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1.
JAMA ; 322(18): 1780-1788, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714986

RESUMO

Importance: Additional treatment options are needed for patients who do not achieve sufficient reduction in low-density lipoprotein cholesterol (LDL-C) level with available lipid-lowering therapies. Objective: To assess the efficacy of bempedoic acid vs placebo in patients at high cardiovascular risk receiving maximally tolerated lipid-lowering therapy. Design, Setting, and Participants: Phase 3, randomized, double-blind, placebo-controlled clinical trial conducted at 91 clinical sites in North America and Europe from November 2016 to September 2018, with a final date of follow-up of September 22, 2018. A total of 779 patients with atherosclerotic cardiovascular disease, heterozygous familial hypercholesterolemia, or both met randomization criteria, which included LDL-C level 70 mg/dL (1.8 mmol/L) or greater while receiving maximally tolerated lipid-lowering therapy. Interventions: Patients were randomized 2:1 to treatment with bempedoic acid (180 mg) (n = 522) or placebo (n = 257) once daily for 52 weeks. Main Outcomes and Measures: The primary end point was percent change from baseline in LDL-C level at week 12. Secondary measures included changes in levels of lipids, lipoproteins, and biomarkers. Results: Among 779 randomized patients (mean age, 64.3 years; 283 women [36.3%]), 740 (95.0%) completed the trial. At baseline, mean LDL-C level was 120.4 (SD, 37.9) mg/dL. Bempedoic acid lowered LDL-C levels significantly more than placebo at week 12 (-15.1% vs 2.4%, respectively; difference, -17.4% [95% CI, -21.0% to -13.9%]; P < .001). Significant reductions with bempedoic acid vs placebo were observed at week 12 for non-high-density lipoprotein cholesterol (-10.8% vs 2.3%; difference, -13.0% [95% CI, -16.3% to -9.8%]; P < .001), total cholesterol (-9.9% vs 1.3%; difference, -11.2% [95% CI, -13.6% to -8.8%]; P < .001), apolipoprotein B (-9.3% vs 3.7%; difference, -13.0% [95% CI, -16.1% to -9.9%]; P < .001), and high-sensitivity C-reactive protein (median, -18.7% vs -9.4%; difference, -8.7% [asymptotic confidence limits, -17.2% to -0.4%]; P = .04). Common adverse events included nasopharyngitis (5.2% vs 5.1% with bempedoic acid and placebo, respectively), urinary tract infection (5.0% vs 1.9%), and hyperuricemia (4.2% vs 1.9%). Conclusions and Relevance: Among patients at high risk for cardiovascular disease receiving maximally tolerated statins, the addition of bempedoic acid compared with placebo resulted in a significant lowering of LDL-C level over 12 weeks. Further research is needed to assess the durability and clinical effect as well as long-term safety. Trial Registration: ClinicalTrials.gov Identifier: NCT02991118.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Idoso , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Método Duplo-Cego , Quimioterapia Combinada , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hiperlipidemia Familiar Combinada/sangue , Masculino , Pessoa de Meia-Idade
3.
Clin Investig Arterioscler ; 31(2): 89-92, 2019.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-30738610

RESUMO

A 60-year-old male with familial combined hyperlipidemia, ischemic heart disease and type 2 diabetes. Since childhood, intolerance to intense exercise. The patient was diagnosed of McArdle's disease after an episode of rhabdomyolysis associated with statins as treatment after a myocardial infarction. Since then, he had been treated with diet, fibrates and ezetimibe with good tolerance, despite this, LDL cholesterol (cLDL) remained >180mg/dl. He started to be treated with alirocumab 150mg/sc every 14 days, with excellent clinical response and a decrease in cLDL to 15mg/dl. Our case shows that PCSK9 inhibitors are effective and safe in patients with muscle diseases who have statin contraindication, and they are a good therapeutic tool for these patients.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doença de Depósito de Glicogênio Tipo V/etiologia , Pró-Proteína Convertase 9/antagonistas & inibidores , Rabdomiólise/induzido quimicamente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Rabdomiólise/complicações , Fatores de Risco , Resultado do Tratamento
4.
J Clin Lipidol ; 12(1): 33-43, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29174439

