From the TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston (M.L.O., J.F.K., X.R., S.A.M., M.S.S.); the Icahn School of Medicine, Mount Sinai Hospital, New York (R.S.R.); the Division of Cardiology, Geneva University Hospitals, Geneva, and the Institute of Primary Health Care, University of Bern, Bern - both in Switzerland (B.G.); Global Development, Amgen, Thousand Oaks (J.A.G.L., B.K., H.W., Y.W., H.K.), and the David Geffen School of Medicine, University of California, Los Angeles, Los Angeles (N.E.L.) - both in California; Flourish Research and the Charles E. Schmidt College of Medicine, Florida Atlantic University - both in Boca Raton (S.J.B.); Crossroads Clinical Research, Mooresville, NC (E.S.); and the Department of Medicine, Université de Montréal, Montreal, and ECOGENE-21, Chicoutimi, QC - both in Canada (D.G.).
N Engl J Med. 2022 Nov 17;387(20):1855-1864. doi: 10.1056/NEJMoa2211023. Epub 2022 Nov 6.
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. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).
背景：脂蛋白(a)被认为是动脉粥样硬化性心血管疾病的一个潜在风险因素。Olpasiran 是一种小干扰 RNA，可减少肝脏中脂蛋白(a)的合成。
方法：我们进行了一项随机、双盲、安慰剂对照、剂量发现试验，纳入了已确诊的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。患者被随机分配至接受四种剂量的 Olpasiran（每 12 周 10 mg、每 12 周 75 mg、每 12 周 225 mg 或每 24 周 225 mg）或匹配的安慰剂，皮下给药。主要终点是从基线到 36 周时脂蛋白(a)浓度的变化百分比（报告为安慰剂调整后的平均百分比变化）。还评估了安全性。
结果：在 281 名入组患者中，基线时脂蛋白(a)的中位数浓度为 260.3 nmol/L，低密度脂蛋白胆固醇的中位数浓度为 67.5 mg/dL。基线时，88%的患者正在接受他汀类药物治疗，52%的患者正在接受依折麦布治疗，23%的患者正在接受前蛋白转化酶枯草溶菌素 9（PCSK9）抑制剂治疗。36 周时，安慰剂组脂蛋白(a)浓度平均增加 3.6%，而 Olpasiran 治疗以剂量依赖性方式显著且大大降低了脂蛋白(a)浓度，导致安慰剂调整后的平均百分比变化分别为-70.5%（10 mg 剂量）、-97.4%（75 mg 剂量）、-101.1%（每 12 周 225 mg 剂量）和-100.5%（每 24 周 225 mg 剂量）（与基线相比，所有比较均<0.001）。整个试验组的不良反应总体发生率相似。最常见的与 Olpasiran 相关的不良反应是注射部位反应，主要是疼痛。
结论：Olpasiran 治疗可显著降低已确诊的动脉粥样硬化性心血管疾病患者的脂蛋白(a)浓度。需要更长和更大规模的试验来确定 Olpasiran 治疗对心血管疾病的影响。（由 Amgen 资助；OCEAN[a]-DOSE ClinicalTrials.gov 编号，NCT04270760）。
N Engl J Med. 2022-11-17
N Engl J Med. 2017-3-17
N Engl J Med. 2020-3-18
N Engl J Med. 2018-11-7
J Am Coll Cardiol. 2024-8-27
N Engl J Med. 2017-3-17
N Engl J Med. 2020-4-16
Pharmaceuticals (Basel). 2025-7-24
Proc (Bayl Univ Med Cent). 2025-7-9
Am Heart J Plus. 2025-7-21
J Clin Med. 2025-7-14
Curr Cardiovasc Risk Rep. 2025-12
Mol Med Rep. 2025-10
Nat Rev Cardiol. 2025-7-17
Circ Genom Precis Med. 2025-7-3
Pharmaceutics. 2025-6-11
Zotero 插件