PPARγ agonists: safety issues in heart failure

PPARgamma agonists (or thiazolidinediones, TZD) are popular oral drugs for glycaemic control in patients with diabetes mellitus. However, side-effects of fluid retention, oedema and congestive heart failure have been reported in the literature as well as observed in clinical registries and trials. Concerns regarding the safety of TZD use in patients with underlying heart failure have been implicated by its propensity to cause fluid retention. There is relatively good documentation in the literature that TZDs do not produce adverse haemodynamic consequences. TZD-induced fluid retention is often sub-acute in nature, developed over weeks to months following initiation, and primarily located in the periphery. Drug withdrawal may lead to complete resolution of fluid retention. Current approval of TZD use in patients with mild (NYHA class I - II) and stable heart failure is supported by existing literature and clinical experience. There have been few reports of severe adverse consequences following drug withdrawal, and emerging data are suggesting potential benefits of TZDs in the diabetic population with or without underlying heart failure. Future research should therefore be directed at better understanding PPARgamma-related mechanisms of renal sodium retention and endothelial vascular permeability of the periphery, as well as development of newer compounds without this side-effect.