Stafford and Elasy additional worsening of insulin resistance at this stage of progression (DeFronzo 2004). Cardiovascular disease is the primary morbidity for patients with DM2 (Howard et al 2002). The onset of insulin resistance itself seems to be an early event in the progression of DM2, precedes the development of overt hyperglycemia, and may contribute substantially to the development of cardiovascular disease independent of the hyperglycemia associated with DM2 (Meigs et al 2000; DeFronzo 2004). In the Framingham offspring study, elevated levels of fasting insulin were associated with impaired fibrinolysis and hypercoagulability, despite normal glucose tolerance (Meigs et al 2000). In the same study population, those with impaired fasting glucose had a 2.8 fold relative risk of cardiovascular events over a 4-year follow up period (Meigs et al 2002). Vascular dysfunction has been identiﬁed in several groups of patients with normal blood glucose levels but insulin resistance including; ﬁrst degree relatives of patients with DM2 (Balletshofer et al 2000), patients with previous history of gestational diabetes (Bergholm et al 2003), patients with metabolic syndrome and patients with polycystic ovarian syndrome (reviewed in Caballero 2005). In the San Antonio heart study, impaired glucose tolerance was associated with hypertension, dyslipidemia, obesity and metabolic syndrome (Haffner et al 1990). Importantly, the risk of myocardial infarction (MI) in patients with known DM2, but without overt cardiovascular disease, is equal to patients who have had a previous MI but are free of diabetes (Haffner et al 1998). This observation has lead many to recommend the treatment of individuals with diabetes as comparable to an individual with known coronary heart disease. Still, insulin resistance itself appears to be an important risk factor for car- diovascular disease, even before the onset of hyperglycemia or DM2 (Wilson et al 2002, 2005). Thiazolidinediones (TZDs) comprise a class of oral agents for the management of DM2 that, in addition to improvements in glycemic control, improve insulin resis- tance and thus have potential cardiovascular beneﬁts beyond glycemic control alone. TZDs emerged for clinical use in the late 1990s. TZDs are ligands for the transcription fac- tor peroxisome proliferator-activated receptor-γ (PPARγ), a member of the nuclear receptor superfamily. PPARγ is expressed predominantly in adipose tissue, but also in macro- phages, beta cells of the pancreas, endothelial cells and other tissues (Kato et al 1999; Kersten et al 2000). The Olefsky group noted increased insulin sensitivity and lower blood pressure in obese patients without diabetes who were treated with troglitazone (Nolan et al 1994). There is some evidence 504 in animal models and in human studies that TZD treatment may preserve beta cell function, one of the important changes in the progression from IGT to DM2. Ovalle and colleagues studied a small group of DM2 patients poorly controlled on metformin and sulfonylurea and added either rosiglitazone or insulin. Both groups achieved similar glycemic control, but only the rosiglitazone group had improved beta cell function as indicated by several clinical measures (Ovalle and Bell 2004). Most additional studies have noted lower fasting and postprandial blood glucose, free fatty acids and fasting insulin levels, suggesting that TZDs improve insulin sen- sitivity (reviewed in Yki-Jarvinen 2004). For women with gestational diabetes, a state which reﬂects IGT, TZD treat- ment prevented the progression to DM2 (TRIPOD/PIPOD) (Xiang et al 2006). Pioglitazone has been shown to be effective in secondary prevention of macrovascular events in patients with known macrovascular disease. Over a 34 month placebo-controlled RCT, Pioglitazone reduced risk in the secondary composite endpoint of all cause mortal- ity, non fatal MI and stroke. A1C, triglycerides, LDL were all decreased and HDL was increased signiﬁcantly. There was an increase in congestive heart failure on pioglitazone (Dormandy et al 2005). A meta-analysis of 23 RCTs revealed a similar decrease in A1C (1–1.5%), but with an increase in weight (approximately 3 kg). Pioglitazone decreased TG, increased HDL and had no effect on LDL or total cholesterol. Rosiglitazone increased HDL, but was neutral on triglycer- ides and increased TC and LDL (Chiquette et al 2004). A similar result on lipids is reported comparing addition of pioglitazone or rosiglitazone to patients on glimeperide which found pioglitazone addition lowered TC, LDL, TG and raised HDL, where rosiglitazone addition increased TC, LDL and TG, with no change on HDL (Derosa et al 2005a). This dif- ference may be due to activation of PPARα by pioglitazone in addition to PPARγ, by contrast to rosiglitazone which more selectively activates PPARγ (Kersten et al 2000). In addition to insulin resistance and beta cell failure, the other principle pathophysiologic defect in DM2 is excessive hepatic gluconeogenesis (Magnusson et al 1992). Metformin is a member of the biguanide class of antidiabetic agents. Its principle clinical efﬁcacy lies in its action to block hepatic gluconeogensis, and increase hepatic insulin sensitivity, and to a lesser extent increase insulin-mediated glucose uptake in fat and muscle tissue (Rossetti et al 1990; Perriello et al 1994; Bailey and Turner 1996; Large and Beylot 1999; Hundal et al 2000). Biguanide-containing compounds have been used since ancient times for the treatment of diabetes. Metformin Vascular Health and Risk Management 2007:3(4)