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1.
Wiad Lek ; 72(11 cz 2): 2210-2213, 2019.
Artigo em Polonês | MEDLINE | ID: mdl-31860838

RESUMO

Cardiovascular disease is the leading cause of death among patients with chronic kidney disease (CKD). Primary and secondary prevention of cardiovascular events is one of the major CKD patients' treatment targets. Dyslipidaemia is the important modifiable risk factor in general population. Each 1.0 mmol reduction in LDL cholesterol with statins reduces annual rate of heart attack, coronary revascularization or ischemic stroke by 20% leading to 10% reduction of all-cause mortality. Adding ezetimibe, an inhibitor of intestinal lipids absorption, further reduces LDL cholesterol by 20%. Optimal lipid lowering treatment for CKD patients remains unclear. Cardiovascular risk reduction observed with statins therapy decreases together with a progression of the disease, moreover patients with advanced CKD treated with high doses of statins have an increased risk of adverse events. These patients might benefit from adding ezetimibe to moderate dose statin therapy for prevention of cardiovascular events.


Assuntos
Dislipidemias , Ezetimiba/uso terapêutico , Insuficiência Renal Crônica , Doenças Cardiovasculares , LDL-Colesterol , Dislipidemias/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases
2.
Prog Cardiovasc Dis ; 62(5): 395-400, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31715195

RESUMO

Statin therapy is effective in primary and secondary prevention, but substantial residual risk remains on statin treatment, especially among high risk and very high risk patients. Add-on therapy with ezetimibe and proprotein convertase subtilisin /kexin type 9 (PCSK9) inhibitors provides additional risk reduction through further reduction in low density lipoprotein cholesterol. Elevated triglycerides/triglyceride rich lipoproteins contribute to atherogenesis and to the residual risk on statin therapy. Addition of icosapent ethyl to statins has recently been shown to markedly lower risk of ASCVD events in patients with established atherosclerotic CVD (ASCVD) and high risk patients with type II diabetes mellitus. These data are discussed in the context of current guidelines and synthesized in a decision pathway to guide combination lipid-lowering therapy in patients at high ASCVD risk.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Ácido Eicosapentaenoico/análogos & derivados , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores de Serino Proteinase/uso terapêutico , Biomarcadores/sangue , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Ácido Eicosapentaenoico/efeitos adversos , Ácido Eicosapentaenoico/uso terapêutico , Ezetimiba/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Guias de Prática Clínica como Assunto , Pró-Proteína Convertase 9/metabolismo , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento , Triglicerídeos/sangue
3.
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.
Adv Clin Exp Med ; 28(9): 1243-1248, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31430072

RESUMO

BACKGROUND: FoxP3 is a marker of human T regulatory cells (Tregs), which are supposed to play an important role in the pathophysiology of atherosclerosis. Interleukin 10 (IL-10) is a cytokine with pleiotropic, immunoregulatory properties, produced mostly by Tregs and B regulatory cells. Due to their anti-inflammatory action, both Tregs and IL-10 are believed to inhibit plaque development and decrease atherosclerosis progression. The effect of hypolipidemic drugs - statins or ezetimibe - on FoxP3-positive Tregs and anti-inflammatory cytokines, such as IL-10, is still unclear. OBJECTIVES: The objective of the study was to investigate the effects of 3 different therapies of equivalent hypolipidemic activity: atorvastatin, rosuvastatin, and combination therapy of atorvastatin and ezetimibe on FoxP3-Tregs transcription factor and IL-10 mRNA expression in peripheral blood mononuclear cells (PBMCs) from patients with stable coronary artery disease (CAD). MATERIAL AND METHODS: Sixty-five patients with diagnosed CAD participated in the study. They were randomly assigned to 3 therapeutic groups: atorvastatin at a dose of 40 mg/day (A40 group); rosuvastatin 20 mg/day (R20 group); and atorvastatin 10 mg/day combined with ezetimibe 10 mg/day (A10+E10 group). After 1 month and 6 months of therapy, the mRNA expression for FoxP3 and IL-10 in PBMCs was evaluated using real-time polymerase chain reaction (RT-PCR) and lipid parameters. RESULTS: An improvement in lipid parameters was observed in each of the groups studied; however, hypolipidemic treatment did not induce any change in FoxP3 and IL-10 mRNA expression. After 6 months, an increase in FoxP3 mRNA expression was noted in A40 group as compared to R20 group. CONCLUSIONS: None of the therapies of equal hypolipidemic efficacy affected FoxP3 and IL-10 mRNA expression in patients with stable CAD.


