Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies: A Phase 3 Randomized Clinical Trial.

Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined.

Enlicitide，一种口服的前蛋白转化酶枯草溶菌素/kexin 9（PCSK9）抑制剂，与安慰剂相比，LDL-C降低了60%；其与其他口服非他汀类治疗药物的疗效尚未被检验。

This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies.

本研究评估了新型口服PCSK9抑制剂enlicitide与其它口服非他汀类药物的疗效。

Methods

In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days.

在这项第三阶段、随机、双盲、活性对照试验中，年龄≥18岁的他汀类药物治疗患者，如果LDL-C≥55 mg/dL且有既往主要动脉粥样硬化心血管疾病（ASCVD）事件，或者LDL-C≥70 mg/dL且为首次事件的中高风险患者，按照2:1:1:2的比例随机分配至每日一次20 mg enlicitide（n = 101）、180 mg bempedoic acid（n = 50）、10 mg ezetimibe（n = 50）或180 mg bempedoic acid加10 mg ezetimibe（n = 100）治疗，持续56天。

The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C).

主要终点是基线至第56天低密度脂蛋白胆固醇（LDL-C）的平均百分比变化；次要终点包括载脂蛋白B（ApoB）和非高密度脂蛋白胆固醇（nonHDL-C）的平均百分比变化。

Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs.

安全性终点包括总体不良事件（AEs）和因不良事件导致的停药。

Results

Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001).

在301名随机参与者中（平均年龄64.4岁，37%为女性，98%接受中到高强度的他汀类药物治疗），有298人（99.0%）完成了试验。从基线到第56天，LDL-C的平均百分比变化为：enlicitide组为-64.6%（95%置信区间：-68.3%至-60.9%），bempedoic acid组为-6.3%（95%置信区间：-13.5%至0.8%），ezetimibe组为-27.8%（95%置信区间：-32.3%至-23.4%），bempedoic acid加ezetimibe组为-36.5%（95%置信区间：-40.8%至-32.2%）；enlicitide在所有比较中均优于对照组（所有P < 0.001）。

Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001).

enlicitide组在降低ApoB和非HDL-C方面也更为显著（所有P < 0.001）。

Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms.

各治疗组中因不良事件（AEs）导致的参与者比例和因不良事件导致的停药比例相似。

Conclusions

In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone.

在有重大动脉粥样硬化性心血管疾病（ASCVD）事件史或首次事件风险增加的他汀类药物治疗成人中，enlicitide相较于其他口服非他汀类药物，实现了更低的低密度脂蛋白胆固醇（LDL-C）、载脂蛋白B（ApoB）和非高密度脂蛋白胆固醇（nonHDL-C）水平，展示了其作为重要附加治疗选择的潜力，当仅使用他汀类药物无法达到LDL-C目标时。

(A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366).

(一项评估Enlicitide癸酸酯[MK-0616，口服PCSK9抑制剂]与依折麦布或Bempedoic酸或依折麦布和Bempedoic酸在高胆固醇血症成人中的疗效和安全性的研究[MK-0616-018][CORALreef AddOn; NCT06450366])。