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Metformin-related vitamin B12 deficiency
Medical and Geriatric Unit, Shatin Hospital, New Territories, Hong Kong, China
Address correspondence to: Kin Wah Liu. Email: firstname.lastname@example.org
Metformin is an invaluable hypoglycaemic agent. We report two cases who had symptomatic vitamin B12 deficiency relatedto metformin use; the mechanisms are discussed. The clinician must be aware of the possibility of metformin-associated B12deficiency in users who suffer cognitive impairment, peripheral neuropathy, subacute combined degeneration of the cord oranaemia.
Keywords: Metformin, elderly, Vitamin B12 deficiency
Case report 1
The UK Prospective Diabetes Study Group 34 showed
An 82-year-old Asian non-vegetarian had type 2 diabetes
metformin to be an effective hypoglycaemic agent with
mellitus for 20 years. Medications included metformin 1 g
less weight gain, and decreased hypoglycaemia, myocar-
BD for many years and famotidine for gastritis. She pre-
dial infarction, stroke and death . Gastrointestinal
sented with memory loss and progressive leg weakness.
side-effects and lactic acidosis related to metformin are
Her legs were hypotonic with decreased power, absent
commonly recognised; however, the associated vitamin
reflexes and bilateral extensor plantar reflexes. Vibration
B12 deficiency is less well known. Two cases illustrate
and proprioception sense were impaired. The gait was
ataxic with a positive Romberg’s test. Mini mental state
Metformin-related vitamin B12 deficiency
examination (MMSE) was 9/30. Her haemogloblin level
dependent membrane action. The resulting B12 deficiency
was 10.3 g/dl with mean corpuscular volume (MCV) 99.7 fl.
can be reversed by administering calcium , and this seems
Vitamin B12 level was 97 pmol/l with normal folate level
and negative anti-intrinsic factor antibodies. Vitamin B12-
Diabetes is associated with neuropathy, cognitive
deficient subacute combined degeneration of cord and cog-
impairment, several causes of anaemia and is on everyone’s
nitive impairment related to metformin was suspected.
list of causes of absent ankle reflexes with upgoing plantars;
Metformin was stopped, diabetes was stabilised on sulfony-
however, it is vital to consider co-existent B12 deficiency,
lurea and insulin, and she was given vitamin B12 1000 μg
on alternate days for five doses followed by vitamin B12
The value of routine screening for B12 deficiency
1000 μg on a monthly basis. This led to improvements in
(recommended by some ) is unknown, but the clini-
gait, lower limb power, MMSE (20/30) and haematological
cian must be aware of this association. The optimum
management of such patients is uncertain; although
Case report 2
some withdraw metformin and fully investigate thepatient, others take a more pragmatic approach to con-
A non-vegetarian diabetic patient had taken over the coun-
tinue the metformin, a valuable drug which may not be
ter metformin for 8 years, with diarrhoea for 2 years. Her
the cause of the deficiency, and to replace the B12 with
haemoglobin level was 9.4 g/dl (MCV 104 fl) and B12 level
was 125 pmol/l. Anti-parietal cell and anti-intrinsic factorantibodies were negative. Upper gastrointestinal endoscopy
and small bowel enema were normal. Schilling test showedintestinal malabsorption. The diarrhoea and haematological
abnormalities resolved on stopping the metformin and
• The clinician must be aware of the possibility of metformin-
replacing the B12 in the similar manner as patient in case
related B12 deficiency in diabetic older patients and test
These two patients had B12 deficiency associated with
Vitamin B12 deficiency affects approximately 20% of
UK Prospective Diabetes Study (UKPDS) Group. Effect of
elderly people , although the prevalence varies greatly
intensive blood-glucose control with metformin on complica-tions in overweight patients with type 2 diabetes (UKPDS 34).
depending on population studied and B12 cut-off used.
Many factors contribute to the deficiency including
Andres E, Loukili NH, Noel E et al.
Vitamin B12 (cobalamin)
diet, gastrointestinal pathology, autoimmune disease and
deficiency in elderly patients. CMAJ 2004; 171: 251–9.
Adams JF, Clark JS, Ireland JT, Kesson CM, Watson WS. Mal-
Several studies have screened outpatients taking bigua-
absorption of vitamin B12 and intrinsic factor secretion during
nides for B12 deficiency. Thirty per cent of 46 patients
biguanide therapy. Diabetologia 1983; 24: 16–8.
undergoing biguanide therapy developed B12 malabsorp-
Tomkin GH, Hadden DR, Weaver JA et al.
tion, which resolved in half on stopping the drug . In 71
of patients on long term meformin therapy. BMJ 1971; 2: 685–7.
metformin patients, 21 had low B12 absorption, and four
Filioussi K, Bonvoas S, Katsaros T. Should we screen diabetes
had low B12 levels . Fifty-four of 600 patients on long-
patients using biguanides for megaloblastic anaemia? AustFam Physician 2004; 32: 383–4.
term biguanides had B12-related megaloblastic anaemia .
Scarpello JHB, Hodgson E, Howlett HCS. Effect of met-
What is the mechanism?
formin on bile salt circulation and intestinal motility in Type 2diabetes mellitus. Diabet Med 1998; 15: 651–6.
Diabetic people may have slow intestinal transit causing
Bauman WA, Shaw S, Jayatilleke E, Spungen AM, Herbert V.
bacterial overgrowth and B12 malabsorption; however,
Increased intake of calcium reverses vitamin B12 malabsorp-
metformin does not alter oral–caecal transit time , and
tion induced by metformin. Diabetes Care 2000; 23: 1227–31.
there was no evidence of bacterial overgrowth related tometformin in a controlled trial . The B12-intrinsic factorcomplex uptake by ileal cell membrane receptors is known
Received 14 March 2004; accepted in revised form 6 December
to be calcium-dependent, and metformin affects calcium-
CIRCULAIRE N° 1651 DU 17/10/2006 Objet : Composition d’une petite pharmacie mise à la disposition du personnel. Réseaux : CF Niveaux : Tous − Mesdames et Messieurs les Préfets (ètes), Directeurs (trices) des établissements d’enseignement et assimilés organisé par la Communauté française ; − Administrateurs (trices) des internats, homes − Directeurs (t
The new england journal of medicineIntensive Lipid Lowering with Atorvastatin John C. LaRosa, M.D., Scott M. Grundy, M.D., Ph.D., David D. Waters, M.D., Charles Shear, Ph.D., Philip Barter, M.D., Ph.D., Jean-Charles Fruchart, Pharm.D., Ph.D., Antonio M. Gotto, M.D., D.Phil., Heiner Greten, M.D., John J.P. Kastelein, M.D., James Shepherd, M.D., and Nanette K. Wenger, M.D., for the Treatin