Assuntos
Anticolesterolemiantes , Doença da Artéria Coronariana , Inibidores de Hidroximetilglutaril-CoA Redutases , Anticolesterolemiantes/uso terapêutico , Atorvastatina/uso terapêutico , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/metabolismo , Ezetimiba/uso terapêutico , Fatores de Transcrição Forkhead/metabolismo , Regulação da Expressão Gênica , Humanos , Interleucina-10/metabolismo , Leucócitos Mononucleares , RNA Mensageiro
6.
Rev Port Cardiol ; 38(6): 391-405, 2019 06.
Artigo em Inglês, Português | MEDLINE | ID: mdl-31324407

RESUMO

Reducing low-density lipoprotein cholesterol (LDL-C) levels is one of the most important strategies for reducing the risk of cardiovascular events. However, in clinical practice, a high proportion of patients do not achieve recommended LDL-C levels through lifestyle and lipid-lowering therapy with statins and ezetimibe. PCSK9 inhibitors (PCSK9i) are a new therapeutic option that significantly (50-60%) reduces LDL-C levels, which in clinical trials translates into an additional reduction in risk for cardiovascular events, and has a good safety profile. However, it is a high-cost therapy, and therefore its use in clinical practice should take its cost-effectiveness into account. Priority should be given to use in patients at higher cardiovascular risk and those in whom high LDL-C levels persist despite optimal lipid-lowering therapy. This consensus document aims to summarize the main data on the clinical use of PCSK9i and to make recommendations for Portugal on the profile of patients who may benefit most from this therapy.


Assuntos
LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/efeitos dos fármacos , Dislipidemias/sangue , Dislipidemias/epidemiologia , Humanos , Incidência , Portugal/epidemiologia
7.
Expert Opin Pharmacother ; 20(16): 2007-2017, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31344332

RESUMO

Introduction: Cardiovascular disease (CVD) frequently co-exists with chronic kidney disease (CKD). Patients with concomitant CVD and CKD are at very high risk of CVD events. Areas covered: This narrative review discusses the use of hypolipidaemic drugs in patients with both CVD and CKD. Current guidelines are considered together with the evidence from randomised controlled clinical trials. Expert opinion: Statins are the first-line lipid-lowering therapy in patients with CVD and CKD. Some statins require dose adjustments based on renal function, whereas atorvastatin does not. Ezetimibe can be prescribed in patients with CVD and CKD, usually combined with a statin. According to current guidelines, statin±ezetimibe therapy should not be initiated, but should be continued, in dialysis-treated CKD patients. Fenofibrate (dose adjusted or contra-indicated according to renal function) and omega 3 fatty acids lower triglyceride levels; whether they also exert cardiorenal benefits in patients with CVD and CKD remains to be established. The use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, cholesterol-reducing nutraceuticals, bempedoic acid and apabetalone in such patients should be investigated. Patients with concomitant CVD and CKD should be treated, in terms of lipid-lowering therapy, early and intensively to minimize their very high risk and possibly, progression of CKD.


Assuntos
Doenças Cardiovasculares/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Insuficiência Renal Crônica/tratamento farmacológico , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/patologia , LDL-Colesterol/sangue , Ezetimiba/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Fenofibrato/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia
8.
Expert Opin Pharmacother ; 20(14): 1719-1729, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31232617

RESUMO

Introduction: Cardiovascular disease is an important cause of morbidity and mortality in persons with human immunodeficiency virus (PWH). The risk of atherosclerotic cardiovascular disease (ASCVD) is higher in PWH compared to uninfected persons. Dyslipidemia is a critical link in the pathogenesis of ASCVD in PWH. Chronic inflammation associated with HIV infection may drive both dyslipidemia and ASCVD. Areas covered: The authors review the evidence for using lipid-lowering therapy in PWH and includes an overview of the utility and complexity of using statins in PWH, in particular, drug interactions, safety, and efficacy. In addition, data covering alternate therapies like omega-3 fatty acids, fibrates, niacin, ezetimibe, and PCSK-9 inhibitors are reviewed. Expert opinion: Dyslipidemia is a common problem in PWH. The risk of ASCVD is higher in PWH. Lipid-lowering therapy reduces the risk of ASCVD, but clinical endpoint trials are lacking in PWH. Statin therapy is the mainstay of primary prevention for ASCVD. The timing of when to initiate primary prevention with statins in PWH is unclear. Beyond statins, there are limited data that other lipid-lowering agents have utility in PWH. Ongoing trials like the REPRIEVE trial will inform the community about the optimal approach to lipid-lowering therapy in PWH.


