CME: Lipoprotein(a) Revisited - 2026 Update
Updated: Oct 11
What is Lipoprotein(a), why is it important, and how are elevated levels treated?
Cardiology
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Elevated lipoprotein(a) [Lp(a)] is a genetically determined risk factor for both cardiovascular disease and calcific aortic valve disease (CAVD). This article discusses what Lp(a) is, why elevated levels are associated with disease, and how high Lp(a) levels are currently managed.
Lp(a) was discovered in 1963 by Kåre Berg, who identified it in the low-density lipoprotein (LDL-C) fraction of serum. He subsequently established the association between elevated Lp(a) and coronary artery disease.[1]
Lp(a) is a lipoprotein that contains apolipoprotein B-100 (apoB-100), which is bound to apolipoprotein(a) [apo(a)]. ApoB-100 is bound to the surface of an LDL-like lipid core and is atherogenic. Apo(a) can carry proinflammatory and proatherogenic oxidized phospholipids.[1] Apolipoproteins are proteins that bind to lipids and help form lipoprotein particles.
Genetic Variation
Approximately 70% to more than 90% of the variation in Lp(a) levels is genetically determined, though environmental factors and medical conditions may also play a role.[1] Lp(a) levels can vary depending on patient ethnicity and the type of assay used, making standardization of normal ranges difficult. Individuals of Black African or South Asian descent generally have higher median Lp(a) levels than those of White or East Asian descent.[1] However, current recommendations are to apply Lp(a)-based risk categories across racial and ethnic groups rather than using different treatment thresholds according to race or ethnicity.[2]
Plasma Lp(a) levels are predominantly determined by the two alleles of the LPA gene, with other genetic loci playing minor roles. The LPA gene is thought to have evolved from the gene encoding plasminogen. Circulating Lp(a) concentrations can vary more than 1,000-fold between individuals (ranging from <0.1 mg/dL to >300 mg/dL). Plasma Lp(a) levels are largely unaffected by age, sex, fasting status, diet, or physical activity.[3]
Lipoprotein (a) Structure
[4]
Structurally, Lp(a) has an LDL-like core. Apo(a) binds to apoB-100 via a single disulfide bond (A) at a location near the LDL receptor binding site (B). Apo(a) has kringle structures KIV and KV. There are 10 variants of apo(a) KIV of which type 2 is present in multiple forms. Apo(a) binds to proinflammatory and proatherogenic oxidized phospholipids (C). Apo(a) also has a protease domain (D) that lacks proteolytic activity.
Lp(a) is synthesized in the liver. Lp(a) concentrations are strongly influenced by the number of kringle IV (KIV) repeats in an individual's apo(a), which is determined by the LPA gene. The term “kringle” derives from a Scandinavian pretzel-like pastry because of the resemblance in shape. It is a protein folded in on itself in a loop that becomes part of a larger molecule.
While there are ten subtypes of KIV, KIV type 2 (KIV-2) can be repeated from 2 to 40 times in an apo(a) molecule. The number of KIV type 2 repeats is thought to be responsible for most of the genetic variation seen. Individuals having smaller apo(a) molecules with less than 22 KIV type 2 repeats have, on average, markedly higher Lp(a) concentrations than individuals having larger apo(a) isoforms with more than 22 KIV type 2 repeats. There is also a kringle V (KV) that can be found in Lp(a), but it only appears once and does not repeat like the KIV type 2.[3]
Adverse Effects
The apoB-containing component of Lp(a) is thought to contribute to its atherogenicity because of its similarity to LDL. Although there are far fewer circulating Lp(a) particles than LDL particles, Lp(a) may be selectively retained in the arterial wall through interactions between apo(a) and extracellular matrix proteins. Lp(a) also carries oxidized phospholipids, which can promote inflammation and may contribute to vascular calcification. Apo(a) can interact with fibrin, fibrinogen, and endothelial cells through its lysine-binding site, and apo(a) has been identified in human atheromas and calcified aortic valves.[1]
Cardiovascular Events
One study found that each doubling of the Lp(a) level was associated with a 22% greater risk of myocardial infarction.[5] A meta-analysis of patients with familial hypercholesterolemia found that elevated Lp(a) was associated with cardiovascular disease, with an odds ratio of 2.57.[6] Another large study found that the risk of heart failure increased with higher levels of Lp(a).[7]
