A review of trials evaluating nonstatin lipid-lowering therapies.

Recently reported clinical trials raise doubts on the effectiveness of nonstatin lipid-lowering therapies in reducing the residual risk of cardiovascular events after statin monotherapy. Addition of -torcetrapib to statin therapy increased overall mortality in coronary patients despite a marked increase in high-density lipoprotein cholesterol. Combining ezetimibe with statin therapy neither further reduces carotid atherosclerosis nor slows aortic stenosis, and it has not been shown to be superior to statin monotherapy in reducing cardiovascular events. Clinical trials currently in progress will more clearly delineate the cardiovascular effects of adding either ezetimibe or extended-release niacin/laropiprant to statin therapy.

Not getting to goal: the clinical costs of noncompliance.

BACKGROUND: Cardiovascular disease is characterized by significant prevalence and cost in the managed care setting. Despite overwhelming evidence in favor of statin use for lowering low-density lipoprotein cholesterol (LDL-C), medication compliance to these agents remains suboptimal, as it does in other disease states. OBJECTIVE: To establish the benefits of statin therapy in cardiovascular disease, demonstrate the current lack of compliance to lipid-lowering agents, and present potential interventions to improve medication compliance. SUMMARY: As evidenced by a consistent body of clinical trial data, intensive LDL-C reduction plays a critical role in the mitigation of cardiovascular risk. Yet, the effectiveness of lipid-lowering strategies is offset to a significant degree by both physician and patient factors that limit goal attainment. Despite extensive evidence demonstrating the benefits of lipid-lowering therapy, many patients are still not getting to goal because the transition from physician awareness to clinical practice is lagging. Patient noncompliance to therapy also limits goal attainment, thus resulting in poor health outcomes and increasing managed care costs. CONCLUSION: To overcome the issues surrounding LDL-C goal attainment, interventions designed to increase goal attainment should be based not only on the conclusions of clinical trials but also on successful patientand provider-focused behavioral strategies. Interventions for improving adherence to lipid-lowering medication will provide an opportunity to decrease morbidity, mortality, and hospitalization associated with cardiovascular disease.

Targeting the anti-inflammatory effects of high-density lipoprotein.

The effects of systemic inflammation can impair the anti-inflammatory functions of high-density lipoprotein (HDL) particles. In patients with atherosclerosis and/or inflammatory conditions, HDLs can be modified such that they paradoxically increase the recruitment and activation of macrophages, upregulate the expression of endothelial cell adhesion molecules, and participate in the oxidation of low-density lipoproteins (LDLs). Statins, apolipoprotein A-I mimetic peptides, and therapeutic lifestyle changes appear to mitigate these proinflammatory features of HDLs. In the future, characterizing and targeting functional aspects of HDLs may prove to offer therapeutic advantages over current treatment strategies.

HDL function as a target of lipid-modifying therapy.

High-density lipoprotein (HDL) is conventionally believed to possess many features that protect against atherosclerosis. However, these lipoproteins may be modified in certain individuals and/or circumstances to become pro-inflammatory. The ability of HDL to inhibit or paradoxically to enhance vascular inflammation, lipid oxidation, plaque growth, and thrombosis reflects changes in specific enzyme and protein components. The anti-inflammatory and pro-inflammatory functional properties of HDL can now be assessed using cell-based and cell-free assays. Acute or chronic systemic inflammation and the metabolic syndrome appear to render HDL pro-inflammatory. In contrast, statins and experimental agents such as apolipoprotein A-1 mimetics render HDL more anti-inflammatory. The 2 main classes of existing drugs for HDL modification are fibric acid derivatives, also known as "fibrates," and niacin- containing compounds. In several controlled and prospective intervention studies, patients with low HDL-C and additional risk factors benefited from treatment with fibrates or niacin. However, an increase in HDL-C did not lead to a decrease in cardiovascular events in all trials.

The two faces of the 'good' cholesterol.

Although a low level of high-density lipoprotein (HDL) cholesterol is a useful clinical predictor of coronary heart disease, raising the HDL cholesterol level does not necessarily lower this risk. Part of the explanation for this paradox may be that, under certain conditions, HDL either can be less functional as an antioxidant or can even enhance the oxidation and inflammation associated with atherosclerotic plaque. Thus, the functional properties of HDL--not simply the level--may need to be considered and optimized.

High-density lipoprotein as a therapeutic target: a systematic review.