RESUMO

BACKGROUND: Familial dyslipidemias of either heterozygous (heFH) or combined (FCH) type lead to accelerated atherogenesis and increased cardiovascular risk. OBJECTIVE: The aim of this study was to investigate in statin-naïve adult patients with familial dyslipidemias whether inflammatory activation and liver, spleen and bone marrow metabolic activity differ compared with normolipidemic subjects and between dyslipidemic groups. METHODS: Fourteen patients with FCH, 14 with heFH, and 14 normolipidemic individuals were enrolled. Serum lipids, high-sensitivity C-reactive protein, and fibrinogen levels were measured, followed by 18F-fluorodeoxyglucose positron-emission tomography/computed tomography imaging. Radiotracer uptake in the aortic wall, spleen, bone marrow, and liver was quantified as tissue-to-background ratio (TBR). RESULTS: Patients with heFH had significantly higher low-density lipoprotein levels compared with those with FCH and controls (P < .001). However, aortic TBRs were higher in FCH compared with heFH patients and controls (P = .02 and P < .001, respectively). FCH patients exhibited higher FDG uptake in the spleen compared with controls (P = .05). In addition, FCH exhibited higher bone marrow FDG uptake compared with heFH patients and controls (P = .03 and P = .02, respectively). FCH had higher liver uptake compared with heFH patients and controls (P < .001 for both). Significant correlations were observed between inflammatory biomarkers and imaging indices as well as between aortic TBR and FDG uptake of hematopoietic organs and liver. CONCLUSIONS: Systemic, as well as vascular inflammation and spleen, bone marrow, and hepatic metabolic activity are increased in patients with FCH despite lower levels of low-density lipoprotein.


Assuntos
Medula Óssea/metabolismo , Hiperlipidemia Familiar Combinada/patologia , Hiperlipoproteinemia Tipo II/patologia , Fígado/metabolismo , Baço/metabolismo , Adulto , Biomarcadores/sangue , Medula Óssea/diagnóstico por imagem , Proteína C-Reativa/análise , Estudos de Casos e Controles , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/metabolismo , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/metabolismo , Inflamação/metabolismo , Lipoproteínas LDL/sangue , Fígado/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Baço/diagnóstico por imagem
5.
Angiology ; 69(3): 242-248, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28681648

RESUMO

We assessed the incidence of diabetes mellitus (DM) in patients with heterozygous familial hypercholesterolemia (HeFH) and familial combined hyperlipidemia (FCH) treated with statins. Participants (n = 280) of mean age 59 ± 5 years were included (90 patients with HeFH, 112 patients with FCH, and 78 aged-matched participants). The median statin intensity treatment product (statin intensity in arbitrary equivalence units × duration of statin therapy in months) was 119 and 85 for patients with HeFH and FCH, respectively, at 10-year follow-up. The incidence of DM was significantly lower in patients with HeFH compared to the patients with FCH (2% vs 20%) and the reference group (2% vs 17%) during the 10-year follow-up period (all Ps < .001). Impaired fasting blood glucose at entry ( P < .001) and central obesity ( P = .02) were the only independent predictors of DM. The incidence of DM was significantly lower in older patients with HeFH compared to either aged-matched patients with FCH or individuals not receiving statins. Statins did not increase risk of DM in aging patients with FCH. These findings have implications, given the importance of high-intensity statin therapy for prevention of cardiovascular events, especially in patients with HeFH, a population with high cardiovascular risk.


Assuntos
Diabetes Mellitus Tipo 2/epidemiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Fatores Etários , Idoso , Estudos de Casos e Controles , Esquema de Medicação , Feminino , Seguimentos , Humanos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipoproteinemia Tipo II/complicações , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
6.
J Lipid Res ; 58(7): 1315-1324, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28392500

RESUMO

Small dense LDL (sdLDL) has been reported to be more atherogenic than large buoyant LDL (lbLDL). We examined the metabolism and protein composition of sdLDL and lbLDL in six subjects with combined hyperlipidemia on placebo and rosuvastatin 40 mg/day. ApoB-100 kinetics in triglyceride-rich lipoproteins (TRLs), lbLDL (density [d] = 1.019-1.044 g/ml), and sdLDL (d = 1.044-1.063 g/ml) were determined in the fed state by using stable isotope tracers, mass spectrometry, and compartmental modeling. Compared with placebo, rosuvastatin decreased LDL cholesterol and apoB-100 levels in TRL, lbLDL, and sdLDL by significantly increasing the fractional catabolic rate of apoB-100 (TRL, +45%; lbLDL, +131%; and sdLDL, +97%), without a change in production. On placebo, 25% of TRL apoB-100 was catabolized directly, 37% was converted to lbLDL, and 38% went directly to sdLDL; rosuvastatin did not alter these distributions. During both phases, sdLDL apoB-100 was catabolized more slowly than lbLDL apoB-100 (P < 0.01). Proteomic analysis indicated that rosuvastatin decreased apoC-III and apoM content within the density range of lbLDL (P < 0.05). In our view, sdLDL is more atherogenic than lbLDL because of its longer plasma residence time, potentially resulting in more particle oxidation, modification, and reduction in size, with increased arterial wall uptake. Rosuvastatin enhances the catabolism of apoB-100 in both lbLDL and sdLDL.


