Lipoprotein(a): Cardiovascular Risk and Emerging Targeted Therapies

Lipoprotein(a) [Lp(a)] is a genetically determined, low-density lipoprotein-like particle that has emerged as an important and independent contributor to atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Elevated Lp(a) concentrations, defined as approximately 125 nmol/L (≥ 50 mg/dL) by most consensus thresholds, affect an estimated 20% of the general population and confer lifelong inherited cardiovascular risk that is not adequately captured by standard lipid panels. Epidemiological, observational and genetic studies consistently show that elevated Lp(a) concentrations are associated with increased risk of coronary heart disease, myocardial infarction, ischemic stroke, peripheral artery disease and calcific aortic valve stenosis. Unlike low-density lipoprotein (LDL) cholesterol, Lp(a) levels remain relatively stable throughout life and are only minimally influenced by lifestyle interventions or most conventional lipid-lowering therapies. This creates a clinically relevant therapeutic gap, particularly in patients with premature cardiovascular disease, recurrent events despite optimal LDL cholesterol control, or otherwise unexplained residual risk. Traditional lipid-lowering strategies remain essential to reduce global cardiovascular risk, but they have limited ability to directly modify Lp(a)-mediated risk. PCSK9 inhibitors and inclisiran produce modest (approximately 20-30%) Lp(a) reductions, and lipoprotein apheresis may be useful in highly selected patients, but none represents a broadly applicable Lp(a)-specific therapy. Recent advances have changed this landscape. Antisense oligonucleotides, small interfering RNA therapies and oral small-molecule inhibitors have demonstrated profound and durable Lp(a) reductions, frequently exceeding 80-100% with small interfering RNA (siRNA)-based agents (olpasiran, zerlasiran, lepodisiran), up to 80% with the antisense oligonucleotide pelacarsen, and up to 85% with the oral small-molecule muvalaplin, in phase 1 and phase 2 clinical trials. However, the central question remains whether pharmacological Lp(a) lowering translates into fewer cardiovascular events. Current evidence supports strong biological efficacy, but definitive proof of clinical benefit awaits ongoing randomized cardiovascular outcomes trials, including Lp(a)HORIZON (pelacarsen), OCEAN(a)-Outcomes (olpasiran) and ACCLAIM-Lp(a) (lepodisiran). This narrative review summarizes the biology and epidemiological relevance of Lp(a), quantifies its association with cardiovascular events, reviews the effect of traditional lipid-lowering therapies on Lp(a) and critically discusses emerging Lp(a)-targeted treatments and future directions.