Stafford and Elasy A RCT with pioglitazone randomized 328 patients to pioglitazone-metformin or metformin-placebo for 16 weeks and found the pioglitazone group had a signiﬁcant A1c decrease of 0.83% compared to placebo-metformin. There was a signiﬁcant improvement in insulin resistance by HOMA-IR (Einhorn et al 2000). When a sulfonylurea is used with metformin as a control group rather than placebo-metformin, several studies have demonstrated similar glycemic control (Charbonnel et al 2005; Matthews et al 2005; Umpierrez et al 2006). Two studies by the same group compared more long term combination use of piogli- tazone added to metformin (Charbonnel et al 2005; Matthews et al 2005). One was a one year double blind study that com- pared metformin-pioglitazone combination with metformin- gliclazide. The authors found similar decreases in A1C and FPG with each treatment (Matthews et al 2005). The study that went for two years also found similar reductions in A1C, and slightly better FPG with metformin-pioglitazone com- bination compared with metformin-gliclazide (Charbonnel et al 2005). These results suggest that the glycemic effects of combination therapy with metformin-pioglitazone can be sustained for at least two years. Of note, similar improvements in glycemic control with the combined use of metformin and thiazolidinediones were noted in Mexicans, who have a signiﬁcant burden of diabetes (Gomez-Perez et al 2002). Weissman and colleagues in a multi-center double blind RCT with 766 subjects compared adding rosiglitazone to 1000 mg of metformin with dose escalation of metformin for 24 weeks. They found improve- ments in FPG and A1C with rosiglitazone-metformin over metformin dose escalation (Weissman et al 2005), a potential beneﬁt for patients unable to tolerate full dose metformin. In an open labeled RCT, Dailey and colleagues added rosi- glitazone vs. placebo to patients already on metformin and glyburide. They found improved A1C and FPG with the addition of rosiglitazone (Dailey et al 2004). In a randomized, open-label parallel trial either insulin glargine or rosi- glitazone was added to patients with inadequate glycemic control on metformin plus sulfonylurea. These authors found similar improvements in glycemic control with both regimens (Rosenstock et al 2006). Cardiovascular effects of combined use of metformin-TZDs The RCT by Fonseca and colleagues with rosiglitazone described above also looked at secondary endpoints known to be important for cardiovascular health with metformin- rosiglitazone (Fonseca et al 2000). There were small but 506 statistically signiﬁcant increases in HDL cholesterol. There were no changes in triglycerides. Total cholesterol and LDL levels were statistically increased with either rosiglitazone group (LDL levels increased from 112 mg/dl to 133 mg/dl in the 8 mg/d rosiglitazone-metformin group). Free fatty acid levels, which are a potential mediator of insulin resis- tance, were decreased in both rosiglitazone groups. Both rosiglitazone groups had a small but signiﬁcant decrease in hemoglobin levels, weight gain (Fonseca et al 2000). Several other RCTs found worsening lipid proﬁles with the addition of rosiglitazone to metformin (Gomez-Perez et al 2002; Weissman et al 2005; Rosenstock et al 2006). The weight gain and increase in LDL are important considerations in patients already at risk for cardiovascular disease. Two RCTs published with pioglitazone revealed statisti- cally signiﬁcant improvements in TGs and HDL, but little change in TC or LDL (Einhorn et al 2000; Betteridge and Verges 2005), whereas two others from the same group found that at one year of combined therapy with metformin- pioglitazone, TC, HDL and TG were improved, but LDL was elevated (Matthews et al 2005), but at two years pio- glitazone-metformin group had improved TG, HDL and no change in LDL (Charbonnel et al 2005). These studies are somewhat consistent with the more beneﬁcial lipid proﬁle of pioglitazone compared to rosiglitazone as single agents (Chiquette et al 2004). Additionally, pioglitazone inﬂuences LDL particle size with an increase in large LDL particles and a decrease in small particles, consistent with a potentially less atherogenic cholesterol proﬁle (Perez et al 2004). Insulin resistance is a central feature of the metabolic syndrome. An Italian study evaluated addition of glimepiride or rosiglitazone to metformin therapy for patients with poorly controlled DM2, hypertension, obesity and dyslipidemia. They found that addition of rosiglitazone to metformin brought about more rapid improvements in A1C and FPG, but glycemic control was similar at 12 months compared to addition of glimepiride to metformin. They did ﬁnd mod- est but statistically signiﬁcant improvements in systolic blood pressure and diastolic blood pressure in patients on metformin-rosiglitazone compared to the metformin- glimepiride group (Derosa et al 2005b). Side effects and contraindications Weight gain, edema and, depending on which TZD is selected, worsened lipid proﬁles are the most common side effects of adding a TZD to metformin and are similar to the side effects of the TZDs as single agents. The average weight gain on TZDs is 2.7 kg, with a range of 0.7 kg in a Vascular Health and Risk Management 2007:3(4)