CONTEXT: High-density lipoprotein cholesterol (HDL-C) is a cardiovascular risk factor that is gaining substantial interest as a therapeutic target. OBJECTIVES: To review the current and emerging strategies that modify high-density lipoproteins (HDLs). DATA SOURCES: Systematic search of English-language literature (1965-May 2007) in MEDLINE and the Cochrane database, using the key words HDL-C and apolipoprotein A-I and the subheadings reverse cholesterol transport, CVD [cardiovascular disease] prevention and control, drug therapy, and therapy; review of presentations made at major cardiovascular meetings from 2003-2007; and review of ongoing trials from ClinicalTrials.gov and current guidelines from major cardiovascular societies. STUDY SELECTION AND DATA EXTRACTION: Study selection was prioritized to identify randomized controlled trials over meta-analyses over mechanistic studies; identified studies also included proof-of-concept studies and key phase 1 through 3 trials of novel agents. Study eligibility was assessed by 2 authors; disagreements were resolved by consensus with the third. DATA SYNTHESIS: Of 754 studies identified, 31 randomized controlled trials met the inclusion criteria. Currently available therapeutic and lifestyle strategies, when optimized, increase HDL-C levels by 20% to 30%. While basic and small pilot studies have shown promise, proof that increasing HDL-C levels confers a reduction in major cardiovascular outcomes independent of changes in levels of low-density lipoprotein cholesterol or triglycerides has been more elusive. Some novel therapeutic agents in human studies appear to effectively increase HDL-C levels, whereas other novel strategies that target HDL metabolism or function may have minimal effect on HDL-C levels. CONCLUSIONS: At present there is modest evidence to support aggressively increasing HDL-C levels in addition to what is achieved by lifestyle modification alone. Ongoing clinical trials that target specific pathways in HDL metabolism may help expand cardiovascular treatment options.

Reduced treatment success in lipid management among women with coronary heart disease or risk equivalents: results of a national survey.

BACKGROUND: This survey assessed and compared National Cholesterol Education Program (NCEP) Third Adult Treatment Panel lipid treatment goal achievement for men versus women undergoing treatment of dyslipidemia. METHODS: Patients receiving treatment for dyslipidemia from physicians (N = 376) in the United States who were high prescribers of lipid medications were enrolled in the NCEP Evaluation Project Utilizing Novel E-Technology (NEPTUNE) II. Data from a single office visit were collected and entered into the NEPTUNE software on a personal digital assistant and uploaded to a central database via the Internet. RESULTS: Of the 4885 patients evaluated, 2103 (43%) were women. NCEP Third Adult Treatment Panel low-density lipoprotein cholesterol (LDL-C) goal achievement was similar between women and men with 0 or 1 risk factor (89% and 88%, respectively) and 2 or more risk factors (75% and 76%, respectively). However, fewer women than men achieved goal in the coronary heart disease and risk equivalents (CHD + CHD RE) category (50% vs 60%, respectively; P < .001). Logistic regression analyses examining the association between sex and LDL-C treatment goal achievement, and evaluating potential confounding by other predictors of treatment success, indicated an age-adjusted odds ratio of 0.66 (95% confidence interval, 0.56-0.77; P < .001) and a multivariate odds ratio of 0.76 (95% confidence interval, 0.62-0.93; P = .009) for women compared with men in the CHD + CHD RE category. CONCLUSIONS: Female sex was associated with lower likelihood of LDL-C goal achievement among patients with CHD + CHD RE. This relationship remained significant after adjustment for other significant predictors of treatment success.

Apolipoprotein A-I mimetic peptides.

Despite identical amino acid composition, differences in class A amphipathic helical peptides caused by differences in the order of amino acids on the hydrophobic face results in substantial differences in antiinflammatory properties. One of these peptides is an apolipoprotein A-I (apoA-I) mimetic, D-4F. When given orally to mice and monkeys, D-4F caused the formation of pre-beta high-density lipoprotein (HDL), improved HDL-mediated cholesterol efflux, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. In apolipoprotein E (apoE)-null mice, D-4F increased reverse cholesterol transport from macrophages. Oral D-4F reduced atherosclerosis in apoE-null and low-density lipoprotein (LDL) receptor-null mice. In vitro when added to human plasma at nanomolar concentrations, D-4F caused the formation of pre-beta HDL, reduced lipoprotein lipid hydroperoxides, increased paraoxonase activity, and converted HDL from pro-inflammatory to antiinflammatory. Physical-chemical properties and the ability of various class A amphipathic helical peptides to activate lecithin cholesterol acyltransferase (LCAT) in vitro did not predict biologic activity in vivo. In contrast, the use of cultured human artery wall cells in evaluating these peptides was more predictive of their efficacy in vivo. We conclude that the antiinflammatory properties of different class A amphipathic helical peptides depends on subtle differences in the configuration of the hydrophobic face of the peptides, which determines the ability of the peptides to sequester inflammatory lipids. These differences appear to be too subtle to predict efficacy based on physical-chemical properties alone. However, understanding these physical-chemical properties provides an explanation for the mechanism of action of the active peptides.

