Stafford and Elasy resistance, or lipotoxicity (the concept of lipotoxicity is reviewed in Unger (2005)). Ye and colleagues demonstrated by hyperinsulinemic clamp studies in rats that both metformin and rosiglitazone improved insulin sensitivity, by improv- ing insulin-mediated suppression of hepatic glucose output (Ye et al 2004). Rosiglitazone additionally enhanced free fatty acid (FFA) clearance, measured by 3H-R-bromopalmitate tracer technique (Ye et al 2004). Rosiglitazone increased FFA uptake by adipose and reduced uptake by the liver and muscle, as well as decreased liver long-chain CoA accumulation, a potential mediator of fatty-acid induced insulin resistance (Lee et al 1994; Ye et al 2004). Additionally this group has demonstrated that pioglitazone protects from FFA-induced insulin resistance in the liver (Ye et al 2002). In addition to fatty acids, many inﬂammatory mediators, when elevated, can cause insulin resistance in animal models and may contribute to the pathogenesis of DM2. These in- clude CRP, an important protein in leptin action (Chen et al 2006), and TNFα (reviewed in Moller 2000). In one double blind RCT of patients with metabolic syndrome, rosiglitazone 8 mg qd for 12 wks, increased adiponectin, lowered resistin, CRP and TNFα (Samaha et al 2006). Adiponectin levels are inversely correlated with cardiovascular risk, thus an increase would be predicted to beneﬁt cardiovascular health (Pischon et al 2004). Lowering levels of resistin, CRP and TNFα should contribute to improved insulin resistance. In the study by Samaha, however, despite beneﬁcial changes in inﬂam- matory mediators of insulin resistance, there was very little improvement in other clinical parameters known to contribute to cardiovascular risk, with an increase in total cholesterol, and no signiﬁcant changes in HDL or LDL (Samaha et al 2006). In addition to the effects on FFA ﬂux and glucose, TZD treatment may have beneﬁcial effects on vascular health directly. PPAR gamma is expressed in endothelial cells, and may have important role in vascular restenosis (reviewed in (Bruemmer et al 2005). In cultured endothelial cells ligand activation of PPAR gamma has been shown to inhibit thrombin-induced endothelin-1 production (Delerive et al 1999) and plasminogen activator inhibitor type 1 expression (Kato et al 1999). In people, progression of carotid intima-media thickness, a marker of atheroscle- rotic disease, is improved with pioglitazone (Mazzone et al 2006). In one double blind RCT, diabetic patients were treated with metformin or rosiglitazone. In the rosiglitazone group, intra-arterial acethylcholine-mediated vasoidailation (an indicator of arterial endothelial function) was improved by 40% and correlated with a decrease in FFA and TNFα (Natali et al 2004). 508 In summary, the combined use of metformin and a TZD have signiﬁcant improvements in glycemic control. The main efﬁcacy of combined therapy seems to be the effect of met- formin to decrease endogenous glucose production and that of TZDs to improve insulin sensitivity, together targeting two key pathophysiologic defects in DM2. Single pill combina- tions of both rosiglitazone-metformin (Avandamet™), and pioglitazone-metformin (Actoplus Met™) are available in Europe and the US. It is important to emphasize that potential cardiovascular beneﬁts from the combined use of metformin and a TZD are not established in clinical trials. While there is data on the cardiovascular beneﬁt of both drugs individually, UKPDS for metformin and PROactive for pioglitazone (UKPDS 1998; Dormandy et al 2005), little distal outcome data for the combined use of these agents in terms of morbidity or mortality is currently available. The RECORD (rosiglitazone evaluated for cardiac outcomes and regulation of glycemia in diabetes) study is underway, one arm of which will test rosiglitazone added to metformin for cardiovascular outcomes and progression of diabetes (Ovalle and Bell 2004). Search criteria In addition to the authors’ personal knowledge of the literature in this ﬁeld, databases reviewed include medline/ pubmed 1966 to May Week 5 2006, Cochrane Central Reg- ister of Controlled Trials, Cochrane Database of Systematic Reviews, EBM Reviews-Database of Abstracts of Reviews of Effects, ACP Journal Club 1991 to May/June 2006. Search terms included Rosiglitazone/troglitazone/pioglitazone AND Metformin, thiazolidinedione, vascular, cardiovascular, endothelial, diabetes, insulin resistance. Abbreviations Thiazolidinedione (TZD), type two diabetes mellitus (DM2), impaired glucose tolerance (IGT), total cholesterol (TC), triglycerides (TG), low-density lipoproteins (LDL), high- density lipoproteins (HDL), free fatty acids (FFA), fasting plasma glucose (FPG), hemoglobin A1C (A1C), randomized control trial (RCT), Cardiovascular disease (CVD), conges- tive heart failure (CHF). References Bailey CJ, Turner RC. 1996. Metformin. N Engl J Med, 334:574–9. Balletshofer BM, Rittig K, Enderle MD, et al. 2000. Endothelial dysfunction is detectable in young normotensive ﬁrst-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation, 101:1780–4. Basu A, Jensen MD, McCann F, et al. 2006. Effects of pioglitazone versus glipizide on body fat distribution, body water content, and hemodynam- ics in type 2 diabetes. Diabetes Care, 29:510–14. Vascular Health and Risk Management 2007:3(4)