Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study

Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study Ilenia Lorenza Calcaterra, Carmine De Luca, Luigi Junior Valletta, and 8 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9201360/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background Proprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibition represents a cornerstone of lipid-lowering therapy in heterozygous familial hypercholesterolemia (HeFH). Monoclonal antibodies (mAbs) and small interfering RNA (siRNA) targeting PCSK9 provide complementary therapeutic strategies; however, real-world data comparing lipid outcomes and target achievement after switching between these treatments remain limited. Methods The SHIFT-FH study was a retrospective real-world cohort study including genetically confirmed HeFH patients receiving maximally tolerated lipid-lowering therapy and stable PCSK9 monoclonal antibody treatment for ≥6 months. According to routine clinical practice, patients either switched to siRNA therapy (inclisiran; Group 1) or continued monoclonal antibody therapy (Group 2). The primary outcome was achievement of guideline-recommended LDL-C targets at 6 and 12 months. Secondary outcomes included changes in lipid parameters and hepatic safety. Results Forty-eight patients were included (22 in Group 1 and 26 in Group 2; mean age 59.3 ± 12.8 years). At baseline, LDL-C target achievement was lower in patients subsequently switched to siRNA therapy (36.4% vs 80.8%; p = 0.002). At 12 months, target attainment remained lower in Group 1 (22.7% vs 53.8%). Switching to siRNA therapy was associated with a moderate increase in LDL-C levels (Δ +29.6 ± 37.4 mg/dL; p = 0.003), whereas lipid levels remained stable in patients continuing monoclonal antibody therapy. Exploratory analysis suggested a trend toward an inverse association between baseline LDL-C levels and target achievement at follow-up. Liver enzymes remained within the normal range in both groups. Conclusions In this real-world cohort of genetically confirmed HeFH patients, LDL-C target achievement was strongly influenced by baseline lipid burden and differed across therapeutic pathways. Switching between PCSK9-targeting strategies may influence long-term lipid control, highlighting the importance of individualized, target-oriented lipid management. familial hypercholesterolemia PCSK9 inhibition inclisiran monoclonal antibodies LDL-C target achievement real-world study Full Text Supplementary Files SHIFTFHSupplementaryonlinematerial.docx Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 01 Apr, 2026 Reviewers invited by journal 31 Mar, 2026 Editor assigned by journal 24 Mar, 2026 First submitted to journal 23 Mar, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9201360","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":615301747,"identity":"3a203b82-6409-4560-b5b2-1f8620429a54","order_by":0,"name":"Ilenia Lorenza 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Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"familial hypercholesterolemia, PCSK9 inhibition, inclisiran, monoclonal antibodies, LDL-C target achievement, real-world study","lastPublishedDoi":"10.21203/rs.3.rs-9201360/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9201360/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Background\n\nProprotein convertase subtilisin/Kexin type 9 (PCSK9) inhibition represents a cornerstone of lipid-lowering therapy in heterozygous familial hypercholesterolemia (HeFH). Monoclonal antibodies (mAbs) and small interfering RNA (siRNA) targeting PCSK9 provide complementary therapeutic strategies; however, real-world data comparing lipid outcomes and target achievement after switching between these treatments remain limited.\n\nMethods\n\nThe SHIFT-FH study was a retrospective real-world cohort study including genetically confirmed HeFH patients receiving maximally tolerated lipid-lowering therapy and stable PCSK9 monoclonal antibody treatment for ≥6 months. According to routine clinical practice, patients either switched to siRNA therapy (inclisiran; Group 1) or continued monoclonal antibody therapy (Group 2). The primary outcome was achievement of guideline-recommended LDL-C targets at 6 and 12 months. Secondary outcomes included changes in lipid parameters and hepatic safety.\n\nResults\n\nForty-eight patients were included (22 in Group 1 and 26 in Group 2; mean age 59.3 ± 12.8 years). At baseline, LDL-C target achievement was lower in patients subsequently switched to siRNA therapy (36.4% vs 80.8%; p = 0.002). At 12 months, target attainment remained lower in Group 1 (22.7% vs 53.8%). Switching to siRNA therapy was associated with a moderate increase in LDL-C levels (Δ +29.6 ± 37.4 mg/dL; p = 0.003), whereas lipid levels remained stable in patients continuing monoclonal antibody therapy. Exploratory analysis suggested a trend toward an inverse association between baseline LDL-C levels and target achievement at follow-up. Liver enzymes remained within the normal range in both groups.\n\nConclusions\n\nIn this real-world cohort of genetically confirmed HeFH patients, LDL-C target achievement was strongly influenced by baseline lipid burden and differed across therapeutic pathways. Switching between PCSK9-targeting strategies may influence long-term lipid control, highlighting the importance of individualized, target-oriented lipid management.","manuscriptTitle":"Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-03 14:17:43","doi":"10.21203/rs.3.rs-9201360/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2026-04-01T13:30:58+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-03-31T12:56:24+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-03-24T06:12:52+00:00","index":"","fulltext":""},{"type":"submitted","content":"Internal and Emergency Medicine","date":"2026-03-23T09:41:59+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"internal-and-emergency-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"iaem","sideBox":"Learn more about [Internal and Emergency Medicine](http://link.springer.com/journal/11739)","snPcode":"11739","submissionUrl":"https://www.editorialmanager.com/iaem/default.aspx","title":"Internal and Emergency Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b09055df-cf54-4d31-a292-a1dd394f0661","owner":[],"postedDate":"April 3rd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-06T13:41:24+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-03 14:17:43","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9201360","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9201360","identity":"rs-9201360","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}