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

Abstract

<strong>Background </strong>High plasma triglyceride (TG) is an independent risk factor for cardiovascular disease. Fibrates lower TG-levels through PPARα agonism. Currently available fibrates, however, have relatively low selectivity for PPARα.<b></b> <p><strong>Objectives</strong> 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.<b></b></p> <p><strong>Methods A total of </strong>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-C ≤50 mg/dL for men and ≤55 mg/dL for women. Participants were randomized to receive placebo or one of 6 pemafibrate regimens: 0.05 mg BID, 0.1 mg BID, 0.2 mg BID, 0.1 mg QD, 0.2 mg QD, or 0.4 mg QD. The primary endpoints were TG and non-HDL-C level lowering at Week 12.<b></b></p> <p><b>Results</b><b></b></p> <p>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 BID 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-C levels, whereas apoB100 was unchanged. Pemafibrate was safe and well-tolerated, with only minor increases in serum creatinine and homocysteine concentrations.</p> <p><b>Conclusion</b></p> <p>Pemafibrate is effective, safe, and well-tolerated for the reduction of TG in European populations with hypertriglyceridemia despite statin treatment.</p>

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 [PROMI-NENT], NCT03071692) started from March, 2017 [56].…”

The Remnant Lipoprotein Hypothesis of Diabetes-Associated Cardiovascular Disease

“…In this context, it is of note that a recent phase 2 trial on subjects on statins treated with the new triglyceride-lowering PPARα modulator pemafibrate convincingly showed reduced levels of triglycerides, APOC3, and RLPs. 106 Although this 12-week trial suggested that pemafibrate might be effective in preventing CVD events, discontinuation of the large PROMINENT trial (Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients With Diabetes) was announced in April, 2022, because the primary end point (major CVD event) was unlikely to be met. This trial included subjects with T2D and dyslipidemia.…”

“…92 Accordingly, pemafibrate reduced APOC3 but increased LDL cholesterol (leaving total APOB100 levels unchanged) in the phase 2 trial. 106 RLP lowering is unlikely to be effective in preventing CVD risk if it only results in conversion to LDL without efficient removal. RLP lowering leading to increases in LDL cholesterol levels and unchanged total APOB100 levels many not be effective.…”

“…Differential ion mobility analysis may offer a powerful approach for quantifying RLPs and has recently been used to evaluate RLP levels and sizes in humans. 50,106 Analyzing RLPs in mice is even more challenging because there is no clear separation of TRLs, RLPs, and LDL by density ultracentrifugation or differential ion mobility analysis in Ldlr −/− mice. Moreover, contrary to humans who produce APOB48 only in the intestine, making it possible to identify chylomicron remnants by the presence of APOB48 (rather than full-length APOB100-containing VLDL derived from the liver), >75% of serum APOB48 is derived from the liver in mice.…”