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新疗法可降低心血管疾病患者的脂蛋白(a)水平
作者:小柯机器人 发布时间:2020/1/3 20:01:13

美国加利福尼亚大学Sotirios Tsimikas团队近日研究出降低心血管疾病患者脂蛋白(a)水平的疗法。相关论文于2020年1月1日发表在《新英格兰医学杂志》上。

脂蛋白(a)水平是由基因决定的,脂蛋白(a)升高是心血管疾病和主动脉狭窄的危险因素。目前尚未有药物能降低脂蛋白(a)水平。

研究组进行了一项随机、双盲、安慰剂对照、剂量范围试验,共招募了286名确诊心血管疾病的患者,脂蛋白(a)水平均超过150 nmol/dL。将患者随机分组,分别接受肝细胞定向的反义寡核苷酸AKCEA-APO(a)-LRx,这里简称为APO(a)-LRx,每4周20mg、每4周40mg、每4周60mg、每2周20mg、每周20mg治疗,或皮下注射生理盐水安慰剂治疗,为期6-12个月。

6组患者基线时的脂蛋白(a)水平中位值最低为204.5 nmol/dL,最高为246.6 nmol/dL。APO(a)-LRx治疗导致脂蛋白(a)水平呈剂量依赖型下降,其中每4周20mg组下降35%,每4周40mg组下降56%,每2周20mg组下降58%,每4周60mg组下降72%,每周20mg组下降80%,而安慰剂组下降6%,与安慰剂组比较,差异均有统计学意义。而在血小板计数、肝肾指标以及流感样症状方面,所有APO(a)-LRx组与安慰剂组相比均无显著差异。最常见的不良反应为注射部位反应。

综上,APO(a)-LRx用于治疗脂蛋白(a)水平升高的心血管疾病患者,可以剂量依赖的方式来降低脂蛋白(a)水平。

附:英文原文

Title: Lipoprotein(a) Reduction in Persons with Cardiovascular Disease

Author: Sotirios Tsimikas, M.D.,, Ewa Karwatowska-Prokopczuk, M.D., Ph.D.,, Ioanna Gouni-Berthold, M.D.,, Jean-Claude Tardif, M.D.,, Seth J. Baum, M.D.,, Elizabeth Steinhagen-Thiessen, M.D.,, Michael D. Shapiro, D.O.,, Erik S. Stroes, M.D.,, Patrick M. Moriarty, M.D.,, Brge G. Nordestgaard, M.D., D.M.Sc.,, Shuting Xia, M.S.,, Jonathan Guerriero, M.B.A.,, Nicholas J. Viney, B.Sc.,, Louis O’Dea, M.B., B.Ch., B.A.O.,, and Joseph L. Witztum, M.D.

Issue&Volume: 2020-01-01

Abstract: BACKGROUND

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.

METHODS
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)-LRx, referred to here as APO(a)-LRx (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).

RESULTS
The median baseline lipoprotein(a) levels in the six groups ranged from 204.5 to 246.6 nmol per liter. Administration of APO(a)-LRx 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)-LRx 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.

CONCLUSIONS
APO(a)-LRx reduced lipoprotein(a) levels in a dose-dependent manner in patients who had elevated lipoprotein(a) levels and established cardiovascular disease.

DOI: 10.1056/NEJMoa1905239

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa1905239

 

期刊信息

The New England Journal of Medicine:《新英格兰医学杂志》,创刊于1812年。隶属于美国麻省医学协会,最新IF:70.67
官方网址:http://www.nejm.org/
投稿链接:http://www.nejm.org/page/author-center/home