贝匹地酸安全性分析：四项 3 期临床试验的汇总数据。

Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials.

机构信息

Louisville Metabolic and Atherosclerosis Research Center, Louisville, Kentucky, USA.

Department of Hypertension, Medical University of Łódź, Łódź, Poland.

出版信息

J Clin Lipidol. 2020 Sep-Oct;14(5):649-659.e6. doi: 10.1016/j.jacl.2020.08.009. Epub 2020 Sep 2.

DOI:10.1016/j.jacl.2020.08.009

PMID:32980290

Abstract

BACKGROUND

An ongoing need exists for safe and effective lipid-lowering therapies (LLTs) for patients unable to achieve desired lipid levels with current treatment options.

OBJECTIVE

The objective of this study was to describe the safety profile of bempedoic acid, an oral, first-in-class, adenosine triphosphate (ATP)-citrate lyase inhibitor that significantly reduces low-density lipoprotein cholesterol (LDL-C) levels by 17.4%-28.5% vs placebo.

METHODS

This was a pooled analysis of four phase 3, randomized (2:1), double-blind, placebo-controlled studies in patients with hypercholesterolemia who required additional LDL-C lowering, despite stable maximally-tolerated LLT. Patients received 180 mg of bempedoic acid (n = 2424) or placebo (n = 1197) once daily for 12 to 52 weeks. Assessments included treatment-emergent adverse events (TEAEs) and clinical laboratory tests.

RESULTS

Of 3621 patients (the median drug exposure: 363 days), exposure-adjusted TEAE rates were 87.1/100 and 82.9/100 person-years (PY) for bempedoic acid and placebo, respectively. No single TEAE influenced the difference in rates. TEAEs leading to discontinuation occurred at rates of 13.4/100 and 8.9/100 PY for bempedoic acid vs placebo, with the most common cause being myalgia, which occurred less frequently with bempedoic acid vs placebo (1.5/100 vs 2.0/100 PY). Rates of myalgia and muscle weakness were comparable vs placebo. Bempedoic acid was associated with mild increases in blood urea nitrogen, creatinine, and uric acid and decreases in hemoglobin. These laboratory abnormalities were apparent by week 4, stable over time, and reversible after treatment cessation. Gout incidence was 1.6/100 vs 0.5/100 PY in the bempedoic acid vs placebo groups. New-onset diabetes/hyperglycemia occurred less frequently with bempedoic acid vs placebo (4.7/100 vs 6.4/100 PY). The safety profile was consistent across subgroups.

CONCLUSIONS

Bempedoic acid is generally safe and well tolerated among patients with hypercholesterolemia who require additional LLT.

摘要

背景

对于当前治疗方案无法达到理想血脂水平的患者，仍然需要安全有效的降脂治疗（LLT）。

目的

本研究旨在描述苯扎贝特酸的安全性，苯扎贝特酸是一种口服、首创的三磷酸腺苷（ATP）-柠檬酸裂解酶抑制剂，可将低密度脂蛋白胆固醇（LDL-C）水平降低 17.4%-28.5%，优于安慰剂。

方法

这是四项 3 期、随机（2:1）、双盲、安慰剂对照研究的汇总分析，纳入了需要进一步降低 LDL-C 的高胆固醇血症患者，这些患者在接受最大耐受的稳定 LLT 治疗后仍未达到目标。患者每日接受 180mg 苯扎贝特酸（n=2424）或安慰剂（n=1197）治疗 12-52 周。评估包括治疗期间出现的不良事件（TEAE）和临床实验室检查。

结果

在 3621 例患者中（中位药物暴露时间：363 天），苯扎贝特酸和安慰剂的暴露调整不良事件发生率分别为 87.1/100 和 82.9/100 人年（PY）。没有单一的不良事件影响发生率差异。苯扎贝特酸和安慰剂导致停药的不良事件发生率分别为 13.4/100 和 8.9/100 PY，最常见的原因是肌痛，其发生率低于安慰剂（1.5/100 与 2.0/100 PY）。苯扎贝特酸与安慰剂的肌痛和肌肉无力发生率相当。苯扎贝特酸可引起血尿素氮、肌酐和尿酸轻度升高，血红蛋白降低。这些实验室异常在第 4 周时即可观察到，随着时间的推移保持稳定，并在停药后可逆转。苯扎贝特酸组痛风发生率为 1.6/100，安慰剂组为 0.5/100 PY。与安慰剂相比，苯扎贝特酸发生新发糖尿病/高血糖的频率较低（4.7/100 与 6.4/100 PY）。安全性特征在各亚组中一致。