RESUMO
OBJECTIVE: To assess whether Lp(a) (lipoprotein(a)) levels and other lipid levels were predictive of progression of atherosclerosis burden as assessed by carotid magnetic resonance imaging in subjects who have been treated with LDL-C (low-density lipoprotein cholesterol)-lowering therapy and participated in the AIM-HIGH trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes). APPROACH AND RESULTS: AIM-HIGH was a randomized, double-blind study of subjects with established vascular disease, elevated triglycerides, and low HDL-C (high-density lipoprotein cholesterol). One hundred fifty-two AIM-HIGH subjects underwent both baseline and 2-year follow-up carotid artery magnetic resonance imaging. Plaque burden was measured by the percent wall volume (%WV) of the carotid artery. Associations between annualized change in %WV with baseline and on-study (1 year) lipid variables were evaluated using multivariate linear regression and the Bonferroni correction to account for multiple comparisons. Average %WV at baseline was 41.6±6.8% and annualized change in %WV over 2 years ranged from -3.2% to 3.7% per year (mean: 0.2±1.1% per year; P=0.032). Increases in %WV were significantly associated with higher baseline Lp(a) (ß=0.34 per 1-SD increase of Lp(a); 95% confidence interval, 0.15-0.52; P<0.001) after adjusting for clinical risk factors and other lipid levels. On-study Lp(a) had a similar positive association with %WV progression (ß=0.33; 95% confidence interval, 0.15-0.52; P<0.001). CONCLUSIONS: Despite intensive lipid therapy, aimed at aggressively lowering LDL-C to <70 mg/dL, carotid atherosclerosis continued to progress as assessed by carotid magnetic resonance imaging and that elevated Lp(a) levels were independent predictors of increases in atherosclerosis burden.
Assuntos
Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Lipoproteína(a)/sangue , Angiografia por Ressonância Magnética , Placa Aterosclerótica , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Artérias Carótidas/patologia , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/patologia , LDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Fatores de Risco , Fatores de Tempo , Resultado do TratamentoRESUMO
Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the regulation of cholesterol homeostasis. By binding to hepatic low-density lipoprotein (LDL) receptors and promoting their lysosomal degradation, PCSK9 reduces LDL uptake, leading to an increase in LDL cholesterol concentrations. Gain-of-function mutations in PCSK9 associated with high LDL cholesterol and premature cardiovascular disease have been causally implicated in the pathophysiology of autosomal-dominant familial hypercholesterolemia. In contrast, the more commonly expressed loss-of-function mutations in PCSK9 are associated with reduced LDL cholesterol and cardiovascular disease risk. The development of therapeutic approaches that inhibit PCSK9 function has therefore attracted considerable attention from clinicians and the pharmaceutical industry for the management of hypercholesterolemia and its associated cardiovascular disease risk. This review summarizes the effects of PCSK9 on hepatic and intestinal lipid metabolism and the more recently explored functions of PCSK9 in extrahepatic tissues. Therapeutic approaches that prevent interaction of PCSK9 with hepatic LDL receptors (monoclonal antibodies, mimetic peptides), inhibit PCSK9 synthesis in the endoplasmic reticulum (antisense oligonucleotides, siRNAs), and interfere with PCSK9 function (small molecules) are also described. Finally, clinical trials testing the safety and efficacy of monoclonal antibodies to PCSK9 are reviewed. These have shown dose-dependent decreases in LDL cholesterol (44%-65%), apolipoprotein B (48%-59%), and lipoprotein(a) (27%-50%) without major adverse effects in various high-risk patient categories, including those with statin intolerance. Initial reports from 2 of these trials have indicated the expected reduction in cardiovascular events. Hence, inhibition of PCSK9 holds considerable promise as a therapeutic option for decreasing cardiovascular disease risk.