Remnant cholesterol lowering in cardiovascular disease risk reduction in statin trials: meta-regression analyses

Abstract Background Remnant cholesterol is a causal risk factor for cardiovascular disease. Purpose We tested the hypothesis that remnant cholesterol reduction explains part of the cardiovascular disease risk reduction in statin trials. Methods We included statin trials with >1,000 participants and available data on lipid levels. 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. Risk ratios for any statin use and per 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were estimated using meta-regressions. Results We included 29 statin trials with 191,202 participants and 26,639 major cardiovascular events. On an absolute scale when LDL cholesterol was reduced 1 mmol/L (39 mg/dL), remnant cholesterol was reduced 0.17 mmol/L (7 mg/dL) (Figure 1). On a relative scale when LDL cholesterol was reduced 20%, remnant cholesterol was reduced 12%. The risk ratio for statin use versus reference was 0.82 (95% confidence interval: 0.81-0.84) for major cardiovascular events (Figure 2). Risk ratios per 1 mmol/L (39 mg/dL) reductions were 0.82 (0.80-0.83) for LDL cholesterol and 0.37 (0.33-0.41) for remnant cholesterol for major cardiovascular events. Corresponding risk ratios for 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were 0.78 (0.75-0.80) and 0.30 (0.25-0.35) for coronary events, 0.86 (0.82 -0.90) and 0.48 (0.38-0.61) for stroke, and 0.93 (0.91-0.95) and 0.71 (0.62-0.80) for any death, respectively. Conclusions Remnant cholesterol lowering likely explain part of the cardiovascular disease risk reduction in statin trials. Figure 1. Remnant cholesterol reduction as a function of LDL cholesterol reduction. Regressions were calculated using inverse-variance weighted unadjusted linear regressions. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. R-C = Remnant cholesterol. ∆ = change from baseline to 1 year follow-up. Figure 2. RR for MACE for statin use and cholesterol reductions. Risk ratios were calculated using fixed and random effects inverse-variance weighted meta-regressions. CI = confidence interval. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. MACE = major cardiovascular events. R-C = remnant cholesterol. RR = risk ratio.Figure 1Figure 2