RESUMO
BACKGROUND: According to epidemiological studies, there is no clear relationship between the plasma cholesteryl ester transfer protein (CETP) concentration and the development of atherosclerosis in human populations. Although some studies suggest that increased CETP activity relates to undesirable profiles of plasma lipoproteins, promoting an anti-atherogenic plasma lipoprotein profile by drugs that inhibit CETP has not succeeded in preventing atherosclerosis in humans. MATERIALS AND METHODS: This review describes 28 investigations in human populations dealing with plasma CETP, 11 in mice that express human CETP and seven in animals (six in rabbits and one in mice) in which plasma CETP activity was inhibited by drugs. RESULTS: Present review shows that models in mice expressing human CETP are not illuminating because they report increase as well reduction of atherosclerosis. However, investigations in rabbits and mice that develop severe hypercholesterolaemia clearly indicate that impairment of the plasma CETP activity elicits protection against the development of atherosclerosis; in all of these experiments are attained substantial reductions of the atherogenic lipoproteins, namely, plasma apoB containing lipoproteins. CONCLUSION: These models are strong indicators that the benefit in preventing atherosclerosis should be earned in cases of hyperlipidemia by CETP inhibitors.
Assuntos
Anticolesterolemiantes/uso terapêutico , Aterosclerose/tratamento farmacológico , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Hipercolesterolemia/tratamento farmacológico , Amidas , Animais , Anticolesterolemiantes/farmacologia , Apolipoproteínas B/efeitos dos fármacos , Apolipoproteínas B/metabolismo , Aterosclerose/metabolismo , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Proteínas de Transferência de Ésteres de Colesterol/antagonistas & inibidores , Ésteres , Humanos , Hipercolesterolemia/metabolismo , Camundongos , Oxazolidinonas/farmacologia , Oxazolidinonas/uso terapêutico , Quinolinas/farmacologia , Quinolinas/uso terapêutico , Coelhos , Compostos de Sulfidrila/farmacologia , Compostos de Sulfidrila/uso terapêuticoRESUMO
AIMS: The objective was to assess the consistency of effect of switching to ezetimibe/simvastatin 10/20 mg versus doubling the baseline statin dose (to simvastatin 40 mg or atorvastatin 20 mg) or switching to rosuvastatin 10 mg across subgroups of subjects with (n = 617) and without (n = 191) metabolic syndrome (MetS). METHODS: This was a post hoc analysis of a randomized, double-blind, 6-week study of adults 18-79 years with cardiovascular disease and diabetes mellitus with low-density lipoprotein cholesterol (LDL-C) ≥70 and ≤160 mg/dl. The percent change in LDL-C and other lipids was estimated within each subgroup separately. Safety and tolerability were assessed. RESULTS: In subjects with MetS, percent changes in LDL-C and other lipids were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin, except high-density lipoprotein cholesterol and apolipoprotein (Apo) AI (mean percent changes in LDL-C were: -22.49% ezetimibe/simvastatin, -9.64% doubled baseline statin and -19.20% rosuvastatin). In subjects without MetS, percent changes in LDL-C, total cholesterol and Apo B were greater with ezetimibe/simvastatin versus doubling baseline statin or numerically greater versus switching to rosuvastatin (mean percent changes in LDL-C were: -25.14% ezetimibe/simvastatin, -4.75% doubled baseline statin and -19.75% rosuvastatin). Safety profiles were generally similar. CONCLUSION: These results showed that switching to ezetimibe/simvastatin 10/20 mg was more effective at reducing LDL-C, total cholesterol and Apo B versus doubling the baseline statin dose to simvastatin 40 mg or atorvastatin 20 mg or switching to rosuvastatin 10 mg regardless of MetS status. These results were generally similar to those of the full cohort.
