Lipoprotein(a) (Lp(a)) is a specific type of cholesterol particle recognized as an independent, causal risk factor for cardiovascular disease. Similar in structure to low-density lipoprotein (LDL), or “bad cholesterol,” Lp(a) features an additional protein, apolipoprotein(a) (apo(a)), covalently attached to the LDL component. High levels of Lp(a) promote the buildup of plaque (atherosclerosis) and increase the risk of blood clot formation (thrombosis). This unique structure links Lp(a) to both pro-atherosclerotic and pro-thrombotic mechanisms, making elevated levels a concern for heart attack, stroke, and aortic valve stenosis. Measuring Lp(a) is a valuable tool for assessing lifelong cardiovascular risk, especially in individuals with a family history of early heart disease.
Lifestyle Adjustments and Limited Impact
The concentration of Lipoprotein(a) in the blood is overwhelmingly determined by genetics, with the LPA gene accounting for 70% to over 90% of the variation between individuals. Because of this strong genetic control, Lp(a) levels are highly resistant to traditional cholesterol-lowering lifestyle interventions like diet and exercise. For most people, consuming a low-fat diet or engaging in moderate physical activity, while beneficial for overall health, does not meaningfully alter their Lp(a) number.
Standard dietary changes aimed at reducing LDL cholesterol, such as decreasing saturated fat intake, have a negligible impact on Lp(a). Similarly, regular exercise, which favorably affects other lipid markers, does not cause a consistent or significant reduction in Lp(a). Consequently, clinical guidance emphasizes that lifestyle changes are primarily supportive measures rather than direct Lp(a) reducers.
Individuals with high Lp(a) should still focus on aggressive management of all other modifiable cardiovascular risk factors. This includes reducing LDL cholesterol to optimal levels, controlling blood pressure and blood sugar, and maintaining a healthy body weight. By mitigating the risk from factors they can control, patients can help offset the heightened risk associated with their genetically elevated Lp(a). Quitting smoking and achieving target LDL-C levels remain important for cardiovascular risk reduction.
Current Pharmacological Options
No drug is currently approved specifically for the sole purpose of lowering Lp(a), but a few existing agents used to manage high cholesterol have a measurable Lp(a)-lowering side effect. These options are sometimes employed by clinicians for patients with established cardiovascular disease and elevated Lp(a).
Niacin
High-dose Niacin (Vitamin B3) is the most effective oral drug for Lp(a) reduction, typically lowering levels by 20% to 35%. It is believed to interfere with the production of the apolipoprotein(a) component in the liver. However, Niacin’s routine use has decreased due to side effects, such as flushing, and mixed results in large outcome trials. Despite these limitations, it remains a consideration for selected high-risk patients.
PCSK9 Inhibitors
Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) inhibitors, a class of injectable antibody-based therapies, also offer a modest reduction in Lp(a) levels. These drugs, such as evolocumab and alirocumab, are primarily used to dramatically lower LDL cholesterol, but they concurrently decrease Lp(a) by approximately 25% to 30%.
The Lp(a)-lowering effect of PCSK9 inhibitors is achieved through a dual mechanism. As a monotherapy, they reduce the rate of Lp(a) particle production by the liver. When combined with a statin, they also enhance the clearance (catabolism) of Lp(a) particles from the bloodstream. This ability to reduce both LDL-C and Lp(a) makes PCSK9 inhibitors a current treatment option for high-risk patients.
Future-Focused and Novel Treatments
The next generation of therapies for elevated Lp(a) focuses on highly potent, targeted treatments that directly interfere with the particle’s production. These novel treatments use genetic mechanisms to silence the instructions for making the apolipoprotein(a) component in the liver. This approach aims to achieve the substantial reductions necessary to lower cardiovascular risk.
Antisense Oligonucleotides (ASOs)
ASOs are single strands of DNA that target the messenger RNA (mRNA) carrying the genetic code for apolipoprotein(a). When the ASO binds to the complementary mRNA sequence, it triggers a cellular enzyme to degrade the mRNA. This process prevents the genetic message from being translated into the apo(a) protein, halting the assembly of the Lp(a) particle. Pelacarsen, an ASO, has demonstrated the ability to lower Lp(a) levels by 66% to over 90% in clinical trials.
Small Interfering RNAs (siRNAs)
SiRNAs utilize a related mechanism called RNA interference. These double-stranded RNA molecules are delivered to the liver cells, where they are incorporated into a complex that recognizes and cleaves the complementary apolipoprotein(a) mRNA. By destroying the mRNA, the siRNA effectively silences the LPA gene, reducing the production of Lp(a). SiRNA therapies like olpasiran and lepodisiran have achieved sustained Lp(a) reductions of 80% to 95% in clinical studies. Both ASOs and siRNAs are typically conjugated with N-acetylgalactosamine (GalNAc) to ensure specific delivery to the liver. These gene-silencing therapies are currently in advanced clinical trials.