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Effects of Randomized Treatment With Icosapent Ethyl and a Mineral Oil Comparator on Interleukin-1β, Interleukin-6, C-Reactive Protein, Oxidized Low-Density Lipoprotein Cholesterol, Homocysteine, Lipoprotein(a), and Lipoprotein-Associated Phospholipase A2: A REDUCE-IT Biomarker Substudy
Circulation ( IF 37.8 ) Pub Date : 2022-06-28 , DOI: 10.1161/circulationaha.122.059410
Paul M Ridker 1 , Nader Rifai 2 , Jean MacFadyen 1 , Robert J Glynn 1 , Lixia Jiao 3 , Ph Gabriel Steg 4 , Michael Miller 5 , Eliot A Brinton 6 , Terry A Jacobson 7 , Jean-Claude Tardif 8 , Christie M Ballantyne 9 , R Preston Mason 1 , Deepak L Bhatt 1
Affiliation  

Background:REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl—Intervention Trial) reported a 25% relative risk reduction in major adverse cardiovascular events with use of icosapent ethyl compared with pharmaceutical grade mineral oil. The mechanisms underlying this benefit remain uncertain. We explored whether treatment allocation in REDUCE-IT might affect a series of biomarkers in pathways known to associate with atherosclerosis risk.Methods:Serum levels of interleukin-1β, interleukin-6, high-sensitivity C-reactive protein, oxidized low-density lipoprotein cholesterol, homocysteine, lipoprotein(a), and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured at baseline, at 12 months, at 24 months, and at the end-of-study visit among REDUCE-IT participants with triglyceride levels 135 mg/dL and <500 mg/dL who were randomly allocated to treatment with either 4 grams daily of icosapent ethyl or mineral oil used as a comparator.Results:At baseline, median levels of each biomarker were similar in the 2 treatment groups. The levels of biomarkers associated with atherosclerosis increased over time among those allocated to mineral oil treatment; in this group at 12 months, the median percent increases from baseline were 1.5% for homocysteine, 2.2% for lipoprotein(a), 10.9% for oxidized low-density lipoprotein cholesterol, 16.2% for interleukin-6, 18.5% for lipoprotein-associated phospholipase A2, 21.9% for high-sensitivity C-reactive protein, and 28.9% for interleukin-1β (all P values <0.001), with similar changes at 24 months. In the icosapent ethyl group, there were minimal changes in these biomarkers at 12 and 24 months. As such, at study conclusion, between-group treatment differences largely reflected increases in the mineral oil group with median percent differences of 2.4% for lipoprotein(a), 3.0% for homocysteine, 4.2% for oxidized low-density lipoprotein cholesterol, 19.8% for interleukin-6, 26.2% for Lp-PLA2, 38.5% for high-sensitivity C-reactive protein, and 48.7% for interleukin-1β (all P values ≤0.007). These data are consistent with previous REDUCE-IT results in which the median percent change for low-density lipoprotein cholesterol at 12 months was −1.2% among those allocated to icosapent ethyl and 10.9% among those allocated to the mineral oil comparator.Conclusions:Among participants in REDUCE-IT, allocation to icosapent ethyl had minimal effects on a series of biomarkers associated with atherosclerotic disease, whereas levels increased among those allocated to mineral oil. The effect of these findings on interpretation of the overall risk reductions in clinical events observed within REDUCE-IT is uncertain.Registration:URL: https://www.clinicaltrials.gov; Unique identifier: NCT01492361.

中文翻译:

用二十碳五烯乙酯和矿物油比较剂随机治疗对白细胞介素 1β、白细胞介素 6、C 反应蛋白、氧化低密度脂蛋白胆固醇、同型半胱氨酸、脂蛋白 (a) 和脂蛋白相关磷脂酶 A2 的影响:A REDUCE- IT 生物标志物子研究

背景:REDUCE-IT(使用二十碳五烯乙酯减少心血管事件——干预试验)报告说,与药物级矿物油相比,使用二十碳五烯乙酯可使主要不良心血管事件的相对风险降低 25%。这种好处背后的机制仍然不确定。我们探讨了 REDUCE-IT 中的治疗分配是否会影响已知与动脉粥样硬化风险相关的通路中的一系列生物标志物。方法:白细胞介素 1β、白细胞介素 6、高敏 C 反应蛋白、氧化低密度脂蛋白的血清水平在具有甘油三酯水平的 REDUCE-IT 参与者中,在基线、12 个月、24 个月和研究结束访问时测量胆固醇、同型半胱氨酸、脂蛋白 (a) 和脂蛋白相关磷脂酶 A2 (Lp-PLA2) 135 mg/dL 和 <500 mg/dL 被随机分配接受每天 4 克二十碳五烯乙酯或矿物油治疗作为比较。结果:在基线时,2 个治疗组中每种生物标志物的中值水平相似。在分配给矿物油治疗的患者中,与动脉粥样硬化相关的生物标志物水平随着时间的推移而增加;在该组中,第 12 个月时,同型半胱氨酸与基线相比的中位百分比增加为 1.5%,脂蛋白 (a) 为 2.2%,氧化低密度脂蛋白胆固醇为 10.9%,白细胞介素 6 为 16.2%,脂蛋白相关为 18.5%磷脂酶 A2,高敏 C 反应蛋白 21.9%,白细胞介素 1β 28.9%(所有P值 <0.001),在 24 个月时有类似的变化。在 icosapent 乙基组中,这些生物标志物在 12 个月和 24 个月时变化很小。因此,在研究结论中,组间治疗差异主要反映了矿物油组的增加,脂蛋白 (a) 的中位数百分比差异为 2.4%,同型半胱氨酸为 3.0%,氧化低密度脂蛋白胆固醇为 4.2%,19.8%白细胞介素 6、Lp-PLA2 为 26.2%、高敏 C 反应蛋白为 38.5%、白细胞介素 1β 为 48.7%(所有P值≤0.007)。这些数据与之前的 REDUCE-IT 结果一致,其中分配给 icosapent ethyl 的低密度脂蛋白胆固醇的中位百分比变化在 12 个月时为 -1.2%,在分配给矿物油比较剂的患者中为 10.9%。结论:在 REDUCE-IT 的参与者中,分配给 icosapent ethyl 对一系列与动脉粥样硬化疾病相关的生物标志物的影响很小,而分配给矿物油的人的水平增加了。这些发现对解释 REDUCE-IT 中观察到的临床事件总体风险降低的影响尚不确定。注册:URL:https://www.clinicaltrials.gov;唯一标识符:NCT01492361。
更新日期:2022-06-28
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