The effect of concentrated n-3 fatty acids versus gemfibrozil on plasma lipoproteins, low density lipoprotein heterogeneity and oxidizability in patients with hypertrygliceridemia

Abstract

We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs +26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P>0.05). Cu²⁺-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.

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.