RESUMO
Treating cardiovascular disease (CVD) risk factors, including dyslipidemia, is important in HIV care. Low-density lipoprotein cholesterol (LDL-c) target achievement is a readily available benchmark for dyslipidemia control, although use of this target is not uniformly endorsed by professional societies. We examined whether HIV serostatus is associated with not achieving LDL-c target. Among Multicenter AIDS Cohort Study (MACS) participants completing visit 56 (10/1/2011-3/31/2012), we categorized each man as on or off statin therapy and used NCEP ATP III guidelines to determine if each man was at LDL-c target or not at target. We compared proportions of men not at target and determined predictors using multivariate logistic regression. Sixty of 543 (11.1%) HIV-infected men and 87 of 585 (14.9%) HIV-uninfected men not receiving statin therapy were not at target (p=0.07), while 31 of 230 (13.5%) HIV-infected and 29 of 204 (14.2%) HIV-uninfected men receiving statin therapy were not at target (p=0.82). Factors associated with not being at target (among men not receiving statin therapy) included current smoking (OR=2.31, 95% CI 1.31, 4.06) and a diagnosis of hypertension (OR=4.69, 95% CI 2.68, 8.21). Factors associated with not being at target (among men receiving statin therapy) included current smoking (OR=2.72, 95% CI 1.30, 5.67) and diabetes (OR=5.31, 95% CI 2.47, 11.42). HIV-infected and HIV-uninfected men receiving statin therapy demonstrated similar nonachievement of LDL-c targets. Comorbidities (e.g., diabetes) lowered targets and may explain why goals were less likely to be met.
Assuntos
LDL-Colesterol/sangue , Dislipidemias/tratamento farmacológico , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Doenças Cardiovasculares/prevenção & controle , Estudos de Coortes , Dislipidemias/complicações , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVES: We examined the effects of early treatment with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin on the progression of glucose intolerance and cardiovascular remodeling in a model of spontaneously developing type II diabetes mellitus (DM), the Otsuka Long-Evans Tokushima Fatty (OLETF) rats. BACKGROUND: Clinical trials showed that pravastatin prevented new-onset DM in hypercholesterolemic patients, and that it was effective in prevention of cardiovascular events in diabetics. METHODS: The OLETF rats were treated with pravastatin (100 mg/kg/day) from 5 weeks of age and compared with age-matched untreated OLETF rats and normal Long-Evans Tokushima Otsuka (LETO) rats on serial oral glucose tolerance tests (OGTT) and Doppler echocardiography and on histopathological/biochemical analyses of the heart at 30 weeks. RESULTS: The OGTT revealed that 40% and 89% of untreated OLETF rats were diabetic at 20 and 30 weeks, respectively, but 0% and only 30%, respectively, were diabetic in the treated OLETF. Left ventricular diastolic function was found impaired from 20 weeks in untreated OLETF but remained normal in the treated-OLETF. The wall-to-lumen ratio and perivascular fibrosis of coronary arteries were increased in untreated-OLETF but were limited in the treated-OLETF at 30 weeks. Moreover, cardiac expressions of a fibrogenic growth factor, transforming growth factor-beta1 (TGF-beta1), and a proinflammatory chemokine, monocyte chemoattractant protein-1 (MCP-1), were increased in untreated-OLETF. However, in the treated-OLETF, overexpressions of TGF-beta1 and MCP-1 were attenuated, which was associated with overexpression of endothelial nitric oxide synthase (eNOS) (2.5-fold of control LETO). CONCLUSIONS: Early pravastatin treatment prevented cardiovascular remodeling in the spontaneous DM model by retarding the progression of glucose intolerance, overexpressing cardiac eNOS, and inhibiting overexpressions of fibrogenic/proinflammatory cytokines.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pravastatina/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Colesterol/sangue , Primers do DNA , Diabetes Mellitus Tipo 2/sangue , Modelos Animais de Doenças , Teste de Tolerância a Glucose , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Imuno-Histoquímica , Insulina/sangue , Leptina/sangue , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , Óxido Nítrico Sintase Tipo III , Pravastatina/administração & dosagem , RNA Mensageiro/análise , Ratos , Ratos Endogâmicos OLETF , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Crescimento Transformador beta/genética , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta1 , Triglicerídeos/sangue , Fator de Necrose Tumoral alfaRESUMO
