Metformin and vitamin B12 deficiency

Studies have screened outpatients taking biguanides (metformin, phenformin) for B12 deficiency.

• Thirty per cent of 46 patients undergoing biguanide therapy developed B12 malabsorption, which resolved in half on stopping the drug , however it is unwise to assume that malabsorption of vitamin B12 during biguanide therapy will invariably remit on drug withdrawal; whether persistent malabsorption is due to spontaneous failure or intrinsic factor secretion, or to a permanent effect of the drug is a matter of further study (1).

Mechanism for B12 deficiency in diabetic patients on biguanide therapy (2)

• People with diabetes may have slow intestinal transit causing bacterial overgrowth and B12 malabsorption
  • however, metformin does not alter oral-caecal transit time
  • no evidence of bacterial overgrowth related to metformin in a controlled trial (2)
• The B12-intrinsic factor complex uptake by ileal cell membrane receptors is known to be calcium-dependent, and metformin affects calcium-dependent membrane action
  • the resulting B12 deficiency can be reversed by administering calcium, and this seems to be the clearest mechanism (2)

Meformin and anaemia (3):

• a study evaluated the association between metformin use and anemia risk in type 2 diabetes, and the time-course for this, in a randomized controlled trial (RCT) and real-world population data (3)
• the study examined data from two RCTs and real-world population data
  • anemia was defined as a hemoglobin measure of <11 g/dL
    • in the RCTs A Diabetes Outcome Progression Trial (ADOPT; n=3,967) and UK Prospective Diabetes Study (UKPDS; n=1,473), logistic regression was used to model anemia risk and nonlinear mixed models for change in hematological parameters
    • in the observational Genetics of Diabetes Audit and Research in Tayside Scotland (GoDARTS) population (n=3,485), discrete-time failure analysis was used to model the effect of cumulative metformin exposure on anemia risk
  • ADOPT, compared with sulfonylureas, the odds ratio (OR) (95% CI) for anemia was 1.93 (1.10, 3.38) for metformin and 4.18 (2.50, 7.00) for thiazolidinediones
    • in ADOPT, hemoglobin and hematocrit dropped after metformin initiation by 6 months, with no further decrease after 3 years.
  • in UKPDS, compared with diet, the OR (95% CI) was 3.40 (1.98, 5.83) for metformin, 0.96 (0.57, 1.62) for sulfonylureas, and 1.08 (0.62, 1.87) for insulin
    • in UKPDS, hemoglobin fell by 3 years in the metformin group compared with other treatments
    • at years 6 and 9, hemoglobin was reduced in all treatment groups, with no greater difference seen in the metformin group
  • in GoDARTS, each 1 g/day of metformin use was associated with a 2% higher annual risk of anemia
    • in the GoDARTS study, of those who developed anemia in the metformin exposed group compared with the non metformin- exposed group, microcytic anemia was more frequent (12.1% vs. 7.3%) and macrocytic less frequent (7.6% vs. 12.3%), suggesting that the
      anemia is not caused by a B12 deficiency
• the study concluded that "Metformin use is associated with early risk of anemia in individuals with type 2 diabetes, a finding consistent across two RCTs and replicated in one real-world study. The mechanism for this early fall in hemoglobin is uncertain, but given the time course, is unlikely to be due to vitamin B12 deficiency alone"
  • seems unlikely that the mechanism for these early changes in Hb is secondary to B12 deficiency, because individuals should have enough B12 stored to last for between 2 and 5 years
  • main limitation of the reported studies is the lack of B12 measurement and lack of other data to help point to a mechanism mediating the early reduction in Hb caused by metformin treatment

Reference:

• (1) Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Malabsorption of vitamin B12 and intrinsic factor secretion during biguanide therapy. Diabetologia. 1983 Jan;24(1):16-8. doi: 10.1007/BF00275941.
• (2) Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V. 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.
• (3) Donnelly LA, Dennis JM, Coleman RL, Sattar N, Hattersley AT, Holman RR, Pearson ER. Risk of Anemia With Metformin Use in Type 2 Diabetes: A MASTERMIND Study. Diabetes Care. 2020 Oct;43(10):2493-2499. doi: 10.2337/dc20-1104.