Wong Nathan D, Shapiro Michael D
Heart Disease Prevention Program, Division of Cardiology, University of California, Irvine, Irvine, CA, United States.
Knight Cardiovascular Institute, Oregon Health Sciences University, Portland, OR, United States.
Front Cardiovasc Med. 2019 Mar 6;6:14. doi: 10.3389/fcvm.2019.00014. eCollection 2019.
The recent development of monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9), e.g., PCSK9 inhibitors has revolutionized the landscape of lipid management. Many clinical trials assessing this class have demonstrated remarkable and consistent reductions in low-density lipoprotein-cholesterol. Moreover, the GLAGOV trial demonstrated the efficacy of evolocumab, when added to statin therapy, in reducing the progression of atherosclerosis measured by serial intravascular ultrasound, with the first suggestion of continued benefit down to LDL-C levels of 0.5 mmol/L (20 mg/dL). This trial was followed by the FOURIER Cardiovascular Outcomes trial in more than 27,000 patients with stable atherosclerotic cardiovascular disease (ASCVD) where evolocumab reduced the primary endpoint of atherosclerotic events by 15%, without significant safety differences between treatment groups. Furthermore, subgroup analyses suggested greater benefits seen in those with longer exposure to evolocumab recent acute coronary syndrome, multiple myocardial infarctions, multivessel coronary artery disease, peripheral arterial disease, as well as the subgroup who achieved very low low-density lipoprotein-cholesterol levels of below 0.3 mmol/L (10 mg/dL). Moreover, the EBBINGHAUS substudy demonstrated no differences in objectively measured cognitive function between treatment groups. The SPIRE 2 trial evaluating bococizumab in high-risk patients with baseline LDL-C ≥2.6 mmol/L (100 mg/dL) demonstrated significant atherosclerotic risk reduction, but the trial and further development of the drug was prematurely discontinued due to substantial attenuation of the LDL-C effect over time due to the development of neutralizing antibodies. Finally, the ODYSSEY Cardiovascular Outcomes trial testing alirocumab in subjects with recent (<1 year) acute coronary syndrome demonstrated a 15% relative risk reduction in the primary composite outcome, as well as a significant reduction in total mortality. Greater benefits were noted in those whose LDL-C at baseline was 2.6 mmol/L (100 mg/dL) or greater. These trials collectively demonstrate the added efficacy of PCSK9 inhibitors over moderate and high-intensity statin therapy for unprecedented low-density lipoprotein-cholesterol reduction and incremental ASCVD risk reduction.
近期针对前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）的单克隆抗体（如PCSK9抑制剂）的研发彻底改变了血脂管理的格局。许多评估此类药物的临床试验均显示，低密度脂蛋白胆固醇有显著且持续的降低。此外，GLAGOV试验证明，在他汀类药物治疗基础上加用依洛尤单抗，可通过连续血管内超声测量减少动脉粥样硬化进展，首次提示在低密度脂蛋白胆固醇水平降至0.5 mmol/L（20 mg/dL）时仍持续获益。该试验之后是FOURIER心血管结局试验，纳入了超过27000例稳定型动脉粥样硬化性心血管疾病（ASCVD）患者，依洛尤单抗使动脉粥样硬化事件的主要终点降低了15%，各治疗组之间无显著安全性差异。此外，亚组分析表明，在近期急性冠状动脉综合征、多次心肌梗死、多支冠状动脉疾病、外周动脉疾病患者以及低密度脂蛋白胆固醇水平极低（低于0.3 mmol/L，即10 mg/dL）的亚组中，使用依洛尤单抗时间较长者获益更大。此外，EBBINGHAUS子研究表明，各治疗组之间客观测量的认知功能无差异。评估博考izumab用于基线低密度脂蛋白胆固醇≥2.6 mmol/L（100 mg/dL）的高危患者的SPIRE 2试验显示，动脉粥样硬化风险显著降低，但由于随着时间推移，中和抗体的产生导致低密度脂蛋白胆固醇效应大幅减弱，该试验及该药物的进一步研发提前终止。最后，在近期（<1年）急性冠状动脉综合征患者中测试阿利西尤单抗的ODYSSEY心血管结局试验显示，主要复合结局的相对风险降低了15%，总死亡率也显著降低。基线低密度脂蛋白胆固醇为2.6 mmol/L（100 mg/dL）或更高者获益更大。这些试验共同证明，PCSK9抑制剂相较于中等强度和高强度他汀类药物治疗，在降低低密度脂蛋白胆固醇至前所未有的水平以及进一步降低ASCVD风险方面具有额外疗效。
