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1.
Prog Cardiovasc Dis ; 62(5): 375-383, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31733217

RESUMO

The authors review more than three decades of progress in providing clinicians and patients with guidance on risk assessment, patient evaluation and cholesterol management. Beginning with the National Cholesterol Education Program's Initial Adult Treatment Panel report, the cholesterol guidelines increasingly reflect the progress made in understanding the benefits of improved lifestyle and nutrition to improve lipid profiles, major risk factors and reduce ASCVD risk. Moreover, they now provide qualitative and quantitative assessment tools to guide appropriate risk reduction LDL-C lowering therapy. Use of the Pooled Cohort Equations to determine Low, Borderline, Intermediate and High 10-year ASCVD risk is now joined by recognition of conditions and biomarkers that enhance ASCVD risk. This personalizes the risk discussion for the patient. An important addition is the selective use of coronary artery calcium (CAC) scoring to reclassify risk in patients at borderline or intermediate risk, but for whom a risk decision regarding statin therapy is uncertain. In secondary prevention, current guidelines provide criteria for determining a "very high" risk group in whom risk is especially high and in whom aggressive LDL-C lowering can be shown to provide increased absolute benefit. Current guidelines provide a comprehensive look at children and adolescents, young adults, elderly, women and issues specific to women through the life course. They provide guidance for those adults at risk due to severe hypercholesterolemia, persistent hypertriglyceridemia after secondary causes have been addressed, those with inflammatory disorders and HIV, those adults with chronic kidney disease, and those affected by issues of race/ethnicity. They conclude with a brief summary of recommendations emphasizing important concepts for providing safety with LDL-C lowering therapy. This combination of best external evidence and clinical expertise from the expert panel should provide a solid foundation for lipid management of patients at risk for or with clinical ASCVD.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Medicina Baseada em Evidências , Guias de Prática Clínica como Assunto , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Difusão de Inovações , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/história , Medicina Baseada em Evidências/história , Medicina Baseada em Evidências/tendências , Previsões , História do Século XX , História do Século XXI , Humanos , Fatores de Proteção , Fatores de Risco , Resultado do Tratamento
3.
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
4.
Prog Cardiovasc Dis ; 62(5): 414-422, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31669498

RESUMO

Familial hypercholesterolemia (FH) is a frequent genetic disorder characterized by elevated low-density lipoprotein (LDL)-cholesterol (LDL-C) levels and early onset of atherosclerotic cardiovascular disease. FH is caused by mutations in genes that regulate LDL catabolism, mainly the LDL receptor (LDLR), apolipoprotein B (APOB) and gain of function of proprotein convertase subtilisin kexin type 9 (PCSK9). However, the phenotype may be encountered in individuals not carrying the latter monogenic defects, in approximately 20% of these effects of polygenes predominate, and in many individuals no molecular defects are encountered at all. These so-called FH phenocopy individuals have an elevated atherosclerotic cardiovascular disease risk in comparison with normolipidemic individuals but this risk is lower than in those with monogenic disease. Individuals with FH are exposed to elevated LDL-C levels since birth and this explains the high cardiovascular, mainly coronary heart disease, burden of these subjects. However, recent studies show that this risk is heterogenous and depends not only on high LDL-C levels but also on presence of previous cardiovascular disease, a monogenic cause, male sex, smoking, hypertension, diabetes, low HDL-cholesterol, obesity and elevated lipoprotein(a). This heterogeneity in risk can be captured by risk equations like one from the SAFEHEART cohort and by detection of subclinical coronary atherosclerosis. High dose high potency statins are the main stain for LDL-C lowering in FH, however, in most situations these medications are not powered enough to reduce cholesterol to adequate levels. Ezetimibe and PCSK9 inhibitors should also be used in order to better treat LDL-C in FH patients.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Anticolesterolemiantes/efeitos adversos , Aterosclerose/epidemiologia , Aterosclerose/genética , Biomarcadores/sangue , Ezetimiba/uso terapêutico , Predisposição Genética para Doença , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/epidemiologia , Hiperlipoproteinemia Tipo II/genética , Fenótipo , Pró-Proteína Convertase 9/antagonistas & inibidores , Pró-Proteína Convertase 9/metabolismo , Medição de Risco , Fatores de Risco , Inibidores de Serino Proteinase/uso terapêutico , Resultado do Tratamento
5.
Prog Cardiovasc Dis ; 62(5): 384-389, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31669499

