Review Safety issues and prospects for future generations of PPAR modulators Anne Rubenstrunk d , Rémy Hanf d , Dean W. Hum d , Jean-Charles Fruchart a,b,c , Bart Staels a,b,c, ⁎ a Institut Pasteur de Lille, Département d'Athérosclérose, Lille, F-59019, France b Inserm, U545, Lille, F-59019, France c Université de Lille 2, Lille, F-59006, France d Genfit, Loos, F-59006, France Received 27 December 2006; received in revised form 5 February 2007; accepted 13 February 2007 Available online 24 February 2007 Abstract Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARα agonists, such as the already available fibrates, improve dyslipidemia, while PPARγ agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARα/γ agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARγ agonists and dual PPARα/γ agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARγ, PPARα or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects. © 2007 Elsevier B.V. All rights reserved. Keywords: PPAR agonists; Safety issues; Side effects; Fluid retention; Edema; Congestive heart failure; Carcinogenesis; Myopathy; Rhabdomyolysis; Homocysteine; Creatinine; SPPARM 1. Introduction Peroxisome proliferator-activated receptors (PPARs) are nuclear lipid-activated transcription factors that regulate the expression of genes involved in the control of lipid and lipoprotein metabolism, glucose homeostasis and inflammatory processes [13,14]. Their wide range of potential therapeutic actions make them attractive targets for the development of oral agents targeting risk factors associated with the metabolic syndrome, type 2 diabetes and cardiovascular diseases [15], and huge investments have been made in the last decade by several biopharmaceutical companies aiming to develop new PPAR activators with improved efficacy relative to the existing drugs. Biochimica et Biophysica Acta 1771 (2007) 1065 – 1081 www.elsevier.com/locate/bbalip Abbreviations: ADA, American Diabetes Association; CHF, Congestive Heart Failure; EPC, Endothelial Progenitor Cells; FDA, Food and Drug Administration; GFR, Glomerular Filtration Rate; LDL, Low Density Lipoprotein; HDL, High Density Lipoprotein; PPARs, Peroxisome Prolifera- tor-Activated Receptors; SPPARMs, Selective Peroxisome Proliferator-Acti- vated Receptor Modulators; T2D, Type 2 Diabetes; TZD, Thiazolidinedione; VLDL, Very Low Density Lipoprotein ⁎ Corresponding author. Inserm U545, Institut Pasteur de Lille, 01 rue du Professeur Calmette, BP 245, Lille 59019, France. Tel.: +33 3 20 87 73 88; fax: +33 3 20 87 71 98. E-mail address: Bart.Staels@pasteur-lille.fr (B. Staels). 1388-1981/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2007.02.003