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Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-? Modulator (SPPARM?), in Dyslipidemic Patients with Renal Impairment.

ABSTRACT: Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-? modulator (SPPARM?) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2?0.4 mg/day pemafibrate was administered for 52 weeks to 189 patients with hypertriglyceridemia and an estimated glomerular filtration rate (eGFR) ? 45 mL/min/1.73 m² on statin or regardless of eGFR when statin was not administered. Post-hoc analyses were performed on subgroups stratified by baseline eGFR. Triglyceride levels decreased by 45.9% at week 52 (last-observation-carried-forward). These reductions were not correlated with baseline eGFR. The eGFR < 30 mL/min/1.73 m² subgroup showed the greatest reduction in chylomicron, very low-density lipoprotein, small low-density lipoprotein cholesterol levels, and an increase in high-density lipoprotein cholesterol levels. The incidences of adverse events and adverse drug reactions were 82.0% and 31.7%, respectively, and these were not associated with baseline eGFR. In CKD patients, pemafibrate blood concentrations were not elevated. Pemafibrate showed a good safety profile and efficacy in correcting lipid abnormalities in a broad range of patients, including those with CKD.

SUBMITTER: Yokote K

PROVIDER: S-EPMC6386904 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment.

Yokote Koutaro K Yamashita Shizuya S Arai Hidenori H Araki Eiichi E Suganami Hideki H Ishibashi Shun S Of The K-Study Group On Behalf OB

International journal of molecular sciences 20190206 3

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor-α modulator (SPPARMα) with a favorable benefit-risk balance. Previous clinical trials of pemafibrate used stringent exclusion criteria related to renal functions. Therefore, we investigated its safety and efficacy in a broader range of patients, including those with chronic kidney disease (CKD). In this multicenter, single-arm, open-label, phase III trial, 0.2⁻0.4 mg/day pemafibrate was administered for 52 weeks ...[more]

PMID: 30736366

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Project description:BACKGROUND New pharmacological approaches are needed to prevent stent restenosis. This study tested the hypothesis that pemafibrate, a novel clinical selective PPARα (peroxisome proliferator-activated receptor α) agonist, suppresses coronary stent-induced arterial inflammation and neointimal hyperplasia. METHODS AND RESULTS Yorkshire pigs randomly received either oral pemafibrate (30 mg/day; n=6) or control vehicle (n=7) for 7 days, followed by coronary arterial implantation of 3.5 × 12 mm bare metal stents (2-4 per animal; 44 stents total). On day 7, intracoronary molecular-structural near-infrared fluorescence and optical coherence tomography imaging was performed to assess the arterial inflammatory response, demonstrating that pemafibrate reduced stent-induced inflammatory protease activity (near-infrared fluorescence target-to-background ratio: pemafibrate, median [25th-75th percentile]: 2.8 [2.5-3.3] versus control, 4.1 [3.3-4.3], P=0.02). At day 28, animals underwent repeat near-infrared fluorescence-optical coherence tomography imaging and were euthanized, and coronary stent tissue molecular and histological analyses. Day 28 optical coherence tomography imaging showed that pemafibrate significantly reduced stent neointima volume (pemafibrate, 43.1 [33.7-54.1] mm3 versus control, 54.2 [41.2-81.1] mm3; P=0.03). In addition, pemafibrate suppressed day 28 stent-induced cellular inflammation and neointima expression of the inflammatory mediators TNF-α (tumor necrosis factor-α) and MMP-9 (matrix metalloproteinase 9) and enhanced the smooth muscle differentiation markers calponin and smoothelin. In vitro assays indicated that the STAT3 (signal transducer and activator of transcription 3)-myocardin axes mediated the inhibitory effects of pemafibrate on smooth muscle cell proliferation. CONCLUSIONS Pemafibrate reduces preclinical coronary stent inflammation and neointimal hyperplasia following bare metal stent deployment. These results motivate further trials evaluating pemafibrate as a new strategy to prevent clinical stent restenosis.

Dataset Information

Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-? Modulator (SPPARM?), in Dyslipidemic Patients with Renal Impairment.

Publications

Long-Term Efficacy and Safety of Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated Receptor-α Modulator (SPPARMα), in Dyslipidemic Patients with Renal Impairment.

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