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Metformin and vitamin B12 deficiency?

Posted in Clinical & Translational, Clinical Diagnostics, Curation, Diabetes Mellitus, Endocrine Diseases, Folate and B12, Hematology, Hematopoiesis, tagged Drug therapy, metformin, Nutrition Disorders, Outcomes research, type 2 diabetes on March 14, 2016| Leave a Comment »

Metformin and vitamin B12 deficiency?

Larry H. Bernstein, MD, FCAP, Curator

LPBI

 

Years of taking popular diabetes drug tied to risk of B12 deficiency

BY KATHRYN DOYLE  http://www.reuters.com/article/us-health-metformin-b12-deficiency-idUSKCN0WC211

(Reuters Health) – – People taking metformin, a common type 2 diabetes medication, for several years may be at heightened risk of vitamin B12 deficiency and anemia, according to a new analysis of long-term data.

Metformin helps to control the amount of sugar, or glucose, in the blood by reducing how much glucose is absorbed from food and produced by the liver, and by increasing the body’s response to the hormone insulin, according to the National Institutes of Health.

“Metformin is the most commonly used drug to treat type 2 diabetes, so many millions of people are taking it, usually for a prolonged period (many years),” said senior study author Dr. Jill P Crandall of Albert Einstein College of Medicine in New York City, by email.

“Smaller numbers of people take metformin for prevention of diabetes or treatment of polycystic ovary syndrome,” Crandall told Reuters Health.

The researchers used data from the Diabetes Prevention Program and the Diabetes Prevention Program Outcomes Study, which followed participants at high risk for type 2 diabetes for more than 10 years.

The study began with more than 3,000 people age 25 years and older with high blood sugar. The participants were randomly assigned to receive either 850 milligrams of metformin twice daily, placebo medication or an intensive lifestyle program than did not include medication. For the new analysis only those taking placebo or metformin were considered, and about 50 participants were excluded after having weight-loss surgery, which would affect their diabetes outcomes.

During follow-up, the participants provided blood samples at the five- and 13-year points.

Using these blood samples, the researchers found that at year five, average B12 levels were lower in the metformin group than the placebo group, and B12 deficiency was more common, affecting 4 percent of those on metformin compared to 2 percent of those not taking the drug.

Borderline low B12 levels affected almost 20 percent of those on metformin and 10 percent of those taking placebo.

Average vitamin B12 levels were higher by year 13 than in year five, but B12 deficiency was also more common in both the metformin and placebo groups, as reported in the Journal of Clinical Endocrinology and Metabolism.

Vitamin B12 deficiency may lead to nerve damage which can be severe and may be irreversible, Crandall said.

“Severe and prolonged B12 deficiency has also been linked to impaired cognition and dementia,” she said. “It can also cause anemia (low red blood cell count) – fortunately, this condition is reversible with treatment.”

More people in the metformin group were also anemic at year five than in the placebo group.

There are more than three million cases of vitamin B12 deficiency each year in the U.S., which can be caused by diet or certain medical conditions. Symptoms include fatigue, and numbness or tingling.

Humans do not make vitamin B12 and need to consume it from animal sources or supplements. Vegetarians may get enough from eating eggs and dairy products, but vegans need to rely on supplements or fortified grains.

Doctors who prescribe metformin to patients long-term for type 2 diabetes, gestational diabetes, polycystic ovarian syndrome or other indications should consider routine measurement of vitamin B12 levels, the authors conclude.

“The FDA and organizations such as the American Diabetes Association do not have any formal recommendations for B12 monitoring for people taking metformin,” Crandall said. “That said, our study (and others) suggests that a small but significant number of people may develop deficiency.”

“People who are taking metformin should ask their doctor about measuring their B12 level,” she said.

Restoring healthy B12 levels is easy to accomplish with pills or monthly injections, she added.

“The risk of B12 deficiency should not be considered a reason to avoid taking metformin,” Crandall said.

SOURCE: bit.ly/1SWRxed Journal of Clinical Endocrinology and Metabolism, online February 22, 2016.

 

Long-term Metformin Use and Vitamin B12 Deficiency in the Diabetes Prevention Program Outcomes Study

 Vanita R ArodaMD¹, Sharon L EdelsteinScM², Ronald B GoldbergMD³, William C KnowlerMD, DrPH⁴, …., Marinella G TemprosaPhD², Neil H WhiteMD⁹, Jill P CrandallMD¹⁰, and Diabetes Prevention Program Research Group

http://dx.doi.org/10.1210/jc.2015-3754#sthash.ievZyXLD.dpuf    The Journal of Clinical Endocrinology & Metabolism    2016 Feb 22; jc20153754

Context:

 Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use.

Objective:

 To assess risk of B12 deficiency with metformin use in the DPP/DPPOS

Design:

 Secondary analysis from DPP/DPPOS. Participants were assigned to placebo (n=1082, PLA) or metformin (n=1073, MET) for 3.2 years; MET received open-label metformin for an additional 9 years.

Setting:

27 study centers in the US

Patients:

 DPP eligibility: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. Analytic population: participants with available stored samples. B12 levels were assessed at 5 (n=857, n=858) and 13 years [n=756, n=764] in PLA and MET, respectively.

