Nonetheless, the contraindication to metformin use in patients with HF has been removed.151 Metformin, which is excreted by the kidneys, remains contraindicated in patients with renal insufficiency, a comorbid condition particularly relevant in patients with HF. The package in- sert states that metformin should not be used in men with serum creatinine levels 1.5 mg/dL and in women but the exact level of renal insufficiency precluding metformin use remains contro- In the United Kingdom, National Institute for Health and Clinical Excellence guidelines suggest that metformin can be used to an estimated glomerular fil- (with a dose reduction advised at an estimated glomerular filtration rate <45 Given these concerns, metformin should be used cautiously (or avoided) in patients at risk for worsening renal dysfunction (eg, acute decompen- sated HF). Further prospective human studies are neces- sary to assess the potential benefits and safety of met- formin in patients with diabetes mellitus and HF. Thiazolidinediones have been associated with fluid retention and increased rates of HF in randomized, controlled trials of patients predominantly free of HF at The exact mechanisms contributing to in- creased HF events with thiazolidinediones are not known, but the predominant proposed mechanism relates to thiazolidinedione-associated volume expansion resulting from increased renal sodium reabsorption159 rather than a direct effect on myocardial structure and function.160 Prospective, randomized, controlled studies specifically in patients with established HF and diabetes mellitus have demonstrated increased rates of edema, a need for in- creased HF medications, and increased HF hospitaliza- tion in patients treated with thiazolidinediones compared with patients treated with placebo or sulfonylurea.161,162 Given these findings, caution is urged for the use of thia- zolidinediones in all patients with signs and symptoms of HF, and initiation of either agent is contraindicated in patients with NYHA class III to IV HF155,163 (Table 6). 