Metformin is widely considered to be a first-line treatment for type 2 diabetes, and it has been prescribed to over 120 million people worldwide.
It’s a safe bet that a large proportion of those people are deficient in vitamin B12, thanks to the use of this medication.
While the percentages vary, studies consistently show that metformin impairs vitamin B12 absorption. In one multicenter randomized trial, metformin was associated with a 19% decrease in vitamin B12 concentration compared to placebo (de Jager J, et al. BMJ (Clinical Research Ed.) 2010; 340, c2181).
In a cross-sectional cohort study, patients on long-term metformin therapy had 26.7% lower cobalamin levels, 21.6% lower holotranscobalamin and 9.7% higher homocysteine compared with people in the control group (Hermann L, et al. The British Journal of Diabetes & Vascular Disease. 2004; 4(6), 401–406).
Commonly cited figures are that 10-30% of people with diabetes who take metformin will have decreased vitamin B12. This is most likely an underestimation.
Given its impact on vitamin B12 absorption, it might make sense for doctors to consider pairing B12 supplements with their metformin prescriptions.
Signs of Deficiency
Vitamin B12 is the largest and most complex of the vitamins. It is the only one that contains a metal ion—cobalt--and the only one that requires a transporter in the small intestine. It is required for proper red blood cell formation, neurological function, and DNA synthesis. It is also a co-factor for methionine synthase and L-methylmalonyl-CoA mutase. The former is needed for the formation of S-adenosylmethionine (SAMe), a universal methyl donor for almost 100 different substrates.
Symptoms of B12 deficiency include: megaloblastic anemia, fatigue, weakness, constipation, loss of appetite, weight loss, numbness and tingling in the hands and feet, difficulty maintaining balance, depression, confusion, dementia, poor memory, soreness of the mouth or tongue, low blood leukocyte and thrombocyte counts, shortness of breath, palpitations, pallor, gait abnormalities, vitiligo, osteoporosis, and hyperpigmentation.
Insufficient vitamin B12 can also result in folate trapping, which reduces the amount of folate available for important DNA functions.
To understand metformin’s impact on B12 levels, one needs to understand how this is absorbed.
In the acidic environment of the stomach, B12 is protected by binding with R-proteins. When it reaches the more alkaline environment of the small intestine, pancreatic enzymes degrade the R-proteins, allowing vitamin B12 to bind to intrinsic factor (IF) forming an IF-B12 complex. This complex is then taken up by receptors on enterocytes in the ileum. But this only occurs in the presence of calcium.
Metformin affects cubam, the receptor on surface of the ileal cell. For cubam to escort the IF-B12 complex into the enterocyte, calcium is required.
Metformin gives a positive charge to the surface of the cell membranes, displacing divalent cations. This alters membrane potentials, making it more difficult to transport the IF-B12 complexes into the cells. In a sense, metformin acts as a calcium channel blocker (Bauman W, et al. Diabetes Care. 2000; 23(9), 1227–1231).
The drug also impacts the enterohepatic circulation, which usually provides 3 to 8 mcg daily of vitamin B12 through reabsorption in the small intestine.
It is worth noting that about 1% of ingested vitamin B12 can be absorbed passively. So if dietary intake is high enough and other factors that impair absorption are not present, vitamin B12 status can be maintained even during prolonged treatment with metformin.
That said, few people with diabetes are able to maintain sufficient B12 levels from dietary intake alone.
There are a number of factors that interfere with vitamin B12 absorption. Many of these are common in diabetic patients, and they compound metformin’s negative impact. They include:
- Pancreatic insufficiency: Inadequate release of bicarbonate decreases the pH of the small intestine. This lessens the release of B12 from R-proteins.
- Proton Pump Inhibitor Use: Long-term PPI use is associated with reductions in vitamin B12 status. The evidence isn’t consistent about impact, but PPI’s ranked second among pharmaceuticals in total sales in 2013 (Zdilla M. Clinical Diabetes. 2015; 33(2), 90–95)
- Vegan and vegetarian diets: Elimination of animal-derived foods, in the absence of supplementation, can significantly limit B12 intake
- Alcohol abuse: Depletes vitamin B12
- Crohn’s or Celiac Disease: Decreases absorptive surface in the small intestine
- Age: Digestive function is often impaired in individuals over the age of 60. Atrophic gastritis is thought to affect 10-30% of older adults, resulting in decreased hydrochloric acid secretion in the stomach.
- H2 Receptor Antagonist Use: These drugs slow hydrochloric acid release in the stomach and can result in vitamin B12 deficiency when used for extended periods.
- Gastric bypass: Can impact vitamin B12 status by reducing intrinsic factor production
- Dysbiosis or parasitic infections: Some bacteria and parasites, e.g., tape worms, use vitamin B12 reducing availability for absorption
Assessment of vitamin B12 status can be challenging, and this is one of the confounding factors that make it difficult to put the metformin-B12 research into meaningful clinical perspective.
The challenges are at least three-fold. First, many experts feel the reference range for vitamin B12 deficiency in the US is entirely too low. Second, the various markers used to assess vitamin B12 status all have limitations. And, finally, because the body stores a fairly large amount of B12 (unlike other water-soluble vitamins), it can take a long time for impaired absorption to be reflected by any of the markers.
In some studies, serum B12 below 150 pmol/L is considered deficient, and 150 – 220 pmol/L is deemed borderline. Other authors consider levels below 200 pmol/L to be deficient. Some people will experience symptoms of deficiency with readings between 200 and 350 (or even 500). The Japanese government considers vitamin B12 below 500 – 550 pg/mL to be deficient.