Assuntos
Azetidinas/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , LDL-Colesterol/efeitos dos fármacos , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Síndrome Metabólica/tratamento farmacológico , Sinvastatina/uso terapêutico , Adolescente , Adulto , Idoso , Anticolesterolemiantes/uso terapêutico , Apolipoproteínas B/sangue , Apolipoproteínas B/efeitos dos fármacos , Atorvastatina , Glicemia/efeitos dos fármacos , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/prevenção & controle , LDL-Colesterol/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Angiopatias Diabéticas/sangue , Angiopatias Diabéticas/prevenção & controle , Método Duplo-Cego , Esquema de Medicação , Combinação de Medicamentos , Quimioterapia Combinada , Combinação Ezetimiba e Simvastatina , Jejum , Feminino , Fluorbenzenos/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Pessoa de Meia-Idade , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Rosuvastatina Cálcica , Sulfonamidas/uso terapêutico , Resultado do TratamentoRESUMO
BACKGROUND: In addition to lipid-lowering and insulin-sensitizing actions, statins (HMG-CoA reductase inhibitors) and metformin may have pleiotropic effects. OBJECTIVE: To study the effect of simvastatin and metformin on insulin sensitivity and inflammatory markers. METHODS: Forty-one subjects with body mass index (BMI) 25-39.9 kg/m(2) and impaired glucose tolerance were randomized to receive simvastatin or metformin for 16 weeks. Blood samples were obtained for measurement of metabolic and inflammatory parameters before and after each treatment. RESULTS: As expected, when compared with simvastatin, metformin therapy resulted in significant reductions in mean BMI, fasting plasma glucose, and homeostasis model assessment-insulin resistance (HOMA-IR), whereas simvastatin treatment resulted in significantly reduced total cholesterol, low-density lipoprotein-cholesterol (LDL-C), and apolipoprotein B levels. Independently of the medication used, significant decreases in C-reactive protein (CRP) and interleukin (IL)-6 were detected from baseline to treatment end. CRP showed a mean reduction of 0.12 +/- 0.04 mg/dL (p = 0.002) over the 16-week intervention period and IL-6 a mean reduction was 0.35 +/- 0.17 pg/mL (p = 0.046). No change was observed in the tumor necrosis factor-alpha levels. Baseline values of CRP and IL-6 and their percentage declines were correlated (r = 0.71 and r = 0.67, respectively; p < 0.001). In simvastatin recipients, no correlation was detected between reductions in CRP or IL-6 and lipids, whereas in metformin recipients, reductions in inflammatory markers were not correlated to BMI and HOMA-IR. CONCLUSION: Our findings suggest that both metformin and simvastatin have similar beneficial effects on low-grade inflammation, in addition to their classical effects on glucose and lipid metabolism. Moreover, they confirm the importance of treating at-risk individuals even before the precipitation of overt diabetes mellitus or full-blown metabolic syndrome.
Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Hipoglicemiantes/uso terapêutico , Resistência à Insulina , Síndrome Metabólica/tratamento farmacológico , Metformina/uso terapêutico , Sinvastatina/uso terapêutico , Adolescente , Adulto , Idoso , Apolipoproteínas B/efeitos dos fármacos , Biomarcadores/sangue , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Índice de Massa Corporal , Proteína C-Reativa/efeitos dos fármacos , LDL-Colesterol/sangue , Feminino , Homeostase , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hipoglicemiantes/administração & dosagem , Inflamação/sangue , Inflamação/tratamento farmacológico , Interleucina-6/sangue , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Metformina/administração & dosagem , Pessoa de Meia-Idade , Sinvastatina/administração & dosagemRESUMO
