Abstract
Fenofibrate is a fibric acid derivative with lipid-modifying effects that are mediated by the activation of peroxisome proliferator-activated receptor-α. Fenofibrate also has a number of nonlipid, pleiotropic effects (e.g. reducing levels of fibrinogen, C-reactive protein, and various pro-inflammatory markers, and improving flow-mediated dilatation) that may contribute to its clinical efficacy, particularly in terms of improving microvascular outcomes.
The beneficial effects of fenofibrate on the lipid profile have been shown in a number of randomized controlled trials. In primary dyslipidemia, fenofibrate monotherapy consistently decreased triglyceride (TG) levels to a significantly greater extent than placebo; significantly greater increases in high-density lipoprotein cholesterol (HDL-C) levels and significantly greater reductions in low-density lipoprotein cholesterol (LDL-C) and total cholesterol (TC) levels were also seen in some trials. Monotherapy with fenofibrate or gemfibrozil had generally similar effects on TG and HDL-C levels, although in one trial, TC and LDL-C levels were reduced to a significantly greater extent with fenofibrate than with gemfibrozil. Fenofibrate monotherapy tended to improve TG and HDL-C levels to a significantly greater extent than statin monotherapy in primary dyslipidemia, whereas statin monotherapy decreased LDL-C and TC levels to a significantly greater extent than fenofibrate monotherapy. Fenofibrate also had a beneficial effect on atherogenic dyslipidemia in patients with the metabolic syndrome or type 2 diabetes mellitus, reducing TG levels, tending to increase HDL-C levels, and promoting a shift to larger low-density lipoprotein particles.
In terms of cardiovascular outcomes, fenofibrate did not reduce the risk of coronary heart disease (CHD) events to a greater extent than placebo in patients with type 2 diabetes in the FIELD trial. However, the risk of some nonfatal macrovascular events (e.g. nonfatal myocardial infarction, revascularization) and certain microvascular outcomes (e.g. amputation, first laser therapy for diabetic retinopathy, progression of albuminuria) was reduced to a significantly greater extent with fenofibrate than with placebo. Subgroup analysis revealed a significant reduction in the cardiovascular disease (CVD) event rate among fenofibrate recipients in the subgroup of patients with marked hypertriglyceridemia or marked dyslipidemia at baseline.
In the ACCORD Lipid trial, there were no significant differences between patients with type 2 diabetes and a high risk of CVD events who received fenofibrate plus simvastatin and those who received placebo plus simvastatin for any of the primary or secondary cardiovascular outcomes. However, fenofibrate plus simvastatin was of benefit in patients who had markedly high TG levels and markedly low HDL-C levels at baseline. In addition, fenofibrate plus simvastatin slowed the progression of diabetic retinopathy.
Fenofibrate is generally well tolerated. Common adverse events included increases in transaminase levels that were usually transient, minor, and asymptomatic, and gastrointestinal signs and symptoms.
In conclusion, monotherapy with fenofibrate remains a useful option in patients with dyslipidemia, particularly in atherogenic dyslipidemia characterized by high TG and low HDL-C levels.
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Various sections of the manuscript reviewed by: J. Ducobu, Université de Mons-Hainaut, Mons, Belgium; M.B. Elam, Department of Pharmacology and Medicine, University of Tennessee Health Sciences Center-Memphis, Memphis, TN, USA; M. Farnier, Point Medical, Dijon, France; K.G. Parhofer, Medical Department II Grosshadern, University of Munich, Munich, Germany; P. Poirier, Université; Laval, Québec, QC, Canada; J. Saltevo, Department of Internal Medicine, Central Hospital of Middle Finland, Jyväskylä, Finland; G.F. Watts, School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
Data Selection
Sources: Medical literature (including published and unpublished data) on ‘fenofibrate’ was identified by searching databases since 1988 (including MEDLINE, EMBASE, and inhouse AdisBase), bibliographies from published literature, clinical trial registries/databases, and websites (including those of regional regulatory agencies and the manufacturer). Additional information (including contributory unpublished data) was also requested from the company developing the drug.
Search strategy: MEDLINE, EMBASE, and AdisBase search terms were ‘fenofibrate’ and (‘hyperlipidemias’ or ‘hyperlipidaemia’ or ‘dyslipidemias’ or ‘dyslipidemia’ or ‘dyslipidaemia’). Searches were last updated 31 May 2011.
Selection: Studies in patients with primary dyslipidemia, the metabolic syndrome, or type 2 diabetes mellitus who received fenofibrate. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Fenofibrate, dyslipidemia, metabolic syndrome, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability.
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Keating, G.M. Fenofibrate. Am J Cardiovasc Drugs 11, 227–247 (2011). https://doi.org/10.2165/11207690-000000000-00000
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DOI: https://doi.org/10.2165/11207690-000000000-00000