Assuntos
LDL-Colesterol/química , LDL-Colesterol/metabolismo , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/metabolismo , Tamanho da Partícula , Proteômica , Rosuvastatina Cálcica/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/uso terapêutico
7.
Adv Ther ; 34(5): 1200-1210, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28432645

RESUMO

INTRODUCTION: Homozygous familial hypercholesterolaemia (HoFH) is a rare form of inherited dyslipidemia resistant to conventional cholesterol-lowering medications so that lipoprotein apheresis (LA) is usually required. Lomitapide has been approved for the treatment of HoFH. The aim of this study was to evaluate the benefits of lomitapide in HoFH patients followed with the usual clinical care. METHODS: Clinical and biochemical data were retrospectively collected in 15 HoFH patients (10 with mutations in the LDLR gene and 5 in the LDLRAP1 gene) treated for at least 6 months with lomitapide in addition to lipid-lowering therapies (LLT) in different Lipid Clinics across Italy. RESULTS: The mean follow-up period was 32.3 ± 29.7 months. During background therapies, HoFH patients showed a mean LDL-C level of 426.0 ± 204.0 mg/dl. The addition of lomitapide at the average dosage of 19 mg/day lowered LDL-C levels by 68.2 ± 24.8%. At their last visit, 60% of patients showed LDL-C <100 mg/dl and 46.6% <70 mg/dl. During follow-up, 8 of 10 patients receiving LA (80%) stopped this treatment due to marked LDL-C reduction. A wide range (13-95%) of individual LDL-C reduction was observed, but this was not related to genotype. During follow-up, 53.3% of patients reported at least one episode of diarrhea, but none was referred as severe; none had liver transaminase >5× ULN or had to stop treatment due to side effects. A subset of patients was evaluated by liver ultrasound and fibroscan (n = 5) or nuclear magnetic resonance with spectroscopy (MRS) (n = 1) not showing clinical evidence of liver damage. CONCLUSION: In this real-world experience, lomitapide was confirmed to be a very powerful cholesterol-lowering agent in HoFH showing a good safety profile.


Assuntos
Anticolesterolemiantes/uso terapêutico , Benzimidazóis/uso terapêutico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Homozigoto , Humanos , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo II/genética , Itália , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
9.
Lipids ; 50(5): 447-58, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25809021

RESUMO

Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypothesis was that maximal dose rosuvastatin would decrease the apoB-100 production rate (PR), as well as increase apoB-100 fractional catabolic rate (FCR). Eight subjects received placebo, rosuvastatin 5 mg/day, and rosuvastatin 40 mg/day for 8 weeks each in sequential order. The kinetics of apoB-100 in TRL and LDL and apoA-I in HDL were determined at the end of each phase using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Rosuvastatin at 5 and 40 mg/day decreased LDL cholesterol by 44 and 54% (both P < 0.0001), triacylglycerol by 14% (ns) and 35% (P < 0.01), apoB by 30 and 36% (both P < 0.0001), respectively, and had no significant effects on HDL cholesterol or apoA-I levels. Significant decreases in plasma markers of cholesterol synthesis and increases in cholesterol absorption markers were observed. Rosuvastatin 5 and 40 mg/day increased TRL apoB-100 FCR by 36 and 46% (both ns) and LDL apoB-100 by 63 and 102% (both P < 0.05), respectively. HDL apoA-I PR increased with low dose rosuvastatin (12%, P < 0.05) but not with maximal dose rosuvastatin. Neither rosuvastatin dose altered apoB-100 PR or HDL apoA-I FCR. Our data indicate that maximal dose rosuvastatin treatment in subjects with combined hyperlipidemia resulted in significant increases in the catabolism of LDL apoB-100, with no significant effects on apoB-100 production or HDL apoA-I kinetics.


