PPAR dual agonists: Are they opening Pandora's box?

Cardiovascular disorders are the major cause of mortality in patients of diabetes mellitus. Peroxisome proliferator activated receptors (PPARs) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of three subtypes such as PPAR alpha, PPAR-gamma and PPAR delta/beta. Activation of PPARa reduces triglycerides and involves in regulation of energy homeostasis. Activation of PPAR gamma causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR delta enhances fatty acid metabolism. Current therapeutic strategies available for the treatment of diabetes do not inhibit the associated secondary cardiovascular complications. Hence, the development of multimodal drugs which can reduce hyperglycemia and concomitantly inhibit the progression of secondary cardiovascular complications may offer valuable therapeutic option. Several basic and clinical studies have exemplified the beneficial effects of PPAR alpha and PPAR gamma ligands in preventing the cardiovascular risks. The PPAR alpha/gamma dual agonists are developed to increase insulin sensitivity and Simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of Type II diabetes with secondary cardiovascular complications. However, PPAR alpha/gamma dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. The ongoing basic studies have elucidated the cardio protective role of PPAR delta. Therefore, further studies are on the track to develop PPAR alpha/delta and PPAR gamma/delta dual agonists and PPAR alpha/gamma/delta pan agonists for the treatment of diabetic cardiovascular complications. The present review critically analyzes the protective and detrimental effect of PPAR agonists in diabetic cardiovascular complications. Moreover, the newly developed PPAR alpha/delta and PPAR gamma/delta dual agonists and PPAR alpha/gamma/delta pan agonists have also been discussed which may open a new vista in the management of diabetic cardiovascular complications in near future. (c) 2007 Elsevier Ltd. All rights reserved.