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期刊来源：N Engl J Med

原文链接：https://doi.org/10.1056/NEJMoa2404147

摘要内容如下：

背景

血管生成素样3（ANGPTL3）抑制脂蛋白和内皮脂肪酶以及肝脏对富含甘油三酯的脂蛋白残余物的摄取。与非携带者相比，ANGPTL3功能缺失携带者的甘油三酯、低密度脂蛋白（LDL）胆固醇、高密度脂蛋白（HDL）胆固醇和非HDL胆固醇水平较低，患动脉粥样硬化性心血管疾病的风险较低。佐达西兰是一种靶向肝脏ANGPTL3表达的RNA干扰（RNAi）疗法。

方法

我们进行了一项双盲、安慰剂对照、剂量范围的2B期试验，以评估佐达西兰治疗成人混合性高脂血症（空腹甘油三酯水平为150至499 mg/DL，LDL胆固醇水平≥70 mg/DL或非HDL胆固醇水平≥100 mg/DL）的安全性和有效性。符合条件的患者以3:1的比例随机分配，在第1天和第12周接受皮下注射佐达西兰（50、100或200 mg）或安慰剂，并随访至第36周。主要终点是从基线到第24周甘油三酯水平的百分比变化。

结果

共有204名患者接受了随机分组。在第24周，在佐达西兰组中观察到ANGPTL3水平相对于基线的显著平均剂量依赖性降低（与安慰剂组相比的变化差异，50mg组为-54个百分点，100mg组为-70个百分点，200mg组为-74个百分点），并且观察到甘油三酯水平的显著剂量依赖性降低（与安慰剂组相比的变化差异，-51个百分点，-57个百分点，-63个百分点，分别）（所有比较p<0.001）。与安慰剂相比，与基线相比变化的其他差异包括：对于非HDL胆固醇水平，50 mg组为-29个百分点，100 mg组为-29个百分点，200 mg组为-36个百分点；对于载脂蛋白B水平，分别为-19个百分点、-15个百分点和-22个百分点；对于LDL胆固醇水平，分别为-16个百分点、-14个百分点和-20个百分点。我们观察到接受最高剂量佐达西兰的原有糖尿病患者的糖化血红蛋白水平短暂升高。

结论

在混合性高脂血症患者中，佐达西兰与24周时甘油三酯水平显著下降相关。（由Arrowhead Pharmaceuticals资助；Arches-2 ClinicalTrials.gov编号，NCT04832971。）

英文原文如下：

Abstracts

BACKGROUND  Angiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.

METHODS  We conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.

RESULTS  A total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, -54 percentage points with 50 mg, -70 percentage points with 100 mg, and -74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, -51 percentage points, -57 percentage points, and -63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, -29 percentage points with 50 mg, -29 percentage points with 100 mg, and -36 percentage points with 200 mg; for apolipoprotein B level, -19 percentage points, -15 percentage points, and -22 percentage points, respectively; and for LDL cholesterol level, -16 percentage points, -14 percentage points, and -20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.

CONCLUSIONS  In patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.).

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