PPAR agonists: multimodal drugs for the treatment of type-2 diabetes

Patients with type-2 diabetes mellitus (T2DM) are considered to be at particularly high risk for cardiovascular disease. Over the last decade, the members of the peroxisome proliferator-activated receptor (PPAR) subfamily of nuclear receptors have emerged as valuable pharmacological targets whose activation can normalize metabolic dysfunctions and reduce some cardiovascular risk factors associated with T2DM. PPARalpha agonists, such as the fibrates, can correct dyslipidemia. PPARgamma agonists, such as the thiazolidinediones, act as insulin sensitizers and improve insulin resistance in patients with T2DM. Because of restricted potency and certain side-effects of PPAR agonists, as well as the increasingly epidemic incidence of T2DM, there is a real need for the development of selective PPAR agonists with improved clinical efficacy. This chapter focuses on the PPAR agonists currently used in the clinic, as well as on the discovery and development of the next generation of PPAR agonists.