Expert Commentary: The Safety of Fibrates in Lipid-Lowering Therapy

Published:November 30, 2006DOI:
      The use of fibrates in the management of lipoprotein disorders has a history dating back to the mid-1960s. This group of drugs has now been tested in several large long-term trials with cardiovascular end points. Overall, there is good evidence for the reduction of cardiovascular disease in primary prevention studies and in those of subjects with manifest disease. More recent trials have suffered from high interference due to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) introduction, particularly in their placebo control groups. However, there is very good evidence for overall safety from a combined study of >20,000 patients in these controlled clinical trials lasting approximately 5 years. Abdominal pain has been observed more frequently in the statin vs placebo group. Myopathy, liver enzyme elevations, and cholecystitis have been potential adverse reactions of interest. However, these have occurred at a very low rate and are rarely found to be statistically more frequent in the active-treatment group compared with the subjects taking placebo. The recent Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study found a slightly higher incidence of pancreatitis, deep venous thrombosis, and pulmonary embolism. Small creatinine and homocysteine elevations are observed in many patients taking fibrates, and the effect of this on long-term outcomes is under study. The FIELD study also described a significant reduction in the rates of progression of proteinuria and vascular retinopathy with fibrate therapy. To date, there has been no study exclusive to patients with elevated triglycerides, raising the question of the potential benefit of these drugs in patients with the lipid abnormalities most effectively treated with fibrates.
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        • Krey G.
        • Braissant O.
        • L’Horset F.
        • Kalkhoven E.
        • Perroud M.
        • Parker M.G.
        • Wahli W.
        Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay.
        Mol Endocrinol. 1997; 11: 779-791
        • Li A.C.
        • Glass C.K.
        PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis.
        J Lipid Res. 2004; 45: 2161-2173
        • de Gennes J.L.
        • Maunand B.
        • Salmon D.
        • Laudat P.
        • Truffert J.
        Results of atromid or CPIB treatment with and without androsterone in hyperlipemia (110 therapeutic trials in 2 years).
        Bull Mem Soc Med Hop Paris. 1965; 116: 759-784
        • Brown W.V.
        Treatment of hypercholesterolemia with fenofibrate: a review.
        Curr Med Res Opin. 1987; 11: 321-330
        • Brown W.V.
        • Dujovne C.A.
        • Farquhar J.W.
        • Feldman E.B.
        • Grundy S.M.
        • Knopp R.H.
        • Lasser N.L.
        • Mellies M.J.
        • Palmer R.H.
        • Samuel P.
        • Schonfeld G.
        • Superko H.R.
        Effects of fenofibrate on plasma lipids: double blind, multicenter study in patients with type IIA or IIB hyperlipidemia.
        Arteriosclerosis. 1986; 6: 678-680
        • Slowe I.A.
        • Carter A.C.
        • Feldman E.B.
        Divergent effects in the treatment of hyperlipemia.
        Arch Intern Med. 1965; 116: 523-530
        • Quarfordt S.
        • Levy R.I.
        • Fredrickson D.S.
        On the lipoprotein abnormality in type 3 hyperlipoproteinemia.
        J Clin Invest. 1971; 50: 754-761
        • Morganroth J.
        • Levy R.I.
        • Fredrickson D.S.
        The biochemical, clinical, and genetic features of Type III hyperlipoproteinemia.
        Ann Intern Med. 1975; 82: 158-174
        • Zelis R.
        • Mason D.T.
        • Braunwald E.
        • Levy R.I.
        Effects of hyperlipoproteinemias and their treatment on the peripheral circulation.
        J Clin Invest. 1970; 49: 1007-1015
        • Stamler J.
        The coronary drug project—findings with regard to estrogen, dextrothyroxine, clofibrate and niacin.
        Adv Exp Med Biol. 1977; 82: 52-75
      1. A co-operative trial in the primary prevention of ischaemic heart disease using clofibrate: report from the Committee of Principal Investigators.
        Br Heart J. 1978; 40: 1069-1118
      2. W.H.O. cooperative trial on primary prevention of ischaemic heart disease using clofibrate to lower serum cholesterol: mortality follow-up.