Like many issues in nutrition, there’s no widely agreed-upon scientific consensus with regard to B12 levels, nor is there agreement about the ideal compound to measure. The following measures are commonly used in clinical studies:
- Serum B12: This is the typical marker used to assess vitamin B12 status, but it does not necessarily reflect the intracellular availability of vitamin B12. Holotranscobalamin II represents biologically active vitamin B12 that can be delivered to cells. The marker needs more study, but is thought to detect suboptimal levels of vitamin B12 earlier than methylmalonic acid or homocysteine.
- Homocysteine: Low vitamin B12 status is associated with increased levels of homocysteine, but other factors such as insufficient folate can also increase homocysteine. This is also a later stage marker, and cannot be used to detect early stages of deficiency.
- Methylmalonic Acid (serum): A build-up of this metabolite in serum is often indicative of insufficient vitamin B12; however, it can be elevated if there is bacterial overgrowth (Lindenbaum J, et al. American Journal of Hematology. 1990; 34(2), 99–107). Metformin is thought to increase bacterial growth in the intestine. Among elderly people with diabetes, methylmalonic acid levels are significantly elevated even when controlling for vitamin B12 concentration, suggesting another independent mechanism (Reinstatler L. Diabetes Care. 2012; 35(2), 327–333).
- Methylmalonic Acid (urinary): For most groups, this urine test is considered the more accurate measure of methylmalonic acid. However, kidney dysfunction, not uncommon in poorly controlled diabetes, can cause elevations (Lindenbaum J, et al. American Journal of Hematology. 1990; 34(2), 99–107).
Not only can the body store 2,500 mcg or more of vitamin B12, it will preserve serum levels at the expense of other tissues. Consequently, it can take up to a year of “negative” vitamin B12 balance before serum vitamin B12 levels drop enough to show up as deficiency (Bauman W, et al. Diabetes Care. 2000; 23(9), 1227–1231)
If serum vitamin B12 is low or borderline, practitioners will generally recommend supplementation. But what happens in cases when symptoms and risk factors are suggestive, but serum levels are “normal?”
One researcher suggests that for patients on metformin, a baseline measurement and screening at intervals of no more than 1-2 years seems prudent (Wile D, et al. Diabetes Care. 2010; 33(1), 156–161).
This time lag has significance for study design and interpretation, and may explain the inconsistencies between various metformin trials with regard to impact on B12. In short trials of several months’ duration, the metformin-induced malabsorption may not show up, leading to a general underestimation of the significance of this effect.
Can Calcium Correct the Problem?
At least one study has shown that calcium supplementation will counteract metformin’s impact on vitamin B12 (Bauman W, et al. Diabetes Care. 2000; 23(9), 1227–1231). However, there are potential drawbacks to consider before supplementing with calcium.
Bear in mind that calcium has more nutrient-to-nutrient interactions than vitamin B12. For example, it will interfere with magnesium, zinc, and iron absorption. It also has more nutrient-drug interactions, affecting antibiotics, antacids, thyroid hormones, thiazide diuretics (Stargrove M, et al. 2008).
Calcium supplementation is also contraindicated for people with chronic kidney impairment—a fairly common end-organ result of diabetes. In addition, there are concerns about calcium supplementation and increased risk of myocardial infarction in some populations (Bolland M, et al. The BMJ. 2010; 341). Given that people with diabetes are already at higher risk of CVD, this needs to be carefully considered.
While promising in terms of correcting metformin-induced vitamin B12 deficiency, calcium supplementation definitely needs more study.
While We Are Waiting…
Metformin is a valuable tool in diabetes management, but while both the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) recognize the risk vitamin B12 deficiency associated with this drug, neither organization--nor any other major medical organization for that matter—have advocated B12 supplementation or provided screening and supplementation guidelines.
Vitamin B12 is relatively inexpensive, easy to administer, and generally safe. Given the high prevalence of diabetes, the potential underestimation of deficiency in the medical literature, and most importantly, the significant and sometime irreversible impacts of vitamin B12 deficiency, it certainly makes good clinical sense to consider supplementation for any diabetic patient taking this drug.
But keep in mind that neither the current Institute of Medicine recommended intake of 2.4 mcg, nor the 6 mcg typically found in many over-the-counter supplements will address metformin-induced vitamin B12 deficiency. Daily dosages of 500 – 600 mcg or more are needed (Zdilla M. Clinical Diabetes. 2015; 33(2), 90–95)
As mentioned earlier, a very small percentage of vitamin B12 can be absorbed passively in the small intestine. Doses of 1000 mcg will result in approximately 10 mcg being absorbed, which more than meets the recommended daily intake.
Vitamin B12 is generally considered safe even in doses of 10 mg/day or more. However, a very small percentage of people experience side effects at high doses, and there aren’t any studies on the long-term safety of high-dose B12 for people who have renal or hepatic issues. People with cancer should probably avoid vitamin B12 supplementation.
In addition to supplementing with B12 itself, it is also important to ensure that patients are getting adequate amounts of cofactors – folate, potassium, and trimethylglycine. Magnesium, which isn’t a B12 cofactor per se, is important for ensuring potassium balance.
Sherryl Van Lare recently earned her Master’s degree in Nutrition and Integrative Health from the Maryland University of Integrative Health (MUIH) in Laurel, MD. She is currently a teaching assistant at MUIH as well as a clinical nutrition intern providing community nutrition education, conducting culinary demonstrations, working with individual clients, and writing articles. She is pursuing certification as a Certified Nutrition Specialist.