Lipoprotein(a) (Lp(a)) is a cholesterol-carrying particle in the blood that poses a significant, independent risk for cardiovascular disease. It is structurally similar to low-density lipoprotein (LDL) but features an additional protein, apolipoprotein(a) (apo(a)), which is covalently attached to the LDL-like core. High levels of Lp(a) contribute to atherosclerosis, heart attack, and stroke. Unlike LDL cholesterol, which is managed with medications and lifestyle changes, reducing high Lp(a) levels presents a unique challenge.
Understanding Lipoprotein(a) and Its Genetic Nature
The Lp(a) particle consists of an LDL core, containing cholesterol and apolipoprotein B100 (apoB100), bound to apolipoprotein(a) (apo(a)). This apo(a) component is highly similar to plasminogen, a protein involved in dissolving blood clots, which contributes to Lp(a)’s clot-promoting properties.
The concentration of Lp(a) is overwhelmingly determined by genetics, with the LPA gene accounting for 70% to over 90% of individual variability. The LPA gene contains variable repeating DNA segments, resulting in different sizes of the apo(a) protein. Shorter versions of apo(a) are associated with higher Lp(a) levels, while longer versions correlate with lower levels. Because Lp(a) concentration is genetically set, it remains stable throughout adult life. Clinicians are concerned when levels exceed 50 mg/dL or 125 nmol/L, identifying increased risk for atherosclerotic disease.
Lifestyle and Dietary Approaches for Modest Reduction
General heart-healthy lifestyle interventions have a minimal direct impact on Lp(a) concentration. Standard dietary recommendations aimed at lowering LDL cholesterol may sometimes slightly increase Lp(a) levels. However, adopting a whole-food, plant-based diet has shown potential in small studies, with reported Lp(a) reductions of around 15% to 16% in certain populations.
The supplement niacin (Vitamin B3) has historically been used and can reduce Lp(a) levels by 20% to 30% at high, pharmacological doses. Niacin is thought to work by downregulating the LPA gene expression, but individual response is highly variable. Its use is often limited by side effects like flushing, and large clinical trials have not demonstrated a clear cardiovascular benefit when added to statin therapy. Supplements like L-carnitine and L-lysine are often discussed online for Lp(a) reduction, but robust clinical evidence supporting their efficacy remains scarce.
Current Pharmacological Reduction Strategies
Standard cholesterol-lowering drugs like statins, the most commonly prescribed class for high cholesterol, do not reduce Lp(a) and may sometimes slightly raise its concentration. While statins are foundational for cardiovascular risk management by lowering LDL, they are not a specific strategy for reducing Lp(a). A more effective current pharmacological option is the use of PCSK9 inhibitors, which are injectable antibody medications. These drugs primarily target LDL receptors but have a beneficial secondary effect, lowering Lp(a) levels by approximately 15% to 30%.
PCSK9 inhibitors, such as evolocumab and alirocumab, are considered for high-risk patients with elevated Lp(a) despite optimal treatment for other risk factors. The mechanism involves reducing Lp(a) production by the liver and enhancing its clearance. For individuals with extremely high Lp(a) levels and progressive cardiovascular disease, Lipoprotein Apheresis is an option. This mechanical procedure functions like dialysis, filtering the blood to remove Lp(a) and other apoB-containing lipoproteins, resulting in a significant reduction of 60% to 70% during the treatment session.
Emerging and Future Targeted Therapies
The most promising future treatments for Lp(a) are highly targeted genetic therapies that directly interfere with the production of the apo(a) protein in the liver. These investigational drugs use nucleic acid technology to prevent the formation of the Lp(a) particle. Antisense Oligonucleotides (ASOs), such as pelacarsen, work by binding to the messenger RNA (mRNA) from the LPA gene. This binding causes the mRNA to be degraded, preventing the liver from manufacturing the apo(a) protein needed to form Lp(a).
Similarly, Small Interfering RNA (siRNA) therapies, including drugs like olpasiran and lepodisiran, use a related approach to silence the LPA gene’s instructions. These new agents have shown unprecedented efficacy in clinical trials, achieving dramatic Lp(a) reductions, often in the range of 80% to 98%. While these therapies are not yet commercially available, they are expected to revolutionize the management of high Lp(a) once approved.