R E V I E W Treatment update: thiazolidinediones in combination with metformin for the treatment of type 2 diabetes John M Stafford1 Tom Elasy2 1Division of Diabetes Endocrinology and Metabolism, Vanderbilt University; 2Vanderbilt Eskind Diabetes Clinic, Vanderbilt University Medical Center Correspondence: John Stafford Vanderbilt University Medical Center, 718 Preston Research Building, Nashville, TN 37232-6303, USA Tel +1 615 936 1653 Fax +1 615 936 1667 Email john.stafford@vanderbilt.edu Abstract: Type 2 diabetes mellitus (DM2) is characterized by excessive hepatic gluconeo- genesis, increased insulin resistance and a progressive inability of pancreatic beta cells to produce sufﬁcient insulin. DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reﬂecting the establishment of insulin resistance and beta cell dysfunction. Insulin resistance not only contributes to impaired glycemic control in DM2, but to the development of hypertension, dyslipidemia and endothelial dysfunction. Cardiovascular disease is the primary morbidity for patients with DM2. The onset of insulin resistance and cardiovascular insult likely occurs well before the onset of IGT is detected clinically. Biguanides and thiazolidinediones (TZDs) are two classes of oral agents for the management of DM2 that improve insulin resistance, and thus have potential cardiovascular beneﬁts beyond glycemic control alone. Metformin additionally inhibits hepatic gluconeogenesis. The combined use of two of these agents targets key pathophysiologic defects in DM2. Single pill combinations of rosiglitazone/metformin and pioglitazone/metformin have recently been approved for use in the US and Europe. This article reviews the clinical data behind the use of metformin in combination with TZDs for the management of diabetes, its impact on vascular health, side effects and potential mechanisms of action for combined use. Keywords: thiazolidinediones; metformin; Type 2 diabetes Rationale for the combined use of thiazolidinediones and metformin from a cardiovascular perspective Type 2 diabetes mellitus (DM2) is characterized by defects both in insulin secretion and insulin action (Ginsberg et al 1975; DeFronzo et al 1985; Lillioja et al 1988). With the use of the euglycemic insulin clamp technique, over the past two decades, it has become clear that DM2 evolves as a progression from normal glucose tolerance, to impaired glucose tolerance (IGT) to frank diabetes mellitus, reﬂecting the establishment of insulin resistance and beta cell dysfunction (Ginsberg et al 1975; DeFronzo et al 1985; Lillioja et al 1988; and reviewed in Granner and O’Brien (1992) and DeFronzo (2004)). This progression has been demonstrated in many populations, and is strongly correlated with the progression of obesity (Lillioja et al 1988). The progression from normal glucose homeostasis to IGT is associated with an increase in fasting plasma insulin and glucose-stimulated insulin secretion (post-prandial), and a decrease in sensitivity to insulin action (Saad et al 1988, 1989). The progression from IGT to frank DM2 is associated with an inability of the pancreatic beta cells to continue this excess secretion of insulin (Polonsky et al 1996; Roe et al 1996), however signiﬁcant beta cell dysfunction may occur much earlier (DeFronzo 2004). There is only a minimal Vascular Health and Risk Management 2007:3(4) 503–510 © 2007 Dove Medical Press Limited. All rights reserved 503