has been used clinically for over 40 years, though it has only been approved in the United States since 1995. Follow up of patients enrolled in United Kingdom prospective diabetes study (UKPDS 34) suggest that the complications of diabetes can be related to those caused by hyperglycemia and those related to insulin resistance. In this study, a subgroup of obese patients treated with metformin had signiﬁcantly lower risk of any diabetes-related endpoint, all cause mortality, and stroke when compared to patients achieving similar glycemic con- trol with a sulfonylurea or insulin therapy (UKPDS 1998). Treatment or prevention of insulin resistance can prevent the progression from impaired glucose tolerance to overt diabetes. The diabetes prevention trial demonstrated that an intensive diet and exercise program for patients with IGT reduced the risk of progression to diabetes by 58%, and metformin treatment reduced progression to DM2 by 31% (Knowler et al 2002). Similarly, troglitazone or pioglitazone treatment of women with a history of gestational diabetes helped to prevent progression to overt DM2 and to preserve beta cell function (Xiang et al 2006). In the DREAM study, patients with impaired fasting glucose or impaired glucose tolerance, or both were randomized to receive rosiglitazone 8 mg daily or placebo and followed for three years. The composite outcome was a combination of development of diabetes or death. 26% of patients in the placebo group developed the primary outcome versus only 11% in the rosi- glitazone group (Gerstein et al 2006). Since insulin resistance itself contributes to risk of cardiovascular disease, treatment of insulin resistance is a potential pathophyisiologic target for the prevention of CVD, not just diabetes. Combined use of metformin and TZDs has theoretical beneﬁt as it targets two main pathophysiologic defects in DM2, increased gluconeogenesis and insulin resistance. Clinical trials of combination use metformin/thiazolidinediones Effects on glycemic control As of May 2006, at least twelve clinical trials have been published in peer-reviewed journals designed to evaluate addition of TZD to metformin for the treatment of diabetes (Inzucchi et al 1998; Einhorn et al 2000; Fonseca et al 2000; Gomez-Perez et al 2002; Dailey et al 2004; Charbonnel et al 2005; Matthews et al 2005; Derosa et al 2005b; Weiss- man et al 2005; Kendall et al 2006; Rosenstock et al 2006; Umpierrez et al 2006). The initial study that demonstrated efﬁcacy and metabolic effects of the combined use of met- formin and TZDs was performed by the Shulman group at Vascular Health and Risk Management 2007:3(4) Thiazolidinediones in combination with metformin Yale (Inzucchi et al 1998). This study of 29 patients random- ized to receive either metformin or troglitazone for three months, after which they were placed on both agents. Post- prandial glucose was measured by mixed meal test. Insulin sensitivity was assessed with hyperinsulinemic-eugylcemic clamp at baseline, after three months of monotherapy and after three months of combination therapy. After three months of monotherapy, both metformin and troglitazone had similar decreases in fasting and postprandial plasma glucose levels. Metformin decreased endogenous glucose production, while troglitazone did not, consistent with the known effects of metformin on hepatic gluconeogeneis. Metformin had a 13% increase in insulin-mediated glucose disposal, while troglitazone had a 54% increase. Thus as single agents, metformin and troglitazone achieved similar glycemic control, metformin primarily through decreasing hepatic glucose production and troglitazone by improving insulin sensitivity. During combination therapy FPG was decreased an additional 41 mg/dl (18%), and postprandial glucose was decreased and additional 54 mg/dl (21%), both signiﬁcant changes from monotherapy. Adding troglitazone to metformin did not further decrease endogenous glu- cose production, however signiﬁcantly increased glucose disposal. The addition of metformin to the troglitazone group produced only a modest increase in glucose disposal (Inzucchi et al 1998). Thus the main efﬁcacy of combined therapy seemed to be the effect of metformin to decrease endogenous glucose production and that of troglitazone to improve insulin sensitivity, together targeting two patho- physiologic defects in DM2. Troglitazone was taken off the market in 1999 because of concerns for hepatic toxicity. Subsequent studies of TZDs were with either rosiglitazone or pioglitazone. The ﬁrst randomized controlled trial of the combined use of metformin with TZD in a large population was with rosiglitazone, published in 2000. In this study, 348 dia- betic patients were randomized to metformin plus placebo, metformin plus 4 mg/d rosiglitazone or metformin plus 8 mg/d rosiglitazone for 26 weeks. The primary endpoint was glycemic control. In this interval, addition of 4 mg rosiglitazone to metformin lowered FPG by 33 mg/dl, A1C by 0.56. The 8 mg dose of rosiglitazone, lowered FPG by 48 mg/dl and A1C by 0.78, all statistically signiﬁcant changes. Treatment effects were seen by as early as 4 weeks of treatment. Insulin sensitivity was assessed by the homeo- stasis model of assessment (HOMA), and both groups had increased sensitivity compared to the metformin-placebo group (Fonseca et al 2000). 505