Introduction: The thiazolidinedione (TZD) drugs, including pioglitazone (Actos) and rosiglitazone (Avandia), are commonly prescribed in patients with type 2 diabetes mellitus (T2DM), largely due to their favorable effects on hyperglycemia, insulin sensitivity, and cardiometabolic profile. However, the data are sparse assessing the effects of TZDs on micro- and macrovascular disease risk.
Discussion: Although no studies have been published on microvascular clinical outcomes, both TZDs significantly reduce the urine albumin-to-creatinine ratio. TZDs have consistently been associated with favorable effects on atherosclerosis and cardiovascular disease (CVD) risk. Only one study has been published to date specifically designed to assess the effects of a TZD (pioglitazone) on macrovascular outcomes, the PROactive trial. In this trial, pioglitazone versus placebo was associated with a non-significant 10% reduction in the combined primary endpoint of mortality, coronary and peripheral vascular events, and revascularizations. No individual trial has been published specifically assessing the CVD effects of rosiglitazone, but several meta-analyses and a published interim report from an ongoing trial (RECORD) point to safety concerns regarding rosiglitazone use and the risk of myocardial infarctions (MI), leading to amplified warnings in the product labeling for rosiglitazone to reflect these concerns.
Conclusion: All published trials and meta-analyses of TZDs have consistently shown increased risk of heart failure (HF) with both TZDs, though the actual placebo-subtracted incidence of HF is low (<0.5% per year). The initiation of either TZD is contraindicated in patients with NHYA class III or IV HF, and cautions exist for their use in any patient with heart failure. Much uncertainty remains regarding the aggregate CVD effects of the TZDs, and several trials are presently underway to further address these issues.