Selective Peroxisome Proliferator-Activated Receptor Alpha Modulators (SPPARMα) in the Metabolic Syndrome: Is Pemafibrate Light at the End of the Tunnel?

Jean-Charles Fruchart, Michel P Hermans, Jamila Fruchart-Najib, Tatsuhiko Kodama, Jean-Charles Fruchart, Michel P Hermans, Jamila Fruchart-Najib, Tatsuhiko Kodama

Abstract

Purpose of review: Adoption of poor lifestyles (inactivity and energy-dense diets) has driven the worldwide increase in the metabolic syndrome, type 2 diabetes mellitus and non-alcoholic steatohepatitis (NASH). Of the defining features of the metabolic syndrome, an atherogenic dyslipidaemia characterised by elevated triglycerides (TG) and low plasma concentration of high-density lipoprotein cholesterol is a major driver of risk for atherosclerotic cardiovascular disease. Beyond lifestyle intervention and statins, targeting the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα) is a therapeutic option. However, current PPARα agonists (fibrates) have limitations, including safety issues and the lack of definitive evidence for cardiovascular benefit. Modulating the ligand structure to enhance binding at the PPARα receptor, with the aim of maximising beneficial effects and minimising adverse effects, underlies the SPPARMα concept.

Recent findings: This review discusses the history of SPPARM development, latterly focusing on evidence for the first licensed SPPARMα, pemafibrate. Evidence from animal models of hypertriglyceridaemia or NASH, as well as clinical trials in patients with atherogenic dyslipidaemia, are overviewed. The available data set the scene for therapeutic application of SPPARMα in the metabolic syndrome, and possibly, NASH. The outstanding question, which has so far eluded fibrates in the setting of current evidence-based therapy including statins, is whether treatment with pemafibrate significantly reduces cardiovascular events in patients with atherogenic dyslipidaemia. The PROMINENT study in patients with type 2 diabetes mellitus and this dyslipidaemia is critical to evaluating this.

Trial registration: ClinicalTrials.gov NCT03350165.

Keywords: Metabolic syndrome; Non-alcoholic fatty liver disease; Pemafibrate; SPPARM; Selective peroxisome proliferator-activated receptor alpha modulator; Triglycerides.

Conflict of interest statement

J-C Fruchart and J Fruchart-Najib report personal fees from Kowa Company; MP Hermans reports no conflict of interest; T Kodama is the recipient of a research grant from Kowa Company.

Figures

Fig. 1
Fig. 1
Dyslipidaemia is an important feature of the metabolic syndrome. Overproduction of large very low-density lipoprotein particles is a fundamental defect contributing to the increase in the triglyceride pool. This initiates a sequence of lipoprotein changes, leading to higher levels of remnant particles, an increase in small, dense low-density lipoprotein particles and lower plasma concentration of high-density lipoprotein cholesterol. IDL, intermediate-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; TG, triglyceride
Fig. 2
Fig. 2
Pemafibrate is the realisation of the SPPARMα concept. Understanding binding interactions at the PPAR have been critical in driving the development of SPPARMα. Systematic structural modifications based on a precision medicine approach led to the creation of pemafibrate. This agent demonstrated an enhanced fit completely within the ligand binding domain of PPARα, in contrast to the linear structure of conventional fibrates such as fenofibrate. PPARα, peroxisome proliferator-activated receptor alpha
Fig. 3
Fig. 3
Pemafibrate favourably impacts the atherogenic dyslipidaemia of the metabolic syndrome. Pooled analysis of more than 1200 patients with atherogenic dyslipidaemia showed that pemafibrate treatment for 12 weeks lowered triglycerides (TG) and associated atherogenic lipoproteins and raised HDL-C, irrespective of statin therapy. Data from Yamashita et al [•]. apo, apolipoprotein; C, cholesterol; HDL-C, high-density lipoprotein cholesterol

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    1. A study of pemafibrate in patients with nonalcoholic fatty liver disease (NAFLD). Identifier: NCT03350165. (Accessed 15 July 2020).

Source: PubMed

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