RESUMEN

Background: In 2019, the European Atherosclerosis Society (EAS) published updated guidelines, recommending even lower blood cholesterol targets than previously. In patients with familial hypercholesterolaemia (FH), who have very elevated blood cholesterol levels and are at ('Very') 'High risk' of atherosclerotic cardiovascular disease (ASCVD), this represents a real challenge. Anti-Proprotein convertase subtilisin/kexin type 9 monoclonal antibody (anti-PCSK9 mAb) has been commercially available for FH in Belgium since 2015. Our study aims to investigate the real-life efficacy of anti-PCSK9 mAb in FH patients. Method: We sourced patients from the EAS FH Studies Collaboration database (an international database on FH in which Belgium participates). We only retained patients using anti-PCSK9 mAb and followed at our Lipid Clinic. Results: Of the 239 subjects included in this study (mean age: 56 years), 85% were considered at 'Very High Risk' (56% with a history of ASCVD), the remaining 15% were at 'High Risk'. The PCSK9 mAb treatment reduced LDL-C levels by 54% within the first year. This reduction was maintained over the follow-up (FU) period (3.0 ± 1.8 years). The EAS targets were reached in 50% of the subjects, 93% of whom were also treated with statins. The treatment was very well tolerated. At the end of the observation period, 96% patients continued receiving PCSK9 mAb. Conclusions: Anti-PCSK9 mAb are a safe and effective therapeutic option for lowering LDL-C levels in FH patients. It allowed a significant portion of our FH patients to reach their lipid targets, mainly in those with combined therapy with statin and/or ezetimibe.

RESUMEN

Familial hypercholesterolaemia is one of the most common genetic diseases, and its first symptoms occur in childhood. Proper diagnosis and treatment prevent young patients from severe consequences in their future. The treatment of this dyslipidaemia is still evolving, and new promising agents are being discovered. In this review we summarize the old and new treatment methods of familial hypercholesterolaemia, giving an update estimated on the latest publications.

Asunto(s)

Hiperlipoproteinemia Tipo II , Niño , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico

RESUMEN

BACKGROUND: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. OBJECTIVES: The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). STUDY DESIGN: ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Asunto(s)

Anticolesterolemiantes , Enfermedades Cardiovasculares , Hiperlipoproteinemia Tipo II , Adolescente , Adulto , Anticolesterolemiantes/efectos adversos , Enfermedades Cardiovasculares/tratamiento farmacológico , Niño , LDL-Colesterol , Método Doble Ciego , Humanos , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamiento farmacológico , Hiperlipoproteinemia Tipo II/genética , ARN Interferente Pequeño/efectos adversos

RESUMEN

Dysbetalipoproteinaemia (or type III hyperlipoproteinaemia) is a severe mixed hyperlipidaemia resulting from the accumulation of remnant chylomicron and VLDL particles in plasma, also called ß-VLDL. It is caused by a defect in the recognition by hepatic LDL and lipoprotein receptor-related protein (LRP) of ß-VLDL. Mutations in the APOE gene, especially in subjects homozygous for the ɛ2/ɛ2 allele, are responsible for this lack of receptor recognition. Dysbetalipoproteinaemia represents 2-5% of the mixed dyslipidaemias seen in Lipid Units, is highly atherogenic and predisposes to diffuse atheromatosis, either coronary, peripheral vascular, or carotid, so early diagnosis and treatment is necessary. The presence of hypertriglyceridaemia, with non-HDL cholesterol/apolipoprotein B ratios>1.43 (in mg/dL) followed by APOE genotyping is the method of choice in the diagnosis of dysbetalipoproteinaemia. It is a dyslipidaemia that responds well to hygienic-dietary treatment, although the combination of statin and fenofibrate is often necessary to achieve optimal control.

