Comparison of effects of bezafibrate and fenofibrate on circulating proprotein convertase subtilisin/kexin type 9 and adipocytokine levels in dyslipidemic subjects with impaired glucose tolerance or type 2 diabetes mellitus: Results from a crossover study

Background: Bezafibrate and fenofibrate show different binding properties against peroxisome proliferator-activated receptor subtypes, which could cause different clinical effects on circulating proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and on various metabolic markers. Methods: An open, randomized, four-phased crossover study using 400mg of bezafibrate or 200mg of fenofibrate was performed. Study subjects were 14 dyslipidemia with impaired glucose tolerance or type 2 diabetes mellitus (61±16 years, body mass index (BMI) 26±3kg/m ², total cholesterol (TC) 219±53mg/dL, triglyceride (TG) 183±83mg/dL, high-density lipoprotein-cholesterol (HDL-C) 46±8mg/dL, fasting plasma glucose 133±31mg/dL and HbA1c 6.2±0.8%). Subjects were given either bezafibrate or fenofibrate for 8 weeks, discontinued for 4 weeks and then switched to the other fibrate for 8 weeks. Circulating PCSK9 levels and other metabolic parameters, including adiponectin, leptin and urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) were measured at 0, 8, 12 and 20 weeks. Results: Plasma PCSK9 concentrations were significantly increased (+39.7% for bezafibrate and +66.8% for fenofibrate, p<. 0.001) in all patients except for one subject when treated with bezafibrate. Both bezafibrate and fenofibrate caused reductions in TG (-38.3%, p<. 0.001 vs. -32.9%, p<. 0.01) and increases in HDL-C (+18.0%, p<. 0.001 vs. +11.7%, p<. 0.001). Fenofibrate significantly reduced serum cholesterol levels (TC, -11.2%, p<. 0.01; non-HDL-C, -17.3%, p<. 0.01; apolipoprotein B, -15.1%, p<. 0.01), whereas bezafibrate significantly improved glucose tolerance (insulin, -17.0%, p<. 0.05) and metabolic markers (γ-GTP, -38.9%, p<. 0.01; adiponectin, +15.4%, p<. 0.05; urine 8-OHdG/Cre, -9.5%, p<. 0.05). Conclusion: Both bezafibrate and fenofibrate increased plasma PCSK9 concentrations. The addition of a PCSK9 inhibitor to each fibrate therapy may achieve beneficial cholesterol lowering along with desirable effects of respective fibrates.