Oxidized LDL Linked to Metabolic Syndrome

By Todd Neale
LEUVEN, Belgium, 21 may 2008-- Higher levels of oxidized low-density lipoprotein are associated with an increased risk of metabolic syndrome, a longitudinal study showed.
Participants in the highest quintile of oxidized LDL level were 3.5 times more likely to develop metabolic syndrome than those in the lowest quintile (OR 3.5, 95% CI 1.9 to 6.6), Paul Holvoet, Ph.D., of Catholic University of Leuven, and colleagues reported in the May 21 issue of the Journal of the American Medical Association.
Those with the highest levels of oxidized LDL were also at increased risk for three components of metabolic syndrome -- abdominal obesity, high fasting glucose, and high triglycerides.
"As yet, it is not possible to conclude whether oxidized LDL is a marker related to mechanistic underlying factors on the pathway to the development of metabolic syndrome," the researchers said, "or whether it is by itself a functional intermediary in this pathway."
They said, however, that the strength of the association was consistent with a causal role.
David Jacobs Jr., Ph.D., of the University of Minnesota School of Public Health, a co-author of the study, said that more research is needed to determine whether testing for oxidized LDL is clinically useful.
The proportion of LDL that is oxidized ranges from 0.001% in healthy controls to 5% in patients with acute coronary syndrome, the researchers said.
There is evidence from cellular and animal studies that oxidized LDL might be associated with metabolic syndrome, they said, but this theory has not been studied in humans.
So the researchers turned to the Cardiovascular Risk Development in Young Adults (CARDIA) study, conducting the ancillary Young Adult Longitudinal Trends in Antioxidants (YALTA) study.
At the 15-year follow-up of the CARDIA study, they measured oxidized LDL levels in 1,889 participants (ages 33 to 45; 41% black; 56% female) who did not have metabolic syndrome.
Five years later, 12.9% of the participants were diagnosed with metabolic syndrome.
The researchers found that the risk of metabolic syndrome increased significantly as the levels of oxidized LDL increased (P<0.001 for trend) after adjusting for age, sex, race, study center, smoking, body mass index, physical activity, and LDL cholesterol levels.
Compared with the lowest levels of oxidized LDL, the highest levels were also associated with increased risk for the following three components of metabolic syndrome:
Abdominal obesity, with waist circumference of at least 102 cm in men and 88 cm in women, OR 2.1 (95% CI 1.2 to 3.6)
Fasting glucose of 100 mg/dL or higher or taking diabetes medication, OR 2.4 (95% CI 1.5 to 3.8)
Fasting triglycerides of 150 mg/dL or higher, OR 2.1 (95% CI 1.1 to 4.0)
The other elements of metabolic syndrome -- low HDL cholesterol and high blood pressure -- were not significantly associated with oxidized LDL.
LDL cholesterol was not associated with metabolic syndrome or any of its components.
A possible explanation for the association of oxidized LDL with abdominal obesity, the researchers said, is that adipose tissue may increase or decrease enzymes that play a role in modifying oxidation through biochemical reactions.
The link with high fasting glucose levels "could be due to reducing insulin-signaling and reducing glucose uptake," they said.
Also, oxidized LDL might contribute to dyslipidemia by impairing triglyceride storage and secretion, they said.
The study was limited, the authors said, in that it could not prove causality and excluded some participants because of pregnancy or missing samples of data.
The study was supported in part by contracts from the National Heart, Lung, and Blood Institute, with additional funding from the University of Minnesota School of Public Health fund supporting Dr. Jacobs' Mayo professorship, the Interunversitaire Attractiepolen Programma of the Belgian Federal Government, and the Fonds voor Wetenschappelijk Onderzoek-Vlaanderen.
Dr. Holvoet reported being the inventor of the assay for oxidized LDL for which patents have been granted in Europe and the United States.
Primary source: Journal of the American Medical AssociationSource reference:Holvoet P, et al "Association between circulating oxidized low-density lipoprotein and incidence of the metabolic syndrome" JAMA 2008; 299: 2287-2293.