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.     

Genetic determinants of low high-density lipoprotein cholesterol

PURPOSE OF REVIEW: High-density lipoprotein cholesterol (HDL-C) has been well established as an inverse predictor of coronary heart disease (CHD), and in recent years, investigations have focused on the genetic regulation of high-density lipoprotein. Although numerous candidate genes contribute to the low HDL-C phenotype, their impact on CHD is heterogeneous, reflecting diverse gene-gene interactions and gene-environmental relationships. This review summarizes recent data involving HDL regulatory genes and their role in atherothrombosis. RECENT FINDINGS: The primary genetic determinants associated with relative HDL-C deficiency states are the ATP binding cassette protein, ABCA1; apolipoprotein (APO) A1; and lecithin cholesteryl acyl transferase. Other potentially important candidates invoked in low HDL-C syndromes in humans include APOC3, lipoprotein lipase, sphingomyelin phosphodiesterase 1, and glucocerebrosidase. Molecular variation in ABCAI and APOAI and, in selected cases, lecithin cholesteryl acyl transferase deficiency have been associated with increased CHD, whereas two notable variants, APOAIMilano and APOAIParis, are associated with reduced risk. SUMMARY: Low HDL-C syndromes have generally been correlated with an increased risk of CHD. However, single-gene abnormalities responsible for HDL-C deficiency states may have variable effects on atherothrombotic risk.     

Case 2: a patient with low levels of high-density lipoprotein cholesterol

Approximately 11% of all American men >20 years of age have low levels of high-density lipoprotein cholesterol (<35 mg/dl) in isolation, with an even higher prevalence in high-risk populations. One feature of the 1993 National Cholesterol Education Program guidelines-and the focus of this month's CME-accredited case study-is an increased emphasis on high-density lipoprotein cholesterol levels as an important aspect of risk stratification for coronary heart disease.     

Beyond high-density lipoprotein cholesterol levels evaluating high-density lipoprotein function as influenced by novel therapeutic approaches

A number of therapeutic strategies targeting high-density lipoprotein (HDL) cholesterol and reverse cholesterol transport are being developed to halt the progression of atherosclerosis or even induce regression. However, circulating HDL cholesterol levels alone represent an inadequate measure of therapeutic efficacy. Evaluation of the potential effects of HDL-targeted interventions on atherosclerosis requires reliable assays of HDL function and surrogate markers of efficacy. Promotion of macrophage cholesterol efflux and reverse cholesterol transport is thought to be one of the most important mechanisms by which HDL protects against atherosclerosis, and methods to assess this pathway in vivo are being developed. Indexes of monocyte chemotaxis, endothelial inflammation, oxidation, nitric oxide production, and thrombosis reveal other dimensions of HDL functionality. Robust, reproducible assays that can be performed widely are needed to move this field forward and permit effective assessment of the therapeutic potential of HDL-targeted therapies.     

Niacin-ER/statin combination for the treatment of dyslipidemia: focus on low high-density lipoprotein cholesterol

Statins are effective drugs for lowering low-density lipoprotein cholesterol, and their use has been associated with a significant decrease in cardiovascular morbidity and mortality. However, statins are ineffective in lowering plasma triglycerides and lipoprotein(a), or increasing low high-density lipoprotein cholesterol (HDL-C) plasma levels, which are independent risk factors for coronary heart disease. Niacin, on the other hand, is the most potent drug available for lowering plasma levels of triglycerides and lipoprotein(a) and raising HDL-C levels. It follows, then, that a combination of niacin with a statin might be an effective combination in improving all components of the lipid profile. Previous studies have shown that the use of long-acting niacin with a statin, in dose combinations of niacin-ER/lovastatin 1000/20 mg or 2000/40 mg once daily, has been effective in favorably modifying low-density lipoprotein cholesterol, triglycerides, lipoprotein(a), and HDL-C plasma levels. Dyslipidemias often predate the onset of hypertension, and HDL-C has been found to be inversely related to the incidence of hypertension. Normalization of lipid components, including the total cholesterol/HDL-C ratio, is important in the management of hypertensive individuals and patients with the metabolic syndrome or diabetes. Thus, the long-term treatment of dyslipidemias with these two agents may help to modify risk and reduce cardiovascular morbidity and mortality in these patients over and above benefits achieved by lowering blood pressure     

