Treatment of METFORMIN-induced vitamin B12 deficiency

AS A PHARMACIST, you'll get questions about METFORMIN and vitamin B12 deficiency. Up to 1 in 14 patients taking metformin for about 4 years develop B12 deficiency. It's probably even more common with longer use. In one study, this reduction appeared to be due to poor absorption of B12 in the ileum and was corrected by administration of oral calcium carbonate (1.2 g daily). PLUS it lowers serum vitamin B12 concentrations in 5 to 10% but only rarely causes megaloblastic anemia. In some patients with vitamin B12 deficiency, peripheral neuropathy may precede the development of megaloblastic anemia. The dose and duration of use of metformin correlates with the risk of vitamin B12 deficiency. 

          Consider whether metformin may be contributing if you happen to find macrocytic anemia on a routine CBC or in patients with neuropathy. But don't routinely check B12 levels in most metformin patients. Instead, check B12 levels every 2 to 3 years for metformin patients at risk (vegetarians, PPI users, the elderly, etc). Also test if patients develop symptoms (numbness, etc). Don't stop metformin if patients develop B12 deficiency. The benefits of metformin outweigh this concern. Treat B12 deficiency with oral or sublingual vitamin B12. Feel comfortable knowing that oral B12 supplements at these doses work as well as the injectable for mild to moderate deficiency. Save injectable B12 for initial treatment of severe deficiency or for patients with neurologic symptoms.

Vitamin B12 (also called cobalamin) is available as cyanocobalamin, which contains a cyanide (CN) atom introduced during chemical synthesis and hydroxocobalamin. Cyanocobalamin (Neurovit, Neurorubine, Neurobion) is predominantly used in the United States and hydroxocobalamin (Depovit, Biovit) is predominantly used in Europe. Both available in Egypt and are effective in treating vitamin B12 deficiency. 

• Note...!
  Maintenance doses of cyanocobalamin are administered monthly. While maintenance hydroxocobalamin is administered less frequently, once every two to three months.

For oral or sublingual B12, treat with 1000 to 2000 mcg/day. The typical dose for children is 50 to 100 mcg parenterally once per week until the deficiency is corrected and then once per month (cyanocobalamin) or once every other month (hydroxocobalamin). Oral doses of vitamin B12 in children are not well established. The typical dose for adults is 1000 mcg parenterally once per week until the deficiency is corrected and then once per month (cyanocobalamin) or once every other month (hydroxocobalamin). In adults, oral dosing is equally effective, at a dose of 1000 mcg orally once per day.

REFERENCES

• Aroda VR, Edelstein SL, Goldberg RB, Knowler WC, Marcovina SM, Orchard TJ, Bray GA, Schade DS, Temprosa MG, White NH, Crandall JP; Diabetes Prevention Program Research Group. Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study. J Clin Endocrinol Metab. 2016 Apr;101(4):1754-61. Available at: https://academic.oup.com/jcem/article/101/4/1754/2804585

  Buvat, D. (2004). Use of Metformin Is a Cause of Vitamin B12 Deficiency. American Family Physician, [online] 69(2), p.264. Available at: https://www.aafp.org/afp/2004/0115/p264.html
  

  De Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets D, Verburg J, Donker AJ, Stehouwer CD. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ. 2010 May 20;340:c2181. Available at: https://www.bmj.com/content/340/bmj.c2181.long