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