Baseline cholesterol absorption and the response to ezetimibe/simvastatin therapy: a post-hoc analysis of the ENHANCE trial

L Jakulj,M.N Vissers,A.K Groen,B.A Hutten,D Lutjohann,E.P Veltri,J.J.P Kastelein

doi:10.1194/jlr.m001487

Abstract

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDL-cholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). In a posthoc analysis of the two-year ENHANCE trial, we assessed baseline cholesterol-adjusted campesterol (campesterol/TC) and sitosterol/TC ratios in 591 FH patients. Associations with LDL-C changes and changes in cholesterol absorption markers were evaluated by multiple regression analysis. No association was observed between baseline markers of cholesterol absorption and the extent of LDL-C response to ezetimibe/simvastatin therapy (beta = 0.020, P = 0.587 for campesterol/TC and beta<0.001, P = 0.992 for sitosterol/TC). Ezetimibe/simvastatin treatment reduced campesterol levels by 68% and sitosterol levels by 62%; reductions were most pronounced in subjects with the highest cholesterol absorption markers at baseline, the so-called high absorbers (P < 0.001). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. Hence, these data do not support the use of baseline absorption markers as a tool to determine optimal cholesterol lowering strategy in FH patients. However, due to the exploratory nature of any posthoc analysis, these results warrant further prospective evaluation in different populations.

Highlights

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor
Our primary objective was to evaluate whether familial hypercholesterolemia (FH) patients with high baseline absorption markers show stronger LDLC reductions after ezetimibe/simvastatin therapy compared with patients with low baseline absorption markers
We found that low absorbers show more pronounced increases in campesterol/total cholesterol (TC) and sitosterol/TC ratios after simvastatin therapy compared with high absorbers (P < 0.001, Table 3)

Summary

Introduction

Subjects with increased cholesterol absorption might benefit more from statin therapy combined with a cholesterol absorption inhibitor. We assessed whether baseline cholesterol absorption markers were associated with response to ezetimibe/simvastatin therapy, in terms of LDLcholesterol (LDL-C) lowering and cholesterol absorption inhibition, in patients with familial hypercholesterolemia (FH). Baseline cholesterol absorption status does not determine LDL-C lowering response to ezetimibe/simvastatin therapy in FH, despite more pronounced cholesterol absorption inhibition in high absorbers. No markers of basal absorption or synthesis were measured To address this issue, we performed a posthoc analysis of the ENHANCE trial, in which a population of heterozygous FH patients was treated with either ezetimibe/simvastatin combination therapy or simvastatin alone for a period of 2 years [15]. We investigated whether subjects with high baseline synthesis markers showed more pronounced LDL-C reductions after simvastatin therapy when compared with low synthesizers. We assessed whether changes in absorption and synthesis markers after treatment with ezetimibe/simvastatin and simvastatin alone differed between patients with different baseline levels of cholesterol absorption and synthesis

Methods

Results

Conclusion