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Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia

Nature Clinical Practice Cardiovascular Medicine volume 5, pages 497–505 (2008)Cite this article

Abstract

Background Many patients with coronary heart disease do not achieve recommended LDL-cholesterol levels, due to either intolerance or inadequate response to available lipid-lowering therapy. Microsomal triglyceride transfer protein (MTP) inhibitors might provide an alternative way to lower LDL-cholesterol levels. We tested the safety and LDL-cholesterol-lowering efficacy of an MTP inhibitor, AEGR-733 (Aegerion Pharmaceuticals Inc., Bridgewater, NJ), alone and in combination with ezetimibe.

Methods We performed a multicenter, double-blind, 12-week trial, which included 84 patients with hypercholesterolemia. Patients were randomly assigned ezetimibe 10 mg daily (n = 29); AEGR-733 5.0 mg daily for the first 4 weeks, 7.5 mg daily for the second 4 weeks and 10 mg daily for the last 4 weeks (n = 28); or ezetimibe 10 mg daily and AEGR-733 administered with the dose titration described above (n = 28).

Results Ezetimibe monotherapy led to a 20–22% decrease in LDL-cholesterol concentrations. AEGR-733 monotherapy led to a dose-dependent decrease in LDL-cholesterol concentration: 19% at 5.0 mg, 26% at 7.5 mg and 30% at 10 mg. Combined therapy produced similar but larger dose-dependent decreases (35%, 38% and 46%, respectively). The number of patients who discontinued study drugs owing to adverse events was five with ezetimibe alone, nine with AEGR-733 alone, and four with combined ezetimibe and AEGR-733. Discontinuations from AEGR-733 were due primarily to mild transaminase elevations.

Conclusions Inhibition of LDL production with low-dose AEGR-733, either alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL-cholesterol levels.

Key Points

  • Many patients with coronary heart disease cannot achieve current target levels for LDL-cholesterol owing to either intolerance or inadequate response to conventional lipid-lowering therapy; new treatment strategies are required

  • A possible therapeutic approach is inhibition of microsomal triglyceride transfer protein, which is essential for the assembly and secretion of apolipoprotein-B-containing lipoproteins

  • AEGR-733, alone and in combination with ezetimibe, had notable LDL-cholesterol-lowering effects in patients with hyperlipidemia

  • The main side effect associated with AEGR-733 was elevation in transaminase concentrations, which returned to baseline values after cessation of therapy; gastrointestinal side effects were minor

  • Low-dose microsomal triglyceride transfer protein inhibitors, alone or in combination with ezetimibe, could be an effective therapeutic option for patients unable to reach target LDL levels with conventional therapy

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Figure 1: Study profile.
Figure 2: Percentage change from baseline in LDL-cholesterol levels at each of the study visits, by treatment group.

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Author information

Authors and Affiliations

  1. Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Frederick F Samaha

  2. Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA

    Frederick F Samaha

  3. School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA

    James McKenney

  4. Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    LeAnne T Bloedon & Daniel J Rader

  5. Aegerion Pharmaceuticals, Bridgewater, NJ, USA

    William J Sasiela

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  1. Frederick F Samaha
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  4. William J Sasiela
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  5. Daniel J Rader
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Corresponding author

Correspondence to Frederick F Samaha.

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Competing interests

This study was funded by Aegerion Inc.

FF Samaha Samaha is funded by Abbott laboratories, Aegerion Inc., and Merck Inc.

J McKenney provides consulting services for Abbott Laboratories, Aegerion Inc., AstraZeneca, Daiichi Sankyo and Merck Inc.

WJ Sasiela is an employee of Aegerion Inc.

DJ Rader is a stockholder and member of the scientific advisory board in Aegerion Inc.

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Samaha, F., McKenney, J., Bloedon, L. et al. Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia. Nat Rev Cardiol 5, 497–505 (2008). https://doi.org/10.1038/ncpcardio1250

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