Atherosclerosis 154 (2001) 421 – 427 Homocysteine and lipid lowering agents. A comparison between atorvastatin and fenofibrate in patients with mixed hyperlipidemia Philippe Giral a, *, Eric Bruckert a , Nelly Jacob b , M. John Chapman c , Marie-Jose ´ Foglietti b , Ge ´rard Turpin a a Serice d’Endocrinologie -Me ´tabolisme, Centre de De ´tection et de Pre ´ ention de l’Athe ´roscle ´rose, Groupe Hospitalier Pitie ´ , Salpe ˆtrie `re, 47 -83 Bouleard de l’ho ˆpital, 75651 Paris Cedex 13, France b Laboratoire de Biochimie C, Paris, France c INSERM U 321. Lipoprote ´ines et Athe ´roge ´ne `se, Institut Fe ´de ´ratif de Recherche Cœur Muscle Vaisseaux, Groupe Hospitalier Pitie ´ , Salpe ´trie `re, Uniersite ´ Pierre et Marie Curie, Paris, France Received 5 October 1999; received in revised form 3 March 2000; accepted 10 March 2000 Abstract Background : Hyperhomocysteinemia is a risk factor for cardiovascular disease. Elevation in homocysteine levels has recently been demonstrated during lipid lowering treatment with fibrates. We compared the effect of a statin and a fibrate (atorvastatin and fenofibrate) on plasma levels of homocysteine and other thiol compounds in hyperlipidemic patients. Method and results : The study was of open randomized, parallel design with a preliminary screening phase, and a 6 week placebo period. After the placebo period, patients were allocated randomly to atorvastatin or fenofibrate for a 6 month period. Plasma thiols were assayed by high pressure liquid chromatography with fluorescence detection. There were 29 patients in the fenofibrate group and 24 in the atorvastatin group. Fenofibrate induced a significant increase in both homocysteine and cysteine plasma levels ( +35.8 and +18%, respectively, P 0.0001); by contrast, cysteinylglycine remained stable. There were no significant changes in any thiol compounds in the atorvastatin group. Both treatments induced a significant decrease in uric acid, although fenofibrate was noticeably more effective than atorvastatin ( -22.8 and -6.4%, respectively). Fenofibrate induced a non-significant increase in creatinine (12%) while atorvastatin reduced it (4.7%, NS). Conclusion : Our study confirms that the induction of elevations in plasma homocysteine and cysteine levels are a distinct feature of the pleiotropic effects of fibrates. Further studies are needed not only to investigate the potential deleterious effects of this modification, but also to define the specific mechanism which underlies such fibrate-mediated action. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Statin; Fibrate; Thiol compounds; Creatinine www.elsevier.com/locate/atherosclerosis 1. Introduction Prospective and retrospective studies have shown that elevated plasma levels of homocysteine levels are associated with a higher prevalence of occlusive arterial disease independently of conventional risk factors [1 – 3]. B-group vitamins decrease plasma homocysteine levels [4,5]. Pharmacological agents are also known to modify the concentration of plasma homocysteine. Among them, several different classes of lipid lowering drugs (i.e. bile acid resins, niacin and fish oils) have been shown to modify homocysteine levels [6,7]. In contrast, there is no evidence that dyslipidemic patients receiving lipid lowering therapy with HMG-CoA reduc- tase inhibitors (statins) display modification of homo- cysteine levels [8]. Fibrates are widely used as hypolipidemic agents and it is relevant that an increase of levels of sulfur amino acids has recently been demon- strated during treatment with fenofibrate [8 – 10]. Com- plementary data is however required in order to confirm and extend knowledge of the effects of fibrates and statins on plasma thiol compounds. The aim of our study was therefore to compare the effects of atorvas- tatin and fenofibrate on plasma concentrations of thiol compounds (homocysteine, cysteine, cysteinylglycine) in patients with hyperlipidemia. * Corresponding author. Tel.: +33-1-4217-7868; fax: +33-1-4217- 7865. E-mail address: philippe.giral@psl.ap-hop-paris.fr (P. Giral). 0021-9150/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S0021-9150(00)00474-3