Affairs High-Density Lipoprotein Intervention Trial Research Articles

Relation of gemfibrozil treatment and high-density lipoprotein subpopulation profile with cardiovascular events in the Veterans Affairs High-Density Lipoprotein Intervention Trial

The significant cardiovascular disease (CVD) event reduction in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) could not be fully explained by the 6% increase in high-density lipoprotein (HDL) cholesterol with the fibrate gemfibrozil. We examined whether measurement of HDL subpopulations provided additional information relative to CVD risk reduction. The HDL subpopulations were characterized by 2-dimensional gel electrophoresis in subjects who were treated with gemfibrozil (n = 754) or placebo (n = 741). In this study, samples obtained at the 3-month visit were used; and data were analyzed prospectively using CVD events (coronary heart disease death, myocardial infarction, or stroke) during the 5.1 years of follow-up. Analyses in the gemfibrozil arm showed that subjects with recurrent CVD events had significantly higher pre β-1 and had significantly lower α-1 and α-2 HDL levels than those without such events. Pre β-1 level was a significant positive predictor; α-1 and α-2 levels were significant negative risk factors for future CVD events. α-2 level was superior to HDL cholesterol level in CVD-risk assessment after adjustment for established risk factors. Gemfibrozil treatment was associated with 3% to 6% decreases in the small, lipid-poor pre β-1 HDL and in the large, lipid-rich α-1 and α-2 HDL and with increases in the small α-3 (3%) and pre α-3 (16%) HDLs. Although the use of gemfibrozil has been associated with reduction in CVD events in VA-HIT, HDL subpopulation analysis indicates that gemfibrozil-mediated improvement in CVD risk might not be the result of its effects on HDL. It is quite possible that much of the cardiovascular benefits of gemfibrozil are due to a much wider spectrum of effects on metabolic processes that is not reflected by changes in blood lipids and HDL subpopulations.

Obesity and Atherogenic Dyslipidemia

Obesity is associated with an increased risk of coronary heart disease, in part due to its strong association with atherogenic dyslipidemia, characterized by high triglycerides and low high-density lipoprotein (HDL) cholesterol. There has been substantial research effort focused on the mechanisms of the link between obesity and atherogenic dyslipidemia, both in the absence and presence of insulin resistance. After a brief overview of the epidemiology of atherogenic dyslipidemia, this article details the known molecular mechanisms of adipocyte function and its relationship to apoB-containing lipoprotein assembly and metabolism, both in the healthy as well as in the obese states. We also discuss the pathophysiology of low HDL cholesterol in obesity and the implications for cardiovascular disease risk.

Body weight, plasma insulin, and coronary events with gemfibrozil in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT)

Background The Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) showed that gemfibrozil significantly reduced major coronary events in men with known coronary heart disease (CHD). To better understand why therapy was especially effective with obesity, diabetes, and hyperinsulinemia, changes in body weight and plasma insulin were determined after 1 year of gemfibrozil or placebo therapy and related to changes in lipids and CHD events. Results With gemfibrozil significantly more subjects lost weight (51.7% versus 38.6%, P < 0.0001) and significantly fewer subjects gained weight (42.5% versus 54.0%, P < 0.0001) than with placebo. Both a greater loss and smaller gain in weight with gemfibrozil were age-related and significant in subjects ≥66 years (median age), but not in younger subjects. Weight change was paralleled by changes in insulin. With gemfibrozil, CHD events were significantly reduced with weight loss (hazard ratio [HR], 0.61; 95% CI, 0.44–0.84; P = 0.002) and, particularly, with diabetes or hyperinsulinemia (HR, 0.53; 95% CI, 0.34–0.83; P = 0.006). In contrast, CHD events were not significantly reduced without weight loss (HR, 0.83; 95% CI, 0.62–1.12; P = 0.22). Conclusions In VA-HIT, gemfibrozil resulted in weight loss associated with reductions in insulin. With weight loss gemfibrozil produced a significant reduction in CHD events that did not occur in the absence of weight loss.

