Biolo Marta, Galimberti Federica, Portinari Camilla, Bertocco Sandra, Tosin Paola, Casula Manuela, Previato Lorenzo, Zambon Sabina, Simioni Paolo, Zambon Alberto
Department of Medicine - DIMED, Clinica Medica 1, University of Padova, Padua, 35128, Italy.
IRCCS MultiMedica, Sesto San Giovanni (Milan), Milan, Italy.
Curr Atheroscler Rep. 2025 Jul 18;27(1):72. doi: 10.1007/s11883-025-01315-w.
Apolipoprotein C-III (ApoC-III) plays a pivotal role in triglyceride (TG) metabolism by inhibiting lipoprotein lipase and hepatic clearance of TG-rich lipoproteins, contributing to hypertriglyceridaemia and elevated cardiovascular risk, as well as a high risk of acute pancreatitis. This review aims to summarize current evidence on ApoC-III inhibition strategies.
Current treatments targeting Apo C-III include two antisense oligonucleotides (ASOs) (volanesorsen and olezarsen), and a small interfering RNA (siRNA) (plozasiran). Volanesorsen, a second-generation ASO, has shown effectiveness in reducing TG and preventing acute pancreatitis, especially in patients with familial chylomicronemia syndrome (FCS). However, its use is limited by the risk of thrombocytopenia, likely related to its chemical structure rather than ApoC-III inhibition itself. Olezarsen, a third-generation ASO with GalNAc conjugation for targeted liver delivery, offers an improved safety profile and strong efficacy in lowering TG and atherogenic lipoproteins levels, making it a promising candidate for a broader clinical use. Plozasiran, a GalNAc-conjugated siRNA, has shown robust and sustained TG reductions with a favorable safety profile, and early data suggest it may also reduce acute pancreatitis risk. ApoC-III inhibition represents an innovative and effective approach in managing hypertriglyceridaemia and its complications. Further outcome-driven trials are essential to define its role in cardiovascular risk reduction.
载脂蛋白C-III（ApoC-III）通过抑制脂蛋白脂肪酶和富含甘油三酯（TG）的脂蛋白的肝脏清除，在TG代谢中起关键作用，导致高甘油三酯血症、心血管风险升高以及急性胰腺炎的高风险。本综述旨在总结目前关于ApoC-III抑制策略的证据。
目前针对ApoC-III的治疗方法包括两种反义寡核苷酸（ASO）（volanesorsen和olezarsen）以及一种小干扰RNA（siRNA）（plozasiran）。第二代ASO volanesorsen已显示出在降低TG和预防急性胰腺炎方面的有效性，尤其是在家族性乳糜微粒血症综合征（FCS）患者中。然而，其使用受到血小板减少风险的限制，这可能与其化学结构而非ApoC-III抑制本身有关。olezarsen是一种第三代ASO，通过与N-乙酰半乳糖胺（GalNAc）偶联实现肝脏靶向递送，具有更好的安全性，在降低TG和致动脉粥样硬化脂蛋白水平方面疗效显著，使其成为更广泛临床应用的有前景候选药物。plozasiran是一种与GalNAc偶联的siRNA，已显示出强大且持续的TG降低效果以及良好的安全性，早期数据表明它可能还能降低急性胰腺炎风险。ApoC-III抑制代表了一种管理高甘油三酯血症及其并发症的创新且有效方法。进一步的以结果为导向的试验对于确定其在降低心血管风险中的作用至关重要。
