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Recently, pemafibrate, a selective PPARα modulator, has been developed as a treatment for hypertriglyceridemia and has attracted much attention. The aims of this study were to evaluate the efficacy and safety of pemafibrate in hypertriglyceridemia patients under clinical settings. We evaluated changes in lipid profiles and various parameters before and after 24-week pemafibrate administration in patients with hypertriglyceridemia who had not previously taken fibrate medications. There were 79 cases included in the analysis. 24 weeks after the treatment with pemafibrate, TG was significantly reduced from 312 ± 226 to 167 ± 94 mg/dL. In addition, lipoprotein fractionation tests using PAGE method showed a significant decrease in the ratio of VLDL and remnant fractionations, which are TG-rich lipoproteins. After pemafibrate administration, body weight, HbA1c, eGFR, and CK levels were not changed, but liver injury indices such as ALT, AST, and γ-GTP were significantly improved. In this study, pemafibrate improved the metabolism of atherosclerosis-induced lipoproteins in hypertriglyceridemia patients. In addition, it showed no off-target effects such as hepatic and renal damage or rhabdomyolysis. • Efficacy and safety of pemafibrate were evaluated in clinical settings. • Pemafibrate significantly reduced TG-rich lipoproteins and small dense LDL. • No off-target effects were observed after 24 weeks of pemafibrate administration. • Pemafibrate may have potential in the treatment of NAFLD/NASH. [ABSTRACT FROM AUTHOR]

[Display omitted] Given the significance of the intrauterine lipid environment in glucose metabolic homeostasis in offspring, the present study was undertaken to investigate the feasibility and efficacy of pemafibrate, a triglyceride-lowering peroxisome proliferator-activated agent, for maternal high-fat diet (HFD) intake-induced glucose metabolic dysfunction in offspring. A mouse model of HFD-induced gestational obesity was employed, and pemafibrate was orally administered from day 10 of gestation until delivery. The influences of maternal pemafibrate treatment on biological processes and toxicity were evaluated in both newborns and 12-week-old offspring. The findings of a dose-dependent decrease of β cell islet mass and of impairment of glucose tolerance and insulin sensitivity in offspring suggest that maternal pemafibrate intervention can prevent maternal HFD-intake-induced diabetes in offspring. Of particular interest in the prevention of future glucose metabolic dysfunction in offspring, low-dose maternal pemafibrate treatment (0.02 mg/kg/day) had sufficient efficacy and appeared to be safe in offspring. Therefore, pemafibrate may be a potential agent for the prevention of maternal high-fat exposure-induced diabetes in offspring. Abbreviations: CD, control diet; DEG, differentially expressed genes; GTT, glucose tolerance test; HFD, high-fat diet; ITT, insulin tolerance test; MC, 0.5w/v% methyl cellulose 400 solution; PPAR, triglyceride-lowering peroxisome proliferator-activated receptor; RNA-seq, RNA sequencing; TC, total cholesterol; TG, triglycerides. [ABSTRACT FROM AUTHOR]

We present here a 72-y-old Japanese woman with lipoprotein lipase (LPL) deficiency and analyzed her lipolytic enzymes in detail before and after pemafibrate treatment. She had a serum triglycerides (TG) of 22.6 mmol/l at a medical checkup at the age of 52 y. She was referred to our hospital at the age of 61 y. Her serum lipoprotein lipase (LPL) concentration was extremely low, suggesting the clinical diagnosis of LPL deficiency. She experienced an event of acute pancreatitis at the age of 65 y. Next-generation sequencing analysis revealed a homozygous nonsense mutation in the LPL gene, c.1277G > A (p.Trp409Ter). Her serum TG, LPL and hepatic lipase (HL) concentrations were 15.0 mmol/l, 23 ng/ml and 66 ng/ml, respectively. Fifteen minutes after intravenous heparin injection (30 U/kg), her serum TG, LPL and HL concentrations turned to 14.1 mmol/l, 20 ng/ml and 660 ng/ml, respectively. Eight weeks of pemafibrate treatment (0.2 mg/day) caused a modest reductions in serum TG (15.02 → 13.58 mmol/l) and considerable increases in preheparin HL (66 → 76 ng/ml) and PHP-HL (660 → 1118 ng/ml) concentrations and PHP-HL activities (253 → 369U/l) despite almost no effect on LPL concentrations and activities. These findings suggest that HL may contribute to the reduction of plasma TG in LPL deficiency. [ABSTRACT FROM AUTHOR]

