Pleiotropic effects of thiazolidinediones on traditional and non-traditional atherosclerotic risk factors

The thiazolidinediones pioglitazone and rosiglitazone have established efficacy in improving insulin sensitivity, glycaemic control, dyslipidaemia, hypertension and microalbuminuria in patients with type 2 diabetes. As specific agonists of peroxisome proliferator-activated receptor-gamma, thiazolidinediones have also demonstrated protective effects on a variety of atherosclerosis biomarkers and surrogate measures of cardiovascular disease. This paper reviews the evidence for pleiotropic effects on a variety of non-traditional atherosclerotic risk factors. Thiazolidinediones attenuate circulating levels of pro-inflammatory mediators in patients with type 2 diabetes, including C-reactive protein, interleukin-6, CD40L, monocyte chemoattractant protein-1 and metalloproteinase-9. These agents also increase levels of the vascular protective adipokine, adiponectin. The clinical significance of these findings is supported by evidence of improved endothelial dysfunction, reduced carotid intima media thickness and improvements in stenosis following coronary artery stent implantation in patients treated with thiazolidinediones. Limited data suggest that thiazolidinediones might also improve the circulating levels and functional activity of angiogenic endothelial progenitor cells, which independently predict the incidence of cardiovascular events and death. It should be noted that the US Food and Drug Administration and the European Medicines Agency have requested changes to the prescribing information for rosiglitazone to highlight the possibility of an increased risk with this agent in patients with ischaemic heart disease; on review, no such amendment was required for the pioglitazone prescribing information. Both agencies continue to suggest that the benefits of both thiazolidinediones outweight any possible detrimental effects. Further research remains to be conducted to elucidate the potentially differential vascular protective effects of thiazolidinediones. In the US, there are black box heart failure warnings for both agents. In light of the established importance of reducing cardiovascular risk in patients with type 2 diabetes, current evidence continues to support the use of pioglitazone within multifactorial risk management strategies.