RESUMO
BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29â069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95â576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Lipoproteína(a)/sangue , Idoso , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Lipoproteína(a)/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de RiscoRESUMO
BACKGROUND: Dalcetrapib effects on cardiovascular outcomes are determined by adenylate cyclase 9 gene polymorphisms. Our aim was to determine whether these clinical end point results are also associated with changes in reverse cholesterol transport and inflammation. METHODS AND RESULTS: Participants of the dal-OUTCOMES and dal-PLAQUE-2 trials were randomly assigned to receive dalcetrapib or placebo in addition to standard care. High-sensitivity C-reactive protein was measured at baseline and at end of study in 5243 patients from dal-OUTCOMES also genotyped for the rs1967309 polymorphism in adenylate cyclase 9. Cholesterol efflux capacity of high-density lipoproteins from J774 macrophages after cAMP stimulation was determined at baseline and 12 months in 171 genotyped patients from dal-PLAQUE-2. Treatment with dalcetrapib resulted in placebo-adjusted geometric mean percent increases in high-sensitivity C-reactive protein from baseline to end of trial of 18.1% (P=0.0009) and 18.7% (P=0.00001) in participants with the GG and AG genotypes, respectively, but the change was -1.0% (P=0.89) in those with the protective AA genotype. There was an interaction between the treatment arm and the genotype groups (P=0.02). Although the mean change in cholesterol efflux was similar among study arms in patients with GG genotype (mean: 7.8% and 7.4%), increases were 22.3% and 3.5% with dalcetrapib and placebo for those with AA genotype (P=0.005). There was a significant genetic effect for change in efflux for dalcetrapib (P=0.02), but not with placebo. CONCLUSIONS: Genotype-dependent effects on C-reactive protein and cholesterol efflux are supportive of dalcetrapib benefits on atherosclerotic cardiovascular outcomes in patients with the AA genotype at polymorphism rs1967309. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov; Unique Identifiers: NCT00658515 and NCT01059682.
Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Inflamação/tratamento farmacológico , Macrófagos/efeitos dos fármacos , Compostos de Sulfidrila/uso terapêutico , Adenilil Ciclases/genética , Adenilil Ciclases/metabolismo , Idoso , Amidas , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/genética , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Linhagem Celular , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Método Duplo-Cego , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/genética , Ésteres , Feminino , Humanos , Inflamação/sangue , Inflamação/enzimologia , Inflamação/genética , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Farmacogenética , Variantes Farmacogenômicos , Polimorfismo de Nucleotídeo Único , Compostos de Sulfidrila/efeitos adversos , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND: Most patients with acute coronary syndrome (ACS) are treated with statins, which reduce atherogenic triglyceride-rich lipoproteins. It is uncertain whether triglycerides predict risk after ACS on a background of statin treatment. OBJECTIVES: This study examined the relationship of fasting triglyceride levels to outcomes after ACS in patients treated with statins. METHODS: Long-term and short-term relationships of triglycerides to risk after ACS were examined in the dal-OUTCOMES trial and atorvastatin arm of the MIRACL (Myocardial Ischemia Reduction with Acute Cholesterol Lowering) trial, respectively. Analysis of dal-OUTCOMES included 15,817 patients (97% statin-treated) randomly assigned 4 to 12 weeks after ACS to treatment with dalcetrapib (a cholesteryl ester transfer protein inhibitor) or placebo and followed for a median 31 months. Analysis of MIRACL included 1,501 patients treated with atorvastatin 80 mg daily beginning 1 to 4 days after ACS and followed for 16 weeks. Fasting triglycerides at initial random assignment were related to risk of coronary heart disease death, nonfatal myocardial infarction, stroke, and unstable angina in models adjusted for age, sex, hypertension, smoking, diabetes, high-density lipoprotein cholesterol, and body mass index. RESULTS: Fasting triglyceride levels were associated with both long-term and short-term risk after ACS. In dal-OUTCOMES, long-term risk increased across quintiles of baseline triglycerides (p<0.001). The hazard ratio in the highest/lowest quintile (>175/≤80 mg/dl) was 1.61 (95% confidence interval: 1.34 to 1.94). There was no interaction of triglycerides and treatment assignment on the primary outcome. In the atorvastatin group of MIRACL, short-term risk increased across tertiles of baseline triglycerides (p=0.03), with a hazard ratio of 1.50 [corrected] (95% confidence interval: 1.05 to 2.15) in highest/lowest tertiles (>195/≤135 mg/dl). The relationship of triglycerides to risk was independent of low-density lipoprotein cholesterol in both studies. CONCLUSIONS: Among patients with ACS treated effectively with statins, fasting triglycerides predict long-term and short-term cardiovascular risk. Triglyceride-rich lipoproteins may be an important additional target for therapy. (A Study of RO4607381 in Stable Coronary Heart Disease Patients With Recent Acute Coronary Syndrome; NCT00658515).