Background To overcome the concerns associated with the use of fibrates, pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor modulator, was developed. In a previous phase 2 trial, we showed excellent efficacy and safety of pemafibrate in patients with dyslipidemia. Objective The objective of the study was to evaluate the efficacy and safety of pemafibrate over 24 weeks in adults with dyslipidemia in comparison with fenofibrate. Methods In this multicenter, 24-week, double-blind, clinical study, 225 patients with high triglyceride (TG; ≥150 mg/dL [1.7 mmol/L] and <500 mg/dL [5.7 mmol/L]) and relatively low high-density lipoprotein cholesterol (<50 mg/dL [1.3 mmol/L] in men or 55 mg/dL [1.4 mmol/L] in women) levels were randomized to receive either pemafibrate at 0.2 or 0.4 mg/d or fenofibrate 106.6 mg/d. Results Pemafibrate 0.2, 0.4 mg/d and fenofibrate significantly reduced TG levels from baseline by −46.2%, −45.9%, and −39.7%, respectively. As compared with fenofibrate, the least squares mean differences (95% confidence intervals) in TG were −6.5% (−12.0, −1.1) and −6.2% (−11.6, −0.8) in pemafibrate 0.2 and 0.4 mg/d respectively, which showed the superiority of these doses of pemafibrate to 106.6 mg/d of fenofibrate. The incidence rates of adverse drug reactions in pemafibrate groups (2.7% and 6.8%) were significantly lower than that in the fenofibrate group (23.7%). Pemafibrate significantly decreased alanine aminotransferase and gamma-glutamyltransferase levels, whereas fenofibrate increased both of them. The increments of serum creatinine and cystatin C were smaller in pemafibrate than those in fenofibrate. Conclusions Pemafibrate was superior to fenofibrate in terms of serum TG-lowering effect and hepatic and renal safety. [ABSTRACT FROM AUTHOR]

Background and aims Substantial residual cardiovascular risks remain despite intensive statin treatment. Residual risks with high triglyceride and low high-density lipoprotein cholesterol are not the primary targets of statins. K-877 (pemafibrate) demonstrated robust efficacy on triglycerides and high-density lipoprotein cholesterol and a good safety profile as a monotherapy. The aim of these studies was to evaluate the efficacy and safety of K-877 add-on therapy to treat residual hypertriglyceridaemia during statin treatment. Methods The objectives were investigated in two, multicentre, randomised, double-blind, placebo-controlled, parallel group comparison clinical trials: (A) K-877 0.1, 0.2, and 0.4 mg/day in combination with pitavastatin for 12 weeks in 188 patients, (B) K-877 0.2 (fixed dose) and 0.2 (0.4) (conditional up-titration) mg/day in combination with any statin for 24 weeks in 423 patients. Results In both studies, we found a robust reduction in fasting triglyceride levels by approximately 50% in all combination therapy groups, which was significant compared to the statin-monotherapy (placebo) groups ( p < 0.001). High-performance liquid chromatography analysis for lipoprotein subfractions revealed that atherogenic lipoprotein profiles were ameliorated by K-877 add-on therapy, i.e. small low-density lipoproteins decreased whereas larger ones increased, and larger high-density lipoproteins decreased whereas smaller ones increased. The incidence rates of adverse events and adverse drug reactions in K-877 combination therapy groups were comparable to those in statin-monotherapy groups without any noteworthy event in both studies. Conclusions These results strongly support the favourable benefit-to-risk ratio of K-877 add-on therapy in combination with statin treatment. [ABSTRACT FROM AUTHOR]