Assuntos
Apolipoproteína B-100/metabolismo , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/metabolismo , Rosuvastatina Cálcica/administração & dosagem , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Lipoproteínas LDL/metabolismo , Masculino , Pessoa de Meia-Idade , Rosuvastatina Cálcica/farmacologia , Triglicerídeos/metabolismo
10.
Atherosclerosis ; 240(1): 190-6, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25797312

RESUMO

BACKGROUND/OBJECTIVE: Familial Hypercholesterolaemia (FH) is caused by mutations in genes of the Low Density Lipoprotein (LDL) receptor pathway. A definitive diagnosis of FH can be made by the demonstration of a pathogenic mutation. The Wales FH service has developed scoring criteria to guide selection of patients for DNA testing, for those referred to clinics with hypercholesterolaemia. The criteria are based on a modification of the Dutch Lipid Clinic scoring criteria and utilise a combination of lipid values, physical signs, personal and family history of premature cardiovascular disease. They are intended to provide clinical guidance and enable resources to be targeted in a cost effective manner. METHODS: 623 patients who presented to lipid clinics across Wales had DNA testing following application of these criteria. RESULTS: The proportion of patients with a pathogenic mutation ranged from 4% in those scoring 5 or less up to 85% in those scoring 15 or more. LDL-cholesterol was the strongest discriminatory factor. Scores gained from physical signs, family history, coronary heart disease, and triglycerides also showed a gradient in mutation pick-up rate according to the score. CONCLUSION: These criteria provide a useful tool to guide selection of patients for DNA testing when applied by health professionals who have clinical experience of FH.


Assuntos
Apolipoproteína B-100/genética , Análise Mutacional de DNA , Testes Genéticos/métodos , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo II/genética , Mutação , Pró-Proteína Convertases/genética , Receptores de LDL/genética , Serina Endopeptidases/genética , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Biomarcadores/sangue , LDL-Colesterol/sangue , Feminino , Marcadores Genéticos , Predisposição Genética para Doença , Humanos , Hiperlipidemia Familiar Combinada/sangue , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemia Familiar Combinada/epidemiologia , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Pessoa de Meia-Idade , Seleção de Pacientes , Linhagem , Fenótipo , Valor Preditivo dos Testes , Pró-Proteína Convertase 9 , Medição de Risco , Fatores de Risco , Triglicerídeos/sangue , País de Gales/epidemiologia
11.
Clin Investig Arterioscler ; 27(1): 1-8, 2015.
Artigo em Espanhol | MEDLINE | ID: mdl-24882148

RESUMO

OBJECTIVE: To evaluate low-density lipoprotein-cholesterol (LDLc) achieved in patients with genetic dyslipidemia treated during one year in Lipid and Vascular Risk Units (LVRU) of the Spanish Society of Arteriosclerosis (SSA). DESIGN: Observational, longitudinal, retrospective, multicenter national study that included consecutive patients of both sexes over 18 years of age referred due to dyslipidemia to LVRU of the SSA. Information was collected from medical records corresponding to two visits in the lipid unit. RESULTS: A total of 527 patients (mean age 48 years, 60.0% men) diagnosed with genetic dyslipidemia (241 with heterozygous familial hypercholesterolemia, and 286 with familial combined hyperlipidemia) were included. The mean follow-up was 12.9 months. In the last visit, 94% were taking statins, one third combined with ezetimibe, although only 41% were taking a high-intensity hypolipidemic treatment. Overall, 28.5% of patients attained an LDLc level<100 mg/dL, 35.8% decreased their LDLc by >50%, and 53.8% achieved one of the two. Predictors of target LDLc levels in the multivariate analysis were age, smoking habit and the presence of vascular disease. CONCLUSION: Over half of the patients with genetic dyslipidemia followed up by LVRU of SSA achieve LDLc objectives after one year of follow-up. The use of high-intensity hypolipidemic treatment could improve these results.


Assuntos
Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Adulto , Anticolesterolemiantes/administração & dosagem , Quimioterapia Combinada , Ezetimiba/administração & dosagem , Ezetimiba/uso terapêutico , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Retrospectivos , Espanha , Resultado do Tratamento
12.
Atherosclerosis ; 237(1): 140-5, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25238223

