Inhibition of microsomal triglyceride transfer protein alone or with ezetimibe in patients with moderate hypercholesterolemia (original) (raw)
- Clinical Research
- Published: 27 May 2008
Nature Clinical Practice Cardiovascular Medicine volume 5, pages 497–505 (2008)Cite this article
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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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Authors and Affiliations
- Division of Cardiovascular Medicine, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Frederick F Samaha - Philadelphia Veterans Affairs Medical Center, Philadelphia, PA, USA
Frederick F Samaha - School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA
James McKenney - Institute for Translational Medicine and Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
LeAnne T Bloedon & Daniel J Rader - Aegerion Pharmaceuticals, Bridgewater, NJ, USA
William J Sasiela
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- Frederick F Samaha
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Corresponding author
Correspondence toFrederick 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
- Received: 12 November 2007
- Accepted: 21 February 2008
- Published: 27 May 2008
- Issue Date: August 2008
- DOI: https://doi.org/10.1038/ncpcardio1250