Atherosclerosis 155 (2001) 455 – 462 Fenofibrate raises plasma homocysteine levels in the fasted and fed states Rachel Bissonnette a , Eileen Treacy b , Rima Rozen b , Betsie Boucher a , Jeffrey S. Cohn c , Jacques Genest, Jr a, * a Diision of Cardiology, McGill Uniersity Health Center /Royal Victoria Hospital, 687 Pine aenue West, Montreal, Que ´bec, Canada H3A 1A1 b Diision of Medical Genetics, Montreal Children Hospital, McGill Uniersity, Montreal, Que ´bec, Canada c Clinical Research Institute of Montreal, Montreal, Que ´bec, Canada Received 10 February 2000; received in revised form 5 May 2000; accepted 17 June 2000 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 mol/l to FEN: 14.1 3.8 mol/l, 40.4 20.5%, P 0.001) and fed tHcy levels 6 h post-fat load (PL: 11.6 3.3 mol/l vs. FEN: 17.1 5.4 mol/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 mol/l) was PL: 2/20 (10%) and FEN: 9/20 (45%) ( 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. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Fenofibrate; Plasma homocysteine; Coronary artery disease www.elsevier.com/locate/atherosclerosis 1. Introduction Patients with established coronary artery disease (CAD) or with multiple risk factors for the develop- ment of CAD often benefit from risk factor modifica- tion, in order to decrease risk of future cardiovascular events [1]. The benefits of lowering total and LDL-C have been well established in large scale clinical trials both in the secondary [2–4] as well as the primary prevention settings [5,6]. Treatment of patients with elevated plasma triglyceride levels, especially in the presence of reduced levels of HDL-C, has however been a subject of controversy [1,7]. The fibric acid derivatives have been shown to reduce plasma triglyceride levels and increase HDL-C levels significantly and to markedly reduce postprandial triglyceride-rich lipo- proteins [8]. Older trials of prevention of cardiovascular disease have shown a modest effect of fibrates on * Corresponding author. Tel.: +1-514-8421231, ext. 4642; fax: +1-514-9820686. E-mail address: jacques.genest@muhc.mcgill.ca (J. Genest, Jr). 0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII:S0021-9150(00)00584-0