Clinical Trial Design for Triglyceride-Rich Lipoprotein-Lowering Therapies: JACC Focus Seminar 3/3.

Triglyceride-rich lipoproteins (TRLs) are a source of residual risk in patients with atherosclerotic cardiovascular disease, and are indirectly correlated with triglyceride (TG) levels. Previous clinical trials studying TG-lowering therapies have either failed to reduce major adverse cardiovascular events or shown no linkage of TG reduction with event reduction, particularly when these agents were tested on a background of statin therapy. Limitations in trial design may explain this lack of efficacy. With the advent of new RNA-silencing therapies in the TG metabolism pathway, there is renewed focus on reducing TRLs for major adverse cardiovascular event reduction. In this context, the pathophysiology of TRLs, pharmacological effects of TRL-lowering therapies, and optimal design of cardiovascular outcomes trials are major considerations.
Competing Interests: Funding Support and Author Disclosures Dr Malick is funded by a training grant from the New York Academy of Medicine. Dr Do has received grants from AstraZeneca; has received grants and nonfinancial support from Goldfinch Bio; is supported by the National Institute of General Medical Sciences of the National Institutes of Health (R35-GM124836) and the National Heart, Lung, and Blood Institute of the National Institutes of Health (R01-HL139865 and R01-HL155915); is a scientific cofounder, consultant, and equity holder for Pensieve Health; and is a consultant for Variant bio, all not related to this work. Dr Koenig has received consulting fees and lecture fees from AstraZeneca, Novartis, and Amgen; has received consulting fees from Pfizer, The Medicines Company, DalCor Pharmaceuticals, Kowa, Corvidia, Therapeutics, OMEICOS, Novo Nordisk, Esperion, LIB Therapeutics, New Amsterdam Pharma, TenSixteen Bio, Genentech, and Daiichi-Sankyo; has received lecture fees from Berlin-Chemie, Bristol Myers Squibb, and Sanofi; and has received grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics, and Dr Beckmann Pharma. Dr Pradhan has received research grants from Kowa Research Europe, Kowa Research Institute, and Denka; has received consulting fees from Optum, Novo Nordisk, and Reliant Medical Foundation; and has received compensation for CME lectures from Medtelligence, PER, and NACE. Dr Stroes has received lecturing/advisory board fees paid to the institution from Amgen, Sanofi, Esperion, Novo Nordisk, Novartis, Merck, Daiichi-Sankyo, Amarin, and Ionis. Dr Rosenson has received grants from Amgen, Arrowhead, Lilly, Novartis and Regeneron; has received consulting fees from Amgen, Arrowhead, CRISPR Therapeutics, Lilly, Lipigon, Novartis, Precision Biosciences, and Verve; has received an honorarium from nonpromotional educational activities from Amgen and Kowa; has received royalties from Wolters Kluwer; has stock holdings in MediMergent, LLC, all not related to this work; and is supported by National Institute of Aging of the National Institutes of Health (5R01-AG061186-04). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
(Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)