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

Otvos, James D.; Collins, Dorothea; Freedman, David S.; Shalaurova, Irina; Schaefer, Ernst J.; McNamara, Judith; Bloomfield, Hanna E.; Robins, Sander J.

doi:10.1161/circulationaha.105.565135

Cited by 518 publications

(386 citation statements)

References 29 publications

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“…The average cholesterol content of the LDL particles increased in the fenofibratetreated subjects, which explains the nonsignificant reduction in LDL cholesterol. Similar observations were reported in the Veterans Administration HDL Intervention Trial (VA-HIT) with gemfibrozil therapy (16).…”

Section: Safety Studiessupporting

confidence: 81%

“…The effect of gemfibrozil therapy on lipoprotein subclasses and cardiovascular events was reported in the VA-HIT trial (16). Gemfibrozil therapy lowered LDL particles by 5% (mean Ϯ SD 1,352 Ϯ 316 to 1,290 Ϯ 331 nmol/l; P Ͻ 0.0001) due to a 20% reduction in small LDL particles that was offset by a 36% increase in large LDL particles.…”

Section: Safety Studiesmentioning

confidence: 91%

“…Gemfibrozil therapy lowered LDL particles by 5% (mean Ϯ SD 1,352 Ϯ 316 to 1,290 Ϯ 331 nmol/l; P Ͻ 0.0001) due to a 20% reduction in small LDL particles that was offset by a 36% increase in large LDL particles. A 1 SD increase of LDL particles (350 nmol/l) during the trial was associated with a multivariable adjusted risk for CHD events of 1.28 (95% CI 1.12-1.47, P ϭ 0.0003), and small LDL particles were accompanied by a CHD event risk of 1.41 (1.14 -1.73, P ϭ 0.001) (16).…”

Section: Safety Studiesmentioning

confidence: 95%

“…In the VA-HIT study, high levels of LDL particles and low levels of HDL particles were independent predictors of new coronary heart disease (CHD) events (16). Every 1 SD increment in total LDL particles was associated with a 1.19 incremental risk for CHD events in adjusted models (95% CI 1.08 -1.32, P ϭ 0.007).…”

Section: Safety Studiesmentioning

confidence: 99%

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Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

et al. 2007

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OBJECTIVE -The aim of this study was to determine the effects of fenofibrate (160 mg/day) on fasting and postprandial lipoproteins, oxidized fatty acids, and inflammatory mediators in subjects with hypertriglyceridemia and the metabolic syndrome.RESEARCH DESIGN AND METHODS -Fifty-nine subjects with fasting hypertriglyceridemia (Ն1.7 and Ͻ6.9 mmol/l) and two or more of the Adult Treatment Panel III criteria for the metabolic syndrome were randomly assigned to fenofibrate (160 mg/day) or placebo in a double-blind, controlled clinical trial.RESULTS -Fenofibrate treatment lowered fasting triglycerides (Ϫ46.1%, P Ͻ 0.0001) and postprandial (area under the curve) triglycerides (Ϫ45.4%, P Ͻ 0.0001) due to significant reductions in postprandial levels of large (Ϫ40.8%, P Ͻ 0.0001) and medium (Ϫ49.5%, P Ͻ 0.0001) VLDL particles. The number of fasting total LDL particles was reduced in fenofibratetreated subjects (Ϫ19.0%, P ϭ 0.0033) primarily due to reductions in small LDL particles (Ϫ40.3%, P Ͻ 0.0001); these treatment differences persisted postprandially. Fasting and postprandial oxidized fatty acids were reduced in fenofibrate-treated subjects compared with placebo-administered subjects (Ϫ15.3%, P ϭ 0.0013, and 31.0%, P Ͻ 0.0001, respectively), and fenofibrate therapy lowered fasting and postprandial soluble vascular cell adhesion molecule-1 (VCAM-1) (Ϫ10.9%, P ϭ 0.0005, and Ϫ12.0%, P ϭ 0.0001, respectively) as well as fasting and postprandial soluble intercellular adhesion molecule-1 (ICAM-1) (Ϫ14.8%, P Ͻ 0.0001, and Ϫ15.3%, P Ͻ 0.0001, respectively). Reductions in VCAM-1 and ICAM-1 were correlated with reductions in fasting and postprandial large VLDL particles (P Ͻ 0.0001) as well as postprandial oxidized fatty acids (P Ͻ 0.0005).CONCLUSIONS -Triglyceride-lowering therapy with fenofibrate reduced fasting and postprandial free fatty acid oxidation and inflammatory responses, and these antiatherosclerotic effects were most highly correlated with reductions in large VLDL particles. Diabetes Care 30:1945-1951, 2007T he metabolic syndrome represents an agglomeration of interrelated risk factors that include abnormally high fasting triglyceride levels (1,2). In a recent analysis, hypertriglyceridemia (Ն1.7 mmol/l) represented the component of the metabolic syndrome most strongly associated with a history of myocardial infarction and stroke (3). Furthermore, elevated fasting triglyceride levels (Ն1.4 mmol/l) and an enlarged waist circumference (Ͼ89 cm) were the two characteristics of the metabolic syndrome that were associated with the greatest increased risk for all-cause mortality and cardiovascular deaths among postmenopausal women (4).Hypertriglyceridemia signifies the presence of increased plasma triglycerideremnant lipoproteins, and the concentrations of remnant-like lipoproteins are further enhanced postprandially among hypertriglyceridemic subjects (5). Remnant-like proteins have been shown to increase intracellular oxidant concentrations and lipid peroxide levels in culture media and to activate nuclear factor-B ...

