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Clinical Trial
. 2026 Jan 13;335(2):129-139.
doi: 10.1001/jama.2025.20620.

Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial

Christie M Ballantyne  1 , Laura Gellis  2 , Jean-Claude Tardif  3 , Puja Banka  2 , Ann Marie Navar  4 , Emil Andreas Asprusten  5 , Russell Scott  6 , Erik S G Stroes  7 , Samar Froman  2 , Geraldine Mendizabal  8 , Fan Wang  9 , Alberico L Catapano  10   11
Affiliations
Clinical Trial

Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial

Christie M Ballantyne et al. JAMA. .

Abstract

Importance: Persons with heterozygous familial hypercholesterolemia (HeFH) are at increased risk of atherosclerotic cardiovascular disease due to lifelong elevated levels of low-density lipoprotein cholesterol (LDL-C). Many patients with HeFH do not achieve guideline-recommended LDL-C goals with the currently available lipid-lowering therapies.

Objective: To evaluate the efficacy of enlicitide decanoate (an oral proprotein convertase subtilisin/kexin type 9 inhibitor) vs placebo in adults with HeFH requiring further lowering of LDL-C levels despite use of statin therapy.

Design, setting, and participants: This phase 3, randomized clinical trial included persons aged 18 years or older with HeFH currently using lipid-lowering therapy (taking at least a moderate- or high-intensity statin) and either an LDL-C level of 55 mg/dL or greater and a history of major atherosclerotic cardiovascular disease or an LDL-C level of 70 mg/dL or greater without a history of major atherosclerotic cardiovascular disease. The trial was conducted at 59 sites across 17 countries; the first participant was screened on August 8, 2023, and the last follow-up visit occurred on April 7, 2025.

Interventions: Participants were randomized (2:1) to 20 mg of enlicitide (n = 202) or placebo (n = 101) once daily for 52 weeks.

Main outcomes and measures: The primary outcome was the mean percentage change in LDL-C level at week 24. The secondary outcomes included the mean percentage change in LDL-C level at week 52, the mean percentage change at week 24 in levels of non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein B, and the median percentage change at week 24 in lipoprotein(a).

Results: Of the 303 participants (mean age, 52.4 [SD, 13.5] years; 51% were female) randomized, 293 (96.7%) completed the trial. The mean LDL-C level was 119.0 mg/dL (SD, 41.0 mg/dL) at baseline, all had statin current use (81.5% were taking a high-intensity statin), and 64.4% were taking ezetimibe. The mean percentage change in LDL-C level at week 24 was -58.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, -59.4% [95% CI, -65.6% to -53.2%]; P < .001). The mean percentage change in LDL-C level at week 52 was -55.3% in the enlicitide group vs 8.7% in the placebo group (between-group difference, -61.5% [95% CI, -69.4% to -53.7%]; P < .001). At week 24, the mean percentage change in non-HDL-C level was -52.3% in the enlicitide group vs 2.1% in the placebo group (between-group difference, -53.0% [95% CI, -58.5% to -47.4%]; P < .001), the mean percentage change in apolipoprotein B level was -48.2% vs 1.8%, respectively (between-group difference, -49.1% [95% CI, -54.0% to -44.3%]; P < .001), and the median percentage change in lipoprotein(a) level was -24.7% vs -1.6% (between-group difference, -27.5% [95% CI, -34.3% to -20.6%]; P < .001). The incidence of adverse events, serious adverse events, and study discontinuation due to adverse events was similar between groups.

Conclusions: Among adults with HeFH, treatment with enlicitide was well tolerated and significantly reduced levels of LDL-C, apolipoprotein B, non-HDL-C, and lipoprotein(a).

Trial registration: ClinicalTrials.gov Identifier: NCT05952869.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ballantyne reported receiving institutional grants from Abbott Diagnostic, the American Diabetes Association, the American Heart Association, Akcea Therapeutics, Amgen, Arrowhead, Eli Lilly, Ionis, Merck, the National Institutes of Health, NewAmsterdam Pharma, Novartis, Novo Nordisk, and Roche Diagnostic and receiving personal fees from 89Bio, Abbott Diagnostics, Amgen, Arrowhead, AstraZeneca, Denka Seiken, Esperion, Genentech, Heartflow, Ionis, Eli Lilly, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk, and Roche Diagnostic. Drs Gellis, Banka, Mendizabal, and Wang and Ms Froman reported being employees of Merck Sharp & Dohme, LLC, a subsidiary of Merck & Co, Inc and may own stock and/or hold stock options in Merck & Co. Dr Tardif reported receiving grants from Boehringer-Ingelheim, Ceapro, DalCor Pharmaceuticals, Merck, Novartis, Novo-Nordisk, Pfizer, and Verve Therapeutics; receiving personal fees from DalCor Pharmaceuticals, Merck, and Pfizer; having a minor equity interest in DalCor Pharmaceuticals; and having a patent on pharmacogenomics-guided cholesteryl ester transfer protein inhibition licensed to DalCor Pharmaceuticals and a patent pending with the Montreal Heart Institute (Institut de Cardiologie de Montreal) on the use of colchicine after myocardial infarction. Dr Navar reported receiving institutional grants from Amgen, Esperion, and Merck and receiving personal fees from the American Medical Association (for serving as a Deputy Editor of JAMA Cardiology), Amgen, Arrowhead, Bayer, Esperion, Janssen, Eli Lilly, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk, Pfizer, Roche, and Silence Therapeutics. Dr Stroes reported receiving personal fees (paid to his institution) and institutional grants from Amgen, Ionis, Merck, Novartis, Novo Nordisk, and Ultragenyx. Dr Catapano reported receiving grants from Viatris, Ultragenyx, Chiesi, and Amarin and receiving personal fees from Amarin, Amgen, AstraZeneca, Chiesi, Daiichi Sankyo, Eli Lilly, Esperion, Ionis Pharmaceutical, Medscape, Menarini, Merck Sharp & Dohme, NewAmsterdam Pharma, Novartis, Novo Nordisk, Regeneron, Recordati, Sanofi, Ultragenyx, and Viatris. No other disclosures were reported.

Comment in

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