Metformin and MTHFR: Potential for Decreased Methylation

Diabetes Type II is highly prevalent and one of the fastest growing medical conditions in the United States.

The best way to reduce becoming a type 2 diabetic is by choosing a healthy diet and lifestyle. Period.

For many, the transition to a healthy lifestyle and diet takes time and may be difficult.

Thus, many are on medications which help stabilize blood sugar levels via various mechanisms.

These medications, especially when combined with the C677T MTHFR defect, may increase homocysteine levels due to the decreased amounts of methylcobalamin and methylfolate.

A published case study[1] provides evidence of this significant interaction:

Vitamin B12 deficiency may be induced by long-term use of metformin, which may in turn lead to hyperhomocysteinemia. Thus, hyperhomocysteinemia may increase the risk of vascular thrombosis in diabetic patients, when metformin is used and a homozygous methylenetetrahydrofolate reductase (MTHFR) C677T mutation is present. We report a 65-year-old Taiwanese diabetic woman who was treated with metformin for 6 years and who had suffered from swelling of the left lower extremity for 3 months. Ascending venography confirmed the diagnosis of proximal deep vein thrombosis, while hyperhomocysteinemia, megaloblastic anemia caused by vitamin B12 deficiency, and a homozygous C677T mutation of the MTHFR gene were also found. She had no identifiable venous thrombotic risk factors other than hyperhomocysteinemia, which seemed to be caused by both MTHFR C677T homozygous mutation and vitamin B12 deficiency. With the substitution of insulin injection for metformin, short-term supplement of vitamin B12, and anticoagulant therapy for the deep vein thrombosis, her anemia and hyperhomocysteinemia recovered rapidly. The deep vein thrombosis also responded well. Our findings highly suggested the role of metformin in causing vitamin B12 deficiency, which may serve as an additional risk factor for venous thrombosis in diabetic patients. Our report also highlights the need to check vitamin B12 levels during metformin treatment.

While this individual responded well to vitamin B12 alone, it is recommended to also supplement with methylfolate due to the C677T MTHFR mutation.

Talk with your doctor about supplementing you with methylcobalamin and methylfolate if you are taking Metformin.

Be sure to have your doctor evaluate your vitamin B12 levels – and ideally your methylfolate levels. Consider taking Active B12 with Methylfolate. This provides both methylcobalamin (active form of vitamin B12) and methylfolate. Begin by taking 1/2 tablet daily and work up. Work with your doctor to identify what amount is best for you.

Effective ways to evaluate your B12 level is to have your doctor check your:

  • MCV
  • MCH
  • urinary methylmalonic acid
  • WBC

Take Home Points:

  1. Type 2 Diabetes is mainly caused by poor dietary and lifestyle choices. Improve these areas and eliminate your diabetes.
  2. Metformin increases vitamin B12 deficiency.
  3. B12 deficiency causes potential for increased homocysteine.
  4. MTHFR C677T variants typically have increased levels of homocysteine – if untreated.
  5. The combination of MTHFR C677T and Metformin reduces one’s ability to adequately methylate.
  6. Supplement with vitamin B12 and methylfolate if using Metformin and/or having the C677T MTHFR variant.

Question for You:

  • You taking Metformin and have MTHFR C677T? Were you aware of this connection?


10 Responses to “Metformin and MTHFR: Potential for Decreased Methylation”

  1. April April 2, 2012 at 7:24 pm # Reply

    Does the same apply to those with A1298C? I’m pregnant and have been taking Metformin for 5 years. I do not have type 2 diabetes though. I have PCOS. Is insulin really an alternative for me?

  2. Lynn_M April 3, 2012 at 2:29 pm # Reply

    There are glycemic-control drugs other than Metformin that are prescribed for Type 2 diabetics. Do these other drugs interact with MTHFR the same way Metformin does?

    • Dr Ben April 3, 2012 at 6:07 pm # Reply

      Hi Lynn –

      I’m educating myself on this – once I know, this article will be updated.

      • Alexia Guevara April 11, 2012 at 8:42 pm # Reply

        I found your website a blessing. I recently received the following test results.
        MUTATION C667T AB Homozygous
        MUTATION A1298C Negative

        What does any of this mean? I had to get this test done prior to IVF. Im in tears because I feel like I am in a world of unkown.

        Also, my doctor has me on Metformin…is this bad?

