When high is low: Raising low levels of high-density lipoprotein cholesterol

Low serum levels of high-density lipoprotein cholesterol (HDL-C) are highly prevalent and are recognized as an independent risk factor for cardiovascular morbidity (myocardial infarction, stroke, peripheral arterial disease, and restenosis after coronary stenting) and mortality. HDL plays an important role in modulating atherogenesis, although its functions are varied and complex and the mechanisms for its antiatherogenic effects have not been completely elucidated. The inverse relationship between HDL-C and cardiovascular risk is well established, and epidemiologic studies and clinical trials have provided ample evidence that higher levels of HDL-C are vasculoprotective. Although considerable interest exists in the development of novel approaches to raise serum HDL-C and to augment HDL functionality, this article discusses currently available therapies to raise suboptimal levels of this important lipoprotein.     

Moderate alcohol consumption and coronary artery disease. A review

An inverse association between moderate alcohol consumption and coronary artery disease has been demonstrated in epidemiologic studies of diverse design. These include ecologic correlations, case-control, longitudinal and clinical studies. The consistency, strength and independence of the inverse relationship argues persuasively for a causal association. These data also suggest that both abstention and heavy alcohol use are associated with an increased risk for coronary artery disease. The effect of moderate alcohol consumption on lipoprotein and apolipoprotein levels is a biologically plausible and likely mechanism for this inverse association. Alcohol consumption elevates HDL cholesterol, although it is unclear whether the HDL subfractions HDL-2 and HDL-3 are beneficially altered. Recent evidence, however, suggests that the apolipoproteins may be more important indicators of coronary artery disease, and moderate alcohol consumption does beneficially alter these proteins. Alcohol may also affect coronary artery disease by other mechanisms, which may include fibrinolytic activity, coagulation, blood pressure, coronary vasoreactivity, and sociobehavioral factors.     

High-density Lipoprotein

Epidemiological data clearly show an inverse relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular risk. The HDL-mediated reverse cholesterol transport protects against atherosclerosis and raises the question whether therapeutic strategies to increase HDL levels can cause additional protection from coronary heart disease (CHD). The HDLs are a heterogeneous class of lipoproteins, the metabolism is complex and in certain aspects not well understood. This makes it impossible to predict whether a specific HDL intervention does actually protect against CHD. The currently used medications for raising HDL are fibrates and nicotinic acid; however, these drugs have additional effects on other lipoprotein classes and the benefits have not been finally proven in outcome studies. A promising possibility to raise HDL levels was thought to be the inhibition of cholesterol ester transfer protein (CETP); however, the first two substances tested, torcetrapib and dalcetrapib, failed to show a clinical benefit, and data for anacetrapib are not yet available. It is concluded that there is no proof of concept that therapeutic HDL elevation has a protective effect on cardiovascular events.     

Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease

In this study, niacin was added to existing therapy for 3 months in 54 subjects with stable coronary artery disease. Average total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were similar between groups. Three months of niacin treatment increased total HDL by 7.5% and decreased triglycerides by 15% compared with baseline values (p <0.005 for each), whereas total cholesterol and LDL levels remained unchanged. Addition of niacin resulted in a 32% increase in large-particle HDL (p <0.001), an 8% decrease in small-particle HDL (p = 0.0032), an 82% increase in large-particle LDL (p = 0.09), and a 12% decrease in small-particle LDL (p = 0.008). Niacin decreased lipoprotein-associated phospholipase A2 and C-reactive protein levels (20% and 15%, respectively, p <0.05 for the 2 comparisons). No significant changes from baseline were seen in any tested parameter in subjects who received placebo. In conclusion, addition of niacin to existing medical regimens for patients with coronary artery disease and already well-controlled LDL levels favorably improves the distribution of lipoprotein particle sizes and inflammatory markers in a manner that would be expected to confer atheroprotection. The effect of altering lipoprotein particle distribution and inflammatory markers on surrogate markers of atherosclerosis and clinical cardiovascular events in this population remains unclear.     

