Lipoprotein(a) in clinical practice: What clinicians need to know

WHAT IS LIPOPROTEIN(A)?

Lipoprotein(a) is a lipoprotein particle comprising the LDL-like component apolipoprotein B covalently bound to a protein called apolipoprotein(a) that structurally resembles plasminogen. The resulting complex resembles a ball (the apolipoprotein B) with a tail (the apolipoprotein[a]).

The LPA gene, which codes for apolipoprotein(a), is highly polymorphic, with many variants that affect the length of the tail. This is how genetics controls the plasma concentration: people whose lipoprotein(a) has a shorter tail have higher plasma concentrations of the substance, perhaps because the liver cells that make lipoprotein(a) can make more of it faster if it is smaller.

Lipoprotein(a) shares LDL-C’s atherogenic properties, infiltrating the arterial intima and promoting oxidation and inflammation. Oxidized phospholipids on lipoprotein(a) enhance endothelial dysfunction by increasing permeability and adhesion-molecule expression, facilitating monocyte infiltration and foam cell formation.

Apolipoprotein(a) competitively inhibits fibrinolysis by interfering with plasminogen activation, potentially leading to thrombosis.⁷

NO CONSENSUS ON HOW TO SCREEN

There is no consensus on screening for elevated lipoprotein(a). European,⁶ Canadian,⁸ and National Lipid Association⁹ guidelines recommend measuring lipoprotein(a) at least once in all adults to identify those at higher cardiovascular risk, whereas the 2018 American College of Cardiology and American Heart Association guideline¹⁰ recommends testing people who have a family history of atherosclerotic cardiovascular disease or a personal history of it not explained by major risk factors.

We favor measuring it at least once in all individuals. Given the strong effect of genetics on plasma levels, it is reasonable to measure lipoprotein(a) at least once in all individuals. Additionally, testing is particularly important for patients with a history of premature atherosclerotic cardiovascular disease events, a family history of premature atherosclerotic cardiovascular disease, or recurrent cardiovascular events despite optimal LDL-C lowering. Measuring lipoprotein(a) is particularly useful in patients with a strong family history of premature atherosclerotic cardiovascular disease because genetically mediated elevations in lipoprotein(a) may partly explain such clusters of early cardiovascular events. This approach facilitates earlier, more aggressive management of cardiovascular risk.

Although lipoprotein(a) levels are mostly genetically determined and minimally affected by lifestyle changes, identifying those with high lipoprotein(a) (> 125 nmol/L or > 50 mg/dL) can refine cardiovascular risk prediction and prompt earlier, more aggressive management of other modifiable risk factors such as elevated LDL-C and hypertension.⁶

We used to think that an individual’s lipoprotein(a) level was largely stable throughout life, and in clinical practice, a single lifetime lipoprotein(a) test for all patients was sufficient for risk stratification. However, emerging data suggest a person’s lipoprotein(a) level may vary from measurement to measurement in specific circumstances.^11–15 For example, levels can modestly rise in hypothyroidism, nephrotic syndrome, pregnancy, and acute inflammatory states.⁴ That said, lipoprotein(a) levels do not need to be remeasured in most patients unless the initial measurement was taken during an acute inflammatory episode.

In terms of estimating atherosclerotic cardiovascular disease risk, there are no widely used risk calculators that incorporate lipoprotein(a) levels. However, clinicians should treat elevated lipoprotein(a) as a causal risk factor for atherosclerotic cardiovascular disease, albeit without currently approved therapies. If lipoprotein(a) is elevated, the patient should be viewed with greater urgency for risk reduction, and risk reduction measures should be intensified.

WHAT IS THE UPPER LIMIT OF NORMAL?

Lipoprotein(a) levels can be reported as either mass concentrations (in mg/dL) or particle concentrations (in nmol/L). Historically, a conversion factor of 2 to 2.5 times the mass concentration in mg/dL has been used to estimate particle concentrations in nmol/L; however, this practice is now discouraged owing to significant variability in lipoprotein(a) assays and lack of standardization. Current recommendations are to measure lipoprotein(a) in nmol/L rather than mg/dL for greater accuracy and consistency.⁴

Professional societies define the following lipoprotein(a) levels as elevated:

• European Atherosclerosis Society⁶: greater than or equal to 50 mg/dL or 125 nmol/L; values < 30 mg/dL or 75 nmol/L are normal, while 30–50 mg/dL or 75–125 nmol/L is a “gray zone” in which risk should be assessed on an individual basis, taking into account other risk factors

• American College of Cardiology and American Heart Association¹⁰: greater than or equal to 50 mg/dL or 125 nmol/L

• Canadian Cardiovascular Society⁸: greater than or equal to 50 mg/dL or 100 nmol/L

• National Lipid Association⁹: greater than or equal to 50 mg/dL or 125 nmol/L.

