Metformin is the preferred initial glucose-lowering agent for treating type 2 diabetes mellitus (T2DM).1 With more than 80 million prescriptions for metformin filled per year, it is the most commonly used T2DM medication in the United States. A potential adverse effect of long-term metformin treatment is vitamin B12 (cobalamin) deficiency due to decreased absorption. Undetected and untreated, B12 deficiency can lead to a range of clinical problems, including reversible megaloblastic anemia and demyelinating neurologic disease. These disorders can be prevented, however, with early detection of B12 deficiency and initiation of replacement therapy.
Frequency of Metformin-Associated B12 Deficiency
An association between metformin therapy and B12 deficiency was first reported in 1969. Since then, many small, short-term studies have reported an increased risk for biochemical vitamin B12 deficiency in patients taking metformin, with an incidence ranging from 5.6% to 36%.2-4 A large long-term study published in 2016 reaffirmed that B12 deficiency affects a small but significant proportion of patients taking metformin.5 This study analyzed data on 1,800 participants from the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study who were at high risk for T2DM. The participants were randomly assigned to receive metformin 850 mg twice daily or placebo for 3.2 years, and those in the metformin group received metformin for an additional 9 years. Vitamin B12 levels were measured at 5 years and 13 years. At 5 years, low B12 levels occurred in significantly more participants in the metformin group (4.3%) than in the placebo group (2.3%). In addition, low and borderline-low B12 levels were found in more than 19% of metformin patients but in less than 10% of placebo patients.
Effects of B12 Deficiency
Vitamin B12 is a water-soluble micronutrient necessary for the formation of red blood cells and for the normal functioning of the central nervous system. The principal source of B12 is animal proteins (fish, meat, poultry, eggs, and dairy products). The daily recommended dietary amount for adults is 2.4 Î¼g.
Deficiency of vitamin B12 can result in neurologic, cognitive, and hematologic manifestations, most notably peripheral neuropathy, cognitive impairment, and macrocytic anemia. Other neurologic abnormalities associated with B12 deficiency include diminished vibration, position, and touch sense; ataxia; numbness or tingling in the arms and legs; muscle weakness; hypo/hyperreflexia; and loss of balance. Patients and clinicians often misinterpret the neurologic signs and symptoms of vitamin B12 deficiency as those of diabetic neuropathy.2 Also, vitamin B12 deficiency can increase the severity of peripheral neuropathy in patients with T2DM.6 In addition to memory impairment, neurocognitive symptoms attributable to B12 deficiency include confusion, personality changes, delirium, and depression.
It can take up to 5 years before a deficiency manifests itself clinically, and NPs should be aware and alert to the possibility of B12 deficiency in their patients on prolonged metformin. Furthermore, patients can have more than one factor that contributes to B12 deficiency. Common causes include dietary deficiency (eg, vegan or vegetarian diet, low intake of meat or dairy products), use of proton-pump inhibitors or H2 blockers, and poor B12 absorption due to age-related changes in the stomach (eg, atrophic gastritis). The prevalence of B12 deficiency in those older than 60 years is between 10% and nearly 20%.7,8 Because multiple causes can coexist in elderly patients, including poor absorption, protracted metformin use, and reduced dietary intake, these patients have the greatest risk for B12 deficiency and should be carefully monitored for signs of deficiency.
There are no well-recognized clinical guidelines that provide recommendations on the frequency or dose of vitamin B12 supplementation for patients with T2DM who take metformin. One author recommends oral vitamin B12 500 to 1,000 Î¼g monthly.9 This is the advice I follow in my practice. Additional sources focus on routine testing of vitamin B12 levels in patients on metformin, which is helpful though costly.
NPs who prescribe metformin for an extended period, no matter the indication (eg, T2DM prevention and treatment, polycystic ovary syndrome), should consider B12 supplementation as well as perform routine measurement of vitamin B12 levels, both when starting metformin and at intervals of no more than one to two years thereafter (note that the optimal frequency has not been determined, and metformin can begin to decrease serum B12 levels in as little as three months).6 A recent study showed that clinicians initially prescribing metformin measure vitamin B12 levels less than half the time.10 In this study of 5,131 patients with T2DM who started taking metformin during a 5-year study period (2008-2013), only 44.5% had vitamin B12 tested.
