Vitamin B₁₂ deficiency in diabetic patients treated with metformin: A narrative review

Metformin is the most prescribed oral hypoglycemic drug and is considered by many health practitioners as the first-line treatment for non-insulin-dependent diabetes mellitus (T2DM). It is used either as a monotherapy or adjuvant to other anti-hyperglycemic agents. Most of its side effects are usually mild and self-limiting. However, several studies have shown an association between the use of metformin and low vitamin B₁₂ levels in diabetic patients. The current review aimed to provide a literature review of the current published reports on the association, the possible mechanisms, and the related individualized risk factors that might lead to this incidence. The most accepted mechanism of the effect of metformin on vitamin B₁₂ level is related to the absorption process where metformin antagonism of the calcium cation and interference with the calcium-dependent IF-vitamin B₁₂ complex binding to the ileal cubilin receptor. In addition, many risk factors have been associated with the impact of metformin on vitamin B₁₂ levels in diabetic patients such as dose and duration where longer durations showed a greater prevalence of developing vitamin B₁₂ deficiency. Male patients showed lower levels of vitamin B₁₂ compared to females. Black race showed a lower prevalence of vitamin B₁₂ deficiency in metformin-treated patients. Moreover, chronic diseases including T2DM, hyperlipidemia, coronary artery disease, polycystic ovary disease (PCOD), obesity, and metformin therapy were significantly associated with increased risk of vitamin B₁₂ deficiency.