RESUMO

The 2018 AHA/ACC cholesterol guideline builds on the 2013 ACC/AHA cholesterol guideline statin recommendations to provide more detailed recommendations for the use of nonstatin therapy risk stratification for primary prevention statin use. New information has become available after the development of the 2018 AHA/ACC cholesterol guideline that can further inform clinical practice. Proprotein convertase subtilisin kexin type-9 (PCSK9) monoclonal antibodies are now a reasonable or even good value following over 60% reductions in their acquisition price, and the identification of high risk patient groups most likely to benefit from further low-density lipoprotein cholesterol (LDL-C) lowering. Meta-analyses and clinical trial data now show that patients with LDL-C ≥ 100 mg/dl are more likely to experience progressively greater reductions in the risk of cardiovascular and total mortality and coronary heart disease events for progressively higher LDL-C levels. Icosapent ethyl, a highly concentrated form of modified EPA has been shown to reduce cardiovascular events in high risk patients with moderate hypertriglyceridemia on statin therapy. Comparisons with other statin guidelines revealed that statin initiation for those with ≥7.5% 10-year atherosclerotic cardiovascular disease (ASCVD) risk is the most effective strategy for reducing the most ASCVD events for the proportion of the population treated. Data from younger populations finally became available for coronary artery calcium (CAC) scoring (mean age of 51 years) which confirmed the value of CAC > 0 for identifying individuals at increased ASCVD risk most likely to benefit from statin initiation. This analysis also found that statins could keep CAC = 0 in those with risk factors. Epidemiologic pooling studies now clearly show that LDL-C and non-high-density lipoprotein cholesterol levels in young adulthood confer excess risk for ASCVD later in life. Accumulating data support earlier risk factor intervention trials as the next research priority.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Guias de Prática Clínica como Assunto , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Humanos , Fatores de Proteção , Fatores de Risco , Resultado do Tratamento
6.
Expert Opin Drug Metab Toxicol ; 15(11): 897-911, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31648563

RESUMO

Introduction: Statins are prescribed widely for cholesterol-lowering therapy, but it is known that their efficacy and safety profiles vary, despite the shared pharmacophore and pharmacological target. The immense body of related clinical and preclinical data offers a unique opportunity to explore the possible factors underlying inter-statin and inter-individual variabilities.Area covered: Clinical and preclinical data from various statins were compiled with regard to the efficacy (cholesterol-lowering effect) and safety (muscle toxicity). Based on the compiled data, dose- and exposure-response relationships were explored to obtain mechanistic and quantitative insights into the variations in the efficacy and safety profiles of statins.Expert opinion: Our analyses indicated that the inter-statin variability in the cholesterol-lowering effect may be mainly attributable to variations in potency of inhibition of the pharmacological target, rather than variations in drug exposure at the site of drug action. However, the drug exposure at the sites of drug action (i.e., the liver for efficacy and the muscle for safety) may contribute to the differences in the efficacy and safety observed in individual patients.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Doenças Musculares/induzido quimicamente , Animais , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Relação Dose-Resposta a Droga , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/epidemiologia
7.
Expert Opin Drug Saf ; 18(12): 1191-1201, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31623472