But the gradient of risk is continuous: the higher the level, the higher the risk.¹⁶ The cutoffs are pragmatic guides, but clinicians should interpret lipoprotein(a) in the broader context of each patient’s total risk-factor profile. Patel et al¹⁶ reported that every 50 nmol/L increment raises the risk of atherosclerotic cardiovascular disease by about 11%.

WHEN LIPOPROTEIN(A) IS ELEVATED

In patients who have elevated lipoprotein(a) and intermediate-to-high risk of atherosclerotic cardiovascular disease, intensive LDL-C lowering is recommended, targeting at least a 50% reduction from baseline, an LDL-C concentration lower than 70 mg/dL, or both. Although elevated lipoprotein(a) by itself is not an indication for statin therapy per contemporary treatment guidelines, its presence supports earlier or more aggressive preventive therapy, including, potentially, LDL-C management.

Ancillary tests such as coronary artery calcium may further refine risk in these individuals when used in a guideline-concordant and evidence-based fashion to inform shared decision-making on statin initiation or intensification.

All patients should be counseled about standard lifestyle changes, and, when appropriate, can be offered a referral to a lipidologist or preventive cardiologist or to clinical trials evaluating emerging lipoprotein(a)-lowering therapies.

LIPOPROTEIN(A) LEVELS CAN FLUCTUATE

Although most guidelines still endorse a single lifetime measurement, which is likely adequate for risk assessment in most patients, emerging data reveal that values can fluctuate over time.

The 2024 National Lipid Association update notes that renal or hepatic impairment and major hormonal shifts (eg, menopause) can change a person’s lipoprotein(a) level enough to warrant repeat testing.¹⁷ Lipoprotein(a) levels rise as the estimated glomerular filtration rate falls and often normalizes after a patient receives a kidney transplant.¹⁸ This may be most relevant for individuals whose lipoprotein(a) levels are in the intermediate-risk gray zone.

In the Nashville Biosciences database, Harb and colleagues¹¹ showed that about 53% of participants in the intermediate-risk gray zone (lipoprotein[a] 75–125 nmol/L or 30–50 mg/dL) moved across guideline risk categories when tested again. The placebo group in the trial of an experimental drug for lowering lipoprotein(a) (more about this below) showed up to 20% intraindividual variability in lipoprotein(a) measurements.¹²

More studies are needed to further define when repeat lipoprotein(a) testing is clinically indicated. Repeat testing is generally advised for patients in the gray zone.

EXISTING LIPID-LOWERING DRUGS HAVE VARYING EFFECTS ON LIPOPROTEIN(A)

There are no approved therapies for elevated lipoprotein(a). Current management focuses on controlling concurrent risk factors, particularly LDL-C, to reduce atherosclerotic cardiovascular disease risk.⁷ Current lipid-lowering therapies have varying effects on lipoprotein(a) (Table 1).^19–26

Statins are first-line therapies for lowering LDL-C levels to reduce the risk of atherosclerotic cardiovascular disease,²⁷ but they slightly increase or have neutral effects on lipoprotein(a) levels. A meta-analysis found no consistent impact²⁸; the Scandinavian Simvastatin Survival Study¹⁹ reported increases of up to 15%, while atorvastatin lowered levels by about 13% in the Collaborative Atorvastatin Diabetes Study.²⁰ In general, the benefits of statins (potent LDL-C reduction, plus any putative additional “pleiotropic” effects) may typically outweigh any small risk increment that may be attributable to a minor rise in lipoprotein(a).

Ezetimibe modestly lowers lipoprotein(a) (by about 7%) when used alone,²¹ but has little additional effect when used with statins.^28,29

Bile acid sequestrants and fibrates generally do not lower lipoprotein(a) and may slightly increase levels.³⁰

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (alirocumab, evolocumab) significantly lower LDL-C and have modest effects on lipoprotein(a) as well. The ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab)^22,23,31 and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk)²⁴ trials showed these drugs had greater cardiovascular benefits in patients with high baseline lipoprotein(a). In FOURIER, evolocumab reduced absolute cardiovascular risk by 2.41% in patients with lipoprotein(a) greater than 120 nmol/L, compared with 1.41% in those with lower levels.^4,24,30

Inclisiran, a small-interfering RNA targeting PCSK9, lowered lipoprotein(a) levels by about 22% in the ORION (Inclisiran for Participants With Atherosclerotic Cardiovascular Disease and Elevated Low-Density Lipoprotein Cholesterol) trials,²⁵ and clinical outcomes studies are ongoing.

