Abstract 12384: Novel Approach to Residual Risk, K-877, a Potent and Selective PPAR-α Modulator (SPPARMα), Added-on to Pitavastatin in Japanese Patients With Dyslipidemia

Abstract

Background: Residual cardiovascular risk remains despite intensive treatment with statins. K-877, a Selective PPAR-α Modulator (SPPARMα), has shown significant reductions in atherogenic lipids with fewer adverse effects than existing PPARα agonists. We hypothesized that combination with pitavastatin may provide further reduction in atherosclerotic risk, particularly in dyslipidemic patients with hypertriglyceridemia, than statin alone. Methods: This was a multi-center double-blind parallel-group study. A total of 188 patients with fasting high TG (≥200, <1000 mg/dL) and non-HDL-C (≥150 mg/dL), treated with pitavastatin (once daily, 2 mg/day) were randomized to 12-week treatment groups; placebo (n=46), twice-daily K-877 0.1 (n=45), 0.2 (n=49) and 0.4 mg/day (n=48). The primary endpoint was the percentage change in TG from baseline and incidence of adverse drug reactions (ADRs) and adverse events (AEs). Results: Fasting TG reduction was as follows; placebo: -6.9%, K-877 0.1, 0.2 and 0.4 mg: -46.1%, -53.4% and -52.0%. All K-877 groups had significant reductions compared with placebo (P<0.001). Fasting non-HDL-C reductions were -5.9% with placebo and -11.3, -14.1 and -13.3% with K-877 0.1, 0.2 and 0.4 mg, respectively. Significant increase in HDL-C, and reductions in VLDL-C, remnant lipoprotein cholesterol and apoCIII compared to placebo were found in all K-877 groups (P<0.01). Although K-877 had a neutral effect on total LDL-C, HPLC analysis revealed a significant reduction of very small LDL-C with K-877 compared to the placebo group (P<0.05). Moreover, the highest dose of K-877 (0.4 mg/day) showed significant reduction of fasting blood glucose and HOMA-R compared to placebo (P=0.003 and 0.019, respectively). The incidence of AEs and ADRs in the K-877 groups was similar to that in placebo group. The study discontinuation rates were similar across all groups. Conclusions: K-877 significantly improved plasma lipoprotein profiles in dyslipidemia patients on stable statin treatment without increasing the rates of AEs/ADRs. Thus K-877 may be a useful therapy to reduce residual cardiovascular risk in dyslipidemia.