Although combination therapy using 3-hydroxy-3-methylglutaryl coenzyme A (HMG-Co-A) reductase inhibitors and fibrates is efficacious in combined hyperlipidemia, such treatment has been associated with myopathy. For this reason, we studied the effects of fluvastatin and gemfibrozil, alone or in combination, on muscle. A total of 21 patients with combined hyperlipidemia were recruited who were matched for age, body mass index, and baseline levels of total cholesterol, low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides, creatine phosphokinase, and myoglobin. Patients were randomized to three groups for 6-week treatment with fluvastatin at 40 mg/day, gemfibrozil at 600 mg twice daily, or a combination of the two drugs. Parameters for muscle damage were rises in levels of serum creatine phosphokinase and myoglobin compared with pre-exercise levels; these were assessed 1 hr and 8 hr after a 45 min lean body mass standardized ergometer test, which was performed before and after treatment in all patients. Biopsies from the quadriceps muscle were taken 48 hr after each test. Fluvastatin lowered total cholesterol and LDL-C by 23% and 35%, respectively (p < 0.01), with no effects on triglycerides and HDL-C. Gemfibrozil lowered triglycerides by 40% (p < 0.01) but did not lower total cholesterol or LDL-C significantly. The combination therapy decreased total cholesterol, LDL-C, and triglycerides by 28%, 29%, and 39%, respectively (p < 0.05). Pre-exercise creatine phosphokinase and myoglobin levels were not affected by treatment in any group.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Genfibrozila/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipidemias/tratamento farmacológico , Indóis/uso terapêutico , Músculo Esquelético/efeitos dos fármacos , Anticolesterolemiantes/administração & dosagem , Biópsia , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Creatina Quinase/sangue , Método Duplo-Cego , Combinação de Medicamentos , Teste de Esforço , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Fluvastatina , Genfibrozila/administração & dosagem , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemias/classificação , Indóis/administração & dosagem , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/anatomia & histologia , Músculo Esquelético/metabolismo , Mioglobina/sangue , Placebos , Estudos Prospectivos , Triglicerídeos/sangueRESUMO
The objective of the study was to evaluate the efficacy and safety of fluvastatin in patients with hypercholesterolemia, including heterozygous familial hypercholesterolemia, in a 1-year study (a 12-week open assessment, followed by 40 weeks of active treatment). Of the 337 patients enrolled in the study, the effects of fluvastatin were analyzed in 296 patients at baseline and at 12 weeks. Of these, 265 were receiving 20 mg/day fluvastatin at week 12 and in 20 patients the dose had been increased to 30 mg/day; 11 patients violated the dosing protocol. A total of 229 patients continued into the 40-week, long-term phase, and 212 patients were analyzed at baseline and after 24 and 52 weeks. At the end of treatment, 153 evaluable patients were still taking 20 mg/day fluvastatin, 1 was taking 10 mg/day, and 48 patients were taking 30 mg/day, and 10 were taking 40 mg/day. In the 20 mg/day fluvastatin group, low density lipoprotein cholesterol (LDL-C) levels decreased by 24.1% at week 12 and by 29.3% at week 52. In those patients requiring the higher doses, the corresponding reductions in LDL-C were 20.2% (week 12) and 26.7% (week 52). Total cholesterol was also reduced at week 12 by 17.0% (20 mg/day) and 15.7% (20-30 mg/day), and at week 52 by 20.4% (< or = 20 mg/day) and 19.2% (> or = 30 mg/day). Throughout the study, fluvastatin was generally well tolerated and no serious clinical adverse events were observed. In conclusion, long-term treatment of hypercholesterolemia with fluvastatin at dosages of 20-40 mg daily can be considered both safe and effective.
