Veterans Affairs HDL Intervention Trial Research Articles

Effects of Combination Lipid Therapy in Diabetes Mellitus

Introduction: Diabetes mellitus is a major modifiable risk factor for the development of coronary atherosclerosis. Diabetes mellitus is increasing in incidence and prevalence in the United States and has been termed a coronary equivalent following the epidemiologic demonstration that subjects with type 2 diabetes mellitus without a history of prior atherosclerosis appear to be at the same risk of nondiabetic individuals who had suffered an acute coronary event [1]. Type 2 diabetes is frequently associated with obesity, sedentary lifestyle, hypertension, and dyslipidemia. The role of lipid management in reducing cardiovascular risk in diabetic subjects has been validated in multiple clinical trials. Diabetic dyslipidemia is frequently a mixed pattern and is associated with high triglycerides, low high-density lipoprotein (HDL), and small, dense low-density lipoprotein (LDL). Statin therapy has provided a major mechanism to reduce the risk in diabetic subjects, although the event rates in treated subjects remain significant. However, hypertriglyceridemia is frequently not optimized by statin therapy. The role of combination therapy utilizing a statin with a second agent that demonstrates a predominant effect on hypertriglyceridemia (eg, fibric acid derivatives, nicotinic acid) has theoretic advantages and has been proposed as potential therapy in diabetic subjects. Fibric acid derivatives have been demonstrated to be efficacious in diabetic subjects in a subgroup analysis of the Veterans Affairs HDL intervention trial ((VA-HIT) [2].The VA-HIT study administered gemfibrozil to 2,531 male subjects or in secondary prevention. However, the administration of fenofibrate in the Fenofibrate Intervention and Event lowering in Diabetes (FIELD) trial did not clearly demonstrate clinical benefit [3]. However, the placebo group had a significant utilization of statin therapy. Additionally, a post hoc analysis demonstrated clinical benefit in subjects who were characterized by mixed dyslipidemia (hypertriglyceridemia and low HDL) [4]. Clinical trials of combination therapy have the potential to show cardiovascular risk reduction in diabetic subjects.

Common genetic variation in multiple metabolic pathways influences susceptibility to low HDL-cholesterol and coronary heart disease

A low level of HDL-C is the most common plasma lipid abnormality observed in men with established coronary heart disease (CHD). To identify allelic variants associated with susceptibility to low HDL-C and CHD, we examined 60 candidate genes with key roles in HDL metabolism, insulin resistance, and inflammation using samples from the Veterans Affairs HDL Intervention Trial (VA-HIT; cases, n = 699) and the Framingham Offspring Study (FOS; controls, n = 705). VA-HIT was designed to examine the benefits of HDL-raising with gemfibrozil in men with low HDL-C (≤40 mg/dl) and established CHD. After adjustment for multiple testing within each gene, single-nucleotide polymorphisms (SNP) significantly associated with case status were identified in the genes encoding LIPC (rs4775065, P < 0.0001); CETP (rs5882, P = 0.0002); RXRA (rs11185660, P = 0.0021); ABCA1 (rs2249891, P = 0.0126); ABCC6 (rs150468, P = 0.0206; rs212077, P = 0.0443); CUBN (rs7893395, P = 0.0246); APOA2 (rs3813627, P = 0.0324); SELP (rs732314, P = 0.0376); and APOC4 (rs10413089, P = 0.0425). Included among the novel findings of this study are the identification of susceptibility alleles for low HDL-C/CHD risk in the genes encoding CUBN and RXRA, and the observation that genetic variation in SELP may influence CHD risk through its effects on HDL.

