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The widely acclaimed diabetes drug metformin was linked with impaired brain function in patients who took the drug, although supplementation with vitamin B12 may alleviate metformin-induced deficiencies, according to new research.

In a retrospective study, diabetic patients who were taking metformin had worse cognitive performance than those not taking the drug (odds ratio 2.23, 95% CI 1.05-4.75), , of the University of Melbourne in Australia, and colleagues .

Additionally, patients with diabetes who had vitamin B12 levels less than 250 pmol/L also had worse cognitive performance (OR 2.29, 95% CI 1.12-4.66), and the association between metformin and cognitive impairment was weakened after adjusting for vitamin B12 levels, they stated.

"Increased monitoring of cognitive ability in patients with diabetes who use metformin is warranted, particularly among older adults," they wrote, adding that "prospective trials are warranted to assess the beneficial effects of vitamin B12 and calcium use on cognition in older people with diabetes who are taking metformin."

Metformin has been hailed as a sort of wonder drug, with benefits in a number of comorbidities including heart disease and cancer. But some research has suggested that it's not such a boon to cognitive outcomes, mainly because of its association with vitamin B12 deficiency.

To assess the effects of the drug on cognitive performance, the researchers looked at data from 1,354 patients involved in various trials: the Primary Research in Memory (PRIME) clinics study, the Australian Imaging, Biomarkers, and Lifestyle (ABIL) study, and clinical data from the Barwon region of southeastern Australia.

Moore and colleagues included patients with Alzheimer's disease and mild cognitive impairment, as well as those who were cognitively normal, but excluded those with stroke or neurodegenerative diseases other than Alzheimer's. A subgroup analysis was performed with participants who had diabetes or impaired glucose tolerance.

The studies used the mini-mental state exam (MMSE) to determine cognitive performance.

Participants had a mean age of 73.8 and nearly 60% were female. A little more than half of the participants scored 28-30 on the MMSE (not impaired) while 21.8% had MMSE scores of 24-27 (minimally impaired), 17.7% has MMSE scores of 18-23 (mildly impaired), and 10.1% scored less than 18 on the MMSE (most impaired).

The researchers found, in adjusted analyses, patients with type 2 diabetes had worse cognitive performance than those without the condition (OR 1.51, 95% CI 1.03-2.21).

Among those with diabetes, metformin use was associated with worse cognitive performance (OR 2.23, 95% CI 1.05-4.75).

MMSE scores were lower among those with serum vitamin B12 less than 250 pmol/L (22.9) than those with higher levels (25.0).

"Thus, any effect metformin has on cognitive performance may be at least partially mediated by altering serum vitamin B12 levels," they wrote.

They also determined that patients with diabetes who were taking calcium supplements had better cognitive performance (OR 0.41, 95% CI 0.19-0.92). The researchers suggested that taking calcium and B12 supplements may help alleviate metformin-induced B12 deficiency and lead to better cognitive outcomes.

They cautioned, however, that previous work has shown calcium supplementation to be associated with increased risk of heart disease, so the "safety of calcium supplementation in patients with diabetes treated with metformin would need to be established before such interventions could be recommended."

Moore and colleagues noted that they were limited by a lack of sufficient information on the duration of metformin use, severity of diabetes, or use of other anti-diabetic drugs, which prevented an assessment of those factors on cognitive performance.

They called for prospective trials to further investigate the association among diabetes, cognitive decline, and metformin.

In the meantime, they said clinicians should increase monitoring the cognitive capabilities of patients with diabetes who use metformin.

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