Peroxisome proliferator-activated receptor-alpha (PPARα) levels are markedly lower in the kidneys of chronic kidney disease (CKD) patients. Fibrates (PPARα agonists) are therapeutic agents against hypertriglyceridemia and potentially against CKD. However, conventional fibrates are eliminated by renal excretion, limiting their use in patients with impaired renal function. Here, we aimed to evaluate the renal risks associated with conventional fibrates via clinical database analysis and investigate the renoprotective effects of pemafibrate, a novel selective PPARα modulator mainly excreted into the bile. The risks associated with conventional fibrates (fenofibrate, bezafibrate) to the kidneys were evaluated using the Food and Drug Administration Adverse Event Reporting System. Pemafibrate (1 or 0.3 mg/kg/day) was administered daily using an oral sonde. Its renoprotective effects were examined in unilateral ureteral obstruction (UUO)-induced renal fibrosis model mice (UUO mice) and adenine-induced CKD model mice (CKD mice). The ratios of glomerular filtration rate decreased and blood creatinine increased were markedly higher after conventional fibrate use. Pemafibrate administration suppressed increased gene expressions of collagen-I, fibronectin, and interleukin 1 beta (IL-1β) in the kidneys of UUO mice. In CKD mice, it suppressed increased plasma creatinine and blood urea nitrogen levels and decreased red blood cell count, hemoglobin, and hematocrit levels, along with renal fibrosis. Moreover, it inhibited the upregulation of monocyte chemoattractant protein-1, IL-1β, tumor necrosis factor-alpha, and IL-6 in the kidneys of CKD mice. These results demonstrated the renoprotective effects of pemafibrate in CKD mice, confirming its potential as a therapeutic agent for renal disorders. [Display omitted] • Pemafibrate is a highly active and selective PPARα agonist excreted in bile. • Pemafibrate suppressed renal dysfunction and anemia in adenine-induced CKD mice. • Pemafibrate suppressed increased plasma creatinine and blood urea nitrogen levels. • Pemafibrate is a potential treatment choice for chronic kidney disease. [ABSTRACT FROM AUTHOR]

Background Atherosclerosis is characterized by lipid accumulation and chronic inflammation in the arterial wall. Elevated levels of apolipoprotein (apo) B-containing lipoproteins are a risk factor for cardiovascular disease (CVD). By contrast, plasma levels of functional high-density lipoprotein (HDL) and apoA-I are protective against CVD by enhancing reverse cholesterol transport (RCT). Activation of peroxisome proliferator-activated receptor-α (PPARα), a ligand-activated transcription factor, controls lipid metabolism, cellular cholesterol trafficking in macrophages and influences inflammation. Objective To study whether pharmacological activation of PPARα with a novel highly potent and selective PPARα modulator, pemafibrate, improves lipid metabolism, macrophage cholesterol efflux, inflammation and consequently atherosclerosis development in vitro and in vivo using human apolipoprotein E2 Knock-In (apoE2KI) and human apoA-I transgenic (hapoA-I tg) mice. Approach and results Pemafibrate treatment decreases apoB secretion in chylomicrons by polarized Caco-2/TC7 intestinal epithelium cells and reduces triglyceride levels in apoE2KI mice. Pemafibrate treatment of hapoA-I tg mice increases plasma HDL cholesterol, apoA-I and stimulates RCT to feces. In primary human macrophages, pemafibrate promotes macrophage cholesterol efflux to HDL and exerts anti-inflammatory activities. Pemafibrate also reduces markers of inflammation and macrophages in the aortic crosses as well as aortic atherosclerotic lesion burden in western diet-fed apoE2KI mice. Conclusions These results demonstrate that the novel selective PPARα modulator pemafibrate exerts beneficial effects on lipid metabolism, RCT and inflammation resulting in anti-atherogenic properties. [ABSTRACT FROM AUTHOR]

