Vit B12 deficiency with Metformin

[Guest guest]

The association of metformin treatment with vitamin B12 deficiency was

confirmed in a long-term trial, suggesting that diabetic patients receiving

the popular drug would benefit from vitamin monitoring and perhaps

B12supplementation.

With 4.3 years of treatment in a randomized, placebo-controlled trial, the

hazard ratio for developing vitamin B12 deficiency while on metformin was

5.5 relative to placebo (95% CI 1.6 to 19.1), reported Coen Stehouwer, MD,

of Maastricht University in the Netherlands, and colleagues online in *BMJ*.

" Our study shows that this decrease is not a transitory phenomenon, but

persists and grows over time, " the researchers wrote.

Earlier research had pointed to a causal association between metformin and

vitamin B12 insufficiency, but it was entirely based on short-term studies,

Stehouwer and colleagues indicated.

They analyzed data on 390 type 2 diabetes patients randomized to metformin

or placebo in a study named HOME, designed to examine the effects of

metformin on metabolic parameters and micro- and macrovascular diabetic

complications.

Patients in the study were initially treated with insulin and no other

medications during a 12-week run-in phase. Metformin or placebo was then

added to insulin for a total of 52 months.

Mean duration of diabetes at enrollment was about 13 years, with mean

duration of insulin treatment of 7 years. Patients were generally in late

middle age (mean age 61). Mean glycated hemoglobin levels at baseline were

7.9%.

Their data showed that vitamin B12 levels declined throughout the study,

although the biggest drop occurred within the first few months.

From a mean of about 355 pmol/L at the end of the run-in phase, B12 levels

dropped to about 305 pmol/L after four months, and from there to 280 pmol/L

over the next four years.

Falling vitamin B12 levels were also associated with increased serum

homocysteine, the researchers found. When last measured, patients with

deficiency (defined as less than 150 pmol/L) had mean homocysteine levels of

23.7 μmol/L versus 18.1 μmol/L among those with vitamin B12 levels of 150

pmol/L, classified as low, and 14.9 μmol/L for those with normal vitamin B12

..

These differences were statistically significant, with *P*=0.003 for

deficient versus low, and *P*=0.005 for low versus normal.

But there was no significant relationship between homocysteine levels and

treatment assignments in the trial, Stehouwer and colleagues found. They

indicated that the " relatively low incidence of vitamin B12 deficiency "

probably accounted for the finding.

" As treatment with metformin continues, however, we expect that

vitamin B12levels will continue to decrease, making increases in

homocysteine

concentrations inevitable in time, " the researchers added.

Metformin treatment also appeared to depress folate levels, with a 5%

decline in the active-treatment group (*P*=0.033).

All these associations remained significant after adjusting for age, gender,

insulin dose, smoking status, duration of diabetes, and previous metformin

treatment.

However, adjusting for body mass index and smoking eliminated the

correlation between metformin treatment and folate levels.

Citing earlier research, Stehouwer and colleagues wrote that metformin

appears to reduce B12 levels by inhibiting dietary absorption in the

intestine. Calcium supplements can reverse the malabsorption.

Stehouwer and colleagues argued that the study results " provide a strong

case for routine assessment of vitamin B-12 levels during long-term

treatment with metformin. "

But two British researchers, in an accompanying editorial, weren't so sure.

The study authors' conclusion " is based on findings from patients taking

insulin and with no evidence that monitoring will benefit patients, " wrote

p Vidal-Alaball, MD, and , MBChB, MD, of Cardiff

University in Wales.

They noted that " we have no robust research underpinning the assumption that

people with vitamin B-12 concentrations of 150 pmol/l or less are indeed

vitamin B-12 deficient. Although they may be at higher risk for vitamin B-12

deficiency related effects, these risks are not clearly quantified or always

directly related to vitamin B-12 concentrations. "

They also suggested that dietary changes accompanying metformin treatment

could have accounted for the findings.

" We first need to determine whether simple dietary counselling when

metformin is started and at medication/annual reviews will solve the

problem. If it does not, a trial of screening for vitamin B-12 deficiency in

patients taking metformin would be needed, " Vidal-Alaball and wrote.

Otherwise, they warned, blanket monitoring of all patients on metformin

could place burdens on patients and increase costs without commensurate

improvements in " outcomes that matter to patients. "

*Primary source: *BMJ

Source reference:

de Jager J, et al " Long term treatment with metformin in patients with type

2 diabetes and risk of vitamin B-12 deficiency: randomised placebo

controlled trial " *BMJ* 2010; DOI:

10.1136/bmj.c2181.<http://www.bmj.com/cgi/content/full/340/may19_4/c2181>

*Additional source:* BMJ

Source reference:

Vidal-Alaball J, et al " Reduced serum vitamin B-12 in patients taking

metformin " *BMJ* 2010; DOI:

10.1136/bmj.c2198.<http://www.bmj.com/cgi/doi/10.1136/bmj.c2198>

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--

Ortiz, MS, RD

" I plan on living forever - so far so good "

" Cause of obesity, heart disease and cancer: Look at the end of your fork "