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
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