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia/tratamento farmacológico , Indóis/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Apolipoproteínas A/sangue , Apolipoproteínas B/sangue , Apolipoproteínas E/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Ácidos Graxos Monoinsaturados/administração & dosagem , Fluvastatina , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Indóis/administração & dosagem , Japão , Estudos Longitudinais , Pessoa de Meia-Idade , Placebos , Segurança , Triglicerídeos/sangueRESUMO
The long-term clinical efficacy of fluvastatin was assessed in 24 patients with familial hypercholesterolemia over a total treatment period of 104 weeks. Patients received an initial fluvastatin dose of 20 mg/day for 8 weeks, which was increased to 30 mg/day for a further 16 weeks. From week 24, if serum total cholesterol remained > or = 230 mg/dL, the fluvastatin dose could be increased to 40 or 60 mg/day, as necessary. By the end of treatment, 4 patients were receiving 30 mg/day fluvastatin, 1 patient was receiving 40 mg/day, and 19 patients were receiving 60 mg/day. Serum total cholesterol and low density lipoprotein cholesterol (LDL-C) levels showed a significant decrease from baseline at week 104 (total cholesterol, -26.8 +/- 2.4%; LDL-C, -33.1 +/- 3.3%; p < 0.001). The reductions in total cholesterol and LDL-C were dose-related. Statistically significant (p < 0.05) increases in serum high density lipoprotein cholesterol (HDL-C) were observed at week 24 (12.1 +/- 5.0%) and at week 76 (11.0 +/- 3.3%), although the effect was variable. Nevertherless, at the end of treatment the LDL-C: HDL-C ratio showed a 35% reduction from baseline. Changes in triglyceride levels failed to achieve statistical significance, with a reduction from baseline of -13.9 +/- 7.3% at week 104. Changes in apolipoprotein A-I were variable, with statistically significant (p < 0.01) increases observed at week 24 (7.6 +/- 2.3%) and week 76 (8.4 +/- 2.7%). By contrast, a significant reduction from baseline in apolipoprotein B was achieved by week 12 (-15.0 +/- 2.3%; p < 0.001) and was maintained throughout the study.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Indóis/uso terapêutico , Adulto , Idoso , Anticolesterolemiantes/administração & dosagem , Apolipoproteína A-I/sangue , Apolipoproteínas B/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Fluvastatina , Heterozigoto , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Indóis/administração & dosagem , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placebos , Triglicerídeos/sangueRESUMO
Many patients with severe primary hypercholesterolemia--low density lipoprotein cholesterol (LDL-C) > 240 mg/dL--have heterozygous familial hypercholesterolemia. In such familial hypercholesterolemic patients, the lipid-lowering efficacy of fluvastatin is related to genetic factors, and it is of interest whether the response to treatment differs from that in patients with more moderate hypercholesterolemia. Thus an exploratory analysis of randomized, controlled clinical trials and their open-label extensions (12-78 weeks), conducted worldwide with fluvastatin > or = 20 mg/day (n = 1810) and placebo (n = 783), assessed whether, apart from the potential differences between familial hypercholesterolemic and nonfamilial hypercholesterolemic patients, the response to 40 mg of fluvastatin is influenced by baseline plasma lipid levels in relation to disease severity. Entry criteria included LDL-C > or = 190 mg/dL with < or = 1 risk factor and no coronary artery disease, or > or = 160 mg/dL with > 1 risk factor or definite coronary artery disease. Of these patients, 591 (33%) given fluvastatin (20-40 mg/day) and 187 (24%) given placebo had severe hypercholesterolemia with baseline LDL-C > 240 mg/dL. In controlled studies, the mean +/- SD duration of exposure was 21.1 +/- 16.1 and 19.4 +/- 15.5 weeks for fluvastatin and placebo, respectively, whereas long-term efficacy was assessed after 55.3 +/- 21.7 weeks (fluvastatin) and 21.1 +/- 12.3 weeks (fluvastatin + cholestyramine, after previous monotherapy). In summary, fluvastatin at 40 mg/day lowered LDL-C by 25-26% from baseline in controlled studies (n = 622), and by 27% in long-term studies (32-33% with fluvastatin + cholestyramine; n = 386), irrespective of severity of cholesterolemia.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hipercolesterolemia/tratamento farmacológico , Indóis/uso terapêutico , Idoso , Anticolesterolemiantes/administração & dosagem , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Resina de Colestiramina/administração & dosagem , Resina de Colestiramina/uso terapêutico , Doença das Coronárias/sangue , Doença das Coronárias/complicações , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Fluvastatina , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipercolesterolemia/sangue , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Indóis/administração & dosagem , Sistemas de Informação , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Placebos , Fatores de Risco , Triglicerídeos/sangueRESUMO
