Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52‐week data from the PROVIDE study

Araki, Eiichi; Yamashita, Shizuya; Arai, Hidenori; Yokote, Koutaro; Satoh, Jo; Inoguchi, Toyoshi; Nakamura, Jiro; Maegawa, Hiroshi; Yoshioka, Narihito; Tanizawa, Yukio; Watada, Hirotaka; Suganami, Hideki; Ishibashi, Shun

doi:10.1111/dom.13686

Cited by 36 publications

(20 citation statements)

References 15 publications

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“…Its higher efficacy over fenofibrate has been confirmed by several clinical trials in Japan [ 155 – 158 ]. The safety profile of pemafibrate has shown no clinically adverse effects on renal or hepatic function [ 157 , 159 ], and it is well tolerated over 52 weeks in T2D patients with hypertriglyceridemia [ 159 ], and in patients with impaired kidney function [ 160 ]. Importantly, pemafibrate does not show any drug interactions with various statins as demonstrated in two clinical studies [ 161 ].…”

Section: Current Therapeutic Options Related To Pparα For Treating DCmentioning

confidence: 99%

Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy

Wang

Cai

Jian

et al. 2021

Cardiovasc Diabetol

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The prevalence of cardiomyopathy is higher in diabetic patients than those without diabetes. Diabetic cardiomyopathy (DCM) is defined as a clinical condition of abnormal myocardial structure and performance in diabetic patients without other cardiac risk factors, such as coronary artery disease, hypertension, and significant valvular disease. Multiple molecular events contribute to the development of DCM, which include the alterations in energy metabolism (fatty acid, glucose, ketone and branched chain amino acids) and the abnormalities of subcellular components in the heart, such as impaired insulin signaling, increased oxidative stress, calcium mishandling and inflammation. There are no specific drugs in treating DCM despite of decades of basic and clinical investigations. This is, in part, due to the lack of our understanding as to how heart failure initiates and develops, especially in diabetic patients without an underlying ischemic cause. Some of the traditional anti-diabetic or lipid-lowering agents aimed at shifting the balance of cardiac metabolism from utilizing fat to glucose have been shown inadequately targeting multiple aspects of the conditions. Peroxisome proliferator-activated receptor α (PPARα), a transcription factor, plays an important role in mediating DCM-related molecular events. Pharmacological targeting of PPARα activation has been demonstrated to be one of the important strategies for patients with diabetes, metabolic syndrome, and atherosclerotic cardiovascular diseases. The aim of this review is to provide a contemporary view of PPARα in association with the underlying pathophysiological changes in DCM. We discuss the PPARα-related drugs in clinical applications and facts related to the drugs that may be considered as risky (such as fenofibrate, bezafibrate, clofibrate) or safe (pemafibrate, metformin and glucagon-like peptide 1-receptor agonists) or having the potential (sodium–glucose co-transporter 2 inhibitor) in treating DCM.

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Section: Current Therapeutic Options Related To Pparα For Treating DCmentioning

confidence: 99%

Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy

Wang

Cai

Jian

et al. 2021

Cardiovasc Diabetol

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“…Pemafibrate was approved in Japan 2017 for the treatment of dyslipidemia [28,29,30,31,32,33,34,35,36,37,38]. A phase II study showed that 0.05–0.4 mg/day pemafibrate significantly reduced plasma TG levels (−30.9% to −42.7%) and increased HDL-C levels (11.9% to 21.0%) [29].…”

Section: Pemafibrate As a Novel Spparmαmentioning

confidence: 99%

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate

Sasaki

Raza-Iqbal

Tanaka

et al. 2019

IJMS

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Pemafibrate is the first clinically-available selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that has been shown to effectively improve hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) levels. Global gene expression analysis reveals that the activation of PPARα by pemafibrate induces fatty acid (FA) uptake, binding, and mitochondrial or peroxisomal oxidation as well as ketogenesis in mouse liver. Pemafibrate most profoundly induces HMGCS2 and PDK4, which regulate the rate-limiting step of ketogenesis and glucose oxidation, respectively, compared to other fatty acid metabolic genes in human hepatocytes. This suggests that PPARα plays a crucial role in nutrient flux in the human liver. Additionally, pemafibrate induces clinically favorable genes, such as ABCA1, FGF21, and VLDLR. Furthermore, pemafibrate shows anti-inflammatory effects in vascular endothelial cells. Pemafibrate is predicted to exhibit beneficial effects in patients with atherogenic dyslipidemia and diabetic microvascular complications.

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“…In LDL receptor knockout mice, pemafibrate decreased apoC3 expression and increased plasma LPL activity suggesting increased clearance capacity (79). Similarly, Araki et al observed decreased plasma apoC3 in patients with T2D treated with pemafibrate (77). These studies suggest that pemafibrate could effectively modulate CM production to treat diabetic dyslipidemia.…”

Section: Effects Of Currently Approved Lipid Modifying and Antidiabetmentioning

confidence: 88%

Role of the Gut in Diabetic Dyslipidemia

et al. 2020

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Type 2 diabetes (T2D) is associated with increased risk of cardiovascular disease (CVD). In insulin resistant states such as the metabolic syndrome, overproduction and impaired clearance of liver-derived very-low-density lipoproteins and gut-derived chylomicrons (CMs) contribute to hypertriglyceridemia and elevated atherogenic remnant lipoproteins. Although ingested fat is the major stimulus of CM secretion, intestinal lipid handling and ultimately CM secretory rate is determined by numerous additional regulatory inputs including nutrients, hormones and neural signals that fine tune CM secretion during fasted and fed states. Insulin resistance and T2D represent perturbed metabolic states in which intestinal sensitivity to key regulatory hormones such as insulin, leptin and glucagon-like peptide-1 (GLP-1) may be altered, contributing to increased CM secretion. In this review, we describe the evidence from human and animal models demonstrating increased CM secretion in insulin resistance and T2D and discuss the molecular mechanisms underlying these effects. Several novel compounds are in various stages of preclinical and clinical investigation to modulate intestinal CM synthesis and secretion. Their efficacy, safety and therapeutic utility are discussed. Similarly, the effects of currently approved lipid modulating therapies such as statins, ezetimibe, fibrates, and PCSK9 inhibitors on intestinal CM production are discussed. The intricacies of intestinal CM production are an active area of research that may yield novel therapies to prevent atherosclerotic CVD in insulin resistance and T2D.

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Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52‐week data from the PROVIDE study

Cited by 36 publications

References 15 publications

Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy

Impact of peroxisome proliferator-activated receptor-α on diabetic cardiomyopathy

Gene Expression Profiles Induced by a Novel Selective Peroxisome Proliferator-Activated Receptor α Modulator (SPPARMα) Pemafibrate

Role of the Gut in Diabetic Dyslipidemia

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