1.
Influence of dietary carbohydrate and fat on LDL and HDL particle distributions.
Siri, PW, Krauss, RM
Current atherosclerosis reports. 2005;(6):455-9
Abstract
Variations in the size and density distributions of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particles have been related to risk for cardiovascular disease. In particular, increased levels of small, dense LDL particles, together with reduced levels of large HDL and increases in small HDL, are integral features of the atherogenic dyslipidemia found in patients with insulin resistance, obesity, and metabolic syndrome. Increased dietary carbohydrates, particularly simple sugars and starches with high glycemic index, can increase levels of small, dense LDL and HDL, primarily by mechanisms that involve increasing plasma triglyceride concentrations. Low-carbohydrate diets may have the opposite effects. Diets with differing fatty acid composition can also influence LDL and HDL particle distributions.
2.
Rosuvastatin: a new inhibitor of HMG-coA reductase for the treatment of dyslipidemia.
Rosenson, RS
Expert review of cardiovascular therapy. 2003;(4):495-505
Abstract
Rosuvastatin (Crestor, AstraZeneca) is a synthetic statin that represents an advance on the pharmacologic and clinical properties of other agents in this class. Relative to other statins, rosuvastatin possesses a greater number of binding interactions with HMG-CoA reductase and has a high affinity for the active site of the enzyme. Rosuvastatin is relatively hydrophilic and is selectively taken up by, and active in, hepatic cells. Rosuvastatin has the longest terminal half-life of the statins and is only minimally metabolized by the cytochrome P450 (CYP 450) enzyme system with no significant involvement of the 3A4 enzyme. Consistent with this finding is the absence of clinically significant drug interactions between rosuvastatin and other drugs known to inhibit CYP 450 enzymes. In patients with hypercholesterolemia, rosuvastatin 10-40 mg has been shown to reduce low-density lipoprotein cholesterol (LDL-C) levels by 52-63%, as well as increase high-density lipoprotein cholesterol (HDL-C) levels by up to 14% and reduce triglycerides (TG) by up to 28%. Studies have shown that rosuvastatin is superior to atorvastatin, simvastatin and pravastatin in reducing LDL-C and favorably modifying other components of the atherogenic lipid profile. The significant decreases in LDL-C with rosuvastatin treatment should help to improve attainment of lipid goals and reduce the requirement for dose titration. In addition, the effects of rosuvastatin on HDL-C and TG levels will be of benefit in treating patients with abnormalities such as mixed dyslipidemia and the metabolic syndrome. Rosuvastatin is well tolerated, with a safety profile comparable with that of other currently available statins.
3.
The central roles of obesity-associated dyslipidaemia, endothelial activation and cytokines in the Metabolic Syndrome--an analysis by structural equation modelling.
Chan, JC, Cheung, JC, Stehouwer, CD, Emeis, JJ, Tong, PC, Ko, GT, Yudkin, JS
International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 2002;(7):994-1008
Abstract
HYPOTHESIS The multi-faceted components of the metabolic syndrome now include markers of inflammation and endothelial activation. Despite this growing body of epidemiological data, standard statistical methods fail to evaluate the nature of these associations adequately. In this pilot study, we hypothesize that obesity may lead to endothelial activation which is in part mediated by dyslipidaemia and proinflammatory cytokines. These factors interact to give rise to hyperinsulinaemia, hypertension and an anti-fibrinolytic state. To test this hypothesis, we used confirmatory factor analysis and structural equation modelling to fit these data to a model designed on theoretical grounds. METHODS Metabolic syndrome variables, cytokines (IL6 and TNFalpha), markers of inflammation and endothelial activation were measured in 107 Caucasian non-diabetic subjects aged 40-75 y. Using confirmatory factor analysis, we identified six factors to represent composite measurements of blood pressure, obesity, dyslipidaemia, hyperinsulinaemia, endothelial activation and the anti-fibrinolytic state. We fitted these variables to two separate models, one using IL-6 and the other TNFalpha as the cytokine, and examined the inter-relationships (path analysis) amongst these variables, based on the above hypothesis. RESULTS Men were centrally more obese and had increased markers of endothelial activation, inflammation and the anti-fibrinolytic state as well as