RESUMO

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are novel drugs that have been developed since the discovery of the PCSK9 protein in 2003. In addition to background statin treatment, they reduce low-density lipoprotein cholesterol (LDL-C) to unprecedented levels and have shown encouraging results in improving cardiovascular events. Concerns regarding the safety of PCSK9 inhibitors and very low LDL-C have somewhat been allayed after several longer-term prospective studies.Areas covered: A comprehensive literature search was carried out including article searches in electronic databases (EMBASE, PUBMED, OVID) and reference lists of relevant articles. This review examines novel research concerning PCSK9 monoclonal antibodies and cardiovascular outcomes with a special focus on their safety and tolerability. The safety of very low LDL-C concentrations and the link between LDL-C lowering and diabetes is also discussed.Expert opinion: PCSK9 monoclonal antibodies when added to background statin therapy, lowers LDL-C to previously unattainable levels. This is safe with little undesirable effects and impacts positively on cardiovascular disease. Current guidance limits their use to primary prevention. Cost effectiveness should be taken into consideration before allowing a wider use of this new class of cholesterol lowering therapy and more data on their long-term safety is welcome.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Pró-Proteína Convertase 9/antagonistas & inibidores , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Prevenção Primária , Pró-Proteína Convertase 9/imunologia
10.
J Oleo Sci ; 68(9): 811-816, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31413246

RESUMO

Cardiovascular disease (CVD) has emerged as the leading cause of dealth worldwide today. Lowering circulating total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) is one of the most effective approaches of CVD prevention. Dietary guidelines and health organizations approved using plant sterols (PS) as the alternative to conventional method in attenuating circulating TC and LDL-C levels and risk of CVD. However, current findings apprear to be controversial on the efficacy of PS. Giving the rise of the field "Nutrigenetics", single nucleotide polymorphisms (SNPs) such as CYP7A1-rs3808607 have been identified that strongly associate with cholesterol metabolism in response to PS intake, towards causing inter-individual variations. This review article aims to discuss the efficacy of dietary PS in managing cholesterol levels based on findings from recent studies. The scope includes reviewing evidence on supporting the efficacy, the metabolic claims, inter-individual variations as well as sitosterolemia associated with PS intake.


Assuntos
Anticolesterolemiantes/uso terapêutico , Fitosteróis/uso terapêutico , Animais , Anticolesterolemiantes/efeitos adversos , Doenças Cardiovasculares/dietoterapia , Colesterol/sangue , Colesterol/metabolismo , Colesterol 7-alfa-Hidroxilase/genética , LDL-Colesterol/sangue , LDL-Colesterol/metabolismo , Humanos , Fitosteróis/efeitos adversos , Polimorfismo de Nucleotídeo Único
11.
EuroIntervention ; 15(12): e1099-e1106, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31334703

RESUMO

AIMS: We aimed to assess the effect of 10 mg/day of rosuvastatin plus eicosapentaenoic acid (EPA) versus 2.5 mg/day of rosuvastatin on the extent of neoatherosclerosis using optical coherence tomography (OCT). METHODS AND RESULTS: We randomly assigned 50 patients with non-obstructive neoatherosclerotic plaques detected on OCT to receive either rosuvastatin 10 mg/day and EPA 1,800 mg/day (intensive therapy group) or rosuvastatin 2.5 mg (standard therapy group). Follow-up OCT was performed one year later to evaluate serial changes in neoatherosclerosis. The serum low-density lipoprotein cholesterol (LDL-C) level decreased significantly from baseline to 12-month follow-up in the intensive therapy group (89 mg/dL to 70 mg/dL; p<0.001), while no change occurred in the standard therapy group. Lipid index change and percent changes in macrophage grade were significantly lower in the intensive therapy group than in the standard therapy group (-53.6 vs 310.1, p=0.001; -37.0% vs 35.3%, p<0.001; respectively). Percent changes in lipid index and macrophage grade were positively correlated with the changes in serum LDL-C and C-reactive protein levels, and negatively correlated with the change in serum EPA/arachidonic acid and 18-hydroxyeicosapentaenoic acid (EPA bioactive metabolite) level. CONCLUSIONS: Compared with rosuvastatin 2.5 mg/day, rosuvastatin 10 mg/day and EPA 1,800 mg/day significantly stabilised non-obstructive neoatherosclerotic plaques. CLINICAL TRIAL REGISTRATION: UMIN ID: UMIN000012576. https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000014711.


