Vitamin B12 & Metformin – What's the Connection?

From the Desk of Dr. Z: AgelessRx Co-founder and Chief Medical Officer, Dr. Sajad Zalzala offers his insightful perspective on topics related to longevity. With a wealth of experience and a deep-seated passion for disease prevention and extending healthy lifespans, Dr. Z is dedicated to sharing his knowledge on the secrets to longevity. Today, he shares his knowledge on the connection between Metformin and B12, and why it’s important to supplement with B12 while taking Metformin.

Important takeaways from this blog post:

Metformin has been observed to lower Vitamin B12 levels
The B12-Metformin connection is complicated and nuanced
Patients at risk of low B12 levels should supplement with B12 when taking Metformin

Metformin & 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. Long-term use of Metformin does seem to lower B12 serum levels—the level of B12 found circulating within your blood. The medical literature advising caution with Metformin, or recommending a B12 supplement to counter a potential deficiency, overlooks important information.

The Science Behind Metformin and B12

Though Metformin may interfere with the absorption of B12, scientists don’t fully understand the extent of this interference. 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 shots, or have their B12 levels checked. As a Board Certified Family Physician, I like to see B12 levels in the upper normal range, around 800 ng/mL.

Until next time!

Dr. Z

FAQs

Does it matter what form of B12 I take?
Though all B12 is cobalamin, some wonder if, for example, Methylcobalamin is better than Cyanocobalamin. These are the two most common forms of B12. While there is some dispute in the medical community over which form is more effective, the general consensus is that any B12 is good for you, and no single form of B12 has been shown to be superior to any other. You can take Methylcobalamin just as well as Cyanocobalamin and still receive the same energy-boosting benefits.

Are B12 shots better than B12 pills?
B12 shots provide more bioavailable cobalamin than B12 pills or tablets, allowing our system to absorb the nutrients better. You can still take B12 orally for a reliable boost of energy, but many find it more convenient to take a B12 shot once or twice a week for long-lasting energy, rather than taking one or two pills a day.

Are there any side effects of B12 shots?
Many patients tolerate B12 well, either when injected or taken orally, with very few instances of side effects. The most common side effect of B12 shots is rash or irritation at the injection site. If this happens to you, try switching injection sites on your next dose and treat the affected area with a warm compress. Some may experience headache, fever, nausea, diarrhea, or fatigue with larger B12 doses. However, high B12 doses are most often for patients with B12 deficiency. When B12 is provided with a doctor-guided titration schedule and controlled doses, like at AgelessRx, these side effects become less common.

References

Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.