DOCSLIB.ORG

Pemafibrate (K-877), a Novel Selective Peroxisome Proliferator-Activated

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Pemafibrate (K-877), a Novel Selective Peroxisome Proliferator-Activated Fruchart Cardiovasc Diabetol (2017) 16:124 DOI 10.1186/s12933-017-0602-y Cardiovascular Diabetology REVIEW Open Access Pemafbrate (K‑877), a novel selective peroxisome proliferator‑activated receptor alpha modulator for management of atherogenic dyslipidaemia Jean‑Charles Fruchart* Abstract Despite best evidence-based treatment including statins, residual cardiovascular risk poses a major challenge for clini‑ cians in the twenty frst century. Atherogenic dyslipidaemia, in particular elevated triglycerides, a marker for increased triglyceride-rich lipoproteins and their remnants, is an important contributor to lipid-related residual risk, especially in insulin resistant conditions such as type 2 diabetes mellitus. Current therapeutic options include peroxisome proliferator-activated receptor alpha (PPARα) agonists, (fbrates), but these have low potency and limited selectivity for PPARα. Modulating the unique receptor–cofactor binding profle to identify the most potent molecules that induce PPARα-mediated benefcial efects, while at the same time avoiding unwanted side efects, ofers a new therapeutic approach and provides the rationale for development of pemafbrate (K-877, Parmodia™), a novel selective PPARα modulator (SPPARMα). In clinical trials, pemafbrate either as monotherapy or as add-on to statin therapy was efec‑ tive in managing atherogenic dyslipidaemia, with marked reduction of triglycerides, remnant cholesterol and apoli‑ poprotein CIII. Pemafbrate also increased serum fbroblast growth factor 21, implicated in metabolic homeostasis. There were no clinically meaningful adverse efects on hepatic or renal function, including no relevant serum creati‑ nine elevation. A major outcomes study, PROMINENT, will provide defnitive evaluation of the role of pemafbrate for management of residual cardiovascular risk in type 2 diabetes patients with atherogenic dyslipidaemia despite statin therapy. Keywords: Peroxisome proliferator-activated receptor alpha, SPPARM, K-877, Pemafbrate, Fibrates, Residual cardiovascular risk, Triglycerides, Atherogenic dyslipidaemia Background trillion dollars by 2030 [5], will be in regions which can ill Preventing cardiovascular disease (CVD) is a key chal- aford such costs. lenge facing clinicians world-wide this century. Despite Low-density lipoprotein cholesterol (LDL-C) is improvement in CVD mortality in developed regions, undoubtedly the primary priority for lipid manage- low to middle-income countries have a growing burden ment to prevent CVD [6, 7]. Statins, the cornerstone of of CVD mortality and disability, driven by increasing LDL-C lowering therapy, have proven efcacy in reduc- rates of obesity, diabetes and dyslipidaemia [1–3]. Indeed, ing the risk of a CVD event by 20–30%, but still leave a with the exception of the USA, the top 10 countries for high residual cardiovascular risk [8]. In part, this may diabetes prevalence in 2040 will be emerging economies, be reduced by further lowering of LDL-C with non- led by China and India [4]. Consequently, much of the statin therapy, as shown by the Examining Outcomes future societal burden of CVD, estimated to exceed one in Subjects With Acute Coronary Syndrome: Vytorin Ezetimibe/Simvastatin) vs Simvastatin (IMPROVE-IT) *Correspondence: jean‑[email protected] trial with ezetimibe [9], and the Further Cardiovascular R3i Foundation, St. Alban‑Anlage 46, Basel, Switzerland Outcomes Research With PCSK9 Inhibition in Subjects © The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/ publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Fruchart Cardiovasc Diabetol (2017) 16:124 Page 2 of 12 With Elevated Risk (FOURIER) trial with evolocumab atherogenic dyslipidaemia, typically associated with [10]; however, there is also the need to consider other insulin resistant conditions [7, 23]. While evidence in lipid abnormalities. A growing body of evidence high- both primary and secondary prevention settings is sup- lights the relevance of atherogenic dyslipidaemia, char- portive of their use [24, 25], the lack of a defnitive mor- acterised by increased triglyceride (TG)-rich lipoproteins tality beneft has led many clinicians to view these agents and their remnants (for which elevated TGs are a metric), as ‘second choice’. Despite this, there is support from often with subnormal plasma concentrations of high- subgroup analyses of the major fbrate trials that target- density lipoprotein cholesterol (HDL-C), and an increase ing these treatments to patients with atherogenic