Assuntos
Aterosclerose/tratamento farmacológico , Ácido Eicosapentaenoico/uso terapêutico , Rosuvastatina Cálcica/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , Relação Dose-Resposta a Droga , Ácido Eicosapentaenoico/administração & dosagem , Ácido Eicosapentaenoico/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases , Estudos Prospectivos , Rosuvastatina Cálcica/administração & dosagem , Rosuvastatina Cálcica/efeitos adversos , Tomografia de Coerência Óptica , Resultado do Tratamento
12.
J Nippon Med Sch ; 86(3): 187-190, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31292332

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that targets the low-density lipoprotein (LDL) receptor for lysosomal degradation. PCSK9 impedes the receptor-mediated clearance of LDL-cholesterol, thereby increasing serum LDL-cholesterol levels. Evolocumab, a human monoclonal antibody against PCSK9, effectively reduces serum LDL-cholesterol levels. We report the first known case of a patient who developed an atopic dermatitis (AD)-like rash during evolocumab therapy. A 43-year-old Japanese man with heterozygous familial hypercholesterolemia was treated with subcutaneous injection of 140 mg evolocumab biweekly, for 16 months. The therapy was then changed to subcutaneous injection of 420 mg evolocumab monthly. A few days after the first dose, the patient experienced pruritus and rash on his extremities. The rash worsened, while the pruritus subsided, then relapsed after the second and third doses. He had erythema and excoriation on his legs, lichenification over his popliteal fossa, xerosis on his forearms, an increased serum IgE level, and a family history of AD in his siblings. We made a provisional diagnosis of AD characterized by enhanced type 2 helper T (Th2) activity and treated him with topical corticosteroids and oral anti-histamines. His rash improved and did not relapse after the fifth dose; however, his LDL-cholesterol level increased. PCSK9 or oxidized LDL activates macrophages or dendritic cells, respectively, and enhances their activity to induce Th1 cells antagonizing Th2 cells. We hypothesized that high-dose evolocumab may suppress Th1 activity to antagonize Th2, and unmask Th2 disposition based on the patient's atopic diathesis, triggering the rash mimicking AD. Clinicians should be aware of rash development during evolocumab therapy.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Dermatite Atópica/induzido quimicamente , Exantema/induzido quimicamente , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Hiperlipoproteinemia Tipo II/genética , Adulto , Dermatite Atópica/imunologia , Exantema/imunologia , Humanos , Hiperlipoproteinemia Tipo II/imunologia , Injeções Subcutâneas , Masculino , Terapia de Alvo Molecular , Pró-Proteína Convertase 9/imunologia , Pró-Proteína Convertase 9/fisiologia , Células Th1/imunologia , Células Th2/imunologia
13.
High Blood Press Cardiovasc Prev ; 26(3): 199-207, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236902

RESUMO

Proprotein convertase subtilisin/kexin type 9 (PCSK9)-related discoveries of the turn of the century have translated into substantial novelty in dyslipidemia treatment in the last 5 years. With chronic preventable atherosclerotic cardiovascular diseases (ASCVD) representing an epidemic of morbidity and mortality worldwide, low-density lipoprotein cholesterol (LDL-c) reduction represents a public health priority. By overcoming two major statin-related issues, namely intolerance and ineffectiveness, PCSK9 inhibitors have offered a safe and effective option in selected clinical settings where LDL-c reduction is required. Herein, we recapitulate recent findings, clinical applications, and ASCVD prevention potential of PCSK9 inhibition, with focus on anti-PCSK9 monoclonal antibodies, evolocumab and alirocumab.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Anticolesterolemiantes/uso terapêutico , Aterosclerose/prevenção & controle , LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Aterosclerose/sangue , Aterosclerose/enzimologia , Aterosclerose/epidemiologia , Biomarcadores/sangue , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
14.
Rev Cardiovasc Med ; 20(1): 1-8, 2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-31184090

