Pioglitazone plus glimepiride: a promising alternative in metabolic control

Current approaches to pharmacotherapy of type 2 diabetes focus on two key aspects of hyperglycaemia - insulin secretory dysfunction and insulin resistance. Combining drugs that target both these defects via different mechanisms of action improves long-term glycaemic control and offers a number of additional benefits. A fixed-dose combination of pioglitazone and glimepiride in a single tablet is now available in the US (Duetact(TM)). Both pioglitazone and glimepiride are glucose-lowering agents with distinct mechanisms of action. Pioglitazone is a potent and selective peroxisome proliferator-activated receptor-gamma agonist that improves whole-body insulin sensitivity and augments hepatic glucose uptake. On the other hand, glimepiride acts by releasing insulin from pancreatic beta-cells and improves both first and second phases of insulin secretion. These two therapies have been shown to act synergistically to treat type 2 diabetes - glimepiride therapy achieves rapid reductions in glycated haemaglobin (HbA(1c)), whereas pioglitazone sustains glycaemic control in the longer term. Furthermore, pioglitazone and glimepiride affect a number of pleiotropic markers. In particular, pioglitazone has beneficial effects on the atherogenic diabetic dyslipidaemia that are greater than those seen with rosiglitazone and other oral glucose-lowering agents. This advantage is also seen when comparing pioglitazone and rosiglitazone in combination with glimepiride. In addition, pioglitazone also improves a number of atherosclerotic risk markers that appear to translate into clinical benefits on macrovascular outcomes. Glimepiride may also improve several atherosclerotic risk markers and lipoproteins. This review discusses the potential benefits of combining pioglitazone plus glimepiride on patient compliance, targeting the dual effects of insulin resistance and beta-cell dysfunction and affecting a number of metabolic and cardiovascular parameters.