Cardioprotective Properties of Fibrates

Several large intervention trials have investigated the potential of fibrates to reduce cardiovascular events. The results have varied widely: positive, with gemfibrozil in the primary prevention Helsinki Heart Study (HHS)1 and the secondary prevention Veterans Administration High Density Lipoprotein Intervention Trial (VA-HIT)2; positive, with reservations related to an increase in noncardiovascular mortality in the primary prevention World Health Organization trial (clofibrate)3; and mixed, with bezafibrate in the secondary prevention Bezafibrate Infarction Prevention (BIP) study4 and with fenofibrate in the combined primary and secondary prevention FIELD study,5 in which positive outcomes were observed only in certain subgroups. Reasons for the differences between the outcomes of these studies are not immediately apparent. Article p 1556 It emerged in post hoc subgroup analyses of the HHS,6 VA-HIT,7 and BIP8 data that fibrate-induced reductions in cardiovascular events were especially great (of the order of 30% to 50%) in subjects with evidence of insulin resistance or other features of the metabolic syndrome, such as dyslipidemia and increased body weight. However, this finding was not replicated with fenofibrate in the FIELD study.5 In another post hoc analysis of VA-HIT, it was found that diabetics with preexisting cardiovascular disease derived a major reduction in future events when treated with gemfibrozil,7 but again, this was not confirmed with fenofibrate in FIELD.5 The observation that the cardioprotective effects of gemfibrozil in the HHS and VA-HIT studies were substantially greater than those found with other fibrates in the World Health Organization, BIP, and FIELD studies may reflect no more than the play of chance. It may also reflect differences in the populations studied in the trials. However, it is possible that gemfibrozil has protective properties that are lacking in other fibrates or that other fibrates have adverse …

Low-Density Lipoprotein and High-Density Lipoprotein Particle Subclasses Predict Coronary Events and Are Favorably Changed by Gemfibrozil Therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial

Changes in conventional lipid risk factors with gemfibrozil treatment only partially explain the reductions in coronary heart disease (CHD) events experienced by men in the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT). We examined whether measurement of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle subclasses provides additional information relative to CHD risk reduction. This is a prospective nested case-control study of 364 men with a new CHD event (nonfatal myocardial infarction or cardiac death) during a 5.1-year (median) follow-up and 697 age-matched controls. Nuclear magnetic resonance (NMR) spectroscopy was used to quantify levels of LDL and HDL particle subclasses and mean particle sizes in plasma obtained at baseline and after 7 months of treatment with gemfibrozil or placebo. Odds ratios for a 1-SD increment of each lipoprotein variable were calculated with adjusted logistic regression models. Gemfibrozil treatment increased LDL size and lowered numbers of LDL particles (-5%) while raising numbers of HDL particles (10%) and small HDL subclass particles (21%). Concentrations of these LDL and HDL particles achieved with gemfibrozil were significant, independent predictors of new CHD events. For total LDL and HDL particles, odds ratios predicting CHD benefit were 1.28 (95% CI, 1.12 to 1.47) and 0.71 (95% CI, 0.61 to 0.81), respectively. Mean LDL and HDL particle sizes were not associated with CHD events. The effects of gemfibrozil on NMR-measured LDL and HDL particle subclasses, which are not reflected by conventional lipoprotein cholesterol measures, help to explain the demonstrated benefit of this therapy in patients with low HDL cholesterol.

Peroxisome Proliferator-Activated Receptor-Alpha and Atherosclerosis

Atherosclerosis is an inflammatory process, triggered by the presence of lipids in the vascular wall, and encompasses a complex interaction among inflammatory cells, vascular elements, and lipoproteins through expression of several adhesion molecules and cytokines. Activation of the nuclear receptor, peroxisome proliferator-activated receptor-alpha (PPAR-alpha), has been demonstrated to modulate many aspects of lipoprotein metabolism and inflammation in vitro as well as in animal and human studies. The tissue distribution of PPAR-alpha is extensive, and it is abundantly present in the vascular wall where it may mediate many of antiinflammatory and antiatherogenic effects. Major clinical trials such as the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), the Helsinki Heart Study, and the Diabetes Atherosclerosis Intervention Study (DAIS) have demonstrated the beneficial effects of synthetic agonists of PPAR-alpha, specifically fibric acid derivatives, on cardiovascular disease outcome. Although fibric acid trials have reported cardiovascular risk reduction in patients with dyslipidemia, the favorable alterations in plasma lipids can only partially explain the reduction in cardiovascular events in these studies. One common link among these trials was a cohort with a high prevalence of insulin resistance or diabetes, conditions associated with heightened systemic inflammation and increased risk for development and progression of atherosclerosis. We review the many antiatherogenic effects of PPAR-alpha ligands and evidence from fibric acid trials that individuals with insulin resistance or diabetes benefit the most from these drugs, consistent with their antiinflammatory and antithrombotic properties.

Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease

Background: Limited data suggest that low levels of serum high-density lipoprotein cholesterol (HDL-C) and high levels of triglyceride-rich lipoproteins may be associated with more rapid rates of kidney function loss in individuals with chronic renal insufficiency (CRI). Although fibric acid derivatives increase serum HDL-C levels and decrease triglyceride levels, their effects on renal function are largely unknown. We conducted this study to determine whether gemfibrozil reduced rates of renal function loss in people with moderate CRI. Methods: This was a post hoc subgroup analysis in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized double-blind trial of gemfibrozil versus placebo in 2,531 men with coronary disease, HDL-C levels of 40 mg/dL or less (≤1.0 mmol/L), low-density lipoprotein cholesterol levels of 140 mg/dL or less (≤3.6 mmol/L), and a range of triglyceride values. Moderate CRI is defined as estimated glomerular filtration rate (GFR) of 30 to 59.9 mL/min/1.73 m2 at baseline. Multivariate regression was used to calculate rates of decline in estimated GFR for individuals administered gemfibrozil or placebo, controlling for prospectively determined potential confounders. Results: Change in renal function could be calculated in 1,981 individuals, of whom 399 individuals (20.2%) were eligible for inclusion. Among 399 study subjects, the rate of change in renal function in the gemfibrozil group during a median of 61 months was not significantly different from that in the placebo group (0.49 mL/min/1.73 m2/y faster; 95% confidence interval, 0.09 slower to 1.09 faster; P = 0.10). No clinically relevant effect of gemfibrozil on renal function was observed in groups defined by baseline lipid levels, kidney function, diabetic status, or other components of the metabolic syndrome. The incidence of transient (10% versus 4%; P = 0.01), but not sustained (9% versus 4%; P = 0.07), increases in serum creatinine levels of 0.5 mg/dL or greater (≥44 μmol/L) was significantly greater in the gemfibrozil group. However, in 5 subjects with acute increases in serum creatinine levels, serum creatine kinase levels were significantly elevated as well, suggesting that myocyte toxicity may have been responsible. Even when these individuals were excluded, no clinically significant effect of gemfibrozil on kidney function was observed. Conclusion: Gemfibrozil does not appear to exert a clinically relevant effect on rates of kidney function loss in individuals with moderate CRI, low HDL-C levels, and concomitant coronary disease. Background: Limited data suggest that low levels of serum high-density lipoprotein cholesterol (HDL-C) and high levels of triglyceride-rich lipoproteins may be associated with more rapid rates of kidney function loss in individuals with chronic renal insufficiency (CRI). Although fibric acid derivatives increase serum HDL-C levels and decrease triglyceride levels, their effects on renal function are largely unknown. We conducted this study to determine whether gemfibrozil reduced rates of renal function loss in people with moderate CRI. Methods: This was a post hoc subgroup analysis in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized double-blind trial of gemfibrozil versus placebo in 2,531 men with coronary disease, HDL-C levels of 40 mg/dL or less (≤1.0 mmol/L), low-density lipoprotein cholesterol levels of 140 mg/dL or less (≤3.6 mmol/L), and a range of triglyceride values. Moderate CRI is defined as estimated glomerular filtration rate (GFR) of 30 to 59.9 mL/min/1.73 m2 at baseline. Multivariate regression was used to calculate rates of decline in estimated GFR for individuals administered gemfibrozil or placebo, controlling for prospectively determined potential confounders. Results: Change in renal function could be calculated in 1,981 individuals, of whom 399 individuals (20.2%) were eligible for inclusion. Among 399 study subjects, the rate of change in renal function in the gemfibrozil group during a median of 61 months was not significantly different from that in the placebo group (0.49 mL/min/1.73 m2/y faster; 95% confidence interval, 0.09 slower to 1.09 faster; P = 0.10). No clinically relevant effect of gemfibrozil on renal function was observed in groups defined by baseline lipid levels, kidney function, diabetic status, or other components of the metabolic syndrome. The incidence of transient (10% versus 4%; P = 0.01), but not sustained (9% versus 4%; P = 0.07), increases in serum creatinine levels of 0.5 mg/dL or greater (≥44 μmol/L) was significantly greater in the gemfibrozil group. However, in 5 subjects with acute increases in serum creatinine levels, serum creatine kinase levels were significantly elevated as well, suggesting that myocyte toxicity may have been responsible. Even when these individuals were excluded, no clinically significant effect of gemfibrozil on kidney function was observed. Conclusion: Gemfibrozil does not appear to exert a clinically relevant effect on rates of kidney function loss in individuals with moderate CRI, low HDL-C levels, and concomitant coronary disease.