Background and aims To assess the efficacy and safety of K-877 (Pemafibrate), a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that possesses unique PPARα activity and selectivity, compared with placebo and fenofibrate in dyslipidaemic patients with high triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) levels. Methods and results This study was a double blind, placebo-controlled, parallel-group 12-week clinical trial. The study randomized 224 patients to K-877 0.025, 0.05, 0.1, 0.2 mg BID, fenofibrate 100 mg QD, or placebo (1:1:1:1:1:1) groups. Least squares mean percent changes from the baseline TG levels were −30.9%, −36.4%, −42.6%, −42.7% for the K-877 0.025, 0.05, 0.1, 0.2 mg BID respectively (p < 0.001), which were greater than that of the fenofibrate 100 mg QD (−29.7%, p < 0.001) group. Statistically significant improvements from the baseline HDL-C, very-low-density lipoprotein cholesterol, chylomicron cholesterol, remnant lipoprotein cholesterol, apolipoprotein (apo) B (apoB), and apoC-III were also observed in the K-877 groups. The incidence of adverse events (AEs) in the K-877 groups (32.4–56.8%) was comparable to those in placebo (47.2%) and fenofibrate 100 mg QD (56.8%); adverse drug reactions (ADRs) in the K-877 groups (2.7–5.4%) were less than those in placebo (8.3%) and fenofibrate 100 mg QD (10.8%) groups. Conclusion In dyslipidaemic patients with high TG and low HDL-C, K-877 improved TG, HDL-C, and other lipid parameters without increasing AEs or ADRs, compared to placebo and fenofibrate. K-877 can be expected to improve atherogenicity and to be a new beneficial treatment for dyslipidaemic patients. [ABSTRACT FROM AUTHOR]

Aims: Pemafibrate, a novel selective peroxisome proliferator-activated receptor modulator, was shown to ameliorate lipid abnormalities in a phase III clinical trial of patients with type 2 diabetes mellitus (T2DM). However, its efficacy has not been demonstrated in real-world clinical practice in patients with T2DM.Methods: We performed a multi-center prospective observational study of the use of pemafibrate in patients with T2DM and hypertriglyceridemia versus conventional therapy, with or without a fibrate. The primary outcomes were the changes from baseline in fasting serum triglyceride (TG) and high-density lipoprotein-cholesterol (HDL-C) concentrations at week 52.Results: We recruited 650 patients, and data from 504 (252 per group) were analyzed after propensity score matching. In the pemafibrate group, both TG and HDL-C showed significant improvements (p < 0.001), and several indices reflecting TG-rich lipoproteins, low-density lipoprotein-cholesterol particle size, and liver enzyme elevations were significantly ameliorated compared with the control group, but there was no difference in glycemic control markers. One of the key secondary endpoints showed that switching from conventional fibrates to pemafibrate improved eGFR but increased uric acid concentration.Conclusions: In patients with T2DM, pemafibrate has superior effects on lipid profile as well as liver and renal dysfunction to conventional fibrates. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis is a chronic progressive disease associated with substantial morbidity and mortality despite advances in medical therapy. Increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs) play important roles in the fibrosis-related diseases and their agonists may become effective therapeutic targets. Pemafibrate is a selective PPARα agonist, but the efficacy against pulmonary fibrosis and mechanisms involved have not been systematically evaluated. Thus, the aims of this study were to explore the role of PPARα in the pulmonary fibrosis and to assess the effect of pemafibrate in vivo and in vitro. The effects of pemafibrate were evaluated in bleomycin-challenged murine pulmonary fibrosis model and transforming growth factor-beta 1 (TGF-β1) stimulated lung fibroblasts. Bleomycin instillation induced body weight loss, declined lung function, pulmonary fibrosis, and extensive collagen deposition in the mice, accompanied with decreased pulmonary expression of PPARα, all of which were partially improved by pemafibrate at a dose of 2 mg/kg. Besides, pemafibrate effectively inhibits TGF-β1-induced myofibroblast differentiation and extracellular matrix (ECM) production in vivo and in vitro. Furthermore, we showed that pemafibrate not only inhibited pulmonary expression of NLRP3 and cleaved caspase-1 in bleomycin-inhaled mice, but also repressed activation of NLRP3/caspase-1 axis in TGF-β1 stimulated lung fibroblasts. Our data suggest that pemafibrate exerts a marked protection against from the development of pulmonary fibrosis, which could constitute a novel candidate for the treatment for pulmonary fibrosis. [ABSTRACT FROM AUTHOR]