There appears to be a linear relationship between Lp(a) levels and cardiovascular outcomes, with Lp(a)-associated cardiovascular risk being continuous rather than defined by a single cutoff value. Under the National Lipid Association risk classification, an Lp(a) level of less than 30 mg/dL (75 nmol/L) is generally considered low risk, while a level of 50 mg/dL (125 nmol/L) or higher is considered high risk. Levels between 30 and 50 mg/dL (75–125 nmol/L) are considered intermediate risk.[2]
Researchers using the large UK Biobank database reported that lower LDL-C, total cholesterol, and triglyceride levels were associated with lower cardiovascular risk among individuals with elevated Lp(a).[8,9]
Aortic Valve Calcification
Patients with elevated Lp(a) levels have more rapid aortic valve calcification progression on serial computed tomography scans, and worse clinical outcomes.[1] Other studies found accelerated progression of aortic stenosis in individuals in the top third of measured Lp(a) levels.[1,10] One study identified a single mutation of the LPA gene to be associated with the presence of CAVD with an odds ratio of 2.05.[11] Another study found evidence that suggested lifelong elevations in Lp(a) levels lead to a markedly increased prevalence of CAVD in adulthood.[2,11] A third study found that in patients with diagnosed aortic stenosis, elevated Lp(a) levels and elevated numbers of oxidized phospholipids attached to the Lp(a) molecules were associated with more rapid aortic stenosis progression and need for aortic valve replacement.[10] A meta-analysis looking at CAVD found an association between Lp(a) levels ≥50 mg/dL and CAVD, but there was insufficient evidence to link Lp(a) levels between 30 mg/dL and 50 mg/dL similarly to CAVD. The authors suggested that the magnitude of the Lp(a) concentration might have a dose-response relationship with CAVD.[12]
Stroke
Lp(a) elevation may also be associated with stroke risk, although the evidence is less consistent than for cardiovascular disease. One large study found that subjects with lower Lp(a) levels had significantly fewer strokes than a comparison group with higher Lp(a) levels.[1,13] However, a meta-analysis found evidence supporting an association between elevated Lp(a) and cardiovascular disease, but found no evidence of a relationship to stroke.[14] A recent analysis using UK Biobank data reported that an Lp(a) level > 125 nmol/L was associated with an increased risk of ischemic stroke, but not hemorrhagic stroke.[15]
Thrombosis
Because of Lp(a)’s structural similarity to plasminogen and the ability of apo(a) to interfere with plasmin-mediated fibrinolysis in vitro, investigators have examined whether elevated Lp(a) is associated with thrombotic events. Although some data from trials suggest a positive association between Lp(a) levels and the risk of venous thromboembolism,[16-18] the literature is mixed. Another study found no effect of Lp(a) on venous thromboembolism[19]. Meta-analyses have been both positive and negative for a correlation between Lp(a) levels and venous thrombosis.[20-22]
Diabetes Mellitus
Very low Lp(a) levels have been associated with an increased risk of type 2 diabetes mellitus. Lp(a) levels less than 4 mg/dL were associated with approximately a 20% to 50% higher relative risk of developing diabetes, with those with Lp(a) levels below 1 mg/dL having the highest risk.[23] These findings were confirmed by several other studies.[24,25] One of them also found that prediabetes, insulin resistance, and hyperinsulinemia were all increased in individuals with very low levels of Lp(a).[24] There is some evidence that elevated insulin concentrations may be causally related to lower production of Lp(a), but that may only partially explain the phenomenon.[26]
Testing
The National Lipid Association and the 2026 American College of Cardiology/American Heart Association dyslipidemia guideline recommend measuring Lp(a) at least once in adulthood to improve cardiovascular risk assessment.[2,27]
One of the difficulties in standardizing testing for Lp(a) is that there are a number of different assays available for measuring Lp(a). Because apo(a) isoform size can affect accuracy, current guidelines recommend using assays that are insensitive to apo(a) isoform size and are calibrated to measure Lp(a) concentration in nanomoles per liter (nmol/L). Mass-based Lp(a) measurements, such as those reported in mg/dL, can be affected by substantial variability in apo(a) isoform size resulting from differences in the number of kringle IV type 2 repeats.[1] A significant portion of the medical literature on Lp(a) has been reported in mg/dL units, but current guidelines recommend that nmol/L be used as the preferred unit for reporting Lp(a) concentrations.[1] Although approximately 50 mg/dL corresponds to 125 nmol/L in the National Lipid Association risk classification, the units should not be converted using a fixed conversion factor because the relationship varies with apo(a) isoform size and assay characteristics.[3]