Assuntos
Dislipidemias/tratamento farmacológico , Infecções por HIV/patologia , Hipolipemiantes/uso terapêutico , Antirretrovirais/efeitos adversos , Antirretrovirais/química , Antirretrovirais/uso terapêutico , Interações de Medicamentos , Dislipidemias/etiologia , Ezetimiba/uso terapêutico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/química , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Niacina/uso terapêutico , Medição de Risco
9.
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
10.
Medicina (B Aires) ; 79(2): 104-110, 2019.
Artigo em Espanhol | MEDLINE | ID: mdl-31048275

RESUMO

LDL-cholesterol (LDL-C) lowering is a primary objective in cardiovascular prevention. Recent studies demonstrated clinical benefit when proprotein convertase subtilisin/kexin-9 inhibitors (PCSK9i) were added to the treatment in patients who had not achieved the LDL-C goal despite being treated with high intensity statins and ezetimibe, however the use of these drugs is limited by their cost. The American College of Cardiology, the Argentine Society of Cardiology and the European Society of Cardiology recommend an LDL-C goal less than 70 mg/dl in secondary prevention, determining thresholds of LDL-C to start treatment with PCSK9i of 70, 100 or 140 mg/dl respectively. In order to evaluate the lipid-lowering regimen prescribed in patients hospitalized for acute coronary syndrome or coronary revascularization and analyze the proportion of eligible to be treated with PCSK9i in a real and simulated scenario, we conducted a study that included 351 patients with coronary disease collected from an electronic database of a university hospital. The 48.4% received high intensity statins, 11.4% ezetimibe and 54.7% did not achieve the LDL-C goal of less than 70 mg/dL. Using a simulation model in which all would be treated with high intensity statins and ezetimibe, the eligibility to prescribe PCSK9i was 31.1%, 12.8% and 9.1% according to the C- LDL thresholds determined by the three scientific societies. Our study demonstrated a gap between the consensus recommendations for LDL-C lowering and the current practice that should be minimized to optimize the cost/effectiveness ratio in secondary prevention.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Pró-Proteína Convertase 9/antagonistas & inibidores , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Argentina , Estudos Transversais , Ezetimiba/uso terapêutico , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , Guias de Prática Clínica como Assunto , Fatores Sexuais , Sociedades Científicas , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
11.
Methodist Debakey Cardiovasc J ; 15(1): 32-38, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049147

RESUMO

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease (ASCVD). Statins remain the first-line therapy for patients with elevated LDL-C and increased risk. However, many at-risk patients do not achieve adequate LDL-C lowering with statin monotherapy or do not tolerate statins because of side effects. Recent cardiovascular outcome trials involving ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have demonstrated efficacy of nonstatin therapies in further reducing LDL-C levels and ASCVD risk. This review highlights the available nonstatin therapeutic options and explores important novel therapeutic approaches currently under development.


Assuntos
Doenças Cardiovasculares/prevenção & controle , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Serino Proteinase/uso terapêutico , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/uso terapêutico , Quimioterapia Combinada , Dislipidemias/sangue , Dislipidemias/epidemiologia , Dislipidemias/genética , Ezetimiba/uso terapêutico , Ácidos Graxos/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pró-Proteína Convertase 9/antagonistas & inibidores , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi , Fatores de Risco , Inibidores de Serino Proteinase/efeitos adversos , Resultado do Tratamento
13.
Expert Opin Pharmacother ; 20(8): 917-928, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30908086

RESUMO

INTRODUCTION: Cardiovascular disease is a major cause of morbidity and mortality throughout the world and hypercholesterolemia is one of the key risk factors. Statins are the first line treatment to reduce atherogenic lipids and there is substantial and robust evidence with atorvastatin for reduction of cardiovascular events and mortality. Ezetimibe can be combined with any dose of atorvastatin for incremental lipid-lowering effects. Areas covered: In this review, the authors summarize the pharmacokinetics, pharmacodynamics and clinical efficacy of the components and the combination of ezetimibe and atorvastatin. Clinical benefits have been seen with ezetimibe combined with simvastatin but studies of its combination with atorvastatin are generally limited to the effects on lipid parameters where the addition of ezetimibe to atorvastatin is generally more effective than titrating the atorvastatin dose. Expert opinion: Although there are no cardiovascular outcomes studies with the combination of ezetimibe and atorvastatin, the greater reduction in atherogenic lipids can be assumed to have greater benefits in reducing cardiovascular events. The ezetimibe-atorvastatin combination is very effective in this respect and well tolerated. Fixed-dose combinations improve medication adherence and this combination should be useful for patients who cannot reach their lipid targets with maximally tolerated statin doses.


