Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a meta-analysis of statin trials

Abstract

Background: Levels of atherogenic lipoproteins achieved with statin therapy are highly variable, but the consequence of this variability for cardiovascular disease risk is not well-documented.

Objectives: The aim of this meta-analysis was to evaluate: 1) the interindividual variability of reductions in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), or apolipoprotein B (apoB) levels achieved with statin therapy; 2) the proportion of patients not reaching guideline-recommended lipid levels on high-dose statin therapy; and 3) the association between very low levels of atherogenic lipoproteins achieved with statin therapy and cardiovascular disease risk.

Methods: This meta-analysis used individual patient data from 8 randomized controlled statin trials, in which conventional lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up.

Results: Among 38,153 patients allocated to statin therapy, a total of 6,286 major cardiovascular events occurred in 5,387 study participants during follow-up. There was large interindividual variability in the reductions of LDL-C, non-HDL-C, and apoB achieved with a fixed statin dose. More than 40% of trial participants assigned to high-dose statin therapy did not reach an LDL-C target <70 mg/dl. Compared with patients who achieved an LDL-C >175 mg/dl, those who reached an LDL-C 75 to <100 mg/dl, 50 to <75 mg/dl, and <50 mg/dl had adjusted hazard ratios for major cardiovascular events of 0.56 (95% confidence interval [CI]: 0.46 to 0.67), 0.51 (95% CI: 0.42 to 0.62), and 0.44 (95% CI: 0.35 to 0.55), respectively. Similar associations were observed for non-HDL-C and apoB.

Conclusions: The reductions of LDL-C, non-HDL-C, and apoB levels achieved with statin therapy displayed large interindividual variation. Among trial participants treated with high-dose statin therapy, >40% did not reach an LDL-C target <70 mg/dl. Patients who achieve very low LDL-C levels have a lower risk for major cardiovascular events than do those achieving moderately low levels.

Keywords: LDL-cholesterol; apolipoprotein B; meta-analysis; non–HDL-cholesterol.

Figure 1. Waterfall plots of percentage LDL-C reduction

Waterfall plots present the distribution of percentage LDL-C reduction (1-year minus baseline divided by baseline levels) achieved in trials. Displayed are typical examples of usual-dose statin therapy (pravastatin 40 mg in the LIPID trial, plot A), high-dose statin therapy (rosuvastatin 20 mg in the JUPITER trial, plot B), a dose increase from usual-dose to high-dose statin (atorvastatin 10 mg to 80 mg in the TNT trial, plot C), and a placebo arm (AFCAPS-TexCAPS trial, plot D). LDL-C indicates low-density lipoprotein cholesterol.

Figure 2. Distribution of achieved levels of LDL-C, non-HDL-C and apoB

Histograms displaying the distribution of achieved levels of LDL-C, non-HDL-C and apoB among patients treated with high-dose statin therapy. The results are based on patients assigned to atorvastatin 80 mg in the TNT, IDEAL, and SPARCL trials, and those assigned to rosuvastatin 20 arm in the JUPITER trial. LDL-C indicates low-density lipoprotein cholesterol, non-HDL-C indicates non-high-density lipoprotein cholesterol, apoB indicates apolipoprotein B.

CENTRAL ILLUSTRATION. On-Statin LDL-C Levels and Risk for Major Cardiovascular Events

Distribution of achieved on-statin LDL-C levels (dark blue curve; right y-axis) and the risk of major cardiovascular events (light blue line; left y-axis). The x-axis represents achieved on-statin LDL-C levels. LDL C = low-density lipoprotein cholesterol; HR = hazard ratio.