Remnant cholesterol, LDL cholesterol, and apoB absolute mass changes explain results of the PROMINENT trial
Takahito Doi, Anne Langsted, Børge G. Nordestgaard
Abstract
•Absolute mass changes in remnant cholesterol, LDL cholesterol, and apo B can explain results of the PROMINENT trial. •To reduce ASCVD lipid lowering drugs need to reduce total atherogenic cholesterol and total number of atherogenic particles. •Understanding the potential for causing ASCVD, lipoproteins should be judged by their absolute mass of cholesterol content. Background and aims 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. Methods 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. The endpoint atherosclerotic cardiovascular disease (ASCVD) was cardiovascular death, myocardial infarction, ischemic stroke, and coronary revascularization as defined in PROMINENT. Results In the PROMINENT trial, treatment with pemafibrate resulted in -7mg/dL (-0.18mmol/L;-18%) change in remnant cholesterol, +10mg/dL (+0.26mmol/L;+12%) LDL cholesterol, and +5mg/dL (+0.05g/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 -7mg/dL (-0.18mmol/L) change in remnant cholesterol, 1.04(1.01–1.07) for a +10mg/dL (+0.26mmol/L) change in LDL cholesterol, and 1.02(1.01–1.03) for a +5mg/dL (+0.05g/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. Conclusions Absolute mass changes in remnant cholesterol, LDL cholesterol, and apolipoprotein B can explain results of the PROMINENT trial. The 3mg/dL (0.08mmol/L) higher total atherogenic cholesterol together with 5mg/dL(0.05g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm. 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. The 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 -7mg/dL (-0.18mmol/L;-18%) change in remnant cholesterol, +10mg/dL (+0.26mmol/L;+12%) LDL cholesterol, and +5mg/dL (+0.05g/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 -7mg/dL (-0.18mmol/L) change in remnant cholesterol, 1.04(1.01–1.07) for a +10mg/dL (+0.26mmol/L) change in LDL cholesterol, and 1.02(1.01–1.03) for a +5mg/dL (+0.05g/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 3mg/dL (0.08mmol/L) higher total atherogenic cholesterol together with 5mg/dL(0.05g/L) higher apolipoprotein B seem to explain the trend toward more ASCVD in the pemafibrate arm.