PPAR-γ agonism for cardiovascular and renal protection

Diabetes mellitus is an established risk factor for cardiovascular disease and the leading cause of end-stage renal disease in the Western World. Thiazolidinediones (TZDs) represent a class of antidiabetic agents that exert their glucose-lowering effects by reducing insulin resistance, through stimulation of a type of nuclear receptor, called peroxisome proliferator-activated receptor-γ. Apart from improving glycemic control, TZDs were shown to exert beneficial effects on several components of the metabolic syndrome and cardiovascular risk markers. Furthermore, background and human studies have shown that TZDs reduce urinary albumin and protein excretion and interfere with most of the pathogenentic pathways involved in the development and progression of diabetic nephropathy. On the other hand, currently used TZDs have side effects, most important of which is fluid retention leading to wait gain and heart failure deterioration. With regards to cardiovascular outcomes, the anticipated benefit of TZDs was demonstrated for pioglitazone, whereas a series of previous meta-analyses linking rosiglitazone treatment with increased risk of myocardial infarction and cardiovascular death raised uncertainty around the cardiovascular safety of rosiglitazone. This article will discuss the effects of TZDs on established and emerging cardiovascular risk factors, the data on possible beneficial renal effects of these compounds, and the existing evidence from large-scale clinical trials and meta-analyses on their effects on cardiovascular outcomes, aiming to provide an overview of the cardio- and renoprotective properties of these drugs.