Metformin and Homocysteine Levels

I have been off Metformin for almost a year, now. I was taking the medication at the same time with a statin drug. My liver enzymes (particularly AST) increased to the point where my physician took me off both medications until the enzymes became normal. This took several months. My liver enzymes are now normal, and I requested the doctor to put me back on Metformin, not the statin drug which I think is the culprit. Previously, while I was taking Metformin (500 mg ER Osmotic Tabs, 1x2 for a total of 1,000 mg) lab tests revealed that my homocysteine levels were high, too high, in fact. I was taking sublingual Methylcobalamin and Methyl Folate to supplement the loss in these nutrients due to the Metformin. Didn't seem to work too well. I brought my homocysteine levels down to the upper range of what is considered "normal." As we discussed in the past, there is a downside to methylation for Pca patients. Exogenous supplementation of these vitamins may keep our homocysteine levels normal while, at the same time, contribute to the aggressiveness of our disease.( By the way, when my homocysteine levels were high, my B12 was more than adequate). Anyone on Metformin with similar results? (See: Metformin Treatment and Homocysteine:

A Systematic Review and Meta-Analysis of

Randomized Controlled Trials)

2 Replies

  • Kuanyin,

    It is a reasonable assumption that Metformin is behind excess homocysteine, since Metformin is known to lower vitamin B12 levels. B12 is an essential cofactor in the SAM cycle, whereby a dietary methyl donor (generally folate or folic acid) is used to recycle homocysteine back to methionine, which then converts to SAM, the universal methyl donor in the body. Once SAM drops off its methyl to cells that want it (& PCa is greedy for it), one is left with homocysteine.

    Almost all Metformin studies are diabetes studies. Peripheral neuropathy can be due to a B12 deficiency, & neuropathy is not uncommon in diabetics, so there are a number of studies in this area.

    A Thai study [2] reported that Metformin did not increase homocysteine:

    "Even though the direct effect of metformin treatment on the plasma Hcy could not be concluded from the present study, it was found that there was a significant depletion of level of serum vitamin B12 among patients who had been on long-term metformin treatment. "

    ... whereas a Dutch study [3] did report increased homocysteine:

    "Amongst those who completed 16 weeks of treatment, metformin use, as compared with placebo, was associated with an increase in homocysteine of 4% ... and with decreases in folate [-7% ...] and vitamin B12 [-14% ...]. In addition, the increase in homocysteine could be explained by the decreases in folate and vitamin B12."

    One would not expect population studies related to the SAM cycle to necessarily agree. Different populations differ in their mean baseline levels of folate & B12.

    "Low folate intakes were observed in Norway, Sweden, Denmark and the Netherlands. ... In the countries with a low intake of folate, the recommended levels were generally not achieved, which was also reflected in the folate status." [4]

    Holland does not add folic acid to grains & grain products, as happens in the U.S. & Canada.

    "Low intakes of vitamin B12 were not common". "Vitamin B12 intake was not strongly associated with the vitamin B12 status, which can explain why in the Netherlands and Germany the vitamin B12 status was inadequate, despite sufficient intake levels." [4]

    We require very little B12 & body stores can be quite high. In addition, the body is generally good at recovering used B12. Consequently, it might take years of Metformin use before B12 deficiency symptoms appear.

    Those who have impaired production of intrinsic factor (from gastric parietal cells) - as I have - would be at greatest risk. Alcohol intake also affects B12 uptake.

    My integrative medicine doctor doesn't think much of sublingual B12. He prefers self-administered belly fat injections.

    [1] is the link to the "Systematic Review and Meta-Analysis" you mentioned.






  • Patrick,

    Thank you for your prompt reply: I appreciate it. However, my original question, basically, still remains unanswered. First of all, we are neither the Netherlands nor Germany. In this country, I would venture to say that there is little if any dietary problem with folic acid because we add it to everything: in fact, we may be getting too much of it, especially the folic acid (as opposed to folate). Secondly, my B12 lab results, as I have written, is hundreds of times what the so-called recommended level should be. My dilemma is what we discussed in a previous HealthUnlocked exchange, namely, the problem with hypermethylation which I believe cannot be measured. In the past when I was taking Metformin I noticed a gradual increase in my homocysteine values, even while taking exogenous B12, Folate and B6. What I face is a Hobson's Choice--either, possibly, contribute to the aggressiveness of the disease or increase the possibility of Alzheimer's or heart disease!

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