Effect of gemfibrozil on change in renal function in men with moderate chronic renal insufficiency and coronary disease

Limited data suggest that low levels of serum high-density lipoprotein cholesterol (HDL-C) and high levels of triglyceride-rich lipoproteins may be associated with more rapid rates of kidney function loss in individuals with chronic renal insufficiency (CRI). Although fibric acid derivatives increase serum HDL-C levels and decrease triglyceride levels, their effects on renal function are largely unknown. We conducted this study to determine whether gemfibrozil reduced rates of renal function loss in people with moderate CRI. This was a post hoc subgroup analysis in the Veterans Affairs High-Density Lipoprotein Intervention Trial, a randomized double-blind trial of gemfibrozil versus placebo in 2,531 men with coronary disease, HDL-C levels of 40 mg/dL or less (< or =1.0 mmol/L), low-density lipoprotein cholesterol levels of 140 mg/dL or less (< or =3.6 mmol/L), and a range of triglyceride values. Moderate CRI is defined as estimated glomerular filtration rate (GFR) of 30 to 59.9 mL/min/1.73 m2 at baseline. Multivariate regression was used to calculate rates of decline in estimated GFR for individuals administered gemfibrozil or placebo, controlling for prospectively determined potential confounders. Change in renal function could be calculated in 1,981 individuals, of whom 399 individuals (20.2%) were eligible for inclusion. Among 399 study subjects, the rate of change in renal function in the gemfibrozil group during a median of 61 months was not significantly different from that in the placebo group (0.49 mL/min/1.73 m2/y faster; 95% confidence interval, 0.09 slower to 1.09 faster; P = 0.10). No clinically relevant effect of gemfibrozil on renal function was observed in groups defined by baseline lipid levels, kidney function, diabetic status, or other components of the metabolic syndrome. The incidence of transient (10% versus 4%; P = 0.01), but not sustained (9% versus 4%; P = 0.07), increases in serum creatinine levels of 0.5 mg/dL or greater (> or =44 micromol/L) was significantly greater in the gemfibrozil group. However, in 5 subjects with acute increases in serum creatinine levels, serum creatine kinase levels were significantly elevated as well, suggesting that myocyte toxicity may have been responsible. Even when these individuals were excluded, no clinically significant effect of gemfibrozil on kidney function was observed. Gemfibrozil does not appear to exert a clinically relevant effect on rates of kidney function loss in individuals with moderate CRI, low HDL-C levels, and concomitant coronary disease.

Gemfibrozil for secondary prevention of cardiovascular events in mild to moderate chronic renal insufficiency

