Lipoprotein (a): Underrecognized Risk with a Promising Future

Abstract

Lipoprotein a (Lp(a)) is a lipid biomarker that binds cholesterol and bears independent cardiovascular risk. Strategies to lower the level of Lp(a) and mitigate such risk are important both for primary and secondary prevention. Currently there are no approved therapies targeting Lp(a) directly. Lipid lowering therapies prescribed routinely may have no effect on Lp(a) levels. Some agents such as niacin and estrogens can significantly decrease Lp(a), but their use is not recommended due to their adverse safety profile. Statins increase Lp(a) levels by 10-20%, questioning the benefit of such therapy when this biomarker is elevated. The Food and Drug Administration (FDA) endorses new agents to address dyslipidemia such as proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9-i) and Inclisiran, a small interfering RNA. These approaches have been shown to also significantly reduce Lp(a), but more clinical data is needed before implementing their use in clinical practice. Clinical trials are currently ongoing to test the efficacy of newly developed antisense oligonucleotides and small interfering RNAs targeting the gene encoding for Lp(a) in hepatocytes, while other investigations assess small molecules that inhibit Lp(a) assembly. This review summarizes the pathophysiology and clinical implications of Lp(a) elevation, and focuses on proposed Lp(a) therapies and the current state of the clinical trials of such novel agents.

Keywords: ASCVD risk; gene interference therapies; lipoprotein (a).

Fig. 1.

Lipoprotein a structure. The major components are the apolipoprotein a (Apo(a)) and the apolipoprotein B-100 (ApoB-100) linked by a disulphide bond. Notice the Kringle domains within Apo(a), which confer Lipoprotein a (Lp(a)) its unique structure. CE, cholesteryl esters; FC, free cholesterol; OxPL, oxidized phospholipids; PL, phospholipids; TG, triglycerides; KIV, kringle IV (fourth - roman) domain.

Fig. 2.

Lipoprotein a is involved in the onset and progression of several pathologies. ASCVD, atherosclerotic cardiovascular diseases; Lp(a), lipoprotein a.

Fig. 3.

Mechanisms of action of Antisense Oligonucleotides, Small Interfering RNAs and Small Molecules. Apo(a), Apolipoprotein(a); ApoB-100, apolipoprotein B-100; ASO, antisense oligonucleotides; dsRNA double-stranded ribonucleic acid; mRNA, messenger ribonucleic acid; RISC, RNA-induced silencing complex; RNaseH1, ribonuclease H1; siRNA, small interfering ribonucleic acid; ssDNA, single-stranded deoxyribonucleic acid; KV: kringle V; S-S, disulfide bond. Created with BioRender.com.