Drugs and the Peroxisome Proliferator Activated Receptors

Fibrates and thiazolidinediones, modulators of PPARα and γ nuclear receptors respectively, are classes of drugs in current use. Their use in clinical medicine has varied depending on the evidence at the time. There have been agents within each group that have been withdrawn due to concern of adverse events. In the case of fibrates there possibly is a current resurgence based on early evidence of microvascular benefit in patients with T2DM. The use of pioglitazone, the only thiazolidinedione marketed, appears to be on the wane due to possible associations with cancer having already led to its withdrawal in certain countries. The dual PPARα/γ agonists are not in current use with muraglitazar and tessaglitazar withdrawn for differing reasons. Furthermore there is the possibility of PPARß/δ activators being developed.

It is clear that heterogeneity even within a class of drug exists and this may be dependent not just on the pharmacokinetics and pharmacodynamics of the drug, but also the complexity of the PPAR receptor with associated effects. We hope that this brief chapter, including a description of gene expression, nuclear receptors followed by details of PPAR and their ligands, will leave the reader with an appreciation of the complexity that PPAR agonism leads to and the heterogeneity of effects that has added to some of the confusion existing.

Keywords: Cholesterol, co-activators, co-repressor, fatty acids, fibrates, gene expression, glitazars, HDL-C, lipid metabolism, metabolic syndrome, nuclear receptors, paradoxical HDL-C change, PPARα, PPARβ/δ, PPARγ, randomised controlled trials/meta-analysis, statins, thiazolidinediones, triglycerides, Type 2 diabetes.