THERAPY AND CLINICAL TRIALS: Edited by Erik S.G. Stroes and Gerald F. WattsSPPARM alpha: the Lazarus effectFruchart, Jean-Charlesa; Santos, Raul D.b,cAuthor Information aR3i Foundation, Basel, Switzerland bHospital Israelita Albert Einstein cLipid Clinic, Heart Institute (InCor) University of Sao Paulo Medical School Hospital, Sao Paulo, Brazil Correspondence to Jean-Charles Fruchart, President, R3i Foundation, Picassoplatz 8, CH-4010 Basel, Switzerland. Tel: +41 61 560 24 24; fax: +41 560 24 25; e-mail: [email protected]@yahoo.fr Current Opinion in Lipidology: December 2019 - Volume 30 - Issue 6 - p 419-427 doi: 10.1097/MOL.0000000000000640 Buy Metrics Abstract Purpose of review Atherogenic dyslipidaemia, characterized by high plasma triglycerides (a surrogate for triglyceride-rich remnant lipoproteins) and low high-density lipoprotein cholesterol (HDL-C), is prevalent in patients with type 2 diabetes mellitus (T2DM) and contributes to a high modifiable residual cardiovascular risk. Fibrates are effective in managing hypertriglyceridaemia but lack consistent cardiovascular benefit in clinical trials and exhibit pharmacokinetic interaction with statins (gemfibrozil) and renal and hepatic safety issues (fenofibrate). The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm offers potential for improving potency, selectivity and the benefit-risk profile. Recent findings The present review discusses evidence for the novel SPPARMα agonist, pemafibrate. Clinical trials showed robust lowering of triglyceride-rich lipoproteins, elevation in HDL-C and nonlipid beneficial effects including anti-inflammatory activity. There was a favourable safety profile, with no increase in serum creatinine, evident with fenofibrate, and improved renal and hepatic safety. The cardiovascular outcomes study PROMINENT is critical to confirming the SPPARMα concept by validating reduction in residual cardiovascular risk in patients with T2DM and long-term safety. Summary SPPARMα offers a new paradigm for reducing residual cardiovascular risk in T2DM. PROMINENT will be critical to differentiating the first SPPARMα, pemafibrate, as a novel therapeutic class distinct from current fibrates. Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.