Dysfunctional HDL and atherosclerotic cardiovascular disease.

High-density lipoproteins (HDLs) protect against atherosclerosis by removing excess cholesterol from macrophages through the ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) pathways involved in reverse cholesterol transport. Factors that impair the availability of functional apolipoproteins or the activities of ABCA1 and ABCG1 could, therefore, strongly influence atherogenesis. HDL also inhibits lipid oxidation, restores endothelial function, exerts anti-inflammatory and antiapoptotic actions, and exerts anti-inflammatory actions in animal models. Such properties could contribute considerably to the capacity of HDL to inhibit atherosclerosis. Systemic and vascular inflammation has been proposed to convert HDL to a dysfunctional form that has impaired antiatherogenic effects. A loss of anti-inflammatory and antioxidative proteins, perhaps in combination with a gain of proinflammatory proteins, might be another important component in rendering HDL dysfunctional. The proinflammatory enzyme myeloperoxidase induces both oxidative modification and nitrosylation of specific residues on plasma and arterial apolipoprotein A-I to render HDL dysfunctional, which results in impaired ABCA1 macrophage transport, the activation of inflammatory pathways, and an increased risk of coronary artery disease. Understanding the features of dysfunctional HDL or apolipoprotein A-I in clinical practice might lead to new diagnostic and therapeutic approaches to atherosclerosis.

Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment.

BACKGROUND: The inflammatory/antiinflammatory properties of HDL were compared with HDL cholesterol in 2 groups of patients and in age- and sex-matched control subjects. METHODS AND RESULTS: Group 1 consisted of 26 patients not yet taking a statin who presented with coronary heart disease (CHD) or CHD equivalents by National Cholesterol Education Program Adult Treatment Panel III criteria studied before and 6 weeks after 40 mg/d of simvastatin. Group 2 consisted of 20 patients with documented CHD and HDL cholesterol > or =84 mg/dL. The inflammatory/antiinflammatory properties of HDL were determined by the ability of the subject's HDL to alter LDL-induced monocyte chemotactic activity (MCA) in a human artery wall coculture. Induction of MCA by a control LDL was determined in the absence or presence of the subject's HDL. Values in the absence of HDL were normalized to 1.0. Values >1.0 after the addition of HDL indicated proinflammatory HDL; values <1.0 indicated antiinflammatory HDL. Group 1 values before simvastatin were LDL cholesterol, 118+/-24 mg/dL; HDL cholesterol, 57+/-13 mg/dL; triglycerides, 125+/-64 mg/dL; and high-sensitivity C-reactive protein (hs-CRP), 1.7+/-1.9 mg/L; and MCA values were 1.38+/-0.91, compared with 0.38+/-0.14 for control subjects (P=1.5x10(-5)). After simvastatin, values were LDL cholesterol, 73+/-24 mg/dL; HDL cholesterol, 61+/-14 mg/dL; triglycerides, 99+/-52 mg/dL; and hs-CRP, 1.3+/-1.3 mg/L; and MCA values were 1.08+/-0.71. In group 2, values were LDL cholesterol, 108+/-34 mg/dL; HDL cholesterol, 95+/-14 mg/dL; triglycerides, 89+/-44 mg/dL; and hs-CRP, 0.8+/-0.7 mg/L; and MCA values were 1.28+/-0.29, compared with 0.35+/-0.11 for control subjects (P=1.7x10(-14)). Similar results were obtained with the cell-free assay. CONCLUSIONS: The inflammatory/antiinflammatory properties of HDL distinguished patients from control subjects better than HDL cholesterol and were improved with simvastatin.

Results of the National Cholesterol Education (NCEP) Program Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II survey and implications for treatment under the recent NCEP Writing Group recommendations.

