From the Imperial Centre for Cardiovascular Disease Prevention, Department of Primary Care and Public Health, Imperial College London, London (K.K.R.); the Louisville Metabolic and Atherosclerosis Research Center, Louisville, KY (H.E.B.); the University of Milan and Multimedica IRCCS, Milan (A.L.C.); Esperion Therapeutics, Ann Arbor, MI (N.D.L., L.T.B., L.R.S., P.L.R.); and Baylor College of Medicine, Houston (C.M.B.).
N Engl J Med. 2019 Mar 14;380(11):1022-1032. doi: 10.1056/NEJMoa1803917.
Short-term studies have shown that bempedoic acid, an inhibitor of ATP citrate lyase, reduces levels of low-density lipoprotein (LDL) cholesterol. Data are limited regarding the safety and efficacy of bempedoic acid treatment in long-term studies involving patients with hypercholesterolemia who are receiving guideline-recommended statin therapy.
We conducted a randomized, controlled trial involving patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both. Patients had to have an LDL cholesterol level of at least 70 mg per deciliter while they were receiving maximally tolerated statin therapy with or without additional lipid-lowering therapy. (Maximally tolerated statin therapy was defined as the highest intensity statin regimen that a patient was able to maintain, as determined by the investigator.) Patients were randomly assigned in a 2:1 ratio to receive bempedoic acid or placebo. The primary end point was safety, and the principal secondary end point (principal efficacy end point) was the percentage change in the LDL cholesterol level at week 12 of 52 weeks.
The trial involved 2230 patients, of whom 1488 were assigned to receive bempedoic acid and 742 to receive placebo. The mean (±SD) LDL cholesterol level at baseline was 103.2±29.4 mg per deciliter. The incidence of adverse events (1167 of 1487 patients [78.5%] in the bempedoic acid group and 584 of 742 [78.7%] in the placebo group) and serious adverse events (216 patients [14.5%] and 104 [14.0%], respectively) did not differ substantially between the two groups during the intervention period, but the incidence of adverse events leading to discontinuation of the regimen was higher in the bempedoic acid group than in the placebo group (162 patients [10.9%] vs. 53 [7.1%]), as was the incidence of gout (18 patients [1.2%] vs. 2 [0.3%]). At week 12, bempedoic acid reduced the mean LDL cholesterol level by 19.2 mg per deciliter, representing a change of -16.5% from baseline (difference vs. placebo in change from baseline, -18.1 percentage points; 95% confidence interval, -20.0 to -16.1; P<0.001). Safety and efficacy findings were consistent, regardless of the intensity of background statin therapy.
In this 52-week trial, bempedoic acid added to maximally tolerated statin therapy did not lead to a higher incidence of overall adverse events than placebo and led to significantly lower LDL cholesterol levels. (Funded by Esperion Therapeutics; CLEAR Harmony ClinicalTrials.gov number, NCT02666664.).
短期研究表明，ATP 柠檬酸裂解酶抑制剂苯扎贝特酸可降低低密度脂蛋白（LDL）胆固醇水平。关于苯扎贝特酸在接受指南推荐的他汀类药物治疗的高胆固醇血症患者的长期研究中的安全性和疗效的数据有限。
我们进行了一项随机对照试验，涉及动脉粥样硬化性心血管疾病、杂合子家族性高胆固醇血症或两者兼有患者。患者在接受最大耐受他汀类药物治疗（无论是否联合其他降脂药物）时，LDL 胆固醇水平必须至少为每分升 70 毫克。（最大耐受他汀类药物治疗定义为患者能够维持的最高强度他汀类药物治疗，由研究者确定。）患者以 2:1 的比例随机分配接受苯扎贝特酸或安慰剂。主要终点是安全性，主要次要终点（主要疗效终点）是 52 周内第 12 周 LDL 胆固醇水平的变化百分比。
试验涉及 2230 名患者，其中 1488 名被分配接受苯扎贝特酸治疗，742 名接受安慰剂治疗。基线时的平均（±SD）LDL 胆固醇水平为 103.2±29.4mg/dL。不良事件的发生率（苯扎贝特酸组 1487 例中的 1167 例[78.5%]和安慰剂组 742 例中的 584 例[78.7%]）和严重不良事件（苯扎贝特酸组 216 例[14.5%]和安慰剂组 104 例[14.0%]）在干预期间两组之间差异不大，但苯扎贝特酸组因不良事件导致治疗方案中断的发生率高于安慰剂组（162 例[10.9%]比 53 例[7.1%]），痛风的发生率也较高（苯扎贝特酸组 18 例[1.2%]比安慰剂组 2 例[0.3%]）。第 12 周时，苯扎贝特酸使平均 LDL 胆固醇水平降低 19.2mg/dL，与基线相比变化为-16.5%（与安慰剂相比，从基线变化的差异为-18.1 个百分点；95%置信区间，-20.0 至-16.1；P<0.001）。安全性和疗效结果一致，与背景他汀类药物治疗的强度无关。
在这项为期 52 周的试验中，与安慰剂相比，苯扎贝特酸联合最大耐受他汀类药物治疗并未导致总体不良事件发生率更高，且 LDL 胆固醇水平显著降低。（由 Esperion 治疗公司资助；CLEAR Harmony 临床试验.gov 编号，NCT02666664。）
