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Results of the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that therapy with the fibric acid gemfibrozil significantly reduced the incidence of coronary artery disease events in men with known coronary artery disease and a low level of high-density lipoprotein cholesterol (HDL-C). Coronary artery disease event reduction was inversely related to levels of HDL-C achieved with gemfibrozil and, even at relatively low concentrations of HDL-C, coronary artery disease event reduction with gemfibrozil was significantly greater than with placebo. Subjects with a low HDL-C level who were recruited for VA-HIT had a high prevalence of features of the metabolic syndrome with obesity, type 2 diabetes, and hyperinsulinemia. These individuals especially benefited from gemfibrozil, and thus, fibrate therapy may have an increasing role in reducing coronary artery disease risk in a setting of an increasing worldwide prevalence of obesity and diabetes.
Am J Cardiol 2001 Dec 20
PMID:Targeting low high-density lipoprotein cholesterol for therapy: lessons from the Veterans Affairs High-density Lipoprotein Intervention Trial. 1178 26

The inverse relation between coronary artery disease and the concentration of high-density lipoprotein cholesterol (HDL-C) is well established. A low HDL-C concentration is frequently accompanied by the features of the metabolic syndrome found in patients with type 2 diabetes and in individuals who are abdominally obese. Results from 3 independent trials are consistent in showing that fenofibrate is able to increase HDL-C levels across a wide range of dyslipidemic states. The HDL-C-increasing effect of fenofibrate is proportionately greater when baseline levels are low. Comparing results from published trials, the absolute increase in HDL-C produced by fenofibrate is greater than that with statins across all baseline HDL-C levels, and a 40-mg/dL treatment target HDL-C level is more likely to be achieved with fenofibrate therapy. Fenofibrate has favorable pleiotropic effects on several features of the metabolic syndrome, which are likely to explain the clinical benefits of fibrate therapy, beyond an impact on HDL-C levels. The additional reciprocal beneficial effect of fenofibrate in lowering low-density lipoprotein cholesterol (LDL-C) benefits those patients with low HDL-C and moderately increased LDL-C; the American Diabetes Association now recommends fibrate therapy in this case. Another trial, the Diabetes Atherosclerosis Intervention Study (DAIS) has also provided angiographic evidence to show that fenofibrate treatment may slow coronary artery disease progression in type 2 diabetes. Treatment effects on apolipoproteins suggest that not all fibrates affect HDL-C to an equal degree. A trial with fenofibrate focusing on coronary artery disease risk and mortality reduction in patients with type 2 diabetes that is currently under way, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial is expected to report in 2005.
Am J Cardiol 2001 Dec 20
PMID:Increasing high-density lipoprotein cholesterol: an update on fenofibrate. 1178 28

Epidemiologic studies have consistently implicated low plasma high-density lipoprotein cholesterol as an important, independent risk factor for the development of coronary heart disease. However, clinical trials specifically designed to evaluate the role of lipid therapy in patients with low high-density lipoprotein cholesterol have only been recently reported. They include two trials with angiographic end points, the Lopid Coronary Angiography Trial and the Bezafibrate Coronary Atherosclerosis Intervention Trial, and three clinical end points trials, the Air Force/Texas Coronary Atherosclerosis Prevention study, the Department of Veterans Affairs High-Density Lipoprotein Intervention Trial, and the Bezafibrate Infarction Prevention study. These and other trials clearly indicate that persons with coronary heart disease and high low-density lipoprotein cholesterol (>130 mg/dL [3.36 mmol/L]), with or without low high-density lipoprotein cholesterol, benefit from statin therapy. The Air Force/Texas Coronary Atherosclerosis Prevention study showed that persons at high risk of coronary heart disease but without known disease, who have moderate levels of low-density lipoprotein cholesterol as well as low levels of high-density lipoprotein cholesterol, also appear to benefit from statin therapy although the cost effectiveness of this approach is unclear. The results from the Department of Veterans Affairs High Density Lipoprotein Intervention Trial provide convincing evidence that patients without high low-density lipoprotein cholesterol and with established coronary heart disease and low high-density lipoprotein cholesterol benefit from gemfibrozil. This drug may be particularly beneficial for patients who, in addition to low high-density lipoprotein cholesterol, present with other features of the metabolic syndrome, such as obesity, glucose intolerance, and high triglycerides. Whether other fibrates, niacin, or statins lower coronary heart disease risk in persons with low high-density lipoprotein cholesterol in the absence of high or moderately high low-density lipoprotein cholesterol is unknown. (c)2000 by CHF, Inc.
Prev Cardiol 2000
PMID:High-density lipoprotein and coronary heart disease: lessons from recent intervention trials. 1183 14

