Efficacy and Safety of Coadministration of Fenofibrate and Ezetimibe Compared with Each as Monotherapy in Patients with Type IIb Dyslipidemia and Features of the Metabolic Syndrome A Prospective, Randomized, Double-Blind, Three-Parallel Arm, Multicenter, Comparative Study

Background: Patients with type IIb, or mixed, dyslipidemia have high levels of low-density lipoprotein cholesterol (LDL-C) with predominance of small dense LDL particles, high levels of triglycerides (TG), and low levels of high-density lipoprotein cholesterol (HDL-C). Fenofibrate significantly reduces TG and, more moderately, LDL-C, increases HDL-C and produces a shift from small to large LDL particle size; the main effect of ezetimibe is a reduction in LDL-C levels. Combined treatment with fenofibrate and ezetimibe may correct all the abnormalities of type IIb dyslipidemia. Objective: To assess the efficacy and safety of coadministration of fenofibrate (NanoCrystal®) and ezetimibe in patients with type IIb dyslipidemia and the metabolic syndrome compared with administration of fenofibrate and ezetimibe alone (ClinicalTrials.gov Identifier: NCT00349284; Study ID: CLF178P 04 01). Methods: This was a prospective, randomized, double-blind, three-parallel arm, multicenter, comparative study. Sixty ambulatory patients (mean age 56 years; 50% women, 50% men) were treated in each group. For inclusion in the study, patients were required to have LDL-C ≥4.13 mmol/L (≥ 160 mg/dL), TG ≥1.71 mmol/L and ≤4.57 mmol/L (≥150 mg/dL and ≤405 mg/dL), and at least two of the following National Cholesterol Education Program Adult Treatment Panel III criteria for the metabolic syndrome: low HDL-C or increased fasting plasma glucose, blood pressure, or waist circumference. Patients received fenofibrate 145 mg, ezetimibe 10 mg, or coadministration of both (fenofibrate/ezetimibe) daily for 12 weeks. The outcome measures were changes in lipids and related parameters, apolipoproteins, glucose metabolism parameters, and high-sensitivity C-reactive protein (hsCRP). Results: Fenofibrate/ezetimibe was more effective than either fenofibrate or ezetimibe in reducing LDL-C (-36.2% vs -22.4% and -22.8%, respectively), non-HDL-C (-36.2% vs -24.8% and -20.9%, respectively), total cholesterol (TC) [-27.9% vs -18.9% and -17.1%, respectively], apolipoprotein B (-33.3% vs -24.5% and -18.7%, respectively), TC/HDL-C ratio (-34.2% vs -23.0% and -17.0%, respectively), and apolipoprotein B/apolipoprotein AI ratio (-37.5% vs -27.0% and -17.7%, respectively) [p<0.001 for all comparisons between fenofibrate/ezetimibe and monotherapies]. Fenofibrate/ezetimibe was as effective as fenofibrate and more effective than ezetimibe in reducing remnant-like particle cholesterol (-36.2% and -30.7% vs -17.3%, respectively), and in increasing LDL size (+2.1% and + 1.9% vs + 0.7%, respectively), apolipoprotein AI (+7.9% and + 5.1% vs + 0.2%, respectively) and apolipoprotein All (+24.2% and + 21.2% vs +2.7%, respectively). Fenofibrate/ezetimibe and fenofibrate were equally effective in reducing TG (both -38.3%) and in increasing HDL-C (+11.5% and + 7.9%, respectively; p=0.282). Ezetimibe had minor effects on TG (-10.4%) and HDL-C ( + 2.2%). Among patients with low HDL-C at baseline (<1.29 mmol/L [<50 mg/dL] in women, <1.03 mmol/L [<40 mg/dL] in men), normalization of HDL-C was observed in 52.9% with fenofibrate/ezetimibe and in 58.8% with fenofibrate, compared with 20.0% with ezetimibe. Changes in hsCRP were -25.9% with fenofibrate/ezetimibe, -27.8% with fenofibrate, and -10.2% with ezetimibe (not statistically significant). None of the treatments altered glucose metabolism parameters. Conclusion: In patients with type IIb dyslipidemia and features of the metabolic syndrome, coadministration of fenofibrate 145mg and ezetimibe 10 mg daily was more effective than either monotherapy in reducing LDL-C, non-HDL-C, apolipoprotein B, and cardiovascular risk ratios, and was as effective as fenofibrate 145mg alone in reducing TG and in increasing HDL-C in patients with low baseline HDL-C levels.