Interventions:

 Metformin 850 mg twice daily versus placebo (DPP); open-label metformin in MET (DPPOS)

Main Outcome Measures:

 B12 deficiency, anemia, peripheral neuropathy

Results:

 Low B12 (≤203 pg/ml) occurred more often in MET than PLA at 5 years (4.3% vs 2.3%, p=0.02) but not at 13 years (7.4% vs. 5.4%, p=0.12). Combined low and borderline-low B12 (≤298 pg/ml) was more common in MET at 5 (19.1% vs 9.5%, p<0.01) and 13 years (20.3% vs 15.6%, p=0.02). Years of metformin use was associated with increased risk of B12 deficiency (OR B12 deficiency/year metformin use, 1.13, 95% CI 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels.

Conclusions:

 Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.

 

Metformin linked to vitamin B₁₂ deficiency

David Holmes   Nature Reviews Endocrinology(2016)    http://dx.doi.org:/10.1038/nrendo.2016.39

Secondary analysis of data from the Diabetes Prevention Program Outcomes Study (DPPOS), one of the largest and longest studies of metformin treatment in patients at high risk of developing type 2 diabetes mellitus, shows that long-term use of metformin is associated with vitamin B₁₂deficiency.

Aroda, V. R. et al. Long-term metformin use and vitamin B₁₂ deficiency in the Diabetes Prevention Program Outcomes Study. J. Clin. Endocrinol. Metab. http://dx.doi.org/10.1210/jc.2015-3754 (2016)

 

Long-term Follow-up of Diabetes Prevention Program Shows Continued Reduction in Diabetes Development

http://www.diabetes.org/newsroom/press-releases/2014/long-term-follow-up-of-diabetes-prevention-program-shows-reduction-in-diabetes-development.html

San Francisco, California
June 16, 2014

Treatments used to decrease the development of type 2 diabetes continue to be effective an average of 15 years later, according to the latest findings of the Diabetes Prevention Program Outcomes Study, a landmark study funded by the National Institutes of Health (NIH).

The results, presented at the American Diabetes Association’s 74th Scientific Sessions®, come more than a decade after the Diabetes Prevention Program, or DPP, reported its original findings. In 2001, after an average of three years of study, the DPP announced that the study’s two interventions, a lifestyle program designed to reduce weight and increase activity levels and the diabetes medicinemetformin, decreased the development of type 2 diabetes in a diverse group of people, all of whom were at high risk for the disease, by 58 and 31 percent, respectively, compared with a group taking placebo.

The Diabetes Prevention Program Outcomes Study, or DPPOS, was conducted as an extension of the DPP to determine the longer-term effects of the two interventions, including further reduction in diabetes development and whether delaying diabetes would reduce the development of the diabetes complications that can lead to blindness, kidney failure, amputations and heart disease. Funded largely by the NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the new findings show that the lifestyle intervention and metformin treatment have beneficial effects, even years later, but did not reduce microvascular complications.

Delaying Type 2 Diabetes

Participants in the study who were originally assigned to the lifestyle intervention and metformin during DPP continued to have lower rates of type 2 diabetes development than those assigned to placebo, with 27 percent and 17 percent reductions, respectively, after 15 years.

“What we’re finding is that we can prevent or delay the onset of type 2 diabetes, a chronic disease, through lifestyle intervention or with metformin, over a very long period of time,” said David M. Nathan, MD, Chairman of the DPP/DPPOS and Professor of Medicine at Harvard Medical School. “After the initial randomized treatment phase in DPP, all participants were offered lifestyle intervention and the rates of diabetes development fell in the metformin and former placebo groups, leading to a reduction in the treatment group differences over time.  However, the lifestyle intervention and metformin are still quite effective at delaying, if not preventing, type 2 diabetes,” Dr. Nathan said. Currently, an estimated 79 million American adults are at high-risk for developing type 2 diabetes.

Microvascular Complications
The DPPOS investigators followed participants for an additional 12 years after the end of the DPP to determine both the extent of diabetes prevention over time and whether the study treatments would also decrease the small vessel -or microvascular- complications, such as eye, nerve and kidney disease. These long-term results did not demonstrate significant differences among the lifestyle intervention, metformin or placebo groups on the microvascular complications, reported Kieren Mather, MD, Professor of Medicine at Indiana University School of Medicine and a study investigator.

“However, regardless of type of initial treatment, participants who didn’t develop diabetes had a 28 percent lower occurrence of the microvascular complications than those participants who did develop diabetes. These findings show that intervening in the prediabetes phase is important in reducing early stage complications,” Dr. Mather noted. The absence of differences in microvascular complications among the intervention groups may be explained by the small differences in average glucose levels among the groups at this stage of follow-up.

Risk for Cardiovascular Disease

The DPP population was relatively young and healthy at the beginning of the study, and few participants had experienced any severe cardiovascular events, such as heart attack or stroke, 15 years later. The relatively small number of events meant that the DPPOS researchers could not test the effects of interventions on cardiovascular disease. However, the research team did examine whether the study interventions, or a delay in the onset of type 2 diabetes, improved cardiovascular risk factors.

