The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential

Fruchart, Jean-Charles and Santos, Raul D. and Aguilar-Salinas, Carlos and Aikawa, Masanori and Al Rasadi, Khalid and Amarenco, Pierre and Barter, Philip J. and Ceska, Richard and Corsini, Alberto and Després, Jean-Pierre and Duriez, Patrick and Eckel, Robert H. and Ezhov, Marat V. and Farnier, Michel and Ginsberg, Henry N. and Hermans, Michel P. and Ishibashi, Shun and Karpe, Fredrik and Kodama, Tatsuhiko and Koenig, Wolfgang and Krempf, Michel and Lim, Soo and Lorenzatti, Alberto J. and McPherson, Ruth and Nuñez-Cortes, Jesus Millan and Nordestgaard, Børge G. and Ogawa, Hisao and Packard, Chris J. and Plutzky, Jorge and Ponte-Negretti, Carlos I. and Pradhan, Aruna and Ray, Kausik K. and Reiner, Željko and Ridker, Paul M. and Ruscica, Massimiliano and Sadikot, Shaukat and Shimano, Hitoshi and Sritara, Piyamitr and Stock, Jane K. and Su, Ta-Chen and Susekov, Andrey V. and Tartar, André and Taskinen, Marja-Riitta and Tenenbaum, Alexander and Tokgözoğlu, Lale S. and Tomlinson, Brian and Tybjærg-Hansen, Anne and Valensi, Paul and Vrablík, Michal and Wahli, Walter and Watts, Gerald F. and Yamashita, Shizuya and Yokote, Koutaro and Zambon, Alberto and Libby, Peter (2019) The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential. Cardiovascular Diabetology, 18 (1). ISSN 1475-2840

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Abstract

In the era of precision medicine, treatments that target specific modifiable characteristics of high-risk patients have the potential to lower further the residual risk of atherosclerotic cardiovascular events. Correction of atherogenic dyslipidemia, however, remains a major unmet clinical need. Elevated plasma triglycerides, with or without low levels of high-density lipoprotein cholesterol (HDL-C), offer a key modifiable component of this common dyslipidemia, especially in insulin resistant conditions such as type 2 diabetes mellitus. The development of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) offers an approach to address this treatment gap. This Joint Consensus Panel appraised evidence for the first SPPARMα agonist and concluded that this agent represents a novel therapeutic class, distinct from fibrates, based on pharmacological activity, and, importantly, a safe hepatic and renal profile. The ongoing PROMINENT cardiovascular outcomes trial is testing in 10,000 patients with type 2 diabetes mellitus, elevated triglycerides, and low levels of HDL-C whether treatment with this SPPARMα agonist safely reduces residual cardiovascular risk.

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