The Long and Short of Metformin-Related Vitamin B12 Deficiency

We applaud Ting et al¹ for their study demonstrating the risk of vitamin B₁₂ deficiency with increasing dose and duration of metformin use. In contrast to previous reports, their study demonstrated no excess risk of vitamin B₁₂ deficiency among metformin users who currently use histamine₂-receptor blockers or proton pump inhibitors.¹ This statement should be interpreted very cautiously, although the authors allude to the fact that the lack of association in their study may stem from imprecise hospital-based medication records and inability to track the use of histamine₂-receptor blockers or proton pump inhibitors. Gastrointestinal symptoms can be a limiting factor in optimizing metformin therapy, and metformin has been recognized not to alter intestinal motility or bacterial overgrowth.^1- 2 Interestingly, almost one half of adult consumers of over-the-counter histamine₂-receptor blockers have been reportedly using these drugs in a manner inconsistent with Food and Drug Administration labeling, and this off-label use was associated with substitution for physician care.³ This has indeed clearly demonstrated that the over-the-counter use of such drugs are rampant, hence contributing to the reasons for the spectacular and rapid decline in antireflux surgery.⁴ Histamine₂-receptor blockers or proton pump inhibitors impair the absorption of protein-bound dietary vitamin B₁₂ and contribute to the development of B₁₂ deficiency with prolonged use.⁵ The inhibition of acid secretion by the gastric parietal cells results in decreased gastric acid and pepsin secretion required for the cleavage of dietary B₁₂.⁵ As an illustrative example, some of the reports cited from the literature do not even take into account the plausible role of histamine₂-receptor blockers or proton pump inhibitors, and to our knowledge, a therapeutic trial of metformin therapy has never been attempted to identify whether metformin was genuinely the cause of vitamin B₁₂ deficiency.⁵ This has particular inference, especially when the study by Ting et al¹ has not been able to identify the exact mechanism of metformin-related vitamin B₁₂ deficiency but only supports the notion of a causal relationship.⁵