The guidelines of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program are similar to prior recommendations in focusing on elevations of low-density lipoprotein (LDL) cholesterol as the primary target of therapy and in gauging the intensity of therapy to the degree of coronary heart disease risk. New elements in the current guidelines include: quantification of risk, heightened attention to the risk imparted by low high-density lipoprotein levels, utilization of non-high-density lipoprotein cholesterol levels in risk assessment for hypertriglyceridemic individuals, and emphasis on the metabolic syndrome. Nonetheless, the current guidelines are not perfect. The recommended algorithm for treatment is excessively complex; this complexity may keep the guidelines from being widely used. This complexity is generated by a hybrid scheme of risk assessment utilizing both counting of categorical coronary heart disease risk factors and calculation of coronary heart disease using the Framingham model. This hybrid method also results in undesirable inconsistencies in treatment. ATP III explicitly agrees that the therapeutic LDL goal should be determined by the burden of non-LDL risk factors. However, the current guidelines violate this principle by giving the baseline LDL cholesterol level a role in determining the therapeutic LDL goal. Additionally, the ATP III guidelines lead to under-treatment of women. Simplification should be a goal of the next iteration of the guidelines. Specific suggestions are given for simplification of the guidelines and for enhanced treatment of women. Furthermore, it is urged that the risk-assessing spreadsheet be provided in an "unlocked" form so that its details can be inspected.
Prev Cardiol 2002
PMID:Perspectives: some thoughts on the Adult Treatment Panel III report. 1198 54

Because cardiovascular disease (CVD) is the most important cause of death in women in the United States, it is imperative that the main risk factors for CVD in women be identified and modified. The risk factors that have the strongest impact on the incidence of CVD in women are not necessarily the same as those for men. The risk for women increases at menopause, most likely because of the decrease in levels of circulating estrogen. The classic risk factor for CVD is altered lipid levels. In middle-aged women, elevated low-density lipoprotein cholesterol levels are somewhat less important relative to lowered levels of high-density lipoprotein cholesterol and elevated triglyceride levels as independent risk factors. The metabolic syndrome, which encompasses a range of conditions known to be CVD risk factors, also has a greater impact on the incidence of CVD in women than in men. Various emerging risk factors appear to be important indicators for vascular disease in women, including C-reactive protein, homocysteine, and lipoprotein(a) levels. Many of these risk factors are affected by hormone replacement therapy, which may diminish CVD risk in postmenopausal women. Because of the complex origin of CVD, it is important to target the full array of risk factors for modification, rather than focusing on a single factor or treatment to the exclusion of other important markers.
Am J Cardiol 2002 Jun 20
PMID:Risk factors for coronary artery disease in women. 1208 1

The third Adult Treatment Panel of the National Cholesterol Education Program has recently issued revised guidelines for the treatment of cholesterol in adults. Increased attention to the metabolic syndrome and diabetes, including the inaccuracy of the low-density lipoprotein cholesterol (LDL-C) measurement in these patients because of elevated triglycerides is highlighted. To overcome the inaccuracy of the Friedewald equation in calculating LDL-C when the triglycerides are elevated, measuring non-high-density lipoprotein (non-HDL-C) may provide a better means to follow these patients toward their treatment goals. Recently, non-HDL-C was shown to be a better predictor of cardiovascular death than LDL-C, even in patients with triglyceride levels below 200 mg/dL. The authors review the basis for using non-HDL-C as a treatment target for cholesterol, in comparison with other lipoproteins.
Prev Cardiol 2002
PMID:Perspectives: The significance of measuring non-HDL-cholesterol. 1209 59

Hyperandrogenemia and low levels of sex hormone binding globulin (SHBG) are frequently found in women with metabolic syndrome, which is characterized by low high-density lipoprotein cholesterol, hypertriglyceridemia, obesity, and hyperinsulinemia. The specific contribution of these various factors to coronary heart disease (CHD) is controversial. The coronary angiograms of 87 consecutive postmenopausal women were evaluated using 2 semiquantitative scoring systems to estimate the extent of focal and diffuse vessel wall alterations. Fasting sera were analyzed for levels of glucose, lipids, insulin, leptin, dehydroepiandrosterone sulfate, testosterone, and SHBG. Obesity was assessed by measuring body mass index, waist-to-hip ratio, skinfold thicknesses, and body impedance. After adjusting for age, there were significant differences in 55 women with CHD compared with 32 women without CHD: higher levels of low-density lipoprotein cholesterol (159 +/- 51 vs 132 +/- 39 mg/dl), apolipoprotein B (121 +/- 33 vs 102 +/- 29 mg/dl), triglycerides (115 vs 91 mg/dl), and basal insulin (7.5 vs 4.6 mU/L), as well as lower levels of high-density lipoprotein cholesterol (59.9 +/- 18.0 vs 69.0 +/- 17.1 mg/dl), SHBG (44.6 vs 68.1 nmol/L) and the quantitative insulin sensitivity check index (0.66 +/- 0.41 vs 0.93 +/- 0.73). Multivariate analysis by logistic regression identified age (odds ratio [OR] 1.22, 95% confidence intervals [CI] 1.09 to 1.37), smoking (OR 11.46, 95% CI 2.56 to 51.39), SHBG (OR 0.98, 95% CI 0.96 to 0.99), and apolipoprotein B (OR 1.02, 95% CI 1.01 to 1.04) as independently associated with the presence of CHD. Thus, low plasma levels of SHBG are associated with CHD in women independently of insulin, obesity markers, and dyslipidemia.
Am J Cardiol 2002 Aug 15
PMID:Relation of serum levels of sex hormone binding globulin to coronary heart disease in postmenopausal women. 1216 Dec 23