This study assessed the long-term use of fluvastatin, alone or in combination with bezafibrate, in patients with severe familial hypercholesterolemia who, in a previous study, did not achieve target levels (European Atherosclerosis Society) of low density lipoprotein cholesterol (LDL-C) with fluvastatin at 60 mg/day plus bezafibrate 200 mg/day, with or without cholestyramine (CME) at 8 g/day. This open-label study comprised 3 periods: period I, 6 weeks of fluvastatin at 40 mg twice daily (at breakfast and at bedtime); period II, fluvastatin at 80 mg/day (40 mg at breakfast, 40 mg at bedtime), and bezafibrate at 200 mg/day (at lunchtime) for 6 weeks in patients not achieving LDL-C target levels; and period III, force-titration of fluvastatin to 800 mg/day (as in period II) and bezafibrate at 400 mg/day (slow release) in patients receiving combination treatment. Patients were excluded if, during the previous study, they had experienced a serious drug-related adverse event or deterioration in liver or kidney function (liver enzymes > 3 times upper limit of normal). The standard physical and laboratory evaluations were performed at regular intervals. Lipid profiles were determined from 12-hour fasting blood samples. All adverse events occurring or worsening during the study, whether spontaneously reported or elicited by questioning, and regardless of relationship to study medication, were recorded.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/uso terapêutico , Bezafibrato/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Indóis/uso terapêutico , Anticolesterolemiantes/administração & dosagem , Anticolesterolemiantes/efeitos adversos , Bezafibrato/administração & dosagem , Bezafibrato/efeitos adversos , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Resina de Colestiramina/administração & dosagem , Resina de Colestiramina/efeitos adversos , Resina de Colestiramina/uso terapêutico , Preparações de Ação Retardada , Combinação de Medicamentos , Ácidos Graxos Monoinsaturados/administração & dosagem , Ácidos Graxos Monoinsaturados/efeitos adversos , Fluvastatina , Heterozigoto , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hidroximetilglutaril-CoA Redutases/efeitos adversos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/genética , Indóis/administração & dosagem , Indóis/efeitos adversos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Estudos Longitudinais , Placebos , Segurança , Triglicerídeos/sangueRESUMO
Familial hypercholesterolemia carries a markedly increased risk of coronary artery disease. Reduction of plasma low density lipoprotein cholesterol (LDL-C) levels to the normal range may prevent premature atherosclerosis and usually requires a combination of cholesterol-lowering drugs such as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors plus resins or fibrates. The current, 60-week, open-label investigation involved 22 patients whose plasma LDL-C had not reached the target level for prevention of coronary artery disease in 3 previous studies using fluvastatin alone and in combination with other cholesterol-lowering medications. At the beginning of the current study, patients were stabilized on fluvastatin monotherapy at 40 mg/day. After 6 weeks, the daily treatment changed to a combination of fluvastatin 40 mg/day in the evening and bezafibrate 400 mg/day in the morning. After a further 6 weeks, a lunchtime dose of cholestyramine 8 g/day was added, to form triple cholesterol-lowering therapy. Efficacy was determined by plasma lipid/lipoprotein analysis. Baseline levels were assessed after 4 weeks of placebo treatment, prior to active treatment, in the first fluvastatin study. Safety analyses included liver and renal function tests, creatine phosphokinase levels and blood counts. Compliance was determined by counting the fluvastatin capsules, bezafibrate tablets, and cholestyramine sachets returned by the patients at each visit. The triple-drug combination used in this study was more effective than the double therapy and resulted in stabilization of the LDL-C:high density lipoprotein cholesterol (HDL-C) ratio, at a reduction from baseline ranging from -40.4 to -52.5%.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Anticolesterolemiantes/uso terapêutico , Bezafibrato/uso terapêutico , Resina de Colestiramina/uso terapêutico , Ácidos Graxos Monoinsaturados/uso terapêutico , Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Indóis/uso terapêutico , Adulto , Anticolesterolemiantes/administração & dosagem , Bezafibrato/administração & dosagem , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Resina de Colestiramina/administração & dosagem , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/prevenção & controle , Creatina Quinase/sangue , Combinação de Medicamentos , Ácidos Graxos Monoinsaturados/administração & dosagem , Feminino , Fluvastatina , Humanos , Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipoproteinemia Tipo II/sangue , Indóis/administração & dosagem , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Pessoa de Meia-Idade , Cooperação do Paciente , Placebos , Segurança , Triglicerídeos/sangueRESUMO
Single-drug therapy is often not sufficient to lower total and low-density lipoprotein (LDL) cholesterol levels in patients with familial hypercholesterolemia to desirable or target levels. Therefore, combination drug therapy is often necessary. The most potent therapy to achieve this goal is a combination of a 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitor, which reduces cholesterol synthesis, and a bile acid sequestrant, which indirectly depletes the intrahepatic cholesterol pool. LDL cholesterol reductions reportedly vary between 52 and 54% in short-term trials. Combining a bile acid sequestrant with nicotinic acid reduces LDL cholesterol 34-55%, and with a fibrate, 12-42%. The triple-drug regimen of bile acid sequestrant, an HMG CoA reductase inhibitor, and nicotinic acid is even more effective, achieving reductions of 59-67%. All these regimens elevate high-density lipoprotein cholesterol levels concomitantly by 2-37%.