Assuntos
Atorvastatina/administração & dosagem , Ezetimiba/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Doenças Cardiovasculares/prevenção & controle , Combinação de Medicamentos , Ezetimiba/uso terapêutico , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Fatores de Risco , Sinvastatina/administração & dosagem , Sinvastatina/uso terapêutico
14.
Maturitas ; 124: 93-99, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30910278

RESUMO

The impact of dyslipidaemias on the risk of cardiovascular disease (CVD) is well documented. However, it is often under-estimated and, sometimes, suboptimally managed in the elderly population. The prevalence of dyslipidaemias seems to decline from the 7th decade of life in both genders. The association of dyslipidaemias with CVD weakens after the 7th decade, perhaps due to other age-related comorbidities. Low-density lipoprotein cholesterol remains the main target in the management of CVD risk. Although the evidence is not robust for the elderly, statins are the cornerstone of the management of CVD. Statins do have a potentially beneficial role in elderly individuals with established CVD and/or a history of type 2 diabetes mellitus. Data on their use in other elderly populations are inconsistent. There is no clear evidence for a beneficial effect of other hypolipidaemic drug categories in the elderly, such as ezetimibe, fibrates, niacin, omega-3 fatty acids and the new proprotein convertase subtilisin/kexin type 9 inhibitors. Their use should be balanced against possible adverse effects, such as the increased risk of myopathy with fibrates. Potential drug-drug interactions should be also taken into account. In conclusion, there is a need to establish the most effective lipid-lowering strategy in the elderly population with respect to CVD risk reduction, in future well-designed trials.


Assuntos
Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Idoso , LDL-Colesterol/sangue , Dieta , Dislipidemias/sangue , Dislipidemias/terapia , Ezetimiba/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Ácidos Fíbricos/uso terapêutico , Humanos , Pró-Proteína Convertase 9/antagonistas & inibidores
15.
Expert Opin Pharmacother ; 20(7): 791-803, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30810432

RESUMO

INTRODUCTION: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.


Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hiperlipidemias/tratamento farmacológico , ATP Citrato (pro-S)-Liase/antagonistas & inibidores , ATP Citrato (pro-S)-Liase/genética , ATP Citrato (pro-S)-Liase/metabolismo , Animais , Anticolesterolemiantes/efeitos adversos , Aterosclerose/tratamento farmacológico , Proteína C-Reativa/metabolismo , Ensaios Clínicos como Assunto , Ácidos Dicarboxílicos/efeitos adversos , Quimioterapia Combinada , Ezetimiba/uso terapêutico , Ácidos Graxos/efeitos adversos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Fígado/metabolismo
16.
Pharmazie ; 74(1): 8-14, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30782243

RESUMO

This study aimed to conduct a network meta-analysis of the efficacy and safety of different doses of alirocumab in reducing low-density lipoprotein cholesterol levels. In the present study, a total of 16 studies were selected, published between January 2012 and October 2016. Pair-wise and network meta-analyses was used to carry out a direct and indirect comparison of the three treatment strategies of alirocumab in patients with hypercholesterolemia. The efficacy and safety of these different treatment strategies were analyzed. Results revealed that alirocumab could significantly reduce LDL-c levels, compared with placebo (relative effect 95 % CI: -71.45 [-91.16, -50.44], -74.32 [-90.40, -58.63] and -77.28 [-92.21, -61.90]) and ezetimibe (EZE) (relative effect 95 % CI: -37.2 [-61.21, -12.41], -40.07 [-56.92, -24.22] and -43.00 [-68.39, -17.91]). The comparison of the three treatment strategies of alirocumab indicated no significant differences in reducing the levels of LDL-c, TGs, TC, Lp (a), Apo B and SAEs, LTTD, IST, ACE, MD and NC. For the probabilities of 75 mg, 75-150 mg and 150 mg of alirocumab, the best treatment for EZE and placebo were 50 %, 68 %, 82 %, 1 % and 0 %, according to LDL-c level. The results of the benefit-risk analysis of efficacy and safety revealed that the logarithmic scale was 0.016 for 75 mg vs. 75-150 mg of alirocumab and 0.125 for 75-150 mg vs. 150 mg of alirocumab. The PCSK9 inhibitor alirocumab presents a significantly greater reducing effect on the levels of LDL-c compared with EZE, and the different doses of alirocumab exhibited no significant difference in the efficacy of LDL-c for hypercholesterolemia. An alirocumab dose of 75-150 mg Q2W might be the best choice due to its most favorable balance between efficacy and safety.


