Effects of pioglitazone on lipid and lipoprotein metabolism

Type 2 diabetes is associated with an increased risk of cardiovascular disease (CVD). A major contributing factor to this risk is the abnormal lipid profile known as dyslipidaemia, which is characterized by low HDL cholesterol (HDL-C), raised triglycerides (TGs) and a predominance of small, dense LDL cholesterol (LDL-C) particles. Statins are now widely used first-line in patients with type 2 diabetes due to their proven efficacy in reducing LDL-C and cardiovascular risk. However, despite the use of statins, the absolute risk of CVD in patients remains elevated, highlighting the need to target all aspects of the diabetic lipid profile such as raised TGs or low HDL-C levels. Insulin resistance is thought to be central in the pathogenesis of diabetic dyslipidaemia; therefore, improving insulin sensitivity with a thiazolidinedione offers an attractive treatment option. Indeed, pioglitazone, a member of the peroxisome proliferator-activated receptor-gamma family, has been shown in clinical trials to improve both blood glucose levels and the lipid profile when used either as monotherapy or in combination with other oral antidiabetic agents. In the monotherapy setting, pioglitazone has been associated with greater decreases in TGs and increases in HDL-C when compared with glibenclamide or metformin. Studies investigating the effects of pioglitazone add-on therapy to either metformin or sulphonylurea treatments have shown sustained improvements in serum levels of TGs and HDL-C and favourable effects on LDL-C particle size. In comparison with rosiglitazone, pioglitazone has different and potentially favourable effects on plasma lipids. The recent PROspective pioglitAzone Clinical Trial In macroVascular Events study has given weight to the hypothesis that the beneficial metabolic effects of pioglitazone may be associated with reductions in cardiovascular risk in patients with type 2 diabetes.