“We found that cardiovascular risk factors, such as hypertension, are generally improved by the lifestyle intervention and somewhat less by metformin,” said Ronald Goldberg, MD, Professor of Medicine at the University of Miami and one of the DPPOS investigators. “We know that people with type 2 diabetes are at much higher risk for heart disease and stroke than those who do not have diabetes, so a delay in risk factor development or improvement in risk factors may prove to be beneficial.”

Long-term Results with Metformin

The DPP/DPPOS is the largest and longest duration study to examine the effects of metformin, an inexpensive, well-known and generally safe diabetes medicine, in people who have not been diagnosed with diabetes. For DPPOS participants, metformin treatment was associated with a modest degree of long-term weight loss. “Other than a small increase in vitamin B-12 deficiency, which is a recognized consequence of metformin therapy, it has been extremely safe and well-tolerated over the 15 years of our study,” said Jill Crandall, MD, Professor of Medicine at Albert Einstein College of Medicine and a DPPOS investigator. “Further study will help show whether metformin has beneficial effects on heart disease and cancer, which are both increased in people with type 2 diabetes.”

Looking to the Future

In addition to the current findings, the DPPOS includes a uniquely valuable population that can help researchers understand the clinical course of type 2 diabetes.  Since the participants did not have diabetes at the beginning of the DPP, for those who have developed diabetes, the data show precisely when they developed the disease, which is rare in previous studies. “The DPP and DPPOS have given us an incredible wealth of information by following a very diverse group of people with regard to race and age as they have progressed from prediabetes to diabetes,” said Judith Fradkin, MD, Director of the NIDDK Division of Diabetes, Endocrinology and Metabolic Diseases. “The study provides us with an opportunity to make crucial discoveries about the clinical course of type 2 diabetes.”

Dr. Fradkin noted that the study population held promise for further analyses because researchers would now be able to examine how developing diabetes at different periods of life may cause the disease to progress differently. “We can look at whether diabetes behaves differently if you develop it before the age of 50 or after the age of 60,” she said. “Thanks to the large and diverse population of DPPOS that has remained very loyal to the study, we will be able to see how and when complications first develop and understand how to intervene most effectively.”

She added that NIDDK had invited the researchers to submit an application for a grant to follow the study population for an additional 10 years.

The Diabetes Prevention Program Outcomes Study was funded under NIH grant U01DK048489 by the NIDDK; National Institute on Aging; National Cancer Institute; National Heart, Lung, and Blood Institute; National Eye Institute; National Center on Minority Health and Health Disparities; and the Office of the NIH Director; Eunice Kennedy Shriver National Institute of Child Health and Human Development; Office of Research on Women’s Health; and Office of Dietary Supplements, all part of the NIH, as well as the Indian Health Service, Centers for Disease Control and Prevention and American Diabetes Association. Funding in the form of supplies was provided by Merck Sante, Merck KGaA and LifeScan.

The American Diabetes Association is leading the fight to Stop Diabetes® and its deadly consequences and fighting for those affected by diabetes. The Association funds research to prevent, cure and manage diabetes; delivers services to hundreds of communities; provides objective and credible information; and gives voice to those denied their rights because of diabetes. Founded in 1940, our mission is to prevent and cure diabetes and to improve the lives of all people affected by diabetes. For more information please call the American Diabetes Association at 1-800-DIABETES (1-800-342-2383) or visit http://www.diabetes.org. Information from both these sources is available in English and Spanish.

Association of Biochemical B₁₂Deficiency With Metformin Therapy and Vitamin B₁₂Supplements  

The National Health and Nutrition Examination Survey, 1999–2006

Lael Reinstatler, Yan Ping Qi, Rebecca S. Williamson, Joshua V. Garn, and Godfrey P. Oakley Jr.
Diabetes Care February 2012 vol. 35 no. 2 327-333      http://dx.doi.org:/10.2337/dc11-1582

OBJECTIVE To describe the prevalence of biochemical B₁₂deficiency in adults with type 2 diabetes taking metformin compared with those not taking metformin and those without diabetes, and explore whether this relationship is modified by vitamin B₁₂supplements.

RESEARCH DESIGN AND METHODS Analysis of data on U.S. adults ≥50 years of age with (n = 1,621) or without type 2 diabetes (n = 6,867) from the National Health and Nutrition Examination Survey (NHANES), 1999–2006. Type 2 diabetes was defined as clinical diagnosis after age 30 without initiation of insulin therapy within 1 year. Those with diabetes were classified according to their current metformin use. Biochemical B₁₂ deficiency was defined as serum B₁₂concentrations ≤148 pmol/L and borderline deficiency was defined as >148 to ≤221 pmol/L.

RESULTS Biochemical B₁₂ deficiency was present in 5.8% of those with diabetes using metformin compared with 2.4% of those not using metformin (P = 0.0026) and 3.3% of those without diabetes (P = 0.0002). Among those with diabetes, metformin use was associated with biochemical B₁₂ deficiency (adjusted odds ratio 2.92; 95% CI 1.26–6.78). Consumption of any supplement containing B₁₂ was not associated with a reduction in the prevalence of biochemical B₁₂deficiency among those with diabetes, whereas consumption of any supplement containing B₁₂ was associated with a two-thirds reduction among those without diabetes.

