Lipoprotein(a): Bridging the gap between risk prediction, measurement, and emerging therapeutics

Lipoprotein(a) [Lp(a)] is a genetically determined lipoprotein and a well-established causal risk factor for atherosclerotic cardiovascular disease (ASCVD). Despite increasing recognition in clinical guidelines, Lp(a) testing remains underused, and targeted therapies are only now emerging. This narrative review summarizes the biology, cardiovascular risk, measurement challenges, emerging therapies, and translational barriers of Lp(a), highlighting its role in contemporary cardiovascular prevention. Lp(a) promotes cardiovascular disease through pro-atherogenic, pro-inflammatory, and prothrombotic mechanisms mediated by lipid deposition, oxidized phospholipids, and impaired fibrinolysis. Elevated Lp(a) independently predicts coronary artery disease (CAD), ischemic stroke, peripheral artery disease, and calcific aortic valve disease across diverse populations. However, widespread clinical implementation is limited by apo(a) isoform heterogeneity, assay variability, inconsistent reporting in mg/dL and nmol/L, and low testing rates despite recommendations for once-in-a-lifetime screening. Novel Lp(a)-targeted therapies, including antisense oligonucleotides, small interfering RNAs, and the oral small-molecule inhibitors, have demonstrated sustained reductions in Lp(a) concentrations exceeding 80% in early-phase clinical trials, with favorable safety profiles. Lp(a) is an important residual cardiovascular risk factor with promising targeted therapeutic options. However, important translational gaps remain, including assay standardization, validated treatment thresholds, and definitive cardiovascular outcome data. Recent Lp(a)HORIZON phase 3 evidence has shown that substantial Lp(a) lowering does not necessarily reduce cardiovascular events, while other ongoing phase 3 outcome trials will further determine whether Lp(a)-lowering therapies improve clinical outcomes and establish their role in routine cardiovascular prevention.