Assuntos
Síndrome Coronariana Aguda/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Triglicerídeos/sangue , Síndrome Coronariana Aguda/tratamento farmacológico , Idoso , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Jejum , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Recidiva , Medição de RiscoRESUMO
BACKGROUND: Heterozygous familial hypercholesterolaemia is characterised by low cellular uptake of LDL cholesterol, increased plasma LDL cholesterol concentrations, and premature cardiovascular disease. Despite intensive statin therapy, with or without ezetimibe, many patients are unable to achieve recommended target levels of LDL cholesterol. We investigated the effect of PCSK9 inhibition with evolocumab (AMG 145) on LDL cholesterol in patients with this disorder. METHODS: This multicentre, randomised, double-blind, placebo-controlled trial was undertaken at 39 sites (most of which were specialised lipid clinics, mainly attached to academic institutions) in Australia, Asia, Europe, New Zealand, North America, and South Africa between Feb 7 and Dec 19, 2013. 331 eligible patients (18-80 years of age), who met clinical criteria for heterozygous familial hypercholesterolaemia and were on stable lipid-lowering therapy for at least 4 weeks, with a fasting LDL cholesterol concentration of 2·6 mmol/L or higher, were randomly allocated in a 2:2:1:1 ratio to receive subcutaneous evolocumab 140 mg every 2 weeks, evolocumab 420 mg monthly, or subcutaneous placebo every 2 weeks or monthly for 12 weeks. Randomisation was computer generated by the study sponsor, implemented by a computerised voice interactive system, and stratified by LDL cholesterol concentration at screening (higher or lower than 4·1 mmol/L) and by baseline ezetimibe use (yes/no). Patients, study personnel, investigators, and Amgen study staff were masked to treatment assignments within dosing frequency groups. The coprimary endpoints were percentage change from baseline in LDL cholesterol at week 12 and at the mean of weeks 10 and 12, analysed by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT01763918. FINDINGS: Of 415 screened patients, 331 were eligible and were randomly assigned to the four treatment groups: evolocumab 140 mg every 2 weeks (n=111), evolocumab 420 mg monthly (n=110), placebo every 2 weeks (n=55), or placebo monthly (n=55). 329 patients received at least one dose of study drug. Compared with placebo, evolocumab at both dosing schedules led to a significant reduction in mean LDL cholesterol at week 12 (every-2-weeks dose: 59·2% reduction [95% CI 53·4-65·1], monthly dose: 61·3% reduction [53·6-69·0]; both p<0·0001) and at the mean of weeks 10 and 12 (60·2% reduction [95% CI 54·5-65·8] and 65·6% reduction [59·8-71·3]; both p<0·0001). Evolocumab was well tolerated, with rates of adverse events similar to placebo. The most common adverse events occurring more frequently in the evolocumab-treated patients than in the placebo groups were nasopharyngitis (in 19 patients [9%] vs five [5%] in the placebo group) and muscle-related adverse events (ten patients [5%] vs 1 [1%]). INTERPRETATION: In patients with heterozygous familial hypercholesterolaemia, evolocumab administered either 140 mg every 2 weeks or 420 mg monthly was well tolerated and yielded similar and rapid 60% reductions in LDL cholesterol compared with placebo. FUNDING: Amgen Inc.
Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Pró-Proteína Convertases/antagonistas & inibidores , Adolescente , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , LDL-Colesterol/efeitos dos fármacos , LDL-Colesterol/metabolismo , Método Duplo-Cego , Esquema de Medicação , Feminino , Heterozigoto , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Pró-Proteína Convertase 9 , Serina Endopeptidases , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Eprotirome is a liver-selective thyroid hormone receptor agonist that has been shown to lower plasma LDL cholesterol concentrations in previous phase 1 and 2 studies of patients with dyslipidaemia. We aimed to assess the long-term safety and efficacy of 50 µg and 100 µg eprotirome in patients with familial hypercholesterolaemia. METHODS: For this randomised, double-blind, placebo-controlled, parallel-group, phase 3 clinical trial, we enrolled patients between Oct 3, 2011, and Feb 14, 2012, at 53 sites in 11 countries in Europe, Africa, and south Asia. Patients were eligible for enrolment if they were aged 18 years or older, diagnosed with heterozygous familial hypercholesterolaemia, and had not reached target LDL cholesterol concentrations after at least 8 weeks of statin therapy with or without ezetimibe. We used a computer-generated randomisation sequence to allocate patients to one of three groups: 50 µg eprotirome, 100 