CONCLUSIONS Metformin therapy is associated with a higher prevalence of biochemical B₁₂ deficiency. The amount of B₁₂recommended by the Institute of Medicine (IOM) (2.4 μg/day) and the amount available in general multivitamins (6 μg) may not be enough to correct this deficiency among those with diabetes.

It is well known that the risks of both type 2 diabetes and B₁₂deficiency increase with age (1,2). Recent national data estimate a 21.2% prevalence of diagnosed diabetes among adults ≥65 years of age and a 6 and 20% prevalence of biochemical B₁₂ deficiency (serum B₁₂<148 pmol/L) and borderline deficiency (serum B₁₂ ≥148–221 pmol/L) among adults ≥60 years of age (3,4).

The diabetes drug metformin has been reported to cause a decrease in serum B₁₂ concentrations. In the first efficacy trial, DeFronzo and Goodman (5) demonstrated that although metformin offers superior control of glycosylated hemoglobin levels and fasting plasma glucose levels compared with glyburide, serum B₁₂ concentrations were lowered by 22% compared with placebo, and 29% compared with glyburide therapy after 29 weeks of treatment. A recent, randomized control trial designed to examine the temporal relationship between metformin and serum B₁₂ found a 19% reduction in serum B₁₂ levels compared with placebo after 4 years (6). Several other randomized control trials and cross-sectional surveys reported reductions in B₁₂ranging from 9 to 52% (7–16). Although classical B₁₂ deficiency presents with clinical symptoms such as anemia, peripheral neuropathy, depression, and cognitive impairment, these symptoms are usually absent in those with biochemical B₁₂ deficiency (17).

Several researchers have made recommendations to screen those with type 2 diabetes on metformin for serum B₁₂ levels (6,7,14–16,18–21). However, no formal recommendations have been provided by the medical community or the U.S. Prevention Services Task Force. High-dose B₁₂ injection therapy has been successfully used to correct the metformin-induced decline in serum B₁₂ (15,21,22). The use of B₁₂supplements among those with type 2 diabetes on metformin in a nationally representative sample and their potentially protective effect against biochemical B₁₂ deficiency has not been reported. It is therefore the aim of the current study to use the nationally representative National Health and Nutrition Examination Survey (NHANES) population to determine the prevalence of biochemical B₁₂deficiency among those with type 2 diabetes ≥50 years of age taking metformin compared with those with type 2 diabetes not taking metformin and those without diabetes, and to explore how these relationships are modified by B₁₂ supplement consumption.

Design overview

NHANES is a nationally representative sample of the noninstitutionalized U.S. population with targeted oversampling of U.S. adults ≥60 years of age, African Americans, and Hispanics. Details of these surveys have been described elsewhere (23). All participants gave written informed consent, and the survey protocol was approved by a human subjects review board.

Setting and participants

Our study included adults ≥50 years of age from NHANES 1999–2006. Participants with positive HIV antibody test results, high creatinine levels (>1.7 mg/dL for men and >1.5 mg/dL for women), and prescription B₁₂ injections were excluded from the analysis. Participants who reported having prediabetes or borderline diabetes (n = 226) were removed because they could not be definitively grouped as having or not having type 2 diabetes. We also excluded pregnant women, those with type 1 diabetes, and those without diabetes taking metformin. Based on clinical aspects described by the American Diabetes Association and previous work in NHANES, those who were diagnosed before the age of 30 and began insulin therapy within 1 year of diagnosis were classified as having type 1 diabetes (24,25). Type 2 diabetes status in adults was dichotomized as yes/no. Participants who reported receiving a physician’s diagnosis after age 30 (excluding gestational diabetes) and did not initiate insulin therapy within 1 year of diagnosis were classified as having type 2 diabetes.

Outcomes and follow-up

The primary outcome was biochemical B₁₂ deficiency determined by serum B₁₂ concentrations. Serum B₁₂ levels were quantified using the Quantaphase II folate/vitamin B₁₂ radioassay kit from Bio-Rad Laboratories (Hercules, CA). We defined biochemical B₁₂ deficiency as serum levels ≤148 pmol/L, borderline deficiency as serum B₁₂ >148 to ≤221 pmol/L, and normal as >221 pmol/L (26).

The main exposure of interest was metformin use. Using data collected in the prescription medicine questionnaire, those with type 2 diabetes were classified as currently using metformin therapy (alone or in combination therapy) versus those not currently using metformin. Length of metformin therapy was used to assess the relationship between duration of metformin therapy and biochemical B₁₂ deficiency. In the final analysis, two control groups were used to allow the comparison of those with type 2 diabetes taking metformin with those with type 2 diabetes not taking metformin and those without diabetes.

To determine whether the association between metformin and biochemical B₁₂ deficiency is modified by supplemental B₁₂ intake, data from the dietary supplement questionnaire were used. Information regarding the dose and frequency was used to calculate average daily supplemental B₁₂ intake. We categorized supplemental B₁₂ intake as 0 μg (no B₁₂ containing supplement), >0–6 μg, >6–25 μg, and >25 μg. The lower intake group, >0–6 μg, includes 6 μg, the amount of vitamin B₁₂ typically found in over-the-counter multivitamins, and 2.4 μg, the daily amount the IOM recommends for all adults ≥50 years of age to consume through supplements or fortified food (1). The next group, >6–25 μg, includes 25 μg, the amount available in many multivitamins marketed toward senior adults. The highest group contains the amount found in high-dose B-vitamin supplements.

