Fenofibrate in the Management of Abdominal Aortic Aneurysms

In a pre-clinical study we examined the effect of oral fenofibrate added to drinking water (approximate dose based on average drinking rates 100mg/kg/d) over a 4 week period on aortic dilatation induced by angiotensin II infusion in apolipoprotein e deficient mice [1]. This model is currently the most commonly used animal model of AAA and has a number of pathological similarities to the human condition but like all animal models of complex diseases cannot be considered to be completely comparable [2]. These studies demonstrated that: a) Fenofibrate inhibited aortic dilatation: mean suprarenal aortic diameters were 1.51+/-0.13 and 2.10+/-0.14mm in fenofibrate treated and control mice, respectively, n=27, P=0.001; b) Fenofibrate reduced aortic concentration of osteopontin (OPN): median suprarenal aortic OPN concentrations were 126 and 3198 pg/mg protein in fenofibrate treated and control mice, respectively, n=15, P=0.006; c) Fenofibrate reduced aortic infiltration by macrophages: median suprarenal aortic CD68 staining areas were 4% (interquartile range 2.5-3.9) and 13% (interquartile range 8.4-20.0) in fenofibrate treated and control mice, respectively, n=10, P<0.01. We have previously shown that OPN is upregulated in human AAA [3] and marked macrophage infiltration is a consistent feature of human AAA [4]. OPN is a known macrophage chemokine and thus aortic OPN would be expected to promote macrophage influx to the aorta. The ability of fenofibrate to downregulate OPN may be critical in reducing macrophage infiltration (and associated release of proteolytic enzymes) and limiting AAA expansion. Within the mice model the downregulation of OPN and inflammation appeared to occur rapidly. Fenofibrate also raises HDL in some human subjects and high HDL has been associated with protection from AAA [5]. The effect of fenofibrate in the mouse model cannot be explained by HDL mechanisms however since this medication does not increase HDL in apolipoprotein e deficient mice [6]. In humans therefore it is postulated that a short cause of fenofibrate will inhibit AAA OPN expression, associated macrophage based inflammation and possibly also induce other beneficial effects by raising HDL. FAME is a multi-centre, randomised, double-blind, placebo-controlled clinical trial. Participants will be randomised to receive fenofibrate (145mg once a day for 4+/-2 weeks) or placebo (once a day for 4+/-2 weeks), in a parallel group, double blind design. Randomisation lists will be generated by a statistician and provided to the study centres ensuring both Investigators and participants are blinded to drug assignment. REFERENCES 1.Moran CS, McCann M, Karan M, Norman P, Ketheesan N, Golledge J. Association of osteoprotegerin with human abdominal aortic aneurysm progression.Circulation. 2005;111:3119-25. 2. Golledge J, Clancy P, Jamrozik K, Norman PE. Obesity, adipokines, and abdominal aortic aneurysm: Health in Men study. Circulation. 2007;116:2275-9. 3. Golledge J, Muller R, Clancy P, McCann M, Norman PE. Evaluation of the diagnostic and prognostic value of plasma D-dimer for abdominal aortic aneurysm. Eur Heart J. 2010 Jun 8. 4. Golledge J, van Bockxmeer F, Jamrozik K, McCann M, Norman PE. Association between serum lipoproteins and abdominal aortic aneurysm. Am J Cardiol. 2010;105:1480-4. 5. Golledge J, Muller J, Daugherty A, Norman P. Abdominal aortic aneurysm: pathogenesis and implications for management. Arterioscler Thromb Vasc Biol. 2006;26:2605-13. 6. Golledge J, Cullen B, Rush C, Moran CS, Secomb E, Wood F, Daugherty A, Campbell JH, Norman PE. Peroxisome proliferator-activated receptor ligands reduce aortic dilatation in a mouse model of aortic aneurysm. Atherosclerosis. 2010;210:51-6.