PPAR-β/δ agonists for Type 2 diabetes and dyslipidemia: an adopted orphan still looking for a home

BACKGROUND: The identification of small molecule agonists for the nuclear receptor peroxisome proliferator-activated receptor beta/delta (PPAR-beta/delta, NR1C2) has enabled the characterization of this receptor's functions in preclinical models. Subsequently, a number of small molecule agonists of PPAR-beta/delta have been progressed into clinical trials. OBJECTIVE: This review will examine the major preclinical findings that underpin the hypothesis that PPAR-beta/delta agonists may be beneficial in treating dyslipidemia and Type 2 diabetes, as well as emerging clinical data with a variety of PPAR-beta/delta agonists. METHODS: The literature concerning preclinical experiments that combine in vivo and in vitro mechanistic studies are reviewed and compared with the results of the early clinical trials. CONCLUSIONS: Thus far, the activities of the agonists seen in the clinic are broadly similar to those seen in preclinical models. However, it is still not known if PPAR-beta/delta agonists will truly be differentiated enough from current treatments to justify their use in treating dyslipidemia or Type 2 diabetes. Major challenges for the development of PPAR-beta/delta agonists exist and the path forward is as yet undefined.