Small-interfering RNA (siRNA) to PCSK9

In addition, two placebo-controlled phase III trials (ORION-10 and ORION 11) revealed inclisiran, a long-acting siRNA blocking PCSK9 synthesis, is able to lower Lp(a) by around 18% and 25%, respectively.15 Inclisiran is also not currently licensed for lowering Lp(a).


Niacin is considered a broad-spectrum lipid-lowering medication. It facilitates the degradation of all ApoB-containing lipoproteins including Lp(a), the level of which can be reduced by 30–40%.5 Niacin was often used to treat high Lp(a) levels until its market withdrawal by the European Medicines Authority (EMA) in 2013, when two large trials revealed lack of improved cardiac outcomes and increased risk of serious adverse events associated with niacin.1


Mipomersen is an antisense oligonucleotide that binds to the messenger RNA of ApoB, triggering its degradation. Mipomersen reduces the ApoB-containing lipoprotein production (including Lp[a] and LDL) by preventing the translation of ApoB protein.8 It decreases Lp(a) levels by 20–30%, but the hepatic side effects, including steatosis and raised transaminases, has led to limited use, and it is not currently approved by the EMA.1

Antisense oligonucleotides

Antisense oligonucleotides, designed to target the RNA for the hepatic LPA gene, are able to reduce Apo(a) production. Recently, three clinical trials have been conducted with promising results,1 and have demonstrated a reduction in Lp(a) concentration by up to 90%.2 Antisense oligonucleotides are being evaluated in phase III studies to see whether Lp(a) reduction translates to improved cardiovascular outcomes.3 Additionally siRNA therapies targeting Lp(a) mRNA are also under development.16


The Roux-en-Y gastric bypass bariatric procedure showed positive effects on reducing Lp(a) levels in a recent prospective study.17

Hormonal drugs, such as oestrogen and testosterone, have both been shown to reduce Lp(a) level modestly, but are not necessarily associated with reduced cardiovascular risk.18

Anacetrapib is a CEPT (cholesteryl ester transfer protein) inhibitor, which inhibits the transfer of cholesterol esters to increase HDL-cholesterol and reduce LDL-cholesterol levels. Additionally, Lp(a) levels have been shown to decrease by around 35% in a randomised-controlled trial for anacetrapib. However, despite the promising results, the development of this therapy has been halted.5


There is enhanced awareness that Lp(a) concentration, which is strongly genetically predetermined, is an independent risk factor for cardiovascular disease. Although the observational and retrospective evidence from clinical studies suggests that lowering Lp(a) may reduce cardiovascular risk, there is no selective therapeutic management approved so far. Promising selective interventions in development, such as antisense oligonucleotides and siRNA therapies, need proper randomised-controlled trials in both primary and the secondary prevention cohorts, to assess their effect on Lp(a)-lowering and cardiovascular risk reduction.1 In addition, optimising other risk factors, such as intensive therapy to reduce LDL-cholesterol, plays a key role in managing patients with high Lp(a). A recent study estimated that the required reduction in Lp(a) would be approximately 250 nmol/L to reach the same potential cardiovascular risk reduction effect as 1 mmol/L lowering of LDL-cholesterol.19 Therefore, the Lp(a) concentration should not be assessed in isolation. Whether antiplatelet therapy should be used in primary prevention in this group of patients needs further prospective investigation. Finally, when establishing cut-off Lp(a) values to assess the cardiovascular risk and guide management, ethnicity is an important aspect to take into consideration, as Lp(a) concentration differs greatly across ethnic groups.1

Key messages

  • Lipoprotein(a) (Lp[a]) is an independent risk factor for cardiovascular disease
  • There is no selective therapeutic management approved so far to lower the concentration of Lp(a) and non-selective lipoprotein apheresis has limited use, applying to extreme cases
  • The current management of raised Lp(a) is focused on optimising other risk factors such as smoking, diet, hypertension, diabetes and high low-density lipoprotein (LDL)-cholesterol level to reduce the overall cardiovascular risk

Conflicts of interest

WY: None declared. JC has received lecture honoraria, consultancy fees, and/or research funding from Akcea, Silence Therapeutics and Novartis.



Wei Yang
Registrar in Metabolic Medicine, Imperial College London 

Jaimini Cegla
Consultant in Metabolic Medicine

Division of Diabetes, Endocrinology and Metabolism, 6th Floor Commonwealth Building, Hammersmith Hospital, Du Cane Road, London, W12 0NN 

([email protected])

Articles in this supplement

Lipoprotein(a): a historical perspective
Lipoprotein(a): mechanisms of pathogenicity
Lipoprotein(a): marker and target in calcific aortic valve disease
How to measure lipoprotein(a) and in whom


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