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Metformin Associated with Vitamin B Deficiency and Cognitive Impairment

Apr 27, 2019
 

Author: Steve Freed, R.PH., CDE


This is not the first study showing these negative effects of metformin.

In this study, data from 4,160 community-dwelling older adults without dementia were evaluated to investigate the impact of hyperglycemia and metformin use on relevant vitamin B biomarkers and cognitive outcomes. Metformin use was associated with a significantly higher risk of vitamin B12 and vitamin B6 deficiency. Even with hyperglycemia, metformin use was associated with a significantly increased risk of cognitive dysfunction.

Emerging evidence suggests that deficiencies of folate-related B-vitamins can arise with metformin treatment and are independently linked with cognitive dysfunction, a co-morbidity of diabetes. To determine the impact of hyperglycemia and metformin use on relevant B-vitamin biomarkers and cognitive outcomes in older adults, community-dwelling older people (74.1 ± 8.3 years, n = 4,160) without dementia, were recruited to the TUDA cohort study in 2008-2012, and were classified as normoglycemic (n = 1856) or hyperglycemic, based on glycosylated hemoglobin (HbA1c) ≥ 5.7% (39 mmol/mol), either with (n = 318) or without (n= 1986) metformin treatment. Biomarkers of folate, vitamin B12, vitamin B6 and riboflavin were measured. Cognitive assessments included the Repeatable Battery for Assessment of Neuropsychological Status (RBANS) and the Frontal Assessment Battery (FAB).

From the results it was found that metformin use was associated with higher risk of deficiency of vitamin B12 (combined B12 index ≤ -1; odds ratio (95% CI): 1.45 (1.03-2.02)) and vitamin B6 (plasma pyridoxal 5-phosphate <30.0 nmol/L; 1.48 (1.02-2.15)). Fortified foods when eaten regularly had a positive impact on all relevant B-vitamin biomarkers, even with hyperglycemia. After adjustment for relevant co-variates, metformin use was associated with an increased risk of cognitive dysfunction as assessed using the RBANS (1.36 (1.03-1.80) and FAB (1.34 (1.03-1.74).

The conclusions showed that the use of metformin in older adults is associated with poorer cognitive performance; B-vitamin deficiency may be implicated. Fortified foods can optimize B-vitamin status and may be beneficial for maintaining better cognitive health in older people with or at risk of diabetes.

In another published study in Diabetes Care 2013 they also looked at metformin associations with serum vitamin B12, calcium supplements, and cognitive impairment in patients with diabetes, and what they found was that participants with diabetes (n = 126) had worse cognitive performance than participants who did not have diabetes (n = 1,228; adjusted odds ratio 1.51 [95% CI 1.03–2.21]). Among participants with diabetes, worse cognitive performance was associated with metformin use (2.23 [1.05–4.75]). After adjusting for age, sex, level of education, history of depression, serum vitamin B12, and metformin use, participants with diabetes who were taking calcium supplements had better cognitive performance (0.41 [0.19–0.92]).

From the results it was concluded that metformin use was associated with impaired cognitive performance. Vitamin B12 and calcium supplements may alleviate metformin-induced vitamin B12 deficiency and were associated with better cognitive outcomes. 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.

In the National Health and Nutrition Examination Survey, 1999–2006, they used the results to describe the prevalence of biochemical B12 deficiency in adults with type 2 diabetes taking metformin compared with those not taking metformin and those without diabetes, and explore whether this relationship is modified by vitamin B12 supplements.                                                                  What they found was that biochemical B12 deficiency was present in 5.8% of those with diabetes using metformin compared with 2.4% of those not using and 3.3% of those without diabetes.  Among those with diabetes, metformin use was associated with biochemical B12 deficiency. Consumption of any supplement containing B12 was not associated with a reduction in the prevalence of biochemical B12 deficiency among those with diabetes, whereas consumption of any supplement containing B12 was associated with a two-thirds reduction among those without diabetes.

So, it was concluded that metformin therapy is associated with a higher prevalence of biochemical B12 deficiency. The amount of B12 recommended by the Institute of Medicine (IOM) (2.4 μg/day) and the amount available in general multivitamins (6 μg) may not be enough to correct this deficiency among those with diabetes.

Practice Pearls

  • These findings suggest that metformin use is associated with poor cognitive performance in older adults.
  • Metformin therapy is associated with a higher prevalence of biochemical B12 deficiency.
  • Cognitive performance may be improved with regular consumption of fortified foods to optimize vitamin B status.

The Journal of Clinical Endocrinology & Metabolism, jc.2018-01791, https://doi.org/10.1210/jc.2018-01791 Published: 28 March 2019; Diabetes Care 2013;36:2981–2987