Ezetimibe and pemafibrate are lipid-lowering drugs and promote reverse cholesterol transport. However, it is unknown whether cholesterol is mainly excreted by hepatobiliary excretion or by non-biliary transintestinal cholesterol efflux (TICE). We evaluated the effects of ezetimibe and pemafibrate on hepatic and intestinal cholesterol transporter regulation in Sham-operated rats, and examined the effects of these drugs on TICE in bile duct-ligated rats. Seven-week-old male Sprague-Dawley rats were treated as follows for two weeks: 1) Sham, Sham operation; 2) BDL, bile duct ligation; 3) E-Sham, Sham + ezetimibe; 4) E-BDL, BDL + ezetimibe; 5) P-Sham, Sham + pemafibrate; and 6) P-BDL, BDL + pemafibrate. Blood, liver, jejunum, and feces were collected 72 h post-surgery. Hepatic cholesterol levels were decreased in P-Sham and E-Sham, and were lower in E-BDL and P-BDL than in BDL. Fecal cholesterol levels increased in E-Sham and P-Sham compared with Sham, and were higher in E-BDL and P-BDL than in BDL. In liver, Abcg5 mRNA showed induction in E-Sham, Abcg5 and Abca1 mRNA were induced in P-Sham, Abcg5 mRNA was reduced in E -BDL, and Abca1 mRNA was increased in P-BDL. In jejunum, Abcg5 mRNA was induced in E-Sham. Abcg8 mRNA was induced in E-Sham and P-Sham. NPC1L1 mRNA showed reduced expression in P-Sham and P-BDL. SR-B1 mRNA was reduced in P-Sham, and the expression decreased in P-BDL. LDL receptor mRNA was induced in BDL and P-BDL. Ezetimibe and pemafibrate may promote TICE by increasing Abcg5/g8, while pemafibrate may inhibit intestinal cholesterol absorption by decreasing SR-B1 and NPC1L1. • Ezetimibe and pemafibrate exert on cholesterol efflux via TICE as well as biliary route. • TICE can be stimulated by ezetimibe and pemafibrate by inducing intestinal Abcg5/g8. • Pemafibrate may block intestinal cholesterol absorption by reducing SR-B1 and NPC1L1. [ABSTRACT FROM AUTHOR]

Background Cardiovascular risk is negatively correlated with cholesterol efflux capacity (CEC) from macrophages to high-density lipoproteins (HDLs) and positively correlated with fasting and nonfasting triglyceride-rich lipoproteins (TRLs). Pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator, robustly decreases the fasting TRL level, increases the HDL cholesterol (HDL-C) level, and improves the atherogenic lipoprotein subclass profile, with an adverse event rate comparable to that of placebo treatment in previous clinical studies. Objective This study aimed to investigate the effects of pemafibrate on CEC and postprandial hyperlipidemia. Methods Using a single-center, double-blind, randomized, two-by-two crossover design, 33 patients were assigned to receive either 0.4 mg/d pemafibrate (twice daily) or placebo first. The assigned study drug was administered for 4 weeks. Subsequently, the alternate study drug was administered for another 4 weeks. CEC was measured using HDLs obtained from fasting blood samples. A meal tolerance test was performed to examine the postprandial lipid levels at weeks 0, 4, and 8. Results CEC, HDL-C, and apolipoprotein A-I levels increased after pemafibrate treatment compared with placebo administration. Moreover, the percent change in CEC was correlated with that of HDL-C and apolipoprotein A-I levels. TRL levels markedly decreased after pemafibrate treatment in both fasting and nonfasting states. Conclusions These findings suggest that pemafibrate enhances reverse cholesterol transport and may retard the progression and even promote the regression of atherosclerosis by comprehensively ameliorating the atherogenic lipid profile. Graphical abstract Highlights • Pemafibrate increases cholesterol efflux capacity of high-density lipoprotein (HDL) from macrophages. • Pemafibrate increases HDL-cholesterol (HDL-C), HDL 3 -C, preβ1 HDL, and apoA-I levels. • HDL-C, HDL 2 -C, and apoA-I levels are correlated with cholesterol efflux capacity. • Pemafibrate ameliorates both fasting and postprandial hyperlipidemia. • These effects may cooperatively retard atherosclerosis progression. [ABSTRACT FROM AUTHOR]