Division of Cardiology Department of Internal Medicine UT Southwestern Medical Center Dallas TX.
J Am Heart Assoc. 2020 Dec 15;9(24):e018136. doi: 10.1161/JAHA.120.018136. Epub 2020 Dec 2.
Background Anacetrapib is the only cholesteryl ester transfer protein inhibitor proven to reduce coronary heart disease (CHD). However, its effects on reverse cholesterol transport have not been fully elucidated. Macrophage cholesterol efflux (CEC), the initial step of reverse cholesterol transport, is inversely associated with CHD and may be affected by sex as well as haptoglobin copy number variants among patients with diabetes mellitus. We investigated the effect of anacetrapib on CEC and whether this effect is modified by sex, diabetes mellitus, and haptoglobin polymorphism. Methods and Results A total of 574 participants with CHD were included from the DEFINE (Determining the Efficacy and Tolerability of CETP Inhibition With Anacetrapib) trial. CEC was measured at baseline and 24-week follow-up using J774 macrophages, boron dipyrromethene difluoride-labeled cholesterol, and apolipoprotein B-depleted plasma. Haptoglobin copy number variant was determined using an ELISA assay. Anacetrapib increased CEC, adjusted for baseline CEC, risk factors, and changes in lipids/apolipoproteins (standard β, 0.23; 95% CI, 0.05-0.41). This CEC-raising effect was seen only in men ( interaction=0.002); no effect modification was seen by diabetes mellitus status. Among patients with diabetes mellitus, anacetrapib increased CEC in those with the normal 1-1 haptoglobin genotype (standard β, 0.42; 95% CI, 0.16-0.69) but not the dysfunctional 2-1/2-2 genotypes ( interaction=0.02). Conclusions Among patients with CHD, anacetrapib at a dose linked to improved CHD outcomes significantly increased CEC independent of changes in high-density lipoprotein cholesterol or other lipids, with effect modification by sex and a novel pharmacogenomic interaction by haptoglobin genotype, suggesting a putative mechanism for reduced risk requiring validation.
阿昔单抗是唯一被证明可降低冠心病（CHD）的胆固醇酯转移蛋白抑制剂。然而，其对胆固醇逆向转运的影响尚未完全阐明。巨噬细胞胆固醇外排（CEC）是胆固醇逆向转运的初始步骤，与 CHD 呈负相关，并且可能受到性别以及糖尿病患者中血红蛋白结合数变异的影响。我们研究了阿昔单抗对 CEC 的影响，以及这种影响是否受性别、糖尿病和血红蛋白多态性的影响。
共有 574 名来自 DEFINE（评估阿昔单抗抑制 CETP 的疗效和耐受性）试验的 CHD 患者被纳入本研究。使用 J774 巨噬细胞、硼二吡咯甲川荧光染料标记的胆固醇和载脂蛋白 B 耗尽的血浆，在基线和 24 周随访时测量 CEC。使用 ELISA 测定血红蛋白结合数变异。阿昔单抗增加了 CEC，调整了基线 CEC、危险因素和脂质/载脂蛋白的变化（标准β，0.23；95%置信区间，0.05-0.41）。这种 CEC 升高的效果仅见于男性（交互作用=0.002）；糖尿病状态没有观察到效应修饰。在糖尿病患者中，阿昔单抗增加了正常 1-1 血红蛋白基因型患者的 CEC（标准β，0.42；95%置信区间，0.16-0.69），但不能增加功能异常的 2-1/2-2 基因型患者的 CEC（交互作用=0.02）。
在 CHD 患者中，与改善 CHD 结局相关的阿昔单抗剂量显著增加了 CEC，独立于高密度脂蛋白胆固醇或其他脂质的变化，并且受到性别和血红蛋白基因型的新型药物基因组相互作用的影响，提示降低风险的潜在机制需要进一步验证。