µg eprotirome, or placebo. This trial was planned for 52-76 weeks, with primary efficacy analysis at 12 weeks, but it was prematurely terminated when another study found that eprotirome causes cartilage damage in dogs. Although it was impossible to meet the predefined study outcomes, we analysed changes in the concentrations of LDL cholesterol and other lipids, liver parameters, thyroid hormone concentrations, and adverse effects of treatment with eprotirome versus placebo at 6 weeks of treatment. Analysis was done in all patients who received 6 weeks of treatment. This study is registered with ClinicalTrials.gov, number NCT01410383. FINDINGS: We enrolled 236 patients, randomly allocating 80 to receive placebo, 79 to receive 50 µg eprotirome, and 77 to receive 100 µg eprotirome. 69 patients reached the 6 week timepoint (23 given placebo, 24 given 50 µg eprotirome, and 22 given 100 µg eprotirome). Mean LDL cholesterol concentrations increased by 9% (95% CI -2 to 20) in the placebo group, decreased by 12% (-28 to 4%; p=0.0677 vs placebo) in the 50 µg eprotirome group, and decreased by 22% (-32 to -13%; p=0.0045 vs placebo) in the 100 µg eprotirome group. We noted statistically significant increases between both eprotirome groups and placebo in aspartate aminotransferase (AST; p<0.0001), alanine aminotransferase (ALT; p<0.0001), conjugated bilirubin (p=0.0006), and gamma-glutamyltranspeptidase (p<0.0001). Four patients had to discontinue or interrupt study treatment before trial termination due to AST increases between the upper limit of normal (ULN) and six times ULN, and ALT concentrations between three and seven times ULN. Although we detected no changes in serum concentrations of thyroid-stimulating hormone or free tri-iodothyronine, free tetra-iodothyronine decreased by 19% (23 to 16) in the 50 µg eprotirome group and 27% (30 to 23) in the 100 µg eprotirome group (p<0.0001 vs placebo for both groups). INTERPRETATION: Our findings show that eprotirome can lower LDL cholesterol concentrations in patients with familial hypercholesterolaemia when added to conventional statin treatment with or without ezetimibe, but that it has the potential to induce liver injury. These findings, along with findings of cartilage damage in dogs, raise serious doubts about selective thyroid hormone mimetics as a therapeutic approach to lower LDL cholesterol concentrations. FUNDING: Karo Bio AB.
Assuntos
Anilidas/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Doença Hepática Induzida por Substâncias e Drogas/epidemiologia , LDL-Colesterol/efeitos dos fármacos , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Fígado/efeitos dos fármacos , África , Alanina Transaminase/efeitos dos fármacos , Análise de Variância , Anilidas/efeitos adversos , Anticolesterolemiantes/efeitos adversos , Apolipoproteína B-100/efeitos dos fármacos , Ásia , LDL-Colesterol/sangue , Método Duplo-Cego , Europa (Continente) , Feminino , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/epidemiologia , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
BACKGROUND: In acute coronary syndromes, C-reactive protein (CRP) strongly relates to subsequent death, but surprisingly not to recurrent myocardial infarction. Other biomarkers may reflect different processes related to these outcomes. We assessed 8 inflammatory and vascular biomarkers and the risk of death and recurrent nonfatal cardiovascular events in the 16 weeks after an acute coronary syndrome. METHODS AND RESULTS: We measured blood concentrations of CRP, serum amyloid A (SAA), interleukin-6 (IL-6), soluble intercellular adhesion molecule (ICAM), soluble vascular cell adhesion molecule (VCAM), E-selectin, P-selectin, and tissue plasminogen activator antigen (tPA) 24 to 96 hours after presentation with acute coronary syndrome in 2925 subjects participating in a multicenter study. Biomarkers were related to the risk of death, and recurrent nonfatal acute coronary syndromes (myocardial infarction or unstable angina) over 16 weeks using Cox proportional hazard models. On univariate analyses, baseline CRP (P=0.006), SAA (P=0.012), and IL-6 (P<0.001) were related to death, but not to recurrent nonfatal acute coronary syndromes. VCAM and tPA related to the risk of death (P<0.001, P=0.021, respectively) and to nonfatal acute coronary syndromes (P=0.021, P=0.049, respectively). Adjusting for significant covariates reduced the strength of the associations; however, CRP and SAA continued to relate to death. CONCLUSIONS: In acute coronary syndromes, the CRP inflammatory axis relates to the risk of death and may reflect myocardial injury. VCAM and tPA may have greater specificity for processes reflecting inflammation and thrombosis in the epicardial arteries, which determine recurrent coronary events.
