The Cleveland Clinic Coordinating Center for Clinical Research, Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio.
Eli Lilly, Indianapolis, Indiana.
JAMA Cardiol. 2018 May 1;3(5):401-408. doi: 10.1001/jamacardio.2018.0569.
A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial.
To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease.
DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017.
Evacetrapib, 130 mg, or matching placebo.
The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina.
For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59.
Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.
对胆固醇酯转移蛋白抑制剂 dalcetrapib 的一项遗传药理学分析报告称，在一项总体试验结果呈中性的情况下，ADCY9 基因（rs1967309）的单核苷酸多态性（SNP）与主要不良心血管事件的减少之间存在关联。
确定对于高危血管疾病患者，另一种胆固醇酯转移蛋白抑制剂 evacetrapib 是否可以复制与 ADCY9 基因 SNP 相关的主要不良心血管事件减少的关联。
设计、设置和参与者：这是一项嵌套病例对照研究，对 12092 名患者的评估中对 rs1967309 SNP 进行了检查，这些患者来自接受高危血管结局患者的胆固醇酯转移蛋白抑制作用评估（ACCELERATE）试验中的临床效果评估，这是一项随机、双盲、安慰剂对照的 3 期试验，在 2012 年 10 月至 2013 年 12 月期间对高危血管疾病患者进行了随机分组。基因分型于 2017 年 1 月至 2017 年 3 月进行，数据分析于 2017 年 7 月至 2017 年 11 月进行。
evacetrapib，130 mg，或匹配的安慰剂。
主要分析使用条件逻辑回归模型来评估 evacetrapib 与安慰剂相比在每个基因型下的主要不良心血管事件的比值比（OR）。基本模型包括调整年龄、性别和前 5 个主成分。额外的模型包括心血管危险因素，以调整选择对照患者的潜在偏差。主要的主要不良心血管事件终点是心血管原因死亡、心肌梗死、中风、冠状动脉血运重建或不稳定型心绞痛住院的复合事件。
对于报告具有 dalcetrapib 有益作用的 AA 基因型患者，evacetrapib 与安慰剂相比的 OR 为 0.88（95%CI，0.69-1.12）。对于 AG 基因型患者，OR 为 1.04（95%CI，0.90-1.21）。对于报告有 dalcetrapib 有害作用证据的 GG 基因型患者，evacetrapib 的 OR 为 1.18（95%CI，0.98-1.41）。3 种基因型之间的交互 P 值为 P=0.17，趋势 P 值为 P=0.06。当调整心血管危险因素时，AA 基因型患者的 evacetrapib OR 为 0.93（95%CI，0.73-1.19），AG 基因型患者为 1.05（95%CI，0.91-1.22），GG 基因型患者为 1.02（95%CI 0.85-1.24）；交互 P=0.71，趋势 P=0.59。
遗传药理学分析并未显示 ADCY9 SNP（rs1967309）与胆固醇酯转移蛋白抑制剂 evacetrapib 的心血管获益或危害之间存在显著关联。