Asunto(s)

Hiperlipoproteinemia Tipo III , Apolipoproteínas B , Apolipoproteínas E , Colesterol , Humanos , Hiperlipoproteinemia Tipo III/genética , Hiperlipoproteinemia Tipo III/terapia , Lipoproteínas IDL , Triglicéridos

RESUMEN

CASES REPORT: Three cases are presented of patients with familial hyperchylomicronaemia and lipaemia retinalis, in whom an analysis is made of the fundoscopic characteristics of each of them. DISCUSSION: The typical appearance of the retinal fundus is pale salmon coloured and corresponds to levels of severe lipaemia retinalis. As regards the findings, the vascular tree tonality is probably the best exploratory evidence to help in the ophthalmological diagnosis.

RESUMEN

Lipoprotein apheresis reliably reduces low-density lipoprotein (LDL) cholesterol in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). Besides lowering lipoproteins and triglycerides, apheresis also decreases levels of essential omega-6 and omega-3 polyunsaturated fatty acids (n-6 and n-3 PUFAs) in blood plasma. In contrast, heparin-induced extracorporeal low-density lipoprotein precipitation (HELP) lipid apheresis might increase the formation of potentially pro-inflammatory and pro-thrombotic lipid mediators derived from n-6 and n-3 PUFAs. The study presented here analyzed lipid mediator profiles in the plasma of patients with hyperlipidemia treated by one of three different apheresis methods, either HELP, direct absorption (DA), or membrane filtration (MDF), in a direct pre- and post-apheresis comparison. Using gas chromatography and liquid chromatography tandem mass spectrometry (LC-MS/MS) we were able to analyze fatty acid composition and the formation of lipid mediators called oxylipins. Our data illustrate-particularly in HELP-treated patients-significant decreases of essential omega-6 and omega-3 polyunsaturated fatty acids in blood plasma but significant increases of PUFA-derived lipoxygenase-, as well as cyclooxygenase- and cytochrome P450-derived lipid mediators. Given that n-3 PUFAs in particular are presumed to be cardioprotective and n-3 PUFA-derived lipid mediators might limit inflammatory reactions, these data indicate that n-3 PUFA supplementation in the context of lipid apheresis treatment might have additional benefits through apheresis-triggered protective n-3 PUFA-derived lipid mediators.

Asunto(s)

Eliminación de Componentes Sanguíneos/métodos , Ácidos Grasos Omega-3/aislamiento & purificación , Ácidos Grasos Omega-6/aislamiento & purificación , Lipoproteínas LDL/aislamiento & purificación , Eliminación de Componentes Sanguíneos/efectos adversos , Cromatografía Liquida , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Femenino , Cromatografía de Gases y Espectrometría de Masas , Heparina , Humanos , Lipoproteínas LDL/sangre , Masculino , Persona de Mediana Edad , Espectrometría de Masas en Tándem

RESUMEN

BACKGROUND AND AIMS: Chylomicronemia can be either monogenic or multifactorial. The monogenic form, namely familial chylomicronemia syndrome (FCS), is a rare autosomal recessive disease that strongly predisposes to pancreatitis. However, the clinical variables differentiating FCS from multifactorial chylomicronemia (MCM) are not well established. The aims of the present study were to describe a well-defined cohort of FCS subjects and to investigate the differences between patients with FCS and MCM. METHODS: A total of 25 FCS and 36 MCM patients were included in the present study. FCS patients were genetically confirmed, whereas MCM patients had negative genetic testing, triglycerides above 10 mmol/L at least once and the presence of both chylomicrons and VLDL in plasma. RESULTS: FCS patients presented a significant higher frequency of pancreatitis (60% vs. 6%), multiple pancreatitis (48% vs. 3%) and abdominal pain (63% vs. 19%) and a lower frequency of metabolic abnormalities than in the MCM group (p < 0.0001). In addition, the frequency of cardiovascular events was higher in the MCM group than in the FCS group (17% vs. 0%), although the difference was not statistically significant (p = 0.07). In a univariate regression model, the significant predictors of FCS were age at first manifestation (ß = -2.11, p = 0.0005), body mass index (BMI) (ß = -1.82, p < 0.001) and gamma-glutamyl transferase (GGT) (ß = -1.64, p = 0.001). CONCLUSIONS: Our study identified several variables that significantly differentiates FCS from MCM patients. These results need to be replicated in larger cohorts to identify the independent predictors of FCS.

