• Dr Sajad Zalzala

Vitamin B12 and Metformin – What is the Connection?

Important takeaways from this blog post:

  1. Metformin has been observed to lower Vitamin B12 levels

  2. The B12-Metformin connection is complicated and nuanced

  3. Patients at risk of low B12 levels should supplement with B12 when taking Metformin

  4. Methylcobalamin (B12) at 500-1000mcg per day is preferred

Metformin and B12 Levels

Metformin has often been accused of lowering vitamin B12 levels in patients taking the medication long term, however, this has been shown to only be a half truth. Observationally, long-term use of Metformin does, in fact, seem to lower B12 serum levels—the level of B12 found circulating within your blood. The medical literature stating that Metformin should be used with caution due to this, or similar literature recommending a B12 supplement to offset a potential deficiency, are overlooking some important information.

The Science Behind Metformin and B12

While it is thought that Metformin somehow interferes with the absorption of B12, the extent of this interference is not fully understood. Although most studies show an association with Metformin and B12 deficiency, most of the data is observational. A cross-sectional, controlled study on Metformin that included both diabetic and non-diabetes patients showed no that “irrespective of Metformin use, no significant difference in the serum levels of vitamin B12 was observed, both in patients with and without diabetes” (5). In other words, Metformin may not actually be causing a decline in B12 after all.


Now, serum B12 levels are a good starting point, but not the best measures of the body’s amount and utilization of Vitamin B12. We have learned that not all low-serum B12 means a deficiency. On the flip side, not all high or “in-range” serum B12 means that a person is sufficient (or even optimal). Why? Read on…


Serum B12 as Markers of B12 Levels

The active form of Vitamin B12 is called holotranscobalamin. The metabolic marker of B12 is Methylmalonic Acid, often referred to as MMA. When Vitamin B12 is internalized and properly utilized, there are B12-dependent intercellular enzyme activities that are properly maintained, as well—methionine synthase and methylmalonyl-CoA mutase. In turn, when these enzyme activities are functioning well, plasma total homocysteine and MMA will fall within their respective reference ranges.


So, why is all this important in serum B12 levels giving us a potentially inaccurate picture of B12 utilization? It turns out that serum Vitamin B12 levels can actually be low, while plasma total homocysteine and MMA levels can be well within range. What does this mean? Even though a serum Vitamin B12 test may indicate low B12 levels in this situation, a patient would actually be showing very sufficient utilization of Vitamin B12. This situation is exactly what was seen in the National Health and Nutrition Examination Survey (1) which included 1,621 patients with diabetes—575 of which were taking Metformin. Overall, the mean serum B12 levels were lower, but plasma total homocysteine levels were still within range in the Metformin patients.


The Connection Between Metformin and B12

One explanation of the lowered levels of serum B12 is that patients taking Metformin may actually be storing more B12 in their liver than those not taking it, as depicted in a recent animal study (4). The best way to determine a suspected Vitamin B12 deficiency is a combined assay of active Vitamin B12 rather than serum, alongside MMA and plasma total homocysteine levels.


As you can see, the link between Metformin and B12 is complicated. It is not fair to demonize Metformin over this issue. It is fair to say, however, that out of an abundance of caution given the importance of Vitamin B12 on health, patients taking Metformin should either supplement with Vitamin B12, or have their B12 levels checked. As a Board Certified Family Physician, I like to see B12 levels in the upper range of normal, somewhere close to 800ng/mL.


Until next time!


Dr. Z


References

1. Reinstatler L, Qi YP, Williamson RS, Garn JV, Oakley GP J. Association of biochemical B₁₂ deficiency with metformin therapy and vitamin B₁₂ supplements: the National Health and Nutrition Examination Survey, 1999-2006. Diabetes Care 2012;35:327–333

2. de Jager J, Kooy A, Lehert P, et al. Long term treatment with metformin in patients with type 2 diabetes and risk of vitamin B-12 deficiency: randomised placebo controlled trial. BMJ 2010;340:c2181

3. Greibe E, Trolle B, Bor MV, Lauszus FF, Nexo E. Metformin lowers serum cobalamin without changing other markers of cobalamin status: a study on women with polycystic ovary syndrome. Nutrients 2013;5:2475–2482

4. Greibe E, Miller JW, Foutouhi SH, Green R, Nexo E. Metformin increases liver accumulation of vitamin B12 - an experimental study in rats. Biochimie 2013;95:1062–1065

5. Rodríguez-Gutiérrez, René et al. Metformin Use and Vitamin B12 Deficiency: Untangling the Association. The American Journal of the Medical Sciences, Volume 354, Issue 2, 165 - 171

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