HDL biogenesis and functions: Role of HDL quality and quantity in atherosclerosis

Coronary heart disease (CHD) is a leading cause of death in western societies. In the last few decades, a number of epidemiological studies have shown that a disproportion between atheroprotective and atherogenic lipoproteins in plasma is one of the most important contributors towards atherosclerosis and CHD. Thus, based on the classical view, reduced HDL cholesterol levels independently predict one's risk factor for developing cardiovascular disease, while elevated HDL levels protect from atherosclerosis. However, more recent studies have suggested that the relationship between HDL and cardiovascular risk is more complex and extends beyond the levels of HDL in plasma. These studies challenge the existing view on HDL and cardiovascular risk and trigger a discussion as to whether low HDL is a causal effect for the development of heart disease. In this article we provide a review of the current literature on the biogenesis of HDL and its proposed functions in atheroprotection. In addition, we discuss the significance of both HDL quality and quantity in assessing cardiovascular risk.     

HDL therapy for cardiovascular diseases: the road to HDL mimetics

3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are currently the drug of choice for the clinical management of elevated low-density lipoprotein (LDL) cholesterol. Although statin treatment provides an overall improvement in outcomes, clinical trial data reveal a significant number of cardiac events despite reaching targeted LDL levels. A low serum high-density lipoprotein (HDL) cholesterol level is an independent predictor of cardiovascular risk. Accordingly, there has been interest in determining whether HDL elevation, in addition to LDL lowering, further reduces risk in patients with coronary artery disease. Several commonly prescribed lipid-lowering therapies modestly raise HDL, but their use may be limited by the development of adverse reactions. Emerging data suggest that HDL quality and function may also be significantly reduced by atherosclerosis and other inflammatory diseases. The goal of this review is to discuss the current status of HDL therapeutics, with emphasis on a novel class of agent, the apolipoprotein A-I mimetic peptides, which improve the functional properties of HDL cholesterol.     

失功能高密度脂蛋白与心血管疾病研究进展

高密度脂蛋白胆固醇被认为是心血管疾病的重要保护因素,它在血清中的水平与心血管疾病风险呈负相关。然而在心血管疾病中,高密度脂蛋白的蛋白质、脂质或microRNAs等发生变化,使其转变为失功能高密度脂蛋白,失功能高密度脂蛋白具有促进动脉粥样硬化、促氧化、促炎等特性。本文对失功能高密度脂蛋白的结构和功能改变进行概括。     

Prognostic value of high-density lipoproteins in the cardiology unit]

BACKGROUND: Clinical and epidemiological studies have shown an inverse and independent association between high-density lipoproteins (HDL) and risk of developing coronary artery disease. The aim of this study was to estimate the prevalence of the phenotype characterized by low HDL values and to assess the impact of HDL plasma levels on the prognosis of patients hospitalized in the cardiologic unit of our Institute, during 30 months of follow-up. METHODS: Between February 1999 and February 2002, 1169 patients (778 men and 391 women) who had undergone hospitalization, were enrolled in a cardiovascular registry. The lipid profile was evaluated for all patients; a subgroup (n = 626) underwent coronary angiography. Patients were followed up for a mean period of 30 months, during which the frequency of revascularization procedures (coronary angioplasty or bypass), myocardial infarction and death were recorded. RESULTS: Nearly half of the subjects (45%, of which 77% men) showed HDL values < 40 mg/dl, and 25% of the population (80% men) were characterized by extremely reduced HDL concentrations (< or = 35 mg/dl). Patients with coronary atherosclerosis showed HDL levels lower than those of subjects with negative angiography (41.0 +/- 10.8 vs 46.6 +/- 10.9 mg/dl, p < 0.0005). An inverse relationship was found between HDL and coronary artery disease: the risk of developing the illness decreased by 4% for each increase of 1 mg/dl in HDL (p < 0.005); in males < 60 years and females < 65 years, the coronary artery disease risk association increased by 3% (p < 0.005). The risk of interventions decreased by 2% for each increase of 1 mg/dl in HDL (p < 0.01), both in the total population and in males < 60 years and females < 65 years. Finally, patients with HDL < 40 mg/dl showed a higher risk of revascularization interventions (+25%, p < 0.01) in comparison to the subjects with HDL > 40 mg/dl. CONCLUSIONS: This study demonstrates: a) the high prevalence of the phenotype characterized by low plasma concentrations of HDL among patients hospitalized in a cardiologic unit; b) lower HDL values in subjects with coronary atherosclerosis compared to subjects with normal coronary angiography; c) the inverse relationship between HDL and coronary atherosclerosis; d) the prognostic value of HDL as a predictor of surgical revascularization.     

LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study

Diabetes has been shown to increase the risk of coronary heart disease in all populations studied. However, there is a lack of information on the relative importance of diabetes-associated risk factors for cardiovascular disease (CVD), especially the role of lipid levels, because low density lipoprotein (LDL) cholesterol often is not elevated in diabetic individuals. The objective of this analysis was to evaluate CVD risk factors in a large cohort of diabetic individuals and to compare the importance of dyslipidemia (ie, elevated triglycerides and low levels of high density lipoprotein [HDL] cholesterol) and LDL cholesterol in determining CVD risk in diabetic individuals. The Strong Heart Study assesses coronary heart disease and its risk factors in American Indians in Arizona, Oklahoma, and South/North Dakota. The baseline clinical examinations (July 1989 to January 1992) consisted of a personal interview, physical examination, and drawing of blood samples for 4549 study participants (2034 with diabetes), 45 to 74 years of age. Follow-up averaged 4.8 years. Fatal and nonfatal CVD events were confirmed by standardized record review. Participants with diabetes, compared with those with normal glucose tolerance, had lower LDL cholesterol levels but significantly elevated triglyceride levels, lower HDL cholesterol levels, and smaller LDL particle size. Significant independent predictors of CVD in those with diabetes included age, albuminuria, LDL cholesterol, HDL cholesterol (inverse), fibrinogen, and percent body fat (inverse). A 10-mg/dL increase in LDL cholesterol was associated with a 12% increase in CVD risk. Thus, even at concentrations well below the National Cholesterol Education Program target of 130 mg/dL, LDL cholesterol is a strong independent predictor of coronary heart disease in individuals with diabetes, even when components of diabetic dyslipidemia are present. These results support recent recommendations for aggressive control of LDL cholesterol in diabetic individuals, with a target level of <100 mg/dL.     

Small LDL and its clinical importance as a new CAD risk factor: a female case study

The underlying metabolic cause of coronary heart disease in many patients is not high blood cholesterol. In fact, the Framingham study has reported that 80% of individuals who go on to have coronary artery disease have the same total blood cholesterol values as those who do not go on to have a cardiovascular event. The most common metabolic contributor to coronary artery disease is the atherogenic lipoprotein profile, characterized by an abundance of highly atherogenic small, dense low-density lipoprotein particles and a deficiency of the high-density lipoprotein (HDL) subtype most associated with coronary artery disease protection (HDL(2b)). This trait is present in 50% of men with coronary artery disease and is not reflected by total or low-density lipoprotein cholesterol values. While fasting triglycerides tend to he higher, and HDL cholesterol lower in patients with the atherogenic lipoprotein profile, the majority have triglyceride and HDL cholesterol values generally accepted to be in the "normal" range. An abundance of basic science and clinical trial evidence convincingly indicates that the presence of an atherogenic lipoprotein profile signifies a three-fold increased risk for a cardiovascular event and rapid arteriographic progression, but it also identifies a group of patients who respond particularly well to specific therapeutic interventions. Often the most effective interventions are the least expensive.     

Therapies to increase high-density lipoprotein cholesterol and their effect on cardiovascular outcomes and regression of atherosclerosis

Epidemiological studies have shown that decreased level of high-density lipoprotein (HDL) cholesterol (C) is an independent inverse predictor of coronary artery disease (CAD) even in patients with normal levels of low-density lipoprotein (LDL)-C. There is an abundance of evidence in favor of statins and aggressive LDL-C lowering therapy for both primary and secondary prevention of CAD. In contrast, the evidence for reduction of CAD risk with HDL-C raising therapy is relatively thin, partly due to the paucity of effective and safe drugs for increasing HDL-C level. However, there are emerging new therapies for raising HDL-C level and growing evidence in favor of pharmacologic therapies to raise HDL-C level. We present in this article a review of pharmacologic therapies that are currently available to increase HDL-C level, their safety and efficacy in relation to cardiovascular endpoints.     

