Because of their wide range of actions on
glucose homeostasis, lipid metabolism and vascular
inflammation,
peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes,
dyslipidemia and
atherosclerosis. In clinical practice,
PPARalpha agonists, such as the already available
fibrates, improve
dyslipidemia, while
PPARgamma agonists, such as
thiazolidinediones, improve
insulin resistance and diabetes. The complementary action of simultaneous activation of each
PPAR in patients suffering from
metabolic syndrome and
type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual
PPARalpha/gamma agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various
PPAR agonists including novel specific
PPARgamma agonists and dual
PPARalpha/gamma agonists. These safety concerns include potential carcinogenicity in rodents, signs of
myopathy and
rhabdomyolysis, increase in plasma
creatinine and
homocysteine,
weight gain, fluid retention, peripheral
edema and potential increased risk of
cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of
PPARgamma,
PPARalpha or both (class effect) or due to a
PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the
PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative
PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of
PPAR agonists that could be of concern when considering the development of new
PPAR agonists. The selective modulation of
PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.