hyperinsulinaemia and dyslipidaemia, compared with women. Obesity indexes (both body mass index and waist-hip ratio) were strongly associated with multiple cardiovascular risk factors. Both IL6 and TNFalpha were correlated with age, male gender, obesity indexes and markers of endothelial activation. Only IL-6 was associated with smoking while TNFalpha was correlated with hyperinsulinaemia. In the TNFalpha model, 61% of the obesity variance was explained by male gender, 36% of TNFalpha variance by age and dyslipidaemia, 43% of dyslipidaemia variance by age and obesity, 33% of hyperinsulinaemia variance by dyslipidaemia and a non-smoking state, 29% of anti-fibrinolytic state variance by hyperinsulinaemia, 65% of endothelial activation variance by TNFalpha, dyslipidaemia and hyperinsulinaemia, 34% of blood pressure variance by hyperinsulinaemia and endothelial activation. In the IL-6 model, we observed similar relationships except that 23% of IL6 variance was explained by smoking and age. CONCLUSIONS Using confirmatory factor analysis and structural equation modelling, we found that obesity, dyslipidemia and cytokines were the principal explanatory variables for the various components of the metabolic syndrome, with IL6 and TNFalpha having different explanatory variables and effects. These complex inter-relationships were in part mediated by hyperinsulinaemia and endothelial activation. While this hypothetical model was based on scientific evidence, supported by rigorous analysis, it requires further confirmation in large-scale prospective studies. Given the complexity of the biological system and its interactions with exogenous factors, structural equation modelling provides a useful scientific tool for hypothesis testing, complementary to the more traditional experimental and cohort studies.
4.
Comparative tolerability of the HMG-CoA reductase inhibitors.
Farmer, JA, Torre-Amione, G
Drug safety. 2000;(3):197-213
Abstract
The availability of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has revolutionised the treatment of lipid abnormalities in patients at risk for the development of coronary atherosclerosis. The relatively widespread experience with HMG-CoA therapy has allowed a clear picture to emerge concerning the relative tolerability of these agents. While HMG-CoA reductase inhibitors have been shown to decrease complications from atherosclerosis and to improve total mortality, concern has been raised as to the long term safety of these agents. They came under close scrutiny in early trials because ocular complications had been seen with older inhibitors of cholesterol synthesis. However, extensive evaluation demonstrated no significant adverse alteration of ophthalmological function by the HMG-CoA reductase inhibitors. Extensive experience with the potential adverse effect of the HMG-CoA reductase inhibitors on hepatic function has accumulated. The effect on hepatic function for the various HMG-CoA reductase inhibitors is roughly dose-related and 1 to 3% of patients experience an increase in hepatic enzyme levels. The majority of liver abnormalities occur within the first 3 months of therapy and require monitoring. Rhabdomyolysis is an uncommon syndrome and occurs in approximately 0.1% of patients who receive HMG-CoA reductase inhibitor monotherapy. However, the incidence is increased when HMG-CoA reductase inhibitors are used in combination with agents that share a common metabolic path. The role of the cytochrome P450 (CYP) enzyme system in drug-drug interactions involving HMG-CoA reductase inhibitors has been extensively studied. Atorvastatin, cerivastatin, lovastatin and simvastatin are predominantly metabolised by the CYP3A4 isozyme. Fluvastatin has several metabolic pathways which involve the CYP enzyme system. Pravastatin is not significantly metabolised by this enzyme and thus has theoretical advantage in combination therapy. The major interactions with HMG-CoA reductase inhibitors in combination therapy involving rhabdomyolysis include fibric acid derivatives, erythromycin, cyclosporin and fluconazole. Additional concern has been raised relative to overzealous lowering of cholesterol which could occur due to the potency of therapy with these agents. Currently, there is no evidence from clinical trials of an increase in cardiovascular or total mortality associated with potent low density lipoprotein reduction. However, a threshold effect had been inferred by retrospective analysis of the Cholesterol and Recurrent Events study utilising pravastatin and the role of aggressive lipid therapy is currently being addressed in several large scale trials.