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Terapia de Alvo Molecular , Pró-Proteína Convertases/antagonistas & inibidores , Adipócitos/metabolismo , Animais , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Encéfalo/metabolismo , Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/genética , LDL-Colesterol/metabolismo , Ensaios Clínicos como Assunto , Predisposição Genética para Doença , Humanos , Hiperlipoproteinemias/genética , Incidência , Mucosa Intestinal/metabolismo , Fígado/metabolismo , Camundongos , Mutação , Oligonucleotídeos Antissenso/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Pró-Proteína Convertase 9 , Pró-Proteína Convertases/química , Pró-Proteína Convertases/deficiência , Pró-Proteína Convertases/genética , Pró-Proteína Convertases/fisiologia , Estrutura Terciária de Proteína , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Receptores de LDL/metabolismo , Serina Endopeptidases/química , Serina Endopeptidases/deficiência , Serina Endopeptidases/genética , Serina Endopeptidases/fisiologia , Relação Estrutura-AtividadeRESUMO
Dyslipidemia is an established risk factor for the development of atherosclerotic cardiovascular disease. Statin therapy has been proven in a number of clinical trials to lower the risk of acute cardiovascular events and is the mainstay of cholesterol treatment. Despite current optimal treatment for dyslipidemia, many patients fail to reach adequate cholesterol treatment goals and remain at a significantly increased risk of cardiovascular events. Given this residual risk, there is a critical need for additional lipid therapies that could augment the ability of statins to lower the burden of atherogenic lipoproteins and, in some cases, raise levels of high-density lipoproteins. A number of novel lipid-altering therapies have been developed and are currently in clinical trials. In this review, we discuss these promising therapies, which include PCSK9 inhibitors, apolipoprotein B antisense oligonucleotides, microsomal transfer protein inhibitors, thyroid mimetics, and cholesteryl ester transfer protein inhibitors. Although statin therapy is the current recommended primary treatment for dyslipidemia, emerging novel agents may become adjuvant therapies in the treatment of atherosclerotic heart disease.
Assuntos
Aterosclerose , Dislipidemias , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipídeos/sangue , Aterosclerose/epidemiologia , Aterosclerose/etiologia , Aterosclerose/prevenção & controle , Ensaios Clínicos como Assunto/métodos , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/epidemiologia , Saúde Global , Humanos , Incidência , Fatores de RiscoRESUMO
BACKGROUND: While HIV infection is associated with increased cardiovascular risk, benefit from statin is not well established in HIV-infected adults. We assessed whether statins are associated with a decrease in carotid artery intima-media thickness (cIMT) progression and all-cause mortality in HIV-infected adults who are at elevated ASCVD risk and recommended for statins. METHODS: Carotid IMT was measured at baseline and follow-up in 127 HIV-infected adults who meet ACC/AHA criteria to be on statins. Inverse probability of treatment weighting (IPTW) was used to address selection bias. Multivariable models were used to control for baseline characteristics. RESULTS: 28 subjects (22%) were on statins and 99 subjects (78%) were not. Mean cIMT at baseline was 1.2 mm (SD = 0.34) in statin users and 1.1 mm (SD = 0.34) in non-users, and the multivariable adjusted difference was 0.05mm (95%CI -0.11, 0.21 p = 0.53). After 3.2 years of follow-up, average cIMT progression was similar in statin users and non-users (0.062mm/yr vs. 0.058 mm/yr) and the multivariable adjusted difference over the study period was 0.004 mm/yr (95% CI -0.018, 0.025, p = 0.74). All-cause mortality appeared higher in non-statin users compared with statin users, but the difference was not significant (adjusted HR = 0.74, 95%CI 0.17-3.29, p = 0.70). CONCLUSION: In a HIV cohort who had elevated ASCVD risk and meet ACC/AHA criteria for statins, treatment with statins was not associated with a reduction in carotid atherosclerosis progression or total mortality. Future studies are needed to further explore the impact of statins on cardiovascular risk in the HIV-infected population.