Assuntos
Síndrome Coronariana Aguda/imunologia , Síndrome Coronariana Aguda/mortalidade , Mediadores da Inflamação/sangue , Síndrome Coronariana Aguda/sangue , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Idoso , Idoso de 80 Anos ou mais , Austrália , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Progressão da Doença , Intervalo Livre de Doença , Europa (Continente) , Feminino , Humanos , Interleucina-6/sangue , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Análise Multivariada , América do Norte , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Recidiva , Medição de Risco , Fatores de Risco , Proteína Amiloide A Sérica/metabolismo , África do Sul , Fatores de Tempo , Ativador de Plasminogênio Tecidual/sangue , Molécula 1 de Adesão de Célula Vascular/sangueRESUMO
We determined the ability of in-trial measurements of triglycerides (TGs) to predict new cardiovascular events (CVEs) using data from the Incremental Decrease in End Points through Aggressive Lipid Lowering (IDEAL) and Treating to New Targets (TNT) trials. The trials compared atorvastatin 80 mg/day with moderate-dose statin therapy (simvastatin 20 to 40 mg/day in IDEAL and atorvastatin 10 mg/day in TNT) in patients with clinically evident coronary heart disease or a history of myocardial infarction. The outcome measurement in the present research was CVE occurring after the first year of the trial. After adjusting for age, gender, and study, risk of CVEs increased with increasing TGs (p <0.001 for trend across quintiles of TGs). Patients in the highest quintile had a 63% higher rate of CVEs than patients in the lowest quintile (hazard ratio 1.63, 95% confidence interval 1.46 to 1.81) and the relation of TGs to risk was apparent even within the normal range of TGs. The ability of TG measurements to predict risk decreased when high-density lipoprotein cholesterol and apolipoprotein B:apolipoprotein A-1 were included in the statistical analysis, and it was abolished with inclusion of further variables (diabetes, body mass index, glucose, hypertension, and smoking; (p = 0.044 and 0.621, respectively, for trend across quintiles of TGs). Similar results were obtained in patients in whom low-density lipoprotein cholesterol had been lowered to guideline-recommended levels. In conclusion, even slightly increased TG levels are associated with higher risk of recurrence of CVEs in statin-treated patients and should be considered a useful marker of risk.
Assuntos
Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Infarto do Miocárdio/sangue , Infarto do Miocárdio/etiologia , Triglicerídeos/sangue , Adulto , Idoso , Colesterol/sangue , Estudos de Coortes , Doença da Artéria Coronariana/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/tratamento farmacológico , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Recidiva , Estudos Retrospectivos , Fatores de RiscoAssuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , LDL-Colesterol/sangue , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Quinolinas/uso terapêutico , Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , Proteínas de Transferência de Ésteres de Colesterol , HDL-Colesterol/sangue , Medicina Baseada em Evidências , Ezetimiba , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hipercolesterolemia/complicações , Hipercolesterolemia/tratamento farmacológico , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Quinolinas/efeitos adversos , Sinvastatina/efeitos adversos , Sinvastatina/uso terapêutico , Resultado do TratamentoRESUMO
OBJECTIVE: To examine the relationship of baseline tissue plasminogen activator (t-PA) to early cardiovascular risk after an acute coronary syndrome, and the effect of intensive statin therapy. METHODS: We measured plasma t-PA in 2860 of the 3086 (93%) subjects in the MIRACL study, an international randomized trial of atorvastatin 80mg daily versus placebo in patients with acute coronary syndromes. The relationship of t-PA to death, non-fatal acute myocardial infarction, cardiac arrest, or worsening angina over 16 weeks was assessed by Cox Proportional Hazards. D-dimer was measured in a random sample of 395 subjects. RESULTS: Higher baseline t-PA was significantly related to the risk of recurrent events (HR=1.25, p=0.0014). This relationship was unaffected by adjustment for age, sex, troponin, hsCRP, and lipids (HR=1.17, p=0.029), but was attenuated by adjustment including body mass index and smoking (HR=1.14, p=0.08). D-dimer and t-PA concentrations were not related. Atorvastatin reduced the risk of recurrent events, but did not affect t-PA or D-dimer concentrations or the relationship of t-PA to outcomes. CONCLUSION: In patients with acute coronary syndromes, increasing t-PA concentration was related to a higher early risk of recurrent events, paradoxically reflecting impaired endogenous fibrinolysis. This relationship is due in part to the association of t-PA with age, body mass index and smoking. Although statins lower the risk of recurrent events after acute coronary syndromes, it is unlikely that this benefit is achieved through thrombolytic and fibrinolytic pathways.
Assuntos
Síndrome Coronariana Aguda/tratamento farmacológico , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Ativador de Plasminogênio Tecidual/sangue , Idoso , Atorvastatina , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , RiscoRESUMO
Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.
Assuntos
Glicemia/metabolismo , Carbamatos/uso terapêutico , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Insulina/análogos & derivados , Lipídeos/sangue , Piperidinas/uso terapêutico , Idoso , Apolipoproteínas/sangue , Glicemia/efeitos dos fármacos , Peptídeo C/sangue , Colesterol/sangue , Estudos Cross-Over , Esquema de Medicação , Feminino , Humanos , Insulina/sangue , Insulina/uso terapêutico , Insulina Aspart , Proteína 1 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/metabolismo , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Proinsulina/sangueRESUMO
OBJECTIVES: This study was designed to assess the relationship of high-density-lipoprotein cholesterol (HDL-C), HDL particle size, and apolipoprotein A-I (apoA-I) with the occurrence of coronary artery disease (CAD), with a focus on the effect of very high values of these parameters. BACKGROUND: High plasma levels of HDL-C and apoA-I are inversely related to the risk of CAD. However, recent data suggest that this relationship does not hold true for very high HDL-C levels, particularly when a preponderance of large HDL particles is observed. METHODS: We conducted a post-hoc analysis of 2 prospective studies: the IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering; n = 8,888) trial comparing the efficacy of high-dose to usual-dose statin treatment for the secondary prevention of cardiovascular events, and the EPIC (European Prospective Investigation into Cancer and Nutrition)-Norfolk case-control study, including apparently healthy individuals who did (cases, n = 858) or did not (control patients, n = 1,491) develop CAD during follow-up. In IDEAL, only HDL-C and apoA-I were available; in EPIC-Norfolk, nuclear magnetic resonance spectroscopy-determined HDL particle sizes were also available. RESULTS: In the IDEAL study, higher HDL-C proved a significant major cardiac event risk factor following adjustment for age, gender, smoking, apoA-I, and apoB. A similar association was observed for HDL particle size in EPIC-Norfolk. Increased risk estimates were particularly present in the high ends of the distributions. In contrast, apoA-I remained negatively associated across the major part of its distribution in both studies. CONCLUSIONS: When apoA-I and apoB are kept constant, HDL-C and HDL particle size may confer risk at very high values. This does not hold true for very high levels of apoA-I at fixed levels of HDL-C and apoB. These findings may have important consequences for assessment and treatment of CAD risk.
