Remnant cholesterol lowering in cardiovascular disease risk reduction in statin, ezetimibe, and PCSK9 inhibitor trials: meta-regression analyses

AIMS: We tested the hypothesis that remnant cholesterol reduction is associated with part of the cardiovascular risk reduction in statin, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor trials.

METHODS: We included statin, ezetimibe, and PCSK9 inhibitor trials of 1,000 participants or more and lipid level data. Baseline and follow-up low-density lipoprotein (LDL) and remnant cholesterol levels were extracted. LDL and remnant cholesterol reductions were differences between intervention and reference groups at year one. We calculated risk ratios for major adverse cardiovascular events per 1 mmol/L (39 mg/dL) and 1 standard deviation reductions in LDL and remnant cholesterol using meta-regressions.

RESULTS: A total of 43 trials of 327,264 participants with 42,016 major adverse cardiovascular events where included. Remnant cholesterol was reduced 0.19 mmol/L per 1 mmol/L LDL cholesterol reduction, and 11% per 20% LDL cholesterol reduction. Fixed/random effects risk ratios (95% confidence intervals) for major adverse cardiovascular events per 1 mmol/L reductions were 0.84 (0.82-0.85)/0.82 (0.78-0.85) for LDL and 0.36 (0.33-0.40)/0.27 (0.20-0.36) for remnant cholesterol. Corresponding, estimates per 1 standard deviation reductions were 0.93 (0.92-0.93)/0.91 (0.90-0.93) and 0.92 (0.92-0.93)/0.90 (0.88-0.92), respectively. Fixed/random effects risk ratios per 1 mmol/L reductions were 0.88 (0.85-0.91)/0.82 (0.74-0.91) for LDL cholesterol adjusted for remnant cholesterol reductions and 0.74 (0.60-0.92)/0.92 (0.45-1.187) for remnant cholesterol adjusted for LDL cholesterol reductions. Corresponding estimates per 1 standard deviation reductions were 0.94 (0.93-0.96)/0.92 (0.88-0.96) and 0.98 (0.96-0.99)/0.99 (0.94-1.05), respectively.

CONCLUSION: Remnant cholesterol lowering is associated with part of the cardiovascular risk reduction in statin, ezetimibe, and PCSK9 inhibitor trials.