美国布列根和妇女医院Michelle L. O’Donoghue团队研究了小干扰RNA降低心血管疾病脂蛋白（a）水平的效果。这一研究成果发表在2022年11月6日出版的《新英格兰医学杂志》上。

脂蛋白（a）是动脉粥样硬化性心血管疾病的推定危险因素。Olpasiran是一种小干扰RNA，可减少肝脏中脂蛋白（a）的合成。

研究组进行了一项随机、双盲、安慰剂对照、剂量发现试验，招募患有动脉粥样硬化性心血管疾病且脂蛋白（a）浓度超过150 nmol/L的患者。患者被随机分配接受四种剂量的olpasiran（每12周10mg，每12周75mg，每12周225mg，或每24周225mg）或匹配的安慰剂中的一种，皮下给药。主要终点是脂蛋白（a）浓度从基线到第36周的百分比变化（报告为安慰剂校正后的平均百分比变化）。还评估了安全性。

在281名入组患者中，基线时脂蛋白（a）的中位浓度为260.3 nmol/L，低密度脂蛋白胆固醇的中位数为67.5 mg/dL。基线时，88%的患者接受他汀类药物治疗，52%的患者服用依折麦布，23%的患者使用枯草杆菌前蛋白转化酶-可欣9型（PCSK9）抑制剂。

在36周时，安慰剂组的脂蛋白（a）浓度平均增加了3.6%，而olpasiran治疗以剂量依赖性的方式显著且实质性地降低了脂蛋白（b）浓度，10mg剂量组安慰剂校正后的平均百分比变化为−70.5%，75mg剂量组为-97.4%，每12周225 mg剂量组为−101.1%，每24周225 mg剂量组为-100.5%（与基线相比差异均具有统计学意义）。各试验组的不良事件总发生率相似。最常见的olpasiran相关不良事件是注射部位反应，主要是疼痛。

研究结果表明，olpasiran治疗显著降低了动脉粥样硬化性心血管疾病患者的脂蛋白（a）浓度。为了确定Olpasiran疗法对心血管疾病的疗效，需要进行更长期、更大规模的试验。

附：英文原文

Title: Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease | NEJM

Author: Michelle L. O’Donoghue, M.D., M.P.H.,, Robert S. Rosenson, M.D.,, Baris Gencer, M.D., M.P.H.,, J. Antonio G. López, M.D.,, Norman E. Lepor, M.D.,, Seth J. Baum, M.D.,, Elmer Stout, M.D.,, Daniel Gaudet, M.D., Ph.D.,, Beat Knusel, Ph.D.,, Julia F. Kuder, M.A.,, Xinhui Ran, M.S.,, Sabina A. Murphy, M.P.H.,, Huei Wang, Ph.D.,, You Wu, Ph.D.,, Helina Kassahun, M.D.,, and Marc S. Sabatine, M.D., M.P.H.

Issue&Volume: 2022-11-06

Abstract:

Background

Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver.

Methods

We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed.

Results

Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin–kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of 70.5% with the 10-mg dose, 97.4% with the 75-mg dose, 101.1% with the 225-mg dose administered every 12 weeks, and 100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain.

Conclusions

Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease.

DOI: 10.1056/NEJMoa2211023

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2211023