Assuntos
Apolipoproteína A-I/sangue , HDL-Colesterol/sangue , Doença da Artéria Coronariana/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Idoso , Apolipoproteína A-I/efeitos dos fármacos , Apolipoproteínas B , Biomarcadores/sangue , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/fisiopatologia , Doenças Cardiovasculares/prevenção & controle , Estudos de Casos e Controles , HDL-Colesterol/efeitos dos fármacos , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/fisiopatologia , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Medição de Risco , Fatores de RiscoRESUMO
OBJECTIVE: Patients with acute coronary syndromes have an increased risk of stroke. We measured markers of inflammation in the MIRACL study, a randomized trial of atorvastatin versus placebo in acute coronary syndromes, to assess the relationship of inflammation to stroke. METHODS AND RESULTS: Baseline C-reactive protein (CRP), serum amyloid A (SAA), and interleukin-6 (IL-6) were collected in 2926 (95%) subjects. Baseline markers were related to stroke risk over the 16 weeks of the study. Subjects who subsequently experienced a stroke had higher CRP (27.5 versus 10.2 mg/L, P=0.0032), SAA (30.5 versus 16.0 mg/L, P=0.031), IL-6 (11 231 versus 6841 pg/L, P=0.004), and troponin (6.03 versus 3.19 ng/mL P=0.0032). The risk of stroke was related to greater CRP, SAA, and IL-6 in the placebo group only. Similarly, there was a graded increase in risk of stroke across quartiles of inflammatory markers in the placebo patients only. CONCLUSIONS: In acute coronary syndromes, the early risk of stroke relates to both heightened inflammation and size of myocardial necrosis. Treatment with atorvastatin abrogated the risk associated with elevated markers of inflammation in this study, a finding that provides a novel rationale for the use of statins in acute coronary syndromes.
Assuntos
Síndrome Coronariana Aguda/complicações , Proteína C-Reativa/efeitos dos fármacos , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Pirróis/uso terapêutico , Proteína Amiloide A Sérica/efeitos dos fármacos , Acidente Vascular Cerebral/prevenção & controle , Síndrome Coronariana Aguda/tratamento farmacológico , Síndrome Coronariana Aguda/fisiopatologia , Idoso , Atorvastatina , Proteína C-Reativa/fisiologia , LDL-Colesterol/efeitos dos fármacos , Feminino , Humanos , Inflamação/fisiopatologia , Interleucina-6/sangue , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Curva ROC , Fatores de Risco , Proteína Amiloide A Sérica/metabolismo , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/imunologiaRESUMO
Astaxanthin, the main carotenoid pigment in aquatic animals, has greater antioxidant activity in vitro (protecting against lipid peroxidation) and a more polar configuration than other carotenoids. We investigated the effect of three-month astaxanthin supplementation on lipid peroxidation in healthy non-smoking Finnish men, aged 19-33 years by using a randomized double-blind study design. Also absorption of astaxanthin from capsules into bloodstream and its safety were evaluated. The intervention group received two 4-mg astaxanthin (Astaxin) capsules daily, and the control group two identical-looking placebo capsules. Astaxanthin supplementation elevated plasma astaxanthin levels to 0.032 pmol/L (p < 0.001 for the change compared with the placebo group). We observed that levels of plasma 12- and 15-hydroxy fatty acids were reduced statistically significantly in the astaxanthin group (p = 0.048 and p = 0.047 respectively) during supplementation, but not in the placebo group and the change of 15-hydroxy fatty acid was almost significantly greater (p = 0.056) in the astaxanthin group, as compared with the placebo group. The present study suggests that intestinal absorption of astaxanthin delivered as capsules is adequate, and well tolerated. Supplementation with astaxanthin may decrease in vivo oxidation of fatty acids in healthy men.