RESUMO

Cardiovascular disease is the leading cause of morbidity and mortality globally, as estimated by the World Health Organization, where in 2016, 15.2 million deaths were attributed to ischemic heart disease and stroke. It is therefore essential to try to reduce the incidence of Cardiovascular disease by controlling modifiable risk factors. One such major modifiable risk factor is cholesterol, which influences the pathogenesis and progression of atherosclerosis. Statins are often prescribed to lower blood levels of low density lipoprotein cholesterol, thereby reducing the risk of Cardiovascular disease by approximately 25-35%. However, there is an increasing number of patients (in particular those with intolerance to statin therapy and those with familial hypercholesterolemia) for whom statin therapy alone is not enough to control low density lipoprotein cholesterol. In this review, the regulation of cholesterol metabolism will be discussed with an emphasis on novel cholesterol lowering drugs used in clinical trials. These second-generation drugs, monoclonal antibodies against the low density lipoprotein receptor gene known as proprotein convertase subtilisin/kexin type 9 inhibitors, are expected to be prescribed to patients who are intolerant to statins, as well as in conjunction with statins. Future perspectives of the clinical use of these drugs is also discussed.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/enzimologia , Dislipidemias/epidemiologia , Humanos , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
15.
Chem Pharm Bull (Tokyo) ; 67(5): 419-425, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31061366

RESUMO

Patients with type 2 diabetes (T2DM) and hyperlipidemia are with high risk of myocardial infarction (MI) or coronary death events. The combined use of ezetimibe and atorvastatin could improve treatment efficacy and safety. To explore the efficacy and safety of ezetimibe in combination with atorvastatin for the treatment of patients with T2DM and acute coronary syndrome (ACS). This was a non-randomized cohort study of 95 consecutive, treatment-naïve patients with T2DM and ACS treated at the Quanzhou First Hospital of Fujian Province between February 2014 and March 2016. According to the treatment strategy they selected, the patients were categorized into the atorvastatin (n = 46) and atorvastatin + ezetimibe (n = 49) groups. The patients were followed up at 2 weeks and 12 months. The primary endpoints included the incidence of adverse cardiovascular events and changed in blood lipids and high-sensitivity C-reactive protein (hs-CRP). At 12 months, serum total cholesterol (TC), triglycerides, and low-density lipoprotein cholesterol (LDL-C) levels were significantly lower, and high-density lipoprotein cholesterol (HDL-C) levels were significantly higher in the atorvastatin + ezetimibe (EZ) group than in the atorvastatin group (all p < 0.05). The LDL-C control rate at 12 months was significantly higher in the atorvastatin + EZ group compared with the atorvastatin group (p = 0.006). Seven patients in the atorvastatin group were re-hospitalized for angina pectoris, while only one patient in the atorvastatin + EZ group was re-hospitalized for angina pectoris (p = 0.02). The efficacy of atorvastatin + EZ in treating T2DM patients accompanied with ACS was significantly higher than using atorvastatin alone. This combined strategy has good safety profile, and could be recommended for clinical application.


Assuntos
Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/tratamento farmacológico , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Ezetimiba/uso terapêutico , Síndrome Coronariana Aguda/sangue , Anticolesterolemiantes/efeitos adversos , Atorvastatina/efeitos adversos , Proteína C-Reativa/análise , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Quimioterapia Combinada , Ezetimiba/efeitos adversos , Feminino , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Miocárdio/enzimologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-31049144

RESUMO

Given its role in many biochemical processes essential to life, cholesterol remains a topic of intense research. Of all the plasma lipids, cholesterol is distinctive because it is a precursor to steroidogenic molecules, some of which regulate metabolism, and its blood concentration in the form of low- and high-density lipoprotein cholesterol (HDL-C) are positive and negative risk factors for atherosclerotic cardiovascular disease (ASCVD). New research, however, has challenged the widely held belief that high HDL-C levels are atheroprotective and is showing that both low and high plasma HDL-C levels confer an increased risk of ASCVD. Furthermore, it is disputing the widely cited mechanism involved in reverse cholesterol transport. This review explores the evolution of cholesterol research starting with the Gofman and Framingham studies, the development of traditional and emerging lipid-lowering therapies, and the role of reverse cholesterol transport in HDL cardioprotection.


Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Aterosclerose/etiologia , Colesterol na Dieta/efeitos adversos , Colesterol na Dieta/sangue , HDL-Colesterol/efeitos adversos , HDL-Colesterol/sangue , LDL-Colesterol/efeitos adversos , LDL-Colesterol/sangue , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/genética , Aterosclerose/prevenção & controle , Transporte Biológico , Humanos , Placa Aterosclerótica , Prognóstico , Fatores de Proteção , Fatores de Risco
17.
Methodist Debakey Cardiovasc J ; 15(1): 39-46, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049148

RESUMO

High-density lipoprotein (HDL) is a protein-lipid nanoparticle that has predominately been characterized by its cholesterol concentration (HDL-C). Recent studies have challenged the presumed inverse association between HDL-C and cardiovascular events, suggesting a more U-shaped association. This has opened new opportunities to evaluate more novel measures of HDL metabolism, such as HDL particle number (HDL-P) and one of HDL's key functions, cholesterol efflux. Both HDL-P and cholesterol efflux are inversely associated with incident cardiovascular events and may perhaps be better targets for intervention. This review includes recent research on the emerging U-shaped association between HDL-C and cardiovascular events, recent observational studies related to HDL-P, and the effects of established and novel interventions on cholesterol efflux.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , HDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Animais , Anticolesterolemiantes/efeitos adversos , Transporte Biológico , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Proteínas de Transferência de Ésteres de Colesterol/sangue , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Exercício , Humanos , Comportamento de Redução do Risco , Resultado do Tratamento
18.
Methodist Debakey Cardiovasc J ; 15(1): 70-76, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049152

RESUMO

Besides the well-known hepatobiliary pathway of cholesterol excretion into the feces, transintestinal cholesterol excretion (TICE) is a second major pathway through which cholesterol is disposed from the body. In the process of TICE, cholesterol is taken up from lipoprotein particles at the basolateral side of the enterocyte and translocates towards the apical side of the enterocyte. At the apical side, the ATP-binding cassette transporters G5 and G8 form a heterodimer that transports cholesterol into the intestinal lumen. A substantial amount of the secreted cholesterol is likely reabsorbed by the cholesterol influx transporter Niemann-Pick C1-Like 1 (NPC1L1) since recent data indicate that inhibition of NPC1L1 increases the efficacy of TICE for disposal of cholesterol via the feces. The pathways and proteins involved in intracellular cholesterol trafficking in the enterocyte have not yet been identified. Therefore, in addition to discussing known mediators of TICE, this review will also examine potential candidates involved in cholesterol translocation in the enterocyte. Both the cholesterol reuptake and efflux pathways can be influenced by pharmaceutical means; thus, the TICE pathway is a very attractive target to increase cholesterol excretion from the body and prevent or mitigate atherosclerotic cardiovascular disease.


Assuntos
Anticolesterolemiantes/uso terapêutico , Doenças Cardiovasculares/prevenção & controle , Colesterol/sangue , Dislipidemias/tratamento farmacológico , Enterócitos/efeitos dos fármacos , Eliminação Intestinal/efeitos dos fármacos , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Animais , Anticolesterolemiantes/efeitos adversos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , Regulação para Baixo , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Enterócitos/metabolismo , Fezes/química , Humanos , Proteínas de Membrana Transportadoras/metabolismo
19.
BMJ Case Rep ; 12(5)2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068355

