Increased intake of calcium reverses vitamin B12 malabsorption induced by metformin

Diabetes Care. 2000 Sep;23(9):1227-31. doi: 10.2337/diacare.23.9.1227.


Objective: Of patients who are prescribed metformin, 10-30% have evidence of reduced vitamin B12 absorption. B12-intrinsic factor complex uptake by ileal cell surface receptors is known to be a process dependent on calcium availability Metformin affects calcium-dependent membrane action. The objective of this study was to determine the magnitude and mechanism of the reduction in serum vitamin B12 after metformin administration.

Research design and methods: A comparative study design was employed using 2 groups (metformin and control). A total of 21 patients with type 2 diabetes received sulfonylurea therapy; 14 of these 21 patients were switched to metformin. Monthly serum total vitamin B12 measurements and holotranscobalamin (holoTCII) (B12-TCII) were performed. After 3 months of metformin therapy, oral calcium supplementation was administered.

Results: Serial serum vitamin B12 determinations revealed a similar decline in vitamin B12 and holoTCII. Oral calcium supplementation reversed the metformin-induced serum holoTCII depression.

Conclusions: Patients receiving metformin have diminished B12 absorption and low serum total vitamin B12 and TCII-B12 levels because of a calcium-dependent ileal membrane antagonism, an effect reversed with supplemental calcium.

Publication types

  • Clinical Trial
  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adult
  • Calcium Carbonate / therapeutic use*
  • Calcium, Dietary / therapeutic use*
  • Dietary Supplements
  • Ethnicity
  • Humans
  • Hypoglycemic Agents / adverse effects*
  • Intestinal Absorption / drug effects*
  • Male
  • Metformin / adverse effects*
  • Middle Aged
  • Vitamin B 12 / blood
  • Vitamin B 12 / pharmacokinetics*


  • Calcium, Dietary
  • Hypoglycemic Agents
  • Metformin
  • Calcium Carbonate
  • Vitamin B 12