Cardiovascular Events With Increased Lipoprotein-Associated Phospholipase A 2 and Low High-Density Lipoprotein-Cholesterol

Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), a proinflammatory enzyme that predominantly circulates with low-density lipoprotein (LDL), has been shown in general populations to predict cardiovascular (CV) events. We sought to determine whether increased Lp-PLA(2) would also predict CV events in the absence of high LDL-cholesterol (LDL-C), in a population with low high-density lipoprotein-cholesterol (HDL-C). Plasma Lp-PLA(2) activity was measured at baseline and after 6 months on-trial in 1451 men with low HDL-C (mean, 32 mg/dL) and low LDL-C (mean 110 mg/dL), randomized to either placebo or gemfibrozil therapy in the Veterans Affairs HDL Intervention Trial (VA-HIT). Over a quartile range of increasing Lp-PLA(2) there was a significant increase in LDL-C and decrease in HDL-C (P < 0.0001), and an increased percentage of myocardial infarction (MI), stroke, or CHD death (P=0.03 for trend). In Cox models, adjusted for major CV risk factors, a 1-SD increase in Lp-PLA(2) was associated with a significant increase in CV events (hazard ratio [HR] 1.17 95% CI 1.04 to 1.32). Although gemfibrozil reduced Lp-PLA(2) only modestly (6.6%), at higher levels of Lp-PLA(2) gemfibrozil produced a significant reduction in CV events. In VA-HIT, a population with low HDL-C and LDL-C, high Lp-PLA(2) independently predicted CV events that were reduced by gemfibrozil.

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.

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.

Lipid-lowering therapy in type 2 diabetes: a review of the evidence

Current treatment guidelines highlight the importance of lipid-lowering therapy in reducing cardiovascular risk in patients with type 2 diabetes. Statins have been shown to be effective in reducing cardiovascular risk in patients with diabetes, but they fail to address adequately the coronary risk associated with low plasma levels of high-density lipoprotein cholesterol (HDL-C) and elevated triglycerides, commonly reported in these patients. Fibrates are effective against all three components of the atherogenic dyslipidaemic profile that characterises type 2 diabetes. Clinical studies such as the Veterans Affairs HDL Intervention Trial (VA-HIT), which showed a marked and statistically significant reduction in coronary heart disease death and stroke, as well as the Diabetes Atherosclerosis Intervention Study (DAIS), which showed that treatment with fenofibrate produced significantly less progression in markers of focal coronary artery disease, support a role for fibrate therapy in cardiovascular risk reduction in type 2 diabetes. Together, these data provided the rationale for the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, the largest study to date in patients with type 2 diabetes.

Codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene is associated with increased cardiovascular risk in the dyslipidemic diabetic participants of the veterans affairs HDL intervention trial (VA-HIT)

The threonine (Thr) for alanine (Ala) codon 54 polymorphism of the fatty acid binding protein (FABP) 2 gene, when compared to the wild type, is associated with dyslipidemia. Since dyslipidemia is common in diabetes and is associated with increased cardiovascular risk, we tested the hypothesis that Thr-54 is associated with increased cardiovascular risk in patients with diabetes. The secondary prevention veterans affairs HDL intervention trial (VA-HIT) was carried out in patients with dyslipidemia. The DNA of trial participants ( n = 776) was screened for the Thr-54 polymorphism and cardiovascular endpoints were monitored. The polymorphism was detected in 370 (47.7%). For first occurrence of the primary endpoint [myocardial infarction (MI) or coronary heart disease (CHD) death] the hazard ratio (HR) and confidence intervals (Cox proportional hazards model) was 2.5 (1.2, 5.3) p = .02 in diabetic carriers of Thr-54 versus carriers without diabetes or fasting glucose >7 mmol/L. For the expanded endpoint (stroke, MI or CHD death), the corresponding HR was 3.0 (1.4, 5.4) p = .0003 and for the stroke alone the corresponding HR was 3.5 (1.4–8.9) p = .01. The higher cumulative incidence of the expanded endpoint in diabetic participants carrying the FABP2 polymorphism versus non-diabetic carriers was consistently present throughout the 5 years of the study ( p = .0002). We conclude that based on the VA-HIT data, the Thr-54 polymorphism of the FABP2 gene is associated with a 2–3.5-fold increase in cardiovascular risk in dyslipidemic men with diabetes compared to their non-diabetic counterparts.

