INTRODUCTION: Evinacumab, a monoclonal antibody targeting angiopoietin-like protein 3 (ANGPTL3), has emerged as a promising therapeutic option for severe dyslipidemias. We have conducted a systematic review to evaluate its efficacy across different clinical settings. METHODS: This systematic review and meta-analysis was conducted in accordance with PRISMA guidelines and registered in PROSPERO (CRD42026142022). Eligible studies included randomized controlled trials, open-label extension studies, single-arm studies, and observational cohorts involving healthy individuals and patients with hypercholesterolemia or hypertriglyceridemia. Due to the small number of available studies and the absence of the data required for quantitative pooling in other clinical settings, a single-arm meta-analysis was performed exclusively in patients with hypercholesterolemia receiving evinacumab 15 mg/kg every 4 weeks. RESULTS: Overall, 17 studies were included in the systematic review. In hypercholesterolemia, evinacumab consistently reduced LDL-C levels by approximately 50%, with reductions ranging from 42% to 82% across studies. Long-term extension and real-world data confirmed sustained efficacy. Meta-analysis of seven studies including 357 patients receiving evinacumab 15 mg/kg intravenously every 4 weeks demonstrated significant reductions in LDL-C [mean difference (MD) - 48.56%], non-HDL-C (MD - 50.19%), apolipoprotein B (MD - 40.51%), and triglycerides (MD - 53.13%). In hypertriglyceridemia, qualitative evidence showed marked triglyceride lowering, particularly in multifactorial chylomicronemia syndrome, with reductions frequently exceeding 60-80%, whereas responses were limited in familial chylomicronemia syndrome. CONCLUSIONS: Evinacumab provides substantial and sustained lipid-lowering effects, particularly in homozygous familial hypercholesterolemia. Emerging evidence also supports a potential role in severe hypertriglyceridemia, although further studies are needed to define its clinical benefits in this setting.
BACKGROUND: Patients with severe hypertriglyceridemia (HTG) with hyperchylomicronemia (HC) are at especially high risk for recurrent acute pancreatitis (AP), a leading gastrointestinal cause of hospitalizations. OBJECTIVE: To describe the real-world frequency, cost, duration, and mortality rates of AP hospitalizations among patients with HC in the United States. METHODS: Data were derived from the Healthcare Cost and Utilization Project Nationwide Readmissions Database (2017-2021). Hospitalizations with any diagnostic code for AP were selected. Unadjusted per-person annual AP hospitalizations, costs, duration, and mortality were analyzed for patients with AP, AP+HTG, or AP+HC. Days between AP hospitalizations were calculated for patients with ≥4 hospitalizations. Regression modeling determined the impact of HC, demographics, comorbidities, and select procedures on outcomes. RESULTS: Overall, 788,715 patients had 968,359 AP hospitalizations (mean [SD]: 1.2 [0.7]). Mean (SD) annual AP hospitalization cost was $24,387 ($55,591), length of stay (LOS) 7.2 (10.9) days, and in-hospital mortality rate 3.3%; 14% had >1 AP hospitalization/y. Patients with AP+HC had 2.0 (1.6) AP hospitalizations, with an annual cost of $40,440 ($51,442) and 12.2 (13.9) hospitalization days/y, and were younger, with a 1.5% in-hospital mortality rate. The average time between hospitalizations was 48.9 to 55.9 days. HC added significantly to the cost (P < .01) and days (P < .0001) of AP hospitalizations. CONCLUSION: Patients with AP+HC hospitalizations have significantly greater acute healthcare utilization, with 67% more annual hospitalizations, 66% higher costs, and 71% higher LOS than overall patients hospitalized for AP or hospitalized for HTG-associated AP not diagnosed as chylomicronemia. Interventions targeting triglyceride reduction and addressing the risk of AP in such patients are needed.