        Lancet. 1980; 2: 379-385
        • Heady J.A.
        • Morris J.N.
        • Oliver M.F.
        WHO clofibrate/cholesterol trial: clarifications.
        Lancet. 1992; 340: 1405-1406
        • Davidson M.H.
        • Armani A.
        • McKenney J.M.
        • Jacobson T.A.
        Safety considerations with fibrate therapy.
        Am J Cardiol. 2007; 99: 3C-18C
        • Manninen V.
        • Elo M.O.
        • Frick M.H.
        • Haapa K.
        • Heinonen O.P.
        • Heinsalmi P.
        • Helo P.
        • Huttunen J.K.
        • Katianiemi P.
        • Koskinen P.
        • et al.
        Lipid alterations and decline in the incidence of coronary heart disease in the Helsinki Heart Study.
        JAMA. 1988; 260: 641-651
        • Grundy S.M.
        • Ahrens Jr, E.H.
        • Salen G.
        Mechanism of action of clofibrate on cholesterol metabolism in patients with hyperlipidemia.
        J Lipid Res. 1972; 13: 531-551
        • Keech A.
        • Simes R.J.
        • Barter P.
        • Best J.
        • Scott R.
        • Taskinen M.R.
        • Forder P.
        • Pillai A.
        • Davis T.
        • Glasziou P.
        • et al.
        Effects of long-term fenofibrate therapy on cardiovascular events in 9795 people with type 2 diabetes mellitus (the FIELD study): randomised controlled trial.
        Lancet. 2005; 366: 1849-1861
        • Langer T.
        • Levy R.I.
        Acute muscular syndrome associated with administration of clofibrate.
        N Engl J Med. 1968; 279: 856-858
        • McGarvey J.F.
        Premature contractions and clofibrate.
        JAMA. 1973; 225: 638
        • Tobert J.A.
        Efficacy and long term adverse effect pattern of lovastatin.
        Am J Cardiol. 1988; 62: 28J-34J
        • Illingworth D.R.
        • Bacon S.
        Influence of lovastatin plus gemfibrozil on plasma lipids and lipoproteins in patients with heterozygous familial hypercholesterolemia.
        Circulation. 1989; 79: 590-596
        • Staffa J.A.
        • Chang J.
        • Green L.
        Cerivastatin and reports of fatal rhabdomyolysis.
        N Engl J Med. 2002; 346: 539-540
        • Jones P.H.
        • Davidson M.H.
        Reporting rate of rhabdomyolysis with fenofibrate + statin versus gemfibrozil + any statin.
        Am J Cardiol. 2005; 95: 120-122
        • Tsimihodimos V.
        • Kakafika A.
        • Elisaf M.
        Fibrate treatment can increase serum creatinine.
        Nephrol Dial Transplant. 2001; 16 ([letter]): 1301
        • Tsimihodimos V.
        • Miltiadous G.
        • Bairaktari E.
        • Elisaf M.
        Possible mechanisms of the fibrate-induced increase in serum creatinine.
        Clin Nephrol. 2002; 57: 407-408
        • Genest J.
        • Frohlich J.
        • Steiner G.
        Effect of fenofibrate-mediated increase in plasma homocysteine on the progression of coronary artery disease in type 2 diabetes mellitus.
        Am J Cardiol. 2004; 93: 848-853
        • Syvanne M.
        • Whittall R.A.
        • Turpeinen U.
        • Nieminen M.S.
        • Frick M.H.
        • Kesaniemi Y.A.
        • Pasternack A.
        • Humphries S.E.
        • Taskinen M.R.
        Serum homocysteine concentrations, gemfibrozil treatment, and progression of coronary atherosclerosis.
        Atherosclerosis. 2004; 172: 267-272
        • Ansquer J.C.
        • Foucher C.
        • Rattier S.
        • Taskinen M.R.
        • Steiner G.
        • DAIS Investigators
        Fenofibrate reduces progression to microalbuminuria over 3 years in the placebo-controlled study in type 2 diabetes: results from Diabetes Atherosclerosis Intervention Study (DAIS).
        Am J Kidney Dis. 2005; 45: 485-493