Lipoprotein(a) as a Pharmacological Target: Premises, Promises, and Prospects

Abstract

Atherosclerotic cardiovascular disease is a major health concern worldwide and requires effective preventive measures. Lp(a) (lipoprotein [a]) has recently garnered attention as an independent risk factor for astherosclerotic cardiovascular disease, with proinflammatory and prothrombotic mechanisms contributing to its atherogenicity. On an equimolar basis, Lp(a) is ~5 to 6 times more atherogenic than particles that have been widely associated with adverse cardiovascular outcomes, such as LDL (low-density lipoprotein). Lp(a) can enter the vessel wall, leading to the accumulation of oxidized phospholipids in the arterial intima, which are crucial for initiating plaque inflammation and triggering vascular disease progression. In addition, Lp(a) may cause atherothrombosis through interactions between apoA (apolipoprotein A) and the platelet PAR-1 (protease-activated receptor 1) receptor, as well as competitive inhibition of plasminogen. Because Lp(a) is mostly determined on genetic bases, a 1-time assessment in a lifetime can suffice to identify patients with elevated levels. Mendelian randomization studies and post hoc analyses of randomized trials of LDL cholesterol–lowering drugs showed a causal link between Lp(a) concentrations and cardiovascular outcomes, with therapeutic reduction of Lp(a) expected to contribute to estimated cardiovascular risk mitigation. Many Lp(a)-lowering drugs, including monoclonal antibodies, small interfering ribonucleic acids, antisense oligonucleotides, small molecules, and gene editing compounds, are at different stages of clinical investigation and show promise for clinical use. In particular, increased Lp(a) testing and treatment are expected to have a substantial impact at the population level, enabling the identification of high-risk individuals and the subsequent prevention of a large number of cardiovascular events. Ongoing phase 3 trials will further elucidate the cardiovascular benefits of Lp(a) reduction over the long term, offering potential avenues for targeted interventions and improved cardiovascular outcomes.