Time-averaged low-density lipoprotein cholesterol lowering with evolocumab: Pooled analysis of phase 2 trials

Abstract

LDL-C is the pivotal risk factor for atherosclerotic cardiovascular disease, and the benefit from LDL-C lowering is proportional to the magnitude of reduction. Clinical trials demonstrate that evolocumab reduces LDL-C levels by approximately 60% when measured at the trough of drug effect, which may underestimate cumulative LDL-C reduction. We obtained a time-averaged estimate of LDL-C lowering that included both peaks and troughs. Pooled analysis of 5 phase 2 trials included patients with hypercholesterolemia who received placebo or evolocumab (140 mg every 2 weeks [Q2W] or 420 mg monthly [QM]). Percent changes from baseline LDL-C and free serum PCSK9 were averaged across weeks 9-12. In 372 patients, time-averaged percent reduction from baseline in LDL-C with evolocumab vs placebo was 67.6% (95% CI: 63.9-71.3) with Q2W dosing and 65.0% (95% CI: 60.7-69.3) with QM dosing. The time-averaged measure yielded LDL-C reductions for evolocumab that exceeded measurements at the end of dosing intervals and may provide a better estimate of cardiovascular benefit during long-term therapy.

Keywords: Cardiovascular risk reduction; Evolocumab; Hypercholesterolemia; Lipid lowering; Methods; PCSK9 inhibitor.

Conflict of interest statement

Declaration of Competing Interest BS, HW, and MLM are employees of Amgen Inc. and may own Amgen stock. RPG reports clinical trials/research support from Amgen, Anthos Therapeutics, Daiichi-Sankyo, and Ionis; honoraria for lectures/continuing medical education programs from Amgen, Centrix, Daiichi-Sankyo, Dr. Reddy's Laboratories, Medical Education Resources (MER), Medscape, Menarini, Merck, Pfizer, SAJA Pharmaceuticals, Servier, Shanghai Medical Telescope, and Voxmedia; and consulting for Amarin, Amgen, CryoLife, CSL Behring, CVS Caremark, Daiichi-Sankyo, Esperion, Gilead, Hengrui, Inari, Janssen, Novartis, Pfizer, PhaseBio Pharmaceuticals, St. Lukes, and Samsung. MSS reports research grant support through Brigham and Women's Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Bayer, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; and consulting for Althera, Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Bristol-Myers Squibb, DalCor, Dr. Reddy's Laboratories, FibroGen, IFM Therapeutics, Intarcia, Merck, Moderna, Novo Nordisk, and Silence Therapeutics. FJR reports personal fees from Amgen, Sanofi-Aventis, Regeneron, and Novartis (outside the submitted work). TT reports grants from Bayer and Astellas (outside the submitted work). MJK is employed by Jacksonville Center for Clinical Research, a company that has received research funds and consulting fees from Amgen, Pfizer, Regeneron, Sanofi, and The Medicines Company. He is also an unpaid member of the Northeast Florida AHA Board. EAS has received fees for consulting from Gemphire, CymaBay, and AstraZeneca; has received expert witness fees from Amgen; and is a founder and CEO of LIB Therapeutics.

Copyright © 2022. Published by Elsevier Inc.