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Reduced High-density Lipoprotein Cholesterol in Patients Receiving Rosiglitazone and Fenofibrate

2008; Elsevier BV; Volume: 121; Issue: 10 Linguagem: Inglês

10.1016/j.amjmed.2008.06.019

1555-7162

César Venero, Paul M. Thompson, Antonio B. Fernández,

Metabolism, Diabetes, and Cancer

Rosiglitazone and pioglitazone are peroxisome proliferator-activated receptor (PPAR)-γ ligands combined frequently with fibrates, PPAR-α agonists, to treat hypertriglyceridemia. Such treatment routinely increases high-density lipoprotein (HDL)-C concentrations.1Seber S. Ucak S. Basat O. Altuntas Y. The effect of dual PPAR alpha/gamma stimulation with combination of rosiglitazone and fenofibrate on metabolic parameters in type 2 diabetic patients.Diabetes Res Clin Pract. 2006; 71: 52-58Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar We report 3 cases of decreases in serum HDL-C during combined rosiglitazone and fenofibrate therapy. A 66-year-old woman with type 2 diabetes mellitus, dyslipidemia, and coronary artery disease was treated with aspirin, metoprolol, metformin, fluvastatin, rosiglitazone, and hydrochlorothiazide. Because of hypertriglyceridemia, metformin was increased and fenofibrate was added. Her HDL-C decreased from 46 mg/dL to 10 to 15 mg/dL (Figure 1). On the basis of reports of decreased HDL-C with rosiglitazone,2Shetty C. Balasubramani M. Capps N. et al.Paradoxical HDL-C reduction during rosiglitazone and fibrate treatment.Diabet Med. 2007; 24: 94-97Crossref PubMed Scopus (19) Google Scholar, 3Ebcioglu Z. Morgan J. Carey C. Capuzzi D. Paradoxical lowering of high-density lipoprotein cholesterol level in 2 patients receiving fenofibrate and a thiazolidinedione.Ann Intern Med. 2003; 139: W80Crossref PubMed Google Scholar, 4Goldberg R.B. Mendez A. Severe acquired (secondary) high-density lipoprotein deficiency.J Clin Lipidol. 2007; 1: 41-56Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar her medication was switched to pioglitazone. Her HDL-C increased to 47 mg/dL without other changes in lifestyle or medication. A 71-year-old man with venous thrombosis, hypertension, type 2 diabetes mellitus, dyslipidemia, and coronary artery disease was treated with amlodipine, warfarin, rosiglitazone, valsartan/hydrochlorothiazide, and atenolol. Because of hypertriglyceridemia, fenofibrate was started and rosiglitazone was increased. His HDL-C decreased from 37 to 23 mg/dL (Figure 1). After 18 months, his medication was switched to pioglitazone. His HDL-C increased to 31 mg/dL without other change in lifestyle or medication. A 64-year-old woman with type 2 diabetes mellitus, hypertension, hypercholesterolemia, and coronary artery disease was treated with metoprolol, glipizide, aspirin, niacin, metformin, and warfarin. She was administered simvastatin and rosiglitazone. Glipizide was discontinued. Because of hypertriglyceridemia, fenofibrate was started 8 weeks later. Her HDL-C decreased from 42 mg/dL to 17 mg/dL (Figure 1). The fenofibrate was discontinued, and her HDL-C increased to 43 mg/dL without additional change in lifestyle or medication. We report 3 patients with 35% to 77% decreases in their HDL-C levels when treated with rosiglitazone and fenofibrate. HDL-C levels increased with cessation of rosiglitazone (patients 1 and 2) or fenofibrate (patient 3). The combination of rosiglitazone and fenofibrate has been documented to decrease HDL-C in 27 previous patients,2Shetty C. Balasubramani M. Capps N. et al.Paradoxical HDL-C reduction during rosiglitazone and fibrate treatment.Diabet Med. 2007; 24: 94-97Crossref PubMed Scopus (19) Google Scholar, 3Ebcioglu Z. Morgan J. Carey C. Capuzzi D. Paradoxical lowering of high-density lipoprotein cholesterol level in 2 patients receiving fenofibrate and a thiazolidinedione.Ann Intern Med. 2003; 139: W80Crossref PubMed Google Scholar, 4Goldberg R.B. Mendez A. Severe acquired (secondary) high-density lipoprotein deficiency.J Clin Lipidol. 2007; 1: 41-56Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 5Normen L. Frohlich J. Montaner J. et al.Combination therapy with fenofibrate and rosiglitazone paradoxically lowers serum HDL cholesterol.Diabetes Care. 2004; 27: 2241-2242Crossref PubMed Scopus (29) Google Scholar, 6Keidar S. Guttmann H. Stam T. et al.High incidence of reduced plasma HDL cholesterol in diabetic patients treated with rosiglitazone and fibrate.Pharmacoepidemiol Drug Saf. 2007; 16: 1192-1194Crossref PubMed Scopus (17) Google Scholar yet many clinicians are unaware of this possibility. Rosiglitazone and troglitazone are the thiazolidinediones associated with this paradoxical HDL-C reduction, whereas fenofibrate, bezafibrate, and ciprofibrate are the associated fibric acid derivatives.4Goldberg R.B. Mendez A. Severe acquired (secondary) high-density lipoprotein deficiency.J Clin Lipidol. 2007; 1: 41-56Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar We are unaware of documented decreases in HDL-C with gemfibrozil and thiazolidinedione therapy. In patients with decreased HDL-C related to fibrates and rosiglitazone, HDL-C returned to baseline on withdrawing the offending agent or on switching to gemfibrozil or pioglitazone.2Shetty C. Balasubramani M. Capps N. et al.Paradoxical HDL-C reduction during rosiglitazone and fibrate treatment.Diabet Med. 2007; 24: 94-97Crossref PubMed Scopus (19) Google Scholar, 3Ebcioglu Z. Morgan J. Carey C. Capuzzi D. Paradoxical lowering of high-density lipoprotein cholesterol level in 2 patients receiving fenofibrate and a thiazolidinedione.Ann Intern Med. 2003; 139: W80Crossref PubMed Google Scholar, 4Goldberg R.B. Mendez A. Severe acquired (secondary) high-density lipoprotein deficiency.J Clin Lipidol. 2007; 1: 41-56Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 6Keidar S. Guttmann H. Stam T. et al.High incidence of reduced plasma HDL cholesterol in diabetic patients treated with rosiglitazone and fibrate.Pharmacoepidemiol Drug Saf. 2007; 16: 1192-1194Crossref PubMed Scopus (17) Google Scholar It is possible that when a fibrate and thiazolidinedione are given simultaneously, competition at the PPAR receptor or transcription level antagonizes the independent effect of both drugs on HDL-C metabolism. Because such a reaction is rare, individual metabolic or genetic factors may affect its incidence. This paradoxical response of HDL-C to some PPAR ligands has not been widely recognized. We suggest that clinicians be aware that rosiglitazone with fenofibrate may reduce HDL-C levels and consider alternative medications should a decrease in HDL-C occur.