Asunto(s)

VLDL-Colesterol/sangre , Quilomicrones/sangre , Hiperlipoproteinemia Tipo I/sangre , Adulto , Biomarcadores/sangre , Diagnóstico Diferencial , Ensayo de Inmunoadsorción Enzimática , Femenino , Pruebas Genéticas , Humanos , Hiperlipoproteinemia Tipo I/diagnóstico , Hiperlipoproteinemia Tipo I/genética , Masculino , Triglicéridos/sangre

RESUMEN

BACKGROUND AND AIMS: Familial hypercholesterolaemia (FH) is widely underdiagnosed. Cascade testing (CT) of relatives has been shown to be feasible, acceptable and cost-effective in the UK, but requires a supply of index cases. Feasibility of universal screening (US) at age 1-2 years was recently demonstrated. We examined whether this would be a cost-effective adjunct to CT in the UK, given the current and plausible future undiagnosed FH prevalence. METHODS: Seven cholesterol and/or mutation-based US ±â€¯reverse cascade testing (RCT) alternatives were compared with no US in an incremental analysis with a healthcare perspective. A decision model was used to estimate costs and outcomes for cohorts exposed to the US component of each strategy. RCT case ascertainment was modelled using recent UK CT data, and probabilistic Markov models estimated lifetime costs and health outcomes for the cohorts screened under each alternative. 1000 Monte Carlo simulations were run for each model, and average outcomes reported. Further uncertainty was explored deterministically. Threshold analysis investigated the association between undiagnosed FH prevalence and cost-effectiveness. RESULTS: A strategy involving cholesterol screening followed by diagnostic genetic testing and RCT was the most cost-effective modelled (incremental cost-effectiveness ratio (ICER) versus no US £12,480/quality adjusted life year (QALY); probability of cost-effectiveness 96·8% at £20,000/QALY threshold). Cost-effectiveness was robust to both deterministic sensitivity analyses and threshold analyses that modelled ongoing case ascertainment at theoretical maximum levels. CONCLUSIONS: These findings support implementation of universal cholesterol screening followed by diagnostic genetic testing and RCT for FH, under a UK conventional willingness-to-pay threshold.

Asunto(s)

Análisis Químico de la Sangre/economía , Colesterol/sangre , Análisis Mutacional de ADN/economía , Costos de la Atención en Salud , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/economía , Tamizaje Masivo/economía , Mutación , Factores de Edad , Toma de Decisiones Clínicas , Análisis Costo-Beneficio , Técnicas de Apoyo para la Decisión , Árboles de Decisión , Marcadores Genéticos , Predisposición Genética a la Enfermedad , Humanos , Hiperlipoproteinemia Tipo II/sangre , Hiperlipoproteinemia Tipo II/genética , Lactante , Cadenas de Markov , Tamizaje Masivo/métodos , Modelos Económicos , Fenotipo , Valor Predictivo de las Pruebas , Pronóstico , Calidad de Vida , Años de Vida Ajustados por Calidad de Vida , Factores de Tiempo , Reino Unido