Although cardiovascular disease and low high-density lipoprotein (HDL) cholesterol are common in people with renal insufficiency, data addressing the cardiovascular benefits of fibric acid derivatives in this population are sparse. We conducted a post hoc subgroup analysis of a randomized double-blind, placebo-controlled trial to determine whether gemfibrozil is effective and safe for secondary prevention of cardiovascular events in individuals with chronic renal insufficiency (CRI). Using an analysis plan that was developed a priori, we analyzed data from the Veterans' Affairs High-Density Lipoprotein Intervention Trial (VA-HIT) study; a randomized trial of gemfibrozil versus placebo in 2531 men with established coronary disease, an HDL cholesterol level of 40 mg/dL (1.0 mmol/L) or less, and a low-density lipoprotein (LDL) cholesterol level of 140 mg/dL (3.6 mmol/L) or less. Of these, 1046 men had CRI as defined by creatinine clearance </=75 mL/min using the Cockcroft-Gault equation, 99.8% of whom had either mild or moderate renal impairment (creatinine clearance 60-75 or 30-59.9 mL/min, respectively). The incidence of the primary outcome (coronary death or nonfatal myocardial infarction) was lower in participants with CRI who received gemfibrozil compared to placebo [hazard ratio (HR) 0.73; 95% CI 0.56-0.96, P= 0.02). The cumulative incidence of the primary end point was reduced from 24.3% to 18.2%. In subjects with CRI, gemfibrozil also significantly reduced the risk of the combined outcome of coronary death, nonfatal myocardial infarction, or stroke (HR 0.74, 95% CI 0.58-0.95, P= 0.02), but not the need for coronary revascularization (HR 0.85, 95% CI 0.66-1.10, P= 0.21) or total mortality (HR 1.03, 95% CI 0.78-1.35, P= 0.85). The overall incidence of adverse effects was similar in individuals receiving gemfibrozil and placebo. However, the risk of sustained increases in serum creatinine was increased in gemfibrozil recipients compared with placebo (5.9 vs. 2.8%, P= 0.02). Gemfibrozil appears effective for secondary prevention of cardiovascular events in individuals with mild to moderate chronic renal insufficiency and HDL cholesterol of 40 mg/dL or less. However, the benefit and safety of gemfibrozil in people with more severe impairment of kidney function requires further study.

The role of fibrates in managing hyperlipidemia: mechanisms of action and clinical efficacy.

At a time when the lipid management guidelines give more and more emphasis to the identification and treatment of high-risk patients with the metabolic syndrome and diabetes, there is an obvious need to balance the known effects of low-density lipoprotein (LDL) lowering with the new evidence of clinical efficacy derived from the adjustment of high-density lipoprotein (HDL) and triglyceride levels. Whereas the statins remain the drug of choice for patients who need to reach the LDL goal, fibrate therapy may represent the best intervention for subjects with atherogenic dyslipidemia and an LDL already close to goal. In addition, the concomitant use of fibrates may significantly reduce cardiovascular risk in patients whose LDL is controlled by statin therapy. In this review, we evaluate the pharmacologic properties of the fibrate drugs, with particular attention to the effects of peroxisome proliferator activated receptor a activation in the control of dyslipidemia as well as in the attenuation of arterial inflammation. Clinical trials of fibrates, such as the Helsinki Heart Study, Veterans Affairs High-density lipoprotein Intervention Trial, Diabetes Atherosclerosis Intervention Study, and Bezafibrate Infarction Prevention trial, have conjured up a scenario for the clinical utility of fibrates and their possible superiority to statins in the management of obese, insulin-resistant, and diabetic patients presenting with near-goal LDL and inappropriate HDL and triglyceride levels.

Role of fibric acid derivatives in the management of risk factors for coronary heart disease.

Although elevated low-density lipoprotein (LDL)-cholesterol is a well established coronary heart disease (CHD) risk factor, the ability to adequately discriminate high-risk individuals by this risk factor alone is limited and other metabolic risk variables are known to modulate CHD risk. For instance, it has been reported that the cluster of metabolic disturbances observed among individuals with abdominal obesity, the so-called metabolic syndrome, is associated with a substantially increased risk of CHD. Among the features of the dyslipidaemic profile observed in these individuals, the high triglyceride-low high-density lipoprotein (HDL)-cholesterol dyslipidaemia is predictive of an elevated risk of CHD. Fibric acid derivatives (fibrates) have been used in clinical practice for more than 2 decades as a class of agents known to decrease triglyceride levels while substantially increasing HDL-cholesterol levels, with a limited but significant additional lowering effect on LDL-cholesterol levels. Although the clinical benefits of HMG-CoA reductase inhibitors (statins) have been well documented by primary and secondary prevention trials that justify their widespread use, it was not until the publication of the VA-HIT (Veterans Affairs High-Density Lipoprotein Intervention Trial) that the relevance of identifying HDL-cholesterol as a therapeutic target to reduce the risk of recurrent CHD events was finally confirmed. The clinical benefits of fibrate therapy are especially important in the subpopulation of patients with low HDL-cholesterol levels with the metabolic syndrome, particularly in patients with type 2 diabetes mellitus or in abdominally obese, hyperinsulinaemic patients. Evidence also suggests that there is a 'fibrate effect' that mediates the reduction in CHD risk beyond the favourable impact of these agents on HDL-cholesterol levels. This last notion is consistent with the pleiotropic effects of fibrates which are known to be related to their mechanisms of action. Through peroxisome proliferator-activated alpha-receptors, fibrates have a significant impact on the synthesis of several apolipoproteins (apo) and enzymes of lipoprotein metabolism as well as on the expression of several genes involved in fibrinolysis and inflammation. Fibrate therapy has been reported to decrease apo CIII levels (a powerful inhibitor of lipoprotein lipase) and increase apo AI levels, as well as to increase lipoprotein lipase activity. Such changes contribute to improve the catabolism of triglyceride-rich lipoproteins, leading to a substantial increase in HDL-cholesterol levels accompanied by a shift in the size and density of LDL particles (from small, dense LDL particles to larger, more buoyant cholesteryl ester-rich LDL). It is proposed that some of these pleiotropic effects could explain some of the clinical benefits of fibrate therapy beyond its HDL-raising properties, particularly among patients with abdominal obesity, hyperinsulinaemia or type 2 diabetes with both low HDL- and low/normal LDL-cholesterol levels.

