Response to Rosenfeld

To the Editor: We appreciate Dr. Rosenfeld bringing attention to a recent report by Imfeld et al. (1) suggesting that long-term metformin use may increase the risk for Alzheimer’s disease in elderly patients with diabetes mellitus. In fact, a number of clinical and preclinical reports within the past 5 years have provided conflicting data on the relationship between Alzheimer’s disease and metformin. In neuronal cell cultures, metformin can increase production of β-amyloid peptides via transcriptional upregulation of β-secretase activity (2). However, in a mouse model of type 2 diabetes, metformin treatment was associated with a reduction in phosphorylated tau and total tau proteins, primary components of neurofibrillary tangles (3). Imfeld et al. observed a modest increase in risk for Alzheimer’s disease (adjusted odds ratio=1.71, 95% confidence interval [CI]=1.12–2.60) in 7,086 individuals age 65 years and older with diabetes (mean age, 80.7 years) and long-term metformin use (1). In contrast, a prospective cohort study of 127,209 individuals age 50 years and older without dementia, followed over an 8-year period, found that type 2 diabetes was associated with a more than twofold greater risk of dementia and that metformin reduced this risk by about 25% (4). Taken together, these data indicate the need for further research to better understand the potential relationship between metformin and Alzheimer’s disease. Currently, the available data do not support indefinite use of metformin for weight loss in overweight patients with schizophrenia given that the longest studies have lasted 24 weeks. However, because of excess mortality due to cardiovascular disease in schizophrenia, metformin may have a long-term role because of its ability to reduce cardiometabolic risk factors. Longer studies that include an assessment of both cardiometabolic risk factors and cognitive functioning can help further address the long-term risks and benefits of metformin use in overweight patients with schizophrenia.