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Section: Safety Studiessupporting

confidence: 81%

Section: Safety Studiesmentioning

confidence: 91%

Section: Safety Studiesmentioning

confidence: 95%

Section: Safety Studiesmentioning

confidence: 99%

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Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

et al. 2007

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“…The difference between PIO and ROSI on lipids and lipoproteins may be one of these. Whether these differences are clinically relevant is not known, since evidence for cardiovascular benefit exists for interventions that may increase larger HDL 2 particles with nicotinic acid (39) as well as those that appear to increase small HDL particles with fibrates (40).…”

Section: Serum Aposmentioning

confidence: 99%

Pioglitazone and Rosiglitazone Have Different Effects on Serum Lipoprotein Particle Concentrations and Sizes in Patients With Type 2 Diabetes and Dyslipidemia

et al. 2007

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OBJECTIVE -Associated with insulin resistance in type 2 diabetes are increased serum triglycerides, decreased HDL cholesterol, and a predominance of large VLDL, small LDL, and small HDL particles. The comparative effects of thiazolidinedione insulin sensitizers on serum lipoprotein particle concentrations and sizes in type 2 diabetes are not known. We studied the effects of pioglitazone (PIO) and rosiglitazone (ROSI) treatments on serum lipoprotein particle concentrations and sizes in type 2 diabetic patients with dyslipidemia. RESEARCH DESIGN AND METHODS-This is a prospective, randomized, doubleblind, multicenter, parallel-group study. After a 4-week placebo washout period, patients randomized to PIO (n ϭ 369) were treated with 30 mg q.d. for 12 weeks followed by 45 mg q.d. for another 12 weeks, while patients randomized to ROSI (n ϭ 366) were treated with 4 mg q.d. followed by 4 mg b.i.d. for the same intervals. Lipoprotein subclass particle concentrations and sizes were determined by proton nuclear magnetic resonance spectroscopy at baseline and end point (PIO [n ϭ 333] and ROSI [n ϭ 325] patients).RESULTS -PIO treatment increased total VLDL particle concentration less than ROSI treatment and decreased VLDL particle size more than ROSI. PIO treatment reduced total LDL particle concentration, whereas ROSI treatment increased it. Both treatments increased LDL particle size, with PIO treatment having a greater effect. Whereas PIO treatment increased total HDL particle concentration and size, ROSI treatment decreased them; both increased HDL cholesterol levels.CONCLUSIONS -PIO and ROSI treatments have different effects on serum lipoprotein subclass particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia.

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Hypertriglyceridemia and Its Pharmacologic Treatment Among US Adults—Invited Commentary

Thompson¹,

Gau²

2009

Arch Intern Med

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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

Abstract: 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.

Cited by 518 publications

References 29 publications

Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

Fenofibrate Therapy Ameliorates Fasting and Postprandial Lipoproteinemia, Oxidative Stress, and the Inflammatory Response in Subjects With Hypertriglyceridemia and the Metabolic Syndrome

Pioglitazone and Rosiglitazone Have Different Effects on Serum Lipoprotein Particle Concentrations and Sizes in Patients With Type 2 Diabetes and Dyslipidemia

Hypertriglyceridemia and Its Pharmacologic Treatment Among US Adults—Invited Commentary

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