HDL in atherosclerosis: actor or bystander?

Despite dramatic improvement in treatments for reducing risk for coronary heart disease (CHD), it is still the leading cause of mortality in the developed world. In the past decade, a major improvement in reducing low-density lipoprotein (LDL) cholesterol has been achieved with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). This approach has been shown to be beneficial in both primary and secondary prevention of CHD. On the other hand, while a reduced high-density lipoprotein (HDL) cholesterol level is an independent CHD risk factor, no HDL cholesterol goal has yet been established. The Helsinki Heart Study and the Veterans Affairs High-density Lipoprotein Intervention Trial documented that increasing HDL cholesterol with gemfibrozil significantly decreases coronary events or stroke in CHD patients either with elevated non-HDL cholesterol or normal LDL cholesterol levels plus low HDL cholesterol. Investigations with statins have focused on their efficacy not only in significantly decreasing total cholesterol, LDL cholesterol, and triglyceride levels but also in increasing HDL cholesterol concentrations. The two different classes of drugs (statins and fibrates) have different effects on the various HDL subspecies. As new members of these drug classes and other novel drugs are emerging, there is interest in clarifying whether HDL is only a bystander (an indicator for other CHD risk factors) or it has an active role in the development of CHD. If HDL has an active role, there is a need to determine if any HDL subspecies are protective. It is now clear that HDL plays a pivotal role in cellular cholesterol efflux via the interaction of apolipoprotein A-I with the ATP binding cassette transporter A-1. Thereafter the cholesterol is esterified by lecithin:cholesterol acyltransferase; HDL is remodeled by cholesterol ester transfer protein (CETP) and hepatic lipase. The cholesterol in HDL can either be transferred to apolipoprotein B-containing particles via CETP or delivered directly to the liver with the help of scavenger receptor B1.

Targeting low high-density lipoprotein cholesterol for therapy: lessons from the Veterans Affairs High-density Lipoprotein Intervention Trial

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.

Differentiating the effects of raising low levels of high-density lipoprotein cholesterol versus lowering normal triglycerides: further insights from the veterans affairs high-density lipoprotein intervention trial

In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), a 6% increase in high-density lipoprotein cholesterol (HDL-C) was associated with a 22% reduction in the incidence of fatal and nonfatal myocardial infarction and death from coronary artery disease. A curvilinear correlation was demonstrated between incremental changes in HDL-C and outcome. However, triglyceride levels, which decreased by 31%, were not predictive of clinical events. Some design limitations may be implicated in this lack of statistical correlation between triglycerides and outcome. Evidence from other studies, notably the Framingham Heart Study, the Prospective Cardiovascular Münster Heart Study (PROCAM), and the Baltimore Coronary Observational Long-Term Study (COLTS) suggest that the triglyceride cutpoint of 200 mg/dL is too high. The Bezafibrate Infarction Prevention (BIP) trial found a significant correlation between reduction in death from coronary artery disease and nonfatal MI and reduced triglycerides in a subset of patients with baseline triglycerides >200 mg/dL.

High-density lipoprotein and coronary heart disease: lessons from recent intervention trials.

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.