2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T530,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.31:Tc3d,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. 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. 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. Participants were randomized (2:1) to 20 mg of enlicitide (n = 202) or placebo (n = 101) once daily for 52 weeks. 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). 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. 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). ClinicalTrials.gov Identifier: NCT05952869.32:T1416, 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 &lt; .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 &lt; .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 &lt; .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 &lt; .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 &lt; .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 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Heterozygous Familial Hypercholesterolemia: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Heterozygous Familial Hypercholesterolemia (condition). Clinician-written summaries and actionable practice insights. 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Patients with Lp(a) ≥150 nmol/L had a similar absolute reduction (−32.3 nmol/L) despite a lower percentage reduction. LDL-C fell by 37.0% (−35 mg/dL) and apoB by 21.3% (−20 mg/dL).","limitations":"- 12-week follow-up only; long-term Lp(a)-lowering durability and cardiovascular outcome impact are unknown.\n- Pooled analysis design limits causal inference compared to a prospectively powered single trial.\n- Median baseline Lp(a) of 42.9 nmol/L is relatively low, meaning many patients had modest absolute reductions.","practice_takeaway":"Obicetrapib lowers Lp(a), LDL-C, and apoB simultaneously, with clinically meaningful absolute Lp(a) reductions even in patients with mildly elevated levels (≥50–<150 nmol/L) who would not qualify for RNA-targeted therapies. Clinicians managing high-risk patients with moderately elevated Lp(a) may consider obicetrapib as a multi-lipid-lowering option pending longer-term outcomes data."}},{"doi":"10.1056/nejmoa2601283","pmid":"42187087","title":"In Vivo Base Editing of\n PCSK9\n with VERVE-102 for Hypercholesterolemia","journal_title":"New England Journal of Medicine","journal_issn":"0028-4793","published_at":"2026-05-25T00:00:00.000Z","url":"https://doi.org/10.1056/nejmoa2601283","source_score":607,"is_retracted":false,"is_open_access":false,"raw_metadata":{"pubmed":true,"crossref":true,"unpaywall":true},"created_at":"2026-05-29T13:23:18.224Z","updated_at":"2026-05-29T13:23:18.224Z","tags":[{"paper_doi":"10.1056/nejmoa2601283","tag_type":"age_group","value":"adult","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"brand","value":"VERVE-102","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"category","value":"Medicine, General & Internal","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"condition","value":"Heterozygous Familial Hypercholesterolemia","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"condition","value":"Hypercholesterolemia","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"condition","value":"Premature Coronary Artery Disease","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"generic","value":"PCSK9 adenine base editor (VERVE-102)","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"impact_flag","value":"practice_changing","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"level_of_evidence","value":"3","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"modality","value":"Base Editing Gene Therapy","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"modality","value":"Lipid Nanoparticle","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"sample_size","value":"n=35","value_numeric":35},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"study_design","value":"Phase 1 Clinical Trial","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"warning","value":"Follow-up duration varied widely across participants; only 15 of 35 had ≥1 year of follow-up, limiting durability conclusions.","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"warning","value":"One serious adverse event (aspiration pneumonitis) was noted in a participant with GERD; causality relative to infusion procedure vs. underlying disease is not clearly adjudicated in the abstract.","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"warning","value":"The 'practice_changing' impact flag reflects the novelty and magnitude of effect, but this is Phase 1 data only — efficacy and safety confirmation from larger trials is needed before clinical use.","value_numeric":null},{"paper_doi":"10.1056/nejmoa2601283","tag_type":"warning","value":"VERVE-102 has no approved nonproprietary INN; the generic tag reflects a descriptive label based on available information.","value_numeric":null}],"summaries":{"what_studied":"Phase 1, open-label, single-ascending-dose trial of VERVE-102 — an adenine base-editing therapy delivered via GalNAc-lipid nanoparticle to inactivate hepatic *PCSK9* — in 35 adults with heterozygous familial hypercholesterolemia or premature coronary artery disease, across six doses (0.3–1.0 mg/kg total RNA).","key_result":"At the highest dose (1.0 mg/kg), VERVE-102 reduced PCSK9 by 88% and LDL cholesterol by 62% (absolute: −78 mg/dL); reductions appeared durable for at least 1 year in 15 participants. No dose-limiting toxicities occurred, though mild-to-moderate infusion-related reactions and transient ALT elevations were observed.","limitations":"Small sample size (n=35) with heterogeneous follow-up duration; open-label design without a placebo arm; long-term safety and durability beyond 1 year remain unknown.","practice_takeaway":"A single infusion of VERVE-102 produced large, sustained LDL reductions in high-risk patients — potentially offering a 'one-and-done' alternative to chronic PCSK9 inhibitor therapy. Clinicians should note this is Phase 1 data; larger trials are needed before clinical adoption."