Lipoprotein(a) Lowering Medications - Another Step Forward in Atherosclerosis Management

Abstract

Lipoprotein(a) (Lp(a)) is a variant of low-density lipoprotein (LDL), where apoB-100 is covalently bound to a glycoprotein(a) molecule, characterized by multiple “kringle” repeats. This modification endows Lp(a) with several proatherogenic properties. These are: foam cell formation, increased oxidized lipids deposition in the subendothelium, and procoagulant state through the plasminogen-like property of glycoprotein(a), leading to plasminogen activator inhibitor consumption. All these findings and the association with an increased cardiovascular risk in patients with high Lp(a) levels, independent of statin treatment, has necessitated the development of drugs targeting Lp(a). Of those, the antisense oligonucleotides (ASOs) and small inhibitory RNA (siRNAs) are the most prominent classes of Lp(a)-lowering agents. Several clinical trials have revealed promising results in treatment of patients with elevated Lp(a) and safe drug profiles. Pelacarsen is an ASO which is specific to the liver and is currently in phase 2 and 3 clinical trials. Olpasiran, SLN360 and LY3819469 are siRNA agents currently being assessed in phases 1, 2, and 3. The initial results from all clinical trials point to effectiveness and safety. Long term application and effects are still to be evaluated.

Conclusion: 

ASO and siRNA agents targeting Lp(a) appear to be promising treatment options for patients with elevated Lp(a) in addition to the classical therapies with statins or other cholesterol lowering drugs.