Thrombolysis in Myocardial Infarction (TIMI) Study Group, Brigham and Women's Hospital, Harvard Medical School, 7th Floor, 60 Fenwood Road, Boston, MA 02115, USA.
Pfizer, Inc., New York, NY, USA.
Eur J Prev Cardiol. 2024 Aug 9;31(10):1216-1223. doi: 10.1093/eurjpc/zwae090.
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.
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.
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.
残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越来越被认可的危险因素，治疗选择有限。血管生成素样蛋白 3（ANGPTL3）是富含甘油三酯脂蛋白代谢的关键蛋白，是一个很有前途的靶点。
TRANSLATE-TIMI 70 是一项双盲、安慰剂对照的随机试验，测试了七种剂量方案的 vupanorsen，一种针对 ANGPTL3 的反义寡核苷酸，用于非高密度脂蛋白胆固醇（HDL-C）≥100mg/dL 和甘油三酯 150-500mg/dL 的成年人。本分析的主要终点是 24 周时残胆固醇（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。286 例患者入组，中位年龄 64 岁，44%为女性。中位基线残胆固醇和 VLDL-C 分别为 42 和 31mg/dL（参考值：<30mg/dL）。与安慰剂相比，vupanorsen 在 24 周时将残胆固醇降低 42-59%（P<0.001），在最高剂量时达到 18mg/dL 的中位数水平。在此期间，VLDL-C 降低了 52-67%（P<0.001），在最高剂量时达到了 2.5mg/dL 的中位数水平。vupanorsen 降低残胆固醇和 VLDL-C 的效果与剂量呈正相关，并与 ANGPTL3 抑制的程度直接相关：在 ANGPTL3 抑制 90%的情况下，残胆固醇和 VLDL-C 分别降低 61%和 81%。
ANGPTL3 蛋白合成的抑制显著降低了高甘油三酯血症患者的残胆固醇和 VLDL-C。降低幅度与 ANGPTL3 抑制程度相关。这些发现支持 ANGPTL3 抑制作为降低富含甘油三酯脂蛋白胆固醇的有前途的靶点。
