The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertrygliceridemia
Introduction
Subjects with moderate hypertriglyceridemia are considered to be at increased risk for coronary heart disease (CHD), especially men over age 50 with low high density lipoprotein (HDL) cholesterol levels [1]. Several potential mechanisms have been suggested to contribute to this phenomenon, including an enhanced atherogenic potential of low density lipoprotein (LDL) in the hypertriglyceridemic subjects [2], [3], [4]. LDL isolated from hypertriglyceridemic subjects is polydisperse defined by the presence of multiple LDL subfractions over a broad density range, with the mean LDL subfractions being abnormally small and dense [4], [5]. This dense LDL subfraction profile has been associated with an increased risk of CHD [6], [7], [8]. In addition, LDL isolated from hypertriglyceridemic subjects is more prone to in vitro oxidative modification than LDL from normotriglyceridemic subjects [4]. The oxidative modification of LDL has been implicated in the initiation and progression of atherosclerosis [9]. So, LDL in hypertriglyceridemic subjects is characterized by a dense LDL subfraction profile and an enhanced susceptibility to oxidation, both contributing to an enhanced atherogenic potential of LDL and thus increased risk of atherosclerosis.
Because of the reported increased risk for premature atherosclerosis, treatment with lipid-lowering drugs is frequently indicated. Both marine n-3 fatty acids (FA) and fibrates are very potent hypotriglyceridemic agents; however, both can also raise LDL cholesterol concentrations, especially in hypertriglyceridemic subjects [10], [11], [12], [13]. Only a few studies are available that address the effect of n-3 FA [14], [15], [16] and fibrates [4], [17] on LDL heterogeneity. Furthermore, dietary n-3 FA are incorporated into lipoproteins, thereby potentially affecting the susceptibility of LDL to oxidative modification. There are conflicting results, however, between studies on the effects of n-3 fatty acid supplementation on LDL oxidizability [16], [18], [19], [20], [21], [22], [23], whereas only few studies report the effect of fibrates on this parameter [4], [17], [24].
The present study was undertaken to compare directly the effects of concentrated n-3 FA (Omacor®) vs gemfibrozil on LDL heterogeneity and LDL oxidizability in hypertriglyceridemic patients.
Section snippets
Patients
A total of 30 patients with primary hypertriglyceridemia (triglyceride (TG) levels between 4.0 and 28.0 mmol/l), confirmed by repeated measurements, were recruited from the outpatient lipid clinic of Nijmegen University Hospital (18 patients) and Amsterdam Academic Medical Centre (12 patients). Exclusion criteria were secondary causes for dyslipidemia, including a history of diabetes mellitus, or apolipoprotein phenotype E2/E2. The participants continued their standard lipid-lowering diet
Patients
Analysis was based on intention-to-treat, but two subjects were not included in the final analysis. One subject (Omacor group) developed excessive hypertriglyceridemia (TG=56.5 mmol/l) after he stopped his regular medication. One subject (gemfibrozil group) was not willing to continue the trial after randomization.
At baseline, the gemfibrozil group (n=13) and the Omacor group (n=15) were similar in mean age and body mass index (BMI) (mean age 52.7±6.9 vs 48.3±8.3 years, respectively; BMI
Discussion
The underlying cause of the increased tendency toward cardiovascular diseases in patients with hypertriglyceridemia is probably related to the enhanced atherogenic potential of their lipoproteins. Possible mechanisms contributing to this increased atherogenicity include the presence of small, dense LDL and the enhanced susceptibility to oxidative modification. In this report we described the baseline lipoprotein concentrations, the LDL subfraction profile and LDL oxidizability of patients with
Conclusion
Gemfibrozil and Omacor have anti-atherogenic properties, as both therapies reduce the atherogenic potential of the lipoproteins by decreasing the concentration of cholesterol-enriched VLDL and increasing HDL concentration. Although total plasma LDL cholesterol concentration increases, the atherogenic potential of LDL seems to be less, as judged by the presence of a more buoyant LDL subfraction profile. In contrast to gemfibrozil, Omacor increased the susceptibility of LDL to oxidation in vitro.