dyslip- in small dense LDL particle numbers, typically seen in idaemia signifcantly reduces CVD risk (with or without insulin resistant conditions such as type 2 diabetes mel- statin treatment) [26]; the ACCORDION study, involv- litus, as a contributor to lipid-related residual cardio- ing passive extended follow-up of the Action to Con- vascular risk, as well as the risk of silent coronary artery trol Cardiovascular Risk in Diabetes (ACCORD) study, disease [11–13]. Overproduction of very low-density showed that this beneft persisted over the long-term lipoproteins (VLDL), with increased secretion of TGs [27]. Additionally, the Bezafbrate Infarction Prevention and apolipoprotein (apo) B100, appears to be a key driver (BIP) study showed long-term beneft in reducing mor- of this dyslipidaemia. tality, more so in individuals with baseline hypertriglyc- Inhibition of cholesteryl ester transfer protein (CETP), eridaemia [28]. which mediates the heteroexchange of triglycerides from With escalating rates of diabetes, obesity and CVD, VLDL or LDL and cholesteryl esters from HDL, was con- especially in developing regions, management of ath- sidered a possible therapeutic approach. However, the erogenic dyslipidaemia, as well as metabolic abnormali- frst three CETP inhibitors had either safety issues (torce- ties and chronic infammation typically associated with trapib) or no efect on clinical cardiovascular outcomes these conditions, is now a priority for reducing residual in high-risk patients (dalcetrapib, evacetrapib) [14–16]. cardiovascular risk. Tis scenario highlights the need for Te last of these agents, anacetrapib, was very recently new therapeutic options. Selective PPARα modulators– shown to have a modest albeit statistically signifcant SPPARMα agents—could well provide one approach to beneft over 4 years in the Randomized EValuation of resolving this challenge, and ofer a more accessible ther- the Efects of Anacetrapib Trough Lipid-modifcation apeutic approach to managing this dyslipidaemia [29]. (REVEAL) trial, although the role of HDL-raising in this outcome remains a matter for scientifc conjecture [17]. Search strategy Tere has also been a renewed focus on the management Tis review describes the profle of a novel SPPARMα, of elevated TGs and remnant cholesterol (the cholesterol determined using a search methodology as follows. Te contained in TG-rich lipoproteins). Support for the ath- literature was searched using Medline, Current Contents, erogenicity of remnant cholesterol is based on the totality PubMed, and relevant references with the terms ‘residual of evidence from observational studies showing an asso- cardiovascular risk’, ‘peroxisome proliferator-activated ciation between elevated remnant cholesterol and ischae- receptor’, ‘pemafbrate’, ‘K-877’, ‘atherogenic dyslipidae- mic heart disease, as well as genetic insights which show mia’, ‘triglycerides’, ‘type 2 diabetes’, ‘clinical trials.’ Main that remnant cholesterol is causal for ischaemic heart articles published in English between 2000 and 2017 were disease independent of HDL-C [18, 19]. Most recently, reviewed and included. Te author also requested infor- remnant cholesterol has been implicated as a contributor mation regarding clinical trials and preclinical studies to the increased CVD risk associated with obesity [20]. with pemafbrate from Kowa Company, Ltd., Japan. Tese fndings have prompted a rethink of the role of lipid targets beyond LDL-C, with for example, the Amer- New thinking: the rationale for SPPARMs ican Diabetes Association recommending TG-lowering PPARs are nuclear hormone receptors which bind to as an important secondary target in patients with dia- DNA as a heterodimer with the Retinoid X Recep- betes [21]. It should be noted, however, that for isolated tor (RXR), and together they recognise specifc DNA severe hypertriglyceridaemia, intervention is indicated sequences in and around target genes referred to as due to pancreatitis risk not for prevention of CVD [22]. PPAR response elements (PPREs). Tere are three difer- With growing recognition of the importance of tar- ent types of PPARs, ɑ, β and γ [30]. PPARα is abundantly geting atherogenic dyslipidaemia comes a re-eval- expressed in highly active metabolic tissues such as the uation of available therapeutic options. Fibrates, liver, kidney, heart, muscle, brown adipose tissue, as peroxisome proliferator-activated receptor (PPAR) α well as the vascular wall (smooth muscle cells, endothe- agonists, are the most logical option as an add-on to lial cells and
Load more

Recommended publications
  • Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
    CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products.
