Increased Risk of Cognitive Impairment in Patients With Diabetes Is Associated With Metformin

OBJECTIVETo investigate the associations of metformin, serum vitamin B₁₂, calcium supplements, and cognitive impairment in patients with diabetes.RESULTSParticipants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B₁₂, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).CONCLUSIONSMetformin use was associated with impaired cognitive performance. Vitamin B₁₂ and calcium supplements may alleviate metformin-induced vitamin B₁₂ deficiency and were associated with better cognitive outcomes. Prospective trials are warranted to assess the beneficial effects of vitamin B₁₂ and calcium use on cognition in older people with diabetes who are taking metformin.In 2010, more than 346 million people had diabetes worldwide. Recent studies from the U.K. (1) and Italy (2) reported that the adult prevalence of diabetes was approximately 4.2%. In the U.S., the prevalence of diabetes in the adult population may be as high as 14% when undiagnosed cases are included (3). The prevalence of diabetes may be higher in some developing nations: in the developing region of southern China it was reported to be 21.7% in 2010 (4). The prevalence of diabetes is more than 20% in some Pacific Island nations, reaching 47% in 22- to 64-year-old American Samoans (5).In diabetes, hyperglycemia activates the cellular signaling protein kinase C, which induces production of the vasoconstrictor protein endothelin-1. Excess intracellular glucose is converted to sorbitol by the enzyme aldose reductase. When intracellular levels of glucose are high, this process exhausts the energy substrate NADPH, resulting in oxidative stress. High intracellular sorbitol levels cause osmotic stress and cell death. These biochemical changes in hyperglycemia are a proposed mechanism for macrovascular and microvascular complications and neuropathy (6–8). Diabetes is associated with a faster rate of cognitive decline in those with mild cognitive impairment (MCI) (9) and an increased risk for developing Alzheimer disease (AD) (10).Approximately 90% of patients with diabetes have type 2 diabetes (1). The biguanide metformin is a first-line treatment for type 2 diabetes, increasing glucose uptake in muscle while reducing liver gluconeogenesis (the synthesis of glucose from amino acids). These effects are mediated by activation of the cellular signaling protein AMP–activated protein kinase (11).Metformin first became available in the U.K. in 1958 and entered the Canadian market in 1971, but it has been available in the U.S. only since 1995. In a survey of 65,000 U.S. war veterans (12), metformin use among those with diabetes increased from 29% in 2000 to 63% in 2005. Among 242 Australian veterans who had diabetes, metformin was used by 75% in 2005 but decreased to 57% in 2009 (13).The rate of vitamin B₁₂ deficiency among patients who are taking metformin is reported to approach 30% (14–16). A drug interaction between metformin and the cubilin receptor inhibits the uptake of vitamin B₁₂ from the distal ileum, lowering serum vitamin B₁₂ levels. In a long-term, randomized, placebo-controlled trial, metformin therapy in type 2 diabetes was associated with a 19% reduction in serum vitamin B₁₂ concentrations compared with placebo (17). In a case-control study, Wile and Toth (18) reported that metformin use was associated with reduced vitamin B₁₂ levels and more severe peripheral neuropathy in patients with diabetes.In a prospective trial, calcium supplements were reported to reverse the drug interaction that causes vitamin B₁₂ deficiency induced by metformin (19). The clinical significance of alleviating metformin-induced vitamin B₁₂ malabsorption by calcium supplementation has not been previously investigated. By correcting vitamin B₁₂ levels in patients with diabetes who use metformin, calcium supplements may help to preserve cognitive function. In addition, neuronal signaling in memory and learning involves a calcium-mediated process, so calcium supplementation may also have a direct effect on the brain. Calcium dysregulation is the subject of one proposed theory for age-related cognitive changes and AD (20). The risks and potential benefits of calcium supplementation on cognition and for alleviating vitamin B₁₂ malabsorption merit further investigation.The amyloid plaques seen in the brains of patients with AD are formed by aggregation of Aβ peptides. In cell cultures, Chen and colleagues (21) reported that activation of AMP–activated protein kinase by metformin increased the expression of β-secretase, an enzyme that increases the formation of Aβ peptides. One recent case-control study that included 14,172 participants 65 years of age or older reported that taking metformin over the long term increased the risk of AD (odds ratio [OR] 1.71 [95% CI 1.12–2.60]) (22).Recent studies of murine models of diabetes indicate that metformin may attenuate irregularities in phosphorylation of tau proteins (23) or may facilitate neuroneogenesis (24) and so may be of benefit to those with AD. In 25,393 patients older than 50 years with type 2 diabetes, metformin was reported to reduce the risk of dementia by 24% (hazard ratio 0.76 [95% CI 0.58–0.98]) (25). The purpose of our study was to investigate the associations of metformin, serum vitamin B₁₂ levels, and cognition in a sample of patients with diabetes.