The most recent national survey of compliance with the National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) guidelines was completed before ATP III and showed significant underachievement of low-density lipoprotein (LDL) cholesterol goals. The NCEP Evaluation ProjecT Utilizing Novel E-Technology (NEPTUNE) II was a national survey conducted in 2003. Of the 4,885 patients, 67% achieved their LDL cholesterol treatment goal, including 89%, 76%, and 57%, respectively, in the 0 or 1 risk factor, > or = 2 risk factors or coronary heart disease (CHD), and CHD risk equivalent categories. The percentage with triglyceride concentrations > or = 200 mg/dl (2.25 mmol/L) in each risk category who achieved their LDL cholesterol and non-high-density lipoprotein cholesterol goals was 64%, 52%, and 27%, respectively. Patients with diabetes (55%) and other CHD risk equivalents (40%) were less likely to have achieved their LDL cholesterol targets than those with CHD (62%). Of the 1,447 patients with cardiovascular disease, 75% could be classified as very high risk according to the new July 2004 NCEP Writing Group recommendations, and 17.8% of those at very high risk had an LDL cholesterol level of <70 mg/dl (<1.81 mmol/L). In conclusion, these results suggest improved lipid management compared with previous surveys. The largest treatment gaps were found for features new to ATP III as of July 2004, including goal achievement for patients with CHD risk equivalents and for non-high-density lipoprotein cholesterol targets. Most of those (75%) with cardiovascular disease in NEPTUNE II would be considered very high risk and candidates for aggressive therapy to reach the new optional treatment goals.

Evidence for a combined approach to the management of hypertension and dyslipidemia.

The recognition that hypertension and dyslipidemia coexist more often than would be expected by chance and that their combination increases the risk of coronary heart disease (CHD) has important implications for patient management. Patients with cardiovascular disease (CVD) and healthy individuals with multiple CVD risk factors--including concomitant dyslipidemia and hypertension-are the primary focus of updated treatment guidelines for CVD prevention. There is a need for a treatment paradigm shift from the diagnosis and treatment of individual CVD risk factors to the assessment and management of total CVD risk. Goals for each CVD risk factor need to be intensified when multiple sources of risk are present. Patients who have no overt disease but who have multiple CVD risk factors are now understood to be at high risk and should be the target of aggressive primary preventive strategies to avert unnecessary morbidity and mortality. It is also becoming clear that CVD risk factors interact at the level of the endothelium to promote atherosclerosis. Furthermore, recent clinical trials, including those assessing atherosclerotic progression and CVD endpoints, have demonstrated the effectiveness of interventions targeted at multiple risk factors for CVD.

Future directions in lipid therapies.

Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterol-absorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.

JCL roundtable: HDL in the primary care setting.

One of the most difficult and confusing issues for clinical lipidologists and physicians in general has been the management of low concentrations of high-density lipoprotein cholesterol. We know this to be a very powerful predictor of risk in scores of community-based and clinical trial cohorts. Raising this number in many patients would seem to provide a great therapeutic opportunity, but so far this concept has been very difficult to prove. I have been joined for this discussion by a cardiovascular epidemiologist, Dr. Rachel Mackey, from the University of Pittsburgh and two clinical lipidologists who have studied and written in depth about this problem. These are Dr. Benjamin Ansell from the University of California in Los Angeles and Dr. Peter Toth from Johns Hopkins University School of Medicine. Our objective in this discussion is to give primary care clinicians our thoughts about the recent research findings and the implications of these data on the best clinical practice.

Altered lipoprotein metabolism in chronic inflammatory states: proinflammatory high-density lipoprotein and accelerated atherosclerosis in systemic lupus erythematosus and rheumatoid arthritis.

In this review, the authors discuss the formation and structure of high-density lipoproteins (HDLs) and how those particles are altered in inflammatory or stress states to lose their capacity for reverse cholesterol transport and for antioxidant activity. In addition, abnormal HDLs can become proinflammatory (piHDLs) and actually contribute to oxidative damage. The assay by which piHDLs are identified involves studying the ability of test HDLs to prevent oxidation of low-density lipoproteins. Finally, the authors discuss the potential role of piHDLs (found in some 45% of patients with systemic lupus erythematosus and 20% of patients with rheumatoid arthritis) in the accelerated atherosclerosis associated with some chronic rheumatic diseases.

The paradox of dysfunctional high-density lipoprotein.

PURPOSE OF REVIEW: This review addresses how, in atherosclerosis or systemic inflammation, HDL can lose its usual atheroprotective characteristics and even paradoxically assume proinflammatory properties. RECENT FINDINGS: Specific chemical and structural changes within HDL particles can impede reverse cholesterol transport, enhance oxidation of LDL, and increase vascular inflammation. HDL may be viewed as a shuttle that can be either anti-inflammatory or proinflammatory, depending on its cargo of proteins, enzymes, and lipids. Some therapeutic approaches that reduce coronary risk, such as statins and therapeutic lifestyle changes, can favorably moderate the characteristics of proinflammatory HDL. In addition, apolipoprotein A-I mimetic peptides and other compounds that target functional aspects of HDL may offer novel approaches to reduction in cardiovascular risk. SUMMARY: Current data suggest that under some conditions HDL can become dysfunctional and even proinflammatory, but this characterization can change with resolution of systemic inflammation or use of certain treatments.