Abstract 17336: Marked Increase of Plasma Fibroblast Growth Factor 21 in Dyslipidemic Patients Treated With K-877, a Novel Highly Potent and Specific Peroxisome Proliferator-Activated Receptor Alpha Agonist
Background: Fibroblast growth factor 21 (FGF21) is an emerging hormonal regulator of lipid and glucose metabolism which decreases triglyceride, enhances insulin sensitivity and suppresses weight gain. K-877 is a novel highly potent and specific peroxisome proliferator-activated receptor alpha (PPARα) agonist. We hypothesize that K-877 has influence on serum FGF21 level in addition to lipid improvement. Here, we aimed at elucidating the effect of K-877 on FGF 21.
Method: A multicenter, randomized, double-blind, placebo- and active-controlled parallel-group phase 2 study was conducted in Japan. A total of 224 dyslipidemia patients with high TG (≥200 mg/dL, <500 mg/dL) and low HDL-C (<50 mg/dL for male, <55 mg/dL for female) were randomly assigned to 12 weeks of treatment with K-877 0.05, 0.1, 0.2, 0.4 mg/day (twice daily), placebo or fenofibrate 100 mg/day (once daily). Serum lipid and FGF 21 levels were measured at baseline and Week 12. A meal test was also performed at Week 12 in order to evaluate postprandial parameters.
Results: After 12 weeks of treatment with K-877, significant reduction in TG and increase in HDL-C (-30.9% to -42.7% and +10.1% to +19.1% from baseline, respectively) were observed. K-877 at the doses of 0.05, 01, 0.2 and 0.4 mg/day significantly increased FGF21 (logarithmic conversion) by 0.15, 0.66, 0.42, 0.78 , respectively, compared to baseline (P<0.001). Increase in FGF 21 was significantly larger at all doses of K-877 except for 0.05 mg/day compared to placebo (P<0.01). On the other hand, no difference was found between fenofibrate and placebo groups (0.16 vs. 0.13, P=NS). Upon meal test at Week 12, K-877 groups increased postprandial FGF21 estimated by area under the curve (AUC) from before meal to 6.5 hours after meal (AUC6.5h) by 3731.721, 4474.508, 5789.447, 8862.041 pg[[Unable to Display Character: ]]h/mL in a dose dependent manner, and these were higher than placebo group and fenofibrate group (2088.550 and 3383.526 pg[[Unable to Display Character: ]]h/mL, respectively).
Conclusions: K-877 reduced TG and increased HDL-C in patients with dyslipidemia. Moreover, K-877 increased FGF 21 both before and after meal. The unique effect of K-877 on FGF 21 may contribute to its potency in improvement of dyslipidemia and also be favorable for improving other metabolic diseases.
- © 2013 by American Heart Association, Inc.