PPAR-α agonists are still on the rise: an update on clinical and experimental findings

ABSTRACT

Introduction: Non-fasting plasma triglyceride (TG) and remnant cholesterol levels, cholesterol content of triglyceride-rich lipoproteins, have been suggested to be an additional cause of cardiovascular diseases; thus, pharmacological TG-lowering with fibrates, activators of PPAR-alpha system, has been linked to risk reduction.

Areas covered: This manuscript reviews available evidence on clinical trials involving highly selective PPAR-α agonists (i.e., pemafibrate) and drugs used in the pre-clinical and experimental setting (e.g., WY14,643). Original publications in English were selected, as well as Abstracts of international meetings’ presentations. Clinical trials were identified using the clinicaltrial.gov database and the EU Clinical Trials Register (clinicaltrialsregister.eu).

Expert opinion: In addition to the aim of improving lipid profile with fibrates, the interest in new PPAR-α activators stems from the need to overcome some of the clinical problems encountered with dose-dependent adverse events; a rise of plasma creatinine, gallstone formation, drug-drug interactions (i.e. gemfibrozil), and myopathy. New PPAR-α agonists improved TG and HDL-C levels as well as other parameters related to TG metabolism (remnant cholesterol and apoB), without raising liver enzymes. Although the use of fibrates is rated ‘second choice’ by many clinicians, new PPAR-α agonists may offer a more accessible route to the management of hypertriglyceridemia, a frequent clinical condition.

KEYWORDS:

• Hypertriglyceridemia
• fibrates
• PPAR-α
• pemafibrate

Article highlights

• Non-fasting plasma triglyceride and remnant cholesterol levels are additional cause of cardiovascular diseases

• Elevated remnant cholesterol levels are causally associated with both low-grade inflammation and ischemic heart disease

• Fibrates could lower risk of CV events in primary prevention trials by 16% with non-significant effects on CV mortality

• PPAR-α agonists may prove to be a challenging pharmacological area for the management of ‘atherogenic dyslipidemia’

• Pemafibrate improves TG, HDL-C, VLDL, remnant cholesterol and apoB levels

• Dose-dependent adverse events encountered with fibrates (plasma creatinine, gallstone formation, drug interactions, and myopathy) are overcome by the new PPAR-α activators.

This box summarizes key points contained in the article.

Declaration of interest

A. Corsini receives fees for consulting and research funding from Mylan, Recordati and Kowa. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This work was supported by Fondazione Cariplo [grant number 2015-0552] and Linea 2, Azione (Intramural grant) received by Università degli Studi di Milano.