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

We appreciate these comments. In response to Novoselsky: the clinical
consequences of metformin-associated vitamin B-12 deficiency have not been
extensively studied. Novoselsky’s data suggest, importantly, that anaemia
may be one such consequence. In addition, Novoselsky’s data certainly do
not exclude other consequences. In fact, a recent studied suggested that
more severe peripheral neuropathy may be another manifestation of
metformin-associated vitamin B-12 deficiency (1).

In response to Wiwanitkit: a number of randomized, placebo controlled
trials have shown that metformin use is associated with a decrease in
vitamin B-12 levels. In addition, a plausible molecular mechanism has been
identified, as discussed in our paper. This makes confounding as an
alternative explanation for our findings extremely unlikely. We agree that
data on the cost-effectiveness of screening strategies for vitamin B-12
deficiency in metformin users are needed.

In response to Patel: we did not state that our data show clinically
symptomatic vitamin B-12 deficiency. Instead, the point we made is that
the vitamin B-12 decrease seen in metformin users (a well-known
phenomenon) is progressive over time and in some individuals reaches
levels at which many (but not all) authorities agree substitution is
required (i.e., <_150 pmol="pmol" l.="l." whether="whether" or="or" not="not" one="one" wishes="wishes" to="to" call="call" this="this" clinical="clinical" deficiency="deficiency" is="is" a="a" matter="matter" of="of" semantics.="semantics." the="the" real="real" dilemma="dilemma" here="here" that="that" manifestations="manifestations" vitamin="vitamin" b-12="b-12" fatigue="fatigue" cognitive="cognitive" changes="changes" neuropathy="neuropathy" anaemia="anaemia" may="may" be="be" subtle="subtle" difficult="difficult" distinguish="distinguish" from="from" symptoms="symptoms" due="due" ageing="ageing" and="and" complications="complications" diabetes="diabetes" irreversible.="irreversible." therefore="therefore" many="many" clinicians="clinicians" choose="choose" treat="treat" individuals="individuals" with="with" levels="levels" below="below" _150="_150" l="l" even="even" in="in" absence="absence" clear="clear" symptoms.="symptoms." we="we" feel="feel" reasonable="reasonable" strategy="strategy" more="more" definitive="definitive" data.="data." strongly="strongly" disagree="disagree" our="our" study="study" should="should" have="have" been="been" extended="extended" for="for" such="such" endpoints="endpoints" occur.="occur." agree="agree" lack="lack" data="data" on="on" holotranscobalamin="holotranscobalamin" ii="ii" methylmalonic="methylmalonic" acid="acid" which="which" provide="provide" precise="precise" estimate="estimate" status="status" limitation="limitation" as="as" acknowledged="acknowledged" paper.="paper." contrary="contrary" patels="patels" assertion="assertion" gave="gave" no="no" specific="specific" advice="advice" how="how" manage="manage" metformin="metformin" users.="users." fact="fact" there="there" paucity="paucity" issue.="issue." efficacy="efficacy" oral="oral" substitution="substitution" users="users" unknown="unknown" problematic="problematic" because="because" thought="thought" induce="induce" malabsorption.="malabsorption." high="high" calcium="calcium" intake="intake" an="an" option="option" but="but" often="often" poorly="poorly" tolerated.="tolerated." it="it" however="however" if="if" deemed="deemed" indicated="indicated" parenteral="parenteral" will="will" effective.="effective." netherlands="netherlands" considered="considered" standard="standard" care="care" what="what" used="used" patients.="patients." prior="prior" use="use" was="was" determinant="determinant" at="at" baseline="baseline" seven="seven" patients="patients" whom="whom" occurred="occurred" cannot="cannot" answered="answered" number="number" cases="cases" too="too" small="small" analysis.="analysis." p="p"/> In response to Beavon: as far as we know, there is no evidence that
metformin can cause neuropathy in the absence of vitamin B-12 deficiency.

In response to the editorial (2): we agree that detailed data on
fatigue, cognitive function, quality of life and neuropathy would have
been valuable, but funding of this trial was limited. Such symptoms can be
subtle, and because we do not know how large the difference between
individuals with and without vitamin B-12 deficiency is likely to be,
sensitive measures would have been needed. In addition, even if such data
would have been available and would not have shown differences, this still
would not exclude that differences could occur at a later point in time,
as the vitamin B-12 decrease on metformin is progressive over time. This
makes it likely that symptoms of vitamin B-12 deficiency will at some
point in time occur in at least some individuals. With regard to
generalizability, diagnosis and management: all patients received general
dietary advice. Although our data pertain to patients treated with
insulin, it is hard to see why the effects of metformin should be
different in patients not on insulin. Holotranscobalamin II may be a
better measure of vitamin B-12 status, but such measurements are not
generally available. With regard to management, we note that there is no
evidence that oral substitution with vitamin B-12 is effective in
metformin users. Parenteral substitution is likely to be effective, but
there are no data on what treatment schedule would be most cost-effective.
With regard to the mechanism: it is unlikely that a metformin-induced
change in dietary habits plays a role, as this would have been likely to
also affect folate levels, which was not the case. In addition, a
plausible molecular mechanism for the effect of metformin has been
identified, as noted above.

Coen D.A. Stehouwer, professor of medicine, Maastricht University
Medical Centre, Maastricht, the Netherlands

Adriaan Kooy, internist for vascular medicine, Bethesda General
Hospital, Hoogeveen, the Netherlands

1. Wile DJ, Toth C. Association of metformin, elevated homocysteine,
and methylmalonic acid levels and clinically worsened diabetic peripheral
neuropathy. Diab Care 2010;33:156-61.

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

Competing interests:
None declared

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