PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome

The discovery of the crucial role of peroxisome proliferator-activated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPAR alpha activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPAR gamma activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPAR alpha- and PPAR gamma-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPAR alpha/gamma agonists, compounds that belong to the glitazar class are in the most advanced stage of development. However, although they demonstrated beneficial impact over selective PPAR agonists by improving both lipid and glucose homeostasis, safety has been a critical issue and has led to the discontinuation of their development because of adverse toxicity profiles. However, the target-related mechanism responsible for the identified safety issues and the relevance of rodent toxicities to the human situation are unclear. Therefore, future development of dual PPAR alpha/gamma agonists with selective PPAR modulator activity appears appropriate and should be feasible.