FIELDS of dreams, fields of tears: a perspective on the fibrate trials

Endpoint studies have been performed with fibrates in coronary heart disease since 1971. The results have been confusing - starting with initial benefits in small studies, but contradicted by either minimal benefits in the Coronary Drug Project or adverse noncardiovascular (non-CV) effects in the World Health Organization Clofibrate Study. Fibrates returned for patients with low HDL-C and low LDL-C after a 25% event reduction were seen in the Veterans Affairs HDL Intervention Trial. The greater prominence ascribed to the lipid triad of the metabolic syndrome and the increasing prevalence of diabetes increased the topicality of fibrates given their main action of converting small dense to light buoyant LDL. The Fenofibrate Intervention in Event Lowering in Diabetes (FIELD) Study has carried on the tradition. Fenofibrate therapy in 9795 patients comprising a mixed low-risk primary and a medium-risk secondary prevention cohort resulted in an 11% reduction in coronary events (p = 0.16), a similar but significant reduction in CV events (p = 0.04; number needed to treat = 70). The benefits were concentrated in primary prevention and on nonfatal myocardial events, but the study was confounded by asymmetrical statin drop-in due to the LDL-C-lowering effect of fenofibrate. Safety was generally good, including in combination with statins, but old concerns about sudden death, pancreatitis and venous thrombosis returned. Unexpected benefits were seen with fenofibrate on microvascular endpoints including microalbuminuria and retinopathy. Fenofibrate is a reasonable second-line therapy for dyslipidaemia in diabetes and safe in combination therapy. Its benefits on microvascular disease and in combination therapy require further confirmation.

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.

LpA-I, LpA-I:A-II HDL and CHD-risk: The Framingham Offspring Study and the Veterans Affairs HDL Intervention Trial

Objective We tested the hypothesis that concentrations of LpA-I and/or LpA-I:A-II HDL subclasses are significantly associated with CHD prevalence and recurrent cardiovascular events. Methods LpA-I levels were determined by differential electroimmunoassay in male participants with ( n = 169) and without CHD ( n = 850) from the Framingham Offspring Study (FOS) and in male participants with CHD from the placebo arm of the Veterans Affairs HDL Intervention Trial (VA-HIT) ( n = 741). Data were analyzed cross-sectionally (FOS) and prospectively (VA-HIT) and were adjusted for established lipid and non-lipid CHD risk factors. Results We observed slightly but significantly higher LpA-I levels in CHD cases compared to all or to HDL-C-matched controls and slightly but significantly higher LpA-I:A-II levels in CHD cases compared to HDL-C-matched controls it the FOS. Neither LpA-I nor LpA-I:A-II levels were significantly different between groups with and without recurrent cardiovascular events in the VA-HIT. No significant differences were observed in LpA-I and LpA-I:A-II levels in low HDL-C (≤40mg/dl) subjects with CHD (VA-HIT, n = 711) and without CHD (FOS, n = 373). Plasma LpA-I concentration had a positive correlation with the large LpA-I HDL particle (α-1) but no correlation with the small LpA-I HDL particle (preβ-1). LpA-I:A-II concentration had a positive correlation with the large (α-2) and an inverse correlation with the small (α-3) LpA-I:A-II HDL particles. Conclusion Our data do not support the hypothesis that CHD prevalence (FOS) or recurrence of cardiovascular events (VA-HIT) are associated with significant reductions in the concentrations of LpA-I and/or LpA-I:A-II HDL subclasses.

The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: The Veterans Affairs HDL Intervention Trial (VA-HIT)

