A review of paradoxical HDL-C responses to fenofibrate, illustrated by a case report Jonathan D. Schofield, BSc, MRCP, Yifen Liu, BSc, Michael W. France, MSc, FRCPath, Lance Sandle, BSc, FRCPath, Handrean Soran, MSc, MD, FRCP * Cardiovascular Trials Unit, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (Drs Schofield, France, and Soran); Cardiovascular Research Group, Core Technology Facility, University of Manchester, Manchester, UK (Drs Schofield, Soran, and Mrs Liu); Department of Clinical Biochemistry, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (Dr France); and Department of Chemical Pathology, Trafford General Hospital, Manchester, UK (Dr Sandle) KEYWORDS: High-density lipoprotein cholesterol; High-density lipoprotein; HDL; Paradoxical reduction in high-density lipoprotein cholesterol; Fenofibrate Abstract: High-density lipoprotein cholesterol (HDL-C) concentration is an independent risk factor for cardiovascular disease. Fibrates are widely used in the management of atherogenic dyslipidemia, princi- pally for their triglyceride-lowering and HDL-C–raising effects. Fibrates may cause paradoxical reduc- tions in HDL-C. These reductions are usually modest, but significant reductions have been observed. The molecular mechanism for these paradoxical reductions remains unexplained despite advances in our understanding of lipid metabolism. This review considers possible mechanisms for this effect, illus- trated by a patient with an observed reduction in HDL-C of 88% after introduction of fenofibrate. Ó 2014 National Lipid Association. All rights reserved. High-density lipoprotein cholesterol (HDL-C) concentra- tion is an independent risk factor for cardiovascular morbidity and mortality. 1 A 6% increase in HDL-C is associated with a 22% reduction in the incidence of myocardial infarction in epidemiological studies. 2 Increasing HDL-C has emerged as an attractive tool for preventing cardiovascular events, 3 despite the failure of recent large randomized clinical trials to demonstrate an improvement in cardiovascular outcomes through the use of niacin and the cholesteryl ester transfer protein (CETP) inhibitors torcetrapib and dalcetrapib. 4 Although both Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study were negative outcome trials, 5,6 fenofibrate, a peroxisome proliferator-activated receptor-a (PPAR-a) agonist, is widely used in the manage- ment of atherogenic dyslipidemia. Its triglyceride (TG)- lowering and HDL-C–raising effect is more pronounced when baseline HDL-C concentration is low. 7 Although ef- fects vary depending on the population, a meta-analysis of 53 clinical studies enrolling 16,802 subjects indicated that fi- brates can be expected to reduce plasma TG levels by 30% to 40% and raise HDL-C levels by 10% to 20%, 8 but there is marked interindividual variability in response to drug ac- tion. 9 The effects of fenofibrate on HDL composition may vary in different lipoprotein phenotypes, and a pharmacoge- netic association might predict response. 10 We report a 63-year-old woman with mixed dyslipide- mia and a family history of premature cardiovascular disease treated with atorvastatin for 10 years, who devel- oped a paradoxical reduction in HDL-C after the introduc- tion of fenofibrate. Her fasting lipid profile before addition of fenofibrate showed total cholesterol (TC) 6.4 mmol/L, * Corresponding author. Cardiovascular Trials Unit, Central Manches- ter University Hospitals, Oxford Road, Manchester M13 9WL UK. E-mail address: hsoran@aol.com Submitted December 19, 2013. Accepted for publication May 18, 2014. 1933-2874/$ - see front matter Ó 2014 National Lipid Association. All rights reserved. http://dx.doi.org/10.1016/j.jacl.2014.05.003 Journal of Clinical Lipidology (2014) 8, 455–459