 

In the final analysis, there were 575 U.S. adults ≥50 years of age with type 2 diabetes using metformin, 1,046 with type 2 diabetes not using metformin, and 6,867 without diabetes. The demographic and biological characteristics of the groups are shown in Table 1. Among metformin users, mean age was 63.4 ± 0.5 years, 50.3% were male, 66.7% were non-Hispanic white, and 40.7% used a supplement containing B₁₂. The median duration of metformin use was 5 years. Compared with those with type 2 diabetes not taking metformin, metformin users were younger (P < 0.0001), reported a lower prevalence of insulin use (P < 0.001), and had a shorter duration of diabetes (P = 0.0207). Compared with those without diabetes, metformin users had a higher proportion of nonwhite racial groups (P< 0.0001), a higher proportion of obesity (P < 0.0001), a lower prevalence of macrocytosis (P = 0.0017), a lower prevalence of supplemental folic acid use (P = 0.0069), a lower prevalence of supplemental vitamin B₁₂ use (P = 0.0180), and a lower prevalence of calcium supplement use (P = 0.0002). There was a twofold difference in the prevalence of anemia among those with type 2 diabetes versus those without, and no difference between the groups with diabetes.    

Association of Biochemical B₁₂Deficiency With Metformin Therapy and Vitamin B₁₂Supplements

Demographic and biological characteristics of U.S. adults ≥50 years of age: NHANES 1999–2006

The geometric mean serum B₁₂ concentration among those with type 2 diabetes taking metformin was 317.5 pmol/L. This was significantly lower than the geometric mean concentration in those with type 2 diabetes not taking metformin (386.7 pmol/L; P = 0.0116) and those without diabetes (350.8 pmol/L; P = 0.0011). As seen in Fig. 1, the weighted prevalence of biochemical B₁₂ deficiency adjusted for age, race, and sex was 5.8% for those with type 2 diabetes taking metformin, 2.2% for those with type 2 diabetes not taking metformin (P = 0.0002), and 3.3% for those without diabetes (P = 0.0026). Among the three aforementioned groups, borderline deficiency was present in 16.2, 5.5, and 8.8%, respectively (P < 0.0001). Applying the Fleiss formula for calculating attributable risk from cross-sectional data (27), among all of the cases of biochemical B₁₂ deficiency, 3.5% of the cases were attributable to metformin use; and among those with diabetes, 41% of the deficient cases were attributable to metformin use. When the prevalence of biochemical B₁₂ deficiency among those with diabetes taking metformin was analyzed by duration of metformin therapy, there was no notable increase in the prevalence of biochemical B₁₂ deficiency as the duration of metformin use increased. The prevalence of biochemical B₁₂ deficiency was 4.1% among those taking metformin <1 year, 6.3% among those taking metformin ≥1–3 years, 4.1% among those taking metformin >3–10 years, and 8.1% among those taking metformin >10 years (P = 0.3219 for <1 year vs. >10 years). Similarly, there was no clear increase in the prevalence of borderline deficiency as the duration of metformin use increased (15.9% among those taking metformin >10 years vs. 11.4% among those taking metformin <1 year; P = 0.4365).

Weighted prevalence of biochemical B₁₂ deficiency and borderline deficiency adjusted for age, race, and sex in U.S. adults ≥50 years of age: NHANES 1999–2006. Black bars are those with type 2 diabetes on metformin, gray bars are those with type 2 diabetes not on metformin, and the white bars are those without diabetes. *P = 0.0002 vs. type 2 diabetes on metformin. †P < 0.0001 vs. type 2 diabetes on metformin. ‡P = 0.0026 vs. type 2 diabetes on metformin.

Table 2 presents a stratified analysis of the weighted prevalence of biochemical B₁₂ deficiency and borderline deficiency by B₁₂supplement use. For those without diabetes, B₁₂ supplement use was associated with an ∼66.7% lower prevalence of both biochemical B₁₂deficiency (4.8 vs. 1.6%; P < 0.0001) and borderline deficiency (16.6 vs. 5.5%; P < 0.0001). A decrease in the prevalence of biochemical B₁₂deficiency was seen at all levels of supplemental B₁₂ intake compared with nonusers of supplements. Among those with type 2 diabetes taking metformin, supplement use was not associated with a decrease in the prevalence of either biochemical B₁₂ deficiency (5.6 vs. 5.3%; P= 0.9137) or borderline deficiency (15.5 vs. 8.8%; P = 0.0826). Among the metformin users who also used supplements, those who consumed >0–6 μg of B₁₂ had a prevalence of biochemical B₁₂ deficiency of 14.1%. However, consumption of a supplement containing >6 μg of B₁₂ was associated with a prevalence of biochemical B₁₂ deficiency of 1.8% (P = 0.0273 for linear trend). Similar trends were seen in the association of supplemental B₁₂ intake and the prevalence of borderline deficiency. For those with type 2 diabetes not taking metformin, supplement use was also not associated with a decrease in the prevalence of biochemical B₁₂ deficiency (2.1 vs. 2.0%; P = 0.9568) but was associated with a 54% reduction in the prevalence of borderline deficiency (7.8 vs. 3.4%; P = 0.0057 for linear trend).