Acknowledgements
This work was supported by a grant from Pronova Biocare AS, Oslo, Norway. The authors acknowledge Dr K. Osmundsen (Pronova Biocare) for providing the Omacor and corn oil capsules. The authors also wish to thank Janine M. Vogelaar and Magda Hectors of the Lipid Research Laboratory, University Hospital Nijmegen, for expert technical assistance.
References (53)
The triglyceride issue: A view from Framingham
Am. Heart J.
(1986)- et al.
Fibric acids: effects on lipids and lipoprotein metabolism
Am. J. Med.
(1987) - et al.
Effects of fish oil fatty acids on low density lipoprotein size, oxidizability and uptake by macrophages
J. Lipid Res.
(1995) - et al.
Comparison of gemfibrozil versus simvastatin in familial combined hyperlipidemia and effects on apolipoprotein-B-containing lipoproteins, low-density lipoprotein subfraction profile and low density lipoprotein oxidizability
Am. J. Cardiol.
(1995) - et al.
Fish oil ingestion in smokers and non-smokers enhances peroxidation of plasma lipoproteins
Atherosclerosis
(1991) - et al.
Hypolipidemic drugs reduce lipoprotein susceptibility to undergo lipid peroxidation: in vitro and ex vivo studies
Atherosclerosis
(1992) - et al.
Single spin density gradient ultracentrifugation method for the detection and isolation of light and heavy low density lipoprotein subfractions
J. Lipid Res.
(1987) - et al.
Protein measurement with the Folin phenol reagent
J. Biol. Chem.
(1951) - et al.
Role of the peroxisome proliferator activated receptor (PPAR) in mediating effect of fibrates and fatty acids on gene expression
J. Lipid Res.
(1996) - et al.
Atorvastatin and gemfibrozil metabolites, but not the parent drugs, are potent antioxidants against lipoprotein oxidation
Atherosclerosis
(1998)
Defective metabolism of hypertriglyceridemic low density lipoprotein in cultured human skin fibroblasts
J. Clin. Invest.
Abnormal regulation of LDL receptor activity and abnormal cellular metabolism of hypertriglyceridaemic low density lipoprotein: normalization with bezafibrate
Eur. J. Clin. Invest.
Identification of multiple dense LDL subfractions with enhanced susceptibility to in vitro oxidation among hypertriglyceridemic subjects. Normalization after clofibrate treatment
Arterioscler. Thromb.
Abnormalities in very low, low and high density lipoproteins in hypertriglyceridemia. Reversal toward normal with bezafibrate treatment
J. Clin. Invest.
Low density lipoprotein subfractions and relationship to other risk factors for coronary artery disease in healthy individuals
Arteriosclerosis
Low density lipoprotein subclass patterns and risk of myocardial infarction
J. Am. Med. Assoc.
Low density lipoprotein particle size and coronary heart disease
Arterioscler. Thromb.
Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity
New Engl. J. Med.
N-3 fatty acids and serum lipoproteins: human studies
Am. J. Clin. Nutr.
Dietary fish oil and blood lipids
Curr. Opin. Lipidol.
Mechanism of action of fibrates
Postgrad. Med. J.
Effect of pravastatin and w-3 fatty acids on plasma lipids and lipoproteins in patients with combined hyperlipidemia
Arterioscler. Thromb.
Effect of dietary supplementation with n-3 polyunsaturated fatty acids on physical properties and metabolism of low density lipoprotein in humans
Arterioscler. Thromb.
Effects of fish oil on oxidation resistance of VLDL in hypertriglyceridemic patients
Arterioscler. Thromb. Vasc. Biol.
Influence of probucol on enhanced LDL oxidation after fish oil treatment of hypertriglyceridemic patients
Arterioscler. Thromb.
Peroxidation of LDL from combined-hyperlipidemic male smokers supplied with omega-3 fatty acids and antioxidants
Arterioscler. Thromb. Vasc. Biol.
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