Metformin and vitamin B12 deficiency: the role of H2 receptor antagonists and proton pump inhibitors
SIR—Liu et al. highlighted an important point, which is well described with regard to metformin therapy [1]. Interestingly, they have categorically stated that: ‘These two patients had B12 deficiency associated with metformin therapy’. However, we feel that in both the patients described in their report, there are alternative causes for the deficiency of vitamin B12, which has not been discussed.The first patient described was also on treatment for gastritis with famotidine; an H2 receptor antagonist (H2RA). The chronic use (> 2 years) of H2RA or proton pump inhibitors (PPI) has been associated with B12 deficiency [2]. H2RAs decrease acid secretion by the gastric parietal cells and gastric acid and pepsin produced by these cells are required for the cleavage of vitamin B12 from dietary sources [2, 3], hence, the potential to cause B12 deficiency. Indeed, the uptake of food-bound B12 in patients on treatment with cimetidine has been demonstrated to be decreased, from a mean of 5.3% without the drug to 2.5% after it, a fall of 53%; P < 0.0001 [4]. This impairment of B12 absorption had raised the possibility more than two decades ago that long-term, full-dose therapy with cimetidine may produce B12 deficiency similar to that seen in other hypochlorhydric states [4].
In the second patient described, no comment has been made on other medications that the patient could have been taking. Nonetheless, this ‘patient had taken over the counter metformin for 8 years, with diarrhoea for 2 years’. It is therefore, likely that the patient could also have been taking an H2RA/PPI over the counter, especially having suffered with gastrointestinal (GI) side effects for 2 years. Neither of the patients had been reassessed for B12 status after suspending metformin for a satisfactory period.
Intrinsic factor (IF), also produced by gastric parietal cells, is required for B12 absorption from the GI tract. As Liu et al. suggested [1], metformin treatment could have been one of the possibilities in the cases reported, as it can result in B12 deficiency mediated by depression of IF secretion.
GI symptoms can be a limiting factor in optimising metformin therapy [5], and the underlying cause remains unclear. Many a time, these patients are prescribed H2RAs/PPIs to help the GI side effects and gradually optimise the dose of metformin. H2RAs/PPIs may therefore impair the absorption of protein-bound dietary B12 and could contribute to the development of B12 deficiency with prolonged use. Patients taking these medications for extended periods of time should be monitored for B12 status. The role of H2RA/PPI affecting the absorption of B12, especially in diabetic patients on metformin therapy with GI side-effects is less commonly perceived in routine daily clinical practice and also needs to be appreciated and recognised even further (Figure 1).
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Competing interests
GIV is a Specialist Registrar and JHBS is a Consultant Physician in Diabetes and Endocrinology and both the authors are involved with the management of elderly diabetic patients in routine daily clinical practice.
1 Diabetes & Endocrinology, University Hospital of North Staffordshire, Stoke-on-Trent ST4 6QG, UK
2 Keele University, UK
* To whom correspondence should be addressed Email: georgeiv{at}doctors.org.uk
References
- Liu KW, Dai LK, Jean W. (2006) Metformin-related vitamin B12 deficiency. Age Ageing 35 200–1.
[Abstract/Free Full Text] - Valuck RJ and Ruscin JM. (2004) A case-control study on adverse effects: H2 blocker or proton pump inhibitor use and risk of vitamin B12 deficiency in older adults. J Clin Epidemiol 57 422–28.[CrossRef][Web of Science][Medline]
- Ruscin JM, Page RL II, Valuck RJ. (2002) Vitamin B (12) deficiency associated with histamine (2)-receptor antagonists and a proton-pump inhibitor. Ann Pharmacother 36 812–16.[Abstract]
- Salom IL, Silvis SE, Doscherholmen A. (1982) Effect of cimetidine on the absorption of vitamin B12. Scand J Gastroenterol 17 129–31.[Web of Science][Medline]
- Scarpello JH, Hodgson E, Howlett HC. (1998) Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med 15 651–56.[CrossRef][Web of Science][Medline]
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  G. I. Varughese, A. A. Tahrani, and J. H. B. Scarpello The Long and Short of Metformin-Related Vitamin B12 Deficiency Arch Intern Med, April 9, 2007; 167(7): 729 - 730. [Full Text] [PDF]
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