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

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.

Trial registration: ClinicalTrials.gov NCT00362180.

Figures

Fig. 1.

IHTG content (A) en ALT (B) in time for the placebo treatment group. Dotted line represents ULN = 5.6% for IHTG content. ALT, alanine aminotransferase; IHTG, intra-hepatic triglyceride content; ULN, upper limit of normal.

Fig. 2.

IHTG content (A) and ALT (B) in time for mipomersen treatment group. Dotted line represents ULN = 5.6% for IHTG content. ALT, alanine aminotransferase; IHTG, intra-hepatic triglyceride content; ULN, upper limit of normal.

Fig. 3.

IHTG content in time for FHBL subjects and both placebo and mipomersen treatment groups. ULN = 5.6% for IHTG content. Closed circles represent FHBL subjects. Closed squares represent treatment group. FHBL, familial hypobetalipoproteinemia; IHTG, intra-hepatic triglyceride content; ULN, upper limit of normal.