Home / Resources / Articles / Link Between Metformin and Neuropathy, B12 Deficiency

Link Between Metformin and Neuropathy, B12 Deficiency

Oct 9, 2015

One of the most common and beneficial T2DM drugs may contribute to neuropathy and vitamin deficiency

The link between metformin and vitamin B12 lowering is well-known and mentioned in American Diabetes Association guidelines as a disadvantage of the drug. However, there are no recommendations for monitoring and prevention of vitamin B12 deficiency for patients taking metformin. Vitamin B12 deficiency is associated with adverse effects such as fatigue, mental status changes, and neuropathy. Given the prevalence of neuropathy in diabetic patients, metformin-induced vitamin B12 deficiency is clinically relevant.


The relationship between vitamin B12 deficiency and metformin was studied in a recent randomized placebo-controlled trial. The trial lasted 52 months and included 390 type 2 diabetes patients. They were treated with 850 mg metformin at doses up to three times a day or placebo. Patients with baseline vitamin B12 deficiency or patients taking vitamin B12 supplements were excluded from the trial.

Metformin use was associated with increased methylmalonic acid (MMA) levels; MMA is a specific biomarker used to detect vitamin B12 deficiency. The increase was 0.04 mmol/liter (95% CI, 0.02 – 0.06; p=0.001). No statistically significant difference in neuropathy score (based on the Valk Score, a validated neuropathy inventory) was found between the metformin and placebo groups. A statistically nonsignificant increase of 0.3 in neuropathy score per gram-year of metformin was found (95% CI, 0.03-0.08; p=0.13).

The study authors argue that taking into account the MMA increase with metformin, metformin use is actually associated with a significant neuropathy score increase of 0.25 points. Finally, MMA did not significantly increase based on B12 concentration, which the authors claim demonstrates that metformin does not disrupt the relationship between B12 and MMA in the body.

Metformin is widely prescribed, so this relationship warrants more investigation. Future studies may clarify the relationship and will help the authors of guidelines decide whether to recommend testing or supplementation.

Practice Pearls:

  • Metformin has been linked with vitamin B12 deficiency.
  • A randomized placebo-controlled trial showed that metformin use is associated with an increase in neuropathy scores for patients.
  • Current guidelines do not offer specific instructions on metformin and B12 deficiency, but future research is warranted.

Out M, Kooy A, Lehert P, et al. “Metformin, methylmalonic acid and the risk of neuropathy: a randomized placebo-controlled trial.” Abstract #220. Presented at the 51st Annual Meeting of the European Association for the Study of Diabetes. 2015.