Assuntos
Doenças das Artérias Carótidas/epidemiologia , Causas de Morte , Infecções por HIV/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Doenças das Artérias Carótidas/diagnóstico , Doenças das Artérias Carótidas/prevenção & controle , Espessura Intima-Media Carotídea , Estudos de Coortes , Progressão da Doença , Feminino , Seguimentos , Infecções por HIV/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND: In vivo testing of the lipid depletion hypothesis in human beings during lipid-modifying therapy has not been possible until recent developments in magnetic resonance imaging (MRI). TRIAL DESIGN: The Carotid Plaque Composition Study is a prospective, randomized study designed to test the lipid depletion hypothesis in vivo. One hundred twenty-three subjects with coronary artery disease (CAD) or carotid disease and with levels of apolipoprotein B > or = 120 mg/dL (low-density lipoprotein levels 100-190 mg/dL) were enrolled and randomized to (1) single therapy--atorvastatin alone, placebos for extended release (ER)-niacin and colesevelam; (2) double therapy--atorvastatin plus ER-niacin (2 g/d), and placebo for colesevelam; (3) triple therapy--atorvastatin, ER-niacin, plus colesevelam (3.8 g/d). All subjects will undergo MRI scans of bilateral carotid arteries at baseline and annually for 3 years for a total of 4 examinations while on active therapy. Among these 123 subjects with mean age of 55 years and mean body mass index of 30 kg/m2, 73% are male, 43% have a family history of premature cardiovascular disease, 37% have had a previous myocardial infarction, 80% have clinically established CAD, 52% are hypertensive, 12% have diabetes, 23% are current smokers, and 47% meet the criteria for metabolic syndrome. The baseline carotid disease is evaluated using a MRI-modified American Heart Association lesion type definition. Of the 123 enrolled subjects, 40% have type III lesions with small eccentric plaque, 52% have type IV to V lesions with a necrotic core, and only 4% have calcified plaque based on the most diseased carotid location. CONCLUSIONS: The Carotid Plaque Composition Study uses a state-of-the-art imaging technology and comprehensive lipid management to test the plaque lipid depletion hypothesis in CAD subjects.
Assuntos
Estenose das Carótidas/diagnóstico , Estenose das Carótidas/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Imageamento por Ressonância Magnética , Alilamina/análogos & derivados , Alilamina/farmacologia , Alilamina/uso terapêutico , Aterosclerose/diagnóstico , Aterosclerose/tratamento farmacológico , Atorvastatina , Cloridrato de Colesevelam , Método Duplo-Cego , Feminino , Ácidos Heptanoicos/farmacologia , Ácidos Heptanoicos/uso terapêutico , Humanos , Hipolipemiantes/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Niacina/farmacologia , Niacina/uso terapêutico , Estudos Prospectivos , Pirróis/farmacologia , Pirróis/uso terapêuticoRESUMO
BACKGROUND: Although HIV is associated with increased atherosclerotic cardiovascular disease (CVD) risk, it is unknown whether guidelines can identify HIV-infected adults who may benefit from statins. We compared the 2013 American College of Cardiology/American Heart Association and 2004 Adult Treatment Panel III recommendations in HIV-infected adults and evaluated associations with carotid artery intima-media thickness and plaque. METHODS AND RESULTS: Carotid artery intima-media thickness was measured at baseline and 3 years later in 352 HIV-infected adults without clinical atherosclerotic CVD and not on statins. Plaque was defined as IMT >1.5 mm in any segment. At baseline, the median age was 43 (interquartile range, 39-49), 85% were men, 74% were on antiretroviral medication, and 50% had plaque. The American College of Cardiology/American Heart Association guidelines were more likely to recommend statins compared with the Adult Treatment Panel III guidelines, both overall (26% versus 14%; P<0.001), in those with plaque (32% versus 17%; P=0.0002), and in those without plaque (16% versus 7%; P=0.025). In multivariable analysis, older age, higher low-density lipoprotein cholesterol, pack per year of smoking, and history of opportunistic infection were associated with baseline plaque. Baseline IMT (hazard ratio, 1.18 per 10% increment; 95% confidence interval, 1.05-1.33; P=0.005) and plaque (hazard ratio, 2.06; 95% confidence interval, 1.02-4.08; P=0.037) were each associated with all-cause mortality, independent of traditional CVD risk factors. CONCLUSIONS: Although the American College of Cardiology/American Heart Association guidelines recommended statins to a greater number of HIV-infected adults compared with the Adult Treatment Panel III guidelines, both failed to recommend therapy in the majority of HIV-affected adults with carotid plaque. Baseline carotid atherosclerosis but not atherosclerotic CVD risk scores was an independent predictor of mortality. HIV-specific guidelines that include detection of subclinical atherosclerosis may help to identify HIV-infected adults who are at increased atherosclerotic CVD risk and may be considered for statins.