RESUMEN

Lipoprotein apheresis has been shown to improve the cardiovascular outcome in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or elevated lipoprotein (a) (Lp(a)). An elevated intake of omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has also been associated with a reduced cardiovascular risk. However, until now only little is known about the effect of apheresis treatment on the levels of omega-6 and omega-3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA) in patients. Using gas chromatography (GC) the present study analyzed the content of n-6 and n-3 PUFA as well as saturated fatty acids and monounsaturated fatty acids in the plasma of 20 patients with hyperlipidemia undergoing regular lipoprotein apheresis procedures in direct pre- and post-therapy measurements. Lipoprotein apheresis uniformly reduced the concentrations of arachidonic acid (AA), EPA and DHA fatty acids analyzed in the plasma. However, the three different apheresis methods analyzed (heparin precipitation, membrane filtration and direct absorption) had different effects on the fatty acid profile in the plasma. We found that heparin precipitation and direct absorption apheresis procedures led to a significant decrease of plasma n-3 and n-6 PUFA by 40-50%. In contrast, patients undergoing membrane filtration apheresis, levels pre- and post-apheresis did not change significantly, with AA and EPA being only reduced by approximately 10% while levels of DHA were maintained pre- and post-apheresis. In contrast, total triglyceride levels were lowered most potently by membrane filtration apheresis. In summary, heparin precipitation and direct absorption apheresis approaches significantly lowered polyunsaturated fatty acids in plasma, while membrane filtration did not. This might have implications for cardiovascular and inflammatory risk/benefit profiles associated with n-6 and n-3 PUFA levels in the body.

Asunto(s)

Eliminación de Componentes Sanguíneos/métodos , Ácidos Grasos Omega-3/sangre , Ácidos Grasos Omega-6/sangre , Hiperlipoproteinemias/terapia , Lipoproteínas/sangre , Absorción Fisicoquímica , Adulto , Anciano , Biomarcadores/sangre , Eliminación de Componentes Sanguíneos/instrumentación , Precipitación Química , Cromatografía de Gases , Femenino , Filtración , Heparina/química , Humanos , Hiperlipoproteinemias/sangre , Hiperlipoproteinemias/diagnóstico , Masculino , Membranas Artificiales , Persona de Mediana Edad , Resultado del Tratamiento , Triglicéridos/sangre

RESUMEN

Lipoprotein apheresis such as heparin-induced extracorporal LowDensityLipoprotein (LDL) Cholesterol precipitation (HELP) reduces apolipoprotein B-containing lipoproteins, most importantly low-density-lipoprotein (LDL), and lipoprotein (a) [Lp(a)]. It is used in patients with atherosclerotic disease and therapy-refractory hypercholesterolemia or progressive atherosclerotic disease in patients with elevated Lp(a). While lipid-lowering effects of lipoprotein apheresis are well-established, there are only sparse data regarding the effect of apheresis on individual omega-6 and omega-3 polyunsaturated fatty acids (n-6 PUFA and n-3 PUFA), such as arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which could increase (AA) or decrease (EPA and DHA) cardiovascular risk. Here we analyzed different omega-6 and omega-3 fatty acids in the blood of patients undergoing a single HELP apheresis procedure using gas chromatography (GC). Furthermore, we assessed the effect of HELP treatment on formation of lipid metabolites and mediators arising from these polyunsaturated fatty acids in the plasma by LC/ESI-MS/MS. Lipoprotein apheresis reduced the concentrations of fatty acids analyzed in the plasma by 40-50%. This was similar for AA, EPA and DHA. The reduction in fatty acid plasma levels was similar to the reduction of total triglycerides. However there was a trend towards an increase of PUFA metabolites associated with platelet activation, such as 12-hydroxyeicosatetraenoic acid (12-HETE) and 14-hydroxydocosahexaenoic acid (14-HDHA). These data indicate that HELP apheresis could interfere with achieving higher levels of n-3 PUFA in the plasma. Lipid apheresis treatment might also increase the formation of potentially pro- as well as anti-inflammatory lipid mediators derived from AA or EPA and DHA.

Asunto(s)

Eliminación de Componentes Sanguíneos , Ácidos Grasos/sangre , Lípidos/química , Lipoproteínas/química , Triglicéridos/química , Ácido 12-Hidroxi-5,8,10,14-Eicosatetraenoico/metabolismo , Adulto , Anciano , Ácidos Docosahexaenoicos/metabolismo , Eritrocitos/metabolismo , Humanos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Oxilipinas/química , Células Plasmáticas/metabolismo , Factores de Riesgo