BACKGROUND: Information is lacking on the effects of hormone replacement therapy in women with diabetes, especially during moderate chronic hyperglycemia. OBJECTIVES: To study the effects of HRT on the lipid profile and the low density lipoprotein subclass distribution in women with type 2 diabetes under satisfactory and non-satisfactory glycemic control. METHODS: Fifty-four postmenopausal women after a 6 week run-in diet were randomized to receive either placebo (HbA1c < 8%, n = 13; HbA1c > 8%, n = 17) or HRT (HbA1c < 8%, n = 11; HbA1c > 8%, n = 13) for 12 weeks. HRT consisted of cyclical conjugated estrogens 0.625 mg/day plus medrogestone 5 mg/day. At the beginning and at the end of each treatment period the LDL subclass distribution was estimated by density gradient ultracentrifugation. RESULTS: At the baseline and during the study, the HbA1c level was significantly higher in hyperglycemic patients than in the near-normoglycemic controls (baseline 10.2 +/- 2.9 vs. 6.5 +/- 0.7%, P < 0.01). They showed a trend for higher total and LDL cholesterol, triglycerides and lower high density lipoprotein-cholesterol compared to near-normoglycemic controls, as well as significantly higher triglyceride concentrations in very low density lipoprotein, intermediate density lipoprotein and LDL-1 particles and cholesterol content in LDL-1 and -2 particles. HRT decreased LDL-cholesterol in both groups. In the normoglycemic patients a small increase in HbA1c was observed (6.5 +/- 0.7 vs. 7.4 +/- 1%, P = 0.04). In all cases, HRT did not modify the proportion of LDL represented by denser LDLs. CONCLUSIONS: HRT did not modify the LDL subclass distribution, even in the presence of moderate chronic hyperglycemia in women with type 2 diabetes.
Assuntos
Apolipoproteínas B/efeitos dos fármacos , Doenças Cardiovasculares/prevenção & controle , Diabetes Mellitus Tipo 2/complicações , Estrogênios Conjugados (USP)/administração & dosagem , Terapia de Reposição Hormonal/efeitos adversos , Lipoproteínas LDL/efeitos dos fármacos , Medrogestona/administração & dosagem , Idoso , Apolipoproteínas B/análise , Glicemia , Doenças Cardiovasculares/etiologia , Diabetes Mellitus Tipo 2/diagnóstico , Método Duplo-Cego , Feminino , Seguimentos , Humanos , Hiperglicemia/diagnóstico , Hiperglicemia/etiologia , Lipoproteínas LDL/análise , Pessoa de Meia-Idade , Pós-Menopausa , Probabilidade , Valores de Referência , Resultado do TratamentoRESUMO
PURPOSE: To evaluate the effects of pravastatin on lipoproteins, Lp (a), apo B and apo A-I and its tolerability in primary hypercholesterolemic patients in our outpatient lipid clinic. METHODS: Twenty-two primary hypercholesterolemic patients were evaluated. They had all been treated previously with other hypocholesterolemic drugs, including the statins, forming a specific and homogeneous group with hypercholesterolemia and definite coronary risk. After 7 weeks with American Heart Association phase I diet and placebo drug, pravastatin was administered during 12 weeks. All patients received an initial daily dose of 10 mg for six weeks. After this period, this dose was increased to 20 mg. The levels of cholesterol, triglycerides, high-density lipoprotein, lipoprotein (a) and apolipoproteins A-1 and B were determined. RESULTS: No changes occurred with diet and placebo, but pravastatin at a daily dose of 10 mg, reduced significantly cholesterol level (7.22%), LDL-cholesterol (13.08%) and increased HDL-cholesterol (7.81%). The results were better with 20 mg, achieving a reduction of (28.21%) in cholesterol, (36.88%) in LDL-cholesterol, (17.06%) in apo B level and an increase of (10.06%) in HDL-cholesterol. The smaller effect observed with the more commonly used dosage (10 mg/day) was most probably due to the characteristics of the sample with already established hypercholesterolemia, being thus dependent of higher concentrations of medications, as observed in previous treatments in our outpatient clinic. Side affects with this drug were rare. No biochemical changes were observed that would interrupt the continuation of therapy. CONCLUSION: Pravastatin was well tolerated and promoted favorable changes in the total cholesterol, LDL, apo B and cholesterol/HDL and LDL/HDL ratios of primary hypercholesterolemic patients.