Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy

Abstract

OBJECTIVE High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG levels through peroxisome proliferator–activated receptor α (PPARα) agonism. Currently available fibrates, however, have relatively low selectivity for PPARα. The aim of this trial was to assess the safety, tolerability, and efficacy of K-877 (pemafibrate), a selective PPARα modulator, in statin-treated European patients with hypertriglyceridemia. RESEARCH DESIGN AND METHODS A total of 408 statin-treated adults were recruited from 68 European sites for this phase 2, randomized, double-blind, placebo-controlled trial. They had fasting TG between 175 and 500 mg/dL and HDL-cholesterol (HDL-C) ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomly assigned to receive placebo or one of six pemafibrate regimens: 0.05 mg twice a day, 0.1 mg twice a day, 0.2 mg twice a day, 0.1 mg once daily, 0.2 mg once daily, or 0.4 mg once daily. The primary end points were TG and non–HDL-C level lowering at week 12. RESULTS Pemafibrate reduced TG at all doses (adjusted P value <0.001), with the greatest placebo-corrected reduction from baseline to week 12 observed in the 0.2-mg twice a day treatment group (54.4%). Reductions in non–HDL-C did not reach statistical significance. Reductions in TG were associated with improvements in other markers for TG-rich lipoprotein metabolism, including reductions in apoB48, apoCIII, and remnant cholesterol and an increase in HDL-C levels. Pemafibrate increased LDL-cholesterol levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations. CONCLUSION Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.

New, Novel Lipid-Lowering Agents for Reducing Cardiovascular Risk: Beyond Statins

“…In clinical trials involving Japanese patients with plasma TG ≥150 or 200 mg/dL while receiving statin therapy, pemafibrate reduced plasma TG levels by 50% from the baseline [ 54 ]. In a phase 2 trial involving a total of 408 statin-treated European patients with plasma TG levels between 175 and 500 mg/dL, the highest dose of pemafibrate tested, 0.2 mg twice a day, reduced plasma TG levels by 54.4% from the baseline [ 55 ]. A phase 3 cardiovascular outcome trial involving 10,000 patients with type 2 diabetes mellitus and plasma TG levels of 200 to 500 mg/dL while receiving statin therapy (Pemafibrate to Reduce Cardiovascular OutcoMes by Reducing Triglycerides IN patiENts With diabeTes [PROMINENT], NCT03071692) started from March, 2017 [ 56 ].…”

Do we need new lipid-lowering agents in the era of PCSK9 inhibitors? Recent advances

“…Pemafibrate stands out as a novel highly selective PPAR-α modulator causing marked reductions of triglycerides and remnant cholesterol particles. A recent study, however, found no significant reductions in non-HDL-C [40], indicating that potential beneficial effects may be related primarily to triglyceride and triglyceride remnant reductions. The ongoing PROMINENT (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes) study has randomized over 10 000 participants with T2DM (primary or secondary prevention), triglycerides of 2.26-5.64 mmol/l and HDL-C levels <1.03 mmol/l, to pemafibrate or placebo, with the study endpoint driven by events.…”

Effect of Pemafibrate on Hemorheology in Patients with Hypertriglyceridemia and Aggravated Blood Fluidity Associated with Type 2 Diabetes or Metabolic Syndrome

“…Since SPPARMα binds directly to DNA promoters and inhibits their transcription, the possibility that pemafibrate-mediated changes in lipid metabolism do not directly reduce TG alone, but are accompanied by increased HDL-C and LDL-C levels (thus the balance of lipid metabolism and the improvement in LDL-C risk are not substantially altered), should be considered in the next research phase [ 28 , 29 , 30 ]. Pemafibrate is a potent and selective synthetic agonist of the nuclear receptor PPARα, which increases the activity of lipoprotein lipase, an enzyme essential for the hydrolysis of VLDL-C and chylomicron triglycerides, and decreases TG levels by lowering hepatic VLDL-C apolipoprotein B levels and TG production [ 31 , 32 , 33 , 34 , 35 , 36 ]. Medium-sized TRL particles have been demonstrated to enter the arterial lumen at a reduced rate compared with that of smaller LDL particles [ 37 , 38 ].…”

“…Medium-sized TRL particles have been demonstrated to enter the arterial lumen at a reduced rate compared with that of smaller LDL particles [ 37 , 38 ]. Due to their larger molecular size, triglyceride-rich lipoproteins entering the intima have greater difficulty moving against the pressure gradient than LDL particles, and are therefore preferentially trapped by arterial luminal components [ 36 , 37 , 38 , 39 ]. In fact, the pemafibrate-mediated reduction of TG and RLP-C is accompanied by slightly increased LDL-C and HDL-C with no overall change in total cholesterol levels, which is similar to the results of the PROMINENT clinical trial [ 23 ].…”