Lipoprotein(a): cardiovascular risk and emerging therapies

ABSTRACT

Introduction

There is abundant evidence that elevated lipoprotein(a) [LP(a)] associates with cardiovascular risk. Most lipid modifying therapies don’t reduce Lp(a), but new technologies are emerging that act upstream, such as antisense oligonucleotides (ASO) and small interfering RNAs (siRNAs) that inhibit the translation of mRNA for proteins specifically involved in lipid metabolism.

Areas covered

Despite the benefit of therapies for the prevention of atherosclerotic cardiovascular disease (ASCVD), Lp(a) is one of the ‘residual risks,’ established by observational and Mendelian randomization studies. Although current established lipid modifying therapies targeting low-density-lipoprotein cholesterol, such as statins and ezetimibe, do not lower Lp(a), ASOs and siRNAs demonstrated significant reduction of Lp(a) by −98 to −101% in recent clinical trials. However, we still don’t know if specifically lowering Lp(a) reduced cardiovascular events, how much Lp(a) lowering is required to produce clinical benefit, and whether diabetes and inflammation have any impact. This review summarizes Lp(a), the knowns and unknowns about Lp(a), and focus emerging treatments.

Expert opinion

New Lp(a) lowering therapies have the potential to contribute to the personalized prevention of ASCVD.

KEYWORDS:

• Lipoprotein(a)
• ASO
• siRNA
• inhibitors of apolipoprotein(a) synthesis
• cardiovascular prevention

Article highlights

• Lp(a) is a significant risk factor for ASCVD and aortic valve calcification.

• There are marked ethnic differences in the population-level distribution of Lp(a), with the highest levels among Africans, followed by South Asians, whites, Hispanics, and East Asians. Therefore, it is desirable to ensure sufficient racial diversity in the design of clinical trials.

• National and international consensus or recommendations suggest that the measurement of Lp(a) levels in subjects in intermediate or high-risk categories based on clinical characteristics or in either all adults at least once.

• Uniformity in the measurement of Lp(a) is desired, and it is recommended that the unit be nmol/L (rather than mg/dl), and there is increasing evidence that the cutoff for Lp(a) is 100–125 nmol/L.

• Investigational drugs using antisense oligonucleotides and small interfering RNAs are currently undergoing clinical trials for their Lp(a)-lowering effects, demonstrated safety and tolerability, and potential for cardiovascular disease risk reduction.

Declaration of interest

SJ Nicholls has received research support from AstraZeneca, New Amsterdam Pharma, Amgen, Anthera, Eli Lilly, Esperion, Novartis, Cerenis, The Medicines Company, Resverlogix, InfraReDx, Roche, Sanofi-Regeneron and LipoScience and consulting and honoraria from AstraZeneca, Amarin, Akcea, Eli Lilly, Anthera, Omthera, Merck, Takeda, Resverlogix, Sanofi-Regeneron, CSL Behring, Esperion, Boehringer Ingelheim, Vaxxinity and Sequiris. M Fujino has received research report from Japan Heart Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.