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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. 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\u2009\u2265\u20096\u00a0months. 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\u00a0months. Secondary outcomes included changes in lipid parameters and hepatic safety. Forty-eight patients were included (22 in Group 1 and 26 in Group 2; mean age 59.3\u2009\u00b1\u200912.8\u00a0years). At baseline, LDL-C target achievement was lower in patients subsequently switched to siRNA therapy (36.4% vs 80.8%;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.002). At 12\u00a0months, 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 (\u0394\u2009+\u200929.6\u2009\u00b1\u200937.4\u00a0mg\/dL;\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.003), 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. 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.\n                  <\/jats:p>","DOI":"10.1007\/s11739-026-04417-8","type":"journal-article","created":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T10:16:19Z","timestamp":1781345779000},"page":"2501-2509","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-world lipid outcomes after switching PCSK9-targeting therapies in heterozygous familial hypercholesterolemia: the SHIFT-FH study"],"prefix":"10.1007","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8077-2809","authenticated-orcid":false,"given":"Ilenia Lorenza","family":"Calcaterra","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmine","family":"De Luca","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi Junior","family":"Valletta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guido","family":"D\u2019Errico","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Ferrandino","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giovanna","family":"Cardiero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Donata","family":"Di Taranto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuliana","family":"Fortunato","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriella","family":"Iannuzzo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Tufano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matteo","family":"Di Minno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,13]]},"reference":[{"issue":"24","key":"4417_CR1","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.119.013225","volume":"8","author":"MP McGowan","year":"2019","unstructured":"McGowan MP, Hosseini Dehkordi SH, Moriarty PM, Duell PB (2019) Diagnosis and treatment of heterozygous familial hypercholesterolemia. 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This article does not contain any studies\nwith animals performed by any of the authors.","order":2,"name":"Ethics","label":"Human and animal rights","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflict of interest related to this work.","order":3,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The study was conducted in accordance with the principles of the Declaration of Helsinki. The study protocol was approved by the local Ethics Committee of the University of Naples Federico II. All participants provided written informed consent for the use of their clinical data for research purposes.","order":4,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"During the preparation of this manuscript, the authors used ChatGPT (OpenAI) to assist in improving the language, structure, and clarity of the text. The AI tool was used exclusively for language polishing and editorial refinement. No scientific content, data analysis, or interpretation was generated by the AI. All outputs were carefully reviewed, edited, and validated by the authors, who take full responsibility for the integrity and accuracy of the final manuscript.","order":5,"name":"Ethics","label":"AI-assisted writing","group":{"name":"EthicsHeading","label":"Declarations"}}]}}