Assuntos
Anticorpos Monoclonais/administração & dosagem , Anticolesterolemiantes/administração & dosagem , Hipercolesterolemia/tratamento farmacológico , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Anticolesterolemiantes/efeitos adversos , Anticolesterolemiantes/uso terapêutico , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Ezetimiba/uso terapêutico , Humanos , Meta-Análise em Rede , Pró-Proteína Convertase 9/antagonistas & inibidores
17.
Medicine (Baltimore) ; 98(6): e14400, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732185

RESUMO

BACKGROUND: The comparative efficacy and safety of PCSK9 inhibitors, statins, and ezetimibe to lower lipid levels in patients with hypercholesterolemia remain unknown. We aimed to investigate the benefits and harms of the lipid-lowering agents in these patients. METHODS: PubMed, Embase, and the Cochrane Library were searched from January 1, 2000 to June 1, 2018 for relevant randomized controlled trials (RCTs). Frequentist network meta-analysis was used to pool all estimates. Ranking probabilities were used to rank the comparative effects of all drugs against placebo. RESULTS: Eighty-four RCTs enrolled 246,706 patients were included. Most of the included were assessed as low risk of bias. The probabilities of PCSK9 inhibitors that ranked first in improving lipid outcomes were all 100%. The probability of statins that ranked first in reducing the risk of cardiovascular (CV) events was 60.6%, and the probability of PCSK9 inhibitor was 37.1%, while no significant difference of efficacy in reducing CV events was observed between the 2 agents (odds ratios [OR] 0.98, 95% CI 0.87-1.11). Statin ranked first in reducing all-cause and CV death. Compared with placebo, statins were associated with reduced risks of all-cause (OR 0.90, 95% CI 0.85-0.96) and CV death (OR 0.83, 95% CI 0.75-0.91) while PCSK9 inhibitors and ezetimibe were not. No agents caused adverse events (including neurocognitive events), except that statins therapy significantly increases the levels of alanine aminotransferase (ALT) (OR 1.89, 95% CI 1.42-2.51) and creatine kinase (CK) (OR 1.45, 95% CI 1.09-1.93) and the incidence of diabetes (OR 1.13, 95% CI 1.02-1.26). CONCLUSIONS: PCSK9 inhibitors were the most effective lipid-lowering agents in improving lipid levels. Furthermore, PCSK9 inhibitors achieved similar CV benefits like statins, while PCSK9 inhibitors were not associated with any increased risk of statin-related side-effects. Thus, PCSK9 inhibitors may also be recommended as promisingly first-line lipid-lowering treatment for patients with hypercholesterolemia, especially for these with statins intolerance or resistance.


Assuntos
Ezetimiba/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Adulto , Idoso , Pesquisa Comparativa da Efetividade , Feminino , Humanos , Hipercolesterolemia/sangue , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Meta-Análise em Rede , Resultado do Tratamento
18.
Kardiol Pol ; 77(2): 207-216, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30740643

