Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies
Journal
Journal of the American College of Cardiology
ISSN
0735-1097
Date Issued
2026-03
Author(s)
Catapano, Alberico L.
Mikhailova, Elina
Navar, Ann Marie
Banka, Puja
Corral, Pablo
Saxena, Manish
Steg, P. Gabriel
Verma, Subodh
Kordahi, Andrew Yacoub
Mendizabal, Geraldine
Zhu, Pengfei
Ballantyne, Christie M.
Hwu, Chii-Min
Yang, Kai-Chien
Liu, Ping-Yen
Hung, Kuo-Chun
Charriere, Sybil
Cariou, Bertrand
Steg, Gabriel
Roubille, Francois
Caspi, Oren
Moravsky, Gil
Vishlitzky, Victor
Katz, Amos
Cuixart, Carlos Brotons
Tinahones Madueno, Francisco Jose
Lorenzo, Nuria Rial
Urquizu-Padilla, Maria
Belmonte, Alex Vila
Gonzalez, Alfonso Soto
Nair, Devaki R.
Saxena, Manish
Srirangalingam, Umasuthan
Zaidman, Cesar Javier
Vottero, Ezequiel Hector
Corral, Pablo
Bays, Harold E.
Broyles, Frances Eileen
Marks, Sheryl M.
Khetan, Shishir Kumar
Matherne, Paul Gerard
Shah, Amit G.
Stumbris, Ronald
Wayne, Jeffrey D.
Naud, Jean-francois
Pandey, A. Shekhar
Tardif, Jean-Claude
Verma, Subodh
Vyselaar, John
Ballantyne, Christie M.
Abstract
Background: Many adults fail to achieve guideline-directed low-density lipoprotein cholesterol (LDL-C) goals on statin monotherapy, requiring additional nonstatin lipid-lowering medication. Enlicitide, an oral proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitor, lowered LDL-C by 60% compared with placebo; its efficacy compared with other oral nonstatin therapies has yet to be examined.
Objectives: This study assessed the efficacy of enlicitide, a novel oral PCSK9 inhibitor, vs other oral nonstatin therapies.
Methods: In this phase 3, randomized, double-blind, active-comparator trial, statin-treated adults aged ≥18 years with LDL-C ≥55 mg/dL and a previous major atherosclerotic cardiovascular disease (ASCVD) event, or LDL-C ≥70 mg/dL if at intermediate to high risk for a first event, were randomized in 2:1:1:2 fashion to 20 mg enlicitide (n = 101), 180 mg bempedoic acid (n = 50), 10 mg ezetimibe (n = 50), or 180 mg bempedoic acid plus 10 mg ezetimibe (n = 100) once daily for 56 days. The primary endpoint was mean percentage change in LDL-C from baseline to day 56; secondary endpoints included mean percentage changes in apolipoprotein B (ApoB) and non-high-density lipoprotein cholesterol (nonHDL-C). Safety endpoints included overall adverse events (AEs) and discontinuations due to AEs.
Results: Among 301 randomized participants (mean age 64.4 years, 37% female, 98% receiving moderate- to high-intensity statin), 298 (99.0%) completed the trial. The mean percentage change in LDL-C from baseline to day 56 was -64.6% (95% CI: -68.3% to -60.9%) with enlicitide, -6.3% (95% CI: -13.5% to 0.8%) with bempedoic acid, -27.8% (95% CI: -32.3% to -23.4%) with ezetimibe, and -36.5% (95% CI: -40.8% to -32.2%) with bempedoic acid plus ezetimibe; enlicitide was superior to each comparator (all P < 0.001). Reductions in ApoB and nonHDL-C were also greater with enlicitide (all P < 0.001). Proportions of participants with AEs and discontinuations due to AEs were similar across treatment arms.
Conclusions: In statin-treated adults with a history of a major ASCVD event or at increased risk for a first event, enlicitide achieved greater reductions in LDL-C, ApoB, and nonHDL-C than other oral nonstatin therapies, demonstrating its potential role as an important add-on option when LDL-C goals are not met with the use of statins alone. (A Study to Evaluate the Efficacy and Safety of Enlicitide Decanoate [MK-0616, Oral PCSK9 Inhibitor] Compared With Ezetimibe or Bempedoic Acid or Ezetimibe and Bempedoic Acid in Adults With Hypercholesterolemia [MK-0616-018] [CORALreef AddOn; NCT06450366).
Subjects
PCSK9
apolipoprotein B
atherosclerotic cardiovascular disease
enlicitide
low-density lipoprotein cholesterol
non–high-density lipoprotein cholesterol
Publisher
Elsevier BV
Type
journal article