New developments in type 2 diabetes mellitus: combination therapy with a thiazolidinedione

Diabetes mellitus (DM) is a serious, chronic metabolic disease affecting approximately 17 million Americans. The microvascular and macrovascular complications of DM are associated with considerable morbidity and mortality.

This article reviews the importance of normalizing blood glucose values to reduce the risk of microvascular and macrovascular complications, discusses available treatment options for type 2 DM, and explores the rationale for combination therapy that includes a thiazolidinedione.

Relevant articles were selected from published reports and conference presentations from the last 10 years on oral agents for monotherapy and combination therapy for type 2 DM. Other sources were identified from the reference lists of selected articles.

Choices for the pharmacologic treatment of hyperglycemia in patients with type 2 DM include thiazolidinediones, insulin secretagogues, biguanides, and alpha-glucosidase inhibitors. Each of these drug classes is effective in lowering blood glucose concentrations; however, they have distinctly different mechanisms of action that target various pathophysiologic causes of type 2 DM and have different adverse-event profiles. in addition, several of these agents provide unique benefits unrelated to their hypoglycemic effects. Thiazolidinediones offer the therapeutic benefits of increasing insulin sensitivity and perhaps preserving beta-cell function. Use of a thiazolidinedione from the time type 2 DM is diagnosed improves insulin sensitivity, thereby improving glycemic control and minimizing complications. Over time, however, many patients with type 2 DM are unable to maintain adequate glycemic control (ie, glycosylated hemoglobin [HbA(1c)] <7%) with monotherapy. Combination therapy with agents from different classes may be necessary to achieve blood glucose control through an additive reduction in HbA(1c). The combination of a thiazolidinedione and a biguanide reduces hyperglycemia, hyperinsulinemia, and insulin resistance and improves factors that have been implicated in the pathogenesis of cardiovascular complications.

Patients with type 2 DM who are not able to maintain their HbA(1c). <7% with monotherapy should be considered candidates for combination therapy. Appropriate combination therapy includes treatment with 2 or more agents with different, complementary mechanisms of action. For example, the combination of a thiazolidinedione and a biguanide improves insulin sensitivity and lowers blood glucose through complementary pathways, and therefore produces an additive effect.