Androgens and coronary artery disease

A significant and independent association between endogenous testosterone (T) levels and coronary events in men and women has not been confirmed in large prospective studies, although cross-sectional data have suggested coronary heart disease can be associated with low T in men. Hypoandrogenemia in men and hyperandrogenemia in women are associated with visceral obesity; insulin resistance; low high-density lipoprotein (HDL) cholesterol (HDL-C); and elevated triglycerides, low-density lipoprotein cholesterol, and plasminogen activator type 1. These gender differences and confounders render the precise role of endogenous T in atherosclerosis unclear. Observational studies do not support the hypothesis that dehydroepiandrosterone sulfate deficiency is a risk factor for coronary artery disease. The effects of exogenous T on cardiovascular mortality or morbidity have not been extensively investigated in prospective controlled studies; preliminary data suggest there may be short-term improvements in electrocardiographic changes in men with coronary artery disease. In the majority of animal experiments, exogenous T exerts either neutral or beneficial effects on the development of atherosclerosis. Exogenous androgens induce both apparently beneficial and deleterious effects on cardiovascular risk factors by decreasing serum levels of HDL-C, plasminogen activator type 1 (apparently deleterious), lipoprotein (a), fibrinogen, insulin, leptin, and visceral fat mass (apparently beneficial) in men as well as women. However, androgen-induced declines in circulating HDL-C should not automatically be assumed to be proatherogenic, because these declines may instead reflect accelerated reverse cholesterol transport. Supraphysiological concentrations of T stimulate vasorelaxation; but at physiological concentrations, beneficial, neutral, and detrimental effects on vascular reactivity have been observed. T exerts proatherogenic effects on macrophage function by facilitating the uptake of modified lipoproteins and an antiatherogenic effect by stimulating efflux of cellular cholesterol to HDL. In conclusion, the inconsistent data, which can only be partly explained by differences in dose and source of androgens, militate against a meaningful assessment of the net effect of T on atherosclerosis. Based on current evidence, the therapeutic use of T in men need not be restricted by concerns regarding cardiovascular side effects. Available data also do not justify the uncontrolled use of T or dehydroepiandrosterone for the prevention or treatment of coronary heart disease.     

HDL cholesterol: physiology, pathophysiology, and management

Numerous epidemiological studies have identified high-density lipoprotein cholesterol (HDL) to be an independent risk factor for coronary heart disease (CHD). HDL is an emerging therapeutic target that could rival the impact of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) on LDL and CHD risk reduction. HDL metabolism, HDL kinetics, the concentration of various HDL subclasses, and other genetic factors affecting HDL functionality may all contribute to the anti-atherogenic properties of HDL; thus, standard plasma measurement may not capture the full range of HDL effects. Algorithms have been suggested to treat low HDL levels in subgroups of patients; however, no formal HDL target goals or treatment guidelines have been implemented as there is a lack of strong clinical evidence to support effective pharmacologic therapy for primary risk reduction. Available therapies have a modest impact on serum HDL levels; however, emerging therapies could have a more significant influence.     

Importance of lipoprotein metabolism parameters in the clinical and angiographic severity of coronary artery disease.

Coronary artery disease that is clinically and angiographically significant is associated to important biochemical parameters with direct interference in lipoprotein and apoprotein metabolism. The purpose of our study was to evaluate the importance of several lipoprotein metabolic parameters in the clinical and angiographic severity of chronic coronary artery disease. In a population with the diagnosis of ischemic coronary artery disease, we assessed the degree of angiographic (single- versus multivessel disease) and clinical (C.C.S. I-IV classification) severities. In each patient, we determined the value of total cholesterol, triglycerides, HDL and LDL cholesterol, HDL 2 and 3, apoprotein AI and B, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. Our results showed that some parameters were significant in the comparison between a normal group and the global coronary artery disease population, such as the value of total cholesterol, HDL cholesterol, HDL 2, apoprotein AI and B lipoprotein (a) and anti-phospholipid antibodies. In the distinction of coronary artery disease subgroups, in relation to C.C.S. < or = 2 and > or = 3 classes, some factors could be discriminated, such as HDL cholesterol, HDL 2, total cholesterol/HDL, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. In the distinction between classes C.C.S. < or = 2 and AMI, the levels of triglycerides, HDL cholesterol, HDL 2, total cholesterol/HDL, lipoprotein (a) and anti-phospholipid antibodies were significant. In the division between single vessel versus multivessel coronary artery disease we found significant values of HDL cholesterol, HDL 2, total cholesterol/HDL, apoprotein AI, lipoprotein (a), anti-phospholipid antibodies and C reactive protein. In conclusion, our present study endorses the clinical role of lipids and plasma lipoproteins in the determination of several cardiovascular risk factors, but introduction of new parameters such as lipoprotein (a) and the anti-phospholipid antibodies can be very useful for a better and global understanding of the pathophysiological processes and distinction of higher risk subgroups for extension and degree of severity of ischemic coronary artery disease.     