    [Show full text]
  • Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis
    Digestive Diseases and Sciences https://doi.org/10.1007/s10620-018-5395-7 ORIGINAL ARTICLE Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis Kirstine S. Tølbøl1,3,4 · Birgit Stierstorfer2 · Jörg F. Rippmann2 · Sanne S. Veidal1 · Kristofer T. G. Rigbolt1 · Tanja Schönberger2 · Matthew P. Gillum4 · Henrik H. Hansen1 · Niels Vrang1 · Jacob Jelsing1 · Michael Feigh1 · Andre Broermann2 Received: 14 June 2018 / Accepted: 22 November 2018 © The Author(s) 2018 Abstract Background There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efcacious drug therapies for the disease. Methods Here, we investigated the development of fbrotic NASH in male Wistar rats fed a choline-defcient L-amino acid- defned (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efcacy in NASH biopsy-confrmed rats. The metabolic profle and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confrmed NASH were selected for pharmacological intervention with vehicle, elafbranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. Results The CDAA diet led to marked hepatomegaly and fbrosis already after 4 weeks of feeding, with further progression of collagen deposition and fbrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supple- mentation enhanced the stimulatory efect of CDAA on gene transcripts associated with fbrogenesis without signifcantly increasing collagen deposition. Pharmacological intervention with elafbranor, but not OCA, signifcantly reduced stea- tohepatitis scores, and fbrosis-associated gene expression, however, was unable to prevent progression in fbrosis scores.
    [Show full text]
  • Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated
    www.nature.com/scientificreports OPEN Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, Received: 25 July 2016 Accepted: 11 January 2017 improves the pathogenesis in Published: 14 February 2017 a rodent model of nonalcoholic steatohepatitis Yasushi Honda1, Takaomi Kessoku1, Yuji Ogawa1, Wataru Tomeno1, Kento Imajo1, Koji Fujita1, Masato Yoneda1, Toshiaki Takizawa2, Satoru Saito1, Yoji Nagashima3 & Atsushi Nakajima1 The efficacy of peroxisome proliferator-activated receptorα -agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptorα modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH. The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide.
    [Show full text]
  • A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)
    ( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61P1/16 (2006.01) A61P3/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/192 (2006.01) C07C 321/28 (2006.01) Declarations under Rule 4.17: (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/IB2020/000808 earlier application (Rule 4.17(iii)) (22) International Filing Date: Published: 25 September 2020 (25.09.2020) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/906,288 26 September 2019 (26.09.2019) US (71) Applicant: ABIONYX PHARMA SA [FR/FR] ; 33-43 Av¬ enue Georges Pompidou, Batiment D, 31130 Bahna (FR). (72) Inventor: DASSEUX, Jean-Louis, Henri; 7 Allees Charles Malpel, Bat. B, 31300 Toulouse (FR). (74) Agent: HOFFMANN EITLE PATENT- UND RECHTSANWALTE PARTMBB, ASSOCIATION NO. 151; Arabellastrasse 30, 81925 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
    [Show full text]
  • The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
    International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development.
