Reprinted from Aguilar et al123 with permission from the American College of Cardiology Foundation. Copyright 2009, American College of Cardiology Foundation. Bozkurt et al was previously contraindicated in individuals with HF because of potential concerns about lactic acidosis.133 Subsequent analyses and reviews have suggested that the risk of lactic acidosis associated with metformin is extremely low in patients with type 2 diabetes mellitus and may not be higher than in diabetic patients not re- ceiving metformin therapy.134 136 In addition, multiple ob- servational studies in patients with diabetes mellitus and established HF have suggested that metformin not only may be safe but also may be associated with improved survival in patients with diabetes mellitus and HF.137 145 Animal studies in HF models have also demonstrated potential cardioprotective effects of metformin therapy on the progression of HF via activation of AMP-activated protein kinase pathways,146 149 inhibition of cardiac fibro- and modulation of cardiomyocyte autophagy.147 It is important to note that prospective, large outcome trials assessing the safety and efficacy of metformin in patients with established HF have not been performed. 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. 