Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease
Selective BET Protein Inhibition with Apabetalone and Cardiovascular Events: A Pooled Analysis of Trials in Patients with Coronary Artery Disease
复制标题
DOI：
10.1007/s40256-017-0250-3
复制
发表时间：
2018-04-01
影响因子：
3
通讯作者：
Schwartz, Gregory G.
中科院分区：
文献类型：
--
作者：
Nicholls, Stephen J.;Ray, Kausik K.;Schwartz, Gregory G.
背景 溴结构域和额外末端 (BET) 蛋白的抑制可以调节脂蛋白和介导动脉粥样硬化的炎症因子。 BET 抑制剂 apabetalone 对心血管事件的影响尚不清楚。 目的 我们的目的是通过对已确诊冠状动脉疾病患者的临床研究进行汇总分析，探讨 apabetalone 对心血管事件发生率的影响。 方法 我们对参加临床试验（ASSERT、ASSURE、SUSTAIN）的冠状动脉疾病患者 (n = 798) 进行汇总分析，评估 3-6 个月的 apabetalone 治疗对血脂参数和冠状动脉的影响动脉粥样硬化。对治疗组中主要不良心血管事件（死亡、心肌梗死、冠状动脉血运重建、心血管原因住院）的发生率进行了评估。 结果 在基线时，接受 apabetalone 治疗的患者更有可能是白种人，有血脂异常病史，并且β受体阻滞剂和抗血小板药物治疗不足。与安慰剂相比，apabetalone 治疗产生了以下剂量依赖性变化：载脂蛋白 A-I (apoA-I) 增加高达 6.7% (P < 0.001)，高密度脂蛋白胆固醇 (HDL-C) 增加高达 6.5% (P < 0.001)，大 HDL 颗粒增加高达 23.3% (P < 0.001)，并且高敏 C 反应蛋白 (hsCRP) 为 21.1% (P = 0.04)。与安慰剂相比，Apabetalone 治疗不影响致动脉粥样硬化脂蛋白。与接受安慰剂治疗的患者相比，接受 apabetalone 治疗的患者经历的主要不良心血管事件较少（5.9 vs. 10.4%；P = 0.02），这一发现在糖尿病患者（5.4 vs. 12.7%；P = 0.02）、基线 HDL-C < 39 mg/dl（5.5 vs. 12.8%；P = 0.01）或 hsCRP 水平升高的患者中更为突出。 （5.4 vs. 14.2%；P = 0.02）。 结论 短期研究的汇总分析表明，与安慰剂治疗的患者相比，使用 BET 蛋白抑制剂 apabetalone 治疗的患者心血管事件较少。 BET 蛋白抑制作为降低心血管风险的新方法值得进一步研究。
Background Inhibition of bromodomain and extra-terminal (BET) proteins can modulate lipoprotein and inflammatory factors that mediate atherosclerosis. The impact of the BET inhibitor, apabetalone, on cardiovascular events is unknown.Objective Our objective was to investigate the impact of apabetalone on cardiovascular event rates in a pooled analysis of clinical studies in patients with established coronary artery disease.Methods We conducted a pooled analysis of patients (n = 798) with coronary artery disease who participated in clinical trials (ASSERT, ASSURE, SUSTAIN) that evaluated the impact of 3-6 months of treatment with apabetalone on lipid parameters and coronary atherosclerosis. The incidence of major adverse cardiovascular events (death, myocardial infarction, coronary revascularization, hospitalization for cardiovascular causes) in the treatment groups was evaluated.Results At baseline, patients treated with apabetalone were more likely to be Caucasian, have a history of dyslipidemia, and be undertreated with -blocker and anti-platelet agents. Treatment with apabetalone produced the following dose-dependent changes compared with placebo: increases in apolipoprotein A-I (apoA-I) of up to 6.7% (P < 0.001), increases in high-density lipoprotein cholesterol (HDL-C) of up to 6.5% (P < 0.001), increases in large HDL particles of up to 23.3% (P < 0.001), and decreases in high-sensitivity C-reactive protein (hsCRP) of - 21.1% (P = 0.04). Apabetalone treatment did not affect atherogenic lipoproteins compared with placebo. Patients treated with apabetalone experienced fewer major adverse cardiovascular events than those treated with placebo (5.9 vs. 10.4%; P = 0.02), a finding that was more prominent in patients with diabetes (5.4 vs. 12.7%; P = 0.02), with baseline HDL-C < 39 mg/dl (5.5 vs. 12.8%; P = 0.01), or with elevated hsCRP levels (5.4 vs. 14.2%; P = 0.02).Conclusion Pooled analysis of short-term studies demonstrated fewer cardiovascular events among patients treated with the BET protein inhibitor, apabetalone, than among those treated with placebo. BET protein inhibition warrants further investigation as a novel approach to cardiovascular risk reduction.