Assuntos
Peroxidação de Lipídeos/efeitos dos fármacos , Adulto , Carotenoides/sangue , Suplementos Nutricionais , Método Duplo-Cego , Ácidos Graxos/sangue , Finlândia , Humanos , Lipídeos/sangue , Masculino , Oxirredução , Placebos , Xantofilas/administração & dosagem , Xantofilas/sangue , Xantofilas/farmacocinéticaRESUMO
BACKGROUND: Familial hypercholesterolemia (FH) is one of the most common genetic metabolic disorders and is associated with a high risk of premature coronary heart disease. Primary prevention directed at lifestyle changes, combined with preventive medical treatment, is the most important way to reduce the risk of coronary heart disease in individuals with FH. Knowledge about the condition and adherence to drug treatment may facilitate reaching treatment goals. OBJECTIVE: The purpose of this study was to describe disease knowledge and adherence to treatment in patients with FH. SUBJECTS AND METHODS: Seventy-four patients, more than 18 years of age, with FH were asked to participate. A questionnaire on disease knowledge about FH and adherence to drug treatment was sent to the patients. Response rate was 92% (n = 68). Drug treatment, laboratory results, blood pressure, and smoking were also documented. RESULTS: Most patients knew about cholesterol, prevention, and the reason for drug treatment but were less informed about the risk of genetic transmission and family history. No significant correlation was found between knowledge and low-density lipoprotein cholesterol level. A significant, negative correlation between adherence and low-density lipoprotein cholesterol level was found (r = -.354, P < .01). CONCLUSIONS: Patients with FH had scant understanding about the risk of genetic transmission and family history. High adherence to drug prescription has significant correlation to low-density lipoprotein cholesterol level.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Hiperlipoproteinemia Tipo II/psicologia , Hiperlipoproteinemia Tipo II/terapia , Cooperação do Paciente/estatística & dados numéricos , Adulto , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , LDL-Colesterol/sangue , Doença das Coronárias/etiologia , Doença das Coronárias/prevenção & controle , Exercício Físico , Feminino , Comportamentos Relacionados com a Saúde , Inquéritos Epidemiológicos , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/complicações , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Autocuidado/estatística & dados numéricos , Distribuição por Sexo , Fatores Socioeconômicos , Suécia , Xantomatose/etiologiaRESUMO
BACKGROUND: Renal transplantation is associated with an increased risk for premature cardiovascular disease. We analyzed the data in the placebo arm of Assessment of Lescol in Renal Transplantation (ALERT) to improve our understanding of the relationship between cardiovascular risk factors and outcomes in this unique population. METHODS: We performed Cox survival analysis for myocardial infarction, cardiac death, and noncardiac death in 1,052 patients recruited to the placebo arm of ALERT. These subjects were aged 30 to 75 years, had stable graft function at least 6 months after transplantation, had a serum total cholesterol level between 155 and 348 mg/dL (4 and 9 mmol/L), and were receiving cyclosporine-based immunosuppression. RESULTS: The results confirm previous studies. In multivariate analysis, preexisting coronary heart disease (hazard ratio [HR], 3.69; P < 0.001), total cholesterol level (HR, 1.55 per 50 mg/dL; P = 0.0045), and prior acute rejection (HR, 2.36; P = 0.0023) were independent risk factors. Conversely, independent risk factors for cardiac death were age (HR, 1.58 per decade; P = 0.0033), diabetes (HR, 3.35; P = 0.0002), ST-T changes on the ECG (HR, 3.17; P = 0.0004), and serum creatinine level (HR, 2.65 per milligram per deciliter; P < 0.0001). CONCLUSION: This analysis confirms that renal transplant recipients share risk factors for myocardial infarction and cardiac death with the general population. However, the pattern of risk factors and their relationship with outcomes is atypical, highlighting the unique nature of cardiovascular risk in transplant recipients.
Assuntos
Doenças Cardiovasculares/epidemiologia , Falência Renal Crônica/cirurgia , Transplante de Rim/estatística & dados numéricos , Adulto , Idoso , Creatinina/sangue , Morte Súbita Cardíaca/epidemiologia , Diabetes Mellitus/epidemiologia , Método Duplo-Cego , Ácidos Graxos Monoinsaturados/uso terapêutico , Feminino , Fluvastatina , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/epidemiologia , Imunossupressores/uso terapêutico , Indóis/uso terapêutico , Falência Renal Crônica/epidemiologia , Masculino , Pessoa de Meia-Idade , Mortalidade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/mortalidade , Obesidade/epidemiologia , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fumar/epidemiologia , Análise de SobrevidaRESUMO
BACKGROUND: The aim of the study was to identity risk factors for long-term renal transplant function and development of chronic allograft nephropathy (CAN) in renal transplant recipients included in the Assessment of Lescol in Renal Transplantation (ALERT) trial. METHODS: The ALERT trial was a randomized, double-blind, placebo-controlled study of the effect of fluvastatin, 40 and 80 mg/day, in renal transplant recipients who were randomized to receive fluvastatin (Lescol) (n = 1,050) or placebo (n = 1,052) over 5 to 6 years of follow-up. Renal endpoints including graft loss or doubling of serum creatinine or death were analyzed by univariate and multivariate regression analysis in the placebo group. RESULTS: There were 137 graft losses (13.5%) in the placebo group, mainly caused by CAN (82%). Univariate risk factors for graft loss or doubling of serum creatinine were as follows: serum creatinine, proteinuria, hypertension, pulse pressure, time since transplantation, donor age, human leukocyte antigen-DR mismatches, treatment for rejection, low high-density lipoprotein cholesterol, and smoking. Multivariate analysis revealed independent risk factors for graft loss as follows: serum creatinine (relative risk [RR], 3.12 per 100-microM increase), proteinuria (RR, 1.64 per 1-g/24 hr increase), and pulse pressure (RR, 1.12 per 10 mm Hg), whereas age was a protective factor. With patient death in the composite endpoint, diabetes mellitus, smoking, age, and number of transplantations were also risk factors. CONCLUSIONS: Independent risk factors for graft loss or doubling of serum creatinine or patient death are mainly related to renal transplant function, proteinuria, and blood pressure, which emphasizes the importance of renoprotective treatment regimens in this population.