RESUMO

Necrotising autoimmune myopathy (NAM) is an immune-mediated myopathy that may be associated with statin use, malignancy or an autoimmune connective tissue disease, but it can also be idiopathic. Anti-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) myopathy is an extremely rare side effect of statin use, occurring in approximately 2-3 out of every 100 000 patients who use statins. Patients typically present with subacute proximal muscle weakness and creatine kinase levels >10 times the upper limit of normal. The diagnosis is suggested by muscle biopsy showing necrotic fibres with minimal inflammation along with positive anti-HMGCR antibodies. Treatment nearly always requires multiple immunosuppressive agents, the earlier use of which is associated with improved outcomes. Reports of statin-induced NAM leading to heart failure are limited. We present the case of a 69-year-old woman with statin-induced NAM who presented with acute systolic heart failure. Early initiation of high-dose corticosteroids and IVIG resulted in significant improvement in her symptoms.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Atorvastatina/efeitos adversos , Insuficiência Cardíaca Sistólica/induzido quimicamente , Hidroximetilglutaril-CoA Redutases/efeitos dos fármacos , Metilprednisolona/administração & dosagem , Debilidade Muscular/induzido quimicamente , Doenças Musculares/induzido quimicamente , Idoso , Creatina Quinase , Feminino , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Debilidade Muscular/fisiopatologia , Doenças Musculares/fisiopatologia , Resultado do Tratamento
20.
Drugs ; 79(7): 751-766, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30989634

RESUMO

AIM: Our aim was to assess the efficacy and safety of mipomersen through a systematic review of the literature and a meta-analysis of the available clinical studies. METHODS: A systematic literature search in SCOPUS, PubMed Medline, ISI Web of Science and Google Scholar databases was conducted up to January 20, 2019, in order to identify clinical trials assessing the effect of mipomersen on lipoproteins, and the safety profile of mipomersen. Effect sizes for lipid changes were expressed as weighted mean differences (WMD) and 95% confidence intervals (CI). For safety analysis, odd ratios (OR) and 95% CI were calculated using the Mantel-Haenszel method. Data were pooled from 13 clinical studies comprising 49 arms, which included 1053 subjects overall, with 729 in the active-treated arm and 324 in the control arm. RESULTS: Meta-analysis of data suggested that mipomersen significantly reduced low-density lipoprotein cholesterol (WMD - 1.52, 95% CI - 1.85 to - 1.19; p < 0.001), total cholesterol (WMD - 1.55, 95% CI - 1.97 to - 1.13; p < 0.001), non-high-density lipoprotein cholesterol (non-HDL-C) (WMD - 1.66, 95% CI - 2.06 to - 1.27; p < 0.001), lipoprotein(a) (WMD - 0.99, 95% CI - 1.37 to - 0.62; p < 0.001), apolipoprotein B (WMD - 1.66, 95% CI - 2.04 to - 1.27; p < 0.001), triglycerides (WMD -0.61, 95% CI - 0.76 to - 0.46, p < 0.001), very-low-density lipoprotein cholesterol (WMD - 0.58, 95% CI - 0.73 to - 0.43; p < 0.001) and apolipoprotein A-I (WMD - 0.25, 95% CI - 0.51 to - 0.001; p = 0.049) without affecting HDL-C levels (WMD 0.11, 95% CI - 0.03 to 0.26; p = 0.124). However, treatment with mipomersen was positively associated with an increased risk of discontinuation of treatment (OR 3.02, 95% CI 1.96-4.65; p < 0.001), injection-site reaction (OR 11.41, 95% CI 7.88-16.52; p < 0.001), hepatic steatosis (OR 4.96, 95% CI 1.99-12.39; p = 0.001), hepatic enzymes elevation (OR 3.61, 95% CI 2.09-6.24; p < 0.001) and flu-like symptoms (OR 2.02, 95% CI 1.45-2.81; p < 0.001). CONCLUSION: Despite favourable effects on the lipid profile, some concerns are reinforced from the safety profile. As a matter of fact, mipomersen therapy is more likely discontinued and associated with increased risk of injection-site reactions, hepatic steatosis, hepatic enzyme elevation, and flu-like symptoms.


Assuntos
Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/farmacologia , Oligonucleotídeos/efeitos adversos , Oligonucleotídeos/farmacologia , Adolescente , Adulto , Idoso , Apolipoproteína A-I/metabolismo , LDL-Colesterol/metabolismo , Fígado Gorduroso/tratamento farmacológico , Feminino , Humanos , Lipídeos , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Triglicerídeos/metabolismo
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