RESUMO

OBJECTIVE: Controversial findings exist regarding potential influence of statin therapy on diabetic incidence. Aim of this study was to investigate the role of long duration statin treatment on diabetes mellitus (DM) incidence of Heterozygous Familial Hypercholesterolemia (hFH) and Familial Combined Hyperlipidemia (FCH) patients. METHODS: Study population consisted of 212 hFH and 147 FCH patients that visited Lipid Outpatient Department (mean follow up of 11 and 10 years respectively). Several clinical data such as history of DM, cardiovascular disease, thyroid function, metabolic syndrome, glucose levels, lipid profile and lifestyle data were obtained. In order to compare the effects of different doses of different types of statins, a "statin treatment intensity product" was used. RESULTS: 14% of FCH and only 1% of hFH patients developed DM during follow up. Although univariate analysis showed a statistical trend (p = 0.06) in the association between new onset DM and statin treatment intensity (STI) in the FCH subgroup of patients with normal baseline glucose levels, this was no longer significant after adjusting for several confounders. Furthermore, the type of statins used did not seem to play a role in the development of DM either in hFH or FCH patients. CONCLUSION: Long duration of high STI does not seem to be associated with diabetic risk in hFH patients. High STI used in the FCH population is not associated with increased risk of new onset DM compared to low STI. Further studies are required in order to clarify the potential diabetogenic effects of statins in these high risk populations.


Assuntos
Complicações do Diabetes/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemia Familiar Combinada/complicações , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemias/complicações , Hiperlipidemias/tratamento farmacológico , Adulto , Antropometria , Glicemia/química , Pressão Sanguínea , Diabetes Mellitus/tratamento farmacológico , Feminino , Heterozigoto , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipidemia Familiar Combinada/genética , Hiperlipidemias/genética , Incidência , Estilo de Vida , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento
13.
Clín. investig. arterioscler. (Ed. impr.) ; 26(2): 49-57, mar.-abr. 2014. ilus, tab
Artigo em Inglês | IBECS | ID: ibc-121523

RESUMO

Background The microsomal triglyceride transfer protein (MTP) is involved in hepatic and intestinal apoB secretion. We studied the effect of the functional MTP-493G/T polymorphism on fasting and postprandial lipoproteins in patients with familial combined hyperlipidemia (FCH) before and after treatment with atorvastatin. Methods Eight FCH heterozygote carriers of the rare -493T allele were compared to 9 matched FCH homozygotes for the wild-type allele in a pilot study. Oral fat loading tests were carried out to measure triglycerides (TG) and apo B48 and B100 in the different fractions of triglyceride-rich lipoproteins (TRLs) before and after treatment with atorvastatin. Results Before treatment, TG were similar between the -493T allele carriers and non-carriers. In the T-allele carriers, a trend was observed for increased postprandial apo B48 and B100 concentrations in Sf >400 and Sf 60–400 compared to non-carriers. After treatment, fasting and postprandial TG were significantly lowered in carriers of the T allele, but atorvastatin had no effect on postprandial TG in non-carriers. Atorvastatin resulted in similar reductions of apo B48 and B100 in TRLs in both groups. Conclusion The MTP-493G/T polymorphism modulates postprandial apo B48 and apo B100 of TRLs in FCH. Atorvastatin decreases postprandial TG in T-allele carriers with FCH


Antecedentes: La Microsomal Triglyceride Transfer Protein (MTP) participa en la secreción hepática e intestinal de apoB. Hemos estudiado el efecto del polimorfismo funcional MTP-493G/T sobre las lipoproteínas en ayunas o posprandiales en pacientes con hiperlipidemia familiar combinada (FCH) antes y después de un tratamiento con atorvastatina. Métodos: Ocho pacientes FCH heterocigotos para el alelo menos frecuente -493T fueron comparados con 9 pacientes FCH homocigotos para el genotipo salvaje. Tras una sobrecarga oral de grasa se cuantificaron los triglicéridos (TG) y las apoB48 yapoB100 de las diferentes fracciones ricas en TG, antes y después del tratamiento con atorvastatina. Resultados: Antes del tratamiento, los TG eran comparables entre portadores y no portadores del alelo -493T. En portadores del alelo T, se observó una tendencia a mayores concentraciones de apoB48 y apoB100 en las fracciones Sf >400 y Sf 60-400, comparado con los no portadores. Tras el tratamiento, los TG basales y posprandiales fueron significativamente más bajos en portadores del alelo T, pero la atorvastatina no tuvo efecto sobre los TG posprandiales en pacientes no portadores de -493T. La atorvastatina indujo disminuciones en apoB48 y apoB100 de las fracciones ricas en TG tanto en portadores como en no portadores. Conclusión: El polimorfismo -493G/T de la MTP modula el contenido en apoB48 y apoB100 delas lipoproteínas ricas en TG posprandiales. La atorvastatina disminuye los TG posprandiales en pacientes FCH portadores del alelo T


Assuntos
Humanos , Hiperlipidemia Familiar Combinada/genética , Abetalipoproteinemia/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hipolipemiantes/farmacocinética , Apolipoproteína B-48/análise , Período Pós-Prandial
14.
Clin Investig Arterioscler ; 26(2): 49-57, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24378322