Comparison of average daily B₁₂ supplement intake by weighted prevalence of biochemical B₁₂ deficiency (serum B₁₂ ≤148 pmol/L) and borderline deficiency (serum B₁₂ >148 to ≤221 pmol/L) among U.S. adults ≥50 years of age: NHANES 1999–2006.

Table 3 demonstrates the association of various risk factors with biochemical B₁₂ deficiency. Metformin therapy was associated with biochemical B₁₂ deficiency (odds ratio [OR] 2.89; 95% CI 1.33–6.28) and borderline deficiency (OR 2.32; 95% CI 1.31–4.12) in a crude model (results not shown). After adjusting for age, BMI, and insulin and supplement use, metformin maintained a significant association with biochemical B₁₂ deficiency (OR 2.92; 95% CI 1.28–6.66) and borderline deficiency (OR 2.16; 95% CI 1.22–3.85). Similar to Table 2, B₁₂ supplements were protective against borderline (OR 0.43; 95% CI 0.23–0.81), but not biochemical, B₁₂ deficiency (OR 0.76; 95% CI 0.34–1.70) among those with type 2 diabetes. Among those without diabetes, B₁₂ supplement use was ∼70% protective against biochemical B₁₂ deficiency (OR 0.26; 95% CI 0.17–0.38) and borderline deficiency (OR 0.27; 95% CI 0.21–0.35).

Polytomous logistic regression for potential risk factors of biochemical B₁₂ deficiency and borderline deficiency among U.S. adults ≥50 years of age: NHANES 1999–2006, OR (95% CI)

The IOM has highlighted the detection and diagnosis of B₁₂ deficiency as a high-priority topic for research (1). Our results suggest several findings that add to the complexity and importance of B₁₂ research and its relation to diabetes, and offer new insight into the benefits of B₁₂ supplements. Our data confirm the relationship between metformin and reduced serum B₁₂ levels beyond the background prevalence of biochemical B₁₂ deficiency. Our data demonstrate that an intake of >0–6 μg of B₁₂, which includes the dose most commonly found in over-the-counter multivitamins, was associated with a two-thirds reduction of biochemical B₁₂ deficiency and borderline deficiency among adults without diabetes. This relationship has been previously reported with NHANES and Framingham population data (4,29). In contrast, we did not find that >0–6 μg of B₁₂ was associated with a decrease in the prevalence of biochemical B₁₂ deficiency or borderline deficiency among adults with type 2 diabetes taking metformin. This observation suggests that metformin reduces serum B₁₂ by a mechanism that is additive to or different from the mechanism in older adults. It is also possible that metformin may exacerbate the deficiency among older adults with low serum B₁₂. Our sample size was too small to determine which amount >6 μg was associated with maximum protection, but we did find a dose-response trend.

We were surprised to find that those with type 2 diabetes not using metformin had the lowest prevalence of biochemical B₁₂ deficiency. It is possible that these individuals may seek medical care more frequently than the general population and therefore are being treated for their biochemical B₁₂ deficiency. Or perhaps, because this population had a longer duration of diabetes and a higher proportion of insulin users compared with metformin users, they have been switched from metformin to other diabetic treatments due to low serum B₁₂ concentrations or uncontrolled glucose levels and these new treatments may increase serum B₁₂ concentrations. Despite the observed effects of metformin on serum B₁₂ levels, it remains unclear whether or not this reduction is a public health concern. With lifetime risks of diabetes estimated to be one in three and with metformin being a first-line intervention, it is important to increase our understanding of the effects of oral vitamin B₁₂ on metformin-associated biochemical deficiency (20,21).

The strengths of this study include its nationally representative, population-based sample, its detailed information on supplement usage, and its relevant biochemical markers. This is the first study to use a nationally representative sample to examine the association between serum B₁₂ concentration, diabetes status, and metformin use as well as examine how this relationship may be modified by vitamin B₁₂ supplementation. The data available regarding supplement usage provided specific information regarding dose and frequency. This aspect of NHANES allowed us to observe the dose-response relationship in Table 2 and to compare it within our three study groups.

This study is also subject to limitations. First, NHANES is a cross-sectional survey and it cannot assess time as a factor, and therefore the results are associations and not causal relationships. A second limitation arises in our definition of biochemical B₁₂ deficiency. There is no general consensus on how to define normal versus low serum B₁₂levels. Some researchers include the functional biomarker methylmalonic acid (MMA) in the definition, but this has yet to be agreed upon (30–34). Recently, an NHANES roundtable discussion suggested that definitions of biochemical B₁₂ deficiency should incorporate one biomarker (serum B₁₂ or holotranscobalamin) and one functional biomarker (MMA or total homocysteine) to address problems with sensitivity and specificity of the individual biomarkers. However, they also cited a need for more research on how the biomarkers are related in the general population to prevent misclassification (34). MMA was only measured for six of our survey years; one-third of participants in our final analysis were missing serum MMA levels. Moreover, it has recently been reported that MMA values are significantly greater among the elderly with diabetes as compared with the elderly without diabetes even when controlling for serum B₁₂ concentrations and age, suggesting that having diabetes may independently increase the levels of MMA (35). This unique property of MMA in elderly adults with diabetes makes it unsuitable as part of a definition of biochemical B₁₂ deficiency in our specific population groups. Our study may also be subject to misclassification bias. NHANES does not differentiate between diabetes types 1 and 2 in the surveys; our definition may not capture adults with type 2 diabetes exclusively. Additionally, we used responses to the question “Have you received a physician’s diagnosis of diabetes” to categorize participants as having or not having diabetes. Therefore, we failed to capture undiagnosed diabetes. Finally, we could only assess current metformin use. We cannot determine if nonmetformin users have ever used metformin or if they were not using it at the time of the survey.