    [Show full text]
  • Effects of Pemafibrate on Glucose Metabolism Markers and Liver
    Yokote et al. Cardiovasc Diabetol (2021) 20:96 https://doi.org/10.1186/s12933-021-01291-w Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efects of pemafbrate on glucose metabolism markers and liver function tests in patients with hypertriglyceridemia: a pooled analysis of six phase 2 and phase 3 randomized double‐blind placebo‐controlled clinical trials Koutaro Yokote1,2*, Shizuya Yamashita3, Hidenori Arai4, Eiichi Araki5, Mitsunori Matsushita6, Toshiaki Nojima7, Hideki Suganami7 and Shun Ishibashi8 Abstract Background: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnor- malities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth efects of pemafbrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. Methods: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo- controlled trials that examined the efects of daily pemafbrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafbrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. Results: The study population was 1253 patients randomized to placebo (n 298) or pemafbrate 0.1 mg/day (n 127), 0.2 mg/day (n 584), or 0.4 mg/day (n 244). Participant mean age= was 54.3 years, 65.4 % had BMI 25 kg/ m2=, 35.8 % had type 2 diabetes,= and 42.6 % had fatty= liver.
    [Show full text]
  • Efficacy and Safety of Pemafibrate Administration in Patients With
    Ida et al. Cardiovasc Diabetol (2019) 18:38 https://doi.org/10.1186/s12933-019-0845-x Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efcacy and safety of pemafbrate administration in patients with dyslipidemia: a systematic review and meta-analysis Satoshi Ida*, Ryutaro Kaneko and Kazuya Murata Abstract Background: Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the ef- cacy and safety of pemafbrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia. Methods: A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the efects of pemafbrate on lipid and glucose metabolism- related parameters in patients with dyslipidemia. For statistical analysis, standardized mean diference (SMD) or odds ratio (OR) and 95% confdence intervals (CIs) were calculated using the random efect model. Results: Our search yielded seven RCTs (with a total of 1623 patients) that satisfed the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration signifcantly decreased in the pemafbrate group (SMD, 1.38; 95% CI, 1.63 to 1.12; P < 0.001) than in the placebo group, with a reduc- tion efect similar to that exhibited− by fenofbrate.− Compared− with the placebo group, the pemafbrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafbrate group showed a signifcant decrease in hepa- tobiliary enzyme activity compared with the placebo and fenofbrate groups; and, total adverse events (AEs) were signifcantly lower in the pemafbrate group than in the fenofbrate group (OR, 0.60; 95% CI, 0.49–0.73; P < 0.001).
    [Show full text]
  • Lessons from Liver-Specific PPAR-Null Mice
    International Journal of Molecular Sciences Review PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice Yaping Wang 1, Takero Nakajima 1, Frank J. Gonzalez 2 and Naoki Tanaka 1,3,* 1 Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Nagano 390-8621, Japan; [email protected] (Y.W.); [email protected] (T.N.) 2 Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] 3 Research Center for Social Systems, Shinshu University, Matsumoto, Nagano 390-8621, Japan * Correspondence: [email protected]; Tel.: +81-263-37-2851 Received: 21 February 2020; Accepted: 9 March 2020; Published: 17 March 2020 Abstract: Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver. Keywords: PPAR; NAFLD; NASH; insulin resistance; liver fibrosis 1. Introduction Administration of Wy-14643, nafenopin, and fibrate drugs to rodents results in hepatic peroxisome proliferation. These agents are thus designated as peroxisome proliferators (PPs) [1]. To explain a mechanism of rapid and drastic changes following PP administration, the involvement of transcription factors was assumed and the first peroxisome proliferator-activated receptor (PPAR, later defined as PPARα (NR1C1)) was identified in 1990 [2].