RESUMO

BACKGROUND: The microsomal triglyceride transfer protein (MTP) is involved in hepatic and intestinal apoB secretion. We studied the effect of the functional MTP-493G/T polymorphism on fasting and postprandial lipoproteins in patients with familial combined hyperlipidemia (FCH) before and after treatment with atorvastatin. METHODS: Eight FCH heterozygote carriers of the rare -493T allele were compared to 9 matched FCH homozygotes for the wild-type allele in a pilot study. Oral fat loading tests were carried out to measure triglycerides (TG) and apo B48 and B100 in the different fractions of triglyceride-rich lipoproteins (TRLs) before and after treatment with atorvastatin. RESULTS: Before treatment, TG were similar between the -493T allele carriers and non-carriers. In the T-allele carriers, a trend was observed for increased postprandial apo B48 and B100 concentrations in Sf >400 and Sf 60-400 compared to non-carriers. After treatment, fasting and postprandial TG were significantly lowered in carriers of the T allele, but atorvastatin had no effect on postprandial TG in non-carriers. Atorvastatin resulted in similar reductions of apo B48 and B100 in TRLs in both groups. CONCLUSION: The MTP-493G/T polymorphism modulates postprandial apo B48 and apo B100 of TRLs in FCH. Atorvastatin decreases postprandial TG in T-allele carriers with FCH.


Assuntos
Proteínas de Transporte/genética , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Pirróis/farmacologia , Adulto , Alelos , Apolipoproteínas B/metabolismo , Atorvastatina , Relação Dose-Resposta a Droga , Feminino , Ácidos Heptanoicos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemia Familiar Combinada/genética , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Polimorfismo Genético , Período Pós-Prandial , Pirróis/administração & dosagem , Triglicerídeos/sangue
15.
Praxis (Bern 1994) ; 102(10): 585-9, 2013 May 08.
Artigo em Alemão | MEDLINE | ID: mdl-23644243

RESUMO

Dyslipidemia is one of the main modifiable cardiovascular risk factors. There is strong evidence for the efficacy of lipid-lowering drugs in secondary prevention, as well as in primary prevention for patients at high cardiovascular risk. In primary prevention, indication for lipid-lowering interventions should be based on an individual assessment of the cardiovascular risk and on the LDL cholesterol level, despite less strong evidence for the efficacy of drug-based interventions in low risk patients. Treatment consists of statins, as well as lifestyle modifications such as body weight control and increased physical exercise. The latter constitute the primary intervention in patients at low cardiovascular risk. Secondary dyslipidemias due to an underlying medical condition and familial dyslipidemias such as Familial Hypercholesterolemia and Familial Combined Hyperlipidemia should be identified and treated accordingly, taking into account that the risk scoring systems are not appropriate in these situations.


Assuntos
Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo IV/diagnóstico , Hiperlipoproteinemia Tipo IV/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Adulto , Idoso , Diagnóstico Diferencial , Feminino , Humanos , Hiperlipidemia Familiar Combinada/genética , Hiperlipoproteinemia Tipo II/genética , Hiperlipoproteinemia Tipo IV/genética , Hipolipemiantes/efeitos adversos , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Suíça
16.
Am J Cardiol ; 110(9): 1296-301, 2012 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-22840347

RESUMO

Addition of fenofibrate to statin therapy might represent a viable treatment option for patients whose high risk for coronary heart disease is not controlled by a statin alone. However, safety of coadministration of statin with fenofibrate has been a great concern. The present study tested the safety of coadministration of statin with fenofibrate. We systematically searched the literature to identify randomized controlled trials examining safety of coadministration of statin with fenofibrate. A meta-analysis was performed to estimate safety of coadministration of statin with fenofibrate using fixed-effects models. There were 1,628 subjects in the identified 6 studies. Discontinuation attributed to any adverse events (4.5% vs 3.1%, p = 0.20), any adverse events (42% vs 41%, p = 0.82), adverse events related to study drug (10.9% vs 11.0%, p = 0.95), and serious adverse events (2.0% vs 1.5%, p = 0.71) were not significantly different in the 2 arms. Incidence of alanine aminotransferase and/or aspartate aminotransferase ≥3 times upper limit of normal in the combination therapy arm was significantly higher than in the statin monotherapy arm (3.1% vs 0.2%, p = 0.0009). In the 6 trials with 1,628 subjects no case of myopathy or rhabdomyolysis was reported. In conclusion, statin-fenofibrate combination therapy was tolerated as well as statin monotherapy. Physicians should consider statin-fenofibrate combination therapy to treat patients with mixed dyslipidemia.


