Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; The Copenhagen General Population Study, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Department of Clinical Biochemistry, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; The Copenhagen General Population Study, Copenhagen University Hospital - Herlev and Gentofte, Herlev, Denmark; Institute of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Atherosclerosis. 2024 Jun;393:117556. doi: 10.1016/j.atherosclerosis.2024.117556. Epub 2024 Apr 20.
The PROMINENT trial, a cardiovascular outcome trial of the triglyceride- and remnant cholesterol-lowering agent pemafibrate, has shown neutral results despite reduction in plasma triglycerides and remnant cholesterol. We tested the hypothesis that absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B explain the results of the PROMINENT trial.
Among 108,431 individuals from the Copenhagen General Population Study (CGPS), those who met the key inclusion criteria of the PROMINENT trial were analyzed to mimic the trial design. Endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT.
In the PROMINENT trial, treatment with pemafibrate resulted in -7 mg/dL (-0.18 mmol/L; -18 %) change in remnant cholesterol, +10 mg/dL (+0.26 mmol/L; +12 %) LDL cholesterol, and +5 mg/dL (+0.05 g/L; +5 %) apolipoprotein B. In the CGPS mimicking PROMINENT, the estimated hazard ratios for ASCVD were 0.97 (95 % confidence interval: 0.94-0.99) for a -7 mg/dL (-0.18 mmol/L) change in remnant cholesterol, 1.04 (1.01-1.07) for a +10 mg/dL (+0.26 mmol/L) change in LDL cholesterol, and 1.02 (1.01-1.03) for a +5 mg/dL (+0.05 g/L) change in apolipoprotein B. When combining absolute changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B, the estimated hazard ratio for ASCVD was 1.05 (0.96-1.14) in the CGPS mimicking PROMINENT compared to 1.03 (0.91-1.15) in the PROMINENT trial.
Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3 mg/dL (0.08 mmol/L) higher total atherogenic cholesterol together with 5 mg/dL (0.05 g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.
尽管降低了血浆甘油三酯和残余胆固醇，降脂剂 pemafibrate 的心血管结局试验 PROMINENT 却显示出中性结果。我们检验了这样一个假设，即残余胆固醇、LDL 胆固醇和载脂蛋白 B 的绝对质量变化可以解释 PROMINENT 试验的结果。
在哥本哈根普通人群研究（CGPS）的 108431 名个体中，分析符合 PROMINENT 试验关键纳入标准的个体，以模拟试验设计。终点动脉粥样硬化性心血管疾病（ASCVD）是心血管死亡、心肌梗死、缺血性卒中和冠状动脉血运重建，定义与 PROMINENT 相同。
在 PROMINENT 试验中，pemafibrate 治疗导致残余胆固醇降低 -7mg/dL（-0.18mmol/L；-18%），LDL 胆固醇增加 10mg/dL（+0.26mmol/L；+12%），载脂蛋白 B 增加 5mg/dL（+0.05g/L；+5%）。在 CGPS 模拟 PROMINENT 的研究中，ASCVD 的估计风险比为 0.97（95%置信区间：0.94-0.99），残余胆固醇降低-7mg/dL（-0.18mmol/L）；LDL 胆固醇升高 10mg/dL（+0.26mmol/L）的风险比为 1.04（1.01-1.07）；载脂蛋白 B 升高 5mg/dL（+0.05g/L）的风险比为 1.02（1.01-1.03）。当联合残余胆固醇、LDL 胆固醇和载脂蛋白 B 的绝对变化时，CGPS 模拟 PROMINENT 的 ASCVD 估计风险比为 1.05（0.96-1.14），而 PROMINENT 试验的风险比为 1.03（0.91-1.15）。
残余胆固醇、LDL 胆固醇和载脂蛋白 B 的绝对质量变化可以解释 PROMINENT 试验的结果。总致动脉粥样硬化胆固醇升高 3mg/dL（0.08mmol/L）和载脂蛋白 B 升高 5mg/dL（0.05g/L）可能解释了在 pemafibrate 治疗组中 ASCVD 发生率增加的趋势。
