CARDIOLOGY EXPRESS REPORT FAX

Publication date: 2006-03-31

Efficacy and Safety of Fibrate/Statin Combination Therapy in Lipid Management—Importance of Fibrate Selection

This report was reviewed for medical and scientific accuracy by John B. Kostis, MD, FACC, John G. Detwiler Professor of Cardiology; Professor of Medicine and Pharmacology; Chairman, Department of Medicine; University of Medicine & Dentistry of New Jersey—Robert Wood Johnson Medical School; New Brunswick, New Jersey.

Expert Commentary

Michael H. Davidson, MD, Associate Professor of Medicine, Rush University; Director, Preventive Cardiology Center, Rush University Medical Center; Chicago, Illinois

There is a large body of evidence indicating that statin therapy effectively reduces low-density lipoprotein (LDL)-cholesterol and lowers morbidity and mortality rates from cardiovascular disease. Despite these advancements however, clinical studies have indicated that approximately two-thirds of all cardiovascular events are not prevented with statin therapy.^1–4 Although lowering LDL-cholesterol produces significant risk reduction in a large percentage of patients, abnormalities in other lipoproteins, such as triglycerides and high-density lipoprotein (HDL)-cholesterol, play an important role in coronary disease events. Monotherapy with higher doses of statins or adding ezetimibe to statin therapy does not correct all of the lipoprotein abnormalities in patients with combined hyperlipidemia. According to current National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII) guidelines, once target LDL-cholesterol goals have been achieved with statins, fibrate or niacin therapy should be considered to optimize triglyceride and HDL-cholesterol levels.⁵ Fibrate therapy reduces triglycerides by 20% to 50% and increases HDL-cholesterol by 10% to 35%; whereas statin therapy increases HDL-cholesterol by 5% to 15% and reduces triglycerides by 10% to 30%.⁶ Thus, the combination of fibrate and statin offers an improved pharmacologic treatment option for total lipid management. However, statin therapy is associated with dose-dependent myopathy and rare instances of rhabdomyolysis.^7–9 These toxicities have been exacerbated by concomitant fibrate therapy; almost exclusively associated with gemfibrozil.

This Cardiology Express Report^TM Fax reviews new evidence that offers insight into the pharmaco-kinetic differentiation between gemfibrozil and fenofibrate and highlights recently published data that support the safety and efficacy of statin/ fenofibrate combination therapy in the management of lipid disorders.

Efficacy and Safety of Fibrate-Statin Combination—the SAFARI Trial

Although the statins effectively lower LDL-cholesterol, and higher doses of statins can improve triglycerides and HDL-cholesterol, statin monotherapy does not correct all lipoprotein abnormalities associated with combined hyperlipidemia (elevated triglycerides, elevated LDL-cholesterol, and multiple lipoprotein abnormalities). Because fibrates and statins regulate lipids by different mechanisms, combination therapy with a fibrate and statin offers desirable benefits in patients with combined hyperlipidemia. The Simvastatin plus Fenofibrate for Combined Hyperlipidemia (SAFARI) trial evaluated over 600 patients with combined hyperlipidemia randomized to simvastatin monotherapy 20 mg/day (n = 207) or simvastatin 20 mg/day plus fenofibrate 160 mg/day (n = 411) for 12 weeks following a 6-week diet and placebo run-in period.¹⁰

The combined administration of fenofibrate and simvastatin resulted in additional improvement in all lipoprotein parameters measured (VLDL-cholesterol, non-HDL-cholesterol, LDL-cholesterol, total cholesterol, VLDL-triglycerides, apolipoprotein A-I, and apolipoprotein B) compared with simvastatin monotherapy.

In particular, median triglyceride levels decreased by -43.0% from baseline with the addition of fenofibrate compared with -20.1% with simvastatin monotherapy (P<.001). In addition, the percentage HDL-cholesterol increase was approximately twice as high in the fenofibrate/simvastatin group compared with s