Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, Charing Cross Hospital, London, England.
The Medicines Company, Parsippany, New Jersey.
JAMA Cardiol. 2019 Nov 1;4(11):1067-1075. doi: 10.1001/jamacardio.2019.3502.
Sustained reductions in low-density lipoprotein cholesterol (LDL-C) with lipid-lowering therapies that require frequent dosing are reliant on patient adherence, and poor adherence is associated with worse clinical outcomes.
To determine whether inclisiran, a small interfering RNA, reduces mean LDL-C exposure with an infrequent dosing regimen.
DESIGN, SETTING, AND PARTICIPANTS: Prespecified analysis of a randomized, double-blind, placebo-controlled multicenter phase 2 clinical trial. Participants were followed up monthly for LDL-C levels and proprotein convertase subtilisin-kexin type 9 (PCSK9) measurements as well as safety until their LDL-C levels had returned to within 20% of their change from baseline (maximum 360 days). The study included patients with elevated LDL-C despite maximally tolerated statin therapy. Data were analyzed between January 11, 2016, and June 7, 2017.
One dose (200, 300, or 500 mg on day 1) or 2 doses (100, 200, or 300 mg on days 1 and 90) of inclisiran sodium or placebo.
Duration of time to return to within 20% of change from baseline for LDL-C levels and time-averaged LDL-C reductions over 1 year.
At baseline, among the 501 participants, 65% were men (n = 326 of 501), mean age was 63 years, 6% had familial hypercholesterolemia (n = 28 of 501), and 69% had established ASCVD (n = 347 of 501). Baseline LDL-C was 128 mg/dL among 501 randomized participants. The percentage of participants who were followed up to day 360 because their LDL-C levels had not returned to within 20% of their change from baseline ranged from 48.3% to 65.0% for those receiving a single dose and between 55.9% and 83.1% of those receiving 2 doses, with similar effects observed for PCSK9. Time-averaged reduction in LDL-C levels over 1 year after a single dose ranged from 29.5% to 38.7% (P < .001 between groups) and from 29.9% to 46.4% (P < .001 between groups) for those who received 2 doses. The 2-dose 300-mg regimen produced the highest proportion of responders at day 360 and the greatest mean reduction in LDL-C over 1 year. Incidence of adverse events was similar through to 1 year.
Treatment with inclisiran resulted in durable reductions in LDL-C over 1 year. Inclisiran may offer a novel approach to LDL-C reduction with the convenience of infrequent dosing.
ClinicalTrials.gov identifier: NCT02597127.
需要频繁给药的降脂疗法可降低 LDL-C（低密度脂蛋白胆固醇）的持续水平，这依赖于患者的依从性，而依从性差与临床结局恶化相关。
确定小干扰 RNA 依洛西单抗能否通过不频繁的给药方案降低平均 LDL-C 暴露量。
设计、环境和参与者：这是一项随机、双盲、安慰剂对照的多中心 2 期临床试验的预设分析。参与者每月接受一次 LDL-C 水平和前蛋白转化酶枯草溶菌素 9（PCSK9）测量以及安全性随访，直到其 LDL-C 水平恢复至基线变化的 20%以内（最长 360 天）。该研究纳入了尽管接受了最大耐受他汀类药物治疗但 LDL-C 仍升高的患者。数据于 2016 年 1 月 11 日至 2017 年 6 月 7 日进行分析。
单次（第 1 天 200、300 或 500mg）或 2 次（第 1 和 90 天各 100、200 或 300mg）给予依洛西单抗钠或安慰剂。
LDL-C 水平恢复至基线变化 20%以内所需的时间和 1 年内平均 LDL-C 降低时间。
在 501 名参与者中，基线时 65%为男性（501 名参与者中的 326 名），平均年龄为 63 岁，6%有家族性高胆固醇血症（501 名参与者中的 28 名），69%有明确的 ASCVD（501 名参与者中的 347 名）。501 名随机参与者的基线 LDL-C 为 128mg/dL。因 LDL-C 水平未恢复至基线变化的 20%而随访至第 360 天的参与者百分比范围为接受单次剂量者的 48.3%至 65.0%，接受 2 次剂量者的 55.9%至 83.1%，PCSK9 也观察到类似的效果。单次剂量后 1 年内 LDL-C 水平的平均降低幅度范围为 29.5%至 38.7%（组间差异 < .001），接受 2 次剂量者的降幅范围为 29.9%至 46.4%（组间差异 < .001）。在第 360 天，接受 300mg 2 剂方案者的应答者比例最高，1 年内 LDL-C 平均降低幅度最大。至 1 年时不良事件的发生率相似。
依洛西单抗治疗可使 LDL-C 在 1 年内持续降低。依洛西单抗可能为 LDL-C 降低提供一种新颖的方法，其优势为不频繁给药。
ClinicalTrials.gov 标识符：NCT02597127。