Treatment
Although elevated Lp(a) is an established cardiovascular risk factor, it has not yet been definitively demonstrated that pharmacologically lowering Lp(a) with drugs targeting Lp(a) reduces cardiovascular events.[1,28] Dietary interventions and lifestyle modifications have minimal effects on reducing Lp(a) levels.[1,4] Consequently, current clinical strategy focuses on aggressively lowering LDL-C and apoB to reduce overall residual risk.[1]
Lipoprotein Apheresis
Lipoprotein apheresis is the only FDA-approved treatment whose indication specifically includes elevated Lp(a), and it is reserved for certain high-risk patients who meet defined criteria.[27,29] Lipoprotein apheresis for Lp(a) is indicated for patients with clinically diagnosed heterozygous familial hypercholesterolemia who have an Lp(a) ≥60 mg/dL (or 130 nmol/L) and documented coronary or peripheral artery disease.[27] (Apheresis for those with homozygous familial hypercholesterolemia is FDA approved when LDL-C >500 mg/dL.)[30]
During a 3- to 4-hour apheresis session, blood is withdrawn and separated into plasma and cellular components. The plasma is passed through adsorbent columns that remove LDL-C and Lp(a), and the treated plasma and cellular components are then reinfused. The Lp(a) level typically is lowered by about 50% to 85%. It is generally performed every two weeks because Lp(a) levels generally return to pretreatment levels between treatments. Apheresis also reduces oxidized phospholipids and lowers LDL-C concentrations by 60% to 85%.
Clinical data suggest lipoprotein apheresis may reduce the risk of cardiovascular events.[1] In one study, patients with Lp(a) levels above the 95th percentile who experienced recurrent major adverse coronary events (MACE) despite maximally tolerated lipid-lowering therapy were started on lipoprotein apheresis. In the study group, Lp(a) levels were lowered by 73% and the MACE rate was 86% lower during the apheresis period than during the pre-apheresis period.[2,31] A similar trial demonstrated that lipoprotein apheresis effectively lowered the incidence of MACE by 78%.[32] In a third investigation, subjects with an Lp(a) level over 50 mg/dL who were treated with apheresis plus statin for 18 months had significantly greater regression of coronary atherosclerotic lesions than the statin-only group.[2,33]
Statins
Statins do not generally reduce Lp(a) and may cause modest increases in Lp(a) levels in some individuals.[1,2,34] The mechanism is not well understood, but increased production of apo(a) has been proposed as one possible explanation.[34,35]
Despite their lack of beneficial effect on Lp(a) levels, discontinuing statin therapy is not recommended given its strong cardiovascular benefit.[27]
PCSK9-Inhibiting Medications
PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors bind to PCSK9, preventing PCSK9-mediated degradation of hepatic LDL receptors and allowing the liver to clear more LDL-C. The mechanism by which LDL receptors reduce Lp(a) is not fully understood, but one theory is that Lp(a) also binds to hepatic LDL receptors, so increasing their availability may enhance Lp(a) clearance.[36]
Clinical trials of PCSK9-inhibiting monoclonal antibodies, such as alirocumab and evolocumab, demonstrated that in addition to lowering LDL-C levels, they can also reduce Lp(a) levels by 15% to 30%.[1,2,6,37] In the ODYSSEY trial, adding alirocumab to optimal statin therapy reduced Lp(a) levels, and greater Lp(a) reduction was associated with a lower risk of MACE compared with controls. However, this benefit was observed only in subjects who had an Lp(a) over 13.7 mg/dL.[38] In a further post-hoc analysis of ODYSSEY data, the association between Lp(a) reduction and cardiovascular benefit was greatest among patients with Lp(a) ≥50 mg/dL (125 nmol/L).[27]
Similarly, the FOURIER trial showed that evolocumab reduced Lp(a) levels by 26.9%. Among patients with higher baseline Lp(a) levels, there was a 23% lower risk of coronary heart disease death, myocardial infarction, or urgent revascularization. However, the amount of cardiovascular risk reduction directly attributable to Lp(a) lowering versus LDL-C lowering remains uncertain.[39]
