Long-term treatment with metformin in type 2 diabetes and methylmalonic acid: Post hoc analysis of a randomized controlled 4.3year trial

J Diabetes Complications. 2018 Feb;32(2):171-178. doi: 10.1016/j.jdiacomp.2017.11.001. Epub 2017 Nov 8.


Aims: Metformin treatment is associated with a decrease of serum vitamin B12, but whether this reflects tissue B12 deficiency is controversial. We studied the effects of metformin on serum levels of methylmalonic acid (MMA), a biomarker for tissue B12 deficiency, and on onset or progression of neuropathy.

Methods: In the HOME trial, 390 insulin-treated patients with type 2 diabetes were treated with metformin or placebo for 52months. In a post hoc analysis, we analyzed the association between metformin, MMA and a validated Neuropathy Score (NPS).

Results: Metformin vs placebo increased MMA at the end of the study (95%CI: 0.019 to 0.055, p=0.001). Mediation analysis showed that the effect of metformin on the NPS consisted of a beneficial effect through lowering HbA1c (-0.020 per gram year) and an adverse effect through increasing MMA (0.042 per gram year), resulting in a non-significant net effect (0.032 per gram year, 95% CI: -0.121 to 0.182, p=0.34).

Conclusion: Metformin not only reduces serum levels of B12, but also progressively increases serum MMA. The increase of MMA in metformin users was associated with significant worsening of the NPS. These results provide further support that metformin-related B12 deficiency is clinically relevant. Monitoring of B12 in users of metformin should be considered.

Trial registration: ClinicalTrials.gov NCT00375388.

Keywords: B12; Complication; Metformin; Methylmalonic acid; Neuropathy; Type 2 diabetes mellitus.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers / blood
  • Diabetes Mellitus, Type 2 / blood
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Female
  • Humans
  • Male
  • Metformin / therapeutic use*
  • Methylmalonic Acid / blood*
  • Middle Aged
  • Randomized Controlled Trials as Topic
  • Retrospective Studies
  • Time Factors
  • Vitamin B 12 / blood
  • Vitamin B 12 Deficiency / blood
  • Vitamin B 12 Deficiency / complications
  • Vitamin B 12 Deficiency / drug therapy*


  • Biomarkers
  • Methylmalonic Acid
  • Metformin
  • Vitamin B 12

Associated data

  • ClinicalTrials.gov/NCT00375388