        Please help! Thank you :)

        • Lynn_M April 12, 2012 at 12:34 am # Reply

          Your test result shows that you a MTHFR genetic variant and you have two genes for the C667T mutation. This could definitely affect a pregnancy. You want to get on a protocol for this mutation and get a good diet and lifestyle going before you go through with IVF. Dr. Ben would say you also need to have your husband tested for MTHFR.

          Dr. Ben has a protocol for the C667 mutation here Read it, and read the other articles and forum questions and answers on this website. There are also discussions on other websites about MTHFR mutations and pregnancy.

          No need for tears. You have a genetic defect, but the effect of it can be bypassed with the right vitamin/mineral supplements, lifestyle, and avoidance of toxic exposures. Be grateful you were tested before IVF. You (and baby) can live a healthy life if you act on the knowledge that is available. However, one piece of commonly offered advice should be totally disregarded. Do not take folic acid. Instead, you need to be on the form of folate that your body can use, which is L-5-methyltetrahydrofolate, aka L-5-MTHF, aka Metafolin.

          I can’t answer your Metformin question.

  3. Helen Hilts MD November 20, 2012 at 3:54 am # Reply

    Dear Dr Lynch, I am a family practice doctor with a special interest in diabetes and prediabetes. Metformin has many benefits for both, mainly thru the reduction of insulin resistance, very important in these people, and very different from the effects of insulin. It’s main purpose is NOT to lower blood sugar tho it helps with that, too. Insulin resistance causes metabolic syndrome and most of the heart disease in diabetics and prediabetics.

    I always recommend my patients eat very low carb and it helps them more than any medication could. I also have many patients with homozygous or hetero MTHFR gene mutations. I have been testing people for about 6 months now.

    I have known that metformin can cause b12 deficiency and may affect folate for years. But anyone with the gene mutation should be on L-methylfolate and methyl cobalamin supplementation anyway, which would almost certainly overcome the small deficiencies caused by metformin.

    Almost all of the Type 2 diabetic patients I have with the MTHFR gene mutations who are already on metformin notice marked improvements in well-being and mood when they start methyl supplementation. I do not think the metformin detracts from this benefit, and the benefit of metformin itself is very important.

    Metformin also helps prevent, and increase remission rates, in many cancers. NIH is funding a very large study on this now.

    Please do not make a blanket statement about stopping metformin or replacing metformin with insulin. They work in different ways.

    • Dr Ben November 20, 2012 at 7:55 pm # Reply

      Dr Hilts –

      Thank you for your comment.

      You are absolutely correct. I have revisited this article and edited it.

      My intention of the article is to caution the potential B12 deficiency and folate interactions with Metformin.

      If one supplements with both these nutrients, then Metformin appears to be a very effective prescription for diabetes management.

      Dr Lynch

    • Luther July 29, 2014 at 10:23 am # Reply

      The problem is that it is quite rare to be tested for mthrfr gene abnormalities. I did not discover low vitamin b12 from metformin until I developed an unbearable nerve damage in my right hand, and began acting paranoid.
      Metformin is effective, but the side effects are much worse than close monitoring of sugar levels, and use of long acting and short acting insulin.
      Liver damage, failing to absorb calcium(leading to oesteoporosis),vitamin b issues, diarrhea, severe fatigue, and stomach pain are just a short list.
      Being homozygous for the 667t mutation puts us at even greater risk of vitamin deficiency.

      So, as a 15yr diabetic, I say metformin is poison.

  4. Sally C. December 18, 2012 at 3:32 am # Reply

    Hi Dr. Ben,

    My mother is heterzygous for both the C677T and A1298C mutations. She has been extremely ill the last several months (COPD, hypophosphatasia, broken vertabrae, MRSA, prednisone dependent, among others). In the nursing home, they gave her insulin for 6 months. Now, after 1 month of Metformin, she has complained again of severe swelling in her lower extremities. The doctors have no explanation. After reading this article, I have ordered her the B12 lozenges and told her to stop the folic acid supplements. Due to hypophosphatasia (alkaline phosphatase deficiency), they want her on “bone” supplements. Is there anything you can recommend? Is there other oral diabetic medications she can take in lieu of insulin? Or is insulin better? Do you know of any link to hypophosphatasia and MTHFR? I inherited the A1298C mutation along with the hypophosphastasia as well as both of my children (both Chromosome 1 linked).



  1. Things That Plague Us: Diabetes • MTHFR Living - March 2, 2014

    […] of cardiovascular disease, which is a leading cause of death in patients with diabetes. Drugs like Metformin may increase homocysteine levels in people with MTHFR C677T. So it is especially important that people with diabetes treat […]

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