Bempedoic acid has generally shown no substantial impact on lipoprotein(a) levels.²⁶

Niacin lowers lipoprotein(a) by 20% to 25%, but its routine use is discouraged because its cardiovascular benefits are limited and it has frequent adverse effects. Further, 2 clinical trials of niacin in patients with established cardiovascular disease and well-controlled LDL-C levels did not demonstrate incremental cardiovascular risk reduction when niacin was added to statin therapy.^32–34

Why niacin did not reduce risk when added to statin therapy is unclear, but we can speculate it has off-target or unfavorable effects that counterbalance its lipoprotein(a)-lowering benefits, or it may not lower lipoprotein(a) enough to show cardiovascular benefits if a patient is already on a statin and has well-controlled LDL-C.

Lipoprotein apheresis is an option for individuals with very high lipoprotein(a) and progressive atherosclerotic cardiovascular disease, reducing lipoprotein(a) by more than 60%.^4,35

EMERGING THERAPIES

Novel lipoprotein(a)-lowering drugs include antisense oligonucleotides, small interfering RNAs, and small-molecule drugs. Some of these drugs are conjugated to N-acetylgalactosamine (GalNAc) and target hepatocytes, the primary site of lipoprotein(a) production, by binding to the asialoglycoprotein receptor on the surface of these cells.

Pelacarsen, an antisense oligonucleotide, degrades lipoprotein(a) messenger RNA. In a phase 2 trial, it lowered lipoprotein(a) levels by 35% to 80%, with peak effects at 16 weeks. Weekly dosing lowered lipoprotein(a) to less than 50 mg/dL in 98% of participants, but levels rebounded after 16 weeks.³⁶ The phase 3 Lp(a)HORIZON (Assessing the Impact of Lipoprotein[a] Lowering With Pelacarsen [TQJ230] on Major Cardiovascular Events in Patients With CVD; NCT04023552) trial is evaluating pelacarsen’s effect on major adverse cardiovascular events, with results expected in 2026.

Olpasiran, a GalNAc-conjugated small interfering RNA, suppresses apolipoprotein(a) messenger RNA production. OCEAN(a)-DOSE (Olpasiran Trials of Cardiovascular Events and Lipoprotein[a] Reduction–Dose Finding Study),³⁷ a phase 2 study, showed placebo-adjusted lipoprotein(a) reductions of up to 100%, sustained for 12 to 24 weeks, with 98% to 100% of patients achieving levels less than 125 nmol/L at higher doses. The phase 3 OCEAN(a)-Outcomes trial (NCT05581303) will assess its impact on major adverse cardiac events, with results anticipated in 2026.

Zerlasiran and lepodisiran are also small interfering RNA therapies that reduce hepatic apolipoprotein(a) production and lower lipoprotein(a) levels by up to 80% to 94%.^38–40

Muvalaplin, an oral small-molecule drug, blocks assembly of the 2 components of lipoprotein(a)—apolipoprotein(a) and apolipoprotein B. In a phase 2 trial, daily doses of 10 to 240 mg over 12 weeks lowered lipoprotein(a) levels by up to 85.8% in patients at high risk, with a safety profile comparable to that of placebo.⁴¹ The MOVE-Lp(a) (Assessing the Impact of Muvalaplin on Major Cardiovascular Events in Adults With Elevated Lipoprotein[a]) randomized placebo-controlled trial (NCT07157774) is evaluating the efficacy of muvalaplin on reducing major cardiovascular events.

Although early data are promising, the role of lipoprotein(a)-lowering therapies in atherosclerotic cardiovascular disease management remains uncertain (Table 2).^{36,37,39–41} Ongoing trials will clarify whether lipoprotein(a) is a residual risk factor or a stand-alone target requiring combination therapy with LDL-Clowering agents. Until lipoprotein(a)-targeted therapies are validated and available, aggressive management of traditional cardiovascular risk factors remains the primary strategy for reducing the risk of atherosclerotic cardiovascular disease.⁴²

THE BOTTOM LINE

Lipoprotein(a) is a prevalent, genetic, independent risk factor for adverse atherosclerotic cardiovascular disease outcomes that is essentially unaffected by life-style changes and currently lacks approved therapies. Intensification of proven preventive and atherosclerotic cardiovascular disease risk-reduction measures is generally indicated in individuals with elevated lipoprotein(a) levels. PCSK9 inhibitors are associated with modest lipoprotein(a) reduction. Emerging RNA-based and small-molecule therapies show promising lipoprotein(a)-lowering effects; ongoing phase 3 trials are evaluating their impact on atherosclerotic cardiovascular disease outcomes.

DISCLOSURES

Dr. Cho has disclosed consulting for AstraZeneca Pharmaceuticals and Esperion; serving as a research principal investigator for AstraZeneca Pharmaceuticals and Novartis Pharmaceuticals; serving as research study chair for Eli Lilly; and serving on the steering committee for CLEAR outcomes for Esperion. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.