Effect of Vupanorsen on Non–High-Density Lipoprotein Cholesterol Levels in Statin-Treated Patients With Elevated Cholesterol: TRANSLATE-TIMI 70
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Published:2022-05-03
Issue:18
Volume:145
Page:1377-1386
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ISSN:0009-7322
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Container-title:Circulation
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language:en
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Short-container-title:Circulation
Author:
Bergmark Brian A.1ORCID, Marston Nicholas A.1ORCID, Bramson Candace R.2, Curto Madelyn2, Ramos Vesper2, Jevne Alexandra1, Kuder Julia F.1, Park Jeong-Gun1, Murphy Sabina A.1, Verma Subodh3ORCID, Wojakowski Wojtek4ORCID, Terra Steven G.2, Sabatine Marc S.1ORCID, Wiviott Stephen D.1ORCID, Carbonneau Diane, Poulin-Robitaille Raphael, Wayne Jeffrey, Lee Keung, Mujica Trenche Samuel, Dzongowski Petros, Gaudet Daniel, Van Joanna, Ajani Dilawar, Bays Harold, O’Mahony John, Janas Adam, Scott John, Moustafa Moustafa Ashraf, Ransom Thomas, Benjamin Sabrina, Aggarwal Naresh, Bogdanski Pawel, Friars Douglas, Schlosser Robert, Okopien Boguslaw, Budhraja Madhusudan, Feld Lawrence, Klaff Leslie, Tellier Guy, Mazza Giuseppe, Wierzbicka Iwona, Jazwinska-Tarnawska Ewa, Boccalandro Fernando, Rosenstock Julio, Marquez Elizabeth, Barbel-Johnson Kim, Madziarska Katarzyna, Heaton Kenneth, Tardif Jean-Claude, Rubino John, Trevino Miguel, Moriarty Katie, Gupta Anil, Wojakowski Wojciech, Fidelholtz James, Gupta Dinesh, Alasaad Hani, Christensen Shane, Shah Parag, Li Stephanie, Sherman Mark, Frechette Andre, Arango Cecilia, Egan Alan, Srivastava Sunny, Bajaj Archna, Ince Jr Carlos, Zurakowski Aleksander
Affiliation:
1. TIMI Study Group, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA (B.A.B., N.A.M., A.J., J.F.K., J.-G.P., S.A.M., M.S.S., S.D.W.). 2. Pfizer, Inc, New York, NY (C.R.B., M.C., V.R., S.G.T.). 3. Department of Surgery, University of Toronto, Canada (S.V.). 4. Medical University of Silesia, Katowice, Poland (W.W.).
Abstract
Background:
Genetic loss-of-function variants in
ANGPTL3
are associated with lower levels of plasma lipids. Vupanorsen is a hepatically targeted antisense oligonucleotide that inhibits Angiopoietin-like 3 (ANGPTL3) protein synthesis.
Methods:
Adults with non–high-density lipoprotein cholesterol (non-HDL-C) ≥100 mg/dL and triglycerides 150 to 500 mg/dL on statin therapy were randomized in a double-blind fashion to placebo or 1 of 7 vupanorsen dose regimens (80, 120, or 160 mg SC every 4 weeks, or 60, 80, 120, or 160 mg SC every 2 weeks). The primary end point was placebo-adjusted percentage change from baseline in non–HDL-C at 24 weeks. Secondary end points included placebo-adjusted percentage changes from baseline in triglycerides, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB), and ANGPTL3.
Results:
Two hundred eighty-six subjects were randomized: 44 to placebo and 242 to vupanorsen. The median age was 64 (interquartile range, 58–69) years, 44% were female, the median non–HDL-C was 132.4 (interquartile range, 118.0–154.1) mg/dL, and the median triglycerides were 216.2 (interquartile range, 181.4–270.4) mg/dL. Vupanorsen resulted in significant decreases from baseline over placebo in non–HDL-C ranging from 22.0% in the 60 mg every 2 weeks arm to 27.7% in the 80 mg every 2 weeks arm (all
P
<0.001 for all doses). There were dose-dependent reductions in triglycerides that ranged from 41.3% to 56.8% (all
P
<0.001). The effects on LDL-C and ApoB were more modest (7.9%–16.0% and 6.0%–15.1%, respectively) and without a clear dose-response relationship‚ and only the higher reductions achieved statistical significance. ANGPTL3 levels were decreased in a dose-dependent manner by 69.9% to 95.2% (all
P
<0.001). There were no confirmed instances of significant decline in renal function or platelet count with vupanorsen. Injection site reactions and >3× elevations of alanine aminotransferase or aspartate aminotransferase were more common at higher total monthly doses (up to 33.3% and 44.4%, respectively), and there was a dose-dependent increase in hepatic fat fraction (up to 76%).
Conclusions:
Vupanorsen administered at monthly equivalent doses from 80 to 320 mg significantly reduced non–HDL-C and additional lipid parameters. Injection site reactions and liver enzyme elevations were more frequent at higher doses, and there was a dose-dependent increase in hepatic fat fraction.
Registration:
URL:
https://clinicaltrials.gov
; Unique identifier: NCT04516291.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Physiology (medical),Cardiology and Cardiovascular Medicine
Cited by
117 articles.
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