Assuntos
American Heart Association , Artérias Carótidas/efeitos dos fármacos , Doenças das Artérias Carótidas/prevenção & controle , Dislipidemias/tratamento farmacológico , Fidelidade a Diretrizes/normas , Infecções por HIV/complicações , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Guias de Prática Clínica como Assunto/normas , Padrões de Prática Médica/normas , Prevenção Primária/normas , Adulto , Doenças Assintomáticas , Biomarcadores/sangue , Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/diagnóstico por imagem , Doenças das Artérias Carótidas/etiologia , Doenças das Artérias Carótidas/mortalidade , Espessura Intima-Media Carotídea , Distribuição de Qui-Quadrado , HDL-Colesterol/sangue , Progressão da Doença , Dislipidemias/diagnóstico , Dislipidemias/etiologia , Dislipidemias/mortalidade , Feminino , Infecções por HIV/diagnóstico , Infecções por HIV/mortalidade , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Placa Aterosclerótica , Modelos de Riscos Proporcionais , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados UnidosRESUMO
BACKGROUND: Cardiovascular disease (CVD) begins early in life and is associated with both the number of risk factors present and length of exposure to these risk factors including hyperlipidemia. OBJECTIVES: The clinical benefit of intensive lipid therapy over 25 years was investigated in the Familial Atherosclerosis Treatment Study-Observational Study. METHODS: Of 175 coronary artery disease subjects with mean low-density lipoprotein cholesterol (LDL-C) of 191 mg/dL and mean age of 50 years, who completed the randomized and placebo-controlled Familial Atherosclerosis Treatment Study, 100 chose receiving lipid management by their physicians (usual care [UC]) and 75 elected to receive an intensive treatment [IT] for lipid management with lovastatin (40 mg/d), niacin (2.5 g/d), and colestipol (20 g/d) from 1989 to 2004, followed by double therapy with simvastatin (40-80 mg/d) and niacin from 2005 to 2006 and by triple therapy of ezetimibe 10 mg and simvastatin 40 to 80 mg/d plus niacin during 2007 to 2012. Deaths from CVD, non-CVD, and any cause were compared between UC and IT using Cox proportional hazards model. RESULTS: UC and IT groups were similar in risk factors with the exception that IT had more severe coronary artery disease. Mean LDL-C levels were 167 mg/dL from 1988 to 2004, 97 from 2005 to 2006, and 96 from 2007 to 2012 in surviving subjects receiving UC. IT lowered LDL-C to 119, 97, and 83 mg/dL in the 3 periods, respectively. Compared with UC, IT significantly reduced total mortality (11.1 vs 26.3 per 1000 person years [PY], hazard ratio [HR] = 0.45, 95% confidence interval [CI]: 0.26-0.77, P = .003) and CVD mortality (10.6 vs 27.7 per 1000 PY, HR = 0.34, 95% CI: 0.15-0.80, P = .009). The non-CVD mortality was also reduced but was not of statistical significance (6.8 vs 12.7 per 1000 PY, HR = 0.55, 95% CI: 0.27-1.14, P = .11). CONCLUSIONS: Long-term intensive lipid therapy significantly reduced total and cardiovascular mortality in Familial Atherosclerosis Treatment Study-Observational Study. These results support the importance of lifetime risk management to improve long-term outcome.
Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Adulto , Aterosclerose/mortalidade , Azetidinas/uso terapêutico , LDL-Colesterol/sangue , Ensaios Clínicos como Assunto , Colestipol/uso terapêutico , Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Lovastatina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacina/uso terapêutico , Modelos de Riscos Proporcionais , Sinvastatina/uso terapêutico , Triglicerídeos/sangueRESUMO
Cardiovascular morbidity and mortality as a result of inhaled tobacco products continues to be a global healthcare crisis, particularly in low- and middle-income nations lacking the infrastructure to develop and implement effective public health policies limiting tobacco use. Following initiation of public awareness campaigns 50 years ago in the United States, considerable success has been achieved in reducing the prevalence of cigarette smoking and exposure to secondhand smoke. However, there has been a slowing of cessation rates in the United States during recent years, possibly caused by high residual addiction or fatigue from cessation messaging. Furthermore, tobacco products have continued to evolve faster than the scientific understanding of their biological effects. This review considers selected updates on the genetics and epigenetics of smoking behavior and associated cardiovascular risk, mechanisms of atherogenesis and thrombosis, clinical effects of smoking and benefits of cessation, and potential impact of electronic cigarettes on cardiovascular health.
Assuntos
Doenças Cardiovasculares/etiologia , Sistemas Eletrônicos de Liberação de Nicotina/efeitos adversos , Fumar/efeitos adversos , Epigênese Genética , Humanos , Fumar/legislação & jurisprudência , Abandono do Hábito de FumarRESUMO
The incidence and prevalence of cardiovascular (CV)-related morbidity and mortality significantly increase with age. In the elderly, hypercholesterolemia with elevated total and low-density-lipoprotein cholesterol is a significant predictor of incident and recurrent CV disease. Multiple lines of evidence have established the benefit of statin therapy to lower cholesterol levels and reduce the risk of CV events as well as prevent progression of subclinical atherosclerotic disease. Elderly patients, particularly those older than 75 years, have not been well represented in randomized clinical trials evaluating lipid lowering therapy. The limited available data from clinical trials do support the benefit of statin therapy in the elderly population. Based upon these data, cholesterol treatment guidelines endorse statin therapy as the primary treatment of hypercholesterolemia in elderly patients, though caution is recommended given the greater number of co-morbid conditions and concern for poly-pharmacy common in the elderly. Additional research is needed to better establish the benefit of statin therapy in the elderly within the context of reducing CV risk, minimizing side effects, and improving overall quality of life.
Assuntos
Doenças Cardiovasculares , Dislipidemias , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Fatores Etários , Idoso , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Dislipidemias/sangue , Dislipidemias/complicações , Dislipidemias/tratamento farmacológico , Humanos , IncidênciaRESUMO
Dyslipidemia is highly prevalent among women. The management of dyslipidemia is a cornerstone in the prevention of both primary and secondary cardiovascular events, such as myocardial infarction, ischemic stroke, and coronary death. All major international guidelines on the treatment of dyslipidemia recommend similar approaches to the management of dyslipidemia in both men and women. Estrogen replacement therapy should not be considered as a therapeutic option for managing dyslipidemia in women. The reduction of atherogenic lipoprotein burden (reducing low-density lipoprotein cholesterol and non-high-density lipoprotein cholesterol based on risk-stratified thresholds and treatment targets) provided the framework for managing dyslipidemia in the US, Europe, Canada, and elsewhere in the world. Very recently, new guidelines in the US have changed this paradigm, whereby rather than focusing on treatment targets, risk now defines the intensity of treatment with statin therapy, with no specific goals for what level of low-density lipoprotein cholesterol should be attained. It is not clear if this will lead to changes in lipid guidelines in other parts of the world. In the meantime, region-specific guidelines should be followed. Lipid lowering with statin therapy does correlate with reductions in cardiovascular event rates in women. The clinical impact of treating dyslipidemias in women with nonstatin drugs (eg, fibrates, nicotinic acid, bile acid-binding resins, omega-3 fish oils) is as yet not determined.
