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Cited by 9Lipid metabolism and disordersLipoproteins and Cardiovascular HealthLymphatic Disorders and Treatments

Contemporary Management of Familial and Multifactorial Chylomicronemia Syndromes in Italy: Insights From the National LIPIGEN Registry

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D’Erasmo, Laura, Tramontano, Daniele, Di Costanzo, Alessia, Casula, Manuela, Galimberti, Federica, Baratta, Francesco, Cefalù, Angelo Baldassare, Tarugi, Patrizia Maria +43 more·2025·Arteriosclerosis, Thrombosis, and Vascular Biology
DOI 10.1161/atvbaha.125.323340PMC PMC12643564
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Abstract

BACKGROUND: We aimed to compare the molecular and clinical characteristics of patients identified in Italy as affected by either familial chylomicronemia syndrome (FCS) or multifactorial chylomicronemia syndrome (MCS) and to assess the overall benefit of novel triglyceride-lowering therapies prescribed to these patients within the routine clinical care. METHODS: From the national LIPIGEN-sHTG (Lipid Transport Disorders Italian Genetic Network—Severe Hypertriglyceridemia) registry, 169 patients (57 FCS, 51 MCS, 61 variant-negative, variant-negative MCS) were retrospectively analyzed. Data on clinical and genetic characteristics, medical history, and medications were collected. Peak triglyceride levels were used to define untreated lipid phenotypes. RESULTS: In FCS, 72% exhibited biallelic LPL and 28% non-LPL variants; in MCS, 38% (n=19) carried LPL variants, and 38% (n=19) carried APOA5 variants, whereas the remaining individuals were carriers of LMF1 (n=3), GPIHBP1 (n=2), and CREB3L3 or GPD1 variants (n=8), respectively. Peak TGs were highest in FCS (3000 mg/dL [interquartile range, 2116.0–4265.0]), followed by MCS (1817 mg/dL [interquartile range, 1370.0–3062.0]) and variant-negative MCS (1340.0 mg/dL [interquartile range, 946.5–2508.5]; P <0.001). FCS showed a 3.4-fold higher risk of acute pancreatitis than others, whereas no significant differences were observed between groups in the prevalence of atherosclerotic cardiovascular diseases. In the subset of patients with FCS receiving novel therapies (lomitapide or volanesorsen; 35%), triglyceride levels decreased by 62%, as compared with an 11% reduction in those on conventional treatment. Across the cohort, posttreatment triglyceride levels were 895 mg/dL in FCS, 352 mg/dL in MCS, and 386 mg/dL in variant-negative MCS. CONCLUSIONS: As compared with MCS, patients with FCS showed a more severe phenotype and higher prevalence of LPL variants. Lomitapide and volanesorsen provide better triglyceride control, yet only one-third of FCS were treated with these drugs in the routine clinical practice.

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  • Hypertriglyceridemia may result from impaired clearance of TRLs, most often due to pathogenic variants in the lipolytic pathway, and may be exacerbated by secondary factors such as diabetes, obesity, alcohol use, and certain medications.

    “HTG may result from impaired clearance of TRLs, most often due to pathogenic variants in the lipolytic pathway, ranging from monogenic defects in LPL gene or its cofactors (APOC2, APOA5, LMF1, and GPIHBP1) to polygenic susceptibility, and may be exacerbated by secondary factors such as diabetes, obesity, alcohol use, and certain medications [5, 6].”

    From Targeting triglycerides for cardiovascular risk reduction (2026) · cites this paper as [5]

    The paper’s introductory passage describes impaired breakdown of triglyceride-rich lipoproteins in familial chylomicronemia caused by variants in LPL or its cofactors, and says diabetes and obesity can amplify genetic effects in multifactorial chylomicronemia. The Discussion also describes severe hypertriglyceridemia without rare pathogenic variants. Our copy does not establish that pathogenic lipolytic-pathway variants are the most common cause of hypertriglyceridemia, or identify alcohol use and medications as exacerbating factors. (LLM, conf=0.86)

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Authors
D’Erasmo, L., Tramontano, D., Di Costanzo, A., Casula, M., Galimberti, F., Baratta, F., Cefalù, A. B., Tarugi, P. M., Calandra, S., Zambon, A., Averna, M., Catapano, A. L., Arca, M., Banderali, G., Bartuli, A., Beccuti, G., Benso, A., Bianconi, V., Bini, S., Biolo, M., Sabrina Buonuomo, P., D’Addato, S., Dal Pino, B., Di Minno, M., Donata Di Taranto, M., Fainelli, G., Giuliana, F., Giammanco, A., Grigore, L., Iannuzzo, G., Lago, J., Lugari, S., Mandraffino, G., Minicocci, I., Mombelli, G., Montalcini, T., Nascimbeni, F., Noto, D., Pavanello, C., Pederiva, C., Pellegatta, F., Piro, S., Pirro, M., Pujia, A., Rizzi, L., Sbrana, F., Scicali, R., Suppressa, P., Toscano, A., Zambon, S., & Grazia Zenti, M.
Affiliations
  • Sapienza University of Rome (IT)
  • Department of Translational and Precision Medicine, Sapienza University of Rome, Italy (L.D., D.T., A.D.C., M. Arca).
  • University of Milan (IT)
  • MultiMedica (IT)
  • Policlinico Umberto I (IT)
  • Department of Health Promotion, Maternal and Child Care, Internal Medicine and Medical Specialities “G. D’Alessandro” (PROMISE), University of Palermo, Italy (A.B.C., M. Averna).
  • University of Modena and Reggio Emilia (IT)
  • University of Padua (IT)
  • National Research Council (IT)
Corresponding author
  • D’Erasmo, Laura
  • Tramontano, Daniele
ORCID
Venue
Arteriosclerosis, Thrombosis, and Vascular Biology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2025-12
Volume
45
Issue
12
Pages
2264-2276
ISSN
  • 1079-5642 (ISSN-L)
  • 1524-4636
DOI
10.1161/atvbaha.125.323340
PMC
PMC12643564
OpenAlex
W4415267046
Cited by
9
References
6
Citations by year
2026: 8 · 2025: 1
FWCI
6.29
Type
journal article
Language
en
Open access
Licence
Locations
  • Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Archivio Istituzionale della Ricerca (Universita Degli Studi Di Milano) (submittedVersion, other-oa)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
  • Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
  • Padua Research Archive (University of Padova) (submittedVersion)
Funders
  • Amgen
  • Sanofi
  • Alexion Pharmaceuticals
  • Ultragenyx Pharmaceutical
  • Amryt Pharma
  • Ministero della Salute
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
  • Health Sciences › Medicine › Surgery › Lipoproteins and Cardiovascular Health
  • Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
Keywords
familial chylomicronemia syndrome, severe hypertriglyceridemia, lipoprotein lipase deficiency, LMF1, GPIHBP1, CREB3L3, GPD1, triglyceride-lowering therapy, lomitapide, volanesorsen, acute pancreatitis, atherosclerotic cardiovascular disease
MeSH terms
Apolipoprotein A-V, Adult, Aged, Hypolipidemic Agents, Female, Humans, Hyperlipoproteinemia Type IV, Italy, Lipoprotein Lipase, Hyperlipoproteinemia Type I, Male, Middle Aged, Mutation, Oligonucleotides, Phenotype, Registries, Retrospective Studies, Triglycerides, Biomarkers, Treatment Outcome, Receptors, Lipoprotein, Genetic Predisposition to Disease

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