Lipoprotein(a) (Lp(a)) is a low-density lipoprotein (LDL) particle that carries cholesterol. Its structure is unique, featuring apolipoprotein(a) (apo(a)) attached to the LDL component. Lp(a) is recognized as an independent risk factor for cardiovascular disease, contributing to atherosclerosis, thrombosis, and aortic stenosis. High levels promote plaque buildup and increase the tendency for blood clots.
A person’s Lp(a) concentration is overwhelmingly determined by genetics, specifically the LPA gene, making it distinct from standard LDL cholesterol. Lp(a) levels generally remain stable throughout adult life and are not responsive to traditional cholesterol-lowering medications. Common drugs like statins are ineffective at reducing Lp(a) and may even cause a slight increase in some individuals. This strong genetic link explains why managing high Lp(a) has historically been a significant challenge.
Managing Cardiovascular Risk Through Lifestyle
Lifestyle changes, such as adopting a heart-healthy diet and engaging in regular physical activity, are crucial for cardiovascular risk management. These modifications effectively control other risk factors, even though they do not substantially alter the genetically determined Lp(a) level. The benefit of these habits is focused on improving the vascular system to counteract the pro-atherogenic and pro-thrombotic effects of elevated Lp(a).
A heart-healthy eating pattern, like the Mediterranean-style diet, emphasizes fruits, vegetables, whole grains, and healthy fats. This diet significantly reduces harmful LDL cholesterol and helps manage blood pressure and blood sugar. Regular physical activity enhances circulation and lowers blood pressure, keeping arteries more elastic. By tightly controlling all other modifiable risk factors, a person can lessen the impact that high Lp(a) has on their long-term health.
Existing Pharmacological Approaches
Physicians currently employ a few pharmacological strategies for patients with high Lp(a), though these drugs were not initially designed for this purpose. High-dose Niacin (nicotinic acid) can reduce Lp(a) levels by up to 30%. Its mechanism involves downregulating the LPA promoter, which controls Lp(a) production.
However, niacin’s clinical use is limited because large-scale trials showed no reduction in major cardiovascular events when added to statin therapy. Furthermore, high-dose niacin is associated with side effects, including flushing, gastrointestinal issues, and an increased risk of developing diabetes. For these reasons, niacin is not widely recommended as a specific therapy for Lp(a) reduction.
Another class of medications, PCSK9 inhibitors, are primarily used to lower LDL cholesterol but offer a modest secondary benefit on Lp(a). These injectable drugs reduce Lp(a) levels by approximately 20% to 27%. While the reduction is not dramatic, it provides a measurable benefit in high-risk patients by addressing two risk factors simultaneously.
For individuals with extremely high Lp(a) levels and established heart disease, lipoprotein apheresis can be used. This specialized mechanical procedure filters the blood to acutely remove Lp(a) and other lipoproteins, leading to a temporary reduction of 50% to 85% after a single session.
Targeted Therapies in Development
Significant Lp(a) reduction involves a new generation of targeted therapies currently in advanced clinical trials. These novel drugs are designed to directly interfere with the genetic instructions for producing the Lp(a) particle, a process known as gene silencing. This approach aims to substantially reduce Lp(a) levels.
One leading therapy is the Antisense Oligonucleotide (ASO), exemplified by the drug pelacarsen. ASOs are short, synthetic nucleic acid strands that bind to the messenger RNA (mRNA) responsible for creating the apo(a) protein in the liver. By intercepting this genetic message, the drug prevents the liver from synthesizing apo(a), stopping the assembly of the Lp(a) particle. Clinical trial data show this mechanism achieves substantial Lp(a) reduction, with some studies demonstrating a drop of up to 80%.
A related approach uses Small Interfering RNA (siRNA), which also targets the apo(a) mRNA to silence the gene. Both ASOs and siRNAs offer administration via intermittent injections, providing long-term, stable control of Lp(a) levels for high-risk individuals. These targeted therapies represent a paradigm shift toward specific, potent reduction of this inherited risk factor. While not yet approved, their progress suggests a future where effective treatment for high Lp(a) will be readily available.