RESUMO
BACKGROUND: Studies have documented the short-term vascular benefits of combination lipid therapy. OBJECTIVE: Our objective was to evaluate the long-term effects of combination lipid therapy on carotid intima-media thickness (CIMT) in patients with coronary artery disease. METHODS: We performed a case-control study in patients who had finished the Familial Atherosclerosis Treatment Study (FATS) and returned to usual care with statin therapy alone or had elected to participate in the 20-year FATS-Observational Study (FATS-OS) and received combination therapy with lovastatin (40 mg/day), niacin (2-3 g/day), and colestipol (20 gm/day) for 11 years, then continued with simvastatin (10-80 mg/day) or lovastatin (40-80 mg/day) plus niacin (2-4 g/day). After 17.8 ± 0.8 years with combination therapy and 19.0 ± 0.8 years with usual care, cholesterol levels and CIMT were collected in 43 FATS-OS patients and 26 usual care patients. RESULTS: Combination therapy group had a greater decrease in total cholesterol (-42 ± 14% vs -31 ± 17%, P = .008) and low-density lipoprotein cholesterol (LDL-C) (-57 ± 13% vs -38 ± 25%, P < .001) and greater increase in high-density lipoprotein cholesterol (HDL-C) (38 ± 43% vs 15 ± 23%, P = .02) as compared with usual care. CIMT (0.902 ± 0.164 vs 1.056 ± 0.169 mm, P < .001) on intensive therapy was significantly less compared with usual care. Multivariate regression analysis (coefficient, 95% CI) showed that combination therapy (-0.13; -0.21 to -0.04, P = .003) and on-therapy LDL-C (0.15; 0.02 to 0.28, P = .03) were significant independent predictors of CIMT. CONCLUSIONS: Prolonged combination lipid therapy is associated with greater improvements in LDL-C and HDL-C levels and less atherosclerotic burden as compared with statin therapy alone.
Assuntos
Aterosclerose/diagnóstico por imagem , Aterosclerose/tratamento farmacológico , Espessura Intima-Media Carotídea , Hipolipemiantes/farmacologia , Adulto , Aterosclerose/sangue , Aterosclerose/complicações , Estudos de Casos e Controles , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Doença da Artéria Coronariana/complicações , Quimioterapia Combinada , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Resultado do TratamentoRESUMO
Although the effect of niacin on the glucose levels in subjects with diabetes mellitus has been investigated, niacin's effects on the glucose levels and atherosclerosis in subjects with normal glucose levels have not been well established. We examined the effect of niacin on the glucose levels, coronary stenosis progression using quantitative coronary angiography, and clinical events in 407 subjects who had a baseline glucose level <100 mg/dl and were enrolled in the Familial Atherosclerosis Treatment Study (FATS), HDL-Atherosclerosis Treatment Study (HATS), Armed Forces Regression Study (AFREGS), or Carotid Plaque Composition by MRI during lipid-lowering (CPC) study testing active niacin therapy. Although the fasting glucose levels increased significantly within 3 years in both subjects treated with niacin (from 85.6 ± 9.5 to 95.5 ± 19.7 mg/dl, p <0.001) and without niacin (from 85.2 ± 9.6 to 90 ± 17.9 mg/dl, p = 0.009), those treated with niacin had a significantly larger increase in glucose levels than those not taking niacin (9.88 vs 4.05 mg/dl, p = 0.002). Overall, 29% of subjects developed impaired fasting glucose within 3 years. Incident impaired fasting glucose was significantly more likely to be observed in subjects treated with niacin than in those who were not. However, the frequency of new-onset diabetes mellitus did not differ significantly between the 2 groups (5.6% vs 4.8%, p = 0.5). Niacin-treated subjects compared to untreated subjects had significantly less change in mean coronary stenosis (0.1 ± 0.3% vs 2 ± 12%, p <0.0001) and less major cardiovascular events (8% vs 21%, p = 0.001). In conclusion, the use of niacin for 3 years in subjects with normal baseline glucose levels was associated with an increase in blood glucose levels and the risk of developing impaired fasting glucose, but not diabetes mellitus, and was associated with a significantly reduced incidence of coronary stenosis progression and major cardiovascular events.
