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Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk

AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceri...

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Autores principales: Tardif, Jean-Claude, Karwatowska-Prokopczuk, Ewa, Amour, Eric St, Ballantyne, Christie M, Shapiro, Michael D, Moriarty, Patrick M, Baum, Seth J, Hurh, Eunju, Bartlett, Victoria J, Kingsbury, Joyce, Figueroa, Amparo L, Alexander, Veronica J, Tami, Joseph, Witztum, Joseph L, Geary, Richard S, O’Dea, Louis St L, Tsimikas, Sotirios, Gaudet, Daniel
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986458/
https://www.ncbi.nlm.nih.gov/pubmed/35025993
http://dx.doi.org/10.1093/eurheartj/ehab820
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author Tardif, Jean-Claude
Karwatowska-Prokopczuk, Ewa
Amour, Eric St
Ballantyne, Christie M
Shapiro, Michael D
Moriarty, Patrick M
Baum, Seth J
Hurh, Eunju
Bartlett, Victoria J
Kingsbury, Joyce
Figueroa, Amparo L
Alexander, Veronica J
Tami, Joseph
Witztum, Joseph L
Geary, Richard S
O’Dea, Louis St L
Tsimikas, Sotirios
Gaudet, Daniel
author_facet Tardif, Jean-Claude
Karwatowska-Prokopczuk, Ewa
Amour, Eric St
Ballantyne, Christie M
Shapiro, Michael D
Moriarty, Patrick M
Baum, Seth J
Hurh, Eunju
Bartlett, Victoria J
Kingsbury, Joyce
Figueroa, Amparo L
Alexander, Veronica J
Tami, Joseph
Witztum, Joseph L
Geary, Richard S
O’Dea, Louis St L
Tsimikas, Sotirios
Gaudet, Daniel
author_sort Tardif, Jean-Claude
collection PubMed
description AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200–500 mg/dL (2.26–5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6–12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222–329) mg/dL [2.96 (2.51–3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. CONCLUSION: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03385239.
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spelling pubmed-89864582022-04-07 Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk Tardif, Jean-Claude Karwatowska-Prokopczuk, Ewa Amour, Eric St Ballantyne, Christie M Shapiro, Michael D Moriarty, Patrick M Baum, Seth J Hurh, Eunju Bartlett, Victoria J Kingsbury, Joyce Figueroa, Amparo L Alexander, Veronica J Tami, Joseph Witztum, Joseph L Geary, Richard S O’Dea, Louis St L Tsimikas, Sotirios Gaudet, Daniel Eur Heart J Clinical Research AIMS: Hypertriglyceridaemia is associated with increased risk of cardiovascular events. This clinical trial evaluated olezarsen, an N-acetyl-galactosamine-conjugated antisense oligonucleotide targeted to hepatic APOC3 mRNA to inhibit apolipoprotein C-III (apoC-III) production, in lowering triglyceride levels in patients at high risk for or with established cardiovascular disease. METHODS AND RESULTS: A randomized, double-blind, placebo-controlled, dose-ranging study was conducted in 114 patients with fasting serum triglycerides 200–500 mg/dL (2.26–5.65 mmol/L). Patients received olezarsen (10 or 50 mg every 4 weeks, 15 mg every 2 weeks, or 10 mg every week) or saline placebo subcutaneously for 6–12 months. The primary endpoint was the percent change in fasting triglyceride levels from baseline to Month 6 of exposure. Baseline median (interquartile range) fasting triglyceride levels were 262 (222–329) mg/dL [2.96 (2.51–3.71) mmol/L]. Treatment with olezarsen resulted in mean percent triglyceride reductions of 23% with 10 mg every 4 weeks, 56% with 15 mg every 2 weeks, 60% with 10 mg every week, and 60% with 50 mg every 4 weeks, compared with increase by 6% for the pooled placebo group (P-values ranged from 0.0042 to <0.0001 compared with placebo). Significant decreases in apoC-III, very low-density lipoprotein cholesterol, non-high-density lipoprotein cholesterol, and apolipoprotein B were also observed. There were no platelet count, liver, or renal function changes in any of the olezarsen groups. The most common adverse event was mild erythema at the injection site. CONCLUSION: Olezarsen significantly reduced apoC-III, triglycerides, and atherogenic lipoproteins in patients with moderate hypertriglyceridaemia and at high risk for or with established cardiovascular disease. TRIAL REGISTRATION NUMBER: NCT03385239. Oxford University Press 2022-01-13 /pmc/articles/PMC8986458/ /pubmed/35025993 http://dx.doi.org/10.1093/eurheartj/ehab820 Text en © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Clinical Research
Tardif, Jean-Claude
Karwatowska-Prokopczuk, Ewa
Amour, Eric St
Ballantyne, Christie M
Shapiro, Michael D
Moriarty, Patrick M
Baum, Seth J
Hurh, Eunju
Bartlett, Victoria J
Kingsbury, Joyce
Figueroa, Amparo L
Alexander, Veronica J
Tami, Joseph
Witztum, Joseph L
Geary, Richard S
O’Dea, Louis St L
Tsimikas, Sotirios
Gaudet, Daniel
Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title_full Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title_fullStr Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title_full_unstemmed Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title_short Apolipoprotein C-III reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
title_sort apolipoprotein c-iii reduction in subjects with moderate hypertriglyceridaemia and at high cardiovascular risk
topic Clinical Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8986458/
https://www.ncbi.nlm.nih.gov/pubmed/35025993
http://dx.doi.org/10.1093/eurheartj/ehab820
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