From the Divisions of Cardiovascular Medicine (S.T.) and Endocrinology and Metabolism (J.L.W.), University of California, San Diego, La Jolla, and Ionis Pharmaceuticals, Carlsbad (S.T., S.X., N.J.V.) - both in California; Akcea Therapeutics, Boston (E.K.-P., J.G., L.O.); Polyclinic for Endocrinology, Diabetes and Preventive Medicine, University of Cologne, Cologne, Germany (I.G.-B.); Montreal Heart Institute, Université de Montréal, Montreal (J.-C.T.); Excel Medical Clinical Trials, Boca Raton, FL (S.J.B.); the Department of Endocrinology and Metabolism, Charité-Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Berlin, Berlin Institute of Health, Berlin (E.S.-T.), and the Division of Geriatrics, University Medicine Greifswald, Greifswald (E.S.-T.) - both in Germany; the Center for Preventive Cardiology, Knight Cardiovascular Institute, Oregon Health and Science University, Portland (M.D.S.); the Department of Vascular Medicine, Academic Medical Center, Amsterdam (E.S.S.); the Division of Clinical Pharmacology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City (P.M.M.); and the Department of Clinical Biochemistry and the Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev (B.G.N.), and the Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen (B.G.N.) - all in Denmark.
N Engl J Med. 2020 Jan 16;382(3):244-255. doi: 10.1056/NEJMoa1905239. Epub 2020 Jan 1.
Lipoprotein(a) levels are genetically determined and, when elevated, are a risk factor for cardiovascular disease and aortic stenosis. There are no approved pharmacologic therapies to lower lipoprotein(a) levels.
We conducted a randomized, double-blind, placebo-controlled, dose-ranging trial involving 286 patients with established cardiovascular disease and screening lipoprotein(a) levels of at least 60 mg per deciliter (150 nmol per liter). Patients received the hepatocyte-directed antisense oligonucleotide AKCEA-APO(a)-L, referred to here as APO(a)-L (20, 40, or 60 mg every 4 weeks; 20 mg every 2 weeks; or 20 mg every week), or saline placebo subcutaneously for 6 to 12 months. The lipoprotein(a) level was measured with an isoform-independent assay. The primary end point was the percent change in lipoprotein(a) level from baseline to month 6 of exposure (week 25 in the groups that received monthly doses and week 27 in the groups that received more frequent doses).
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-L resulted in dose-dependent decreases in lipoprotein(a) levels, with mean percent decreases of 35% at a dose of 20 mg every 4 weeks, 56% at 40 mg every 4 weeks, 58% at 20 mg every 2 weeks, 72% at 60 mg every 4 weeks, and 80% at 20 mg every week, as compared with 6% with placebo (P values for the comparison with placebo ranged from 0.003 to <0.001). There were no significant differences between any APO(a)-L dose and placebo with respect to platelet counts, liver and renal measures, or influenza-like symptoms. The most common adverse events were injection-site reactions.
APO(a)-L reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease. (Funded by Akcea Therapeutics; ClinicalTrials.gov number, NCT03070782.).
脂蛋白(a)水平是由遗传决定的，当水平升高时，是心血管疾病和主动脉瓣狭窄的危险因素。目前还没有批准的药物疗法来降低脂蛋白(a)水平。
我们进行了一项随机、双盲、安慰剂对照、剂量范围的试验，纳入了 286 名患有已确诊心血管疾病且脂蛋白(a)水平至少为 60mg/分升（150nmol/升）的患者。患者接受了肝细胞定向反义寡核苷酸 AKCEA-APO(a)-L（以下简称 APO(a)-L）治疗，分别给予 20、40 或 60mg，每 4 周 1 次；20mg，每 2 周 1 次；或 20mg，每周 1 次，皮下注射，持续 6 至 12 个月。脂蛋白(a)水平采用同型独立测定法进行测量。主要终点为暴露 6 个月（每月剂量组为第 25 周，更频繁剂量组为第 27 周）时脂蛋白(a)水平与基线相比的变化百分比。
6 个治疗组的中位基线脂蛋白(a)水平范围为 204.5 至 246.6nmol/升。APO(a)-L 的给药剂量与脂蛋白(a)水平的降低呈剂量依赖性，20mg/4 周剂量组的平均降低百分比为 35%，40mg/4 周剂量组为 56%，20mg/2 周剂量组为 58%，60mg/4 周剂量组为 72%，20mg/周剂量组为 80%，而安慰剂组为 6%（与安慰剂相比的 P 值范围为 0.003 至 <0.001）。与安慰剂相比，任何 APO(a)-L 剂量与血小板计数、肝肾功能或流感样症状均无显著差异。最常见的不良反应是注射部位反应。
APO(a)-L 可降低脂蛋白(a)水平升高且已确诊心血管疾病患者的脂蛋白(a)水平，呈剂量依赖性。（由 Akcea Therapeutics 资助；ClinicalTrials.gov 编号，NCT03070782。）