High-density lipoprotein cholesterol and coronary artery disease: survey of the evidence

The epidemiologic evidence linking high-density lipoprotein (HDL) levels with coronary artery disease (CAD) is persuasive. Case-control studies have shown CAD patients to have lower HDL levels than control subjects. Several large-scale, observational epidemiologic studies in the United States and abroad have shown a strong independent inverse relation between HDL and CAD. Women have a lower incidence of CAD than men of the same age; this has been attributed to their higher HDL levels. Postmenopausal women taking estrogen replacement therapy have higher HDL and lower low-density lipoprotein (LDL) levels, and a much lower incidence of CAD. Statistical analysis suggests that much of this is attributable to HDL levels. In several clinical trials, reduced levels of total or LDL cholesterol have been accompanied by increased HDL levels. Cox proportional hazards analysis suggests that the increment in HDL levels made an independent contribution to the reduction in CAD risk. In several angiographic studies, the increase in HDL may have contributed to the decreased progression, increased stabilization and possible regression of coronary lesions. Despite this range of impressive evidence, a number of unresolved issues have prevented the emergence of a consensus regarding the prevention of CAD by increasing HDL levels. Between-population comparisons of HDL and CAD do not match the within-population relations. Animal research on the relation between HDL, atherogenesis and CAD has been relatively scanty. Although much evidence suggests that reverse cholesterol transport partially explains the protective effect of HDL, there are still doubts as to its role. Problems with measurement of HDL have inhibited widespread recommendations for its use in prevention programs.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of circulating high-density lipoprotein and triglycerides in coronary artery disease: risk and prevention

A substantial body of evidence suggests that circulating levels of high-density lipoprotein (HDL) and certain triglyceride-carrying lipoproteins may, like low-density lipoprotein (LDL), be important risk factors in the development of atherosclerotic coronary artery disease (CAD). Furthermore, both low HDL cholesterol and high triglyceride levels are frequently associated with other CAD risk factors, whose correction, often by hygienic means, may reduce CAD risk without fear of adverse side effects. However, the available evidence is not yet sufficiently coherent and compelling to justify guidelines (analogous to those for LDL cholesterol) for specific pharmacologic treatment of low plasma HDL cholesterol or moderately elevated plasma triglyceride levels to prevent CAD.     

Effect of low-dose alcohol use versus abstention on apolipoproteins A-I and B

An inverse association between low to moderate alcohol consumption and coronary heart disease has been demonstrated in epidemiologic studies of diverse design. An attempt was made to determine if this association might be due to an effect of alcohol on apolipoproteins A-I and B and to determine if low-dose alcohol intake might have a potentially protective effect by this mechanism in persons at increased risk for coronary heart disease. To address this, an eight-week prospective randomized clinical trial of abstention versus low-dose alcohol consumption, defined as one beverage per day, was conducted in white men, aged 21 to 60 years, most of whom were patients of a preventive cardiology program. Apolipoprotein A-I levels had a mean increase of 9 mg/dl in the 28 participants who drank alcohol compared with a mean decline of 5 mg/dl in the 28 participants who abstained (p less than 0.005). This association was independent of other cardiovascular risk factors. Low-density lipoprotein (LDL)-B levels had a mean increase of 7 mg/dl in both arms of the trial (NS). However, the ratio of apolipoprotein A-I to LDL-B increased by 4 percent in the drinkers and decreased 10 percent in the abstainers (p less than 0.03). No significant changes in mean levels of total high-density lipoprotein (HDL)-, HDL2-, or HDL3-cholesterol were observed with this low dose of alcohol. This effect on apolipoprotein A-I suggests a possible mechanism by which low-dose alcohol may lower the risk of coronary heart disease.     

