Fenofibrate raises plasma homocysteine levels in the fasted and fed states

Abstract

The effect of fenofibrate (FEN), compared with placebo (PL), on total plasma homocysteine (tHcy) levels in the fasted and fed states has been examined. Twenty men with established coronary artery disease (CAD) or with at least two cardiovascular risk factors, who had elevated plasma triglyceride levels (>2.3 mmol/l) and reduced HDL-C levels (<0.91 mmol/l), and in whom a fibric acid derivative was clinically indicated were studied. The study was a randomized, PL controlled, double-blind study designed to test the effect of micronized FEN on postprandial lipemia. Plasma tHcy levels were investigated as a post-hoc analysis. After a 4-week dietary stabilization period, patients were randomized to PL or FEN (200 mg/day) for 8 weeks, followed by an 8-h postprandial study, consisting of 1 g fat/kg body weight (35% cream). The methionine content of cream was approximately 0.53 mg/ml. A 5-week washout period was then followed by a second 8-week treatment period (FEN or PL), at the end of which a second postprandial study was undertaken. Blood was sampled in the fasted state (0 h) and postprandially at 2, 4, 6 and 8 h. Plasma was stored at −80°C for homocysteine, vitamins B 6, B 12 and folate measurements. FEN caused a marked decrease in all triglyceride-rich lipoprotein parameters, no change in LDL-C, and an increase in HDL-C levels. Fen treatment was associated with an increase in fasting tHcy (PL: 10.3±3.3 μmol/l to FEN: 14.1±3.8 μmol/l, 40.4±20.5%, P<0.001) and fed tHcy levels 6 h post-fat load (PL: 11.6±3.3 μmol/l vs. FEN: 17.1±5.4 μmol/l, P<0.001). Homocysteine levels were increased by the fat load; PL: 14% ( P<0.001) and FEN: 21%, P<0.001 at the 2, 4, 6 and 8 h time points. Change in tHcy level on FEN was not associated with changes in plasma levels of folate, vitamins B 6 or B 12 or creatinine. Amino acid analysis revealed that methionine and cysteine were significantly increased on FEN ( P<0.005). The incidence of hyperhomocysteinemia (defined as tHcy level>14 μmol/l) was PL: 2/20 (10%) and FEN: 9/20 (45%) ( χ 2=4.51, P=0.034). There was no correlation between changes in plasma triglyceride levels and tHcy levels. Since tHcy is considered an emerging cardiovascular risk factor, the ability of FEN to increase plasma tHcy levels could potentially mitigate the potential of this drug to protect against cardiovascular disease.