{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T16:14:26Z","timestamp":1792599266675,"version":"4.5.0"},"reference-count":39,"publisher":"American Medical Association (AMA)","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA"],"published-print":{"date-parts":[[2026,1,13]]},"abstract":"\n Importance<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Design, Setting, and Participants<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Interventions<\/jats:title>\n Participants were randomized (2:1) to 20 mg of enlicitide (n\u2009=\u2009202) or placebo (n\u2009=\u2009101) once daily for 52 weeks.<\/jats:p>\n <\/jats:sec>\n \n Main Outcomes and Measures<\/jats:title>\n 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\u2013high-density lipoprotein cholesterol (non\u2013HDL-C) and apolipoprotein B, and the median percentage change at week 24 in lipoprotein(a).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n 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 \u221258.2% in the enlicitide group vs 2.6% in the placebo group (between-group difference, \u221259.4% [95% CI, \u221265.6% to \u221253.2%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). The mean percentage change in LDL-C level at week 52 was \u221255.3% in the enlicitide group vs 8.7% in the placebo group (between-group difference, \u221261.5% [95% CI, \u221269.4% to \u221253.7%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). At week 24, the mean percentage change in non\u2013HDL-C level was \u221252.3% in the enlicitide group vs 2.1% in the placebo group (between-group difference, \u221253.0% [95% CI, \u221258.5% to \u221247.4%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), the mean percentage change in apolipoprotein B level was \u221248.2% vs 1.8%, respectively (between-group difference, \u221249.1% [95% CI, \u221254.0% to \u221244.3%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001), and the median percentage change in lipoprotein(a) level was \u221224.7% vs \u22121.6% (between-group difference, \u221227.5% [95% CI, \u221234.3% to \u221220.6%];\n P<\/jats:italic>\n \u2009&amp;lt;\u2009.001). The incidence of adverse events, serious adverse events, and study discontinuation due to adverse events was similar between groups.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Among adults with HeFH, treatment with enlicitide was well tolerated and significantly reduced levels of LDL-C, apolipoprotein B, non\u2013HDL-C, and lipoprotein(a).<\/jats:p>\n <\/jats:sec>\n \n Trial Registration<\/jats:title>\n \n ClinicalTrials.gov Identifier:\n NCT05952869<\/jats:ext-link>\n <\/jats:p>\n <\/jats:sec>","DOI":"10.1001\/jama.2025.20620","type":"journal-article","created":{"date-parts":[[2025,11,9]],"date-time":"2025-11-09T22:30:22Z","timestamp":1762727422000},"page":"129","source":"Crossref","is-referenced-by-count":73,"title":["Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia"],"prefix":"10.1001","volume":"335","author":[{"given":"Christie M.","family":"Ballantyne","sequence":"first","affiliation":[{"name":"Texas Heart Institute, Baylor College of Medicine, Houston, Texas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Gellis","sequence":"additional","affiliation":[{"name":"Merck & Co, Inc, Rahway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"Tardif","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute, Universit\u00e9 de Montr\u00e9al, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puja","family":"Banka","sequence":"additional","affiliation":[{"name":"Merck & Co, Inc, Rahway, New Jersey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann Marie","family":"Navar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emil Andreas","family":"Asprusten","sequence":"additional","affiliation":[{"name":"Lipid Clinic, Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Scott","sequence":"additional","affiliation":[{"name":"NZ Clinical Research, Christchurch, New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik S. 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