Assuntos
Fenofibrato/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hipolipemiantes/administração & dosagem , Fatores Etários , Idoso , Estudos Cross-Over , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Fenofibrato/efeitos adversos , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/mortalidade , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Gestão da Segurança , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de Sobrevida , Resultado do Tratamento
17.
An. pediatr. (2003, Ed. impr.) ; 77(1): 37-42, jul. 2012. tab, graf
Artigo em Espanhol | IBECS | ID: ibc-101257

RESUMO

La hipecolesterolemia familiar es el tipo de hiperlipidemia primaria hereditaria más frecuente y se asocia con una mayor prevalencia de enfermedad cardiovascular temprana. El ezetimibe reduce el LDL inhibiendo la absorción de esteroles en el enterocito. Objetivo: Mostrar nuestra experiencia en el uso de ezetimibe para el tratamiento de niños y adolescentes con hipercolesterolemia familiar heterocigota, en el corto y mediano plazo. M y M: Estudio longitudinal, retrospectivo, modelo antes-después donde cada paciente fue su propio control. Se incluyeron todos los pacientes que recibieron ezetimibe desde enero 2003 a diciembre 2009. Los pacientes cumplieron un período previo de 6 meses de dieta hipolipemiante y recomendaciones de actividad física. La eficacia se midió según la variación del LDL luego de3 meses de tratamiento. Se midieron los niveles de transaminasas y creatinfosfoquinasa antes y cada 3 meses durante el tratamiento. Se registraron los síntomas y efectos colaterales asociados con la administración de ezetimibe. Los pacientes que alcanzaron los objetivos terapéuticos continuaron con ezetimibe como monodroga, los que no, agregaron estatinas. Resultados: Se incluyeron 32 pacientes con edad media de 9,5 años (rango: 2-15,5). El tiempo total de seguimiento fue de 2,45 años (0,4-5,9 a). Luego de 3 meses de ezetimibe el LDL disminuyó un 25,7%. No se observaron efectos adversos durante el tratamiento como monoterapia. Al final del estudio, 11 pacientes habían agregado estatinas a su tratamiento por no haber alcanzado los objetivos. Conclusión: El ezetimibe resultó ser efectivo y seguro en niños y adolescentes con HF a corto y mediano plazo(AU)


Heterozygous familial hypercholesterolemia (FH) is the most common inherited type of primary hyperlipidemia. Patients with familial hypercholesterolemia have an increased level of LDL cholesterol since childhood, and present early associated cardiovascular disease. Ezetimibe reduces LDL by blocking sterol absorption in enterocytes. Aim: to show our experience on the use of ezetimibe in children and adolescents with familial hypercholesterolemia, with short and medium term follow-up. Patients and Methods: Retrospective and longitudinal study. Patients who were receiving ezetimibe as monotherapy from 2003 to 2009 were included. The primary efficacy parameter was the effect of ezetimibe on the LDL after three months of treatment. Serum levels of aspartate aminotransferase, alanine aminotransferase and creatine kinase were monitored. Patients were asked if they experienced any side effect with the ezetimibe treatment. If the Patients did not achieve therapeutical goals with ezetimibe as monotherapy a statin was added. Outcome at medium term follow-up is analysed. Results: The study included a total of 32 patients. The mean age at the start of ezetimibe was 9.5 years (range: 2 to 15.5). The mean total time of Ezetimibe was 2.45 years (r: 0.4 - 5.9).The decrease in mean LDL levels was -25.7%±12.3 or 59.5±34 mg% (P<.0001; 95% CI: 47.3-71.5, t test). There were no side effects with ezetimibe monotherapy. At the end of the study, 11patients required added statins due to failing to achieve the treatment goal. Conclusions: Ezetimibe is effective and safe for children and adolescents with FH in short and medium term follow-up(AU)


Assuntos
Humanos , Masculino , Feminino , Criança , Adolescente , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticolesterolemiantes/farmacocinética , Esteróis/antagonistas & inibidores , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Triglicerídeos/sangue , Fatores de Risco , Estudos Retrospectivos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico
18.
Life Sci ; 90(21-22): 846-50, 2012 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-22554491

RESUMO

AIM: Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias. MAIN METHODS: We determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH). KEY FINDINGS: At baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 µmol/mmol cholesterol (p=0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 µmol/mmol cholesterol (p=0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 µmol/mmol cholesterol (p=0.0001), and from 75 to 86 102 µmol/mmol cholesterol, (p=0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol. SIGNIFICANCE: Primary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely "synthesis inhibition" dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.


