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). Sulfonylureas are commonly used in diabetic patients with HF. In a study of >16000 Medicare recipients who had been discharged with a diagnosis of HF, approxi- mately half of the patients were treated with sulfonyl- In that observational study, sulfonylurea was not associated with increased mortality (HR, 0.99; 95% Some observation studies have sug- gested improved survival with metformin compared with Prospective, randomized, controlled trials on sulfonylurea use in patients with HF have not been performed. Important adverse effects relevant to patients with HF include the risk of hypoglycemia and weight gain associated with sulfonylurea therapy. The new-generation sulfonylureas (eg, glyburide, gliclazide, glipizide, glimepiride) have largely replaced the first- generation agents (eg, acetohexamide, chlorpropamide, tolazamide, tolbutamide) in routine use because they are more potent, can be administered in lower doses, and can be given on a once-daily basis. A few studies based on older-generation sulfonylureas have led to conflicting results for cardiovascular risk. 