Nonpharmacologic and pharmacologic treatment of patients with low levels of high-density lipoprotein cholesterol

Low levels of high-density lipoprotein cholesterol (HDL-C) constitute a strong risk factor for developing coronary heart disease. This risk can be decreased by even slight improvements in HDL-C levels. This review discussess both pharmacologic and nonpharmacologic treatments of patients with low levels of HDL-C, including lifestyle modifications and the benefits of oral estrogens, niacin, fibrates, statins, and combination drug therapy.     

Raising low levels of high-density lipoprotein cholesterol is an important target of therapy

Recent clinical trials in patients with coronary heart disease indicate, for the very first time, that increasing low levels of high-density lipoprotein (HDL) cholesterol significantly reduces the cumulative occurrence of cardiovascular and cerebrovascular events in patients whose only lipid abnormality was low HDL with normal levels of low-density lipoprotein (LDL) cholesterol and triglycerides. These data provide a compelling scientific basis for a more targeted and segmental approach to managing patients with dyslipidemia, where decreasing elevated levels of LDL cholesterol and increasing low levels of HDL cholesterol should comprise dual targets of pharmacotherapy.     

New perspectives on the management of low levels of high-density lipoprotein cholesterol.

A low serum high-density lipoprotein cholesterol (HDL-C) level is a potent predictor of coronary heart disease (CHD). It has been estimated that 11% of US men have isolated low HDL-C levels, and there is uncertainty regarding the management of these patients. A cause-and-effect relationship between low HDL-C levels and CHD is supported by epidemiological, animal, and human clinical studies. We reviewed the structure and function of HDL-C and its role in preventing atherosclerosis. We then suggested an approach to the patient with isolated low HDL-C that may be useful to the primary care physician. An algorithm was proposed for use in patients with existing CHD, while the decision to treat patients without CHD was based on their score on the Framingham Heart Study risk prediction chart.     

Clinical significance of high-density lipoprotein cholesterol in patients with low low-density lipoprotein cholesterol.

OBJECTIVES: We sought to evaluate the significance of high-density lipoprotein cholesterol (HDL-C) in the context of low low-density lipoprotein cholesterol (LDL-C). BACKGROUND: Earlier studies support an inverse correlation between circulating HDL-C and coronary risk in patients with normal or elevated LDL-C. METHODS: This study involved 4,188 patients attending the Palo Alto Veterans Administration Medical Center or affiliated clinics with LDL-C levels below 60 mg/dl. Outcomes were examined 1 year after the index LDL-C date. The combined primary end point was myocardial injury or hospitalization from ischemic heart disease. The secondary end point was all-cause mortality. RESULTS: Mean HDL-C levels (mg/dl) by quartile (Q) were: Q1 28 mg/dl, Q2 36 mg/dl, Q3 43 mg/dl, and Q4 63 mg/dl. The rate of myocardial injury or hospitalization for ischemic heart disease showed an inverse relationship to HDL-C (adjusted odds ratios: Q1 1.59 [95% confidence interval (CI) 1.16 to 2.19], Q2 1.39 [95% CI 1.01 to 1.92], Q3 1.33 [95% CI 0.96 to 1.84], and Q4 reference) that persisted regardless of statin use or recent myocardial injury. Analyzing HDL-C as a continuous variable revealed a 10% [95% CI 3% to 17%] increase in the combined end point of myocardial injury or hospitalization for ischemic heart disease for every 10-mg/dl decrease in HDL-C. The unadjusted and adjusted incidence of all-cause mortality demonstrated a U-shaped relationship to HDL-C (adjusted odds ratios: Q1 1.13 [95% CI 0.79 to 1.62], Q2 0.97 [95% CI 0.67 to 1.40], Q3 0.74 [95% CI 0.50 to 1.09], and Q4 reference). CONCLUSIONS: The inverse relationship between HDL-C and coronary risk persists even among patients with LDL-C below 60 mg/dl, although a U-shaped relationship is observed between HDL-C and all-cause mortality.     

