Ridker Paul M, Lei Lei, Ray Kausik K, Ballantyne Christie M, Bradwin Gary, Rifai Nader
Center for Cardiovascular Disease Prevention, Divisions of Preventive Medicine and Cardiovascular Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States.
United Kingdom Esperion Therapeutics, Inc., Ann Arbor, Michigan, United States.
J Clin Lipidol. 2023 Mar-Apr;17(2):297-302. doi: 10.1016/j.jacl.2023.02.002. Epub 2023 Feb 14.
While bempedoic acid (BA), an inhibitor of ATP citrate lyase, lowers high-sensitivity C-reactive protein (hsCRP) and low-density lipoprotein cholesterol (LDL-C), the mechanisms underlying the potential anti-inflammatory effects of BA are uncertain, as are effects of this agent on lipoprotein(a). To address these issues, we conducted a secondary biomarker analysis of the randomized placebo-controlled multi-center CLEAR Harmony trial which included 817 patients with known atherosclerotic disease and/or heterozygous familial hypercholesterolemia who were taking maximally tolerated statin therapy and had residual inflammatory risk, defined as a baseline hsCRP ≥2 mg/L. Participants were randomly allocated in a 2:1 ratio to oral BA 180 mg once daily or matching placebo. Placebo-corrected median percent changes (95% CI) from baseline to 12 weeks associated with BA were -21.1% (-23.7 to -18.5) for LDL-C; -14.3% (-16.8 to -11.9) for non-high-density lipoprotein cholesterol; -12.8% (-14.8 to -10.8) for total cholesterol; -8.3% (-10.1 to -6.6) for high-density lipoprotein cholesterol (HDL-C); -13.1% (-15.5 to -10.6) for apolipoprotein B; 8.0% (3.7 to 12.5) for triglycerides; -26.5% (-34.8 to -18.4) for hsCRP; 2.1% (-2.0 to 6.4) for fibrinogen, -3.7% (-11.5, 4.3) for interleukin-6; and 2.4% (0.0 to 4.8) for lipoprotein(a). There was no correlation between BA associated lipid changes and BA associated change in hsCRP (all r<0.05), except for a weak correlation with HDL-C (r = 0.12). Thus, the pattern of lipid lowering and inflammation inhibition with BA is almost identical to what is observed with statin therapy suggesting that BA could be a useful treatment option to address both residual cholesterol risk and residual inflammatory risk. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02666664; https://clinicaltrials.gov/ct2/show/NCT02666664.
虽然ATP柠檬酸裂解酶抑制剂贝派地酸（BA）可降低高敏C反应蛋白（hsCRP）和低密度脂蛋白胆固醇（LDL-C），但其潜在抗炎作用的机制尚不确定，该药物对脂蛋白（a）的影响也不清楚。为解决这些问题，我们对随机、安慰剂对照、多中心的CLEAR Harmony试验进行了二次生物标志物分析，该试验纳入了817例已知动脉粥样硬化疾病和/或杂合子家族性高胆固醇血症患者，这些患者正在接受最大耐受剂量的他汀类药物治疗，且存在残余炎症风险，定义为基线hsCRP≥2mg/L。参与者按2:1的比例随机分配，分别每日口服一次180mg BA或匹配的安慰剂。与BA相关的从基线到12周的安慰剂校正后中位数百分比变化（95%CI）如下：LDL-C为-21.1%（-23.7至-18.5）；非高密度脂蛋白胆固醇为-14.3%（-16.8至-11.9）；总胆固醇为-12.8%（-14.8至-10.8）；高密度脂蛋白胆固醇（HDL-C）为-8.3%（-10.1至-6.6）；载脂蛋白B为-13.1%（-15.5至-10.6）；甘油三酯为8.0%（3.7至12.5）；hsCRP为-26.5%（-34.8至-18.4）；纤维蛋白原为2.1%（-2.0至6.4）；白细胞介素-6为-3.7%（-11.5，4.3）；脂蛋白（a）为2.4%（0.0至4.8）。除了与HDL-C有微弱相关性（r = 0.12）外，BA相关的脂质变化与BA相关的hsCRP变化之间无相关性（所有r<0.05）。因此，BA降低脂质和抑制炎症的模式与他汀类药物治疗所观察到的几乎相同，这表明BA可能是解决残余胆固醇风险和残余炎症风险的一种有用治疗选择。试验注册：ClinicalTrials.gov标识符：NCT02666664；https://clinicaltrials.gov/ct2/show/NCT02666664。