Assuntos
Glicemia/metabolismo , Estenose das Carótidas/tratamento farmacológico , Estenose Coronária/tratamento farmacológico , Hipolipemiantes/uso terapêutico , Lipídeos/sangue , Imageamento por Ressonância Magnética/métodos , Placa Aterosclerótica/tratamento farmacológico , Estenose das Carótidas/sangue , Estenose das Carótidas/complicações , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Angiografia Coronária , Estenose Coronária/diagnóstico , Estenose Coronária/etiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Niacina/uso terapêutico , Placa Aterosclerótica/sangue , Placa Aterosclerótica/complicações , Resultado do TratamentoRESUMO
The lowering of low-density lipoprotein cholesterol (LDL-C) is the primary target of therapy in the primary and secondary prevention of cardiovascular events. Although statin therapy is the mainstay for LDL-C lowering, a significant percentage of patients prescribed these agents either do not achieve targets with statin therapy alone or have partial or complete intolerance to them. For such patients, the use of adjuvant therapy capable of providing incremental LDL-C reduction is advised. One such agent is ezetimibe, a cholesterol absorption inhibitor that targets uptake at the jejunal enterocyte brush border. Its primary target of action is the cholesterol transport protein Nieman Pick C1 like 1 protein. Ezetimibe is an effective LDL-C lowering agent and is safe and well tolerated. In response to significant controversy surrounding the use and therapeutic effectiveness of this drug, we provide an update on the biochemical mechanism of action for ezetimibe, its safety and efficacy, as well as the results of recent randomized studies that support its use in a variety of clinical scenarios.
Assuntos
Anticolesterolemiantes/uso terapêutico , Azetidinas/uso terapêutico , Dislipidemias/tratamento farmacológico , Absorção Intestinal/efeitos dos fármacos , Jejuno/efeitos dos fármacos , Lipídeos/sangue , Animais , Anticolesterolemiantes/efeitos adversos , Azetidinas/efeitos adversos , Biomarcadores/sangue , Dislipidemias/sangue , Ezetimiba , Humanos , Jejuno/metabolismo , Resultado do TratamentoRESUMO
BACKGROUND: The use of combination therapies is needed to treat dyslipidemia in patients with both elevated low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C). We conducted a study to assess the efficacy and safety of combination therapy with statin plus extended-release (ER) niacin and colesevelam, aimed at lowering LDL-C and raising HDL-C, in subjects with atherosclerotic disease. METHODS: This 1-year study randomized 123 subjects with atherosclerotic disease to atorvastatin alone, double therapy with atorvastatin plus ER niacin, or triple therapy with atorvastatin, plus ER niacin and colesevelam. Target LDL-C was ≤80 mg/dL for single and double therapy, and ≤60 mg/dL for triple therapy. Target HDL-C was an increase of ≥10 mg/dL for double and triple therapy. RESULTS: Single therapy, with mean atorvastatin dose 30 mg/day, had a 47% reduction in LDL-C (P < 0.001) from 148 ± 29 mg/dL to 77 ± 15 mg/dL. With the addition of ER niacin, the double therapy had a 25% increase in HDL-C, from 42 ± 11 mg/dL to 53 ± 16 mg/dL (P < 0.001). The triple therapy decreased LDL-C by 57%, from 157 ± 29 mg/dL to 66 ± 18 mg/dL (P < 0.001), and increased HDL-C by 29%, from 40 ± 9 mg/dL to 50 ± 14 mg/dL (P < 0.001). Double and triple therapy required a lower atorvastatin dose of 20 mg/day to reach the target LDL-C levels. On average, 75% and 67% of subjects reached the predefined LDL-C and HDL-C treatment targets. No related myopathy or hepatotoxicity required stopping the therapy. CONCLUSION: This study demonstrated that combination therapy with atorvastatin plus ER niacin and colesevelam can safely and effectively treat dyslipidemia in subjects with atherosclerotic disease.
