Aug 2026· Current Atherosclerosis Reports· Vol 28· 0 citations· 66 references
Medicine
TL;DR
The Lp(a) treatment landscape has moved from basic science to an active late-stage clinical pipeline and positive outcomes from these CVOTs could lead to regulatory approvals and guideline updates affecting hundreds of millions of high-risk patients globally.
Abstract
Lipoprotein(a) [Lp(a)] is a genetically determined, independent risk factor for atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Plasma Lp(a) levels are 70–90% heritable, largely unresponsive to lifestyle changes, and poorly controlled with typical lipid-lowering drugs such as statins and PCSK9 inhibitors. The development of powerful RNA-based therapies offers a new chance to specifically target and significantly lower Lp(a). We examined available phase 1–3 trial data, regulatory updates, and trial registries up to mid-2026 to provide an overview of the current pipeline, ongoing cardiovascular outcomes trials (CVOTs), and new mechanistic and genomic methods. Five agents across three mechanisms have reached late-stage development. Pelacarsen, a GalNAc-conjugated antisense oligonucleotide (ASO), reduces Lp(a) by about 80% via hepatic apo(a) mRNA reduction and is the subject of the phase 3 Lp(a) HORIZON trial, with results due in late 2026. Three small interfering RNA (siRNA) drugs, olpasiran (> 95% reduction, OCEAN(a)-Outcomes), lepodisiran (93.9% reduction lasting over 12 months after one dose, ACCLAIM-Lp(a)), and zerlasiran (96.4% reduction), allow quarterly or possibly yearly dosing. Muvalaplin, the first oral small-molecule Lp(a) inhibitor, interferes with apo(a)-ApoB particle formation and reduces intact Lp(a) by up to 85.8% in phase 2 KRAKEN trials; its phase 3 CVOT (MOVE-Lp(a)) is underway. Additionally, CRISPR/Cas9-based liver gene editing targeting the LPA gene (CTX320) has entered phase 1 studies. All agents have shown good safety so far. The Lp(a) treatment landscape has moved from basic science to an active late-stage clinical pipeline. Positive outcomes from these CVOTs could lead to regulatory approvals and guideline updates affecting hundreds of millions of high-risk patients globally. Recent guidelines now recommend universal Lp(a) measurement, in anticipation of more effective therapies becoming available within the next 1 to 2 years. Created in BioRender. https://biorender.com/y1mu0lh Created in BioRender. https://biorender.com/y1mu0lh
Case-based examples are presented to highlight practical approaches to risk assessment and management of elevated Lp(a) and suggest potential benefit of selective aspirin use.
Timothy McGinnis, David R Saxon· Journal of Clinical Endocrin...· 0 citations
Lipoprotein(a) (Lp(a)) is an elusive yet powerful cardiovascular risk factor, largely independent of LDL cholesterol. Elevated Lp(a) increases the risk of coronary artery disease, stroke, peripheral arterial disease, calcific aortic valve disease, heart failure, and abdominal aortic aneurysm. The challenge is that conventional lipid-lowering therapies have minimal impact on Lp(a), leaving patients with substantial residual risk. While observational and genetic studies generally support Lp(a) as a driver of cardiovascular events, results are not entirely consistent, and risk may differ between primary and secondary prevention. Novel therapies—including antisense oligonucleotides, siRNA therapeutics, CETP inhibitors, and experimental gene-editing approaches—show promising potential, reducing Lp(a) levels by up to 90%. Ongoing phase III trials will clarify whether these reductions translate into meaningful decreases in cardiovascular morbidity and mortality. This review critically examines the current evidence, highlights gaps in knowledge, and discusses emerging therapeutic strategies, emphasizing the need for individualized risk assessment. Lp(a) may soon shift from a “silent threat” to a precise, actionable target in cardiovascular prevention.
Michał Miszczak, P. Piwowarczyk, G. Sobieszek et al.· Biomedicines· 0 citations
Lipoprotein(a) [Lp(a)] has emerged as a major, genetically determined, contributor to residual cardiovascular risk. Accumulating evidence from epidemiological studies, human genetics, and Mendelian randomization has unequivocally established elevated Lp(a) as an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis (CAVS). Lp(a) consists of a low-density lipoprotein-like particle in which apolipoprotein(a) is covalently linked to apolipoprotein B100. This unique structure confers proatherogenic, pro-inflammatory, and antifibrinolytic properties, largely mediated by oxidized phospholipids and the structural homology of apolipoprotein(a) with plasminogen. Circulating Lp(a) concentrations are genetically determined and remain relatively stable throughout life with minimal influence from lifestyle interventions. Conventional lipid-lowering therapies have little or no meaningful effect on circulating Lp(a) concentrations, leaving an important component of residual cardiovascular risk unaddressed. In contrast, RNA-based therapeutics targeting hepatic LPA expression have demonstrated reductions in circulating Lp(a) of up to 80–90% and are currently being evaluated in phase 3 cardiovascular outcome trials. This narrative review summarizes the molecular biology, genetics, epidemiology, pathophysiological mechanisms, and clinical relevance of Lp(a), and critically examines current and emerging therapeutic strategies aimed at reducing Lp(a)-mediated cardiovascular risk.
Lucio Giuseppe Granata, Simona Giubilato, Francesca Campanella et al.· Frontiers in Medicine· 0 citations
INTRODUCTION: Cardiovascular diseases remain the leading cause of global mortality, with atherosclerosis as a central mechanism. Lipoprotein(a) [Lp(a)] is an independent and highly atherogenic risk factor associated with vascular inflammation and thrombosis. Statins do not reduce Lp(a) levels and may even increase them, contributing to residual cardiovascular risk. Novel therapies targeting Lp(a) have emerged as promising strategies. METHODS: A systematic review was conducted according to PRISMA guidelines using PubMed (2016–2026). Clinical trials (phases I–IV) in humans with ≥50 participants and quantitative Lp(a) reduction data were included. Search terms addressed Lp(a), gene silencing, and lipid-lowering therapies. Twelve studies met inclusion criteria. RESULTS: Gene-silencing therapies showed the greatest reductions in Lp(a), with olpasiran, lepodisiran, and zerlasiran achieving reductions above 80–95%. Pelacarsen reduced Lp(a) by up to 80% in a dose-dependent manner. Muvalaplin reduced Lp(a) by up to 85% by inhibiting particle formation. PCSK9 inhibitors such as alirocumab and recaticimab showed moderate reductions (~28–36%), while inclisiran had modest effects (≈15–26%). Treatments were generally well tolerated. DISCUSSION: RNA-based therapies, particularly siRNA and antisense oligonucleotides, demonstrate superior efficacy by directly targeting apolipoprotein(a) synthesis. Alternative approaches such as muvalaplin expand therapeutic options by interfering with particle assembly. CONCLUSION: Emerging Lp(a)-targeted therapies represent a major advance in addressing residual cardiovascular risk, though outcome trials are still needed.
Laís de Barros Glaeser, Sofia Torres Velloso· Procedings of the 51st Congr...· 0 citations
