Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, Reynolds Building, St Dunstans Road, London W6 8RP, UK.
DalCor Pharmaceuticals, Montreal, QC, Canada.
Eur Heart J. 2022 Dec 21;43(48):5047-5057. doi: 10.1093/eurheartj/ehac615.
Patients often require combination therapies to achieve LDL cholesterol (LDL-C) targets for the primary prevention of atherosclerotic cardiovascular disease. This study investigates the effect of inclisiran, a small interfering ribonucleic acid targeting hepatic proprotein convertase subtilisin/kexin type 9 production, in primary prevention patients with elevated LDL-C despite statins.
This pre-specified analysis of the placebo-controlled, randomized ORION-11 trial included 203 individuals at risk of, but without prior, cardiovascular events and LDL-C ≥2.6 mmol/L, despite maximally tolerated statins. Inclisiran 284 mg or placebo was administered on Days 1, 90, and thereafter every 6 months up to 540 days. Co-primary endpoints were percentage LDL-C change from baseline to Day 510 and time-adjusted change from baseline after Day 90 and up to Day 540. Key secondary endpoints included percentage and absolute changes in atherogenic lipoproteins. Safety was assessed over 540 days. The mean baseline (SD) LDL-C was 3.6 (1.5) mmol/L. At Day 510, the placebo-corrected LDL-C change with inclisiran was -43.7% [95% confidence interval (CI): -52.8 to -34.6] with a corresponding time-adjusted change of -41.0% (95% CI: -47.8 to -34.2); (P < 0.0001). The placebo-corrected absolute change in LDL-C at Day 510 with inclisiran was -1.5 mmol/L (95% CI: -1.8 to -1.2), with a respective time-adjusted change of -1.3 mmol/L (95% CI: -1.6 to -1.1). Inclisiran significantly lowered non-HDL cholesterol and apolipoprotein B (apoB) at Day 510 vs. placebo (P < 0.0001 for both), with a greater likelihood of attaining lipoprotein and apoB goals, and was well-tolerated except for mainly mild, treatment-emergent adverse events at the injection site.
Inclisiran was generally well-tolerated in primary prevention patients with elevated LDL-C, who derived significant reductions in atherogenic lipoprotein levels with twice-yearly maintenance dosing.
患者通常需要联合治疗来实现 LDL 胆固醇（LDL-C）目标，以预防动脉粥样硬化性心血管疾病。本研究调查了inclisiran（一种针对肝脏前蛋白转化酶枯草溶菌素/激肽释放酶 9 产生的小干扰 RNA）在 LDL-C 升高的原发性预防患者中的作用，尽管他们接受了他汀类药物治疗。
这是对安慰剂对照、随机 ORION-11 试验的预先指定分析，纳入了 203 名有心血管事件风险但无既往病史的个体，且 LDL-C≥2.6mmol/L，尽管接受了最大耐受剂量的他汀类药物治疗。inclisiran 284mg 或安慰剂在第 1 天、第 90 天及第 90 天后每 6 个月给药一次，直至 540 天。主要复合终点为第 510 天与基线相比的 LDL-C 百分比变化和第 90 天至第 540 天的时间调整后变化。关键次要终点包括致动脉粥样硬化脂蛋白的百分比和绝对值变化。在 540 天内评估安全性。平均基线（SD）LDL-C 为 3.6（1.5）mmol/L。在第 510 天，与安慰剂相比，inclisiran 的 LDL-C 降低了 43.7%[95%置信区间（CI）：-52.8 至-34.6]，相应的时间调整变化为 41.0%（95%CI：-47.8 至-34.2）；（P<0.0001）。与安慰剂相比，inclisiran 在第 510 天的 LDL-C 绝对值降低了 1.5mmol/L（95%CI：-1.8 至-1.2），相应的时间调整变化为 1.3mmol/L（95%CI：-1.6 至-1.1）。与安慰剂相比，inclisiran 在第 510 天显著降低了非高密度脂蛋白胆固醇和载脂蛋白 B（apoB）（均<0.0001），更有可能达到脂蛋白和 apoB 目标，且耐受性良好，除了注射部位的主要轻度、治疗相关不良事件外。
inclisiran 在 LDL-C 升高的原发性预防患者中通常耐受性良好，这些患者在每半年维持治疗后 LDL 胆固醇水平显著降低。
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