OBJECTIVE: This study aimed to evaluate the clinical and functional impact of a novel apolipoprotein A5 (ApoA5) variant by assessing lipoprotein lipase (LPL) activity. SUBJECTS AND METHODS: Demographic and clinical data, including blood lipid levels and body mass index, were retrospectively collected from an endocrinology clinic registry. Ten individuals with familial chylomicronemia syndrome (FCS) carrying a novel APOA5 variant were included. Whole-exome sequencing was performed using the latest generation DNB-SEQ400 platform. LPL activity was measured in post-heparin plasma using a radiometric assay. Statistical analysis: Categorical variables were summarized as frequencies and percentages, and continuous variables as mean ± standard deviation or median (range), as appropriate. Group comparisons were performed using the Mann-Whitney U test or chi-square test. Analyses were conducted using the Statistical Package for the Social Sciences software (v. 25.0). A p-value < 0.05 was considered statistically significant. RESULTS: We report ten cases of FCS with a homozygous missense variant of uncertain significance in APOA5: c.694T>C; p.(Ser232Pro), located in exon 3. In six patients assessed for LPL activity, levels remained consistently below 20% compared to normotriglyceridemic controls. The addition of exogenous serum containing APOA5 restored LPL activity to above 20% in all cases, indicating functional rescue. CONCLUSION: Measurement of LPL activity demonstrated the functional impact of the APOA5 c.694T>C; p.(Ser232Pro) variant. These findings support reclassification of the variant as likely pathogenic and enable differentiation from multifactorial chylomicronemia syndrome.
Monogenic familial chylomicronemia syndrome (FCS) is a rare autosomal recessive disorder caused by disrupted intravascular lipoprotein lipase (LPL) pathways. Phenotypic variation often leads to diagnostic delays. We contrast two unique pediatric presentations of FCS, highlighting distinct pathophysiology. Case 1 describes a 21-month-old girl with eruptive xanthomas, which was initially misdiagnosed as an infectious rash, later revealed to be secondary to severe hypertriglyceridemia of 100.6 mmol/L (reference range < 0.8 mmol/L). Molecular testing confirmed a genetic mutation in the GPIHBP1 gene. Case 2 describes a 2-day-old neonate with incidental finding of lipemia during jaundice evaluation, subsequently revealing a fasting triglyceride level of 8.5 mmol/L. Genetic analysis identified compound heterozygous mutations in the LPL gene. Case 1 required intensive insulin therapy, strict dietary fat restriction and adjunctive gemfibrozil. Case 2 was managed via dietary restriction and medium-chain triglyceride formula supplementation. This two-case series illustrates the diagnostic challenges of FCS in pediatric practice and the contribution of molecular confirmation to establishing the underlying aetiology and informing counselling and long-term management.
OBJECTIVE: Severe hypertriglyceridemia (sHTG) and familial chylomicronemia syndrome (FCS) are metabolic conditions associated with an increased risk of adverse health outcomes. The FCS Symptoms and Impacts Scale (FCS-SIS) was developed to assess the symptoms and impacts of FCS. This study assessed the content validity of the 4 FCS-SIS symptom items in adults with sHTG. METHODS: Two iterative rounds of qualitative interviews were conducted with adults (aged ≥ 18 years) who had clinician-confirmed sHTG (triglycerides ≥ 500 mg/dL) and recently experienced ≥ 2 symptoms of sHTG. Participants described their initial experiences and symptoms of sHTG during concept elicitation. Cognitive debriefing of the 4 FCS-SIS symptom items assessed relevance, interpretability, answerability, and meaningful change. RESULTS: Among 20 participants, the most frequently reported, most bothersome, and most important-to-treat sHTG symptoms were difficulty thinking (n = 20), physical fatigue (n = 20), diarrhea (n = 19), and abdominal pain (n = 18), which the 4 FCS-SIS symptom items assess. Participants reported these items to be easy to understand (n = 20) and, for most items, reported that a 1- to 2-point improvement would be meaningful. CONCLUSION: FCS-SIS symptom items are content-valid items for the assessment of sHTG symptoms in adults with sHTG.