RESUMO

BACKGROUND: Due to the myopathic adverse events of statins, safer alternatives are being studied. Bempedoic acid (ETC-1002) is a novel low-density lipoprotein cholesterol (LDL-C)-lowering agent, currently under trial in hypercholesterolaemic patients. AIM: To investigate the tolerability and efficacy of ETC-1002 in hypercholesterolaemic patients through a systematic review of published randomised controlled trials (RCTs). METHODS: Five databases were searched for RCTs that investigated the safety and efficacy of ETC-1002 in hypercholesterol-aemic patients. The retrieved search results were screened, and then data were extracted and analysed (as mean difference [MD] or odds ratio [OR]) using the RevMan software. RESULTS: Five RCTs (625 hypercholesterolaemic patients) were identified. ETC-1002 was superior to placebo in terms of percent-age changes from baseline in serum levels of LDL-C (MD -26.58, 95% confidence interval [CI] -35.50 to -17.66, p < 0.0001), non-high-density lipoprotein cholesterol (MD -21.54, 95% CI -28.48 to -14.6, p < 0.00001), and apolipoprotein-B (MD -15.97, 95% CI -19.36 to -12.57, p < 0.0001). When compared to ezetimibe, ETC-1002 was superior in reducing LDL-C (-30.1 ± 1.3 vs. -21.1 ± 1.3). Regarding safety, ETC-1002 did not increase the risk of all adverse events (OR 0.58, 95% CI 0.37-0.91, p = 0.02) and arthralgia (OR 0.32, 95% CI 0.13-0.81, p = 0.02) compared to placebo. All other adverse events including myalgia, headache, and urinary tract infections were similar between ETC-1002 and placebo groups. The evidence certainty in the assessed outcomes was moderate to high except for lipoprotein(a), free fatty acids, and very low-density lipoprotein particle number (very low certainty). CONCLUSIONS: ETC-1002 is a safe and effective lipid-lowering agent and may be a suitable alternative in statin-intolerant pa-tients. Well-designed studies are needed to explore the long-term safety and efficacy of ETC-1002 in these patients.


Assuntos
Ácidos Dicarboxílicos/uso terapêutico , Ácidos Graxos/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Idoso , LDL-Colesterol/sangue , Ácidos Dicarboxílicos/efeitos adversos , Ezetimiba/efeitos adversos , Ezetimiba/uso terapêutico , Ácidos Graxos/efeitos adversos , Feminino , Humanos , Hipercolesterolemia/sangue , Hipolipemiantes/efeitos adversos , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
19.
Am J Cardiol ; 123(8): 1193-1201, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30739657

RESUMO

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p <0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.


Assuntos
Síndrome Coronariana Aguda/terapia , Ponte de Artéria Coronária/métodos , Combinação Ezetimiba e Simvastatina/uso terapêutico , Ezetimiba/uso terapêutico , Medição de Risco/métodos , Sinvastatina/uso terapêutico , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/mortalidade , Idoso , Anticolesterolemiantes/uso terapêutico , Causas de Morte/tendências , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Masculino , Pessoa de Meia-Idade , América do Norte/epidemiologia , Fenótipo , Fatores de Risco , Taxa de Sobrevida/tendências , Resultado do Tratamento
20.
Am J Cardiol ; 123(8): 1202-1207, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30736965

RESUMO

In a population with atherosclerotic cardiovascular disease, previous research indicated that approximately 86% can achieve low-density lipoprotein cholesterol (LDL-C) of <70 mg/dL with oral lipid-lowering therapies (LLT) only, whereas 14% would require a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. We aim to estimate these values accounting for varying levels of statin intolerance. A simulation model described previously was used to estimate the utilization of LLT needed to achieve LDL-C <70 mg/dL via an intensification algorithm which maximized statins before adding ezetimibe or a PCSK9 inhibitor. The current analysis took into account varying background rates of statin intolerance. We defined statin intolerance as either partial (inability to tolerate high-intensity statin) or full (inability to tolerate any statin). With treatment intensification and 10% of patients having partial statin intolerance, the use of ezetimibe (± statin ± PCSK9 inhibitor) increased from 32.7% to 34.9%, and the need for a PCSK9 inhibitor (+ ezetimibe ± statin) increased from 14.0% to 15.5%. If, instead, 10% were fully statin intolerant, the use of ezetimibe (± statin ± PCSK9 inhibitor) increased from 32.7% to 38.5%, and the use of a PCSK9 inhibitor (+ ezetimibe ± statin) increased from 14.0% to 19.7%. In conclusion, in our simulation-based study, partial statin intolerance increased the need for nonstatins only modestly (by an absolute 2.2%), whereas having 10% of patients with full statin intolerance increased the need for PCSK9 inhibitors from 14% overall to approximately 20%.


Assuntos
Algoritmos , Aterosclerose/tratamento farmacológico , Atorvastatina/uso terapêutico , LDL-Colesterol/sangue , Tolerância a Medicamentos , Ezetimiba/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Anticolesterolemiantes/uso terapêutico , Aterosclerose/sangue , Doenças Cardiovasculares , Quimioterapia Combinada , Seguimentos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Retrospectivos
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