Assuntos
Ácidos Graxos Monoinsaturados/uso terapêutico , Imunossupressores/uso terapêutico , Indóis/uso terapêutico , Transplante de Rim/imunologia , Adulto , Análise de Variância , Creatinina/sangue , Método Duplo-Cego , Feminino , Fluvastatina , Humanos , Transplante de Rim/patologia , Transplante de Rim/fisiologia , Masculino , Pessoa de Meia-Idade , Placebos , Fatores de Risco , Transplante Homólogo/patologiaRESUMO
The composition of atherosclerotic plaques, not just macroscopical lesion size, has been implicated in their susceptibility to rupture and the risk of thrombus formation. By focusing on the quality of lipids, macrophages, apoptosis, collagen, metalloproteinase expression and plaque integrity, we evaluated the possible anti-atherosclerotic effect of the antioxidants alpha-tocopherol and astaxanthin in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one WHHL rabbits were divided into three groups and were fed a standard diet, as controls (N =10), or a standard diet with the addition of 500 mg alpha-tocopherol per kg feed (N =11) or 100 mg astaxanthin per kg feed (N =10) for 24 weeks. We found that both antioxidants, particularly astaxanthin, significantly decreased macrophage infiltration in the plaques although they did not affect lipid accumulation. All lesions in the astaxanthin-treated rabbits were classified as early plaques according to the distribution of collagen and smooth muscle cells. Both antioxidants also improved plaque stability and significantly diminished apoptosis, which mainly occurred in macrophages, matrix metalloproteinase three expressions and plaque ruptures. Although neither antioxidant altered the positive correlations between the lesion size and lipid accumulation, the lesion size and apoptosis were only positively correlated in the control group. Astaxanthin and alpha-tocopherol may improve plaque stability by decreasing macrophage infiltration and apoptosis in this atherosclerotic setting. Apoptosis reduction by alpha-tocopherol and astaxanthin may be a new anti-atherogenic property of these antioxidants.
Assuntos
Antioxidantes/uso terapêutico , Apoptose/efeitos dos fármacos , Arteriosclerose/prevenção & controle , Hiperlipidemias/tratamento farmacológico , Macrófagos/efeitos dos fármacos , alfa-Tocoferol/uso terapêutico , beta Caroteno/análogos & derivados , beta Caroteno/uso terapêutico , Animais , Antioxidantes/farmacologia , Aorta Torácica/química , Aorta Torácica/patologia , Arteriosclerose/patologia , Movimento Celular/efeitos dos fármacos , Colágeno/análise , Colágeno/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Lipídeos/análise , Macrófagos/fisiologia , Metaloproteinase 3 da Matriz/análise , Metaloproteinase 3 da Matriz/metabolismo , Coelhos , Xantofilas , alfa-Tocoferol/farmacologia , beta Caroteno/farmacologiaRESUMO
BACKGROUND: Living with a genetic predisposition to disease may influence quality of life. The presence of premature disease can lead to an increased focus on family history and genetic predisposition. OBJECTIVE: The purpose of this study was to describe quality of life in patients with the genetic disease, familial hypercholesterolemia, who are at an increased risk of premature coronary heart disease. METHODS: Interviews from 12 adult patients with FH were analyzed using constant comparative analysis. The findings of this qualitative study revealed that for patients, quality of life was equated with harmony in life, the core category. Attaining harmony in life presumes satisfaction and togetherness. Cognizance of the threat of coronary heart disease and impending mortality is balanced by the support of togetherness and satisfaction that builds harmony in life. CONCLUSION: When caring for patients with familial hypercholesterolemia, it is important to meet each patient on his or her own level, and to support balance and their choices for maintaining or regaining harmony in life.
