本文由小咖机器人翻译整理

期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2404143

摘要内容如下：

背景

由于非高密度脂蛋白（HDL）胆固醇水平升高，患有混合性高脂血症的人有患动脉粥样硬化性心血管疾病的风险，这是由富含甘油三酯的脂蛋白中的残余胆固醇引起的。富含甘油三酯的脂蛋白的代谢和清除通过载脂蛋白C3（APOC3）介导的脂蛋白脂酶的抑制而下调。

方法

我们进行了一项为期48周、2B期、双盲、随机、安慰剂对照试验，以评估在混合型高脂血症（即甘油三酯水平为150至499 mg/DL，低密度脂蛋白[LDL]胆固醇水平≥70 mg/DL或非HDL胆固醇水平≥100 mg/DL）患者中使用Plozasiran（一种肝细胞靶向APOC3小干扰RNA）的安全性和有效性。参与者以3:1的比例被分配到四个队列中的每一个队列中接受普洛扎西兰或安慰剂。在前三个队列中，参与者在第1天和第12周接受皮下注射Plozasiran（10 mg、25 mg或50 mg）或安慰剂（每季度剂量）。在第四个队列中，参与者在第1天和第24周接受50 mg的普洛扎西兰或安慰剂（半年剂量）。来自接受安慰剂的参与者的数据被合并。主要终点是第24周空腹甘油三酯水平的百分比变化。

结果

共有353名参与者接受了随机分组。在第24周，与安慰剂组相比，普洛扎西兰组空腹甘油三酯水平显著降低，差异在于10 mg季度剂量组自基线的最小二乘平均百分比变化为-49.8个百分点（95%可信区间[CI]，-59.0至-40.6），25 mg季度剂量组为-56.0个百分点（95%CI，-65.1至-46.8），25 mg季度剂量组为-62.4个百分点（95%CI，-71.5至-53.2），50-mg半年剂量-44.2个百分点（95%CI，-53.4至-35.0）（所有比较P<0.001）。在接受安慰剂的参与者中观察到10%的血糖控制恶化，在接受每季度10毫克剂量的参与者中观察到12%的血糖控制恶化，在接受每季度25毫克剂量的参与者中观察到7%的血糖控制恶化，在接受每季度50毫克剂量的参与者中观察到20%的血糖控制恶化，在接受每半年50毫克剂量的参与者中观察到21%的血糖控制恶化。

结论

在这项涉及混合性高脂血症患者的随机对照试验中，与安慰剂相比，Plozasiran在24周时显著降低了甘油三酯水平。临床结果试验是必要的。（由Arrowhead Pharmaceuticals资助；Muir ClinicalTrials.gov编号NCT04998201。）

英文原文如下：

Abstracts

BACKGROUND  Persons with mixed hyperlipidemia are at risk for atherosclerotic cardiovascular disease due to an elevated non-high-density lipoprotein (HDL) cholesterol level, which is driven by remnant cholesterol in triglyceride-rich lipoproteins. The metabolism and clearance of triglyceride-rich lipoproteins are down-regulated through apolipoprotein C3 (APOC3)-mediated inhibition of lipoprotein lipase.

METHODS  We carried out a 48-week, phase 2b, double-blind, randomized, placebo-controlled trial evaluating the safety and efficacy of plozasiran, a hepatocyte-targeted APOC3 small interfering RNA, in patients with mixed hyperlipidemia (i.e., a triglyceride level of 150 to 499 mg per deciliter and either a low-density lipoprotein [LDL] cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). The participants were assigned in a 3:1 ratio to receive plozasiran or placebo within each of four cohorts. In the first three cohorts, the participants received a subcutaneous injection of plozasiran (10 mg, 25 mg, or 50 mg) or placebo on day 1 and at week 12 (quarterly doses). In the fourth cohort, participants received 50 mg of plozasiran or placebo on day 1 and at week 24 (half-yearly dose). The data from the participants who received placebo were pooled. The primary end point was the percent change in fasting triglyceride level at week 24.

RESULTS  A total of 353 participants underwent randomization. At week 24, significant reductions in the fasting triglyceride level were observed with plozasiran, with differences, as compared with placebo, in the least-squares mean percent change from baseline of -49.8 percentage points (95% confidence interval [CI], -59.0 to -40.6) with the 10-mg-quarterly dose, -56.0 percentage points (95% CI, -65.1 to -46.8) with the 25-mg-quarterly dose, -62.4 percentage points (95% CI, -71.5 to -53.2) with the 50-mg-quarterly dose, and -44.2 percentage points (95% CI, -53.4 to -35.0) with the 50-mg-half-yearly dose (P<0.001 for all comparisons). Worsening glycemic control was observed in 10% of the participants receiving placebo, 12% of those receiving the 10-mg-quarterly dose, 7% of those receiving the 25-mg-quarterly dose, 20% of those receiving the 50-mg-quarterly dose, and 21% of those receiving the 50-mg-half-yearly dose.

CONCLUSIONS  In this randomized, controlled trial involving participants with mixed hyperlipidemia, plozasiran, as compared with placebo, significantly reduced triglyceride levels at 24 weeks. A clinical outcomes trial is warranted. (Funded by Arrowhead Pharmaceuticals; MUIR ClinicalTrials.gov number NCT04998201.).

-----------分割线---------

点击链接：https://www.mediecogroup.com/community/user/vip/categories/ ，成为医咖会员，获取12项专属权益。