Lipoprotein (a): When to Measure and How to Treat?

Purpose of review The purpose of this article is to review current evidence for lipoprotein (a) (Lp(a)) as a risk factor for multiple cardiovascular (CV) disease phenotypes, provide a rationale for Lp(a) lowering to reduce CV risk, identify therapies that lower Lp(a) levels that are available clinically and under investigation, and discuss future directions. Recent findings Mendelian randomization and epidemiological studies have shown that elevated Lp(a) is an independent and causal risk factor for atherosclerosis and major CV events. Lp(a) is also associated with non-atherosclerotic endpoints such as venous thromboembolism and calcific aortic valve disease. It contributes to residual CV risk in patients receiving standard-of-care LDL-lowering therapy. Plasma Lp(a) levels present a skewed distribution towards higher values and vary widely between individuals and according to ethnic background due to genetic variants in the LPA gene, but remain relatively constant throughout a person's life. Thus, elevated Lp(a) (≥50 mg/dL) is a prevalent condition affecting >20% of the population but is still underdiagnosed. Treatment guidelines have begun to advocate measurement of Lp(a) to identify patients with very high levels that have a family history of premature CVD or elevated Lp(a). Lipoprotein apheresis (LA) efficiently lowers Lp(a) and was recently associated with a reduction of incident CV events. Statins have neutral or detrimental effects on Lp(a), while PCSK9 inhibitors significantly reduce its level by up to 30%. Specific lowering of Lp(a) with antisense oligonucleotides (ASO) shows good safety and strong efficacy with up to 90% reductions. The ongoing CV outcomes study Lp(a)HORIZON will provide a first answer as to whether selective Lp(a) lowering with ASO reduces the risk of major CV events. Given the recently established association between Lp(a) level and CV risk, guidelines now recommend Lp(a) measurement in specific clinical conditions. Accordingly, Lp(a) is a current target for drug development to reduce CV risk in patients with elevated levels, and lowering Lp(a) with ASO represents a promising avenue.