RESUMO
A low level of high-density lipoprotein cholesterol (HDL-C) is a risk factor for atherosclerotic disease. Magnetic resonance imaging (MRI) can provide detailed information on carotid atherosclerotic plaque size and composition. The purpose of this study was to correlate HDL levels with carotid plaque burden and composition by MRI. Thirty-four patients with coronary artery disease (CAD) receiving simvastatin plus niacin or placebo for both drugs for three years were randomly selected to undergo MRI of carotid arteries. Atherosclerotic plaque wall volumes (WVs) and plaque components including lipid rich/necrotic core (LR/NC), calcium, fibrous tissue, and loose matrix were measured. Mean WV or atherosclerotic burden was significantly associated with total HDL-C levels (r = -0.39, P = 0.02), HDL(2) (r = -0.36, P = 0.03), HDL(3) (r = -0.34, P = 0.04), and LDL/HDL ratio (r = 0.42, P = 0.02). Plaque lipid composition or LR/NC was significantly associated with HDL(3) (r = -0.68, P = 0.02). Patients with low HDL levels (
Assuntos
Aterosclerose/patologia , Doenças das Artérias Carótidas/patologia , Lipoproteínas HDL/sangue , Imageamento por Ressonância Magnética , Adulto , Aterosclerose/sangue , Aterosclerose/tratamento farmacológico , Doenças das Artérias Carótidas/sangue , Doenças das Artérias Carótidas/tratamento farmacológico , Distribuição de Qui-Quadrado , Angiografia Coronária , Feminino , Humanos , Hipolipemiantes/uso terapêutico , Masculino , Pessoa de Meia-Idade , Niacina/uso terapêutico , Sinvastatina/uso terapêuticoRESUMO
PURPOSE: Cardiovascular magnetic resonance (CMR) can characterize carotid atherosclerosis. The purpose of this study is to evaluate reader agreement of carotid atherosclerotic lesion types by CMR. METHODS: Carotid arteries of 34 patients (29 men, 5 women; mean age, 53 years) were imaged on a 1.5-T scanner. Images with 4 contrast weightings (T1, T2, proton density, and 3-dimensional time-of-flight) were acquired on each axial slice of the carotid arteries. Modified AHA criteria were used for lesion type assessment on the 4 selected axial slices (1 from the common carotid artery, 1 from the carotid bifurcation, and 2 from the internal carotid artery). The modified AHA criteria are as follows: type I-II, near-normal wall thickness without calcification; type III, diffuse wall thickening or small eccentric plaque without calcification; type IV-V, plaque with a lipid rich necrotic core surrounded by fibrous tissue with possible calcification; type VI, complex plaque with a possible surface defect, hemorrhage, or thrombus; type VII, calcified plaque; and type VIII, fibrotic plaque without a lipid core and with possible small calcifications. RESULTS: Of the 272 possible axial slices (34 patients x 2 arteries per patient x 4 slices per artery), 256 slices were available for lesion type assessment. The majority (94%) of the lesions were of type I-II and III. kappa was 0.80 and 0.60 for intra-reader and inter-reader agreement of lesion types, respectively. Inter-reader disagreement for type I-II and type III occurred in 82% of lesions. Weighted kappa was 0.92 and 0.83 for intra-reader and inter-reader agreement of lesion types, respectively. CONCLUSION: The difference between type I-II and III lesions lies in the definition of the vessel wall. The moderate inter-reader agreement suggests further efforts such as establishment of normal carotid artery wall thickness by a quantitative measure are needed for carotid atherosclerotic lesion characterization.