The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) consider metformin, along with lifestyle changes, to be the cornerstone of pharmacological treatment in patients with type 2 diabetes mellitus (T2DM) and recommend it as first line therapy.1,2 Oral antihyperglycemic agents have shown neither benefit nor increases in cardiovascular risk; however, metformin has been shown to be beneficial in regards to improvements in cardiovascular morbidity and mortality.2,3,4 Pharmacological treatment with metformin in T2DM decreases hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity; however, it has also been shown to decrease vitamin B-12 and folic acid concentrations while increasing homocysteine concentrations in previous short-term studies.4,5 While decreased vitamin B-12 and folate concentrations can lead to macrocytic anemia, neuropathy, and mental changes, an increased homocysteine concentration is an independent risk factor for cardiovascular disease, especially in T2DM patients.4 Generally, within 8 years of being diagnosed with T2DM, 45% of patients experience a cardiovascular event; therefore, these factors are important when evaluating the use of metformin.6
de Jager and colleagues4 emphasized this point in a multicenter, randomized, double-blind, placebo-controlled study comparing metformin 850 mg versus placebo, both taken three times daily, in 390 patients with T2DM. The primary end point was the percent change in vitamin B-12, folate, and homocysteine concentrations from baseline at 4, 17, 30, 43, and 52 months. Men and women with T2DM, between the ages of 30 and 80 years who had been diagnosed after 25 years of age, who never had an episode of ketoacidosis, and who were taking oral antihyperglycemic agents, but now take insulin or combination insulin and metformin, were eligible for the study. Exclusion criteria included pregnancy or planning to become pregnant, a Cockroft-Gault estimated creatinine clearance of <50 mL/min, low plasma cholinesterase, patients with NYHA class III or IV, and other medical or psychiatric disease. Baseline characteristics were different in that patients randomized to metformin were older, more likely to have history of cardiovascular disease, and less likely to be a smoker.
When compared to placebo, high-dose metformin was associated with a 19% decrease in vitamin B-12 concentration (95% CI -24% to -14%; p<0.001), a 5% decrease in folate concentrations (95% CI -10% to -0.4%; p=0.033), and a 5% increase in homocysteine concentration (95% CI -1% to 11%; p=0.091). After accounting for body mass index and smoking, the decrease in folate concentrations was not statistically significant (-0.1%; p=0.57). Additionally, the increase in homocysteine concentration was not deemed to have statistical significance. The authors state that the prevalence of vitamin B-12 deficiency was not unexpected. Previous studies found increases in vitamin B-12 deficiency with long-term use of metformin. However, what is more alarming is the finding of a significant association in vitamin B-12 deficiency progression over time.4 With diabetes exponentially increasing and becoming more resistant to antihyperglycemic therapies, we may see a vitamin B-12 deficiency epidemic in the near future.
Some sources recommend that the administration of metformin should include monitoring for signs and symptoms of vitamin B-12 or folic acid deficiency at least every 2 to 3 years; however, it is not routine practice.3,4 With low vitamin B-12 concentrations and high MMA (methylmalonic acid requires vitamin B-12 for its conversion to succinyl coenzyme A, making it a more specific marker for vitamin B-12 deficiency) or both high MMA and high homocysteine concentrations, the administration of vitamin B-12 should be strongly considered to prevent permanent disabilities.7 These disabilities can range from mild paresthesias and numbness to memory loss and psychosis.7 Early treatment is vital because neurological damage can be irreversible.7 Due to efficient enterohepatic recycling, becoming vitamin B-12 deficient can take several years; however, the consequences of delayed treatment can been seen within months.7
There still seems to be a debate on whether to treat vitamin B-12 ...