What ultimately underlies vitamin B12 and folate deficiency in subjects treated with biguanides?

Metformin, the main biguanide in clinical settings, is the most common antidiabetic agent worldwide and has for years been regarded as a safe treatment option mostly for subjects with type II diabetes mellitus. Nevertheless, long-term metformin treatment leads to vitamin B12 and/or folic acid/folate deficiency in a significant portion of metformin recipients. As these deficiencies, and particularly in the case of vitamin B12, may lead to severe suboptimal health outcomes and are frequently encountered, the current review provides a comprehensive insight into the underlying mechanisms.

For this purpose, a literature search in PubMed and SCOPUS was conducted using appropriate keywords.

The mechanisms responsible for the deficiency have not thus far been fully elucidated. Early studies focused mainly on the impaired function of the intrinsic factor, responsible for the absorption of vitamin B12, and several intestinal brush border enzymes. The vitamin deficiency was found to be either temporary or else persistent. Recent studies point to the crucial role of several bacteria and their gut-host interactions, as several mechanisms were observed in experimental studies for the capture of vitamin B12 from the host. Other basic research studies found instead a redistribution of vitamin B12 without a remarkable effect on the total amount. The administration of calcium or miglitol has been found to constitute potential ways to compensate for the deficiencies observed.

A deeper understanding of the mechanisms driving this deficiency will pave the way to a causative treatment for and even prevention of this major side effect.