Stockholm-New research suggests that metformin-associated vitamin B12 deficiency may increase the risk of clinical peripheral neuropathy in patients with diabetes. At the 2015 European Diabetes Association meeting, Dr. Mattijs Out from the Netherlands presented his study and said that the European Association for the Study of Diabetes (EASD) and American Diabetes Association guidelines mention vitamin B12 deficiency among the risks of metformin for the treatment of type 2 diabetes, but do not recommend screening or supplementation recommendations. Dr. Out noted that it is important for metformin to cause vitamin B12 deficiency in patients with diabetes, and that vitamin B12 deficiency can lead to neuropathy or psychiatric changes that may be irreversible and whose effects can be far-reaching, but may be difficult to diagnose clinically because they can be attributed to old age or diabetes itself. Vitamin B12 deficiency, on the other hand, is relatively easy to diagnose and easy to manage, and treatment is inexpensive and effective. The use of metformin has been noted in previous studies to be associated with vitamin B12 deficiency (<150 pmol/L). Concern has arisen that metformin may be a cause of peripheral neuropathy independent of diabetes. In the current study, Dr. Out and colleagues examined for the first time a very specific biologic tissue marker for B12 deficiency: methylmalonic acid (MMA), and looked at its effects through neuropathy scores. They found that the overall increase in MMA offset the benefit of the hypoglycemic effect of metformin. Measuring the relative effects of metformin: glycosylated hemoglobin VSMMA (methylmalonic acid) Dr. Out and colleagues aimed to examine two relative effects of metformin: a decrease in glycosylated hemoglobin (HbA1c), which improves the neuropathy score; and an increase in MMA, a marker of B12 exhaustion, which worsens peripheral neuropathy. Data from the study were obtained from 390 patients with type 2 diabetes treated with insulin in the Netherlands, and subjects were randomly assigned to take 850 mg of metformin or placebo three times a day for a mean of 4.3 years. results from the initial trial in 2010 showed that patients on long-term metformin had a 19% higher risk of developing vitamin B12 deficiency (p<0.001) and a 5% higher homocysteine concentration. cysteine concentrations were 5% higher (P=0.09). However, during the congress question and answer session, some physicians expressed doubts about Dr. Out's findings, stating that they had encountered little to no vitamin B12 deficiency in their decades of metformin use. Conference moderator Professor Schernthaner was also skeptical, feeling that the study was unconvincing and that larger data studies are needed to explore the incidence of vitamin B12 deficiency. Dr. Out pointed out that with more than 100 million metformin prescriptions per year worldwide, many patients may be at risk. We should screen for vitamin B12 deficiency after 4 years of metformin use or supplement all patients with vitamin B12. perhaps develop a metformin-vitamin B12 combination drug.