Long-Term Metformin Linked to Increased Risk of Vitamin B12 Deficiency
Long-term use of metformin may increase the risk of vitamin B12 deficiency and possibly other complications (anemia, neuropathy). These findings come from the Diabetes Prevention Program/Diabetes (DPP)/Diabetes Prevention Program Outcomes Study (DPPOS) and were published in The Journal of Clinical Endocrinology and Metabolism. This is the largest study of its kind to investigate the correlation between B12 levels and metformin.
The participants met the criteria of impaired glucose tolerance and fasting blood glucose 95 to 125mg/dL who were at least 25-years of age and had a BMI of 25kg/m2 or higher. They were assigned to a placebo group (n=902), or a metformin group at 850mg twice daily (n=898). The remaining participants were enrolled in an intensive lifestyle program (ILS).
At a 5 year follow-up, mean levels of B12 were 10% lower in the metformin group versus the placebo. The prevalance of B12 deficiency was greater in the metformin group at 4.3% compared to 2.4% for the placebo group (p=0.2), borderline-low vitamin B12 levels were also much higher in the metformin group at 19.1% vs. 9.5% (p<0.01).
Paradoxically, at the year 13 follow-up mean vitamin B12 levels were greater in both groups compared with year 5, yet the prevalence of vitamin B12 deficiency was also greater in year 13 compared with year 5 in each group. Thirty-eight percent and 45% of the metformin and placebo group, respectively, who were deficient at year 5 remained deficient at year 13.
Tellingly, the 2.4% in the placebo group who were vitamin B12 deficienct at year 5 is the exact same percentage as those in the NHANES report who had type 2 diabetes but weren't taking metformin. Additionally, the prevalence of vitamin B12 deficiency in the metformin group (4.3%) was similar to that seen in the NHANES cross-sectional evaluation of individuals with type 2 diabetes using metformin (5.8%), both at the 5 year follow-up point.
Although the presence of anemia was not different between the two groups at year 5, at the year 13 follow-up there were increases in anemia cases in the metformin group, however the authors note that these increases were nonsignificant.
The currently accepted explanation for the B12 deficiency is caused by the interference of metformin on calcium-dependent membrane action responsible for vitamin B12- intrinsic factor absorption in the terminal ileum. The authors note that although evidence points to metformin exposure creating low B12 levels, assessment of levels in individuals treated with metformin has not been incorporated into practice guidelines.
The authors conclude by stating that “understanding the potential adverse consequences of metformin treatment is essential,” and that “routine measurement of vitamin B12 for metformin-treated individuals should be considered.”
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