Background The Veterans Affairs HDL Intervention Trial (VA-HIT) showed that gemfibrozil, which activates peroxisome proliferator–activator receptor α (PPARα), significantly reduced the risk of cardiovascular (CV) events in men with low HDL cholesterol (<40 mg/dl) and established coronary heart disease. Treatment was particularly beneficial in those with insulin resistance (IR) or diabetes mellitus (DM). We hypothesized that the association between a functional polymorphism at the PPARA locus (L162V) and the risk of a CV event, as well as response to fibrate therapy, might be greatest in those with either IR or DM (DM/IR) in VA-HIT. Methods and results A total of 827 men (placebo, n = 413; gemfibrozil, n = 414) from the VA-HIT were genotyped. This population included a high proportion of subjects with DM/IR. In VA-HIT, the PPARA V162 allele was associated with reduced levels of HDL cholesterol and the presence of DM/IR at baseline. It was also associated with reduced risk of CV events in those with DM/IR but not in those with neither (DM/IR * PPARA genotype, P = 0.005). Among subjects with DM/IR, treatment with gemfibrozil reduced CV events in non-carriers from 29.9 to 17.8% and carriers of the V162 allele from 14.7 to 4.8%. In contrast, carriers of the V162 allele with no DM/IR who were treated with gemfibrozil experienced significantly more CV events than did those who received placebo (20.6% versus 13.6%; P = 0.01). Conclusions The effect of the L162V polymorphism at the PPARA locus on CV risk depends on the presence of DM/IR. Among subjects treated with gemfibrozil, the V162 allele was associated not only with reduced CV risk in subjects with DM/IR, but also with significantly increased CV risk in the absence of these traits, identifying this genetic variant as a potential marker for predicting which subjects may have a favorable response to fibrate therapy.

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.

Value of High-Density Lipoprotein (HDL) Subpopulations in Predicting Recurrent Cardiovascular Events in the Veterans Affairs HDL Intervention Trial

To test the hypothesis whether determination of high-density lipoprotein (HDL) subpopulations provides more power to predict recurrent cardiovascular disease (CVD) events (nonfatal myocardial infarction, coronary heart disease death, and stroke) than traditional risk factors in the Veterans Affairs HDL Intervention Trial (VA-HIT). Apolipoprotein A-I (apoA-I)-containing HDL subpopulations were quantitatively determined by nondenaturing 2D gel electrophoresis. Hazard ratios of recurrent CVD events were calculated by comparing VA-HIT subjects with (n=398) and without (n=1097) such events. Subjects with new CVD events had significantly lower HDL-C, apoA-I, and large cholesterol-rich HDL particle (alpha-1, alpha-2, pre-alpha-1, and pre-alpha-2) levels, significantly higher triglyceride, and small poorly lipidated HDL particle (pre-beta-1 and alpha-3) levels than subjects without such events. Multivariate analyses indicated that alpha-1 and alpha-2 particle levels were significant negative risk factors, whereas alpha-3 level was a significant positive risk factor for new CVD events. Pre-beta-1 level was a significant risk factor for new CVD events only in univariate analysis. A forward selection model indicated that alpha-1 was the most significant risk factor for recurrent CVD events among HDL particles. An altered HDL subpopulation profile marked with low alpha-1 and alpha-2 levels and a high alpha-3 level in coronary heart disease patients indicated an elevated risk for new CVD events. Moreover, alpha-1 and alpha-2 levels were superior to HDL-C levels in risk assessment in patients with low HDL-C in VA-HIT.

Raising HDL-cholesterol and lowering CHD risk: does intervention work?

Epidemiological studies have associated low HDL-cholesterol with an increased risk of morbid coronary events. Accordingly, intervention to correct low HDL-cholesterol may be cardioprotective. A number of randomized intervention studies have addressed this hypothesis using fibrates (the Veterans Affairs HDL Intervention trial, the Helsinki Heart Study, and the Bezafibrate Infarction Prevention trial), or nicotinic acid, alone [Coronary Drug Project (CDP)] or in combination [the HDL Atherosclerosis Treatment Study (HATS) and the Stockholm Ischaemic Heart Disease study (IHD)]. These trials demonstrate conclusively that treatments to increase HDL-cholesterol deliver clinically significant improvements in prognosis. Of these trials, the largest improvement in outcomes occurred in the HATS trial, where the incidence of a combined coronary endpoint (coronary death, non-fatal myocardial infarction, confirmed stroke, or revascularization for worsening ischaemia) was reduced by 60–90% in patients receiving treatment based on nicotinic acid combined with a statin. The benefits of nicotinic acid-based treatment appear to be durable, as significant outcome benefits were visible in the group of patients initially randomized to nicotinic acid in the CDP 15 years after randomization, i.e. 9 years after the end of double-blind treatment. The combination of nicotinic acid with a statin appears to be a rational, effective, and safe strategy for minimizing cardiovascular risk in patients with dyslipidaemia.

