Are post-treatment low-density lipoprotein subclass pattern analyses potentially misleading?

Abstract

Background: Some patients administered cholesterol-lowering therapies may experience an increase in the proportion of small LDL particles, which may be misinterpreted as a worsening of atherosclerotic coronary heart disease risk. This study assessed the lipid effects of adding ezetimibe to atorvastatin or doubling the atorvastatin dose on low-density lipoprotein cholesterol (LDL-C) levels (and the cholesterol content of LDL subclasses), LDL particle number (approximated by apolipoprotein B), and LDL particle size. This was a multicenter, double-blind, randomized, parallel-group study of hypercholesterolemic, high atherosclerotic coronary heart disease risk patients. After stabilization of atorvastatin 40 mg, 579 patients with LDL-C >70 mg/dL were randomized to 6 weeks of ezetimibe + atorvastatin 40 mg or atorvastatin 80 mg. Efficacy parameters included changes from baseline in LDL-C, apolipoprotein B, non-high-density lipoprotein cholesterol (non-HDL-C), and lipoprotein subclasses (Vertical Auto Profile II) and pattern for the overall population, as well as patient subgroups with baseline triglyceride levels <150 mg/dL or ≥150 mg/dL.

Results: Both treatments significantly reduced LDL-C (and the cholesterol content of most LDL subfractions [LDL1-4]) apolipoprotein B, non-HDL-C levels, but did not reduce the proportion of smaller, more dense LDL particles; in fact, the proportion of Pattern B was numerically increased. Results were generally similar in patients with triglyceride levels <150 or ≥150 mg/dL.

Conclusions: When assessing the effects of escalating cholesterol-lowering therapy, effects upon Pattern B alone to assess coronary heart disease risk may be misleading when interpreted without considerations of other lipid effects, such as reductions in LDL-C, atherogenic lipoprotein particle concentration, and non-HDL-C levels.

Trial registration: (Registered at clinicaltrials.gov: Clinical trial # NCT00276484).

Figures

Figure 1

Change in LDL subclass pattern in the overall population and by baseline triglyceride levels (<150 or ≥150 mg/dL) in high risk patients treated for 6 weeks with ezetimibe added to atorvastatin 40 mg vs atorvastatin 80 mg. P-values are for between-treatment comparison (Atorva 40 + EZ vs Atorva 80)

Figure 2

Median percent change from baseline and between-treatment differences (A40+EZ minus A80) in cholesterol content of lipoprotein subclasses (LDL-C1-4) after treatment with ezetimibe added to atorvastatin 40 mg vs doubling to atorvastatin 80 mg for 6 weeks in the overall population and in subgroups with baseline triglyceride <150 or ≥150 mg/dL. Numbers below bars in figures B and C represent the between-treatment difference (95% confidence interval). B. Baseline triglycerides <150 mg/dL. C. Baseline triglycerides ≥150 mg/dL.

Figure 3

Mean % change from baseline in apo B after treatment with ezetimibe added to atorvastatin vs doubling the atorvastatin dose for 6 weeks in the overall population and in subgroups with baseline triglycerides (BL TG) <150 or ≥150 mg/dL. Numbers below bars represent the between treatment difference (95% confidence interval) Overall population, A40 + EZ: n = 277; A80: n = 279; Baseline triglycerides <150 mg/dL, A40 +EZ: n = 136; A80: n = 140; Baseline triglycerides ≥150 mg/dL, A40 +EZ: n = 89; A80: n = 82

Figure 4

Mean % change from baseline in non-HDL-C after treatment with ezetimibe added to atorvastatin vs doubling the atorvastatin dose for 6 weeks in the overall population and in subgroups with baseline triglycerides (BL TG) <150 or ≥150 mg/dL. Numbers below bars represent the between treatment difference (95% confidence interval). Overall population, A40 + EZ: n = 225; A80: n = 222; Baseline triglycerides <150 mg/dL, A40 + EZ: n = 136; A80: n = 140; Baseline triglycerides ≥150 mg/dL, A40 + EZ: n = 89; A80: n = 82