Prospective data from subgroups of clinical trials assessing optimal glycemic targets in pa- tients with HF also are limited. In VADT, which examined an intensive glycemic control strategy compared with standard care, individuals with NYHA class III to IV HF and the outcomes of subsets of dia- betic individuals who may have less advanced HF have not been reported separately.129 In the ACCORD trial, which examined whether a therapeutic strategy targeting normal HbA1c (ie, <6.0%) would reduce the rate of car- diovascular events compared with a strategy targeting HbA1c levels from 7.0% to 7.9% in diabetic patients with established cardiovascular disease (CVD) or high CVD risk, 5% of individuals (n=494) had HF at baseline.130 In ACCORD, there was an unexpected finding of increased mortality in the intensive treatment arm compared with the standard therapy arm.130 This increased hazard was not statistically different in patients with and without HF at baseline (interaction P=0.71).131 Safety and Efficacy of Antihyperglycemic Drugs in Patients With Established HF and Diabetes Mellitus The optimal hyperglycemic therapy in patients with HF with diabetes mellitus has not been well defined, and some antihyperglycemic drugs may pose challenges for patients with HF. In diabetes, metformin is currently recommended as first-line therapy in patients with type 2 diabetes melli- tus in the absence of contraindications.132,133 Metformin Figure 4. The U-shaped association between the proportion of patients who died at the 2-year follow-up according to quintiles (Q) of hemoglobin A1c (HbA1c) in diabetic patients with heart failure, with the lowest risk of death in those patients with modest glucose control (7.1%<HbA1c 7.8%). P=0.001. Error bars indicate 95% confidence intervals. Reprinted from Aguilar et al123 with permission from the American College of Cardiology Foundation. Copyright 2009, American College of Cardiology Foundation. 