Relationship between low levels of high-density lipoprotein cholesterol and metabolic syndrome in Turkish patients

OBJECTIVE: It is stated that high-density lipoprotein cholesterol (HDL-C) levels are low in Turkish people and that this may be related to genetic factors. Low HDL-C is a parameter of the metabolic syndrome (MetS). In this study, the relationship between low HDL-C levels and MetS has been investigated. METHODS AND RESULTS: A total of 720 successive patients, 20 years or older, were categorized into two groups, as those with low-HDL-C (in men < 40 mg/dl, in women < 50 mg/dl) and those without low-HDL-C levels (in men > or = 40 mg/dl, in women > or = 50 mg/dl). The groups were compared according to the frequency of the MetS and the averages of the MetS criteria other than HDL-C. Moreover, two groups were formed with normal (< 150 mg/dl) and high (> or = 150 mg/dl) triglyceride levels and they have been compared with the average HDL-C levels. The frequency of MetS was 70.8% in the group with low-HDL-C and 24.2% in the group without low HDL-C levels (p < 0.001). The averages of the MetS criteria other than the HDL-C were 2.17 +/- 1.19 in the group with low-HDL-C levels and 1.59 +/- 1.15 in the group without low-HDL-C levels (p < 0.001). Average HDL-C level was 48.90 +/- 13.40 mg/dl in the group with normal triglyceride levels and 44.41 +/- 10.26 mg/dl in the group with high triglyceride levels (p < 0.001). CONCLUSIONS: This study shows that low HDL-C is related to the MetS in our patients, a selected group of a population reported to have a low HDL-C average.     

Elevated high-density lipoprotein cholesterol levels in older endurance athletes

To ascertain whether older (masters) athletes exhibit a more favorable plasma lipoprotein/lipid profile than sedentary men of similar age, 14 endurance-trained masters athletes (mean age 60 +/- 2 years [+/- standard error of the mean]), 12 older, untrained-not lean men (mean age 62 +/- 1 years), 9 older untrained-lean men (mean age 61 +/- 2 years), 15 young endurance-trained athletes (mean age 26 +/- 1 years) and 15 young untrained men (mean age 28 +/- 1 years) were studied. The athletes had higher values for maximal oxygen uptake and lower levels of body fatness compared with the untrained men, regardless of age (p less than 0.05). High-density lipoprotein (HDL) cholesterol was markedly higher in the masters athletes than in the other groups (66 vs 42 to 55 mg/dl, p less than 0.05). The total cholesterol (TC) and low-density lipoprotein cholesterol concentrations of the masters athletes generally were higher than those of the younger groups, similar to those of the older lean men, and lower than those of the older-not lean men (p less than 0.05). The TC/HDL cholesterol ratios were similarly low (2.8 to 3.4) for the athletes and the young untrained men compared with the older untrained men (4.0 to 5.6) (p less than 0.05). Thus, some older endurance athletes exhibit markedly higher HDL cholesterol levels and lower TC/HDL cholesterol ratios compared with their sedentary peers. This favorable plasma lipoprotein profile may indicate a reduced risk of developing coronary artery disease for older men who exercise regularly.     

Comparison of gemfibrozil and lovastatin in patients with high low-density lipoprotein and low high-density lipoprotein cholesterol levels.

