Japanese study to more than 3kd in non-Japansese studies (Chiquette et al 2004). In the largest study of TZD combined with metformin, weight gain of about 2 kg occurred on the highest rosiglitazone dose with metformin (Fonseca et al 2000). Frank edema was present in about 4% of patients (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007), and body water retention is felt to contribute to about 75% of the weight gain on TZDs (Basu et al 2006). Insulin is a potent anti-natriuretic hormone (DeFronzo et al 1976), it may be that TZD treatment sensitizes to the anti-natriuretic actions of insulin, contributing to edema. Anemia was present in 4% – likely the result of hemodilution associated with ﬂuid retention. Interestingly, a smaller part of weight gain comes from a re-distribution of fat from the visceral compartment to subcutaneous compartment (Miyazaki et al 2002). This visceral fat is classically considered more pathogenic in diabetes than subcutaneous fat, thus fat re-distribution is likely one of the major mechanisms by which TZDs mediate their beneﬁcial effects on insulin sensitivity (Gastaldelli et al 2002). According to manufactures’ prescribing information, TZD/metformin is contraindicated in patient that exhibit clinical evidence of active liver disease or increased serum transaminase levels, renal disease or renal dysfunction (eg, as suggested by serum creatinine levels 1.5 mg/dL (males), 1.4 mg/dL (females), acute or chronic metabolic acidosis. Although TZDs are contraindicated in acute liver disease, their insulin sensitizing effects may prove to be beneﬁcial in the treatment of non-alcoholic fatty liver disease (reviewed in Caldwell et al (2006)). TZDs should be avoided in patients with CHF, severe edema or macular edema. TZDs are considered class C for pregnancy (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007). Any metformin containing drug should be stopped before radiologic procedures with iodinated IV contrast for risk of lactic acidosis. No data is available for combined use of metformin-TZD in pediatric patients. Rosiglitazone is predominantly metabolized by CYP2C8, and to a lesser extent, CYP2C9. Gemﬁborzil increases rosi- glitazone levels. Rifampin reduceds rosiglitazone levels. Furosimide increases metformin levels, as does Nifedipine. Cationic drugs (eg, amiloride, digoxin, morphine, trim- ethoprim, and vancomycin and others) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing renal excretion (GlaxoSmithKline 2007). Pioglitazone is metabolized by CYP2C8 and to a lesser extent CYP3A4, thus drug inter- actions include midazolam, nifedipine ER, ketoconazole, atorvastatin (Takeda Pharmaceuticals 2007). Full details Vascular Health and Risk Management 2007:3(4) Thiazolidinediones in combination with metformin of cautions, contraindications, drug interactions and phar- macokinetics are available in the prescribing information from the manufactures (GlaxoSmithKline 2007; Takeda Pharmaceuticals 2007). Availability Rosiglitazone-metformin (Avandamet™) is available in the following doses of rosiglitazone/metformin, respectively; 1 mg/500 mg, 2 mg/500 mg, 4 mg/500 mg, 2 mg/1000 mg, 4 mg/1000 mg. Rosiglitazone-metformin can be titrated up to a maximal total daily dose of 8 mg/2000 mg (GlaxoSmithKline 2007). One published study of healthy volunteers received; metformin 500 mg, rosiglitazone 2 mg, or each twice daily for four days. Coadministration of rosiglitazone and metformin had no effects on steady state pharmacokinetics of either drug (Di Cicco et al 2000). Pioglitazone-metformin (Actoplus Met™) is available in doses of pioglitazone/metformin, respectively of; 15 mg/500 mg or 15 mg/850 mg with recommended maximal daily dosing of 45 mg/2550 mg (Takeda Pharmaceuticals 2007). Mechanisms of action The glucose lowering effects of metformin are largely attributable to an increase in glucose uptake by muscle and decrease in hepatic glucose production (Perriello et al 1994; Bailey and Turner 1996; Large and Beylot 1999; Hundal et al 2000). TZDs primarily act to improve insulin sensitiv- ity (reviewed in Yki-Jarvinen 2004). Detailed summaries of the mechanisms of action of both metformin and TZDs have been reviewed elsewhere and are beyond the scope of this review (Bailey and Turner 1996; Kirpichnikov et al 2002; Yki-Jarvinen 2004). This section focuses on potential cellular and molecular mechanisms by which the combined use of metformin and TZD may be beneﬁcial, and also mechanisms of possible side effects. AMP-activated protein kinase (AMPK) is a heterotri- meric complex which responds to the energy status of the cell in that an increase in the AMP:ATP ratio causes threonine phosphorylation, and thus activation of AMPK (Hawley et al 1996). In response to AMPK activation the cell decreases ATP-consuming and increases ATP-producing pathways, thus a potential metabolic sensor for the cell (Hardie et al 1998). Both Metformin and TZDs activate AMPK through distinct pathways, thus AMPK may be a mediator of the protective effects of metformin and TZDs on insulin action (Fryer et al 2002). The efﬁcacy of combination of TZD and metformin may be in part due to prevention of fatty-acid induced insulin 507