Physical activity, C-reactive protein levels and the risk of future coronary artery disease in apparently healthy men and women: the EPIC-Norfolk prospective population study.

BACKGROUND: Physical activity is inversely associated with the risk of future coronary artery disease. Whether this relationship is in part mediated by lower levels of systemic inflammation, as indicated by C-reactive protein concentrations, is unknown. METHODS: We performed a nested case-control study among apparently healthy men and women enrolled in the European Prospective Investigation into Cancer and Nutrition-Norfolk prospective population study, to investigate the relationship among habitual (work-related and leisure time) physical activity, cardiovascular risk factors and the risk of future coronary artery disease. RESULTS: Among men, those with an active lifestyle had a significantly lower risk of future coronary artery disease than those with an inactive lifestyle [odds ratio (OR) 0.65; 95% confidence interval (CI) 0.47-0.90; P for linearity, 0.008], after adjustment for smoking, systolic blood pressure, diabetes, body mass index and low-density lipoprotein and high-density lipoprotein cholesterol. Additional adjustment for C-reactive protein levels attenuated this relationship only slightly (OR 0.68; 95%CI 0.49-0.93; P for linearity, 0.02). Similarly, active women had an adjusted odds ratio of 0.48 (0.28-0.82; P for linearity <0.001) for future coronary artery disease compared with inactive women. Additional adjustment for C-reactive protein levels attenuated this relationship slightly (OR 0.51; 0.30-0.87; P for linearity, 0.003). CONCLUSIONS: We observed that people with an active lifestyle had a substantially lower risk of future coronary artery disease than people with an inactive lifestyle, and that this relationship was partly mediated through lower levels of established cardiovascular risk factors and in addition, C-reactive protein. This observation suggests that reduced systemic inflammation may be one of the mechanisms through which physical activity leads to reduced cardiovascular risk.     

Emerging importance of HDL cholesterol in developing high-risk coronary plaques in acute coronary syndromes

Cardiovascular disease is the principal cause of death in industrialized countries. Hyperlipidemia, with high low-density lipoprotein cholesterol and triglycerides, and low high-density lipoprotein cholesterol levels (<40 mg/dL in men and <45 mg/dL in women), is a known major cardiovascular risk factor. Statins are considered the most potent and effective agents to reduce low-density lipoprotein cholesterol, but they have a variable effect on high-density lipoprotein cholesterol and triglycerides. Different clinical trials with statins have shown a decrease in low-density lipoprotein cholesterol by 35% and a reduction of the incidence of coronary events by as much as 30%. However, 60 to 70% of events still occur, despite remarkable reduction of low-density lipoprotein cholesterol concentration. Recent National Cholesterol Education Program guidelines highlighted the importance of high-density lipoprotein cholesterol concentration in the prevention and treatment of cardiovascular disease. High-density lipoprotein cholesterol is considered an independent risk factor and has an inverse relation with coronary events. The association of low levels of high-density lipoprotein cholesterol with an increased incidence of cardiovascular events implies a critical role of high-density lipoprotein in the protection against atherosclerotic disease and in the progression of coronary atherosclerotic disease. High-density lipoprotein cholesterol appears to exert this protective effect through multiple mechanisms. High-density lipoprotein is not only involved in reverse cholesterol transport, but also prevents endothelial dysfunction; inhibits the homing of monocytes, apoptosis, platelet activation, and factor X activation; and has antioxidant properties. In this article the authors review the available experimental and clinical evidence supporting the importance of high-density lipoprotein cholesterol as a protective factor in coronary artery disease, and the strategies developed to increase high-density lipoprotein cholesterol.     

New developments in the treatment of low high-density lipoprotein cholesterol

Reduced levels of high-density lipoprotein (HDL) cholesterol represent an important risk factor for the development and progression of coronary artery disease. In recent years, clinical outcome studies have verified that statin therapy may reduce the risk of initial or recurrent cardiovascular events in subjects with elevated or “normal” cholesterol levels. Subgroup analysis has also revealed that patients with low HDL benefit from this therapy. Two recently presented outcome trials using fibrate therapy also demonstrated a potential role for these medications in subjects with low HDL. The use of various HDL raising agents, singly or in combination on arteriographic progression and their potential mechanisms of action are reviewed. The latter may be an important consideration in the treatment of high-risk patients with low HDL.