Testing for Vitamin B12 Deficiency
The first step in testing for vitamin B12 deficiency in patients with T2DM is the measurement of vitamin B12 serum levels, with a level >400 pg/mL ruling out deficiency and a level <200 pg/mL in a symptomatic patient confirming its presence.11,12 When serum B12 is between 200 and 400 pg/mL or there is uncertainty about the diagnosis, levels of two metabolites, methyl-malonic acid (MMA) and homocysteine, are checked. Vitamin B12 is a cofactor in the enzymatic reaction that converts MMA to succinyl-CoA, and B12 and folic acid are co-factors in the reaction that converts homocysteine to methionine. Without sufficient B12 to facilitate these reactions, levels of MMA and homocysteine rise.12 Normal ranges for serum homocysteine and MMA concentrations are 5-15 Î¼mol/L and <0.28 Î¼mol/L, respectively.11
Researchers have noted that elevated MMA and homocysteine levels have higher sensitivity and specificity than the serum B12 assay in diagnosing deficiency and that false-positive and false-negative results often occur with the serum B12 assay.9,12 For example, when used as the only lab test for deficiency, the B12 assay can incorrectly identify up to 50% of the time which patients will have a hematologic or neurologic response to treatment.12 It is important to note, however, that MMA and homocysteine are not useful in patients who have already received replacement therapy. In addition, folic acid must be measured along with homocysteine because folic acid deficiency can cause the homocysteine level to rise.12
Low B12 levels are easily restored with B12 (cyanocobalamin) supplements. All patients diagnosed with low levels of vitamin B12 should receive replacement therapy with either oral or parenteral vitamin B12 therapy, which are equally effective.9 Oral therapy is less expensive and more convenient than injection therapy since a healthcare provider must administer the injections in an office setting. In adult patients with T2DM, intramuscular injections (eight to 10 loading injections of 1,000 Î¼g each over one to two weeks, followed by monthly 1,000-Î¼g injections) or oral vitamin B12 1,000 to 2,000 Î¼g daily are sufficient to correct vitamin B12 deficiency.9
Patients should be monitored for response to therapy. For patients with clinical deficiency, effective replacement therapy should lead to a normal blood count after two months of treatment, while improvement in neurologic symptoms begins within one week after initiation of therapy and is usually complete within 6 weeks to 3 months.13 For patients with an asymptomatic biochemical deficiency (ie, subclinical disease), measurement of serum B12 or MMA levels should be done 2 to 3 months after initiation of replacement therapy.12
Once metformin is started, this medication is seldom discontinued unless advanced renal impairment develops. Therefore, most patients will need lifelong maintenance replacement therapy of vitamin B12 following the correction of their deficiency. Maintenance therapy is intramuscular (1,000 Î¼g every month) or oral vitamin B12 1,000 Î¼g daily.9,12
Metformin-associated vitamin B12 deficiency is preventable. NPs should take a proactive approach to prevent it by monitoring vitamin B12 or MMA concentrations during long-term metformin treatment and prescribing replacement therapy when low levels of B12 or increased levels of MMA are found.
- American Diabetes Association. 9. Pharmacologic approaches to glycemic treatment: Standards of Medical Care in Diabetesâ€”2019. Diabetes Care. 2016;42(Supplement 1): S90-S102.
- Zdilla M. Metformin with either histamine H2-receptor antagonists or proton pump inhibitors: a polypharmacy recipe for neuropathy via vitamin B12 depletion. Clin Diabetes. 2015;33:90-95.
- Berchtold P, Bolli P, Arbenz U, Keiser G. [Disturbance of intestinal absorption following metformin therapy (observations on the mode of action of biguanides]. Diabetologia. 1969;5(6):405-412. German.
- Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakely GP. Association of biochemical B12 deficiency with metformin therapy and vitamin B12 supplements. The National Health and Nutrition Examination Survey, 1999- 2006. Diabetes Care. 2012;35:327-333.
- Aroda VR, Edelstein SL, Goldberg RB, et al. Longterm metformin use and vitamin B12 deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016;101:1754-1761.
- Wile DJ, Toth C. Association of metformin, elevated homocysteine, and methylmalonic acid levels and clinically worsened diabetic peripheral neuropathy. Diabetes Care. 2010;33:156-161.
- Baik HW, Russell RM. Vitamin B12 deficiency in the elderly. Annu Rev Nutr. 1999;19:357-377.
- Hunt A, Harrington D, Robinson S. Vitamin B12 deficiency. BMJ. 2014;349:g5226.
- Stabler SP. Vitamin B12 deficiency. N Engl J Med. 2013;368:149-160.
- Fogelman Y, Kitai E, Blumberg G, Golan-Cohen A, Rapoport M, Carmeli E. Vitamin B12 screening in metformin-treated diabetics in primary care: were elderly patients less likely to be tested? Aging Clin Exp Res. 2017;29:135-139.
- Kibirige D, Mwebaze R. Vitamin B12 deficiency among patients with diabetes mellitus: is routine screening and supplementation justified? J Diabetes Metab Disord. 2013;12(1):17.
- Oh RC, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67:979-986,993-994.
- Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008:112:2214-2221.