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Cited by 19Lipoproteins and Cardiovascular HealthCholesterol and Lipid MetabolismLipid metabolism and disorders

Oral PCSK9 Inhibitor Enlicitide Versus Oral Nonstatin Therapies

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Catapano, Alberico L., Mikhailova, Elina, Navar, Ann Marie, Banka, Puja, Corral, Pablo, Saxena, Manish, Steg, P. Gabriel, Verma, Subodh +43 more·2026·JACC
DOI 10.1016/j.jacc.2026.03.036
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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 L…

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  • Ezetimibe and bempedoic acid have minimal or no effect on Lp(a), making PCSK9 inhibitors the most efficacious commercially available option for Lp(a) lowering.

    “Nonetheless, other agents such as ezetimibe and bempedoic acid have minimal or no effect on Lp(a), making PCSK9 inhibitors the most efficacious commercially available option for Lp(a) lowering [24]”

    From Oral PCSK9 inhibitors for elevated LDL-C: A systematic review and meta-analysis of randomized trials (2026) · cites this paper as [24]

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Authors
Catapano, A. L., Mikhailova, E., Navar, A. M., Banka, P., Corral, P., Saxena, M., Steg, P. G., Verma, S., Kordahi, A. Y., Mendizabal, G., Zhu, P., Ballantyne, C. M., Wu, C.-C., Hwu, C.-M., Yang, K.-C., Liu, P.-Y., Hung, K.-C., Charriere, S., Cariou, B., Steg, G., Roubille, F., Caspi, O., Moravsky, G., Vishlitzky, V., Katz, A., Cuixart, C. B., Tinahones Madueno, F. J., Lorenzo, N. R., Urquizu-Padilla, M., Belmonte, A. V., Gonzalez, A. S., Nair, D. R., Saxena, M., Srirangalingam, U., Zaidman, C. J., Vottero, E. H., Corral, P., Bays, H. E., Broyles, F. E., Marks, S. M., Khetan, S. K., Matherne, P. G., Shah, A. G., Stumbris, R., Wayne, J. D., Naud, J.-F., Pandey, A. S., Tardif, J.-C., Verma, S., Vyselaar, J., & Ballantyne, C. M.
Affiliations
  • University of Milan (IT)
  • MSD (UK) Limited (United Kingdom) (GB)
  • Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
  • MSD (China) Investment Co., Ltd. (China) (CN)
Corresponding author
Catapano, Alberico L.
ORCID
Venue
JACC
Publisher
Elsevier BV
Published
2026-07
Volume
88
Issue
3
Pages
340-352
ISSN
0735-1097 (ISSN-L)
DOI
10.1016/j.jacc.2026.03.036
OpenAlex
W7143369042
Cited by
19
References
33
Citations by year
2026: 19
FWCI
120.64
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of the American College of Cardiology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Funders
  • Merck & Co Inc
  • Ministero della Salute
  • Istituto di Ricovero e Cura a Carattere Scientifico
Topics
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
PCSK9 inhibitors, LDL cholesterol lowering, bempedoic acid, ezetimibe, non-statin lipid-lowering therapy, apolipoprotein B, non-HDL cholesterol, atherosclerotic cardiovascular disease, statin-treated patients, LDL-C goal attainment, drug safety, adverse events, combination therapy, hypercholesterolemia
MeSH terms
Proprotein Convertase 9, PCSK9 Inhibitors, Administration, Oral, Aged, Anticholesteremic Agents, Dicarboxylic Acids, Double-Blind Method, Fatty Acids, Female, Humans, Cholesterol, LDL, Male, Middle Aged, Treatment Outcome, Hydroxymethylglutaryl-CoA Reductase Inhibitors

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