Anti-Atherogenic Role of Peroxisome Proliferator-Activated Receptor Ligands

Two families of peroxisome proliferating-activated receptor (PPAR) ligands are utilized clinically to address abnormalities of blood-borne cardiovascular risk factors. PPAR-α ligands, the fibrates, lower plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol leading to positive outcomes in clinical trials such as the Veterans Affairs HDL Intervention Trial. PPAR-γ ligands, the recently introduced family of thiazolidinediones, act as insulin sensitizers to alleviate the hyperglycemia of insulin resistant states such as Type 2 diabetes. The primary aim of treating the cardiovascular risk factors is to reduce the burden of cardiovascular disease, mostly atherosclerotic vascular disease. Considerable evidence is emerging that PPAR ligands can exert anti-atherogenic activity. Although the agents acting on their target nuclear receptors are primarily regulators of gene transcription it may be that some actions are independent of gene transcription and represent direct inhibition of atherogenic signalling pathways in the vasculature. The direct actions including inhibition of vascular smooth muscle cell proliferation and inhibition of glycosaminoglycan elongation on proteoglycans, the latter leading to reduced low-density lipoprotein (LDL) binding, provide in vitro examples of antiatherogenic actions. PPAR ligands reduce atherosclerosis in animal models such as the ApoE-null mouse and PPAR-γ attenuate in-stent restenosis in patients with diabetes. The actions of these agents have lead to suggestions that they may be useful in vascular therapy even in the absence of the underlying risk factor abnormality. However, they may also represent tools and provide insights into areas where agents directly targeting atherosclerotic mechanisms may be developed to provide combined therapy with agents targeting traditional risk factors. Keywords: atherosclerosis, cardiovascular disease, fibrates, glitazones, lipoprotein retention, peroxisome proliferating, activated receptor (ppar)

Antiatherogenic Properties of Fibrates

In an era dominated by the use of statins as agents to reduce cardiovascular risk, fibrates have been largely forgotten. This is despite a remarkably robust evidence base certifying to the cardioprotective effects of these agents. In the Helsinki Heart Study (HHS), a 5-year, double-blind, placebo-controlled trial of the effects of gemfibrozil in 4081 men aged 40 to 55 years who were free of clinically manifest CHD at entry to the study, there was a statistically significant 34% reduction in the incidence of total coronary events from 41.4 per 1000 in the placebo group to 27.3 per 1000 in the gemfibrozil group.1 In the Veterans Affairs High-Density Lipoprotein Intervention Trial (VA-HIT), a 5-year, double-blind, placebo-controlled trial with gemfibrozil in 2531 men with clinical CHD and low levels of both high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, the primary end point (nonfatal myocardial infarction or death attributable to CHD) was reduced significantly by 22% from 21.7% in the placebo group to 17.3% in the gemfibrozil group.2 Positive results have also been obtained in angiographic studies with gemfibrozil in the Lopid Coronary Angiography Trial,3 with bezafibrate in the Bezafibrate Coronary Atherosclerosis Intervention Trial4 and with fenofibrate in the Diabetes Atherosclerosis Intervention Study.5 See page 1193 The cardiovascular benefits of treatment with fibrates appear to be greatest in people with insulin resistance and other features of the metabolic syndrome. In the HHS, a baseline level of serum triglyceride >200 mg/dL or a HDL cholesterol <40 mg/dL or a …

Polymorphisms in the gene encoding lipoprotein lipase in men with low HDL-C and coronary heart disease: The Veterans Affairs HDL Intervention Trial