Our data demonstrate several important conclusions. First, there is a clear association between metformin and biochemical B₁₂ deficiency among adults with type 2 diabetes. This analysis shows that 6 μg of B₁₂ offered in most multivitamins is associated with two-thirds reduction in biochemical B₁₂ deficiency in the general population, and that this same dose is not associated with protection against biochemical B₁₂ deficiency among those with type 2 diabetes taking metformin. Our results have public health and clinical implications by suggesting that neither 2.4 μg, the current IOM recommendation for daily B₁₂ intake, nor 6 μg, the amount found in most multivitamins, is sufficient for those with type 2 diabetes taking metformin.

This analysis suggests a need for further research. One research design would be to identify those with biochemical B₁₂ deficiency and randomize them to receive various doses of supplemental B₁₂chronically and then evaluate any improvement in serum B₁₂concentrations and/or clinical outcomes. Another design would use existing cohorts to determine clinical outcomes associated with biochemical B₁₂ deficiency and how they are affected by B₁₂supplements at various doses. Given that a significant proportion of the population ≥50 years of age have biochemical B₁₂ deficiency and that those with diabetes taking metformin have an even higher proportion of biochemical B₁₂ deficiency, we suggest that support for further research is a reasonable priority.

 

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Discussion:

One research design would be to identify those with biochemical B₁₂ deficiency and randomize them to receive various doses of supplemental B₁₂chronically and then evaluate any improvement in serum B₁₂concentrations and/or clinical outcomes. Another design would use existing cohorts to determine clinical outcomes associated with biochemical B₁₂ deficiency and how they are affected by B₁₂supplements at various doses.

This is of considerable interest.  As far as I can see, there is insufficient data presented to discern all of the variables entangled.  In a study of 8000 hemograms several years ago, it was of some interest that there were a large percentage of patients who were over age 75 years having a MCV of 94 – 100, not considered indicative of macrocytic anemia.  It would have been interesting to explore that set of the data further.

UPDATED 3/17/2020

Nutrients. 2019 May 7;11(5). pii: E1020. doi: 10.3390/nu11051020.

Monitoring Vitamin B₁₂ in Women Treated with Metformin for Primary Prevention of Breast Cancer and Age-Related Chronic Diseases.

Mastroianni A¹, Ciniselli CM², Panella R³, Macciotta A⁴, Cavalleri A⁵, Venturelli E⁶, Taverna F⁷, Mazzocchi A⁸, Bruno E⁹, Muti P¹⁰, Berrino F¹¹, Verderio P¹², Morelli D¹³, Pasanisi P¹⁴.

Author information

Abstract

Metformin (MET) is currently being used in several trials for cancer prevention or treatment in non-diabetics. However, long-term MET use in diabetics is associated with lower serum levels of total vitamin B₁₂. In a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET, whose participants were characterized by different components of metabolic syndrome, we tested the effect of MET on serum levels of B₁₂, holo transcobalamin II (holo-TC-II), and methylmalonic acid (MMA). The study was conducted on 165 women receiving MET or placebo for three years. Results of the study indicate a significant overall reduction in both serum total B₁₂ and holo-TC-II levels according with MET-treatment. In particular, in the MET group 26 of 81 patients and 10 of the 84 placebo-treated subjects had B₁₂ below the normal threshold (<221 pmol/L) at the end of the study. Considering jointly all B₁₂, Holo-TC-II, and MMA, 13 of the 165 subjects (10 MET and 3 placebo-treated) had at least two deficits in the biochemical parameters at the end of the study, without reporting clinical signs. Although our results do not affect whether women remain in the trial, B₁₂ monitoring for MET-treated individuals should be implemented.

ntroduction

Metformin (MET) is the first-line treatment for type-2 diabetes and has been used for decades to treat this chronic condition [1]. Given its favorable effects on glycemic control, weight patterns, insulin requirements, and cardiovascular outcomes, MET has been recently proposed in addition to lifestyle interventions to reduce metabolic syndrome (MS) and age-related chronic diseases [2]. Observational studies have also suggested that diabetic patients treated with MET had a significantly lower risk of developing cancer or lower cancer mortality than those untreated or treated with other drugs [3,4]. For this reason, a number of clinical trials are in progress in different solid cancers.

One of the limitations in implementing long-term use of MET to prevent chronic conditions in healthy subjects relates to its potential lowering effect on vitamin B₁₂ (B₁₂). The aim of the present study was to assess the effect of three years of MET treatment in a randomized, controlled trial considering both B₁₂ levels and biomarkers of its metabolism and biological effectiveness.