Several classes of antihyperglycemic agents are available for the treatment of patients with type 2 diabetes. These agents, including thiazolidinediones, biguanides, insulin secretagogues, alpha-glucosidase inhibitors, and insulin, offer differing mechanisms of actions and can be used either alone or in combination. The thiazolidinediones are a newer class of oral antidiabetic agents that improve glycemic control and may preserve beta-cell function. Clinical trial data suggest that patients with type 2 diabetes experience progressive deterioration of beta-cell function. By decreasing insulin resistance, thiazolidinediones may preserve beta-cell function, and patients may experience prolonged glycemic control. The thiazolidinediones also exert beneficial effects on dyslipidemia, endothelial function, coagulation, and blood pressure. By improving these components of the metabolic syndrome, thiazolidinediones may reduce the incidence of both microvascular and macrovascular complications. This article provides an overview of the role of thiazolidinediones in the treatment of type 2 diabetes.
Am J Cardiol 2002 Sep 05
PMID:Rationale for and role of thiazolidinediones in type 2 diabetes mellitus. 1223 Oct 77

Coronary heart disease is a leading cause of death in industrialized nations. Hyperlipidemia with elevated serum total cholesterol, LDL cholesterol, and triglycerides is a known major cardiovascular risk factor. HDL cholesterol is considered to be protective, so low HDL cholesterol is being recognized as an independent cardiovascular risk factor that contributes to the development of atherosclerosis and related adverse cardiovascular events. The recognition of insulin resistance and metabolic syndrome is a step further in understanding these risk factors. Attempts at reducing serum cholesterol with different strategies in the past have met with limited success until the development of statins. The advent of statins has revolutionized the management of hyperlipidemia. The post-statins era has seen major clinical trials demonstrating the benefit of cholesterol reduction in the setting of both primary and secondary prevention. In general, there appears to be a 25% to 40% relative risk reduction in major adverse cardiovascular events such as death, myocardial infarction, and stroke. The recent megatrials further suggest that aggressive management of cholesterol in patients with high cardiovascular risk may be beneficial. Though the concept of the-lower-the-better may be looming, the question of "How low is good enough?" remains controversial. The results of recent megatrials such as the Heart Protection Study go a step further than the NCEP guidelines and suggest that statin therapy may benefit patients at high risk of cardiovascular disease regardless of their baseline values. We summarize the results of the available large clinical trials in our understanding of the management of dyslipidemia in a setting of primary prevention.
Curr Opin Cardiol 2002 Sep
PMID:Management of dyslipidemia in the primary prevention of coronary heart disease. 1235 27

The three major components of dyslipidemia associated with the metabolic syndrome are increased fasting and postprandial triglyceride-rich lipoproteins (TRLs), decreased high-density lipoprotein (HDL), and increased small, dense low-density lipoprotein (LDL) particles. Insulin resistance and compensatory hyperinsulinemia lead to overproduction of very low-density lipoprotein particles. A relative deficiency of lipoprotein lipase, an insulin-sensitive enzyme, is partly responsible for the decreased clearance of fasting and postprandial TRLs, and the decreased production of HDL particles. The resulting increased concentration of cholesteryl ester-rich fasting and postprandial TRLs is the central lipoprotein abnormality of the metabolic syndrome. The increase of small, dense LDL particles, and decrease of large, buoyant HDL particles are consequential events. All these lipoprotein defects contribute largely to the increased cardiovascular disease risk in individuals with insulin resistance. Peroxisome proliferator-activated receptor (PPAR)a, PPARg, and PPARd agonists seem to improve dyslipidemia of the metabolic syndrome by regulating the expression of important genes involved in the deranged lipoprotein metabolism associated with insulin resistance.
Curr Cardiol Rep 2002 Nov
PMID:Dyslipidemia of the metabolic syndrome. 1237 72


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