Assuntos
Atitude Frente a Saúde , Predisposição Genética para Doença/psicologia , Hiperlipoproteinemia Tipo II/psicologia , Qualidade de Vida/psicologia , Adaptação Psicológica , Adulto , Idoso , Atitude Frente a Morte , Comportamento de Escolha , Doença das Coronárias/etiologia , Medo , Feminino , Conhecimentos, Atitudes e Prática em Saúde , Humanos , Hiperlipoproteinemia Tipo II/complicações , Hiperlipoproteinemia Tipo II/enfermagem , Masculino , Pessoa de Meia-Idade , Modelos Psicológicos , Papel do Profissional de Enfermagem , Pesquisa Metodológica em Enfermagem , Satisfação Pessoal , Pesquisa Qualitativa , Fatores de Risco , Apoio Social , Inquéritos e Questionários , SuéciaRESUMO
BACKGROUND: Patients with acute coronary syndromes have elevated plasma levels of the proinflammatory, prothrombotic cytokine CD40 ligand (sCD40L). Statins inhibit CD40L signaling in vitro, but there are no prospective studies of statins and sCD40L in acute coronary syndromes. METHODS AND RESULTS: We measured sCD40L in subjects with an acute coronary syndrome enrolled in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study. Subjects were randomized in this double-blind trial to atorvastatin 80 mg/d or placebo for 16 weeks. Plasma CD40L was measured from 2908 (94%) of 3086 subjects at baseline and 2352 (76%) at 16 weeks. Odds ratios (ORs) and 95% CIs from logistic regression models assessed the risk of recurrent cardiovascular events over 16 weeks (death, nonfatal myocardial infarction, cardiac arrest, and worsening angina requiring rehospitalization) in the placebo group from baseline sCD40L and the effect of atorvastatin on the risk associated with CD40L in all subjects. The effects of atorvastatin on plasma concentrations of CD40L were assessed by Wilcoxon tests. There was a threshold effect, with only high sCD40L (>90th centile) being a risk factor for a recurrent cardiovascular event (OR 1.86, 95% CI 1.25 to 2.77). This risk was abolished by atorvastatin (OR 1.09, 95% CI 0.69 to 1.76), which reduced the risk by 48%. Atorvastatin had only a modest effect on sCD40L (P=0.08). CONCLUSIONS: In patients with acute coronary syndromes, atorvastatin abrogated the risk of recurrent cardiovascular events associated with high sCD40L. Early statin therapy after acute coronary syndromes counters the risk associated with elevated sCD40L.
Assuntos
Angina Instável/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Ligante de CD40/sangue , Ácidos Heptanoicos/uso terapêutico , Mediadores da Inflamação/sangue , Infarto do Miocárdio/tratamento farmacológico , Pirróis/uso terapêutico , Idoso , Angina Pectoris/epidemiologia , Angina Pectoris/prevenção & controle , Anticolesterolemiantes/administração & dosagem , Arteriosclerose/sangue , Atorvastatina , Biomarcadores , Método Duplo-Cego , Feminino , Parada Cardíaca/epidemiologia , Parada Cardíaca/prevenção & controle , Ácidos Heptanoicos/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/prevenção & controle , Razão de Chances , Pirróis/administração & dosagem , Recidiva , Risco , Solubilidade , Resultado do TratamentoRESUMO
The aim of this study was to evaluate the influence of -tocopherol and astaxanthin on low-density lipoprotein (LDL) oxidation lag time and atherosclerotic lesion formation in Watanabe heritable hyperlipidemic (WHHL) rabbits. Thirty-one, 3-month-old WHHL rabbits were divided into three experimental groups. One group (n=10) was fed standard rabbit feed alone and served as a control, a second group (n=11) was supplied with the same feed containing 500 mg alpha-tocopherol/kg and a third group (n=10) was given a feed containing 100 mg astaxanthin/kg. Plasma lipids, lipoproteins and LDL oxidation lag time were followed for 24 weeks. At the end of the treatment period, the animals were killed and the thoracic aorta was used for evaluation of the degree of atherosclerosis. Colour photographs of the intimal surface of the vessel were taken for determination of the atherosclerotic area. Cross-sections of the thoracic aorta were used for histological examination and for determination of intimal thickening. Specimens of the vessel were used for determination of the tissue cholesterol content. Plasma cholesterol remained at a high level during the time of the experiment and there were no differences between the experimental groups. After 24 weeks, the LDL oxidation lag time was 53.7+/-1.7 min, 109+/-4 min (P<0.001) and 56.4+/-3.4 min (P=0.47) in the control, alpha-tocopherol and astaxanthin groups, respectively. In the thoracic aorta, the atherosclerotic area was 80.7+/-5.1%, 67.1+/-6.7% (P=0.13) and 75.2+/-5.7% (P=0.49) in the control, alpha-tocopherol and astaxanthin groups, respectively. The intimal thickening was 45.6+/-3.2%, 44.0+/-4.1% (P=0.89) and 40.0+/-4.5% (P=0.33) in the control, alpha-tocopherol and astaxanthin groups, respectively. Finally, the cholesterol content was 107+/-9 mol/g, 95.7+/-11.5 mol/g (P=0.31) and 101+/-5 mol/g (P=0.33) in the control, alpha-tocopherol and astaxanthin groups, respectively. It can be concluded that alpha-tocopherol but not astaxanthin prolonged the LDL oxidation lag time. The two antioxidative substances did not prevent atherogenesis in WHHL rabbits in this setting.