Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia

Maartje E Visser,Fatima Akdim,Diane L Tribble,Aart J Nederveen,T Jesse Kwoh,John J.P Kastelein,Mieke D Trip,Erik S.G Stroes

doi:10.1194/jlr.m002915

Abstract

To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intra-hepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). Subjects received a weekly subcutaneous dose of 200 mg mipomersen or placebo for 13 weeks while continuing conventional lipid lowering therapy. The primary endpoint was change in IHTG content from week 0 to week 15 as measured by localized proton magnetic resonance spectroscopy (1H-MRS). Thirteen weeks of mipomersen administration reduced LDL-cholesterol by 22.0 (17.8) % and apoB by 19.9 (17.4) % (both P < 0.01). One of 10 patients (10%) in the mipomersen-treated group developed mild hepatic steatosis at week 15, which was reversible following mipomersen discontinuation. For the group, there was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change -0.1 (0.9). Mipomersen; baseline: 1.2% and week 15: 2.1%; change 0.8 (1.7) (P = 0.0513)]. Mipomersen administration for 13 weeks to subjects with FH is associated with a trend toward an increase in IHTG content. Future studies evaluating the effects of long-term use of mipomersen reaching more profound reductions in apoB are required prior to broader use of this compound.

Highlights

To investigate the impact of mipomersen, an apolipoprotein B-100 synthesis inhibitor, on intrahepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH)
ApoB synthesis inhibition has been put forward as a potentially valuable approach to achieve target levels for LDL-cholesterol in subjects with heterozygous familial hypercholesterolemia (FH), who are characterized by profoundly elevated baseline cholesterol levels and are unable to achieve target levels with conventional lipid lowering therapy [3, 4]
Inhibition of microsomal triglyceride transfer protein (MTP), which is involved in VLDL synthesis downstream of apolipoprotein B-100 (apoB), has been shown to result in hepatic steatosis in both experimental animals and humans [7, 8]

Summary

Introduction

To investigate the impact of mipomersen, an apolipoprotein B-100 (apoB) synthesis inhibitor, on intrahepatic triglyceride content (IHTG content), we conducted a randomized, double-blind, placebo-controlled study in 21 patients with familial hypercholesterolemia (FH). There was a trend toward an increase in IHTG content [placebo; baseline: 1.2% and week 15: 1.1%; change ؊0.1 (0.9). Effect of apolipoprotein-B synthesis inhibition on liver triglyceride content in patients with familial hypercholesterolemia. ApoB synthesis inhibition has been put forward as a potentially valuable approach to achieve target levels for LDL-cholesterol in subjects with heterozygous familial hypercholesterolemia (FH), who are characterized by profoundly elevated baseline cholesterol levels and are unable to achieve target levels with conventional lipid lowering therapy [3, 4]. Inhibition of microsomal triglyceride transfer protein (MTP), which is involved in VLDL synthesis downstream of apoB, has been shown to result in hepatic steatosis in both experimental animals and humans [7, 8]. ApoB is the main structural component of all atherogenic lipid particles and is obligatory for the secretion of

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