}},{"doi":"10.1001/jama.2025.20620","pmid":"41206969","title":"Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia","journal_title":"JAMA","journal_issn":"0098-7484","published_at":"2025-11-09T00:00:00.000Z","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC12598580/","source_score":460,"is_retracted":false,"is_open_access":true,"raw_metadata":{"ooir":{"day":"2026-01-17","doi":"10.1001/jama.2025.20620","days":"7","issn":"0098-7484","rank":"7","field":"Clinical Medicine","score":"460","category":"Medicine, General & Internal","categories":["Medicine, General & Internal"],"_categories":["Medicine, General & Internal"]},"pubmed":{"doi":"10.1001/jama.2025.20620","title":"Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia: A Randomized Clinical Trial.","journal":"JAMA","methods":"","results":"$30","abstract":"$31","keywords":[],"pubmed_id":"41206969","conclusions":"","publication_date":"2025-11-09T00:00:00"},"crossref":{"DOI":"10.1001/jama.2025.20620","URL":"https://doi.org/10.1001/jama.2025.20620","ISSN":["0098-7484"],"link":[{"URL":"https://jamanetwork.com/journals/jama/articlepdf/2841258/jama_ballantyne_2025_oi_250091_1767120340.35474.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":"129","type":"journal-article","issue":"2","score":1,"title":["Efficacy and Safety of Oral PCSK9 Inhibitor Enlicitide in Adults With Heterozygous Familial Hypercholesterolemia"],"author":[{"given":"Christie M.","family":"Ballantyne","sequence":"first","affiliation":[{"name":"Texas Heart Institute, Baylor College of Medicine, Houston, Texas"}]},{"given":"Laura","family":"Gellis","sequence":"additional","affiliation":[{"name":"Merck & Co, Inc, Rahway, New Jersey"}]},{"given":"Jean-Claude","family":"Tardif","sequence":"additional","affiliation":[{"name":"Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada"}]},{"given":"Puja","family":"Banka","sequence":"additional","affiliation":[{"name":"Merck & Co, Inc, Rahway, New Jersey"}]},{"given":"Ann Marie","family":"Navar","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas"}]},{"given":"Emil Andreas","family":"Asprusten","sequence":"additional","affiliation":[{"name":"Lipid Clinic, Oslo University Hospital, Oslo, Norway"}]},{"given":"Russell","family":"Scott","sequence":"additional","affiliation":[{"name":"NZ Clinical Research, Christchurch, New Zealand"}]},{"given":"Erik S. 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Hypercholesterolemia","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"generic","value":"enlicitide","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"level_of_evidence","value":"2","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"modality","value":"PCSK9 Inhibitor","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"sample_size","value":"n=303","value_numeric":303},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"sex","value":"mixed","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"study_design","value":"Randomized Controlled Trial","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"warning","value":"Blinding was not specified in the abstract.","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"warning","value":"No cardiovascular outcomes were reported; results are limited to lipid endpoints.","value_numeric":null},{"paper_doi":"10.1001/jama.2025.20620","tag_type":"warning","value":"Safety event counts were not provided in the abstract.","value_numeric":null}],"summaries":{"what_studied":"A phase 3 randomized trial at 59 sites in 17 countries compared oral enlicitide decanoate 20 mg once daily vs placebo for 52 weeks in adults with heterozygous familial hypercholesterolemia on at least moderate- or high-intensity statins who needed further LDL-C lowering. The primary outcome was mean percentage change in LDL-C at week 24.","key_result":"LDL-C fell by a mean of −58.2% with enlicitide vs +2.6% with placebo at week 24 (between-group difference −59.4% [95% CI, −65.6% to −53.2%]; P<.001) and by −55.3% vs +8.7% at week 52 (difference −61.5% [95% CI, −69.4% to −53.7%]; P<.001). At week 24, non-HDL-C fell −52.3% vs +2.1% (difference −53.0% [95% CI, −58.5% to −47.4%]), apolipoprotein B −48.2% vs +1.8% (difference −49.1% [95% CI, −54.0% to −44.3%]), and lipoprotein(a) median −24.7% vs −1.6% (difference −27.5% [95% CI, −34.3% to −20.6%]); adverse event rates were similar between groups.","limitations":"Outcomes were lipid changes over 24–52 weeks; no cardiovascular event data were reported. Safety was described as similar without event counts, and durability beyond 52 weeks is unknown.","practice_takeaway":"In adults with HeFH on statins who need additional LDL lowering, oral enlicitide produced large, sustained reductions in LDL-C and other atherogenic lipids over 52 weeks with similar adverse events to placebo. It may serve as a potent oral add-on when further LDL reduction is required."}}],"initialOffset":3,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Heterozygous Familial Hypercholesterolemia"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Heterozygous Familial Hypercholesterolemia"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Heterozygous Familial Hypercholesterolemia"}}}]]

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