Search strategy and selection criteria
We conducted the study in accordance with the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [18]. As this is a meta-analysis, there was no need for Institutional Review Board (IRB) approval or patient informed consent. To define the clinical question and formulate a comprehensive search strategy, we applied the PECOS model, focusing on population, intervention, comparison, outcomes, and study design (Table S1 ).
Databases were systematically searched up to November 30, 2024. These included PubMed-Medline, EMBASE, Scopus, Google Scholar, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov, using specific keywords to identify relevant studies: ”Proprotein convertase subtilisin/kexin type 9” OR ”PCSK9 inhibitors” OR ”PCSK9i” OR Angiopoietin-like protein 3 inhibitors” OR ”ANGPTL3 inhibitors” OR ”ANGPTL3 i” OR ”Alirocumab” OR ”Evolocumab” OR ”Evinacumab” AND ”Homozygous Familial Hypercholesterolemia” OR ”Homozygous FH” OR ”HoFH” (Table S2 ).To identify additional relevant studies, references from review articles and abstracts from key congresses, such as the European Society of Cardiology (ESC), European Atherosclerosis Society (EAS), American Heart Association (AHA), and American College of Cardiology (ACC) were reviewed. The wildcard term ”*” was employed to enhance search sensitivity, with the search restricted to human studies published in English and no filters applied. Each article was independently evaluated by two reviewers (M.S. and D.G.). In cases of uncertainty regarding the suitability of a paper, the senior investigators (I.B. and M.B.) were consulted. The selected articles were assessed in full text, and data extraction was performed by the same researchers, while data analysis was conducted by two other researchers (S.B. and I.B.). Typically, the extracted data were compared with the original articles, and errors were corrected as needed. For each trial, the risk of bias was independently assessed by the same investigators using the revised Cochrane risk-of-bias tool for randomized trials (Cochrane RoB2 tool), which evaluates five domains: the randomization process, deviations from intended interventions, missing outcome data, outcome measurement, and the selection of reported results. The risk of bias in each study was categorized as “low,” “high,” or “unclear.” [19].
Articles were considered eligible if they reported the treatment of HoFH patients with PCSK9 inhibitors (PCSK9i) or ANGPTL3 inhibitors (ANGPTL3i) under the following criteria: i) trials investigating the efficacy and/or safety of PCSK9i/ANGPTL3i pre-post-treatment in HoFH patients after treatment with standard lipid-lowering therapy (LLT); ii) studies using genetic and/or clinical criteria for the diagnosis of HoFH according to the available guidelines; and iii) trials with a follow-up period of at least 3 months. Exclusion criteria were: i) insufficient statistical data to test the efficacy and safety of treatment, ii) patients with heterozygous FH, iii) studies not in humans, and iv) ongoing studies (unless they had reported relevant interim results).