Serag Ibrahim, Alkhawaldeh Ibraheem M, Shati Ayed A, Alqahtani Youssef A, Alattar Ahmed, Khader Alkhamaiseh Sara Ahmad, Moawad Mostafa Hossam El Din
Faculty of Medicine, Mansoura University, Mansoura, Egypt.
Faculty of Medicine, Mutah University, Al-Karak, Jordan.
Naunyn Schmiedebergs Arch Pharmacol. 2025 Jul 14. doi: 10.1007/s00210-025-04406-2.
Hypertriglyceridemia and hypercholesterolemia are well-known risk factors for atherosclerotic cardiovascular disease (ASCVD), especially in patients already at elevated cardiovascular risk. Despite current treatment approaches, including lifestyle changes and medication, many individuals do not reach ideal lipid levels, emphasizing the need for new therapeutic options. Olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III (ApoC-III) synthesis, has emerged as a promising candidate to reduce residual cardiovascular risk in these patients.
This systematic review and meta-analysis aimed to assess the effectiveness and safety of different dosages of Olezarsen in patients with high-risk hypertriglyceridemia. Additionally, it explored whether varying dosage regimens impacted lipid outcomes and adverse events.
Following PRISMA guidelines, a comprehensive search was conducted in PubMed, Scopus, Web of Science, and Cochrane Library for randomized controlled trials (RCTs) published in English. The studies included compared different doses of Olezarsen with placebo in high-risk hypertriglyceridemia patients. Primary outcomes were changes in triglycerides (TG), very-low-density lipoprotein cholesterol (VLDL-C), apolipoprotein B (ApoB), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and treatment-emergent adverse events (TEAE). Secondary outcomes included changes in non-HDL-C and total cholesterol (TC). The data were analyzed as mean differences (MD) or odds ratios (OR) using a random-effects model.
Four RCTs (309 participants) were included. The pooled analysis demonstrated significant reductions in TG (MD = -76.11), VLDL-C (MD = -54.95 mg/dL), ApoB (MD = -12.40 mg/dL), non-HDL-C (MD = -18.03 mg/dL), and LDL-C (MD = -10.09 mg/dL) with Olezarsen treatment compared to placebo. Olezarsen also significantly increased HDL-C levels (MD = + 22.60 mg/dL), while total cholesterol remained unchanged. No significant differences in overall adverse events or drug-related adverse events were observed compared to placebo. Subgroup analysis revealed a dose-dependent effect on several lipid parameters without an increase in adverse events with higher doses.
Olezarsen effectively improves key lipid parameters, including TG, VLDL-C, ApoB, non-HDL-C, and LDL-C, while also safely raising HDL-C in patients with high-risk hypertriglyceridemia. Total cholesterol remained stable, and no increase in adverse events was noted. Further studies are needed to determine optimal dosing and long-term cardiovascular benefits.
高甘油三酯血症和高胆固醇血症是动脉粥样硬化性心血管疾病（ASCVD）的众所周知的危险因素，尤其是在心血管风险已经升高的患者中。尽管有当前的治疗方法，包括生活方式改变和药物治疗，但许多个体并未达到理想的血脂水平，这凸显了对新治疗选择的需求。olezarsen是一种靶向载脂蛋白C-III（ApoC-III）合成的反义寡核苷酸，已成为降低这些患者残余心血管风险的有希望的候选药物。
本系统评价和荟萃分析旨在评估不同剂量的olezarsen在高危高甘油三酯血症患者中的有效性和安全性。此外，还探讨了不同的给药方案是否会影响血脂结果和不良事件。
按照PRISMA指南，在PubMed、Scopus、科学网和Cochrane图书馆中对以英文发表的随机对照试验（RCT）进行了全面检索。纳入的研究比较了高危高甘油三酯血症患者中不同剂量的olezarsen与安慰剂。主要结局是甘油三酯（TG）、极低密度脂蛋白胆固醇（VLDL-C）、载脂蛋白B（ApoB）、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）的变化以及治疗中出现的不良事件（TEAE）。次要结局包括非HDL-C和总胆固醇（TC）的变化。使用随机效应模型将数据分析为平均差（MD）或比值比（OR）。
纳入了四项RCT（309名参与者）。汇总分析表明，与安慰剂相比，olezarsen治疗可使TG（MD = -76.11）、VLDL-C（MD = -54.95 mg/dL）、ApoB（MD = -12.40 mg/dL）、非HDL-C（MD = -18.03 mg/dL）和LDL-C（MD = -10.09 mg/dL）显著降低。olezarsen还显著提高了HDL-C水平（MD = +22.60 mg/dL），而总胆固醇保持不变。与安慰剂相比，总体不良事件或药物相关不良事件无显著差异。亚组分析显示，对几个血脂参数有剂量依赖性效应，且高剂量时不良事件未增加。
olezarsen可有效改善关键血脂参数，包括TG、VLDL-C、ApoB、非HDL-C和LDL-C，同时还能安全地提高高危高甘油三酯血症患者的HDL-C。总胆固醇保持稳定，未发现不良事件增加。需要进一步研究以确定最佳剂量和长期心血管益处。
