目的:残余胆固醇和极低密度脂蛋白胆固醇(VLDL-C)是动脉粥样硬化疾病的危险因素,治疗选择很少。血管生成素样3(ANGPTL3),富含甘油三酯的脂蛋白代谢的关键蛋白质,是一个有希望的目标。
结果:TRANSLATE-TIMI70是双盲,安慰剂对照随机试验测试vupanorsen的七个剂量方案,一种针对ANGPTL3的反义寡核苷酸,适用于非HDL-C≥100mg/dL和甘油三酯150-500mg/dL的成人。该分析的主要终点是24周内残留胆固醇(总胆固醇减去直接测量的LDL-C减去HDL-C)和VLDL-C(直接测量)的百分比变化。共有二百八十六名患者入组,平均年龄为64岁,44%为女性。基线残余胆固醇和VLDL-C中位数为42和31mg/dL,分别(参考:<30mg/dL)。与安慰剂相比,Vupanorsen在24周时将残余胆固醇降低了42-59%(P<0.001),在最高剂量下达到18mg/dL的中位数水平。在同一时期,VLDL-C比安慰剂降低52-67%(P<0.001),最高剂量的中位数达到2.5mg/dL的水平。vupanorsen对残余胆固醇和VLDL-C降低的影响是剂量依赖性的,并且与ANGPTL3抑制程度直接相关:在ANGPTL3降低90%时,残余胆固醇和VLDL-C分别下降了61%和81%,分别。
结论:抑制ANGPTL3蛋白合成可显著降低高甘油三酯血症患者的残余胆固醇和VLDL-C。降低的幅度与ANGPTL3抑制的程度相关。这些发现支持ANGPTL3抑制作为降低富含甘油三酯的脂蛋白上的胆固醇的有希望的靶标。
在这项针对286名甘油三酯升高的参与者的随机对照试验中,用Vupanorsen治疗,ANGPTL3抑制剂,与安慰剂相比,残留胆固醇降低高达59%,VLDL胆固醇降低高达67%。治疗效果持续24周,在关键患者亚组之间一致。抑制ANGPTL3可能是治疗甘油三酯升高的患者的有希望的方法。
OBJECTIVE: Remnant cholesterol and very low-density lipoprotein cholesterol (
VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target.
RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and
VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period,
VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and
VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively.
CONCLUSIONS: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and
VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.
In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.