    [Show full text]
  • Review J Atheroscler Thromb, 2019; 26: 389-402
    The official journal of the Japan Atherosclerosis Society and the Asian Pacific Society of Atherosclerosis and Vascular Diseases Review J Atheroscler Thromb, 2019; 26: 389-402. http://doi.org/10.5551/jat.48918 Clinical Applications of a Novel Selective PPARα Modulator, Pemafibrate, in Dyslipidemia and Metabolic Diseases Shizuya Yamashita1, 2, 3, Daisaku Masuda1 and Yuji Matsuzawa4 1Department of Cardiology, Rinku General Medical Center, Osaka, Japan 2Department of Community Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 3Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Osaka, Japan 4Sumitomo Hospital, Osaka, Japan Fasting and postprandial hypertriglyceridemia is a risk factor for atherosclerotic cardiovascular diseases (ASCVD). Fibrates have been used to treat dyslipidemia, particularly hypertriglyceridemia, and low HDL-choles- terol (HDL-C). However, conventional fibrates have low selectivity for peroxisome proliferator-activated receptor (PPAR)α. Fibrates’ clinical use causes side effects such as worsening liver function and elevating the creatinine level. Large-scale clinical trials of fibrates have shown negative results for prevention of ASCVD. To overcome these issues, the concept of the selective PPARα modulator (SPPARMα), with a superior balance of efficacy and safety, has been proposed. A SPPARMα, pemafibrate (K-877), was synthesized by Kowa Company, Ltd. for bet- ter efficacy and safety. Clinical trials conducted in Japan confirmed the superior effects of pemafibrate on triglyc- eride reduction and HDL-C elevation. Conventional fibrates showed elevated liver function test values and worsened kidney function test values, while pemafibrate demonstrated improved liver function test values and was less likely to increase serum creati- nine or decrease the estimated glomerular filtration rate.
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors and Their Novel Ligands As Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease
    cells Review Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease Anne Fougerat 1,*, Alexandra Montagner 1,2,3, Nicolas Loiseau 1 , Hervé Guillou 1 and Walter Wahli 1,4,5,* 1 Institut National de la Recherche Agronomique (INRAE), ToxAlim, UMR1331 Toulouse, France; [email protected] (A.M.); [email protected] (N.L.); [email protected] (H.G.) 2 Institut National de la Santé et de la Recherche Médicale (Inserm), Institute of Metabolic and Cardiovascular Diseases, UMR1048 Toulouse, France 3 Institute of Metabolic and Cardiovascular Diseases, University of Toulouse, UMR1048 Toulouse, France 4 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Clinical Sciences Building, 11 Mandalay Road, Singapore 308232, Singapore 5 Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland * Correspondence: [email protected] (A.F.); [email protected] (W.W.); Tel.: +33-582066376 (A.F.); +41-79-6016832 (W.W.) Received: 29 May 2020; Accepted: 4 July 2020; Published: 8 July 2020 Abstract: Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Exploration and Development of PPAR Modulators in Health and Disease: an Update of Clinical Evidence
    International Journal of Molecular Sciences Review Exploration and Development of PPAR Modulators in Health and Disease: An Update of Clinical Evidence Hong Sheng Cheng 1,* , Wei Ren Tan 2, Zun Siong Low 2, Charlie Marvalim 1, Justin Yin Hao Lee 2 and Nguan Soon Tan 1,2,* 1 School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore; [email protected] 2 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; [email protected] (W.R.T.); [email protected] (Z.S.L.); [email protected] (J.Y.H.L.) * Correspondence: [email protected] (H.S.C.); [email protected] (N.S.T.); Tel.: +65-6904-1294 (H.S.C.); +65-6904-1295 (N.S.T.) Received: 30 September 2019; Accepted: 10 October 2019; Published: 11 October 2019 Abstract: Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that govern the expression of genes responsible for energy metabolism, cellular development, and differentiation. Their crucial biological roles dictate the significance of PPAR-targeting synthetic ligands in medical research and drug discovery. Clinical implications of PPAR agonists span across a wide range of health conditions, including metabolic diseases, chronic inflammatory diseases, infections, autoimmune diseases, neurological and psychiatric disorders, and malignancies. In this review we aim to consolidate existing clinical evidence of PPAR modulators, highlighting their clinical prospects and challenges. Findings from clinical trials revealed that different agonists of the same PPAR subtype could present different safety profiles and clinical outcomes in a disease-dependent manner.
    [Show full text]