Lipoprotein(a) [Lp(a)] has evolved from a biochemical curiosity to a central player in cardiovascular risk assessment, with elevated levels affecting approximately 1.5 billion people worldwide as an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve disease.^1,2

Pathophysiology and Genetics

Lp(a) is a low-density lipoprotein (LDL) particle to which apolipoprotein(a) [apo(a)] is covalently bound. The presence of apo(a) confers proatherogenic, proinflammatory and prothrombotic properties. Plasma concentrations of Lp(a) are approximately 70-90% genetically determined and remain remarkably stable over an individual's lifetime.^1,2

Ethnic differences are substantial, with concentrations lowest in people from China, Europe and Southeast Asia, intermediate in people from South Asia, and highest in Blacks. Concentrations are 17% higher in postmenopausal women than in men.²

Epidemiology and CV Risk

A robust body of observational and Mendelian randomization data establishes a causal relationship between elevated Lp(a) and ASCVD, ischemic stroke and calcific aortic valve stenosis (CAVS).³

A landmark 2024 study from the Women's Health Study of nearly 28,0000 initially healthy U.S. women with 30-year follow-up showed that baseline Lp(a) levels in the highest quintile conferred an adjusted hazard ratio of 1.33 (95% CI, 1.21-1.47) for first major cardiovascular events (myocardial infarction, coronary revascularization, stroke or death from cardiovascular causes) vs. the lowest quintile; this effect was independent of hsCRP and LDL-C.⁴ The results underscore that Lp(a) adds long-term prognostic information, even when measured once mid‐life.

Recent secondary-prevention data further show that in more than 270,000 patients with established ASCVD, higher Lp(a) levels were associated with continuously increasing risk of recurrent ASCVD.⁵ Additionally, Lp(a) has been implicated in the progression of CAVS via deposition of oxidized phospholipids that fuels inflammation and calcification in the valve.⁶

Together, these data point to a continuous risk relationship with Lp(a) with no clear evidence of a threshold effect.⁷ Also, Lp(a) confers risk independent of traditional ASCVD risk factors, including LDL-C and blood pressure.

Because Lp(a) levels are genetically determined and stable over time, a one-time measurement is sufficient for most patients. The 2024 focused update from the National Lipid Association recommends measurement of Lp(a) levels at least once in every adult, with individuals having Lp(a) levels ≥50 mg/dL considered high risk.

An Evolving Therapeutic Landscape

Individuals with Lp(a) levels of 50 mg/dL or higher are at greater risk for ASCVD events and should be treated with lifestyle management such as smoking cessation, physical activity and weight loss, and should receive treatment to lower blood pressure, LDL-C, glucose and other cardiovascular risk factors as recommended by guidelines.⁷

Statins do not meaningfully reduce Lp(a) and may even slightly increase it in some people. PCSK9 inhibitors lower LDL-C by up to 60% and Lp(a) by up to 30% but have not been tested in individuals with high Lp(a) and are not indicated for Lp(a) reduction. Lipoprotein apheresis can reduce Lp(a) by about 35% but is resource-intensive and reserved for extreme cases.

The therapeutic horizon has shifted dramatically with the recent development of RNA-based therapies:

• Lepodisiran: In the phase 2 ALPACA trial presented at ACC.25, a single 400 mg dose achieved a mean Lp(a) reduction of 93.9% at day 180, with this reduction persisting >90% at 360 days after a single injection.⁸ No safety signals were revealed. A phase 3 cardiovascular outcomes trial [ACCLAIM-Lp(a)] is currently enrolling.
• Olpasiran and Zerlasiran: These siRNA agents have achieved >80-90% sustained reduction in Lp(a) with dosing every 12-24 weeks.
• Pelacarsen: Data from a Phase 2 study showed this antisense oligonucleotide reduced Lp(a) levels below the recommended threshold of risk for cardiovascular disease events (<50 mg/dL) in 98% of participants.⁹ Topline results from the Lp(a) HORIZON trial are expected soon.

Other Lp(a)-lowering agents have demonstrated encouraging results in clinical studies, notably muvalaplin, an oral small molecule inhibitor, which reduced Lp(a) by 86% in a recent phase 2 trial.¹⁰

While the magnitude and durability of the reductions seen are striking, no published outcome trial to date has definitively shown that Lp(a) lowering reduces major cardiovascular events. The key question remains unanswered: will reducing Lp(a) translate into improved clinical outcomes? Until then, cardiologists must optimize standard-of-care therapies and counsel patients accordingly.

References

1. Sosnowska B, Toth PP, Razavi AC, et al. 2024: The year in cardiovascular disease – the year of lipoprotein(a). Research advances and new findings. Arch Med Sci 2025;21:355-73.
2. Nordestgaard BG, Langsted A. Lipoprotein(a) and cardiovascular disease. Lancet 2024;404:1255-64.
3. Wong ND, Fan W, Hu X, et al. Lipoprotein(a) and long-term cardiovascular risk in a multi-ethnic pooled prospective cohort. J Am Coll Cardiol 2024;83:1511-25.
4. Ridker PM, Moorthy MV, Cook NR, et al. Inflammation, cholesterol, lipoprotein(a), and 30-year cardiovascular outcomes in women. N Engl J Med 2024;391:2087-97.
5. MacDougall DE, Tybaerg-Hansen A, Knowles JW, et al. Lipoprotein(a) and recurrent atherosclerotic cardiovascular events: the US Family Heart Database. Eur Heart J 2025; May 7: ehaf297.
6. Arsenault BJ, Loganath K, Girard A, et al. Lipoprotein(a) and calcific aortic valve stenosis progression: A systematic review and meta-analysis. JAMA Cardiol 2024;9:835-42.
7. Mora S, Kronenberg F. Lipoprotein(a). JAMA 2025;333:1918-9.
8. Nissen SE, Ni W, Shen X, et al. Lepodisiran – a long-duration small interfering RNA targeting lipoprotein(a). N Engl J Med 2025;392:1673-83.
9. Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med 2020;382:244-55.
10. Nicholls SJ, Ni N, Rhodes GM, et al. Oral muvalaplin for lowering of lipoprotein(a): a randomized clinical trial. JAMA 2025;333:222-31.

Clinical Topics: Dyslipidemia, Advanced Lipid Testing, Lipid Metabolism, Nonstatins

Keywords: Cardiology Magazine, ACC Publications, Cholesterol, LDL, Myocardial Infarction, Risk Factors, Lipoprotein(a)