Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Yamashita, Shizuya; Arai, Hidenori; Yokote, Koutaro; Araki, Eiichi; Suganami, Hideki; Ishibashi, Shun

doi:10.1016/j.jacl.2018.06.010

Cited by 45 publications

(37 citation statements)

References 60 publications

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“…Pemafibrate robustly decreases serum TG levels in fasting and non-fasting or postprandial states and increases serum HDL-C levels [22,23]. Moreover, pemafibrate was superior to fenofibrate in terms of serum TG-lowering effect and hepatic and renal safety [22].…”

Section: Introductionmentioning

confidence: 99%

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Yoshida

Nakamura

Miyoshi

et al. 2020

Cardiovasc Diabetol

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Background Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Methods Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. Results After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. Conclusions Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

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Section: Introductionmentioning

confidence: 99%

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Yoshida

Nakamura

Miyoshi

et al. 2020

Cardiovasc Diabetol

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“… 127) 128) It seems that pemafibrate also enhances reverse cholesterol transport from macrophages to HDL particles and exerts anti-inflammatory activities thus possibly retarding the progression and even promoting the regression of atherosclerosis. 129) 130) Pemafibrate also improves insulin sensitivity by splanchnic glucose uptake from baseline in patients with elevated plasma TGs. 131) In a head-to-head comparison pemafibrate has fewer adverse effects on kidney/liver-related laboratory tests and fewer adverse drug reactions, including those leading to treatment discontinuation, over fenofibrate 200 mg/day.…”

Section: Novel Possibilities For Anti-atherosclerotic Therapy By Lowementioning

confidence: 99%

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Reiner

2018

Korean Circ J

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Although elevated serum low-density lipoprotein-cholesterol (LDL-C) is without any doubts accepted as an important risk factor for cardiovascular disease (CVD), the role of elevated triglycerides (TGs)-rich lipoproteins as an independent risk factor has until recently been quite controversial. Recent data strongly suggest that elevated TG-rich lipoproteins are an independent risk factor for CVD and that therapeutic targeting of them could possibly provide further benefit in reducing CVD morbidity, events and mortality, apart from LDL-C lowering. Today elevated TGs are treated with lifestyle interventions, and with fibrates which could be combined with omega-3 fatty acids. There are also some new drugs. Volanesorsen, is an antisense oligonucleotid that inhibits the production of the Apo C-III which is crucial in regulating TGs metabolism because it inhibits lipoprotein lipase (LPL) and hepatic lipase activity but also hepatic uptake of TGs-rich particles. Evinacumab is a monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) and it seems that it can substantially lower elevated TGs levels because ANGPTL3 also regulates TGs metabolism. Pemafibrate is a selective peroxisome proliferator-activated receptor alpha modulator which also decreases TGs, and improves other lipid parameters. It seems that it also has some other possible antiatherogenic effects. Alipogene tiparvovec is a nonreplicating adeno-associated viral vector that delivers copies of the LPL gene to muscle tissue which accelerates the clearance of TG-rich lipoproteins thus decreasing extremely high TGs levels. Pradigastat is a novel diacylglycerol acyltransferase 1 inhibitor which substantially reduces extremely high TGs levels and appears to be promising in treatment of the rare familial chylomicronemia syndrome.

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“…Pema brate robustly decreases serum TG levels in fasting and non-fasting or postprandial states and increases serum HDL-C levels [22,23]. Moreover, pema brate was superior to feno brate in terms of serum TG-lowering effect and hepatic and renal safety [22].…”

Section: Introductionmentioning

confidence: 99%

Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet

Yoshida

Nakamura

Miyoshi

et al. 2020

Preprint

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Background: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.Methods: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.Results: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.Conclusions: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

show abstract

Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Abstract: 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.

Cited by 45 publications

References 60 publications

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet

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Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia

Abstract: 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.

Cited by 45 publications

References 60 publications

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

Triglyceride-Rich Lipoproteins and Novel Targets for Anti-atherosclerotic Therapy

Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet​

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Combination Therapy with Pemafibrate (K-877) and Pitavastatin Improves Vascular Endothelial Dysfunction in Dahl/Salt-sensitive Rats Fed a High-salt and High-fat Diet