SPPARM alpha agonist for Nutrient and Energy Metabolism – Mechanisms and Therapeutic Opportunities: Jean-Charles Fruchart, Lille/Basel, France
Future CVD management: from gene to phenotype to treatment
Jean-Charles Fruchart is currently Professor at the Pasteur Institute, Lille, France, President of the Residual Risk Reduction Initiative (R3i) Foundation, and a member of the International Atherosclerosis Society board. He discovered the molecular mechanism of action of fibrates through activation of Peroxisome Proliferator-Activated Receptor (PPAR)-alpha and developed with Kowa the first Selective PPAR (SPPARM)alpha, K‑877. Professor Fruchart is the recipient of many awards and honours, including Membership of the Academy of Medicine (1991); “Chevalier de la Légion d’Honneur” (1995); “Great Gold Medal of Pasteur Institute” (1994); Membership of the Academy of Pharmacy (1995); “Galien” of Pharmaceutical Research (1998). “Gold Medal of Foundation Giovanni Lorenzini” award (2003); “Officier de la Légion d’Honneur” (2005); and the Anitschkow Prize (2008).
The 2019 European Society of Cardiology/European Atherosclerosis lipid guidelines reaffirmed low-density lipoprotein cholesterol as the primary lipid target to prevent atherosclerotic cardiovascular disease (ASCVD). Despite optimal treatment, however, high- and very-high-risk individuals continue to experience ASCVD events, underlining the need to intervene against other targets. Accumulating evidence has highlighted a role for atherogenic dyslipidaemia, in particular elevated triglyceride-rich lipoproteins (TRL) and their remnants, in ASCVD.
Beyond statins, current therapeutic approaches for managing elevated triglycerides, a key component of atherogenic dyslipidaemia, are so far limited to fibrates (PPARalpha ligands) and omega-3 fatty acids. Both have safety issues; clinical trials have highlighted an increased risk for atrial fibrillation with omega-3 fatty acids, and reversible elevation of serum creatinine and liver enzymes are well documented for fibrates (notably fenofibrate). Selective modification of the pharmacological characteristics of a PPARα agonist to improve the profile of beneficial effects and address the known safety issues associated with fibrate treatment, offers a tantalising prospect. The example of selective oestrogen receptor modulators provided a blueprint for the SPPARMα concept. Critical to this was understanding the interactions between the ligand and the PPARα receptor at the molecular level, so as to modulate the receptor–cofactor binding profile, and influence potency and selectivity of the ligand.
The SPPARMα concept is now a reality with the licensing of pemafibrate (K-877) in Japan. Clinical evidence to date supports the improved benefit-risk profile of this agent. The key question, however, is whether treatment of atherogenic dyslipidaemia with pemafibrate on top of statin, reduces residual cardiovascular risk, the focus of the ongoing PROMINENT study.
Sasaki Y, Asahiyama M, Tanaka T, Yamamoto S, Murakami K, Kamiya W, Matsumura Y, Osawa T, Anai M, Fruchart JC, Aburatani H, Sakai J, Kodama T. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep 2020;10:7818.
Neeland IJ, Ross R, Després JP, Matsuzawa Y, Yamashita S, Shai I, Seidell J, Magni P, Santos RD, Arsenault B, Cuevas A, Hu FB, Griffin B, Zambon A, Barter P, Fruchart JC, Eckel RH; International Atherosclerosis Society; International Chair on Cardiometabolic Risk Working Group on Visceral Obesity. Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: a position statement. Lancet Diabetes Endocrinol 2019;7:715-725.
Fruchart JC, Santos RD, Aguilar-Salinas C, Aikawa M, Al Rasadi K, Amarenco P, Barter PJ, Ceska R, Corsini A, Després JP, Duriez P, Eckel RH, Ezhov MV, Farnier M, Ginsberg HN, Hermans MP, Ishibashi S, Karpe F, Kodama T, Koenig W, Krempf M, Lim S, Lorenzatti AJ, McPherson R, Nuñez-Cortes JM, Nordestgaard BG, Ogawa H, Packard CJ, Plutzky J, Ponte-Negretti CI, Pradhan A, Ray KK, Reiner Ž, Ridker PM, Ruscica M, Sadikot S, Shimano H, Sritara P, Stock JK, Su TC, Susekov AV, Tartar A, Taskinen MR, Tenenbaum A, Tokgözoğlu LS, Tomlinson B, Tybjærg-Hansen A, Valensi P, Vrablík M, Wahli W, Watts GF, Yamashita S, Yokote K, Zambon A, Libby P. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol 2019;18(1):71.