Intended for healthcare professionals

CCBYNC Open access

Rapid response to:

Research

Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial

BMJ 2010; 340 doi: https://doi.org/10.1136/bmj.c2181 (Published 20 May 2010) Cite this as: BMJ 2010;340:c2181

Rapid Response:

Does a fall in vitamin B12 represent clinically important deficiency?

Both the Dutch multicentre randomised placebo controlled trial[1] and
linked editorial[2] on the association between metformin and the risk of
vitamin B12 deficiency leave some unanswered questions. The achieved
primary outcome measure of a reduction in B12 levels over time shown in
the metformin group has not been demonstrated, as the investigators
suggest, to be clinically important vitamin B12 deficiency. They describe
patients with <_150 pmol="pmol" l="l" levels="levels" as="as" having="having" clinical="clinical" deficiency="deficiency" yet="yet" no="no" simple="simple" and="and" easily="easily" collected="collected" supportive="supportive" data="data" on="on" haemoglobin="haemoglobin" or="or" mean="mean" cell="cell" volume="volume" are="are" presented="presented" nor="nor" any="any" from="from" their="their" outpatient="outpatient" visits.="visits." p="p"/>This is disappointing as the longer follow-up of this study may have been
able to reach clinical endpoints of B12 deficiency, providing a stronger
mandate to that of the paucity of small available studies for their
recommendation of B12 investigation and replacement,[1] with B12 alone or
with calcium (1.2g daily).[3] As B12 deficiency in type 2 diabetics due to
pernicious anaemia is more frequently diagnosed without detectable
intrinsic factor antibodies[4] advice regarding long-term management and
length of follow-up, may not be as clear as the investigators suggest.[1]

It is also unclear whether patients were receiving metformin, and for how
long, prior to stopping all medications and commencing insulin at the
beginning of the study. Given that there were patients with B12 levels
<_150 pmol="pmol" l="l" reported="reported" at="at" baseline="baseline" these="these" data="data" could="could" have="have" been="been" informative="informative" with="with" the="the" mode="mode" of="of" supplementation="supplementation" provided="provided" and="and" time="time" course="course" response.="response." p="p"/> [1] De Jager J, Kooy A, Lehert P, Wulffelé MG, van der Kolk J, Bets
D, et al. Long term treatment with metformin in patients with type 2
diabetes and risk of vitamin B-12 deficiency: randomised placebo
controlled trial. BMJ 2010;340:c2181

[2] Vidal-Alaball J, Butler CC. Reduced serum vitamin B-12 in
patients taking metformin. BMJ 2010;340:c2198

[3] Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V.
Increased intake of calcium reverses vitamin B12 malabsorption induced by
metformin. Diabetes Care 2000;23:1227-31

[4] Chan JC, Liu HS, Kho BC, Lau TK, Li VL, Chan FH, et al.
Longitudinal study of Chinese patients with pernicious anaemia. Postgrad
Med J 2008;84:644-50.

Competing interests:
None declared

Competing interests: No competing interests

03 June 2010
Amit Patel
MRC Chain-Florey Clinical Research Fellow & Specialist Registrar in Haematology
MRC Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, W12 0NN, UK