BACKGROUND--The efficacy of gemfibrozil and lovastatin in the treatment of patients who have an elevated low-density lipoprotein cholesterol (LDL-C) level and a low high-density lipoprotein cholesterol (HDL-C) level was compared. METHODS--After at least 6 weeks of a cholestgerol-lowering diet, 17 patients who had a mean baseline LDL-C level above 4.14 mmol/L (160 mg/dL) and an HDL-C level below 1.03 mmol/L (40 mg/dL) received gemfibrozil 600 mg twice daily and lovastatin 20 mg twice daily each for 6 weeks according to a randomized, crossover, double-blind research design. RESULTS--Lovastatin and gemfibrozil reduced LDL-C levels 34% and 9% and raised HDL-C levels 15% and 18%, respectively. CONCLUSIONS--Lovastatin is more effective in lowering LDL-C levels and is as effective as gemfibrozil in increasing HDL-C levels in these patients.     

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.     

Relationship between total cholesterol/high-density lipoprotein cholesterol ratio, triglyceride/high-density lipoprotein cholesterol ratio, and high-density lipoprotein subclasses

Alterations in plasma lipid levels can influence the composition, content, and distribution of plasma lipoprotein subclasses that affect atherosclerosis risk. This study evaluated the relationship between plasma total cholesterol (TC)/high-density lipoprotein cholesterol (HDL-C) ratio, triglyceride (TG)/HDL-C ratio, and HDL subclass distribution. The apolipoprotein A-I contents of plasma HDL subclasses were quantitated by 2-dimensional gel electrophoresis coupled with immunodetection in 442 Chinese subjects. The particle size of HDL shifted toward smaller size with the elevation of TC/HDL-C and TG/HDL-C ratios. The ratio of large-sized HDL(2b) to small-sized prebeta(1)-HDL (HDL(2b)/prebeta(1)-HDL) was about 4.7 in the subjects with TC/HDL-C of 3.3 or lower and TG/HDL-C of 2.5 or lower, whereas it was only approximately 1.1 in subjects with TC/HDL-C greater than 6 and TG/HDL-C greater than 5. Pearson correlation analysis revealed that the TC/HDL-C ratio was positively correlated with prebeta(1)-HDL and HDL(3a) but negatively correlated with HDL(2a) and HDL(2b), whereas the TC/HDL-C ratio was only inversely correlated with HDL(2b). The TC/HDL-C and TG/HDL-C ratios together may be a good indicator of HDL subclass distribution. When these 2 ratios increased simultaneously, the trend toward smaller HDL size was obvious, which, in turn, indicated that the maturation of HDL might be impeded and the reverse cholesterol transport might be weakened. In addition, the TG/HDL-C ratio might be a more powerful factor to influence the distribution of HDL subclasses.     

Increasing high-density lipoprotein cholesterol in dyslipidemia by cholesteryl ester transfer protein inhibition: an update for clinicians

Reduced HDL cholesterol may be a risk factor comparable in importance to increased LDL cholesterol. Interventions that raise HDL are antiatherosclerotic, presumably through acceleration of reverse cholesterol transport and by antioxidant and antiinflammatory effects. In the hypercholesterolemic rabbit, HDL levels can be increased by >50% by inhibition of cholesteryl ester transfer protein (CETP), a molecule that plays a central role in HDL metabolism. This HDL-raising effect is antiatherosclerotic in moderately severe hyperlipidemia but appears to be ineffective in the presence of severe hypertriglyceridemia. In humans, mutations resulting in CETP inhibition have been associated with both reduced and increased risk of atherosclerosis. Proposed explanations for these apparently disparate observations are that the antiatherosclerotic effect of CETP inhibition varies with either the metabolic milieu or the degree of CETP inhibition. We now have pharmacological inhibitors of CETP that are capable of increasing HDL by as much as 50% to 100% in humans. The importance of this development is that reduced HDL is a risk factor independent of LDL and that these new agents alter HDL by a magnitude comparable to that of statins on LDL. Clinical trials, now beginning, will need to identify the patient subsets in which CETP inhibition may be more or less effective.