Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia
Open accessAbstract
BACKGROUND: Patients with homozygous familial hypercholesterolemia have markedly elevated cholesterol levels, which respond poorly to drug therapy, and a very high risk of premature cardiovascular disease. Inhibition of the microsomal triglyceride transfer protein may be effective in reducing cholesterol levels in these patients. METHODS: We conducted a dose-escalation study to examine the safety, tolerability, and effects on lipid levels of BMS-201038, an inhibitor of the microsomal triglyceride transfer protein, in six patients with homozygous familial hypercholesterolemia. All lipid-lowering therapies were suspended 4 weeks before treatment. The patients received BMS-201038 at four different doses (0.03, 0.1, 0.3, and 1.0 mg per kilogram of body weight per day), each for 4 weeks, and returned for a final visit after a 4-week drug washout period. Analysis of lipid levels, safety laboratory analyses, and magnetic resonance imaging of the liver for fat content were performed throughout the study. RESULTS: All patients tolerated titration to the highest dose, 1.0 mg per kilogram per day. Treatment at this dose decreased low-density lipoprotein (LDL) cholesterol levels by 50.9% and apolipoprotein B levels by 55.6% from baseline (P<0.001 for both comparisons). Kinetic studies showed a marked reduction in the production of apolipoprotein B. The most serious adverse events were elevation of liver aminotransferase levels and accumulation of hepatic fat, which at the highest dose ranged from less than 10% to more than 40%. CONCLUSIONS: Inhibition of the microsomal triglyceride transfer protein by BMS-201038 resulted in the reduction of LDL cholesterol levels in patients with homozygous familial hypercholesterolemia, owing to reduced production of apolipoprotein B. However, the therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation.
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Early preliminary phase III data suggest a reduction in cardiovascular events in line with the achieved LDL-C reduction.
“Early preliminary data from phase III trials suggests a reduction of CV events in line with the LDL-C reduction achieved [286,290,291].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [286]
In phase II trials, evolocumab lowered triglycerides by 26% and raised HDL-C and ApoA-I by 9% and 4%, respectively, with similar findings for alirocumab.
“In phase II trials, evolocumab lowered TG levels by 26%, and raised HDL-C and ApoA-I by 9 and 4%, respectively; similar findings have been reported for alirocumab [286,287].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [286]
PCSK9 inhibitors also lower triglycerides and increase HDL-C and ApoA-I as a function of dosing regimen.
“These highly efficacious LDL-lowering agents also lower TG levels, and increase those of HDL-C and ApoA-I as a function of the dosing regimen.”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [286]
Several outcome trials of adding a PCSK9 inhibitor to high-intensity statin reported similar proportional reductions in major vascular events in women and men.
“Several outcome trials assessing the effects of adding a PCSK9 inhibitor to high-intensity statin therapy have now been reported, with similar proportional reductions in major vascular events in women and men [120,286,290].”
From 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk (2019) · cites this paper as [286]
In a phase-3 study involving subjects with a high risk for cardiovascular events including those with heterozygous FH, administrating PCSK9 inhibitor once every two weeks decreased LDL-C levels by 70-75% with combination oral statins.
“In a phase-3 study involving subjects with a high risk for cardiovascular events including those with heterozygous FH, administrating PCSK9 inhibitor once every two weeks decreased LDL-C levels by 70–75% with combination oral statins682, 683).”
From Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2017 (2018) · cites this paper as [682]
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“Thus, lomitapide, an oral microsomal triglyceride transfer protein inhibitor, reduces LDL cholesterol by 35 to 50% in subjects with homozygous FH.(84,85) Lomitapide has Food and Drug Administration (FDA) and European Medicines Agency (EMA) approval for the treatment of homozygous FH as an adjunct to diet and drug ther…”
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- Authors
- Cuchel, M., Bloedon, L. T., Szapary, P. O., Kolansky, D. M., Wolfe, M. L., Sarkis, A., Millar, J. S., Ikewaki, K., Siegelman, E. S., Gregg, R. E., & Rader, D. J.
- Affiliations
- University of Pennsylvania (US)
- Saint Joseph University (LB)
- Jikei University School of Medicine (JP)
- Bristol-Myers Squibb (United States) (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2007-01-11
- Volume
- 356
- Issue
- 2
- Pages
- 148-156
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2142526970
- Cited by
- 580
- References
- 21
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 30 · 2023: 19 · 2022: 28 · 2021: 15 · 2020: 21 · 2019: 19 · 2018: 24 · 2017: 21 · 2016: 30 · 2015: 48 · 2014: 61 · 2013: 55 · 2012: 41
- FWCI
- 33.52
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k12rr017625-02)
- National Center for Research Resources (K12-RR-017625, M01-RR-00040, M01RR000040)
- Topics
- Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Keywords
- microsomal triglyceride transfer protein, MTP inhibitors, homozygous familial hypercholesterolemia, LDL cholesterol lowering, apolipoprotein B, hepatic steatosis, dose escalation, lipid-lowering therapy
- MeSH terms
- Adolescent, Adult, Alanine Transaminase, Apolipoproteins B, Benzimidazoles, Carrier Proteins, Combined Modality Therapy, Female, Homozygote, Humans, Hyperlipoproteinemia Type II, Cholesterol, LDL, Liver, Male
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