Our goal was to further define the role of LPL gene polymorphisms in coronary heart disease (CHD) risk. We determined the frequencies of three LPL polymorphisms (D9N, N291S, and S447X) in 899 men from the Veterans Affairs HDL Intervention Trial (VA-HIT), a study that examined the potential benefits of increasing HDL with gemfibrozil in men with established CHD and low high density lipoprotein cholesterol (HDL-C; < or =40 mg/dl), and compared them with those of men without CHD from the Framingham Offspring Study (FOS). In VA-HIT, genotype frequencies for LPL D9N, N291S, and S447X were 5.3, 4.5, and 13.0%, respectively. These values differed from those for men in FOS having an HDL-C of >40, who had corresponding values of 3.2% (P = 0.06), 1.5% (P < 0.01), and 18.2% (P < 0.01). On gemfibrozil, carriers of the LPL N9 allele in VA-HIT had lower levels of large LDL (-32%; P < 0.01) but higher levels of small, dense LDL (+59%; P < 0.003) than did noncarriers. Consequently, mean LDL particle diameter was smaller in LPL N9 carriers than in noncarriers (20.14 +/- 0.87 vs. 20.63 +/- 0.80 nm; P < 0.003). In men with low HDL-C and CHD: 1) the LPL N9 and S291 alleles are more frequent than in CHD-free men with normal HDL-C, whereas the X447 allele is less frequent, and 2) the LPL N9 allele is associated with the LDL subclass response to gemfibrozil.

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.

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.

Optimal therapy of low levels of high density lipoprotein-cholesterol.

Plasma levels of high-density lipoprotein-cholesterol (HDL-C) are a powerful independent cardiovascular risk factor, bearing an inverse relationship with atherosclerotic cardiovascular disease (with risk rising sharply when levels are <1.04 mmol/L). Apart from its protective role in atherosclerosis, HDL-C increases fibrinolysis, is an antioxidant to low density lipoprotein-cholesterol (LDL-C), and decreases platelet aggregability. Up to a third of patients with atherosclerotic cardiovascular disease have 'desirable' plasma levels of total cholesterol but low HDL-C levels. Benefits of treating low plasma HDL-C levels were clearly demonstrated in the Veterans Affairs HDL Intervention Trial (VA-HIT) where gemfibrozil reduced nonfatal infarcts and coronary deaths by 22%. This was achieved by a 6% increase in plasma HDL-C levels, and a 24.5% decrease in plasma levels of triglycerides, without any significant decrease in LDL-C levels. Multivariate analyses revealed the rise in plasma HDL-C levels after treatment, but not decreases in plasma levels of triglycerides or LDL-C, predicted coronary artery disease events. The typical patient under consideration in this article is one with plasma levels of HDL-C <1 mmol/L, LDL-C <3.37 mmol/L [either receiving therapeutic lifestyle changes or or LDL-C-lowering therapy comprising a hydroxymethylglutaryl coenzyme-A (HMG-CoA) reductase inhibitor or bile acid sequestrant] and fasting triglycerides <2.26 mmol/L. We propose this dyslipidemia be classified as Type VI phenotype following the Frederickson and Lees classification. High-risk patients (with >/=2 risk factors for atherosclerotic cardiovascular disease, or 10-year cardiovascular risk >20%), patients with established atherosclerotic cardiovascular disease, or type 2 diabetes mellitus, or metabolic syndrome should receive pharmacotherapy. Plasma HDL-C levels >1.16 mmol/L may be considered optimal and between 1 and 1.16 mmol/L as desirable. Fibric acid derivatives, nicotinic acid, HMG-CoA reductase inhibitors, estrogens, and ethanol (not recommended as therapy) increase plasma HDL-C levels. Nicotinic acid is the most potent agent and recent reports indicate that, in contrast to gemfibrozil, it selectively increases antiatherogenic HDL subfraction, lipoprotein (Lp) AI (without apolipoprotein AII), in patients with low plasma HDL-C levels. An extended-release formulation, administered once daily, has improved the tolerability of nicotinic acid. Recent evidence also indicates that nicotinic acid may effectively correct dyslipidemia in patients with diabetes mellitus without significantly compromising glycemic control. Fibric acid derivatives and estrogen raise plasma HDL-C levels by different mechanisms of action, and these agents may be used with nicotinic acid. Combination therapy (especially HMG-CoA reductase inhibitor and nicotinic acid) should be considered in patients with atherosclerotic cardiovascular disease and low plasma HDL-C levels.