Inclisiran, a small interfering RNA (siRNA) targeting PCSK9 synthesis, has been shown in trials to reduce Lp(a) levels by 18% to 26% while lowering LDL-C levels by approximately 50%. One key advantage of inclisiran is that it has a prolonged duration of action, with maintenance doses generally administered every six months.[40,41] Although some early evidence suggests that inclisiran may reduce adverse cardiovascular events, cardiovascular outcomes are still being evaluated in ongoing trials.[42]
Enlicitide, the first oral PCSK9 inhibitor, was approved by the FDA in July 2026. In one large clinical trial, it reduced Lp(a) levels by 28% at week 24 and LDL-C levels by 56% at week 24 and 48% at week 52 compared with placebo. Results of the cardiovascular outcomes trial for enlicitide are expected in 2029.[43,44]
Despite evidence that PCSK9-inhibiting drugs may be beneficial in patients with elevated Lp(a) levels, none are specifically FDA approved for lowering Lp(a).[27]
Drugs Targeting Lp(a)
There are currently five investigational therapies specifically targeting Lp(a). The small interfering RNA (siRNA) agents lepodisiran, olpasiran, and zerlasiran target hepatic production of Lp(a). Pelacarsen is an antisense oligonucleotide that decreases Lp(a) levels by binding to hepatocyte messenger RNA (mRNA), thereby blocking apo(a) production required for Lp(a) assembly. Muvalaplin is an oral agent designed to disrupt the binding of apo(a) to apoB-100, which prevents Lp(a) assembly. In phase II studies, these drugs have been reported to reduce Lp(a), with the siRNA agents (olpasiran, lepodisiran, zerlasiran) achieving the largest reductions, ranging from 94% to 99%, pelacarsen reducing Lp(a) by 80%, and the oral agent muvalaplin reducing it by 86%.[45]
In September 2026, Novartis announced that the phase III Lp(a)HORIZON trial of pelacarsen did not meet its primary endpoint of reducing major cardiovascular events compared with placebo. Although pelacarsen substantially lowered Lp(a) levels, this reduction did not translate into a reduction in cardiovascular events in the overall study population.[28]
Whether other drugs specifically designed to reduce Lp(a) will improve cardiovascular outcomes remains uncertain and will depend on the results of ongoing and future trials.
Niacin
Daily niacin has been shown to lower Lp(a) by 23% in one meta-analysis.[46] It also increases HDL-C and lowers LDL-C. However, randomized trials have failed to demonstrate improved cardiovascular outcomes when niacin is added to baseline statin therapy, and its frequent adverse effects significantly limit its clinical utility.[47]
Summary
Elevated Lp(a) is a known inherited risk factor for both cardiovascular disease and calcific aortic valve disease. Diet and lifestyle changes have little direct effect on Lp(a) levels, although they remain important for reducing overall cardiovascular risk.
Lp(a) levels vary among racial and ethnic groups.
Several assays are available for measuring Lp(a), but methods that are insensitive to apo(a) isoform size are preferred. Lp(a) is frequently reported in mg/dL, although nmol/L is increasingly recommended as the preferred unit for reporting Lp(a) concentrations because it expresses the molar concentration of Lp(a) particles and is less affected by the variance in apo(a) isoform sizes.
Current guidelines recommend measuring Lp(a) at least once in all adults because levels are largely genetically determined and remain relatively stable throughout life. Additional testing may be particularly important in people with premature atherosclerotic cardiovascular disease (ASCVD), a family history of premature ASCVD, familial hypercholesterolemia, or an elevated Lp(a) level in a first-degree relative.[27]
Aggressive management of LDL-C and other modifiable cardiovascular risk factors is currently the principal strategy for reducing cardiovascular risk in patients with elevated Lp(a).
Niacin lowers Lp(a) but has not been shown to improve outcomes when added to statin therapy.
Statins may modestly increase Lp(a) levels in some patients, but this should not be a reason to discontinue statin therapy because statins remain foundational therapy for reducing LDL-C and ASCVD risk.
PCSK9 inhibitors modestly lower Lp(a) levels, although the extent to which their cardiovascular benefit is attributable to Lp(a) reduction remains uncertain. Inclisiran also lowers Lp(a), but cardiovascular outcome data remain under study.
Medications that substantially lower Lp(a) levels are currently being evaluated. In the phase III Lp(a)HORIZON trial, pelacarsen did not reduce the primary cardiovascular event endpoint.
Lipoprotein apheresis substantially lowers Lp(a) but is generally reserved for a narrowly defined group of very high-risk patients who meet FDA-approved criteria.
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initially published February 2023