Cobalamin, also known as B₁₂, is a water-soluble, cobalt-containing vitamin. All forms of B₁₂ are converted intracellularly into adenosyl-Cbl and methylcobalamin—the biologically active forms at the cellular level [5]. Vitamin B₁₂ is a vital cofactor of two enzymes: methionine synthase and L-methyl-malonyl-coenzyme. A mutase in intracellular enzymatic reactions related to DNA synthesis, as well as in amino and fatty acid metabolism. Vitamin B₁₂, under the catalysis of the enzyme l-methyl-malonyl-CoA mutase, synthesizes succinyl-CoA from methylmalonyl-CoA in the mitochondria. Deficiency of B₁₂, thus results in elevated methylmalonic acid (MMA) levels.

Dietary B₁₂ is normally bound to proteins. Food-bound B₁₂ is released in the stomach under the effect of gastric acid and pepsin. The free vitamin is then bound to an R-binder, a glycoprotein in gastric fluid and saliva that protects B₁₂ from the highly acidic stomach environment. Pancreatic proteases degrade R-binder in the duodenum and liberate B₁₂; finally, the free vitamin is then bound by the intrinsic factor (IF)—a glycosylated protein secreted by gastric parietal cells—forming an IF-B₁₂ complex [6]. The IF resists proteolysis and serves as a carrier for B₁₂ to the terminal ileum where the IF-B₁₂ complex undergoes receptor (cubilin)-mediated endocytosis [7]. The vitamin then appears in circulation bound to holo-transcobalamin-I (holo-TC-I), holo-transcobalamin-II (holo-TC-II), and holo-transcobalamin-III (holo-TC-III). It is estimated that 20–30% of the total circulating B₁₂ is bound to holo-TC-II and only this form is available to the cells [7]. Holo-TC-I binds 70–80% of circulating B₁₂, preventing the loss of the free unneeded portion [6]. Vitamin B₁₂ is stored mainly in the liver and kidneys.

Many mechanisms have been proposed to explain how MET interferes with the absorption of B₁₂: diminished absorption due to changes in bacterial flora, interference with intestinal absorption of the IF–B₁₂ complex (and)/or alterations in IF levels. The most widely accepted current mechanism suggests that MET antagonizes the calcium cation and interferes with the calcium-dependent IF–B₁₂ complex binding to the ileal cubilin receptor [8,9]. The recognition and treatment of B₁₂ deficiency is important because it is a cause of bone marrow failure, macrocytic anemia, and irreversible neuropathy [10].

In general, previous studies on diabetics have observed a reduction in serum levels of B₁₂ after both short- and long-term MET treatment [1]. A recent review on observational studies showed significantly lower levels of B₁₂ and an increased risk of borderline or frank B₁₂ deficiency in patients on MET than not on MET [1]. The meta-analysis of four trials (only one double-blind) found a significant overall mean B₁₂ reducing effect of MET after six weeks to three months of use [1]. A secondary analysis (13 years after randomization) of the Diabetes Prevention Program Outcomes Study, which randomized over 3000 persons at high risk for type 2 diabetes to MET or placebo, showed a 13% increase in the risk of B₁₂ deficiency per year of total MET use [3]. In this study, B₁₂ levels were measured from samples obtained in years 1 and 9. Stored serum samples from other time points, including baseline, were not available, and potentially informative red blood cell indices that might have demonstrated the macrocytic anemia, typical of B₁₂ deficiency, were not recorded [3]. The HOME (Hyperinsulinaemia: the Outcome of its Metabolic Effects) study, a large randomized controlled trial investigating the long-term effects of MET versus placebo in patients with type 2 diabetes treated with insulin, showed that the addition of MET improved glycemic control, reduced insulin requirements, prevented weight gain but lowered serum B₁₂ over time, and raised serum homocysteine, suggesting tissue B₁₂ deficiency [4]. A recent analysis of 277 diabetics from the same trial showed that serum levels of MMA, the specific biomarker for tissue B₁₂ deficiency [5], were significantly higher in people treated with MET than those receiving placebo after four years (on average) [4].

The risk of MET-associated B₁₂ deficiency may be higher in older individuals and those with poor dietary habits. Prospective studies have found negative associations between obesity and B₁₂ in numerous ethnicities [11,12]. An energy-dense but micronutrient-insufficient diet consumed by individuals who are overweight or obese might explain this [12]. Furthermore, obesity is associated with low-grade inflammation and these physiological changes have been shown to be associated, in several studies, with elevated C-reactive protein and homocysteine and with low concentrations of B₁₂ and other vitamins [13,14].

As part of a pilot randomized controlled trial of the Mediterranean diet (MedDiet) and MET for primary prevention of breast cancer and other chronic age-related diseases in healthy women with tracts of MS [15] we tested the effect of MET on serum levels of B₁₂, holo-TC-II, and MMA.

Other articles of note on the Mediterranean Diet in this Online Open Access Scientific Journal Include

Micronutrients, Macronutrients and Dietary Patterns: Nutrition and Fertility

Live 2:30-4:30 PM  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health:  October 19, 2018

Live 12:00 – 1:00 P.M  Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health : October 19, 2018

Announcement 11AM- 5PM: Live Conference Coverage  from Mediterranean Diet and Lifestyle: A Symposium on Diet and Human Health @S.H.R.O. and Temple University October 19, 2018

 

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