Assuntos
Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipercolesterolemia/tratamento farmacológico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Hiperlipidemias/tratamento farmacológico , Adulto , Idoso , Atorvastatina , Colesterol/análogos & derivados , LDL-Colesterol/sangue , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Ácidos Heptanoicos/farmacologia , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Fitosteróis/sangue , Pirróis/farmacologia , Sinvastatina/farmacologia , Sitosteroides/sangue
19.
G Ital Nefrol ; 29 Suppl 54: S5-13, 2012.
Artigo em Italiano | MEDLINE | ID: mdl-22388822

RESUMO

Plasma lipid levels are to a large extent determined by genetic factors. In its more extreme forms this is manifested as familial hyperlipidemias, which are an important cause of premature coronary heart disease. It has been demonstrated that rigorous treatment of familial forms reduces the burden of ischemic heart disease. Statins are among the most studied drugs in cardiovascular prevention; a number of large-scale clinical trials have demonstrated that statins substantially reduce cardiovascular morbidity and mortality in both primary and secondary prevention. The currently available evidence suggests that the clinical benefit is largely independent of the type of statin, but depends on the extent of LDL-C lowering. When the most potent statins are insufficient, LDL-C apheresis should be used.


Assuntos
Anticolesterolemiantes/uso terapêutico , Dislipidemias/diagnóstico , Dislipidemias/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Isquemia Miocárdica/prevenção & controle , Pirróis/uso terapêutico , Atorvastatina , Biomarcadores/sangue , Remoção de Componentes Sanguíneos/métodos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Ensaios Clínicos como Assunto , Dislipidemias/sangue , Dislipidemias/dietoterapia , Dislipidemias/terapia , Humanos , Hiperlipidemia Familiar Combinada/diagnóstico , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Resultado do Tratamento , Triglicerídeos/sangue
20.
J Am Coll Nutr ; 31(5): 311-9, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23529988

RESUMO

OBJECTIVE: To assess whether a diet containing foods enriched with ß-glucans (3.6 g/d), folic acid (1600 µg/d), long-chain (800 mg/d) and short-chain (400 mg/d) n-3 fatty acids, and tocopherols (120 mg/d) is able to modulate positively the cardiovascular risk profile in people at slightly increased cardiovascular risk. METHODS: Sixteen subjects with mild plasma lipid abnormalities were studied according to a randomized crossover design. After a 2-week run-in period, they followed a diet containing baked products enriched with active nutrients (active diet) or a diet containing the same products but without active nutrients (control diet) for 1 month and then crossed over to the other diet. At the end of each period, a test meal of the same composition as the corresponding diet was administered, and plasma samples were obtained before and for 6 hours after the meal. Hunger and satiety were evaluated by the visual analog scale at fasting and after the meal. RESULTS: Fasting plasma triglycerides were significantly lower after the active versus the control diet (1.56 ± 0.18 vs 1.74 ± 0.16 mmol/l, p < 0.05), as was the postprandial level of chylomicron triglycerides and the insulin peak (p < 0.05). The active diet also reduced fasting homocysteine (8 ± 0.6 vs 10 ± 0.8 µmol/l, p < 0.05) and the feeling of hunger at the fifth and sixth hour (p < 0.05). CONCLUSIONS: Baked functional products enriched with n-3 fatty acids, folates, ß-glucans, and tocopherols within the context of a balanced diet lower fasting and postprandial plasma triglycerides, fasting homocysteinemia, and the postprandial insulin peak. They induce a greater feeling of satiety with possible beneficial implications on energy intake.


Assuntos
Suplementos Nutricionais , Ácidos Graxos Ômega-3/administração & dosagem , Ácido Fólico/administração & dosagem , Hiperlipidemia Familiar Combinada/tratamento farmacológico , Tocoferóis/administração & dosagem , beta-Glucanas/administração & dosagem , Glicemia , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Quilomícrons/sangue , Estudos Cross-Over , Dieta , Método Duplo-Cego , Ingestão de Energia , Jejum , Feminino , Humanos , Hiper-Homocisteinemia/sangue , Hiper-Homocisteinemia/tratamento farmacológico , Hiperlipidemia Familiar Combinada/sangue , Insulina/sangue , Masculino , Refeições , Pessoa de Meia-Idade , Período Pós-Prandial , Fatores de Risco , Triglicerídeos/sangue
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