Rodent Carcinogenicity Profile of the Antidiabetic Dual PPAR α and γ Agonist Muraglitazar

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors which are members of the nuclear hormone receptor superfamily (Rosen et al., 2000). Three receptor types belonging to this family have been identified including alpha (a), gamma (c), and delta (d)—also called beta. PPARs are potent insulin sensitizers; PPAR a (expressed mainly in the liver, heart, and skeletal muscle) is involved in the metabolism of lipoproteins and fatty acids, while PPAR c (expressed mainly in adipose tissue) is involved in the differentiation of fat cells, as well as the metabolism of fatty acids and glucose (Yki-Jarvinen, 2004). Many agonists of these receptors have been developed for use as therapeutic agents in the treatment of type 2 diabetes, including the marketed PPAR c agonists rosiglitazone and pioglitazone. Diabetes is a chronic, debilitating disease that affects at least 4% of the adult population worldwide (most of whom have type 2 diabetes) (King et al., 1998). The incidence of type 2 diabetes is increasing rapidly in industrialized nations, and it is estimated that there will be 221 million diabetics worldwide by the year 2010 (King et al., 1998). Moreover, since the percentage of type 2 diabetic patients that achieve glycemic control with oral antidiabetic treatments is estimated to be less than 50%, there remains a significant unmet medical need for better control of hyperglycemia in diabetic patients (Koro et al., 2004). Control of the dyslipide- mia which is commonly associated with diabetes (character- ized by elevated levels of triglyceride and decreased levels of high-density lipoprotein cholesterol) is another attractive medical target for treatment in diabetics (Cox, 2005). Muraglitazar is a nonthiazolidinedione, oxybenzylglycine dual PPAR a/c agonist which was previously in development for the treatment of type 2 diabetes and associated dyslipidemia. As a dual PPAR agonist, muraglitazar combines the insulin sensitizing and glucose lowering effects of PPAR c agonism with the antidyslipidemic effects of PPAR a agonism. PPARs have a wide tissue distribution, and 2-year mouse and rat carcinogenicity bioassays for 12 PPAR agonists (six c and six dual a/c agonists, including muraglitazar) reviewed by the United States Food and Drug Administration (U.S. FDA) have