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Diabetes Drug Metformin May Impair Cognition, Study Finds

Metformin use in some patients with type 2 diabetes is associated with cognitive impairment that might
be alleviated with vitamin B12 and calcium supplementation, a new study from Australia suggests.
This isn't the first time metformin has been linked to cognitive problems stemming from vitamin B12
deficiency, but prior data have been conflicting, lead author Eileen M. Moore, PhD, a medical research
scientist in the department of surgery, Deakin University, Geelong Hospital, Barwon Health, Geelong,
Australia, told Medscape Medical News.
Up to 30% of patients taking metformin may be deficient in B12, and this is thought to be due to an
interaction between metformin and a receptor in the distal ileum, leading to some inhibition in the
uptake of the vitamin, she and her colleagues say.
However, she told Medscape Medical News, "Metformin remains a very effective first-line antidiabetic
drug and may reduce cardiovascular risk in patients with diabetes. Clinicians and patients should not be
alarmed by these findings, but the need to monitor and correct vitamin-B12 levels is highlighted."
Adriaan Kooy, MD, PhD, director of the Bethesda Diabetes Research Center, Hoogeveen, the
Netherlands, agrees. "This study…is highly interesting and asks for further research. The malabsorption
of neurovitamins like B12 in metformin users may contribute to neuronal dysfunction — potentially
being misinterpreted as diabetic neuropathy," he noted. However, "it is unknown to [what] extent these
changes might result in cognitive dysfunction," he added.
And he too said there's no reason to panic. "There is insufficient evidence to be really concerned now.
Why did the huge amount of epidemiological data not show any indication? Further evaluation is
needed."
Dr. Moore and colleagues published their results online September 5 in Diabetes Care.
Impaired Cognition Twice as Likely on Metformin
"Since the 1970s, clinicians and scientists have been aware that metformin is associated with lower
vitamin-B12 levels. The hypothesis that this may increase the risk of cognitive impairment seemed
sound," Dr. Moore told Medscape Medical News. However, previous studies in the United Kingdom,
Thailand, and elsewhere "have shown mixed results with regard to metformin use and the risk of
dementia, so we were unsure what to expect," she explained.
She and her colleagues obtained data from several sources throughout Australia: 2 prospective studies
on aging and memory; a clinical population from a cognitive, dementia, and memory services clinic; and
patients with Alzheimer's disease recruited from a private geriatrician's practice.
Altogether, the final analysis included 1354 patients, of whom 104 had type 2 diabetes and 22 had
impaired glucose tolerance. Among these 126 with dysglycemia; 35 were taking metformin and 91 were
not. Dr. Kooy expressed surprise at the high numbers of nonusers, considering that metformin is the
cornerstone of type 2 diabetes treatment. "Are there confounders for 'nonuse'?" he wondered.
Participants were aged 51 to 99 years (mean, 74 years), and 59.5% were female. Scores on the Mini-
Mental State Examination (MMSE), a measure of cognitive ability, were normal (28–30) in about half
(50%), minimally impaired (24–27) in 22%, mildly impaired (18–23) in 18%, and most impaired (less than
18) in 10%.
After adjustment for age, sex, education, and depression, the subjects with type 2 diabetes had worse
cognitive performance (MMSE of <28) than did those without diabetes, with an adjusted odds ratio of
1.51 (P = .033).
And in the diabetes group, cognitive performance was significantly worse among those who were taking
metformin, with an adjusted odds ratio of 2.23. Scores on the MMSE were 22.8 in those on metformin
vs 24.7 for those with diabetes not taking metformin.
Supplement Everyone Taking Metformin?
Also among the participants with diabetes, MMSE scores were lower among those who had serum
vitamin-B12 levels less than 250 pmol/L compared with those who had higher vitamin-B12 levels (MMSE
22.9 vs 25.0, respectively).
Dr. Moore told Medscape Medical News that she recommends clinicians and patients with diabetes
should "aim to maintain good, rather than adequate, serum vitamin-B12 levels" of greater than 300
pmol/L to reduce the risk of cognitive decline later in life.
Because of the malabsorption, patients taking metformin may not receive adequate vitamin B12 from a
well-balanced diet alone, she stressed. And clinicians should also be aware of other risk factors for
vitamin-B12 deficiency, such as strict vegetarian diet, bowel surgery, complications affecting the parietal
cells of the stomach or the distal ileum, or concomitant use of other drugs that depress stomach acid,
she warned.
Finally, vitamin-B12 levels in patients using metformin should be monitored at least yearly, she advises.
Dr. Kooy said that certain other indicators may point to a greater possibility of B12 deficiency in
metformin users, such as use of the drug for longer than 3 years, neuropathy, cognitive dysfunction,
and/or increased mean corpuscular volume.
Cases should be validated with plasma levels of B12 and a methylmalonic-acid measurement, indicating
a B12 deficiency, he said. "Think about B12 deficiency to be treated by neurovitamins and calcium in
metformin users with signs of neuropathy and/or cognitive dysfunction," he suggested.
And with regard to cognitive function, Dr. Moore pointed out that because diabetes itself is also an
independent risk factor for dementia, "Clinicians should consider monitoring cognition in [all] patients
over the age of 50 years who use metformin, especially when there are other risk factors for dementia
present."
Because current treatments for dementia are palliative only, intervention in the early stages of cognitive
decline remains the best option, she stressed.
"Despite metformin's long market history, there currently are no guidelines in many places with regard
to monitoring or supplementing vitamin-B 12 levels or monitoring cognition in patients who use
metformin. Physicians have a very important role to play in identifying those patients who are at
increased risk and taking preventive actions to ensure a good quality of life for their patients into older
age."
Future Steps Should Include Prospective Trial
Dr. Moore also believes that a prospective intervention trial is needed to investigate whether vitamin-
B12 supplementation can prevent or delay the onset of cognitive decline in patients with diabetes who
use metformin, noting that the most effective dose, duration, and timing of supplementation remain to
be determined.
"Previous studies have been too short or have commenced in patients in later stages of cognitive
decline, after irreversible neuronal damage. Supplementation may need to begin in the fifth decade of
life and continue for much longer than previous studies to see an effect," she observed.
Meanwhile, Dr. Kooy's group, which has previously published evidence of a link between metformin and vitamin-B12 deficiency, is working on a solution, with his group testing somenew mechanisms to counteract the effects of B12 malabsorption. This study received support from the National Health and Medical Research Council (NHMRC). One of the 2 prospective studies from which patients for this study were enrolled was funded by Janssen Australia. The other prospective study received support from the Science Industry Endowment Fund, Pfizer International, the Commonwealth Scientific and the Industrial Research Organization, which receives contributions from the following: the University of Melbourne, Neurosciences Australia, Edith Cowan University, Mental Health Research Institute, Alzheimer's Australia, the National Aging Research Institute, Austin Health, University of Western Australia, CogState, Macquarie University, Hollywood Private Hospital, and Sir Charles Gardner Hospital. Dr. Moore has reported no relevant financial relationships. Disclosures for the coauthors are listed in the article. Dr. Kooy has been involved in trials funded by Merck, AstraZeneca, Bristol-Myers Squibb, and Novo-Nordisk, among others. Diabetes Care. Published online September 5, 2013

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