Fenofibrate reduces lipoprotein associated phospholipase A₂ mass and oxidative lipids in hypertriglyceridemic subjects with the metabolic syndrome

Background: Lipoprotein-associated phospholipase A₂ (Lp-PLA₂) is a macrophage-synthesized lipase that is primarily bound to small electronegative low-density lipoproteins (LDLs). Lipoprotein-associated phospholipase A₂ oxidatively modifies LDL and generates the proinflammatory byproducts oxidized fatty acids (ox-FAs) and lysophosphatidylcholine. Fenofibrate reduces Lp-PLA₂ mass; however, it remains unknown whether the anti-inflammatory effects of fenofibrate are related to changes in LDL subclasses. Methods: This was a randomized, double-blind, controlled clinical trial designed to investigate the effects of 3-month treatment with fenofibrate (160 mg/d) on Lp-PLA₂ mass, LDL subclasses, and ox-FAs among 55 hypertriglyceridemic (≥1.7 and <6.78 mmol/L) subjects with the metabolic syndrome. Results: Fenofibrate treatment lowered fasting Lp-PLA₂ mass by 13.2% (-19.0 to -7.7) versus placebo (2.3% [-5.0 to 4.1], P = .0002) and total ox-FA by 15.5% (-34.2 to +1.4) versus an 11.5% increase with placebo (P = .0013). In age-, sex-, and treatment-adjusted models, changes in Lp-PLA₂ mass were associated with reductions in chemical LDL cholesterol (r = 0.59, P < .01) and measured total LDL particles (LDL-Ps) (r = 0.64, P < .01) and small LDL-Ps (r = 0.57, P < .01). In models that included small LDL, effects of fenofibrate on Lp-PLA₂ mass were attenuated (P = .125), but not in models that included LDL cholesterol (P < .0001) and LDL-Ps (P = .005). Changes in Lp-PLA₂ mass were not significantly associated with changes in ox-FA or inflammatory markers. Conclusions: Among hypertriglyceridemic subjects with the metabolic syndrome, fenofibrate therapy reduced Lp-PLA₂ mass, and these changes were associated with fewer small LDL-Ps.