Abstract 10718: Efficacy and Safety of K-877, a Potent and Selective PPAR-a Agonist, in Japanese Patients With Dyslipidemia
Background: Residual cardiovascular risk remains despite intensive treatment with statins. Combination therapy with fibrates may reduce such risk particularly in patients with dyslipidemia. However, recent clinical trial results have not supported this approach. To circumvent the limitations intrinsic to the use of conventional fibrates, we performed a Phase II/III study of K-877, a PPAR-α agonist with a possibly better pharmacological profile of efficacy and safety than fenofibrate (Japic CTI-121764).
Methods: A total of 526 patients with fasting hypertriglyceridemia (≥200, <1000 mg/dL) and low HDL-C (<50 mg/dL for male, <55 mg/dL for female) were randomized to the following 12-week treatment groups in a multi-center double-blind parallel-group study; placebo (n=43), twice-daily K-877 0.1 (n=45), 0.2 (n=128) and 0.4 mg/day (n=85), and once-daily fenofibrate 100 (n=85) and 200 mg/day (n=140). The primary endpoint was the percentage change in TG from baseline and adverse drug reactions (ADRs) / events (AEs).
Results: Fasting TG reduction was as follows; placebo: -2.7%, K-877 0.1, 0.2 and 0.4 mg: -46.3%, -46.7% and -51.8%, fenofibrate 100 and 200 mg: -38.3% and -51.5%. All K-877 groups had significant reductions in TG compared with placebo (P<0.001) and fenofibrate 100 mg (P=0.020, 0.001, <0.001). The reductions in K-877 0.2 and 0.4 mg were similar to fenofibrate 200 mg. HDL-C increases were 20.3% to 24.7% in K-877 and 17.2% to 26.5% in fenofibrate. VLDL-C, RLP-C and apoCIII reductions were found in all drug groups. The incidence of ADRs in K-877 was similar to placebo and fenofibrate 100 mg, and was significantly less than fenofibrate 200 mg (P=0.001, <0.001, 0.011) (placebo: 7.0%, K-877: 4.4%, 7.8% and 11.8%, fenofibrate: 14.1%, 26.4%). Similar results were observed in AEs. The study discontinuation rate in K-877 was less than that in fenofibrate (placebo: 0%, K-877: 6.7%, 5.5%, 5.9%, fenofibrate: 8.2%, 10.7%), and the major reason for discontinuation was abnormal liver function (K-877: 0%, 0.8%, 0%, fenofibrate: 3.5%, 7.9%).
Conclusions: K-877 significantly improved plasma lipoprotein profiles at considerably lower doses. It also caused significantly fewer ADRs. K-877 may be a useful modality to further reduce residual risk in dyslipidemia.
- © 2013 by American Heart Association, Inc.